Surgery: Evidence-

Based Practice

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PMPH_FM.indd ii 5/22/2012 6:23:43 PM
 Surgery: Evidence-
Based Practice

Stephen M. Cohn, MD, FACS

Witten B. Russ Professor of Surgery
Department of Surgery
University of Texas Health Science Center
San Antonio, Texas

Steven T. Brower, MD, FACS

Vice Chairman, Department of Surgery
Chief, Division of Surgical Oncology
Beth Israel Medical Center, NY
Director of Strategic Planning and
Extramural Affairs
Continuum Cancer Centers of New York
New York, New York

2012
PEOPLE’S MEDICAL PUBLISHING HOUSE–USA
SHELTON, CONNECTICUT

PMPH_FM.indd iii 5/22/2012 6:23:43 PM

 People’s Medical Publishing House-USA
2 Enterprise Drive, Suite 509
Shelton, CT 06484
Tel: 203-402-0646
Fax: 203-402-0854
E-mail: info@pmph-usa.com

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12 13 14 15 16/PMPH/9 8 7 6 5 4 3 2 1

ISBN-13: 978-1-60795-109-4
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Editor: Linda Mehta; Copyeditor/Typesetter: Newgen; Cover designer: Marguerite Bunyan

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PMPH_FM.indd iv 5/22/2012 6:23:43 PM

 To my parents, Lee and Iris Cohn, and my family, Sam and Elizabeth Cohn, for their support through the years.
—Stephen M. Cohn

To my family—Joshua, Evan, and Marianne Brower—for their unwavering support .

—Steven T. Brower

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PMPH_FM.indd vi 5/22/2012 6:23:43 PM
 CONTENTS

List of Contributors xiii Commentary 118

Foreword xxix Frederick A. Moore
Basil A. Pruitt, Jr.
14. Zollinger-Ellison Syndrome 119
Preface xxxi
Geoff rey W. Krampitz & Jeff rey A. Norton
Stephen M. Cohn & Steven T. Brower
15. Evidence-Based Bariatric Surgery 132
1. Understanding the Elements that Comprise Amir H. Sharif & Robert L. Bell
Evidence-Based Medicine 1 16. Gastric Adenocarcinoma 146
Joel E. Michalek, John E. Cornell & Brad H. Pollock Antonio I. Picon & Martin S. Karpeh
2. Patient Safety in Surgical Care 14 Commentary 152
Kenneth Stahl & Susan E. Brien Scott A. Hundahl
17. Management of Upper GI Bleeding 154
PART I. THE ESOPHAGUS Bruce A. Crookes
3. Esophageal Perforation 25 Commentary 160
Jonathan B. Lundy & G. Travis Clifton Gregory J. Jurkovich
Commentaries 34
Scott B. Johnson, Jeremy S. Juern & John A Weigelt
PART III. SMALL BOWEL
4. Achalasia and Esophageal Spasms 37 18. Small Bowel Surgery 165
Kalyana C. Nandipati & Edward Lin James H. Lee, John J. Hong, Dale Dangleben &
5. Esophageal Diverticula 45 Michael M. Badellino
G. Travis Clifton & Jonathan B. Lundy Commentary 173
Ronald M. Stewart
6. Gastroesophageal Reflux Disease 59
Alejandro F. Sanz & Blair A. Jobe 19. Crohn’s Disease of the Small Bowel 174
Thomas Donkar, Andrea Bafford &
7. Inguinal Hernias 64 Randolf M. Steinhagen
George Kasotakis & Marc A. de Moya Commentary 184
8. Esophageal Caustic Injury 70 Tomas M. Heimann
Yoram Klein 20. Small Bowel Tumors and Diverticular
9. Esophageal Tumors 74 Disease of SB 186
Daniel S. Oh & Steven R. DeMeester John D. Cunningham & Akintunde Akinleye

10. The Use of Esophageal Stents 83 21. Enterocutaneous Fistula 192

Yaron Perry & Robert Jones Peter A. Learn
Commentary 90 22. Short Bowel Syndrome 196
Scott B. Johnson Andrea MacNeill & S. Morad Hameed
Commentary 203
11. Neoadjuvant and Adjuvant Treatment of
James Davis
Esophageal Cancer 91
J. Camilo Barreto & Mitchell C. Posner
12. Esophageal Atresia and PART IV. LARGE BOWEL
Tracheoesophageal Fistula 97 23. Diverticular Disease of the Colon 207
Miller C. Hamrick, David E. Carney & Brent Izu & A. Peter Ekeh
William C. Boswell Commentary 214
Commentary 104 Richard J. Mullins
Michael Hirsch 24. Crohn’s Colitis and Ulcerative Colitis 215
Kervin Arroyo & Barry Salky
PART II. THE STOMACH 25. Large Bowel Obstruction 221
13. Peptic Ulcer Disease 109 Ryan A. Lawless, Dale A. Dangleben &
Wayne H. Schwesinger Michael M. Badellino

vii

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 viii ■ Contents

Commentary 227 40. Hepatic Infections: Pyogenic Abscess,

Martin A. Schreiber Amebic Abscess, and Hydatid Cyst 329
David M. Levi & Andreas G. Tzakis
26. Radiation Injury to the Small and Large Bowel 228
Ali Y. Mejaddam & David R. King 41. Malignant Liver Tumors 334
Commentary 231 Susanne Carpenter & Yuman Fong
Daniel L. Dent
27. Ischemic Colitis 232 PART VI. PORTAL HYPERTENSION
Thomas D. Conlee, Daniel J. Bonville &
42. Management of Portal Hypertension:
Jonathan J. Canete
A Surgical Perspective 345
Commentary 237
Sukru Emre & Manuel I. Rodriguez-Davalos
Fred A. Luchette
43. Management of Intractable Ascites:
28. Pseudomembranous Colitis 239
The Evidence 353
Burke Thompson
Mark I. E. Cockburn & Adora Fou-Cockburn
Commentary 243
Pamela A. Lipsett 44. Hepatic Encephalopathy 357
Terence O’Keefe & Tun Jie
29. Colon and Rectal Cancer Including Adjuvant 245
Commentary 365
Robert P. Sticca, Erik G. Fetner & Jay M. MacGregor
Jamal J. Hoballah
Commentary 251
Nicholas J. Petrelli 45. Elective Non-hepatic Surgery in
Cirrhotic Patients 366
30. Tumors of the Anal Region 253
Jared C. Brandenberger & Vafa Ghaemmaghami
Marjun P. Duldulao & Julio Garcia-Aguilar
Commentary 371
31. Inherited Colorectal Cancer Syndromes 260 Bruce Gelb & H. Leon Pachter
Vitaliy Y. Poylin, Kristin B. Niendorf &
Robert D. Madoff
PART VII. THE GALLBLADDER
32. Preoperative Bowel Preparation 267 AND BILE DUCTS
John K. Bini
46. Silent Gallstones 375
Commentary 273
Abdul Saied & James C. Doherty
Donald E. Fry
Commentary 379
33. Appendicitis 275 David H. Livingston
Damon Kalcich & Peter P. Lopez
47. Acute Cholecystitis 380
34. Hemorrhoids 287 John S. Oh
Clarence E. Clark III
48. Common Bile Duct Stones 386
Commentary 293
Adrian W. Ong & Charles F. Cobb
Stanley M. Goldberg
49. Benign Biliary Strictures 394
35. Anorectal Fissure, Stricture,
Demetrius Pertsemlidis & David S. Pertsemlidis
Abscess, and Fistula 294
W. Brian Perry & Joshua A. Tyler 50. Gallstone Ileus 399
Commentary 298 David W. Smith & Ara J. Feinstein
Stanley M. Goldberg
51. Bile Duct and Gallbladder Tumors 403
36. Fecal Incontinence and Surgical Management T. Peter Kingham & Michael D’Angelica
of Constipation 299
52. Obstructive Jaundice: Transhepatic
Sarah Pesek & Neil Hyman
and Endoscopic Interventions 410
37. Rectovaginal Fistula 305 Brian J. Dunkin
Joshua D. Schulte, Kelly Ming, Michelle M. Olsen &
Philip F. Caushaj
Commentary 312 PART VIII. THE PANCREAS
Patricia L. Roberts 53. Acute Pancreatitis 421
Stephen W. Behrman
38. Lower Gastrointestinal Bleeding 314
Commentary 429
Kerry G. Bennett & Steven Schwaitzberg
Wayne H. Schwesinger
54. Infected Pancreatic Collections 430
PART V. THE LIVER Nader N. Massarweh & Karen D. Horvath
39. Newer Techniques in Liver Surgery 323 55. Pancreatic Pseudocysts 437
Anil S. Paramesh, Robert Cannon & Joseph F. Buell Olga N. Tucker & Raul J. Rosenthal

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 Contents ■ ix

56. Chronic Pancreatitis 449 Commentary 585

Katherine A. Morgan & David B. Adams Richelle Williams & David P. Winchester
57. Pancreatic Adenocarcinoma 458 73. Breast Cancer: Surgical Therapy 587
Jamii St. Julien, Alexander A. Parikh & Alyssa Gillego, Manjeet Chadha, Beth Freedman &
Nipun G. Merchant Susan K. Boolbol
Commentary 465
74. Breast Cancer: Lymphatic Mapping
Matthew H. G. Katz, Jason B. Fleming,
and Sentinel Lymph Node Biopsy 597
Jeff rey E. Lee & Peter W. T. Pisters
Abigail S. Caudle, Elizabeth A. Mittendorf &
58. Unusual Pancreatic Tumors 467 Henry M. Kuerer
David W. Rittenhouse, Charles J. Yeo, &
75. Systemic Treatment Strategies
Samuel D. Gross
for Early-Stage Breast Cancers 604
Jennifer K. Litton & Kelly K. Hunt
PART IX. THE SPLEEN
76. In Situ Carcinoma of the Breast:
59. Hematologic Indications for Splenectomy 481 Ductal and Lobular Carcinoma 612
Mark T. Muir Jane E. Méndez
60. Tumors, Cysts, and Abscesses of the Spleen 488 77. Male Breast Cancer 617
Robert Benjamin Jessica Keto & Paul Ian Tartter
61. Splenic Salvage 490 78. Breast Reconstruction Following Mastectomy 622
Dror Soffer & Daniel Abraham David M. Adelman & Steven J. Kronowitz
Commentary 496
Sherry Sixta, John B. Holcolm & Jack H. Mayfield
PART XIII. CHEST WALL, MEDIASTINUM,
62. Postsplenectomy Sepsis 498 TRACHEA
Regan J. Berg & Kenji Inaba
79. Lung Cancer Staging 631
Joe B. Putnam, Jr.
PART X. HERNIA
80. Primary Chest Wall Tumors 636
63. Inguinal Hernias 513 Adam H. Lackey, Joseph B. Levin & Harvey I. Pass
George Kasotakis & Marc A. de Moya
81. Tracheostomy: Timing and Techniques 642
64. Recurrent Inguinal Hernia 518 Matthew O. Dolich
H. R. Nanda Kumar & Kent R. Van Sickle Commentary 648
Commentary 523 Matthew E. Lissauer & Thomas M. Scalea
Thomas E. Knuth
82. Pneumothorax and Hemothorax 650
65. Epigastric and Umbilical Hernia 525 Joseph J. DuBose
Rachel Beard & Steven D. Schwaitzberg Commentary 657
66. Incisional and Ventral Hernias 530 J. D. Richardson
Rachel Beard & Steven D. Schwaitzberg
PART XIV. VASCULAR SYSTEM
PART XI. ENDOCRINE GLANDS 83. Abdominal Aortic Aneurysm 661
67. Adrenocortical Tumors and Incidentalomas 537 Boulos Toursarkissian
Paul Karanicolas & Murray Brennan Commentary 667
Gregorio Sicard
68. Pheochromocytoma 544
Raymon H. Grogan & Quan-Yang Duh 84. Aortic Dissection 669
Benjamin J. Pearce
69. Thyroid Nodules 552 Commentary 676
Gerard M. Doherty Karthikeshwar Kasirajan
70. Hyperthyroidism, Thyroiditis, 85. Arterial Pseudoaneurysms and
and Nontoxic Goiter 559 Arteriovenous Fistulae 677
Prashant Khullar & Geeta Lal J. Leigh Eidson III & Marvin D. Atkins
71. Hyperparathyroidism 568 86. Carotid Occlusive and Aneurysmal Disease 684
Jason D. Prescott & Robert Udelsman Matthew J. Sideman & Lori L. Pounds
87. Aortoiliac Occlusive Disease 691
PART XII. THE BREAST Jeff rey S. Horn & William D. Jordan, Jr.
72. Screening, Breast Biopsy, Benign Disease 577 Commentary 697
Adora Fou-Cockburn & Mark I. Cockburn Alan B. Lumsden

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 x ■ Contents

88. Femoropopliteal and Tibioperoneal 102. Soft Tissue Sarcoma 807

Occlusive and Aneurysmal Disease 699 Keila E. Torres & Raphael E. Pollock
Luke X. Zhan & Joseph L. Mills
103. Solitary Neck Mass 814
Commentary 706
Luc G. T. Morris & Ashok R. Shaha
Frank J. Veith
89. Thoracic Outlet Syndromes 707 104. Peripheral Nerve Injury Repair 818
Robert W. Thompson Marisa H. Amaral, Pranay Parikh &
Commentary 721 Joseph H. Shin
Julie Ann Freischlag Commentary 824
Howard T. Wang
90. Peripheral Arterial Embolus 722
Shane O’Keeffe & Eric Endean 105. Necrotizing Soft Tissue Infections
Commentary 728 Including Gas Gangrene 826
Jamal J. Hoballah Kevin M. Schuster & Erik S. Barquist

91. Vascular Syndromes 730 106. Necrotizing Soft Tissue Infections 833
John E. Campbell & Ali F. Aburahma Mark D. Sawyer
Commentary 838
92. Management of Graft Occlusion 735 A. Patchen Dellinger
David Vogel & Anthony J. Comerota
Commentary 741
Daniel B. Walsh PART XVI. PREOPERATIVE AND
93. Vascular Access for Hemodialysis 742 POSTOPERATIVE CARE
Yazan Duwayri & Brian G. Rubin 107. Electrolytes and Fluids 841
94. Atherosclerotic Renovascular Disease 749 Daun J. Milligan, Megan B. Steigelman,
Eric Hager & Luke Marone Tristan T. Lai & Aaron M. Fields
Commentary 754 Commentary 853
Daniel G. Clair David B. Hoyt

95. Acute and Chronic Mesenteric Ischemia 756 108. Surgical Nutrition 854
Luke P. Brewster & Elliot L. Chaikof Jayson D. Aydelotte
Commentary 760 109. Preoperative Risk Factor Assessment
Michael J. Sise of the Surgical Patient 859
96. The Diabetic Foot 762 Edgar Joseph Pierre, Shawn Michael Cantie &
Alexandra A. MacLean & Maria Codreanu Faisal Huda
Commentary 767 Commentary 867
Jodi Walters & David G. Armstrong Elliott Bennett-Guerrero

97. Varicose Veins and Venous Insufficiency 769 110. Perioperative Cardiac Monitoring 869
M. K. Sheehan Steven G. Venticinque
Commentary 772
111. Bacteremia: An Evidence-Based Review of
Seshadri Raju
Recommendations for Elective
98. Deep Venous Thrombosis 775 General Surgery 876
Mark L. Ryan, Chad M. Thorson, Thai Vu, Katherine Hetz, Kevin K. Chung &
Christian A. Otero & Enrique Ginzburg Christopher E. White
Commentary 783 Commentary 882
M. M. Knudson John C. Marshall
99. Pulmonary Embolism 785 112. Prevention of Central Venous
George C. Velmahos Catheter Infections 884
Commentary 791 Antonio Aponte-Feliciano, J. Matthias Walz &
Kenneth L. Mattox Stephen O. Heard
Commentary 890
100. Management of Lymphedema 792
Nicole J. Krumrei & Donald H. Jenkins
Magdiel Trinidad-Hernandez & Peter Gloviczki
113. Surgical Site Infection (SSI) and
Prophylactic Antibiotics 891
PART XV. SKIN AND SOFT TISSUE Robert Krell & Lena M. Napolitano
101. Malignant Melanoma 799 Commentary 899
Robert E. Roses & Daniel F. Roses Timothy C. Fabian

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 Contents ■ xi

114. Management of Acute Myocardial Infarction Commentary 934

and Cardiogenic Shock 901 Suresh Agarwal
Antonio Hernandez
118. Postoperative Hepatic Failure 936
Commentary 907
Joseph Love & Raphael Diaz-Flores
Kenneth Waxman
115. Abnormal Surgical and 119. Acute Renal Dysfunction 942
Postoperative Bleeding 909 Matthew O’Rourke & Jonathan Barasch
Andrew L. Tang, Nicholas Tarmey, Commentary 947
Joseph Dubose & Peter Rhee Rao R. Ivatury

116. Management of Sedation 120. Perioperative Endocrine Dysfunction 949

and Delirium in the ICU 917 Catherine A. Madorin & Kaare J. Weber
Robert Chen & Sangeeta Mehta
117. Postoperative Respiratory Failure 926
Index 955
Mollie M. James & Gregory J. Beilman

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PMPH_FM.indd xii 5/22/2012 6:23:43 PM
 LIST OF CONTRIBUTORS

Daniel Abraham, MD [61] University of Arizona College of Medicine

Director, Yitzhak Rabin Trauma Division Tucson, Arizona
Assistant Professor of Surgery
Division of Surgery Kervin Arroyo, MD [24]
Tel Aviv Sourasky Medical Center Fellow Minimally Invasive Surgery
Tel Aviv, Israel Division of Laparoscopic Surgery
The Mount Sinai Hospital
Ali F. Aburahma, MD [91] New York, New York
Professor of Surgery
West Virginia University Marvin D. Atkins, MD [85]
Director, Vascular Surgery Fellowship Program Texas A&M University Health Science Center
Co-Director, Vascular Center of Excellence Scott and White Hospital & Clinic
Chief of Vascular and Endovascular Surgery Division of Vascular Surgery
Charleston Area Medical Center Temple, Texas
Charleston, West Virginia
Jayson D. Aydelotte, MD [108]
David B. Adams, MD, FACS [56] Associate Professor/Clinical
Professor of Surgery Program Director, Critical Care Fellowship
Head, Section of General and Gastrointestinal Surgery Division of Trauma
Medical University South Carolina University of Texas Health Science Center
Charleston, South Carolina San Antonio, Texas

David M. Adelman, MD, PhD [78] Michael M. Badellino, MD, FACS [18, 25]
Assistant Professor Division of Trauma/Surgical Critical Care
Department of Plastic Surgery, Division of Surgery Program Director, General Surgery Residency
The University of Texas MD Anderson Cancer Center Lehigh Valley Health Network
Houston, Texas Allentown, Pennsylvania

Suresh Agarwal, MD [117C] Andrea Chao Bafford, MD [19]

Chief, Surgical Critical Care
Boston Medical Center
Associate Professor of Surgery
Boston University School of Medicine
Boston, Masachussets
Akinleye Akintunde, MD
Internal Medicine Resident
Overlook Hospital
Summit, New Jersey
Assistant Professor of Surgery
Digestive Health Center
University of Maryland School of Medicine
Baltimore, Maryland
Jonathan Barasch, MD, PhD [119]
[20] Associate Professor of Medicine and Cell Biology
Department of Medicine
Columbia University Medical Center
New York, New York

Marisa H. Amaral, MD [104] Erik S. Barquist, MD, FACS, FCCM [105]

Resident, General Surgery Chief of Surgery
Tufts University School of Medicine Jackson South Community Hospital
Baystate Medical Center Miami, Florida
Springfield, Massachusetts
J. Camilo Barreto, MD [11]
Antonio Aponte-Feliciano, MD [112] Section of General Surgery and Surgical Oncology
Assistant Professor of Anesthesiology Department of Surgery
University of Massachusetts Medical School University of Chicago Pritzker School of Medicine
Department of Anesthesiology and Critical Care Chicago, Illinois
UMASS Memorial Medical Center
Worcester, Massachusetts Rachel Beard, MD [65, 66]
Department of Surgery
David G. Armstrong, DPM, MD, PhD [96C] Beth Israel Deaconess Medical Center Department of Surgery
Southern Arizona Limb Salvage Alliance (SALSA) Cambridge Health Alliance
xiii

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 xiv ■ List of Contributors
Harvard Medical School
Boston, Massachusetts
Stephen W. Behrman, MD, FACS [53]
Associate Professor of Surgery
University of Tennessee, Memphis Health Science Center
Germantown, Tennessee
Greg Beilman, MD [117]
Professor and Vice Chair of Perioperative Services and Quality
Improvement
Chief of General Surgery
Division Director, Critical Care and Acute Care Surgery
University of Minnesota
Minneapolis, Minnesota
Robert L. Bell, MD [15]
Associate Professor of Surgery
Section of Gastrointestinal Surgery
Department of Surgery
Yale University School of Medicine
New Haven, Connecticut
Kerry G. Bennett, MD, MPH
Department of Surgery
St Luke’s Hospital
New Bedford, Massachusetts
Elliott Bennett-Guerrero, MD [109C]
Professor and Director of Perioperative Clinical Research,
Duke Clinical Research Institute
Duke University
Durham, North Carolina
Regan J. Berg, MD [62]
Department of Surgery
University of Southern California
Los Angeles, California
John K. Bini, MD [32]
Clinical Instructor
Division of Trauma
University of Texas Health Science Center
San Antonio, Texas
Daniel J. Bonville, DO, FACS
Department of Surgery
Albany Medical College
Albany, New York
Susan K. Boolbol, MD [73]
Department of Surgery
Chief, Appel-Venet Comprehensive Breast Service
Beth Israel Medical Center
Assistant Professor of Surgery
Albert Einstein College of Medicine
New York, New York
William C. Boswell, MD [12]
Pediatric Surgery
Memorial University Medical Center
Savannah, Georgia
PMPH_FM.indd xiv
Jared C. Brandenberger, MD [45]
Kidney Care and Transplantation Services
University of Washington Medical Center
Seattle, Washington
Murray F. Brennan, MD [67]
Benno C. Schmidt Chair of Clinical Oncology
Department of Surgery
Memorial Sloan-Kettering Cancer Center
New York, New York
Luke P. Brewster, MD, PhD [95]
Assistant Professor of Surgery
Division of Vascular Surgery, Department of Surgery
Emory University School of Medicine
Atlanta, Georgia
Stephen T. Brower, MD [EDITOR]
Vice Chairman, Department of Surgery
Chief, Division of Surgical Oncology
Beth Israel Medical Center
Director of Strategic Planning and Extramural Affairs
Continuum Cancer Centers of New York
[38] New York, New York
Susan Brien, MD Med, CSPQ, FRCSC, CPE [2]
Registrar & Associate Director Professional Affairs
Royal College of Physicians & Surgeons of Canada
Chief of Trauma and Staff Neurosurgeon
Gatineau, Quebec
Adjunct Professor, Department of Surgery
University of Ottawa
Ottawa, Ontario Canada
Joseph F. Buell, MD [39]
Professor of Surgery
Director of the Tulane Transplant Abdominal Institute
Tulane University
New Orleans, Louisiana
John E. Campbell, MD [91]
Assistant Professor of Surgery and Medicine
West Virginia University
Division of Vascular and Endovascular Surgery
[27] Charleston Area Medical Center
Charleston, West Virginia
Jonathan Canete, MD [27]
Assistant Professor of Surgery
Albany Medical Center
Albany, New York
Shawn Michael Cantie, MD [109]
Resident in Anesthesiology
University of Miami School of Medicine
Miami, Florida
David E. Carney, MD [12]
Pediatric Surgery
Memorial University Medical Center
Savannah, Georgia
5/22/2012 6:23:43 PM
 List of Contributors ■ xv

Susanne Carpenter [41] G. Travis Clifton, MD [3, 5]

Department of Surgery Trauma/Burn/Critical Care Surgeon
Memorial Sloan Kettering Cancer Center United States Army Institute of Surgical Research
New York, New York Fort Sam Houston, Texas

Abigail S. Caudle [74] Charles F. Cobb, MD [48]

Assistant Professor Associate Professor of Surgery
Department of Surgical Oncology, Division of Surgery Drexel University College of Medicine
The University of Texas MD Anderson Cancer Department of Surgery
Center Allegheny General Hospital
Houston, Texas Pittsburgh, Pennsylvania

Philip F. Caushaj, MD, PhD, FACS, FASCRS [37] Mark Ian Cockburn, MD [43, 72]
Chief of Colon and Rectal Surgery General and Critical Care Surgery
Director of Minimally Invasive Surgery Stamford Hospital
Kern Medical Center Stamford, Connecticut
Bakersfield, California
Adora Ann Fou-Cockburn, MD, FACS [43, 72]
Manjeet Chadha, MD [73] WestMed Medical Group
Associate Professor of Radiation Oncology Rye, New York
Albert Einstein College of Medicine
Associate Chairman, Radiation Oncology Maria Codreanu, MD [96]
Beth Israel Medical Center General Surgery Resident
Director of Breast and Gynecologic Cancer Programs in New York Hospital-Queens
Radiation Oncology Flushing, New York
Continuum Cancer Centers of New York
New York, New York Stephen M. Cohn, MD, FACS [EDITOR]
Witten B. Russ Professor of Surgery
Elliot L. Chaikof, M.D., PhD [95] Division of Trauma and General Surgery
Chairman of the Roberta and Stephen R. Weiner UT Health Science Center, San Antonio
Department of Surgery San Antonio, Texas
Surgeon-in-Chief
Beth Israel Deaconess Medical Center Anthony J. Comerota, MD, FACS [92]
Boston, Massachusetts Director, Jobst Vascular Institute
Toledo, Ohio
Robert Chen, MD [116] Adjunct Professor of Surgery
Attending Anesthetist and Intensivist University of Michigan
Assistant Professor Section of Vascular Surgery
St. Michael’s Hospital Ann Arbor, Michigan
Department of Anaesthesia
University of Toronto Thomas D. Conlee, MD [27]
Toronto, Ontario, Canada Resident in Surgery
Albany Medical Center
Kevin K. Chung, MD [111] Albany, New York
US Army Institute of Surgical Research
Brooke Army Medical Center John E. Cornell, PhD [1]
San Antonio, Texas Professor, Department of Epidemiology and Biostatistics
University of Texas Health Science Center
Daniel Clair, MD [94C] San Antonio, Texas
Department Chair
Vascular Surgery Bruce Crookes, MD [17]
Cleveland Clinic Associate Professor of Surgery
Cleveland, Ohio Division of Trauma & Acute Care Surgery
Medical University of South Carolina
Clarence E. Clark III, MD [34] Charleston, South Carolina
Assistant Professor of Surgery
Texas A&M Health Science Center John David Cunningham, MD, FACS [20]
Division of Surgical Oncology, Section of Colon and Assistant Professor of Surgery
Rectal Surgery Columbia University
Scott and White Memorial Hospital New York, New York
Temple, Texas Attending Surgeon

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 xvi ■ List of Contributors

Overlook Hospital University of Illinois College of Medicine

Summit, New Jersey Chicago, Illinois

Michael D’Angelica, MD [51] Gerard M. Doherty, MD [69]

Associate Attending Chair, Department of Surgery
Division of Hepatopancreatobiliary Surgery Boston University School of Medicine
Department of Surgery Chief of Surgery
Memorial Sloan-Kettering Cancer Center Boston Medical Center
New York, New York Boston, Massachusetts

Dale A. Dangleben, MD [18, 25] Matthew O. Dolich, MD, FACS [81]

Associate Program Director, General Surgery Residency Professor and Residency Program Director
Program Department of Surgery
Department of Surgery University of California, Irvine
Division of Trauma-Surgical Critical Care/General Surgery Orange, California
Lehigh Valley Health Network
Allentown, Pennsylvania Thomas Donkar, DO, MPH [19]
Resident in Surgery
James W. Davis, MD [22C] Maimonides Medical Center
Professor Brooklyn, New York
Chief of Surgery and Program Director
University of California Major Joseph J. DuBose, MD, FACS [82, 115]
San Francisco, California University of Maryland Medical System
R Adams Cowley Shock Trauma Center
E. Patchen Dellinger, MD [106C] Air Force/C-STARS
Professor and Vice Chairman Baltimore, Maryland
Department of Surgery
Chief, Division of General Surgery Quan-Yang Duh, MD [68]
University of Washington Professor, Department of Surgery
Seattle, Washington University of California, San Francisco
San Francisco, California
Steven R. DeMeester, MD [9]
Associate Professor of Surgery Marjun P. Duldulao, MD [30]
Department of Surgery Department of Oncologic Surgery
University of Southern California, Keck School of Medicine City of Hope Comprehensive Cancer Center
Los Angeles, California Duarte, California

Brian J. Dunkin, MD, FACS [52]

Marc A de Moya, MD [7, 63]
Professor of Clinical Surgery
Division of Trauma, Emergency Surgery & Surgical Critical Care
Weill Cornell Medical College
Massachusetts General Hospital
Boston, Massachusetts Head, Section Endoscopic Surgery
The Methodist Hospital
Daniel L. Dent, MD [26C] Houston, Texas
Distinguished Teaching Professor Yazan Duwayri, MD [93]
General Surgery Residency Program Director Assistant Professor of Surgery
Professor of Surgery Division of Vascular Surgery and Endovascular Therapy
Division of Trauma Department of Surgery
University of Texas Health Science Center Emory University School of Medicine
San Antonio, Texas Atlanta, Georgia
Rafael F. Diaz Flores, MD, MPH [118] J. Leigh Eidson, MD [85]
General Surgery Resident Texas A&M University Health Science Center
Department of Surgery Scott and White Hospital & Clinic
University of Texas Health Science Center Division of Vascular Surgery
San Antonio, Texas Temple, Texas

James C. Doherty MD, MPH [46] Akpofure Peter Ekeh, MD [23]

Director of Trauma Surgery and Critical Care Programs Associate Professor, Surgery
Advocate Christ Medical Center Boonshoft School of Medicine
Oak Lawn, Illinois Wright State University
Clinical Assistant Professor of Surgery Director, Injury Prevention Center

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 List of Contributors ■ xvii

Chief, Division of Trauma, Critical Care, and Emergency Beth Israel Medical Center
General Surgery New York, New York
Miami Valley Hospital
Dayton, Ohio Julio Garcia-Aguilar, MD, PhD [30]
Professor, General Oncologic Surgery
Sukru Emre, MD, FACS [42] Department of Surgery
Professor of Surgery and Pediatrics City of Hope
Yale University School of Medicine Duarte, California
Chief, Section of Transplantation and Immunology
New Haven, Connecticut Bruce E. Gelb, MD [45C]
Assistant Professor
Eric D. Endean, MD [90] Department of Surgery (Transplant)
Professor, Department of Surgery NYU School of Medicine
University of Kentucky College of Medicine New York, New York
Lexington, Kentucky
Vafa Ghaemmaghami, MD, FACS [45]
Timothy C. Fabian, MD, FACS [113C] Interim Program Director
Harwell Wilson Professor and Chairman Phoenix Integrated Residency Program
Department of Surgery
Interim Director, Trauma/Surgical Intensive Care Unit
University of Tennessee Health Science Center
Banner Good Samaritan Medical Center
Memphis, Tennessee
Phoenix, Arizona
Ara J. Feinstein, MD [50]
Alyssa Gillego, MD [73]
Assistant Professor
Attending Surgeon
University of Arizona, Phoenix
Department of Surgery
Trauma, Critical Care and Acute Care Surgery Division
Beth Israel Medical Center
Banner Good Samaritan Medical Center
Phoenix, Arizona New York, New York

Eric G. Fetner, MD [29] Enrique Ginzburg, MD, FACS [98]

Clinical Assistant Professor of Surgery Professor of Clinical Surgery
University of North Dakota School of Medicine DeWitt Daughtry Family Department of Surgery
and Health Sciences Ryder Trauma Center
Grand Forks, North Dakota Miami, Florida

Major Aaron M. Fields, MD [107] Peter Gloviczki, MD [100]

Staff, Anesthesiology and Critical Care Medicine Professor of Surgery
US Air Force, 13th Air Force Chair, Vascular Surgery
Hickam AFB Mayo Clinic
Honolulu, Hawaii Rochester, Minnesota

Jason B. Fleming, MD [57C] Stanley M. Goldberg, MD [34C, 35C]

Associate Professor Colon and Rectal Surgery Associates–Minneapolis
Department of Surgical Oncology Minneapolis, Minnesota
The University of Texas MD Anderson Cancer Center
Houston, Texas Raymon H. Grogan, MD [68]
Section of Endocrine Surgery
Yuman Fong, MD [41]
University of California, San Francisco
Murray F. Brennan Chair in Surgery
San Francisco, California
Memorial Sloan-Kettering Cancer Center
Professor of Surgery
Eric Hager, MD [94]
Weill Cornell Medical College
University of Pittsburgh Medical Center
New York, New York
Division of Vascular and Endovascular Surgery
Julie Ann Freischlag, MD [89C] Pittsburgh, Pennsylvania
The William Stewart Halsted Professor
Chair, Department of Surgery S. Morad Hameed, MD, MPH [22]
Surgeon-in-Chief, Johns Hopkins Hospital Assistant Professor of Surgery and Critical Care Medicine
Baltimore, Maryland Director, General Surgery Residency Program
The University of British Columbia
Beth Friedman, MD [73] Trauma Services
Department of Surgery Vancouver, British Columbia Canada

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 xviii ■ List of Contributors

Miller C. Hamrick, MD [12] University of Alabama Birmingham

Department of Surgery Birmingham, AL
Memorial University Medical Center
Savannah, Georgia Karen D. Horvath, MD, FACS [54]
Professor of Surgery
Stephen O. Heard, MD [112] Residency Program Director
Chair and Professor University of Washington
Department of Anesthesiology Seattle, Washington
University of Massachusetts Medical School
Worcester, Massachusetts David B. Hoyt, MD, FACS [107C]
Executive Director
Tomas M. Heimann, MD, FACS [19C] American College of Surgeons
Professor of Surgery Professor Emeritus, University of California, Irvine
Mount Sinai School of Medicine Chicago, Illinois
New York, New York
Chief, General Surgical Services Faisal Huda, MD [109]
James J. Peters VA Medical Center Resident in Anesthesiology
Bronx, New York University of Miami School of Medicine
Miami, Florida
Antonio Hernandez, MD [114]
Associate Professor Scott A. Hundahl, MD [16C]
Department of Anesthesiology Professor of Clinical Surgery
University of Texas Health Science Center University of California, Davis
San Antonio, Texas Chief of Surgery for VA Northern California
UC Davis Cancer Center
Katherine Hetz, MD [111] Sacramento, California
Department of General Surgery Chief of Surgery
Brooke Army Medical Center VA Northern CA Health Care System
San Antonio, Texas Mather, California
Michael P. Hirsh, MD, FACS, FAAP [12C]
Kelly K. Hunt, MD, FACS [75]
Surgeon-in-Chief
Professor of Surgical Oncology
Chief, Division of Pediatric Surgery and Trauma
The University of Texas MD Anderson Cancer Center
University of Massachusetts Memorial Children’s Medical Center
Houston, Texas
Professor of Surgery and Pediatrics
University of Massachusetts Medical School
Neil Hyman, MD [36]
Worcester, Massachusetts
Samuel B. and Michelle D. Labow Professor of Surgery
Jamal J. Hoballah, MD, MBA, FACS [32C, 44C, 90C] Co-director, Digestive Disease Center
Professor & Chairman University of Vermont College of Medicine
Department of Surgery Burlington, Vermont
American University of Beirut Medical Center
Professor of Surgery Kenji Inaba, MD, FACS, FRCSC [62]
Vascular Surgery Division Assistant Professor of Surgery
The University of Iowa Hospitals and Clinics Medical Director, Surgical ICU
Iowa City, Iowa Program Director, Critical Care Fellowship
University of Southern California
John B. Holcomb, MD, FACS [61C] Los Angeles, California
Vice Chair and Professor of Surgery
Chief, Division of Acute Care Surgery Rao R. Ivatury, MD, FACS, FCCM [121C]
University of Texas Health Science Center Professor of Surgery
Houston, Texas Virginia Commonwealth University
Chair, Division of Trauma, Critical Care & Emergency Surgery
John J. Hong MD [18] VCU Medical Center
Vice Chair for Research Richmond, Virginia
Department of Surgery
Lehigh Valley Health Network Brent Izu, MD [23]
Allentown, Pennsylvania Resident, Department of Surgery
Wright State University
Jeffrey S. Horn, MD [87] Boonshoft School of Medicine
Section of Vascular Surgery and Endovascular Therapy Dayton, Ohio

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 List of Contributors ■ xix

Donald H. Jenkins, MD, FACS [112C] Director of Clinical Research

Division of Trauma, Critical Care and Emergency General Surgery Division of Vascular Surgery
Mayo Clinic Emory University School of Medicine
Rochester, Minnesota Atlanta, Georgia

Tun Jie, MD, MS [44] George Kasotakis, MD [7, 63]

Assistant Professor of Surgery Department of Surgery
General Surgery/Abdominal Transplantation Division of Trauma, Emergency Surgery & Surgical Critical Care
Department of Surgery Harvard Medical School
University of Arizona College of Medicine Massachusetts General Hospital
Tucson, Arizona Boston, Massachusetts

Blair A. Jobe, MD, FACS [6] Matthew H.G. Katz, MD [57C]

University of Pittsburgh Physicians Assistant Professor
Department of Cardiothoracic Surgery Department of Surgical Oncology
Division of Thoracic Surgery Division of Surgery
University of Pittsburgh Medical Center The University of Texas MD Anderson Cancer Center
Pittsburgh, Pennsylvania Houston, Texas

Scott B. Johnson, MD [3C, 10C] Jessica Keto, MD [77]

Associate Professor Breast Surgeon
Head of the Section of General Thoracic Surgery Associate Medical Director
University of Texas Health Science Center Saint Mary’s Comprehensive Breast Center
San Antonio, Texas Grand Rapids, Michigan
William D. Jordan, Jr., MD [87]
Prashant Khullar, MD [70]
Holt A. McDowell Professor of Surgery
Resident
Chief, Section of Vascular Surgery and Endovascular Therapy
Department of Surgery
University of Alabama Birmingham
University of Iowa Health Center
The Kirklin Clinic
Iowa City, Iowa
Birmingham, Alabama

Jeremy Juern, MD [3C] David R. King, MD, FACS, MAJ, MC, USAR [26]
Division of Trauma and Critical Care Assistant Professor
Department of Surgery Division of Trauma, Emergency Surgery, and Surgical Critical Care
Medical College of Wisconsin Harvard Medical School
Milwaukee, Wisconsin Boston, Massachusetts

Gregory J Jurkovich, MD [17C] T. Peter Kingham, MD [51]

Professor of Surgery Assistant Attending
University of Washington Division of Hepatopancreatobiliary Surgery
Chief of Trauma Department of Surgery
Harborview Medical Center Memorial Sloan-Kettering Cancer Center
Seattle, Washington New York, New York

Damon Kalcich, DO [33] Yoram Klein, MD [8]

General Surgery Chief, Department of Trauma and Acute Care Surgery
Sinai Grace Hospital Kaplan Medical Center
Detroit, Michigan Rehovot, Israel

Paul J. Karanicolas, MD, PhD [67] M. Margaret Knudson, MD, FACS [98C]
Fellow, Department of Surgery Professor and Interim Chief of Surgery
Memorial Sloan-Kettering Cancer Center San Francisco General Hospital and Trauma Center
New York, New York UCSF Division of General Surgery
University of California, San Francisco
Martin S. Karpeh, MD [16] San Francisco, California
Chairman, Department of Surgery
Beth Israel Medical Center Thomas E. Knuth, MD, MPH, FACS [64C]
New York, New York Senior Surgeon
Division of Acute Care Surgery
Karthikeshwar Kasirajan, MD, FACS [84C] Henry Ford Hospital
Associate Professor Detroit, Michigan

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 xx ■ List of Contributors

Geoffrey W. Krampitz, MD [14] James H. Lee, MD [18]

Department of Surgery
Stanford University School of Medicine
Stanford, California
Robert Krell, MD [113]
Department of Surgery
Division of Acute Care Surgery
University of Michigan Health Care System
Ann Arbor, Michigan
Steven J. Kronowitz, MD [78]
Professor, Department of Plastic Surgery
University of Texas MD Anderson Cancer Center
Houston, Texas
Nicole J. Krumrei, MD [112C]
Division of Trauma, Critical Care and Emergency
General Surgery
Mayo Clinic
Rochester, Minnesota
Henry M. Kuerer, MD, PhD, FACS [74]
Professor with Tenure
Department of Surgical Oncology
University of Texas MD Anderson Cancer Center
Houston, Texas
Hanuma Reddy Nanda Kumar, MD [64]
General Surgery Resident
Postdoctoral Fellow – Trauma
University of Texas Health Science Center
San Antonio, Texas
Adam H. Lackey, MD [80]
Fellow, Department of Cardiothoracic Surgery
New York University School of Medicine
New York, New York
Chief Surgical Resident
Department of Surgery
Lehigh Valley Health Network
Allentown, Pennsylvania
Jeffrey E. Lee, MD [57C]
Department Chair and Professor
Department of Surgical Oncology
Division of Surgery
Co-Director, Melanoma and Skin Cancer Research Program
The University of Texas MD Anderson Cancer Center
Houston, Texas
David M. Levi, MD, FACS [40]
Professor of Clinical Surgery
Miami Transplant Institute
University of Miami Miller School of Medicine
Miami, Florida
Joseph B. Levin, PA [80]
Research Assistant
Department of Cardiothoracic Surgery
New York University School of Medicine
New York, New York
Edward Lin, DO, FACS [4]
Associate Professor of Surgery
Director, Emory Endosurgery Unit and Gastroesophageal
Treatment Center
Surgical Director, Emory Bariatrics
Department of Surgery
Atlanta, Georgia
Pamela A. Lipsett, MD, FACS [28C]
Professor, Surgery, ACCM and Nursing
Surgical Critical Care Fellowship Director
Johns Hopkins Health System
Baltimore, Maryland

Matthew E. Lissauer, MD [81C]

Tristan T. Lai, MD [107]
Assistant Professor of Surgery
Department of Anesthesiology
Shock Trauma Center
US Air Force
University of Maryland Medical Center
MAJ Wilford Hall Medical Center Baltimore, Maryland
Lackland Air Force Base, Texas
Jennifer K. Litton, MD [75]
Geeta Lal, MD, MSc, FACS [70] Assistant Professor
Assistant Professor Department of Breast Medical Oncology
Division of Surgical Oncology and Endocrine Surgery Division of Cancer Medicine
Department of Surgery The University of Texas MD Anderson Cancer Center
University of Iowa Houston, Texas
Iowa City, Iowa
David H. Livingston, MD [46C]
Ryan A. Lawless, MD [25] Chief, Division of Trauma
Department of Surgery Department of Surgery
Lehigh Valley Health Network UMDNJ-New Jersey Medical School
Allentown, Pennsylvania Newark, New Jersey

Peter A. Learn, MD [21] Peter P. Lopez, MD FACS [33]

Department of Surgery Clinical Assistant Professor of Surgery
San Antonio Military Medical Center Wayne State University School of Medicine
Ft. Sam Houston, Texas Detroit Medical Center

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 List of Contributors ■ xxi

Sinai-Grace Hospital Luke Marone, MD, FACS [94]

Detroit, Michigan University of Pittsburgh Medical Center
Division of Vascular and Endovascular Surgery
Joseph Love, DO, FACS [118] Pittsburgh, Pennsylvania
Assistant Professor of Surgery
Division of Acute Care Surgery John C. Marshall MD, FRCSC, FACS [111C]
The University of Texas Medical School at Houston Chair, Canadian Critical Care Trials Group
Houston, Texas Critical Care, Trauma and General Surgery
St Michael’s Hospital
Fred A. Luchette, MD [27C] Toronto, Ontario Canada
Professor of Surgery
Nader N. Massarweh, MD, MPH [54]
Division of General Surgery
Surgical Resident
Loyola University Chicago
Department of Surgery
Stritch School of Medicine
University of Washington
Chicago, Illinois
Seattle, Washington
Alan B Lumsden, MD [87C] Kenneth L. Mattox, MD [99C]
Chair, Department of Cardiovascular Surgery Professor and Vice Chairman of Surgery
Medical Director, Methodist DeBakey Heart and Vascular Center General Surgery Division of the Michael E. DeBakey
The Methodist Hospital Department of Surgery
Professor of Cardiothoracic Surgery Baylor College of Medicine
Houston, Texas Houston, Texas

Jonathan B. Lundy, MD [3, 5] Sangeeta Mehta, MD, FRCP(C) [116]

Trauma/Burn/Critical Care Surgeon Assistant Professor of Medicine
United States Army Institute of Surgical Research Division of Critical Care Medicine
Fort Sam Houston, Texas University of Toronto
Toronto, Ontario Canada
Jay M. MacGregor, MD [29]
Chief Resident in Surgery Ali Y. Mejaddam, MD [26]
University of North Dakota School of Medicine and Health Sciences Research Fellow in Surgery
Grand Forks, North Dakota Massachusetts General Hospital
Boston, Massachusetts
Alexandra A. MacLean, MD [96]
Medical Director Jane E. Méndez, MD [76]
Medical/Clinical Affairs Professor of Surgery
Energy-Based Devices Boston Medical Center
Covidien Boston, Massachusetts
Boulder, Colorado
Nipun Merchant, MD [57]
Andrea MacNeill, MD [22] Associate Professor of Surgery
Resident, Division of General Surgery Vanderbilt University Medical Center
University of British Columbia Nashville, Tennessee
Vancouver, Canada
MSc Candidate Joel E. Michalek, PhD [1]
University of Oxford Professor and Vice Chairman
Oxford, United Kingdom Department of Epidemiology & Biostatistics
University of Texas Health Science Center
Robert Madoff, MD [31] San Antonio, Texas
Professor, Department of Surgery
University of Minnesota Medical School Daun J. Milligan, MD [107]
Stanley M. Goldberg, MD Endowed Chair in Colon and Critical Care Fellow
Rectal Surgery Department of Surgery
Minneapolis, Minnesota University of Texas Health Science Center
San Antonio, Texas
Catherine A. Madorin, MD [120]
House Staff Joseph L. Mills, MD [88]
Department of Surgery Chief, Division of Vascular and Endovascular Surgery
Mount Sinai School of Medicine Director, Vascular Fellowship and Residency Programs
The Mount Sinai Hospital Professor of Surgery
New York, New York Tucson, Arizona

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 xxii ■ List of Contributors

Kelly Ming, MD [37] University of Minnesota

Senior Surgical Resident Minneapolis, Minnesota
Kalamazoo Center for Medical Studies
Kalamazoo, Michigan Jeffrey A. Norton, MD [14]
The Robert L. and Mary Ellenburg Professor in Surgery
Elizabeth A. Mittendorf, MD [74] Surgical Oncology and General Surgery
Assistant Professor Stanford University School of Medicine
Department of Surgical Oncology Stanford, California
Division of Surgery
Daniel S. Oh, MD [9]
The University of Texas MD Anderson Cancer Center
Assistant Professor of Surgery
Houston, Texas
USC Norris Cancer Hospital
Keck School of Medicine
Frederick A. Moore, MD, FACS, FCCM [13C] Los Angeles, California
Professor and Chief, Acute Care Surgery
Department of Surgery John S. Oh, MD [47]
University of Florida College of Medicine Chief of Trauma
Gainesville, Florida Department of Surgery
Landstuhl Regional Medical Center
Katherine A. Morgan, MD [56] US Army
Associate Professor of Surgery Landstuhl, Germany
Medical University of South Carolina
Charleston, South Carolina Shane D. O’Keeffe, MD [90]
Assistant Professor
Department of Surgery
Luc G.T. Morris, MD [103] University of Kentucky College of Medicine
Head and Neck Service Lexington, Kentucky
Department of Surgery
Memorial Sloan-Kettering Cancer Center Terence O’Keeffe, MD, ChB, MSPH [44]
New York, New York Assistant Professor
Trauma Division
Mark T. Muir, MD [59] Department of Surgery
General Surgery Resident University of Arizona College of Medicine
Department of Surgery Tucson, Arizona
University of Texas Health Science Center
San Antonio, Texas Michelle M. Olson, MD, FACS, FASCRS [37]
Assistant Professor of Surgery
Temple University School of Medicine
Richard J. Mullins, MD, FACS [23C]
Philadelpia, Pennsylvania
Professor of Surgery
Section of Trauma/Critical Care Matthew O’Rourke, MD [119]
Oregon Health & Science University Resident, Department of Pediatrics
Portland, Oregon Columbia University Medical Center
New York, New York
Kalyana Nandipati, MD [4]
Assistant Professor of Surgery Adrian Ong, MD [48]
Department of Surgery Assistant Professor of Surgery
Creighton University School of Medicine Drexel University School of Medicine
Omaha, Nebraska Allegheny General Hospital
Pittsburgh, Pennsylvania
Lena M. Napolitano MD [113]
Christian A. Otero, MD [98]
Professor, Department of Surgery
Division of Trauma and Surgical Critical Care Services
Division Chief, Acute Care Surgery (Trauma, Burn, Critical Care,
University of Miami Miller School of Medicine
Emergency Surgery)
Jackson Memorial Hospital / Ryder Trauma Center
Associate Chair of Surgery for Critical Care
Miami, Florida
Director, Surgical Critical Care
University of Michigan H. Leon Pachter, MD [45C]
Ann Arbor, Michigan George David Stewart Professor of Surgery
Chair & G.D. Stewart Professor Surgery
Kristin B. Niendorf, MS [31] Department of Surgery
Genetic Counselor, Coordinator of the Bernstein Registry NYU Langone Medical Center
Masonic Cancer Center New York, New York

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Alexander A. Parikh, MD [57]
Assistant Professor of Surgery
Division of Surgical Oncology & Endocrine Surgery
Vanderbilt University Medical Center
Nashville, Tennessee
Pranay Parikh, MD [104]
Assistant Professor of Surgery
Division of Plastic Surgery
Tufts University School of Medicine
Baystate Medical Center
Springfield, Massachusetts
Michael D. Pasquale, MD [25]
Chair, Department of Surgery
Division of Trauma-Surgical Critical Care/General Surgery/Burn
Lehigh Valley Health Network
Allentown, Pennsylvania
Harvey I. Pass, MD [80]
Professor, Department of Cardiothoracic Surgery
Director, Division of Thoracic Surgery and Thoracic Oncology
New York University School of Medicine
NYU Langone Medical Center & Cancer Center
New York, New York
Benjamin J. Pearce, MD [84]
Assistant Professor, Vascular Surgery
University of Texas Health Science Center
San Antonio, Texas
W. Brian Perry, M.D., FACS, FASCRS
Department of General Surgery
San Antonio Military Medical Center
San Antonio, Texas
Yaron Perry, MD [10]
Assistant Professor of Surgery
Mercer University School of Medicine
Memorial University Medical Center
Director, Minimally Invasive Thoracic Surgery
Curtis & Elizabeth Anderson Cancer Institute
Savannah, Georgia
David S. Pertsemlidis, MD [49]
Assistant Clinical Professor
Department of Surgery
The Mount Sinai Hospital
New York, New York
Demetrius Pertsemlidis, MD [49]
Clinical Professor of Surgery
Department of Surgery
The Mount Sinai Hospital
New York, New York
Sarah Pesek, MD [36]
Clinical Instructor of Surgery
University of Vermont College of Medicine
Fletcher Allen Health Care
Burlington, Vermont
PMPH_FM.indd xxiii
List of Contributors ■ xxiii
Nicholas J. Petrelli, M.D. FACS [29C]
Professor of Surgery
Bank of America Endowed Medical Director, Helen F.
Graham Cancer Center at Christiana Care
Thomas Jefferson University
Newark, Delaware
Antonio I. Picon, MD [16]
Assistant Professor of Surgery
Beth Israel Medical Center
New York, New York
Edgar Joseph Pierre, MD [109]
Associate Professor of Anesthesia and Surgery
University of Miami School of Medicine
Anesthesiologist
Jackson Memorial Hospital
Miami, Florida
Peter W.T. Pister, MD, FACS [57C]
Professor, Department of Surgical Oncology
Division of Surgery
The University of Texas MD Anderson Cancer Center
Houston, Texas
Brad H. Pollock, MPH, PhD [1]
Dielmann Distinguished University Endowed Professor and
Chairman
Department of Epidemiology & Biostatistics
University of Texas Health Sciences Center
[35] San Antonio, Texas
Raphael E. Pollock, MD, PhD [102]
Professor of Molecular and Cellular Oncology
Professor of Surgery
The University of Texas MD Anderson Cancer Center
Houston, Texas
Mitchell C. Posner MD [11]
Thomas D. Jones Professor and Vice-Chairman
Chief, Section of General Surgery and Surgical Oncology
University of Chicago
Chicago Illinois
Lori Pounds, MD [86]
Assistant Professor/Clinical
Division of Vascular Surgery, Department of Surgery
University of Texas Health Sciences Center
San Antonio, Texas
Vitaliy Y. Poylin, MD [31]
Professor of Surgery
Harvard Medical School
Department of Colon & Rectal Surgery
Beth Israel Deaconess Medical Center
Boston, Massachusetts
Jason D. Prescott, MD [71]
Clinical Fellow in Surgery
Department of Surgery
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 xxiv ■ List of Contributors

Massachusetts General Hospital Daniel F. Roses, MD [101]

Boston, Massachusetts Jules Leonard Whitehill Professor of Surgery and Oncology
New York University School of Medicine
Basil A. Pruitt Jr., MD [Foreword] Director of Surgical Oncology
Professor, Department of Surgery NYU Langone Medical Center
Trauma Division New York, New York
University of Texas Health Sciences Center
San Antonio, Texas Robert E. Roses, MD [101]
Fellow in Surgical Oncology
Joe B. Putnam, Jr., MD [79] The University of Texas MD Anderson Cancer Center
Professor of Surgery and Chairman Houston, Texas
Department of Thoracic Surgery
Ingram Professor of Cancer Research Brian G. Rubin, MD [93]
Professor of Biomedical Informatics Professor, Surgery, Division of General Surgery
Vanderbilt University Medical Center Vascular Surgery Section
Nashville, Tennessee Washington University School of Medicine
St. Louis, Missouri
Seshadri Raju, MD, FACS [97C]
Vascular Surgeon Mark L. Ryan, MD [98]
Flowood, Mississippi Division of Trauma and Surgical Critical Care Services
University of Miami Miller School of Medicine
Peter Rhee, MD, MPH [115] Jackson Memorial Hospital / Ryder Trauma Center
Professor of Surgery Miami, Florida
Chief, Section of Trauma, Critical Care and Emergency
Surgery Abdul Saied, MD [46]
Department of Surgery General Surgery Resident
Arizona Health Sciences Center, University of University of Illinois College of Medicine
Arizona Chicago, Illinois
Tucson, Arizona
Barry Salky, MD FACS [24]
J. David Richardson, MD [82C] Chief, Division of Laparoscopic Surgery (Emeritus)
Professor and Vice Chairman of Surgery Professor of Surgery
Division of General Surgery The Mount Sinai Hospital
University of Louisville School of Medicine New York, New York
Department of Surgery
Alejandro F. Sanz, MD [6]
Louisville, Kentucky
Fellow, Department of Cardiothoracic Surgery
University of Pittsburgh Medical Center
David W. Rittenhouse, MD [58]
Pittsburgh, Pennsylvania
Senior Surgical Resident
Department of Surgery Mark D. Sawyer, MD [106]
Thomas Jefferson University Hospital Assistant Professor
Philadelphia, Pennsylvania Trauma, Critical Care and General Surgery
Mayo Clinic
Patricia L. Roberts MD [37C] Rochester, Minnesota
Chair, Department of Colon and Rectal Surgery
Lahey Clinic Thomas M. Scalea, MD, FACS, FCCM [81C]
Burlington, Massachusetts Physician-in-Chief, Shock Trauma Center
Professor of Surgery Francis X. Kelly/Professor of Trauma Surgery
Tufts University School of Medicine Director, Program in Trauma
Boston, Massachusetts University of Maryland School of Medicine
Baltimore, Maryland
Manuel Rodriguez-Davalos, MD, FACS [42]
Assistant Professor of Surgery (Transplant) and Pediatrics Martin A. Schreiber, MD, FACS [25C]
Yale University School of Medicine Professor of Surgery
New Haven, Connecticut Section of Trauma/Critical Care
Oregon Health & Science University
Raul J. Rosenthal, MD, FACS, FASMBS [55] Portland, Oregon
Department Chair
Bariatric and Metabolic Institute (BMI) Joshua Schulte, MD [37]
Weston, Florida Chief Surgical Resident

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 List of Contributors ■ xxv

Department of General Surgery University of Texas Health Science Center

Michigan State University San Antonio, Texas
Kalamazoo Center for Medical Studies
Kalamazoo, Michigan Michael J. Sise, MD, FACS [95C]
Clinical Professor of Surgery
Kevin Schuster, MD, FACS [105] University of California, San Diego School of Medicine
Assistant Professor of Surgery (Trauma) Trauma Medical Director
Yale School of Medicine Scripps Mercy Hospital
Trauma, Surgical Critical Care and Surgical Emergencies San Diego, California
Yale Medical Group
New Haven, Connecticut Sherry Sixta, MD [61C]
Acute Care Surgery/Surgical Critical Care Fellow
Steven Schwaitzberg, MD [38, 65, 66] University of Texas Health Science Center
Chief of Surgery Houston, Texas
Cambridge Health Alliance
Associate Professor Surgery David W. Smith, MD [50]
Harvard Medical School Surgical Group
Department of Surgery Banner Estrella Medical Center
Cambridge, Massachusetts Phoenix, Arizona

Wayne H. Schwesinger, MD [13, 53C] Dror Soffer, MD [61]

Professor and Interim Chief Director, Yitzhak Rabin Trauma Division
Division of General and Laparoendoscopic Surgery Tel Aviv Sourasky Medical Center
Director and Chief, General Surgery B and Surgical Endoscopy Department of Surgery
University of Texas Health Science Center Tel Aviv, Israel
San Antonio, Texas
Jamii St. Julien, MD, MPH [57]
Post Doctoral Fellow
Ashok R. Shaha, MD [103] TREAT Lung Cancer Program
Jatin P. Shah Chair in Head and Neck Surgery and Oncology Vanderbilt University School of Medicine
Memorial Sloan-Kettering Cancer Center Nashville, Tennessee
New York, New York
Kenneth Stahl, MD, FACS [2]
Amir Sharif, MD [15] Associate Professor of Surgery
Fellow, Minimally Invasive Surgery Director of Patient Safety
Section of Gastrointestinal Surgery DeWitt Daughtry Family Department of Surgery
Department of Surgery William Lehman Injury Research Center Medical Director
Yale University School of Medicine Ryder Trauma Patient Safety Organization
New Haven, Connecticut The University of Miami Leonard M. Miller School of Medicine
Miami, Florida
Maureen K. Sheehan, MD [97]
Assistant Professor of Surgery Megan Steigelman, MD [107]
Division of Vascular/Endovascular Surgery US Air Force General Surgery
University of Texas Health Science Center Travis AFB
San Antonio, Texas Vacaville, California

Joseph H. Shin, MD, FACS [104] Randolph Steinhagen, MD [19]

Chief, Division of Plastic Surgery Professor of Surgery
Tufts University School of Medicine Chief, Division of Colon and Rectal Surgery
Baystate Medical Center The Mount Sinai School of Medicine
Springfield, Massachusetts New York, New York

Gregorio Sicard, MD, FACS [83C] Ronald M. Stewart, MD [18C]

Eugene M. Bricker Professor of Surgery Professor and Chair
Executive Vice Chairman, Department of Surgery Department of Surgery
Washington University School of Medicine Jocelyn and Joe Straus Endowed Chair in Trauma Research
St. Louis, Missouri University of Texas Health Science Center
San Antonio, Texas
Matthew J. Sideman, MD [86]
Associate Professor of Surgery Robert P. Sticca, MD, FACS [29]
Division of Vascular/Endovascular Surgery Professor and Chairman

PMPH_FM.indd xxv 5/22/2012 6:23:44 PM

 xxvi ■ List of Contributors

Department of Surgery The Academic Department of Surgery

University of North Dakota School of Medicine and Health Queen Elizabeth Medical Centre
Sciences Edgbaston Birmingham, West Midlands, United Kingdom
Grand Forks, North Dakota
Joshua A. Tyler, MD [35]
Andrew Tang, MD [115] Department of General Surgery
Assistant Professor San Antonio Military Medical Center
Department of Trauma, Critical Care and Emergency Surgery San Antonio, Texas
Arizona Health Sciences Center, University of Arizona
Tucson, Arizona Andreas G. Tzakis, MD, PhD, FACS [40]
Professor of Surgery
Nicholas Tarmey, MBChB, FRCA, RAMC [115] Miami Transplant Institute
Divsion of Trauma Anesthesiology University of Miami Miller School of Medicine
R. Adams Cowley Shock Trauma Center Baltimore, Baltimore, Miami, Florida
Maryland
Robert Udelsman, MD, MBA [71]
Paul Ian Tartter, MD, FACS [77] Chairman, Department of Surgery
Associate Professor Carmalt Professor of Surgery and Oncology
Division of Breast Surgery Yale University School of Medicine
Department of Surgery Surgeon-in-Chief
St. Luke’s-Roosevelt Hospital Center Yale New Haven Hospital
New York, New York New Haven, Connecticut

Burke Thompson, MD, MPH [28] Kent R. Van Sickle, MD [64]

Central Carolina Surgery Associate Professor of Surgery
Greensboro, North Carolina Director, UTHSCSA Johnson Center for Surgical Innovation
Division of General and Laparoendoscopic Surgery
Robert W. Thompson, MD [89] University of Texas Health Science Center
Professor of Surgery San Antonio, Texas
Center for Thoracic Outlet Syndrome
Section of Vascular Surgery, Department of Surgery Frank J. Veith, MD [88C]
Washington University School of Medicine Professor, Department of Surgery
St. Louis, Missouri New York University School of Medicine
NYU Langone Medical Center
Chad M. Thorson, MD [98] New York, New York
University of Miami Miller School of Medicine
Division of Trauma and Surgical Critical Care Services George C. Velmahos, MD, PhD, MSEd [99]
Jackson Memorial Hospital / Ryder Trauma Center John F. Burke Professor of Surgery
Miami, Florida Harvard Medical School
Chief, Division of Trauma, Emergency Surgery, and Surgical
Keila E. Torres, MD, PhD [102] Critical Care
Assistant Professor Massachusetts General Hospital
Department of Surgical Oncology Boston, Massachusetts
The University of Texas MD Anderson Cancer Center
Houston, Texas Steven G. Venticinque, MD [110]
J. Jeff rey Andrews, MD and R. Brian Smith Endowed
Boulos Toursarkissian, MD [83] Professor and Chair
Professor and Chief University of Texas Health Science Center
Division of Vascular Surgery San Antonio, Texas
University of Texas Health Science Center David Vogel, MD [92]
San Antonio, Texas Senior Vascular Surgery Fellow
Jobst Vascular Institute
Magdiel Trinidad-Hernandez, MD [100] The Toledo Hospital
Assistant Professor of Surgery Toledo, Ohio
Department of Surgery
University of Arizona Thai Vu, MD [98]
Tucson, Arizona Division of Trauma and Surgical Critical Care Services
University of Miami Miller School of Medicine
Olga Tucker, MD, FRCSI, FRCS [55] Jackson Memorial Hospital / Ryder Trauma Center
Senior Lecturer/Consultant Surgeon Miami, Florida

PMPH_FM.indd xxvi 5/22/2012 6:23:44 PM

 List of Contributors ■ xxvii

Daniel B. Walsh, MD [92C] John A. Weigelt, MD [3C]

Medical Director, Referring Physician Services Professor
Vascular Surgery Department of Surgery
Dartmouth-Hitchcock Medical Center Division of Trauma/Critical Care
Lebanon, New Hampshire Medical College of Wisconsin
Milwaukee, Wisconsin
Jodi Walters, MD [96C]
Southern Arizona Limb Salvage Alliance (SALSA) Christopher E. White, MD, MSc, FACS [111]
University of Arizona College of Medicine Department of General Surgery
Tucson, Arizona Brooke Army Medical Center
San Antonio, Texas
J. Matthias Walz, MD [112]
Chief, Vascular Anesthesiology Richelle Williams, MD [72C]
UMass Memorial Medical Center American College of Surgeons
Associate Professor of Anesthesiology Department of Surgery
University of Massachusetts Medical School University of Chicago Pritzker School of Medicine
Worcester, Massachusetts Cancer Programs
Chicago, Illinois
Howard T. Wang, MD [104C]
Associate Professor and Chief
David P. Winchester, MD, FACS [72C]
Plastic and Reconstructive Surgery
American College of Surgeons
Program Director, Plastic Surgery Residency Program
Department of Surgery
Division of Plastic and Reconstructive Surgery
University of Chicago Pritzker School of Medicine
University of Texas Health Science Center
Cancer Programs
San Antonio, Texas
Chicago, Illinois
Kenneth Waxman, MD [114C]
Medical Director Charles J. Yeo, MD, FACS [58]
Cottage Hospital Trauma Center Chair and Samuel D. Gross Professor
Cottage Children’s Hospital Department of Surgery
Santa Barbara, California Thomas Jefferson University Hospitals
Philadelphia, Pennsylvania
Kaare J. Weber, MD [120]
Assistant Professor of Surgery Luke X. Zhan, MD [88]
Department of Surgery Division of Vascular and Endovascular Surgery
Mount Sinai School of Medicine University of Arizona Health Science Center
The Mount Sinai Hospital Southern Arizona Limb Salvage Alliance (SALSA)
New York, New York Tucson, Arizona

PMPH_FM.indd xxvii 5/22/2012 6:23:44 PM

PMPH_FM.indd xxviii 5/22/2012 6:23:44 PM

The practice of surgery has always been evidence-based, with
early “evidence” being the opinion of authorities of the day such
as Hippocrates, Ambroise Paré, John Hunter, and Samuel Gross.
The importance of adding data to support authoritarian opinion
is well illustrated by the largely ignored 17th century observations
of John Woodall on scurvy and the response, even though forty
years delayed, to James Lind’s 18th century study of scurvy. Lind’s
1754 study, considered to be the first controlled clinical trial,
provided the evidence to mandate, in 1795, the use of lemons to
prevent scurvy in British seamen. The importance of evidence is
further exemplified by Florence Nightingale, who has been cred-
ited with being one of the first to use statistics in her studies of
hospital infection in the Crimean War (1854–1856). Her statistics
generated evidence to support improvements in care.
In the past 150 years, authoritative opinion has been more
and more often supported by randomized, controlled clinical tri-
als or correlative laboratory studies that have become progres-
sively more complex and scientifically rigorous as technology has
advanced and sophisticated statistical assays have been utilized.
Today, evidence is instantly available in the publications of the
Cochrane Database of Systemic Reviews and the quality of evi-
dence can be readily graded according to criteria promulgated by
the Oxford Centre for Evidence-Based Medicine.
The textbook has occupied a central role as the transmit-
ter of evidence-based practice to the surgical community at
large, extending from medical students to practicing surgeons.
It too has evolved from a compendium of personal experience
to the present volume for which the editors have selected clini-
cians with broad understanding of evidence-based medicine to
author each chapter. The opening chapter presents a concise yet
xxix
PMPH_FM.indd xxix
FOREWORD
thorough review of the development of evidence-based medicine,
describes the process of data evaluation, gives consideration to
statistical principles and pitfalls, and provides an example of a
recent systematic review, that is, it sets the stage for the follow-
ing chapters. Subsequent chapters bring Socrates to the surgical
textbook by posing questions about the what, when, and why
related to important, typically controversial or uncertain, aspects
of surgical care of specific diseases and conditions. The authors
of those chapters have provided what they consider to be the best
available recent evidence to answer those questions and guide the
readers in making management decisions in their practice of elec-
tive surgery.
Recognizing that evidence-based surgery does not provide a
hard and fast solution to every surgical problem, broadly expe-
rienced more senior surgical authorities provide commentary
for selected chapters. These commentaries illustrate the impor-
tance of integrating the published evidence with surgeon-specific
expertise and individual patient needs in developing a clinically
feasible, patient-centered approach to a surgical problem. An
understanding of that methodology will extend the influence of
this text and enable the readers throughout their surgical careers
to incorporate new findings and study results into their evidence
data base and broaden the applicability of the “refi ned” evidence.
The Socratic process used by the editors to address controversial
aspects of elective surgical management will enhance and expand
the readers’ use of evidence-based surgery to achieve optimum
patient outcomes and document, as did Socrates’ pupil and suc-
cessor Plato, their evidence-based competency.
—Basil A. Pruitt, Jr., MD
5/22/2012 6:23:44 PM
PMPH_FM.indd xxx 5/22/2012 6:23:44 PM

Attention to evidence-based surgical medicine began for the two
editors in 1983 during our surgical residency at Boston Univer-
sity and at morning report at Boston City Hospital Surgical Ser-
vices. Our Chairman of Surgery, Lester.F Williams,James F. Utley
Professor of Surgery, conducted Rounds in a Socratic manner, and
he answered every question with the inquiry “Show me the data.”
He invariably had the data organized within an encyclopedic
brain and instilled within all his residents s a thirst for “Evidence-
Based Medicine” (EBM).
The basic principle guiding the preparation of this text was
that it should be a dynamic, comprehensive reference focused on
the important surgical questions about each disease. The answers
to each clinical question should be authoritative and reflect evi-
denced-based medicine recommendations for level of evidence
and grade of recommendation.
Evidenced-based medicine connotes a commitment on the
part of the author and a confidence level among the readership
that the data presented is obtained from the highest levels of
surgical scientific research and observation. We believe that our
xxxi
PMPH_FM.indd xxxi
PREFACE
distinguished chapter authors have fulfi lled this obligation and
that our readers can be confident in the answers provided to the
questions posed.
The book is organized with a fi nite number of surgical ques-
tions for each chapter subject for general, vascular, and pedi-
atric content. Each question is answered with concise EBM
data,including a table demonstrating the level of evidence and
grade of recommendation. Subsequent editions to the textbook
will easily incorporate new studies and relevant surgical science
questions and answers. We have attempted to combine the best
of EBM for surgery with the most up-to-date, prospective, ran-
domized controlled trials, large meta-analyses, and cohort data
scrutinized for validity and recommendations. We hope that
this data can guide the experienced surgeon as well as the nov-
ice learner through the management and treatment of surgical
diseases.
—Steven T. Brower
—Stephen M. Cohn
5/22/2012 6:23:44 PM
PMPH_FM.indd xxxii 5/22/2012 6:23:44 PM

Understanding the Elements that
Comprise Evidence-Based Medicine
Joel E. Michalek, John E. Cornell, and Brad H. Pollock
INTRODUCTION
Background
The idea of using “evidence” in medicine has been traced to ancient
Greece1 and ancient China,1,2 and testing medical interventions for
safety has existed since Avicenna’s The Canon of Medicine in the 11th
century.3,4 It was only in the 20th century that this effort evolved to
affect nearly all fields of health care. Professor Archie Cochrane’s
book Effectiveness and Efficacy: Random Reflections on Health
Services,5 and his subsequent advocacy for a scientific foundation for
clinical practice, led to increased acceptance of the concepts behind
evidence-based medicine. Cochrane’s work is recognized through
the naming of centers of evidence-based medical research, the
Cochrane Centers, and an international organization, the Cochrane
Collaboration (www.cochrane.org), after him. The goal of this inter-
national collaboration is to collect, evaluate, and summarize all the
best available scientific evidence regarding the benefits and harms
of a medical intervention. Explicit methodologies that are used
to determine “best evidence” were developed by a research group
at McMaster University led by David Sackett and Gordon Guyatt.
Guyatt later used the term “evidence-based” in 1990,6 and the term
“evidence-based medicine” first appeared in the medical literature
in 1992 in a paper by The Evidence-Based Medicine Working Group.7
A recent summary of evidence-based medicine, User’s Guides to the
Medical Literature. A Manual for Evidence-Based Clinical Practice,
has been published.8 Relevant journals include the British Medical
Journal’s Clinical Evidence, the Journal of Evidence-Based Health
Care, and Evidence-Based Health, Policy, all co-founded by Anna
Donald, an Australian pioneer in the discipline.9
Cochrane defines evidence-based medicine as the conscien-
tious, explicit, and judicious use of current best evidence in mak-
ing decisions about the care of individual patients. The practice
of evidence-based medicine means integrating individual clini-
cal expertise with the best available scientific evidence compiled
PMPH_CH01.indd 1
CHAPTER 1
through an objective, rigorous, and critical systematic review
of the available evidence. Guyatt et al. posited two fundamental
principles of evidence-based medicine8: (1) a hierarchy of evidence
to guide clinical decision making; and (2) evidence alone is never
sufficient to make a clinical decision. Decision makers must always
consider tradeoffs between benefits and risks, inconvenience, and
costs associated with alternative management strategies and, in
doing so, consider their patients’ values and preferences.
WHAT IT IS AND WHAT IT ISN’T
In an editorial, David Sackett defined evidence-based medicine
as the explicit and judicious use of current best evidence in mak-
ing clinical decisions about individual patients.1 Evidence regard-
ing the relative benefits and harms of a medical intervention
comes from clinically relevant scientific research, especially from
patient-oriented clinical research into the accuracy and precision
of diagnostic tests (including the clinical examination), the power
of prognostic markers, and the efficacy and safety of therapeutic,
rehabilitative, and preventive regimens. Evidence-based medicine
is not “cookbook” medicine. It requires a bottom-up approach
that integrates best external evidence with individual expertise
and patients’ choice, emphasizing that external evidence can
never replace individual expertise and patient preference.1
In this chapter, we focus on the first principle, systems for rat-
ing evidence, assessing the strength of evidence, and an example
of a systematic review, considered by some to be one of the highest
forms of evidence. Throughout the chapter we attempt to address
aspects of this topic as it pertains to surgery.
SYSTEMS FOR RATING EVIDENCE
The quality and strength of evidence provided by scientific clinical
research is largely determined by study design and the degree to
5/21/2012 7:41:09 PM
 2 ■ Surgery: Evidence-Based Practice
which investigators minimize the risk of bias in the conduct and
reporting of their findings. Consideration of these factors has led
to the development of hierarchies of evidence and various scoring
systems to help clinicians and researchers evaluate the quality and
strength of the available evidence.
Hierarchies of Evidence: At least three hierarchies of evidence
have been published. These hierarchies are largely based on study
design. Evidence derived from a randomized controlled clinical trial
(RCT) or a quantitative summary of treatment effects from multiple
RCTs investigating a common intervention provides the greatest
level of scientific rigor and internal validity. Traditional clinical case
studies and case-series designs represent the weakest level of evi-
dence. Some of the hierarchies incorporate general assessments of
how well the study was designed, conducted, and reported.
US Preventive Services Task Force,65 for example, developed a
system that considers well-designed RCTs as providing the highest
level of evidence and opinions of respected authorities at the low-
est level of evidence:
Level I: Evidence obtained from at least one properly designed
and randomized controlled trial
Level II-1: Evidence obtained from well-designed controlled trials
without randomization
Level II-2: Evidence obtained from well-designed cohort or case-
control analytic studies, preferably from more than one center
or research group
Level II-3: Evidence obtained from multiple time series with or
without intervention. Dramatic results in uncontrolled trials
might also be regarded as this type of evidence
Level III: Opinions of respected authorities, based on clinical
experience, descriptive studies, or reports of expert committees
The UK National Health Service developed a similar system, with
categories labeled A, B, C, and D. This system was developed by the
Oxford Centre for Evidence-Based Medicine (http:/www.cebm.net/
index.aspx?o=1025), and it emphasizes consistency of the evidence
across a variety of study designs, as well as type of study design:
Level A: Consistent RCT, cohort study, all or none, clinical
decision rule validated in different populations
Level B: Consistent retrospective cohort, exploratory cohort,
ecological study, outcomes research, case-control study, or
extrapolation from level A studies
Level C: Case-series study or extrapolation from level B studies
Level D: Expert opinion without explicit critical appraisal, or
based on physiology, bench research, or first principles
The McMaster University group developed a system based largely on
a study design that gives more weight to randomized N of 1 studies
that directly assess the efficacy and safety of a medical intervention at
the individual patient level. In User’s Guides to the Medical Literature.
A Manual for Evidence-Based Clinical Practice, Guyatt et al.8 empha-
sized the importance of the N of 1 studies to address the individual
patient and systematic reviews to guide clinical decision making:
• N of 1 randomized trial
• Systematic reviews of randomized trials
• Single randomized trial
• Systematic review of observational studies addressing patient-
important outcomes
• Single observational study addressing patient-important outcomes
• Physiologic studies (studies of blood pressure, cardiac output,
exercise capacity, bone density, and so forth)
• Unsystematic clinical observations.
PMPH_CH01.indd 2
The N of 1 randomized trial is a study of one patient with repeated
blocks of two or more treatments given in a random order in each
block. The N of 1 study is preferably double-blind and placebo or
otherwise controlled and is intended to address the efficacy and
safety of a single therapy in an individual patient. While this
design has little or no direct application in surgical intervention
research, systematic reviews of randomized and nonrandomized
observational studies can provide substantial evidence about the
efficacy and safety of a surgical intervention.
A systematic review applies the fundamental principles of the
scientific method to the process of reviewing and evaluating the
benefits and harms associated with a medical or surgical inter-
vention. Systematic reviews follow a prespecified protocol with
explicit criteria used to find, select, critique, and synthesize evi-
dence relevant to a well-defined clinical question about diagnos-
tic accuracy, clinical prognosis, or the safety and efficacy of an
intervention. Critical to this process is a careful assessment of the
quality and consistency of the available evidence.
The Grading of Recommendations Assessment, Develop-
ment, and Evaluation (GRADE) Working Group, an international
collaboration of clinical scientists, developed a system for “grad-
ing the quality of evidence and the strength of recommendations”
provided by a systematic review (http://www.gradeworkinggroup.
org/intro.htm). It combines information about study design, con-
sistency of evidence, and risk of bias into a unified system to assess
the quality and strength of the evidence available to assess the effi-
cacy and safety of a medical or surgical intervention.
GRADE Criteria: The GRADE working group was established
in 2008 to develop a new system of rating quality of evidence and
providing medical recommendations that depends less on hierar-
chy and more on the types of evidence and specific strengths and
weaknesses.10 Its primary focus was to develop a set of criteria for
organizations and groups involved in the development of clinical
guidelines to objectively evaluate the degree to which a particu-
lar body of evidence can support a proposed guideline for clinical
practice. Evidence is categorized as being high, low, or very low
grade, and recommendations are given as strong and weak. The
GRADE criteria for assigning grade of evidence are summarized
in Table 1.1.
The strength of a GRADE recommendation (strong or weak)
is based on quality of evidence, uncertainty about the balance
between desirable and undesirable effects, uncertainty or vari-
ability in values and preferences, and uncertainty about whether
the intervention represents a wise use of resources.
The GRADE system provides a detailed and explicit set of cri-
teria for ratings of quality and grading of strength evidence that
makes judgments supporting clinical guidelines and recommenda-
tions more transparent than simple reliance on a hierarchy of evi-
dence.11 While study design provides a starting point for evaluating
the quality and strength of the evidence provided by a single study
or a collection of studies, the GRADE approach acknowledges that
poorly designed and/or executed RCTs can produce biased and
misleading results; well-designed and executed observational stud-
ies can produce quite robust and valid assessments of the compara-
tive effects of a medical or surgical intervention. Collectively, these
methodological concerns address the internal validity or risk of bias
associated with a particular study or collection of studies.
Randomized trials that lack allocation concealment or blind-
ing tend to produce biased results that tend to favor an interven-
tion. Patient attrition and failure to capture primary outcomes
compromise randomization and threaten the integrity of the
5/21/2012 7:41:09 PM
 Evidence-Based Medicine ■ 3

Table 1.1 GRADE Criteria for Rating the Quality and Strength of Evidence Regarding a Medical or
Surgical Intervention
Type of evidence Randomized trial = high
Observational study = low
Any other evidence = very low
Decrease* grade if • Serious or very serious limitation to study quality
• Important inconsistency
• Some or major uncertainty about directness
• Imprecise or sparse data
• High probability of reporting bias
Increase grade if • Strong evidence of association—significant relative risk >2 (<0.5) based on consistent evidence from
two or more observational studies, with no plausible confounders (+1)
• Very strong evidence of association—significant relative risk >5 (<0.2) based on direct evidence with
no major threats to validity (+2)
• Evidence of a dose response gradient (+1)
• All plausible confounders would have reduced the effect (+1)
Range • High-quality evidence
• Moderate-quality evidence
• Low-quality evidence
• Very-low-quality evidence
* Each quality criterion can reduce the quality by one or, if very serious, two levels.

data unless an adequate intent-to-treat analysis is used. Selec-
tive reporting of outcomes tends to overestimate the benefits of
an intervention. Randomized trials that fail to provide a proper
accounting of allocation concealment, blinding, patient attrition,
and missing data, and all prespecified outcomes are penalized
(downgraded) in the GRADE system.
Observational studies that develop and apply appropriate eli-
gibility criteria in selection of exposed and unexposed subjects in
cohort studies or provide adequate matching of cases and con-
trols in case-control studies can provide robust estimates of the
comparative effectiveness of a medical or surgical intervention.
The quality and strength of the evidence from these observational
studies is further upgraded or downgraded based on how com-
pletely exposures and outcomes were ascertained, how adequately
and completely the study controlled for sources of confounding,
and how well the study maintained follow-up on all participants.
The evolution of the GRADE system into a mature comprehen-
sive approach for assessing study quality and strength of evidence
is documented in a new series of articles published in the Journal of
Clinical Epidemiology.11 The value of the GRADE system is widely
recognized and used by a number of government organizations
and professional medical societies to assist in guideline develop-
ment, including the World Health Organization, the American
College of Physicians, The American Thoracic Society, UpToDate
(www.uptodate.com), and at least 20 other organizations. Here we
summarize methods to assess the strength of evidence in terms of
bias, study type, statistical precision, and the choice of endpoint.
ASSESSING THE QUALITY AND
STRENGTH OF EVIDENCE
Four attributes define the strength of evidence. The first is the
level of the evidence—dictated by the type of study design that
was used. The second is the quality of evidence—directly related
to risk of bias. The third is statistical precision—the degree to
which true effects can be distinguished from spurious effects due
to random chance. The fourth is the choice of a study endpoint
to measure an effect—an endpoint’s appropriateness to truly rep-
resent a clinically meaningful effect—and the magnitude of the
observed effect. For practical reasons, the selection of study sub-
jects for a particular study is almost always a compromise. The
degree to which a chosen study population represents an intended
target population must also be considered; selection bias can
compromise a study’s weight of evidence.
STUDY DESIGN
The first step in evaluation of the quality and strength of evidence is
understanding the scope and limitations inherent in the type(s) of
study design(s) used to collect the data. These factors form the basis
for the various hierarchies of evidence described in the preceding
section. Here we describe the scope and limitations of many of the
popular study designs used to collect and report evidence regard-
ing the efficacy and safety of clinical and surgical interventions.
Several different types of studies are used in clinical research.
Researchers have developed and evaluated various ontologies
for study design classifications and developed electronic tools to
assist in classifying published studies according to their design
features.12,13 The primary distinction made in the GRADE system
is between randomized and nonrandomized studies. The latter is
collectively referred to as observational studies.
The simplest observational designs start with case reports and
case series that can be used to document the effects of an inter-
vention or clinical course. However, these sources are subject to
selection bias, often use unblinded subjective rather than blinded
objective outcome assessment, are imprecise due to measurement
errors, and typically include only small number of patients. Case
reports and case series usually have no control groups for compar-
isons. Case-control studies sample patients based on the presence/
absence of a medical condition. Patients with the outcome of interest

PMPH_CH01.indd 3 5/21/2012 7:41:09 PM

 4 ■ Surgery: Evidence-Based Practice
are referred to as the cases, and a group of unaffected subjects
with similar sociodemographic and medical profi les are selected
as controls. Case-control studies usually have little problem
accruing case subjects, are free from the burden of patient recruit-
ment, can be performed in a shorter period of time, and are often
much less expensive to conduct than cohort or other prospec-
tive studies. However, a temporal relationship between cause and
effect can only be inferred and not directly measured because of
the retrospective nature of case-control studies. These studies are
also subject to biased recall of antecedent exposures and selection
bias, especially in the selection of controls. Case-control stud-
ies are most often used for rare outcomes or when there is a long
induction period between an exposure and the outcome.
Prospective cohort studies recruit subjects free of the outcome
of interest and are composed of two or more groups, including
an exposed or index group and a control group. Subjects are then
dynamically followed over time for the occurrence of the outcome
of interest. Recruitment may be selective and based on enrolling an
equal number of subjects from preselected exposures categories;
matching on other factors may reduce confounding and improve
the precision of comparisons across exposure groups. Alterna-
tively, recruitment to cohort studies need not be based on prede-
termined categories of exposure; these are commonly studies with
several exposures of interest. An alternative design is the historical
cohort study. These studies use preexisting information, often in
a comprehensive database, to historically classify exposure status.
The database is then gleaned for information about subsequent
outcome events. Prospective cohort studies can be more expensive
than other designs. An exposure of interest, such as a new surgi-
cal procedure versus a conventional procedure, may be associated
with confounders, known or unknown, measurable or unmeasur-
able. Because cohort studies are not randomized, the distribution
of confounders may not be balanced between the treatment groups,
thus leading to confounding. Prospective studies are more time
consuming than case-control studies. A major advantage of cohort
designs is that they provide a clear picture of the temporal relation-
ship between a cause and an effect. Matching can efficiently reduce
confounding due to a subset of known and measurable confound-
ers. In addition, multiple outcomes can be evaluated in contrast to
case-control studies with a single outcome of interest.
In all but the Guyatt et al.8 hierarchy, RCTs provide the great-
est weight of evidence. In these studies, the allocation of subjects
to an exposure of interest or control is done solely for the purpose
of obtaining an unbiased estimate of the treatment effect. The key
advantage of RCTs is the low likelihood of bias due to confounding.
Although controlling for known confounders can be performed
using techniques such as restriction, stratification, or statistical
adjustment, randomization tends to balance the distribution of all
confounders, known or unknown, measurable or unmeasurable,
between treatment groups. Some RCTs can be blinded. The disad-
vantages of RCTs are possibly high costs and recruitment barriers
(particularly for subjects who do not give consent).
Other study designs are used less frequently in medical
research. Cross-sectional studies collect both exposure and out-
come information simultaneously, may be more applicable for prev-
alent rather than for acute conditions, and do not address cause and
effect temporal relationships. In crossover studies, subjects serve as
their own controls. In a two treatment, two period crossover, half
the study population receives the primary treatment first and then
crosses over to receive the second treatment; the other half receives
the treatments in reverse order. An assumption of crossover studies
PMPH_CH01.indd 4
is that the residual effects of a treatment disappear by the time the
groups are crossed over, and will be violated, for example, with
surgical interventions where a subject’s condition is permanently
altered by the therapy (e.g., limb amputation). Crossover trials,
when possible, are more efficient than parallel arm clinical trials, in
that they require fewer patients than the parallel group design and
have the advantage that every patient will receive all treatments.
BIAS
The strength of scientific evidence provided by an individual
study is dependent on a number of key factors that are associated
with how well a study design is implemented and reported. These
key factors address the internal (risk of bias) and external valid-
ity (generalizability) of a study, and careful consideration of these
factors are essential before attempting to make clinical infer-
ences from a study. Failure to minimize risk of bias undermines
the value of a randomized study, whereas a well-designed cohort
or case-control study that minimizes risk of bias enhances the
strength of its contribution to the body of evidence. Ideally, stud-
ies are both internally and externally valid. Compromised validity
lowers a study’s contribution to the body of evidence.
Bias is a systematic error that affects inferences derived from
the results of a study. Internal validity refers to a study’s lack of bias.
External validity refers to the generalizability of a study, address-
ing whether the results can be extrapolated to another population of
interest. Internal validity should be the primary consideration when
reviewing a study. If a study is not internally valid, one need not
consider whether it is externally valid; that is, biased study results
should never be extrapolated to another population. For interven-
tion studies, internal validity addresses whether observed effects can
be attributed to the treatment effect or whether they are attributed to
alternative explanations such as bias or lack of statistical precision.
The validity of all patient-oriented research studies is strongly
related to the risk of bias inherent in the design and execution
of a study. The higher the risk of bias in an individual study, the
more compromised are its findings. Higher risk of bias tends to
produce overly optimistic estimates of the benefits of a medical or
surgical intervention. The internal validity of a particular study
is affected by observer bias, measurement bias, confounding and
statistical precision. Confounding is the mixing up of sources of
bias with the true effects of an intervention so that the primary
effect under study cannot be separated from the influence of
extraneous factors. For example, failing to account for preopera-
tive disease severity in a randomized trial evaluating two surgical
approaches might lead to confounding if the severity distribution
differed between groups. These potential problems can manifest
themselves in different ways for different study designs.
Measurement bias is inaccuracy related to the method of mea-
suring outcomes for a study. Examples include poorly calibrated
blood pressure readings, inaccurate height measurements, flawed
laboratory methods that give erroneous values or that fails to accu-
rately reflect clinically meaningful categories. Observer bias is inac-
curacy related to measuring a study outcome where the observer
knows the intervention group assignment. A technique known
as blinding is used in randomized and nonrandomized studies
to minimize observer bias. Study participants, health profession-
als involved in patient management, and study personnel respon-
sible for collecting data are denied access to information regarding
treatment assignment or the primary risk factors and outcomes of
5/21/2012 7:41:09 PM

interest. Observer bias is more likely to occur in unblinded studies
when the chosen outcome measure is subjective, such as the occur-
rence of symptoms or toxicities, patient self-report measures, and
interpretations of physical examination findings. Double blinding
is a technique where neither the observer nor the patient knows
the treatment assignment. For many surgical interventions such
as total limb versus partial limb amputation, or for regimens with
very idiosyncratic symptom or toxicity profiles, double blinding
may be impractical or impossible. Surgical studies are more closely
aligned with epidemiological studies in this respect. Blinding of
study personnel responsible for collecting and recording pre-, peri-,
and postoperative information and outcomes is often possible and
an effective way to minimize observer bias in surgical studies.
STATISTICAL PRECISION
It is all too easy to equate evidence with a summary statistic like
median survival time or the relative risk ratio. The evidence from
a single study or even a collection of studies is always captured
with some degree of uncertainty. Proper weighing of the evidence
requires that we pay close attention to the margin of error in our
estimates of the relative efficacy and safety of a medical or sur-
gical intervention. Statistical precision captures and quantifies
the uncertainty surrounding any given estimate. It enables us to
distinguish real effects from those due to random chance, that is,
chance associations. Statistical precision is primarily driven by
sample size. For example, with just 10 subjects (5 in each group) a
randomized clinical trial comparing a new postsurgical antibiotic
regimen to a conventional regimen for sepsis prophylaxis is likely
to result in an extreme finding that can be attributed to random
chance, not the true biological drug effect. This phenomenon is
referred to as a small study effect in systematic reviews and clini-
cal guideline documents, and is associated with the concept of
publication bias. Small studies with statistically significant results
have a greater likelihood of being published than studies, large
or small, that report nonstatistically significant findings. Chance
errors are less likely to occur with larger sample sizes. Trials are
always planned to limit the likelihood of chance errors; acceptable
levels of error (for Type 1 and Type 2 statistical errors) are selected
in advance and the target minimum detectable effect size is cho-
sen. Formal sample size and power calculations are performed
during the study’s design to ensure adequate statistical precision.
EXTERNAL VALIDITY
External validity is a function of whether a study’s results can be
generalized to other clinical settings or populations. The question
is, “Does the study population possess unique characteristics which
might modify the effect of an intervention in a way which would
render it ineffective in some other group?” Subjects enrolled in a
trial may not represent the population to which the intervention
is intended to be applied. Surgical and nonsurgical intervention
studies sometimes enroll subjects at large academic institutions
and the characteristics for these enrolled patients may not repre-
sent patients seen at smaller nonacademic centers. Even within a
center, patients who consent to participate may not represent the
institution’s entire clinical population.
Selection bias can occur with the self-selection of individu-
als who consent to participate in a research study. Both research-
ers and participants may bring a multitude of characteristics to a
PMPH_CH01.indd 5
Evidence-Based Medicine ■ 5
clinical study, some inherent and some acquired. These can include
factors such as gender, race/ethnicity, hair, eye, and skin color,
personality, mental capability, physical status, and psychological
attitudes like motivation or willingness to participate. Differences
in the distribution of these factors between a source population
and a protocol-enrolled study population may introduce selection
bias. For example, some investigators may preferentially select
more athletic-looking subjects for an elective orthopedic surgery
clinical trial. Multicenter trials may improve the generalizability
of a study, but such studies may still suffer from selection bias.
WEIGHT OF EVIDENCE
Study design, lack of bias, statistical precision, and external valid-
ity affect a study’s weight of evidence. Each of these factors must
be considered when evaluating a study. For practical reasons, the
investigator who is designing a new study is always confronted
with tradeoffs between these factors and cost. For example, hav-
ing highly restrictive eligibility criteria reduces the possibility of
confounding but lowers the generalizability of a study. The choice
of an objective endpoint for an antibiotic trial (e.g., death versus
sepsis) decreases observer bias at the cost of decreased statisti-
cal precision—fewer deaths compared to the number of incident
sepsis cases. Investigators are faced with many challenges when
designing intervention studies. Because resources are almost
always limited, design compromises are made that ultimately
affect the overall weight of evidence provided by a study.
COMBINING AND SYNTHESIZING
THE EVIDENCE
Literature reviews are the primary vehicle for collecting, collat-
ing, critiquing, and combining evidence in medical and surgical
research. Ideally, the goals of a literature review are to (1) provide a
comprehensive critical review of the available evidence that identifies
the boundaries of our knowledge, (2) provide insight into sources of
inconsistency in the evidence, and (3) provide a perspective on the
generalizability and applicability of the evidence to mainstream med-
ical and surgical practice.14,15 Historically, literature reviews appear
in various forms. Reviews can be done of single studies. Single stud-
ies may be used as the basis for making treatment decisions. A large
randomized clinical trial that appropriately evaluated a single clini-
cal endpoint with high validity may be sufficient for medical decision
making. Alternatively, narrative reviews or systematic reviews accu-
mulate and evaluate the evidence regarding the efficacy and safety of
a medical or surgical intervention from multiple publications.
Narrative reviews often address a broad set of clinical ques-
tions and are thus less focused on a specific question; they appear
more often in the literature and are more qualitative and less
quantitative than other reviews. In contrast, systematic reviews
are usually focused on a specific clinical issue, incorporate objec-
tive criteria for selection of studies, include an evaluation of qual-
ity and worthiness, and often use a quantitative summary to
synthesize combined results.
NARRATIVE REVIEWS
Narrative reviews are often one of the first academic endeavors that
young physicians complete during their training. The methods used
5/21/2012 7:41:09 PM
 6 ■ Surgery: Evidence-Based Practice
to identify and select studies for inclusion in a narrative review are
driven by subjective judgments that often lack sufficient rigor and
transparency to enable an unbiased assessment of the available evi-
dence. The subjective nature of narrative reviews increases the like-
lihood that inferences are affected by imprecision and bias. Often, a
count of included studies supporting or refuting a particular issue
is determined and a winner is declared. For narrative reviews, little
consideration may be given to issues of study design, sample size,
statistical power, or study validity.
SYSTEMATIC REVIEWS
Systematic reviews are a staple of evidence-based medicine.16
These reviews provide the best means to combine evidence from
multiple studies by following a defined protocol to identify, criti-
cally appraise, summarize, and combine information on a well-
defined clinical problem. They use explicit inclusion/exclusion
criteria that may restrict the inclusion of studies to specific study
designs such as RCTs, or they may include a broader set of designs.
Systematic reviews are labor intensive and costly, and they may
search for and use information from unpublished studies that
meet their prespecified inclusion/exclusion criteria. Reviewers
who undertake a systematic review face a number of challenges,
including critically appraising and combining evidence from
studies that use different designs, or different endpoints, or that
vary by other methodological characteristics.
A protocol for a systematic review follows a strict set of guide-
lines for selecting and amalgamating information from the litera-
ture that ensures transparency and reproducibility of its findings.
Cochrane Collaboration (http://www.cochrane.org/) guidelines
for developing a systematic review protocol requires a background
section explaining the context and rationale for the review; a state-
ment of the objectives; a clear definition of the inclusion and exclu-
sion criteria for studies (including study designs, study populations,
types of interventions, and outcome measures); the search strategy
for identification of studies; and the methodological approach to
the review process, including the selection of trials, assignment of
methodological quality, data handling procedures, and data syn-
thesis. Data synthesis includes statistical considerations such as
choice of summary effect measures, assessment of heterogeneity
of effect across studies, subgroup analyses, use of random or fi xed-
effect statistical models, and assessment of publication bias.
META-ANALYSIS
Systematic reviews often but not always include a meta-analysis.
The goals of meta-analysis are to provide a precise estimate of
the effect, and to determine if the effect is robust across a range
of populations.17 Meta-analyses may also be performed with the
primary intent of identifying differences between studies. Meta-
analyses summarize and describe the pattern of results reported
in the included studies and, when appropriate, calculate pooled
estimate of the effect of an intervention.
Data are first extracted from each individual study and then
used to calculate a point estimate for a treatment effect and a
measure of uncertainty, such as the 95% confidence interval. Th is
is repeated for each of the studies included in the meta-analysis,
and a decision is rendered as to whether the included studies are
PMPH_CH01.indd 6
similar enough with respect to patient populations and outcome
measures to permit combining the individual point-estimates to
estimate the average effect across all of the studies. The decision
to pool or to not pool studies is made by an assessment of the
clinical equivalence of the studies and statistical heterogeneity of
effect across studies. Large variations in the clinical characteris-
tics of the patients, treatment protocols, timing and management
of the intervention, and operational definitions for the primary
and secondary outcomes undermine the clinical equivalence of
the included studies. These sources of variation are often referred
to as sources of clinical heterogeneity, and are the most critical
elements in determining whether it is reasonable or even valid to
combine the individual study estimates into a single global esti-
mate of the relative effectiveness of an intervention. Statistical
heterogeneity suggests that the true underlying treatment effects
in the trials are not identical and that the observed treatment
effects have greater study-to-study differences than one should
expect due to random error alone.
Uncovering, describing, and explaining clinical and statis-
tical heterogeneity across multiple studies is a primary goal of a
meta-analysis, and it is used to elucidate previously unrecognized
differences between studies. Only in the absence of significant
clinical heterogeneity can study results be combined and a single
summary measure of effect calculated.
The calculation of a summary measure of a treatment’s rela-
tive effectiveness relies on the computation of a weighted mean
that gives more weight to results from studies that provide more
precise estimates of the treatment effect. These are normally the
larger and higher quality studies. This simple weighted average is
referred to as a fi xed-effect estimator. Significant statistical het-
erogeneity requires the use of statistical methods that incorporate
the additional uncertainty induced by study-to-study variation in
estimation of a pooled overall measure of a treatment’s effective-
ness. These are referred to as random-effect estimators.
Often, data for all included studies are plotted on a graph
known as a “forest plot,” which includes a graphical representa-
tion of the magnitude of effect for each study and its degree of
uncertainty (plotted as confidence intervals). Meta-regression and
subgroup analyses are often used to assess the influence that study
characteristics have on the magnitude of a treatment effect. These
analyses are prespecified in the protocol and are used to evaluate
the effect of potential confounders and other sources of clinical
and statistical heterogeneity on the treatment effect.
PUBLICATION BIAS
A meta-analysis or a systematic review that includes a meta-analysis
needs to address the issue of publication bias. Publication bias refers
to the tendency on the part of researchers, reviewers, and editors
to submit, accept, and publish studies that report statistically sig-
nificant results that are consistent with theoretical or previously
established empirical expectations.15 The factors shown to influence
publication include reporting significant results, type of research
design, rating of scientific importance, and external funding.18,19 In
the cases where studies with negative results are published, there
appears to be a substantial delay in publication.19
Publication bias is typically reflected in the distribution of
effects reported by smaller studies. Smaller studies with statis-
tically significant results are more likely to be published and
5/21/2012 7:41:09 PM

published earlier than larger studies that fail to fi nd significant
effects for an intervention. Th is phenomenon enhances the trend
toward potentially spurious positive results in a meta-analysis,
since it is always possible that well-designed unpublished stud-
ies exist that fail to support the efficacy of a medical or surgical
intervention. Most methods that are used to detect publication
bias are based on measures of asymmetry in a funnel plot.
A funnel plot is a graph of study-effect estimates against a
measure of its precision. When publication bias is absent, the dis-
tribution of effects conform to an inverted funnel shape with esti-
mates from the most precise studies clustered tightly at the apex.
As precision decreases, the effect estimates at each level of precision
show greater and greater variation around the average estimate.
The smallest studies show the greatest degree of variation. When
publication bias is absent, the funnel plot takes on a distinctive
asymmetric appearance with less precise studies showing a greater
tendency toward large positive effects. Statistical tests are often used
to assess and quantify the degree of asymmetry visualized in the
funnel plot.20,21
SUMMARY
Evidence-based medicine is not limited to the evaluation of RCTs
and meta-analyses. A broad range of external evidence can be
brought to bear on addressing clinical questions. Practice guide-
lines developed using evidence-based medicine can have a positive
effect on patient outcomes. Evidence-based medicine supple-
ments, but does not replace, physicians’ judgments regarding an
individual patient. Surgical practice can benefit from evidence-
based medicine and should be incorporated into the standard of
care. Evidence-based medicine guidelines have reduced mortality
from myocardial infarctions and also improved care for persons
with diabetes and other common medical problems. An example
of evidence-based medicine in surgery is given by a systematic
review of mechanical preparation for elective colorectal surgery,
summarized in the next section.
EXAMPLE
A recent systematic review of mechanical bowel preparation for
elective colorectal surgery published by the Cochrane Collabora-
tion22 and described next provides an example of this important
component of evidence-based medicine.
MECHANICAL BOWEL PREPARATION FOR
ELECTIVE COLORECTAL SURGERY: AN
EXAMPLE OF A SYSTEMATIC REVIEW
Background
For more than a century, surgeons have believed, dogmatically,
that efficient mechanical bowel preparation is an important factor
in preventing infectious complications and anastomotic dehis-
cence after colorectal surgery.23,24 Clinical experience and obser-
vational studies have shown that mechanical removal of gross
feces from the colon has been associated with decreased morbid-
ity and mortality in patients undergoing operations of the colon.25
PMPH_CH01.indd 7
Evidence-Based Medicine ■ 7
Authors were categorical that the most important factor to affect
the outcome of a colonic operation that is within the control of a
surgeon is the degree of emptiness of the bowels.26,27
An early randomized clinical trial questioned this dogma, and
concluded that vigorous mechanical bowel preparation was not nec-
essary, stating “omission of enemas and bowel washes from the pre-
operative procedures will be welcomed by both patients and nursing
staff.”28 The authors of another meta-analysis concurred with this
point of view,29 whereas in another trial30 the authors argued that
preoperative bowel preparation is time consuming and expensive,
unpleasant to the patients—even dangerous on occasions (increased
risk for inflammatory processes)31—and completely unnecessary.
Different methods of mechanical bowel preparation have been
tested and approved. The potential danger of having feces in con-
tact with newly performed anastomosis has led to the construction
of a defunctioning stoma when the colon was not prepared.32,33
Both experimental studies34-36 and clinical trials in emergency
surgery37,38 have been published to support this theory.
In a review of the literature in 1998, Platell and Hall con-
cluded that there was limited evidence in the literature to support
the use of mechanical bowel preparation in patients undergoing
colorectal surgery.39 Platell conducted a randomized trial compar-
ing single phosphate enema with polyethylene glycol (PEG) before
colorectal surgery, and found the results favored the group that
received PEG for bowel preparation.40
In 2002, Fa-Si-Oen was coauthor in a study that prospectively
evaluated a consecutive series of patients who underwent resection
and primary anastomosis and he concluded that “mechanical bowel
preparation is not a sina qua non for safe colorectal surgery.”41
The authors of a trial that analyzed the bowel contents sug-
gested that participants receiving mechanical bowel prepara-
tion had a tendency toward a higher incidence of spillage of
bowel contents compared with participants who did not receive
it, but without statistical significance. Spillage of bowel contents
into the peritoneal cavity may increase the rate of postoperative
complications.42
A recent case-control study that analyzed patients with rectal
cancer who submitted to elective resection with mesorectal exci-
sion concluded that “elective rectal surgery for cancer without
mechanical bowel preparation may be associated with reduced
postoperative morbidity.”43
Randomized trials from several countries have concluded
that the role of bowel preparation in colorectal surgery requires
reevaluation. When analyzed, the individual trial results did not
show any significant difference, and this fact motivated this sys-
tematic review of the literature. In the first version of this review
there were only five included trials.44-48 The first update included
four more studies,31,49-51 whereas the second update included five
more trials.52-56
The objectives of this review were to determine the effective-
ness and risk of prophylactic mechanical bowel preparation for
morbidity and mortality rates in colorectal surgery, with anasto-
motic leakage as the primary outcome.
As the incidence of anastomotic leakage is increasing, the
closer to the anus the anastomosis is applied,57 bowel preparation
might have different effects in colon and rectum. Therefore, analy-
ses were stratified for colonic and rectal surgery as well as for col-
orectal surgery as a whole.
The aim of this update was to determine whether mechani-
cal bowel preparation before elective colorectal surgery is really
essential for patients.
5/21/2012 7:41:09 PM
 8 ■ Surgery: Evidence-Based Practice
METHODS
Types of Studies
The inclusion criteria were
(1) Randomized clinical trials comparing preoperative
mechanical bowel preparation versus no preparation (or
placebo) in
(2) Participants undergoing elective colorectal surgery and in
which
(3) The primary outcome (anastomotic leakage) was clearly stated
in both treatment arms.
All three criteria must have been met for inclusion of a trial.
The exclusion criteria were
(1) Studies evaluating two or more different cleansing methods.
(2) Studies including participants undergoing emergency
surgery.
Types of Participants
The types of participants included patients undergoing elective
colorectal surgery. Both adults and children were eligible for
inclusion.
Types of Interventions
The types of interventions included any strategy in mechani-
cal bowel preparation compared with no mechanical bowel
preparation.
Types of Outcome Measures
Primary Outcome Measures
(1) Anastomotic leakage (defined as a discharge of feces from
the anastomosis site that externalized through the drainage
opening or the wound excision; or could be characterized
on the basis of an abscess adjacent to the site) confirmed by
clinical or radiological investigation.
The types of surgery and sites of anastomosis were
stratified into
(a) Low anterior resection with extraperitoneal anastomosis
(rectum considered to be extraperitoneal); and
(b) Colonic surgery with intraperitoneal anastomosis.
(2) Overall anastomotic leakage: total number of anastomotic
dehiscences in trials (in all of colon and rectum).
Secondary Outcome Measures
(3) Mortality: number of postoperative deaths related to the
surgery.
(4) Peritonitis: presence of postoperative infections in the
abdominal cavity, localized (abscess) or not.
(5) Reoperation: surgical reintervention for anastomotic
complication or peritonitis.
(6) Wound infection: defined as a discharge of pus from the
abdominal wound.
(7) Infection extra-abdominal complication: postoperative
infectious complication at extra-abdominal site.
PMPH_CH01.indd 8
(8) Noninfectious extra-abdominal complication (e.g., deep
venous thrombosis, cardiac complications, wound rupture).
Sensitivity and Subgroup Analyses
(9) Anastomotic leakage and wound infection in studies with
adequate randomization.
(10) Anastomotic leakage and wound infection in studies with
bowel continuity restored.
Search Methods for Identification of Studies
See: Collaborative Colorectal Cancer Review Group search strat-
egy.58 The studies were identified from the following sources:
Cochrane Colorectal Cancer Group Specialized Register,
Cochrane Central Register of Controlled Trials. MEDLINE,
EMBASE, CINAHL, LILACS, SCISEARCH, and the Controlled
Clinical Trials Database.
Additional trials were sought by checking the reference lists
of relevant papers, writing to experts in the field, hand search-
ing journals, and by contacting the authors of relevant papers.
Conference proceedings from major gastrointestinal conferences
(World Congress of Gastroenterology, annual meetings of the
American Society of Colon and Rectal Surgery, annual meetings
of the Association of Coloproctology of Great Britain and Ireland,
annual meetings of the European Association of Coloproctology,
and the Tripartites meetings) were scrutinized back to 1994 (the
last possible retrieval of abstract material). No language restric-
tions or date restrictions were applied in the searches. Searches
were performed on March 13, 2008. One unpublished study was
identified by personal contact with the authors.53
DATA COLLECTION AND ANALYSIS
Locating and Selecting Studies
The reviewers selected the trials to be included in this review inde-
pendently. Disagreements about selection were resolved by con-
sensus (via email correspondence). One unpublished study was
identified through personal contact with the authors.53
Critical Appraisal of Studies
The methodological quality of each trial was assessed by at least
two of the authors. Details of the randomization method, blinding,
whether an intention-to-treat analysis was done, and the number
of participants lost to follow-up was recorded, thus enabling the
risk of bias in individual studies to be evaluated.59 The external
validity of the studies was assessed by analysis of the character-
istics of participants and the interventions as listed below. Dis-
agreements were resolved by consensus.
Participants
Category of disease (colorectal cancer, inflammatory disease,
magacolon, polyposis, diverticular disease), sex of participants,
age, topography of the affected area, operative procedure, anti-
biotic therapy, and surgeon experience were evaluated for each
study. Prestudy calculation of the sample size and whether the
5/21/2012 7:41:09 PM

sample was representative were registered. Duplicate publications
of the same set of data were identified and each sample of partici-
pants was only included once.
Collecting Data
Studies where the allocation of concealment was deemed to be
adequate were included. Where the allocation procedure was
unclear, studies were included if the primary authors stated that
it was a randomized study, but these studies were excluded from a
sensitivity analysis. Data were independently extracted by at least
two of the reviewers and cross-checked. The results of each trial
were summarized in 2 × 2 tables for each outcome. Disagreements
were solved by consensus.
Interventions
The interventions included any type of mechanical bowel prep-
aration (anterograde [oral] or retrograde [enemas]) versus no
mechanical preparation. Data were entered into Review Manager
4.2 by single data-entry (KFG);22 all data entries were controlled
by a second author (PWJ).58
ANALYZING AND PRESENTING RESULTS
Where appropriate, the studies were stratified for different meta-
analyses according to the analysis of the defined outcomes. The
meta-analyses were performed using various techniques (Review
Manager 4.2): for dichotomous outcome measures, the combined
logarithm of the Peto odds ratio (fixed-effect model) was used as the
default. A test for statistical heterogeneity was performed in each
case. Where heterogeneity was encountered, results were reported
as odds ratio (OR) using random-effects modeling. For the analy-
sis, only participants submitted for elective colorectal surgery were
reviewed according to type of intervention and type of participant, to
assess whether there were important differences between them. All
inclusion criteria had to be met. One unpublished study53 described
rectal surgery only. The data were included separately in the strati-
fied analyses. In all other outcomes, the data were compiled with
those from the large Swedish study,54 in which these participants
originally had been included. The included studies were assessed
to determine whether clinical heterogeneity was present. Potential
publication bias in the results of the meta-analysis was assessed
both by inspection of graphical presentations (by means of a funnel
plot: plotting the study weight or sample size [on the Y-axis] against
the OR [on the X-axis]) and by calculating a test of heterogeneity
(standard chi-squared test on N degrees of freedom, where N equals
the number of trials contributing data minus one). The funnel plot
was possible only for an outcome described in more than five tri-
als. Three possible reasons for heterogeneity were prespecified: (1)
responses differ according to difference in the quality of the trial; (2)
responses differ according to sample size; and (3) responses differ
according to clinical heterogeneity. When heterogeneity was discov-
ered, sensitivity-analyses were performed in subgroups.
Sensitivity Analysis
Sensitivity analysis was performed for anastomotic leakage and
wound infection in studies with adequate randomization and in
PMPH_CH01.indd 9
Evidence-Based Medicine ■ 9
studies in which bowel continuity was restored. Since the random-
effects model provides a more conservative estimate of an overall
effect, it was used as the default in these sensitivity analyses.
RESULTS
Description of Studies
Seven new studies were accessed in this update, but two of them
were excluded.40,43 This brought the total number of excluded tri-
als to eight. Three were excluded because of the absence of a con-
trol group30,37,38; one because of an elemental diet in the control
group60; one due to lack of description of the primary outcome
and insufficient description of the secondary outcomes28; one
because it was a retrospective study61; one because the control
group received a single sodium phosphate enema40; and the last
was a case-control study.43
A total of 14 studies were included in the review. Five new
trials were included in this update. 52-56 In addition, two abstracts
that were newly included at the fi rst update have now been pub-
lished as full articles. 31,49 Most of the studies were published in
English, though one was published in Portuguese,62 and another
in Spanish50; both of these were found on the LILACS database.
One study was published as abstract only,44 but data from this
study were retrieved from another publication.29 One of the
authors on a primary study gave supplementary data regarding
rectal cancer to this update of the review.54 These data are cur-
rently unpublished, but have been handled as a separate publica-
tion. Two trial authors supplied supplementary data directly to
two trial authors (PWJ or KFG).48,51 Six of the included trials were
multicentered.31,49,51-54 Only two studies mentioned the educa-
tional status of the surgeon: two of them described the operations
performed by a consultant surgeon or under supervision.45,47; two
trials described operations as having been performed chiefly, or
exclusively, by residents or senior residents.48,56 In one study, 55 all
surgery was performed by one surgeon only. Jung et al.54 men-
tioned that the surgeons involved in the trial specialized in col-
orectal surgery. The other trials did not describe the experience of
the surgeons. The Zmora study was published three times: fi rst as
an abstract,63 then as a full article, 51 and fi nally as an article ana-
lyzing only those participants who underwent left-sided colonic
anastomosis.64
Types of Participants
The inclusion criteria were the same for all studies; that is, par-
ticipants admitted for elective colorectal surgery. One trial
included children.48 Some of them included participants without
anastomosis46,48; one study excluded participants with anastomosis
in only one outcome—anastomosis leakage44; two studies excluded
participants in whom bowel continuity was not restored.45,47 Seven
trials described the two allocation groups as being equal accord-
ing to gender, age, types of operation, and diagnosis.31,45-49,51 One
trial did not give details.44 One called attention to the statistical
difference between the two groups with regard to age, hemoglobin
level, and serum albumin.50 Most trials specified exclusion crite-
ria, but these varied tremendously between trials. One trial did
not provide details of any exclusion criteria,44 whereas in another
trial no participants were excluded.46
5/21/2012 7:41:09 PM
 10 ■ Surgery: Evidence-Based Practice
Types of Interventions
All studies compared no mechanical bowel preparation with a
method of mechanical preparation: PEG solution; laxatives (min-
eral oil, agar, and phenolphthalein); mannitol; enemas (900 mL
water containing 100 mL glycerin); sodium picosulfate 10 mg;
Bisacodyl (10 mg) and enemas; and diets: low and nonresidue.
The duration of follow-up varied between trials, and ranged from
7 days after surgery50 to 3 months.49 The methods used to cleanse
the bowel were PEG31,49,51,55 or sodium phosphate solution56;
although three multicentered trials used both.52-54 Two trials
reported an enema of saline solution before surgery for partici-
pants scheduled for an anterior resection of the rectum.31,51
Types of Outcome Measurements
Primary Outcomes
Anastomotic Leakage
Two studies stratified the anastomosis between rectal and
colonic.45,47 Stratification data were obtained through personal
contact with three trial authors.48,51,54 The other trials did not refer
to the site of the anastomosis.44,46,50,52,56 Two trials excluded anas-
tomosis below the peritoneal line.49,55
Overall Anastomotic Leakage
All of the included trials described this outcome.
Secondary Outcomes
Secondary outcomes included mortality, peritonitis, reoperation,
wound infection, infectious extra-abdominal complications, and
noninfectious extra-abdominal complications.
RISK OF BIAS IN INCLUDED STUDIES
Selection Bias
Selection bias consists of systematic differences in the comparison
groups. In two trials the allocation procedure used randomized
cards.47,48 Fillmann,64 the author who answered our correspon-
dence, described using a random number table for randomization.
In one study a computer generated list was used.51 In these studies
the allocation process was considered sufficient. In others the allo-
cation process was not clearly specified,44,45,50 and thus considered
unclear, which led to the planned sensitivity analysis. In general,
allocation concealment was not sufficiently described in the earlier
trials, but in this update, four of the trials52-55 had adequate alloca-
tion concealment (graded A), and the process of randomization
was well defined. In one of the newer trials,56 however, the alloca-
tion concealment was considered inadequate (grade C) because the
authors used the identification number of the participants (even
or odd) to determine randomization. Two of the conference pro-
ceedings (now published as full articles) explained their methods
of randomization and these were considered adequate.31,49
Performance Bias
Performance bias consists of systematic differences in care pro-
vided, apart from the intervention being evaluated. All trials used
PMPH_CH01.indd 10
prophylactic antibiotics, and all but one described the two alloca-
tion groups as being equal according to gender, age, types of oper-
ation, and diagnosis.44 One trial indicated a difference between the
allocation groups by age, hemoglobin level, and serum albumin.50
The new studies included in this update reported that the groups
were well matched with regard to age, sex, and diagnosis54-56;
though, according to the randomization, in one trial there were
more participants who smoked and had inflammatory bowel dis-
ease in the mechanical bowel preparation group.52 This trial also
included participants with preoperative radiation therapy, whereas
two trials excluded participants who had this treatment49,55; the
others did not mention this point.
Blinding
One trial that was described as a double-blind study used orange
juice as a placebo.46 Another study was described as being single-
blinded, because the surgeons were aware whether bowel prepa-
ration had taken place or not.45 The trial of Pena-Soria55 was
described as single-blinded because the participants were fol-
lowed by an independent observer. Two publications by Jung
et al.53,54 reported that the participating surgeons did not know the
size of the blocks of permutations, and the hospital charts of par-
ticipants were reviewed by a statistician and a surgeon who were
not involved in conducting the study. One of the trials reported
that observers were not blinded, but this fact probably did not
cause bias.52 Investigators assessing the endpoints were blinded to
the use of mechanical bowel preparation in one of the studies.31
Information about blinding was not provided in the other trials.
Attrition Bias
Attrition bias occurs when there are systematic differences in
withdrawals from a trial. In the original review, the Brownson44
and Tabusso50 trials did not describe withdrawals or dropouts.
The Burke trial45 had a 9.1% withdrawal rate (17/186 participants),
but no dropouts; the Santos trial48 had a 5% withdrawal rate (8/157
participants), but no dropouts; whereas the Zmora trial51 had a
8.6% withdrawal rate (35/415 participants). In two of the trials all
participants completed the study (Fillmann, personal correspon-
dence, 1995).47 In three of the new trials included in this update,
all participants finished the study as per protocol31,49,56; however,
77 participants were excluded from the Contant trial52; and, in the
Jung study,54 21 participants were excluded before randomization,
128 did not receive the intervention, 13 were lost to follow-up, and
for 13 the data were not submitted. The Pena-Soria study55 had 2
exclusions preoperatively, and 11 at the point of surgery.
Detection Bias
Detection bias occurs when there are systematic differences in
assessment of outcomes. In the first half of the Burke study,45 the
incidence of anastomotic leaks was established by means of water-
soluble contrast enemas in all participants, but in the second half
of the study enemas were used only on clinical suspicion of leak-
age. This was because two of the six leaks identified on the sev-
enth day after surgery occurred immediately after administration
of the routine water-soluble contrast enema. Contrast radiography
was used to confirm clinical suspicion of anastomotic leaks in
seven trials.31,45-48,52,56 In one trial anastomotic leakage was divided
5/21/2012 7:41:09 PM

into major leakage—that is, clinically significant and leading to a
relaparotomy—and minor leakage—that is, subclinical, which was
verified by radiographic examination and treated conservatively.49
Pena-Soria et al.55 used CT scan with contrast or laparotomy—
major dehiscence—to confirm the clinical suspicion of leakage.
EFFECTS OF INTERVENTIONS
Preparation versus Nonpreparation
Of the 4776 participants in the 14 included RCTs, 2398 were allo-
cated for mechanical bowel preparation (group A), and 2378 for
no preparation (group B), before elective colorectal surgery.
Primary Outcomes
Anastomotic Leakage (Stratified)
(1) Low Anterior Resection
Ten percent of participants in group A (14 out of 139) who had low
anterior resections suffered anastomotic leakage, compared with
6.6% in group B (9 out of 136); the Peto OR was 1.73 (95% confi-
dence interval [CI]: 0.73–4.10 [nonsignificant]), and there was no
statistical heterogeneity.45,47,48,51,53
(2) Colonic Surgery
In group A, 2.9% of participants (32 out of 1226) who had colonic
surgery suffered anastomotic leakage, compared with 2.5% (31 out
of 1228) in group B; the Peto OR was 1.13 (95% CI: 0.69–1.85 [non-
significant]), and there was no statistical heterogeneity.45,47-49,51,54,55
Overall Anastomotic Leakage
Overall anastomotic leakage was 4.2% in group A (102 out of 2398
participants) compared with 3.4% (82 of 2378 participants) in group
B; the Peto OR was 1.26 (95% CI: 0.941–1.69 [nonsignificant]). The
chi-square test for heterogeneity gave the following results: chi-
square = 16.94, df = 12 (P value = 0.15), I2 = 29.2%.31,44-56
Secondary Outcomes
No significant differences between group A and group B were
found with regard to mortality, peritonitis, reoperation, wound
infection, infectious extra-abdominal complications, and nonin-
fectious extra-abdominal complications.
SUMMARY
Until recently it was thought that vigorous preoperative mechani-
cal cleansing of the bowel (mechanical bowel preparation),
together with the use of oral antibiotics, reduced the risk of sep-
tic complications after nonemergency (elective) colorectal opera-
tions. Mechanical bowel preparation was performed routinely
prior to colorectal surgery until 1972, when this procedure started
to be questioned. Well-designed clinical trials were published,
and their results caused colorectal surgeons to doubt this tradi-
tional belief. Preoperative bowel preparation is time consuming
and expensive, unpleasant to the patients, and even dangerous on
occasion (increased risk for inflammatory processes). This review
PMPH_CH01.indd 11
Evidence-Based Medicine ■ 11
identified all known trials that compared any kind of mechanical
bowel preparation with no preparation in patients receiving elec-
tive colorectal surgery. Five new trials were included in this sec-
ond update of the review, bringing the total number of included
trials to 14 (4821 participants). Analysis of these 14 trials showed
no statistically significant differences in how well the two groups
of patients (mechanical bowel preparation group and the no prep-
aration group) did after surgery in terms of leakage at the surgical
joint of the bowel, mortality rates, peritonitis, need for reopera-
tion, wound infection, and other nonabdominal complications.
Consequently, there was no evidence that mechanical bowel prep-
aration improves the outcome for patients. Further research on
mechanical bowel preparation versus no preparation in patients
submitted for elective colorectal surgery is warranted.
CONCLUSION
Cochrane defined evidence-based medicine as the conscientious,
explicit, and judicious use of current best evidence in making deci-
sions about the care of individual patients. The practice of evidence-
based medicine means integrating individual clinical expertise with
the best available external clinical evidence from systemic research.
Since 1990, evidence-based medicine has developed as a topic
of courses, and text books. Relevant to the conduct of evidence-
based medicine, resources including search engines, electronic
journals, and systematic reviews are now widely available. Read-
ers should review the Cochrane Handbook for Systematic Reviews
(http://cochrane-handbook.org/), especially Part 2, Chapter 8,
for a detailed summary of sources of bias and bias assessments. A
sophisticated site for current perspectives on evidence-based medi-
cine is the British National Institute for Health and Clinical Excel-
lence (NICE); the NICE website (http://www.nice.org.uk/) has links
to many resources, guidance, and documents.
In conclusion, we endorse the two basic principles stated by
Guyatt et al.8: (1) evidence-based medicine posits a hierarchy of
evidence as a guide to clinical decision making; and (2) evidence
alone is never sufficient to make a clinical decision. In contrast
to the traditional paradigm of medical practice, evidence-based
medicine places a low value on unsystematic clinical experience
and pathophysiologic rationale, and suggests that interpret-
ing results of clinical research requires a formal set of rules and
places a low value on authority than the traditional paradigm. We
encourage the reader to access the texts and resources mentioned
and to explore this topic more fully.
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 CHAPTER 2
Patient Safety in Surgical Care
Kenneth Stahl and Susan E. Brien
No person is so perfect in knowledge and experiences that
error in opinion or action is impossible. In the art of surgery
error is more likely to occur than in almost any other line of
human endeavor, and it is in this field that it should be most
carefully guarded against, since lack of surgical safeguards
may result in a serious handicap for the rest of the life of the
patient or may even result in the sacrifice of that life.
Max Thorek introduced his 1932 book “Surgical Errors and
Safeguards”1 with these sentences, and the words are as true today
as they were when written over three quarters of a century ago.
The unique risks faced by patients who undergo surgery is sup-
ported by published data from the United States and Canada that
document that approximately half of all errors leading to adverse
outcomes in hospitalized patients are associated with surgical
procedures.2,3 This is further supported by medical legal statistics,
which shows that nearly 50% of successful malpractice claims
were against surgeons in the United States in 20014 and, over the
course of that year, led to a staggering $5.5 billion in payouts.5
The exact number of patients who suffer adverse outcomes
as a result of individual or system errors is difficult to determine.
Most studies of errors document an incidence of between 3.5%
and 10% of hospitalized patients.6,7 Healthcare Grades8 in their
2008 review of hospital error cites a 5.5% incidence of errors in
surgical patients of which 29.1% resulted in fatalities. These statis-
tics indicate that there is an approximate fatality rate of 1% in the
group of all hospitalized surgical patients due to avoidable events.
Another important category of error is shown in the most recent
statistics from the Joint Commission9 that indicates that 13.4% of
sentinel events were related to wrong site surgery, which is a pre-
ventable adverse outcome.
Assuring the safe and error-free care of patients undergo-
ing surgery adds to the already significant responsibilities of sur-
geons. There is a need for surgeons to understand the mechanisms
of error and the risks that patients face while undergoing surgical
procedures, and as Dr. Thorek penned so long ago, “most carefully
guard against” and avoid them in daily practice.
14
PMPH_CH02.indd 14
1. Where and how do errors occur during the care of surgical
patients?
The reasons for these errors and adverse events are numerous. The
larger incidence of errors in surgery is explained in part by the
higher number of treatment events surgical patients undergo dur-
ing an operation compared to hospitalized medical patients and the
increased complexity of the tasks surgeons perform. The complex-
ity of the surgical procedure has been shown to offer more oppor-
tunities for human error to occur in surgical patients than single
event care in nonsurgical medical management.10 The incidence of
errors increases with the complexity of the surgical procedure as
documented in a study of errors in neurosurgical procedures. Out
of 1108 elective neurosurgical procedures reported over a 6-year
period, 87% of patients incurred at least one error, 23% of the errors
were major, and 79% were deemed preventable.11
In a broad sense, errors in the care of surgical patients occur
on both a system level and an individual level. One of the particular
system issues affecting whether or not a surgical patient is at risk
of an adverse event is the type of facility where care is delivered.
Although teaching-affiliated hospitals have been shown to have
lower mortality rates and shorter length of stays, this is not the case
for surgical morbidity. Supported by risk adjustment data, two stud-
ies in the Veterans’ Health Administration care systems found that
university affiliation hospitals were associated with higher surgical
morbidity.12 The reasons for this are variable and include frequent
turnover of key personnel in the care of surgical patients that intro-
duce errors discussed in subsequent sections of this chapter.
A useful construct of the individual human components of
error in surgery is based on the Rasmussen Skill, Knowledge & Rule
Error Model.13 The “skill” level refers to actions that are automatic
and are carried out based on stored patterns of preprogrammed
sets of actions. These are the skills taught to surgical residents and
can be acquired with repetitive training and practice. Failure to
execute these skills correctly leads to procedural complications.
The “rule” level references tasks that are completed using stored
sets of conventions. These rules consist of familiar, rehearsed algo-
rithms such as steps of a surgical procedure or advanced trauma
5/21/2012 7:46:12 PM

life support (ATLS)14 management of injured patients. Failure to
execute these rule patterns correctly leads to both procedural and
cognitive errors. Tasks that use rule-based cognitive mechanisms
require a greater degree of thought than skill-based tasks, as the
rules that need to be applied to complete the clinical task must be
evaluated for appropriateness and then correctly selected. Failure
to carry out any of these steps introduces errors in this process.
On a “knowledge” level, unfamiliar tasks are performed with a
high degree of conscious thought. In this case, the surgeon attempts
to devise a novel solution or find a workable method from a similar
scenario that could be used in a situation that has not previously
been encountered. Failures of knowledge base impact care of surgi-
cal patients on all levels and a specifically critical transition period
in the operating room has been identified. The “pause phenomena”
during surgery is a time when an expert surgeon transitions from
an automatic mode when all is going well, to a more effortful atten-
tive mode when preparing to manage a unique surgical issue. This
has been well studied and is a critical phase of surgical care since
error-free surgical outcomes depend on this transition. Surgeons
need to recognize this as a period of heightened risk and surgical
teams need to perceive these circumstances accurately as extrane-
ous conversations and potential distractions must be eliminated to
achieve successful management of the potential crisis.15
The wealth of today’s technological and medical advances,
added to an increasing acuity of patient illnesses make surgical
care a high-risk and labor intensive profession with a significant
degree of complexity. Because of this complexity, adverse events
and errors are intricate matters involving many levels of the system
all of which are intertwined in a complicated organization. System
errors are best viewed with the now famous Reason “Swiss Cheese”
analogy.16 This model postulates that there are multiple “safety
shields” against error as well as opportunities for multiple levels
of possible error within the system. This ranges from organization,
supervisory, and preconditions for error that represent either fail-
ures of the broad system to catch potential error or actual fostering
of error by setting up conditions where error is likely to occur.
In this model, the individual practitioner occupies a criti-
cal position in the error chain not only as the last opportunity to
catch and prevent a system-based error that has bypassed previous
“shields” but also as a possible source of individual- or skill-based
errors. Because of this unique dual role, the individual final barrier
represents two critical issues in patient care errors. By definition,
any error that passes through holes in the system to the final safety
shield of the individual represents a failure of the system to have
blocked these potential mistakes. Any error that passes past the
individual as the last safety shield is a failure of that individual to
have recognized and stopped the error. Secondarily, any event that
originates within the final safety shield results from procedural,
cognitive, or decision-making factors by the individual. It is very
important to understand that there are no further barriers beyond
which it is possible to catch these individual errors. As we will talk
about later in this chapter, teamwork, communication, and an
awareness of sources of error can strengthen this final safety shield
and support and enhance individual performance in surgery.
This detailed model tells us that safe and error-free delivery of
surgical care is, to a large extent, dependent on detailed internal sys-
tems working smoothly and efficiently together. Systems with this
level of complexity require sophisticated design elements to prevent
the multiplication of human error or generation of errors within
themselves.17 A breakdown in system function at any of these levels
at best fails to catch errors and at worst is the cause of these errors.
PMPH_CH02.indd 15
Patient Safety in Surgical Care ■ 15
Surgery is a dynamic specialty with a multitude of pos-
sible mishaps awaiting patients. Error-free outcomes and surgi-
cal competency are a combination of knowledge of anatomy and
pathophysiology, technical skills, team performance, communica-
tion, and decision making.18 The subsequent chapters of this book
deal with management of specific surgical diseases, and the focus of
this section is not to duplicate that information but to break down
the various phases of delivery of this surgical care and reinforce
the principle that the opportunity for error is introduced at each
of these steps. Overall management of surgical patients involves
the following:
1. Initial assessment of the surgical patient
2. Diagnosis of surgical disease and patient selection
3. Timing of surgical intervention
4. Immediate presurgical care
5. Surgical procedures
6. Postsurgical care
7. Discharge
A recent review of 2015 adverse events by Krizek and coworkers19
identified major categories of surgical errors that included 164
diagnostic errors (7.5%) of which 24 (5.2%) were judged to be seri-
ous. Another 230 (10.5%) errors occurred during surgery (17.9%
serious), 693 (29.3%) during monitoring and daily care of which
19 (17.1%) were judged to be serious. Each of these broad phases of
surgical care will be examined in the following sections to under-
stand sources and risks of error.
PHASE 1: INITIAL ASSESSMENT
OF THE SURGICAL PATIENT
This is one of the most critical aspects of the care surgeons ren-
der to patients since formulating the correct assessment of surgical
disease impacts all further management. It is also one of the most
complicated as occasionally surgeons are faced with a variety of
symptoms from an illness that can appear to be similar to other
surgical or medical diseases. Understanding how surgeons process
complex clinical information and arrive at critical decisions, espe-
cially under conditions of time constraint, fatigue, and stress, are
crucial to making the right decisions when there is no room for
error.20 Faulty decision making is a common source of error on the
basis of the aviation accident data that indicate that 47% to 80% of
accidents are caused by these types of errors.21 Decision-making
skills are among the most important nontechnical skills surgical
trainees need to learn and surgeons need to master. It is not exces-
sive to suggest that decision making is nearly synonymous with
thinking.22
Training methods to sharpen decision-making skills are
included along with the basic sciences of disease that make up
the curriculum taught to medical students and surgical resi-
dents. Teaching decision-making skills with simulations, repeti-
tive task rehearsals, and didactic lessons have been shown to
enhance outcomes in the emergency room 23 and anesthetic care
in the operating room.24 Misjudging the acuity of a patient’s
illness, misinterpreting laboratory or radiographic studies,
or simply imprecise communication of these data can lead to
errors during the initial assessment of surgical patients. Despite
a sophisticated diagnostic armamentarium, the initial assess-
ment remains one of clinical skill, acumen, and experience of
the surgeon.
5/21/2012 7:46:12 PM
 16 ■ Surgery: Evidence-Based Practice
PHASE 2: DIAGNOSIS OF SURGICAL
DISEASE AND PATIENT SELECTION
In a meta-analysis review of 53 literature citations of autopsy data,
Shojania and colleagues25 found a major error rate from 8.4% to
24.4% of class I errors (likely cause of death) that occurred in
4.1% to 6.7% of patients. When surgical patients are reviewed as
an independent group, the diagnostic error rate ranges from 26%
to 47.2% and class I error rate from 5.5% to 11%. Extending this
review to deaths within 30 days of surgery, the incorrect assess-
ment or misdiagnosis rate was between 42.9% and 56.6% with
20.7% judged by autopsy to be the cause of the patient’s death.
Errors in diagnosis and triage for surgical care can occur from
lack of knowledge or unfamiliarity with the clinical presentation
of the disease, errors in communication of data, conflicting infor-
mation, or misinterpretation of existing information.
Recent cognitive psychology literature details a dual model
that is useful to understand some of the thought processes that
surgeons depend on to formulate diagnostic decisions. Th is dual
process model describes two modes of decision making and judg-
ment that depend on pattern recognition. When the initial visual
pattern of a combination of signs and symptoms are recognized,
the first of the two processes is engaged. This system is intuitive
and characterized by reflexive, fast, and effortless reasoning. The
experienced clinician requires few resources and uses pattern
recognition for diagnostic decision making most frequently. If
the clinical pattern is not recognized, an alternative decision-
making skill is required that is analytical and characterized by
more effort, deliberation, and slower reasoning.26 This second rea-
soning process is dependent on a rich knowledge base to arrive at
error-free diagnostic decisions. Diagnostic errors are introduced
when the first mode of decision making is used if there is a fail-
ure to quickly recognize and construct an accurate diagnoses
based on rehearsed algorithms. If a failure in the second mode of
thought process occurs and the surgeon does not possess or seek
adequate knowledge to make the correct diagnosis, a diagnostic
error is likely to occur.
Another source of error in diagnosis can occur when the sur-
geon overrides his or her knowledge base with an incorrect intu-
ition or impulsively rushes to a conclusion. This can occur even
when the surgeon has the appropriate knowledge but fails to apply
it correctly. Clinical decision rules and diagnostic algorithms will
usefully aid in the surgeon’s judgment but this can be defeated as
there is frequently pushback on the part of some clinicians to be
guided by standardized sets of rules. To avoid these types of diag-
nostic errors, surgeons and surgical residents should be encouraged
to supplement their reliance on memory with decision-support
tools, checklists, and diagnostic algorithms to help focus on the
diagnostic process.27
PHASE 3 AND PHASE 4: TIMING OF
SURGERY AND IMMEDIATE
PRESURGICAL CARE
The next phase of surgical care involves selection criteria for surgi-
cal or nonsurgical management and timing the procedure to gain
maximum beneficial outcomes. This involves exchanging and
processing information from many sources. Failure to accurately
communicate this information and weigh it thoughtfully and
logically can result in suboptimal timing and patient selection for
PMPH_CH02.indd 16
surgery with poor outcomes. The judgment to bring a patient to
the operating room, and when that is best done, involves all the
clinical acumen and experience of the surgeon. There is often a
fine balance between patients who are too sick to tolerate surgery
and those who are too sick not to bring to the operating room.
These decisions are based on a careful deliberative process sim-
ilar to that outlined above that includes a complete but sometimes
subtle assessment of the overall condition of the patient. Faulty
risk perception is a factor that can contribute to adverse surgical
outcomes.28 The surgeon must guard against a failure to weigh the
risks a patient faces from their underlying illness and concurrent
diseases such as cardiac or renal dysfunction in the operative plan.
This can be compounded by a rarity of occurrence of certain surgi-
cal diseases that require specialized care. Studies of emergency and
trauma surgery show that these types of errors are frequent causes
of death in patients with otherwise survivable injuries.29
Preparation of the patient by the surgeon for the surgical pro-
cedure is an essential part of patient care that is required to achieve
error-free outcomes. This includes preparation of the surgical team,
which is dealt in detail later in this chapter. The surgeon must be
aware preoperatively that each intervention introduces another
opportunity for error and plan for these contingencies. The poten-
tial sources of error include failing to recognize or correct meta-
bolic derangements and lab abnormalities, assuring preoperative
antibiotic and DVT prophylaxis use and appropriate site and side
markings, as well as failing to carry out a preoperative time out.30
Various models from industry and high-reliability organizations
have been applied to this complex process with significant success.
Timely and appropriate use of preoperative antibiotics, assuring
adequate blood products are available, and preprocedure briefing
with the operative team are all elements of this process that have
been shown to enhance surgical outcomes.31
PHASE 5: SURGICAL PROCEDURES
Excellent surgical outcomes depend on excellent surgical proce-
dures with respect to both cognitive and technical aspects of the
operation. The surgical procedure itself has been the subject of
numerous safety analyses and publications over the last decade.
The nature of this entire text is designed around principles to
avoid errors in the surgical procedure and beyond the scope of
any one chapter.
The system of delivery of surgical care is an area of prime
importance to the surgeon who must assure system safety before
the patient is even brought to the pre-op holding area. This is
another surgical responsibility but the surgeon has direct control
over only a limited number of factors that impact outcomes. The
surgeon as well as surgical team, which includes the intraoperative
personnel and support staffs all the way up to the administrators,
are jointly responsible for creating a culture of safety.32 The envi-
ronment of the operating room is a critical component in ensuring
that surgical care is delivered safely. It is particularly important to
minimize distractions and promote accurate communication of
critical patient information.33 Teamwork in the operating room is
an essential element of these patient safety efforts.34 On an individ-
ual level, meticulous attention to detail, a quiet and interruption
free operating room environment, and training and preparation
for every procedure are necessary for excellent postoperative
outcomes. Planning ahead and use of good situational awareness
and crew resource management skills are equally important and
is discussed subsequently in this chapter.35
5/21/2012 7:46:13 PM

PHASE 6: POSTSURGICAL CARE
Optimum patient outcomes depend on attention to detail during
the postsurgical phase of surgical care. Numerous publications29
have analyzed the postoperative period of surgical care and identi-
fied that approximately 50% of errors occur in this phase of care of
surgical patients.36 In a recent study of 1047 postoperative patients
who were admitted to three study units, one or more adverse
events occurred in 480 patients (45.8%). A total of 2183 errors were
identified, of which 462 (21.2%) were considered serious (poten-
tially life- or limb-threatening event). One hundred seventy-five
patients (17.7%) had at least one serious event.20 These publications
have also outlined that error patterns are not uniquely different
from preoperative patterns of error with similar contributing fac-
tors and similar requirements to minimize these adverse events.
Several potential sources of errors in the immediate postopera-
tive period have been identified and some involve handoff of care
from the operating room team to the postsurgical care team. Stud-
ies have found that the odds of adverse events could decrease from
OR 5.2 to OR 1.5 with standardization of communication and han-
doffs.37 Other postsurgical errors can occur if there is a failure to
renew preoperative medications or failure to provide antibiotic and
DVT prophylaxis. Care of patients who are transferred to the regular
nursing floor or the intensive care unit (ICU) also requires special
attention. Many other postsurgical complications are avoidable and
involve medication errors, falls, respiratory decompensation, and
decubitus ulcers. Surgeons must be aware of these potential issues
and be on guard to prevent those problems that can be avoided.38
PHASE 7: DISCHARGE
Timely and thoughtful discharge of postoperative patients is
another aspect of surgical care that requires careful planning to
avoid potential error. Specific surgical readmission rates have been
quoted to be 11.1% to 20.3% of discharges.39 Readmission rates
after discharge have been used by the Joint Commission and other
accrediting agencies as a metric for assessing the quality of patient
care. Readmission is associated with indicators of standards of care
during the index hospitalization, such as poor resolution of the
main problem, unstable therapy at discharge, and inadequate post-
discharge planning. It has been reported that from 9% to 48% of
all readmissions have been judged to be preventable. Randomized
prospective trials have shown that 12% to 75% of all readmissions
can be prevented by patient education, predischarge assessment,
and domiciliary home care.40 Minimizing errors in the surgical
patient depends on timely and correct discharge procedures.
Answer: Errors can occur in all seven phases of surgical man-
agement. These types of errors include decision errors, knowledge
errors, and procedural errors.
2. Are there unique patterns of errors that occur during surgi-
cal care?
Adverse events and errors in surgical care follow patterns that can
be understood by a careful analysis of the multiple factors and
conditions that contribute to these incidents. For this reason, to
minimize the risk of error it is necessary to study where and how
errors may occur and anticipate these conditions. This makes it
possible to construct individual and system approaches to avoid
them. Overall, a system-oriented approach that emphasizes proac-
tive and preemptive error management is in accordance with the
PMPH_CH02.indd 17
Patient Safety in Surgical Care ■ 17
concepts of preventive medicine and patient safety that lie at the
core of enhancing outcomes for surgical patients.41 However, it is
necessary for the individual surgeon to carefully review individual
as well as team member performances for every operation because
a common reason for adverse outcomes is still human error.42
Another important aspect to prevent errors is to be able to pre-
dict the conditions that lead to errors.43 There are known sets of cir-
cumstances that allow surgeons to make those predictions.28 These
sets of circumstances are known as “Error Producing Conditions,”
and they link traditional systems’ approaches to error with advanced
human factors analysis of individual performance. The top error
producing conditions that have been described in aviation accident
investigation that are also very important in surgical care are
1. Fatigue/physiological degradation
2. High-risk/low-frequency event
3. Time pressure
4. Inadequate standardization
5. Poor information transfer
The day-time mortality rate of a cohort of 20,547 children admitted
to 15 pediatric ICUs compared to night-time admission revealed
that night admission carries an incremental risk of death from
1.1 to 4.5.44 The associated physiological degradation of skills and
judgment that accompanies fatigue requires no further emphasis
than to extrapolate Dawson’s often cited laboratory study45 to the
fatigued surgeon who performs with the same aptitude as a per-
son who is legally drunk. Fatigue acts as a force multiplier on both
individuals and teams, exaggerating small missteps and making it
much more difficult to catch misperceptions and fostering errors
in communications and information exchange.46
The negative impact of fatigue has been well documented in a
retrospective cohort study of general and vascular surgical proce-
dures. Operation start time was the independent variable of inter-
est. Operative cases starting at night demonstrated a strong effect
on morbidity.47 Numerous other studies are found in the litera-
ture specific to physician performance during periods of fatigue.48
Demands for surgery respect no time of the day or night, therefore
surgeons must be aware of the impact of fatigue on performance of
complicated tasks and guard against errors during these periods.
Another source of errors is known as “plan continuation bias,”
which represents the unconscious human bias to pursue a course of
action, a treatment plan, or procedure in spite of changing condi-
tions. Surgeons are goal-directed and oriented toward completing a
course of action and the inability to recognize when modifications
and/or changes in direction are needed leads to adverse events.
This type of task fi xation can be exacerbated by stress, fatigue, and
time compression.49
For surgeons to avoid errors, it is important to understand
these various sets of conditions that make error more likely and
with this information understand the nature and extent of error.
The next step is using this information to account for the condi-
tions that induce error, determine behaviors that prevent or miti-
gate error, and train personnel in use of error avoidance tools.
Answer: Errors in management of surgical patients follow
known patterns of adverse outcomes in other organizations and
impact all aspects of surgical care.
3. Is there efficacy for reducing errors in surgical patients by using
models known to reduce error in other high-risk endeavors?
Organizations that repeatedly carry out potentially dangerous
procedures with minimal error are known as “high-reliability
5/21/2012 7:46:13 PM
 18 ■ Surgery: Evidence-Based Practice
organizations” (HROs) and safety models from these systems can
be used to enhance surgical outcomes. HROs are characterized as
high-risk, error-intolerant systems that are capable of repetitively
carrying out potentially dangerous tasks with virtually no occur-
rence of adverse outcomes. Commercial aviation serves as the pri-
mary example of the HRO safety model as evidenced by a decade
of annual Federal Aviation Authority statistics indicating that the
risk of a major commercial carrier accident ranges from 0.00 to
0.218 per 1,000,000 flight hours.50 An individual must fly 24 hours/
day every day for 570 years before standing a 1% chance of being
involved in a fatal commercial aviation accident. This safety record
is based on a thorough comprehension of the mechanisms of errors
gleaned from collecting incident and error reports. In aviation, as
in other HROs, reporting and avoiding error has become a com-
pulsion and a cultural norm.
Detailed analysis of pertinent adverse events and near miss
case studies have generated a body of knowledge known as high-
reliability theory that defines a number of organizational features
likely to reduce the risk of “organizational accidents” and other
hazards.51 In order to make these principles apply to patient safety
in surgical care, it is necessary to identify specific practices to
adopt from complex, high-risk industries that manage to oper-
ate at consistently high levels of reliability. The primary tasks in
designing a system to prevent errors in surgical care are embrac-
ing principles that make small and potentially preventable errors
visible when they do occur so that they may be intercepted, and
formulate methods for minimizing the impact of adverse events
when they cannot be intercepted.52
HROs manage risks by understanding how errors occur and
anticipating all possible chances for errors. An important prin-
ciple of risk management is trapping small missteps before major
adverse events have a chance to take place. This points out an
important difference between safety designs in health care and
HROs in that HRO systems are engineered with the expectation
that individuals can and will make mistakes and that the system
itself must be engineered to catch these mistakes. Physicians and
nurses have been granted a loftier status. We are expected not to
make mistakes despite operating under stressful conditions in a
system that is not attuned to catching small missteps. The sys-
tem as it exists in health care is not programmed to trap small
errors. For this reason it is important to sustain a mindset that
makes awareness of the potential for errors part of daily surgi-
cal care. Safe outcomes depend on managing those risks well and
continually detecting and intervening in small errors before they
are allowed to produce adverse outcomes.
Another HRO safety model is to continually rehearse famil-
iar scenarios of error and strive to imagine novel ones. Instead
of isolating failures, HROs generalize them, and instead of mak-
ing local repairs, HROs look for system reforms. This is an ideal
model to reduce errors in the care of surgical patients before, dur-
ing, and after surgical interventions.
One of the keys to understanding error threats is derived
from HRO system-wide use of critical incident reporting (CIR)
programs that collect and objectively analyze errors, incidents,
and near misses. The largest critical incident data base is main-
tained by NASA for the FAA known as the Aviation Safety Report-
ing System (ASRS), and it receives over 30,000 reports annually
containing almost 800,000 voluntary, anonymous near misses,
incidents, safety violations, and aviation safety risks.53 Incident
reporting allows for the identification of risks of adverse events
and patterns of risky actions before they propagate through the
PMPH_CH02.indd 18
system and become realized tragedies. Although it is impossible to
know what has not occurred because proactive steps are routinely
taken based on incident reporting to avoid adverse events, the best
gauge of “almost” events is near miss reporting. One method that
has improved reporting is by broadening the targets of incident
reporting to include no harm events and near misses and easing
the disincentive to reporting actual adverse outcomes. This has
been shown to increase reporting by 3 to 300 fold.54 The value of
critical incident reporting and near miss reporting in lowering
adverse outcomes has been demonstrated in every HRO system.55
In order to successfully collect critical incident information,
the data must be used to “generate light not heat” requiring the
system to be totally anonymous and nonpunitive.56 Other impor-
tant characteristics of suitable reporting systems are that they
provide an incentive to report and ensure objective fair reporting
without assigning blame.43 Health care lags significantly behind
in the collecting and analyzing of critical incident data as health
care incident reporting systems collect only 1.5% to 10% of actual
adverse events. The use of CIR systems is gaining momentum in
several specialties such as anesthesia,57 emergency medicine,58 and
critical care.59 Further progress has been made by the National
Patient Safety Foundation that has commissioned the develop-
ment and implementation of an Internet-based CIR system for
use in critical care environments.60 The ultimate aim of incident
reporting in health care and surgery is several-fold. It can be used
to guide focused enhancements in training, organization, and
management, as well as examining past practices to understand
how things might be improved and done differently.
HROs have accomplished their safety goals through multiple
avenues of training in both simulation and didactic training in
nontechnical skills (NTSs). Nontechnical skills are defined as the
cognitive, social, and personal resource skills that complement
and enhance technical skills and as such contribute to safe and
efficient task performance. This is especially applicable to operat-
ing room performance. NTSs focus as much on individual inter-
personal skills as on team dynamics since it is the individual that
is the basic building block from which teams and larger organiza-
tional groupings are formed.61 Some of these nontechnical skills
that have become the foundation of HRO safety are
1. Situational awareness (SA)
2. Crew resource management (CRM)
3. Communication skills
4. Leadership and supervision
5. Human factors (HFs)
These skills are interrelated and revolve on the central axis of
teamwork and communication. Th is is such a crucial aspect of
surgical patient safety and will be dealt with in the fi nal sec-
tion of this chapter. Other HRO safety skills that can be used to
enhance surgical safety require an acknowledgment that surgi-
cal team composition is rarely fi xed due to shift and rotations
patterns and other organizational constraints. The flux of team
composition mandates that each team member carries with him
or her skills that apply regardless of the team make-up at any
given period.
Situational awareness (SA) is simply the big picture; it is “the
accurate perception of what is going on with you, your patient, your
team members and the surrounding environment 5 minutes ago,
NOW and 5 minutes from now.”62 Building SA requires developing
and maintaining an overall dynamic and temporal awareness of
5/21/2012 7:46:13 PM

the clinical entirety based on perceiving all elements in the envi-
ronment, understanding their interrelationship and implications of
each, and using this understanding to think ahead, to predict, and
to anticipate the most likely eventualities. Forming the compos-
ite picture of SA also requires the nontechnical skill of perception,
derived from the clinical experience that comes with repetition, and
develops into astute clinical judgment.63 Prioritizing information
and actions are important aspects of situational awareness in the
care of surgical patients. This fosters quality and timely decisions
and projects the current situation into the future to make educated
guesses as to what lies ahead so that changes in the clinical “big
picture” do not come as unmanageable surprises. Although build-
ing and maintaining SA is largely an individual skill, it requires
team participation in that team members must combine all of
their perceptions and experiences in order to form a correct “big
clinical picture.” This must be shared through accurate and timely
communication with the team allowing all team members to mod-
ify and reassess their clinical impressions as moment to moment
situations change. HROs teach and diligently drill SA skills with
simulation, repetition, team role playing, and supervision and have
demonstrated effectiveness of this training.64
Crew resource management (CRM) is an educational program
that has been developed and based on over three decades of HRO
safety studies. It has evolved from a program focused on individual
attitude and awareness to a broad curriculum of behavioral skills and
teamwork attitudes integrated with technical competencies. CRM
programs evolved steadily, in part because they were informed by
data that validated the importance of human factors. CRM train-
ing results in positive reactions to teamwork concepts, increased
knowledge of teamwork principles, and improved teamwork
performance.65 CRM encompasses skills such as clearly defining
team roles and duties, managing distractions, prioritizing tasks,
and avoiding task overload all of which are integral components of
safe and effective operating room teams. HRO and aviation-based
CRM is defined as maximizing procedural effectiveness by using
all available resources, including “hardware,” “software,” people,
information, and environment. This is closely related to team com-
munication that is dealt with separately in the final section.
Effective leadership and team supervision are crucial require-
ments to reduce adverse outcomes and have been repeatedly empha-
sized in HRO and aviation safety.66 Surgeons provide leadership
in three key areas: strategic direction, monitoring team perfor-
mance, and teaching team members by providing instruction—all
tasks that match those that researchers identified in the func-
tional team leadership literature.67 The characteristics of surgical
leadership in trauma teams have been studied by Yun et al. in a
Level I trauma center.68 They stress the importance of leadership
adaptability since surgeons often work in an uncertain and time-
constrained environment. The ability to get the best performance
from all team members and encourage each person on the team
to share information and knowledge are traits of good leaders and
supervisors that have been emphasized in both the HRO literature
as well as in reviews by the American College of Surgeons.69
Human factors (HF) is the science of understanding and analyz-
ing human physiology and how these factors impact performance.
The most important of these factors is fatigue and awareness of the
impact of fatigue and sleep debt on performance of critical tasks.
Sleep and nap physiology, work attitude, caffeine use, interpersonal
relationships, focus, and work environment are all involved in the
study and management of HF. These factors have been emphasized
in both the HRO safety literature and medical literature.70
PMPH_CH02.indd 19
Patient Safety in Surgical Care ■ 19
The central usable tenet of high-reliability theory in surgi-
cal care is a constant preoccupation with the possibility of error,
and then to use these documented skill sets, as outlined above, to
minimize the occurrence of error or trap small errors before they
cause major patient harm.
Answer: There are useful skills from HROs that have been
shown to reduce adverse outcomes in health care.
4. Can improving teamwork and communication skills of sur-
gical teams mitigate and reduce errors in the care of surgical
patients?
The Joint Commission (2003) statistics have identified 67% of the
root causes of sentinel events are the result of errors of communica-
tion between team members.71 Both medical and surgical team com-
munications have been studied in detail.72 Poor teamwork function
and communication lapses among members of the surgical team
have been shown to be key factors in the occurrence of errors. The
integration of improved communication and teamwork skills must
involve all phases of surgical care. Teamwork and communication
are key competencies to improve surgical patient outcomes.
Use of CRM driven communication skills, as outlined previ-
ously, by surgeons and surgical teams lead to individual and team
situational awareness, judgment, safety, resource preservation, and
timely contingency planning. This important set of skills has been
emphasized in the medical literature to optimize and manage work-
load and task assignments, clinical task planning, and review and
critique strategies.73 Skills such as preprocedure briefings, “time-
outs,” and postprocedure debriefings are essential safety skills to
plan procedures and capture lessons learned during the operation.
CRM skills are an indispensible component of communication in
the operating room, and Level II data support the conclusion that
these skills enhance the performance of the operating team and
patient outcomes.74,75
Additionally, information sharing tools such as simple preop-
erative and surgical checklists have been shown to improve commu-
nication between team members, mitigate potential critical events,
and improve patient outcomes.76,77 One of the challenges in the
implementation of tools that could assist surgical teams in mitigat-
ing errors is the lag in acquiring evidence that an intervention trans-
lates into improved patient outcomes. The use of the World Health
Organization’s surgical check list was reviewed in over 3000 surgical
procedures. This revealed that both the surgical mortality rate and
complication rates were reduced. The checklist includes a presurgi-
cal briefing that is an important part of the CRM philosophy and
serves as a basic plan of the event prior to its commencement. This
briefing communicates key information about the procedure and
scripts possible ways to deal with unexpected events. Following the
briefing, team members are asked to verify their understanding of
the planned procedure, ensuring a shared mental model.78 The mor-
tality rate prior to the implementation of the checklist was 1.5% and
it was reduced to 0.8% following the utilization of the checklist and
the rate of complications decreased from 11.0% to 7.0%.
Failure to communicate critical information in the operating
room occurs in approximately 30% of team exchanges.73 Bollomo79
has documented impressive reductions in mortality, morbid-
ity, and length of stay in patients after major operations after the
implementation of a formal plan to improve team communication
skills. This prospective cohort study shows a reduction in relative
risk of 57.8% (P < .0001) for major complication, reduction in rela-
tive risk of postoperative death by 36.6% (P < .0178), and reduction
5/21/2012 7:46:13 PM
 20 ■ Surgery: Evidence-Based Practice

of postoperative length of stay by 4 days (P < .0092). Observational
studies in the operating room have consistently demonstrated that
training clinicians in interpersonal proficiency, teamwork, and
communication skills provides important safety advantages.80
Practicing teamwork and team communication skills with
simulation has also been effective. Simulation training promotes
expert medical competencies, high performance communications,
and collaboration competencies as well. Review of the current lit-
erature shows that simulation training can promote expert medical
competencies and communication and collaboration competencies
as well.81 Models of health professional training that do not expose
patients to the risk of learner’s error include simulation-based train-
ing methods.82 Such methods have now been incorporated into the
training milestones of general surgery in the United States.83 Many
studies have demonstrated that teamwork simulation training can
improve patient outcomes in high-risk areas of hospital systems.84
In labor and delivery, team training that includes cross-training,
simulation, and practice of technical skills has shown reduction
in errors in the operating room.85 Evidence-based principles that
lead to effective team training include identification of teamwork
as a key competency, emphasis of teamwork rather than task work,
value of feedback, and reinforcement of team behaviors.86 It is nec-
essary for all team members to be included in team training with
simulation. This is important in surgical safety training since qual-
itative studies have shown that surgeons perceive a higher degree
of organizational culture, communication, and teamwork within
the operating rooms than anesthetist and nursing staff.87
With increasing frequency, changes in the surgical staff that
care for patients occur now more than ever; therefore, there is a
need to augment system redundancy to improve the teamwork and
communication strategies to keep patients safe. Ineffective handoffs
of patients between surgical teams are increasingly recognized as
sources of adverse events.88,89 The care of surgical patients is distrib-
uted over time and location requiring effective handoff practices to
ensure appropriate coordination and continuity of care, especially
at care transition points and during shift changes.90 Handoffs of care
of the surgical patient involve precise communication and require
the exchange of important patient data between individuals and
teams members. This is necessary to facilitate uninterrupted patient
care and maintain professional responsibility and accountability.
Formal handoff skills are being integrated in residency training91
and have been a major safety focus of the Agency for Healthcare
Research and Quality.92 Computer and web based tools have been
shown to enhance the accuracy of patient handoffs.93
Adopting these methods of patient safety in surgery is an
important principle that is being influenced by public pressure,
current legislative initiatives, and an unlimited drive on the part of
surgeons to improve professional performance. The sustainability
of patient safety initiatives that reduce errors in health care has
been affected by both organizational culture and the paucity of evi-
dence that these initiatives are effective. Patient safety leaders agree
that organizational culture and the lack of a just culture in medical
education have hindered progress in diminishing adverse events.94
This is perceived as a hidden curriculum that presents a major cul-
tural barrier. The hidden curriculum is the physical and workforce
organizational infrastructure that influences the learning process
and the socialization to professional norms and rituals.95 The use
of high-reliability safety principles and improved teamwork and
communication strategies can only improve patient care if the
environment in which the skills are acquired and practice allows
such behaviors. Informal, everyday learning experiences outside
of the structured learning events not only contribute to the learn-
ing culture but the safety culture as well. It is the responsibility of
individual surgeons to assist in the system-wide adoption of these
principles and to find areas within each individual practice that
this high-reliability mindset can be integrated to “most carefully
guard against” adverse patient outcomes.
Answer: Improving teamwork with information sharing and
team communication of critical patient information contributes
to reducing errors in surgical care.

Clinical Question Summary

Question
1 When and how do errors occur during the
care of surgical patients?
2 Are there unique patterns of errors in
surgical care?
3 Do safety models from other high-risk
endeavors have efficacy for reducing
errors in surgical patients?
4 Can improving teamwork and communication
skills to surgical teams mitigate and reduce
errors in the care of surgical patients?
Answer Grade
Errors can occur in all seven phases of surgical management. These B
consist of decision errors, knowledge errors, and procedural errors.
Errors in management of surgical patients follow known patterns of C
adverse outcomes in other organizations and all as pects of surgical
care.
Safety models based on High-Reliability Organizational theory are B
efficacious to minimize the risks of errors in surgical care.
Improving teamwork and team communication of critical patient B
information contributes to reducing errors in surgical care.

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 PART 1

THE ESOPHAGUS

PMPH_CH03.indd 23 5/21/2012 7:48:24 PM

PMPH_CH03.indd 24 5/21/2012 7:48:25 PM

Esophageal Perforation
Jonathan B. Lundy and G. Travis Clifton
In the byways of surgery there can be few conditions more
dramatic in their presentation and more terrible in their
symptoms than spontaneous perforation of the oesophagus.
Norman Rupert Barrett, 1946
BACKGROUND/OVERVIEW
Spontaneous esophageal rupture has gone by many names includ-
ing atraumatic panmural rupture, barogenic rupture, effort rup-
ture, primary pressure rupture, and emetogenic rupture.1,2 The
first description of spontaneous thoracic esophageal perforation
is credited to Dr Hermann Boerhaave, who in 1724 reported post-
mortem findings of the Grand Admiral of the Dutch fleet who
died after developing postemetic, severe chest pain.3 The epony-
mous entity, now termed Boerhaave’s syndrome, is believed to be
caused by high intraluminal pressure in the esophagus. Intra-
gastric pressures measured during emesis can reach 120 mm Hg.
In the esophagus, this pressure rise may occur in the setting of
a constricted upper esophageal sphincter and result in trans-
mural rupture of the esophagus in the distal portion, typically
the left posterolateral wall (as many as 90%) 2 to 3 cm proximal
to the lower esophageal sphincter.4,5 Spontaneous rupture has
been described involving the mid-thoracic and cervical portion
of the esophagus as well.2 Brinster’s series of esophageal injury
patients outlines the frequency of various etiologies causing
esophageal disruption.6 Iatrogenic perforation, postinstrumen-
tation accounts for 60% of cases, Boerhaave’s syndrome occurs
in 15%, foreign body ingestion in another 12%, trauma in 9%,
operative injury (bariatric/gastroesophageal reflux disease pro-
cedures) in 2%, tumor related causes in 1%, and other causes in
2%. Although Boerhaave’s syndrome is classically described after
emesis, vomiting is not a prerequisite. Esophageal rupture has
been described after strenuous defecation, parturition, asthma,
seizure, and blunt trauma.7 The typical male to female ratio of
spontaneous rupture is 5:1 with the development classically
described between the fourth and sixth decade of life.8 The tear
is usually longitudinal and leads to mediastinal contamination
25
PMPH_CH03.indd 25
CHAPTER 3
with gastric and oral secretions. The mediastinal pleura may ini-
tially remain intact; however, after a short period of soilage, the
layer is prone to breakdown and ipsilateral pleural contamina-
tion. Shock from sepsis with large volumes of fluid sequestration
into these contaminated cavities is often part of the clinical sce-
nario especially when the diagnosis is delayed. Delay in diagnosis
of Boerhaave’s syndrome is unfortunately the norm. Described
as a diagnostic masquerader, it may mimic other disease pro-
cesses causing severe chest pain such as myocardial infarction,
aortic dissection, pancreatitis, pulmonary embolism, peptic
ulcer disease, cholecystitis, and pneumonia.9 The true incidence
of spontaneous esophageal perforation has not been clarified in
the surgical literature.
The initial phase of care of patients with esophageal disrup-
tion consists of resuscitation to include the use of crystalloid
infusion, vasoactive medications in the setting of hypotension
not responsive to volume repletion, broad spectrum antibiotics
for the coverage of flora potentially contaminating the mediasti-
num, and limiting continued contamination by stopping oral
intake. Some experts recommend gentle placement of a naso-
gastric tube for decompression of the stomach.10 A perforation
severity score was described by Abbas and colleagues in their
review of 119 patients with perforation from multiple causes and
included hemodynamic, inflammatory, age-related, and respira-
tory variables.11 Although higher total severity scores correlated
with longer duration of stay and increased morbidity and mor-
tality, the scoring system has not yet been validated. Outcome
following esophageal perforation varies based on etiology, but
classically it is much worse following Boerhaave’s syndrome.
Some reports document mortality between 30% and 40%, with
lower mortality if the diagnosis is made within 24 hours.1,12-14
However, if diagnosis is delayed, the rate of death increases to
greater than 50%.15 Through improved diagnostic and intensive
care capabilities, and aggressive treatment (either operative or
conservative), some recent series document mortality rates less
than 10% even in the setting of diagnostic delay greater than
24 hours.16 The goal of this chapter is to describe the evidence
available to assist in the early diagnosis and in the optimal
5/21/2012 7:48:25 PM
 26 ■ Surgery: Evidence-Based Practice

management strategy for patients suffering esophageal perfo- erature this chapter is based on consists almost entirely of single-
ration. Although the focus is on spontaneous perforation, sig- center, retrospective case series. Uniformly, the evidence is Level
nificant overlap exists in the diagnostic and treatment strategies IV with Grade C or D recommendations made based on pub-
applied to all causes of esophageal perforation. The body of lit- lished findings. (See Table 3.1)

Table 3.1 Evidence-Based Table Based on Type of Intervention for Esophageal Perforation
Year, Author, Number Study Design Findings/Recommendations Level of
Reference # of Evidence
Patients
2010, Keeling 97 Retrospective, single- Primary repair should be considered the first-line 4
et al. #16 center case series treatment even if treatment is carried out beyond
24 hours.
2010, Neel 31 Retrospective, single- Operative intervention with repair recommended even if 4
et al. #64 center case series performed in delayed fashion.
2010, Shaker 27 Retrospective, single- Recommended education of primary providers about 4
et al. #36 center case series early diagnosis and referral of patients with esophageal
perforation.
2010, 44 Retrospective, single- Varied treatments (suture repair, esophagectomy, stent 4
Vallbohmer center case series placement), outcomes greatly improved if treatment
et al. #59 occurred within 24 hours.
2009, Abbas 119 Retrospective, single- Base approach on injury severity and amount of 4
et al. #11 center case series contamination of chest. Nonoperative management
likely successful with favorable clinical and radiographic
findings.
2009, Freeman 19 Retrospective, single- Stent placement viable option for esophageal perforation. 4
et al. #91 center case series
2009, Sutcliffe 21 Retrospective, single- Operative intervention varied based on timing of 4
et al. #53 center case series treatment, state that surgical intervention is superior
to nonoperative treatment.
2009, Wang 18 Retrospective, single- Primary repair appropriate despite delay in treatment. 4
et al. #65 center case series
2008, Cho et al. 10 Retrospective, single- Primary repair acceptable even if delay in treatment 4
#67 center case series beyond 24 hours. Leak more common if treatment is
delayed.
2007, Erdogan 23 Retrospective, single- Primary repair reinforced with fibrin tissue patch is ideal 4
et al. #78 center case series intervention.
2006, Fischer 15 Retrospective, single- Self-expanding metal stents may be utilized for esophageal 4
et al. #90 center case series injury even in setting of delayed presentation.
2005, Chao 28 Retrospective, single- Primary repair even if delay in treatment has occurred. 4
et al. #68 center case series
2005, Vogel 47 Retrospective, single- Advocate aggressive, conservative management with 4
et al. #54 center case series control of sepsis and drainage of esophageal leak. No
deaths occurred in 34 patients treated nonoperatively.
2004, Jourgon 25 Retrospective, single- Long interval between symptom development and 4
et al. #69 center case series treatment does not preclude primary repair.
2004, Gupta 57 Retrospective, single- Recommend esophagectomy for perforation in setting of 4
et al. #87 center case series preexisting esophageal disease.
2003, Kollmar 17 Meta-analysis with Although reported outcomes as a meta-analysis, no 4
et al. #5 retrospective, single- statistical results were given and a very limited number
center case series of sources were utilized in table form. Recommended
primary suture repair only if treated within 12 hours of
symptoms. All other patients should be evaluated for
esophageal resection and two-stage reconstruction.
(Continued)

PMPH_CH03.indd 26 5/21/2012 7:48:25 PM

 Esophageal Perforation ■ 27

Table 3.1 (Continued)

Year, Author, Number Study Design Findings/Recommendations Level of
Reference # of Evidence
Patients
1999, Lawrence 21 Retrospective, single- Recommend primary repair with mediastinal drainage and 4
et al. #57 center case series decompressive gastrostomy even if treated after
24 hours of symptoms.
1998, Altorjay 27 Retrospective, single- Advocate for single-stage resection and reconstruction in 4
et al. #26 center case series setting of perforation.
1997, Kotsis 36 Retrospective, single- No deaths or leaks with primary repair with 4
et al. #82 center case series reinforcement with vascularized tissue.
1996, Wang 27 Retrospective, single- Primary repair appropriate no matter the time from 4
et al. #66 center case series symptom development.
1995, Wright 28 Retrospective, single- Recommend tissue buttressed repair unless patient has 4
et al. #81 center case series nondilatable stricture or malignancy.
1995, Whyte 22 Retrospective, single- Recommend primary repair even with delay unless patient 4
et al. #58 center case series has a distal obstructing lesion or malignancy.
1994, 14 Retrospective, single- Recommend use of autologous muscle tissue to reinforce 4
Richardson center case series repair. In addition, described cohort of patients with
et al. #79 difficult defects that obtained definitive closure with
use of only diaphragmatic muscle flap.
1993, Salo et al. 90 Retrospective, single- Mortality of primary repair 68%, esophagectomy 13%. 4
#86 center case series Recommend staged esophagectomy/reconstruction in
setting of delayed perforation with sepsis.
1989, Pate et al. 34 Retrospective, single- Recommend primary repair with use of pleura or 4
#24 center case series intercostals muscle for reinforcement.
1989, Gouge 18 Retrospective, single- Recommend pleural flap reinforcement of primary repair. 4
et al. #80 center case series Resection appropriate for extensive necrosis/damage.
1987, Nesbitt 115 Retrospective, single- Treatment of choice is primary repair with mediastinal/ 4
et al. #29 center case series pleural drainage despite interval from symptoms.
1984, Ajalat 21 Retrospective, single- Primary repair with chest drainage is procedure of choice. 4
et al. #26 center case series
1981, Michel 85 Retrospective, single- Advocate treatment of thoracic perforation with primary 4
et al. #22 center case series suture repair with pleural wrap reinforcement.
1978, Symbas 9 Retrospective, single- Primary repair reasonable even if patients present late. 4
et al. #71 center case series Recommend gastric decompression and the use of
fundoplication if perforation diagnosed late.
1973, Hardy 36 Retrospective, single- Recommend direct attempt at suture repair when 4
et al. #61 center case series diagnosis is made early. Mediastinal drainage and
gastrostomy only when diagnosed late.
1972, Keighley 12 Retrospective, single- Recommend increasing awareness of diagnosis, identifying 4
et al. #7 center case series full extent of mucosal injury, and direct suture repair of
disruption.
1972, Keighley 33 Retrospective, single- Low, 8% mortality for suture repair for spontaneous 4
et al. #70 center case series perforation.
1965, Foster 42 Retrospective, single- Recommend primary closure and drainage of 4
et al. #60 center case series mediastinum/pleura.

1. What are the most reliable symptoms and physical findings
for diagnosing esophageal perforation?
The classically described Mackler’s triad seen with spontaneous
esophageal perforation consists of antecedent emesis, chest pain,
and subcutaneous emphysema and is frequently absent at initial
presentation leading to a delay in diagnosis.17 Early diagnosis is
difficult as a result of the nonspecific symptoms, physical findings,
and imaging results that are seen after esophageal perforation;
many overlapping with findings of other acute processes. The cor-
rect diagnosis after spontaneous esophageal perforation was made
within 12 hours in only 21% of cases in Abbott’s classic series

PMPH_CH03.indd 27 5/21/2012 7:48:25 PM

 28 ■ Surgery: Evidence-Based Practice
reported in 1970.1 Along with being difficult to diagnose, the high
mortality of spontaneous esophageal perforation has led some to
consider esophageal perforation to be the most lethal perforation
of the gastrointestinal tract.18 Although reported before the avail-
ability of current standards of imaging, antibiotics, nutrition, and
intensive care capabilities, Derbes and Mitchell described in their
series of 157 cases of Boerhaave’s syndrome a mortality of 25% by
12 hours in a subgroup of 71 untreated patients.19 Many case series
in fact include postmortem examples of Boerhaave’s syndrome.20-23
As previously stated, a history of vomiting is not mandatory
for the diagnosis of Boerhaave’s syndrome to exist. Antecedent
emesis occurs in up to 75% of patients in series that report this
history.20,24 Uniformly, chest pain is the most common presenting
symptom in patients suffering Boerhaave’s syndrome.7,20,24-29 Fever
follows as the second most common presenting symptom. Dysp-
nea and subcutaneous emphysema occur less frequently but are
reported in most series as the next most frequent signs on exami-
nation. Subcutaneous emphysema detected by palpation has been
reported in as few as 30% of patients in recent series on the subject
of esophageal perforation and is considered a finding of delayed
presentation/diagnosis.24,30,31
Summary: The most common symptoms associated with
spontaneous esophageal perforation include chest pain, fevers,
and dyspnea. Emesis is common but not mandatory for the devel-
opment of Boerhaave’s syndrome. Subcutaneous emphysema, and
Mackler’s triad (cervical subcutaneous emphysema, emesis, and
chest pain) are typically findings of late presentation/diagnosis.
(Grade C recommendations.)
2. What are the most reliable diagnostic studies to evaluate for
esophageal perforation?
The classic radiographic finding of Naclerio’s V sign was first
reported in 1957 by Dr Emil A. Naclerio.32 The finding represents
localized emphysema outside of the ipsilateral mediastinal and
diaphragmatic pleura without a violation of the pleura itself.20
Naclerio suggested that this finding correlated with early diag-
nosis, and prompt surgery in this setting had a high likelihood
of success. Han and McElvein suggested that at least an hour
must transpire since perforation before the finding of mediastinal
emphysema can develop.33 Chest x-ray is commonly abnormal in
reports of patients with Boerhaave’s syndrome. Bradley reported
100% of chest radiographs were abnormal in his 1981 series.25
Rates of abnormal plain chest roentgenograms range from 85%
to 97% in modern series, meaning that a substantial portion of
patients will have unremarkable plain fi lm imaging.24,27,33,34 The
high rate of normal chest radiographs, make this study less than
ideal for definitively excluding esophageal perforation. The list of
abnormalities that can be found on chest radiograph after sponta-
neous esophageal perforation includes ipsilateral pleural eff usion,
atelecatasis, infi ltrate, hydropneumothorax, tension pneumotho-
rax, subcutaneous emphysema, and normal appearance of the
chest. Panzini reported that pneumomediastinum was the most
common chest x-ray finding in their retrospective case series.35
Most importantly, when caring for a patient with a history of
emesis or the spontaneous development of severe chest pain, who
is found to have an abnormality on chest radiograph listed above,
a high index of suspicion for the diagnosis discussed in this chap-
ter is vital and may be life saving. The fact that the initial evalua-
tion of a patient with chest pain will likely not be carried out by a
PMPH_CH03.indd 28
practitioner with extensive experience with the care of spontane-
ous esophageal perforation makes early diagnosis based on subtle
imaging findings less likely. Shaker et al. have suggested that a
program for educating primary care providers about this uncom-
mon disease is appropriate to ensure more rapid diagnosis and
referral for intervention.36
Because chest radiographs are not often a definitive diagnostic
study, other imaging modalities are typically required. The tools
available include contrast esophagography, computed tomography,
and esophagoscopy using fiberoptic technology. The use of contrast
esophagography provides the theoretic benefit of coating the entire
esophageal mucosa to identify defects. Using fluoroscopy, the study
can be repeated for areas of concern. Historically, it has been rec-
ommended that when evaluating for esophageal extravasation, oral
Gastrograffin be administered first, followed by barium esophago-
gram if the prior procedure is negative, due to reports of barium
inducing a desmoplastic reaction when extravasation occurs, lead-
ing to mediastinitis or peritonitis. It is important to note, however,
that Gastrograffin extravasates in only 50% of cervical perforations
and 80% of thoracic esophageal perforations in some reports.37 In
addition, water soluble agents such as Gastrograffin have been asso-
ciated with pulmonary edema when aspiration occurs. This risk is
most commonly seen when using iodinated agents such as Hypaque
or Renografin.38-40 Barium has a higher density and better mucosal
adherence improving detection of cervical perforation to 60% and
thoracic esophageal perforation to 90%.37 Ultimately, between 25%
and 50% of esophageal perforations not seen with water soluble con-
trast material will be demonstrated with barium.41,42 Rubesin and
Levine published a review paper on the subject of gastrointestinal
perforations and included their institutional experience with the
radiographic diagnosis of these emergencies.43 During their total
of 20 years experience, no cases of barium induced mediastinitis/
peritonitis or pulmonary edema due to aspiration of water soluble
contrast material had occurred. Most experts continue to recom-
mend the initial use of water soluble contrast esophagography fol-
lowed by barium for the detection of esophageal perforation. In
review of available retrospective trials of esophageal perforation
that include the imaging modality used, esophagogram is diagnos-
tic in 73% to 100% of cases.24,29,34,44,45 The disadvantages to relying on
contrast esophagography for diagnosing of esophageal perforation
include upto a 12% false-negative rate and the fact that it requires
in-house technicians to perform (only 11 of 14 patients in Ghanem’s
radiologic diagnosis study of Boerhaave’s syndrome patients were
able to have esophagogram performed).46
Direct visualization of an esophageal defect with fiberoptic
endoscopy is another technique to diagnose rupture. A potential
benefit to esophagogastroduodenoscopy (EGD) over other modal-
ities, especially with modern endoscopic technology, is the poten-
tial for endoluminal therapy. More recent series have reported the
use of esophagoscopy to diagnose perforation with a sensitivity
as high as 100% but a specificity of only 60% to 83%.47 Mizutani
reported 26 total esophageal defects (11 were due to spontaneous
rupture) with 9 of 15 (60%) having a positive EGD.34 Although
some authors suggest that EGD has a higher sensitivity and speci-
ficity, it is dependent on the skill of the endoscopist and there is a
theoretic risk of conversion of a submucosal or small full-thickness
disruption into a more complex process.48
All spontaneous esophageal perforation patients who under-
went computed tomography (CT) (n = 14) in the retrospec-
tive series reported by Ghanem and colleagues had evidence of
5/21/2012 7:48:25 PM

periesophageal air tracks.46 This finding along with periaortic and
perispinal air were also noted to be helpful diagnostic fi ndings on
CT imaging. Ghanem’s report is consistent with other small series
describing CT findings with esophageal perforation.49,50 Less fre-
quent and less specific findings in the setting of esophageal perfo-
ration include esophageal wall thickening, intramural esophageal
hematoma, and mediastinal fluid.50,51 When one combines the
facts that CT imaging can be used quickly without additional per-
sonnel, its technology is continually improving and evolving, and
it has high specificity (as noted earlier), it is likely that CT will
eclipse esophagography as the imaging procedure of choice for the
diagnosis of spontaneous esophageal perforation.
Summary: For the diagnosis of esophageal perforation, no rec-
ommendation can be given for any one specific diagnostic study
over another as various imaging methods appear to be equivalent
in accuracy. (Grade C recommendation.)
3. Is there a role for nonoperative management of patients with
esophageal perforation?
The first series to describe extensive success with nonopera-
tive management of esophageal perforation was the report by
Mengoli and Klassen published in 1965.52 A total of 21 patients
were included, 18 managed conservatively with a remarkable 6%
mortality. Lyons and colleagues compared a group of 18 patients
who underwent esophageal repair with 11 patients treated con-
servatively.13 Mortality was 38% in patients who underwent tho-
racotomy and 9% in patients managed nonoperatively. In 1979,
John Cameron and colleagues first described a set of criteria that
support nonoperative management of a select group of patients
after esophageal perforation.15 The criteria include rupture con-
tainment evidenced by reflux of extraluminal contrast back into
the esophagus, no pleural contamination, and no systemic signs
of uncontrolled sepsis. Abbas and colleagues reported success-
ful nonoperative management of Boerhaave’s syndrome in 10 of
44 patients, with no oral intake for 24 to 72 hours. Despite being
relegated to nonoperative management, this subgroup of patients
typically underwent some form of invasive intervention to include
endoscopy, intraluminal stent placement, thoracostomy tube
placement for pleural or mediastinal drainage, gastrostomy for
decompression, and possible feeding jejunostomy.11 Sutcliffe et al.,
however, reported a case series of 21 patients, and advocated that
operative intervention is superior to nonoperative management if
patients are diagnosed/referred after 24 hours.53 Vogel and col-
leagues have provided the most recent series of patients that con-
tribute support for nonoperative management after esophageal
perforation.54 Their report describes a total of 47 perforations, with
34 of these being managed nonoperatively. Thirteen of 14 patients
with Boerhaave’s were managed conservatively with no deaths
in the nonoperative group. This approach must include frequent
radiologic support to diagnose and treat undrained, intrathoracic
fluid collections and document healing of the esophageal disrup-
tion. The authors report that aggressive, conservative manage-
ment eliminates the source for morbidity and mortality, avoids
major surgical procedures, and allows esophageal healing.
Summary: Patients without signs of systemic sepsis and a
contained esophageal perforation may be managed nonopera-
tively. These patients typically will require some form of invasive
therapy such as tube thoracostomy or feeding access. (Grade C
recommendation.)
PMPH_CH03.indd 29
Esophageal Perforation ■ 29
4. Is there a role for primary repair of intrathoracic esophageal
perforation?
Descriptions of the first two cases of successful repair after spon-
taneous esophageal perforation were reported by Barrett and
Clagett in 1947.55,56 The most frequently utilized technique for
management is simple, direct suture repair in one or multiple lay-
ers. The details of the procedure are as follows: after posterolateral
thoracotomy, all nonviable tissue is debrided and the perforation
is exposed. The mucosal defect is typically larger than the muscu-
lar injury, thereby, myotomy proximal and distal to the injury is
required to define these mucosal edges.7,8 After debridement of the
edges, interrupted sutures are used to close the mucosal defect.57
Several series also advocate an interrupted closure of the muscu-
lar defect. Intraesophageal dilators of 40 F to 46 F may be useful to
ensure that an adequate lumen remains after repair.58 Insufflation
of the repair site to ensure a watertight closure is also described.
Wide drainage of the mediastinum and pleura is prudent. Con-
sideration for enteral feeding access can be made and options
include gastrostomy and jejunostomy; however, these may require
entrance into the peritoneal cavity.
One of the most controversial subjects regarding the man-
agement of Boerhaave’s syndrome is the appropriate intervention
for a patient diagnosed in a delayed fashion. The cutoff time for
increased mortality has typically been set at 24 hours after symp-
tom development. Several series have reported a dramatic increase
in mortality when diagnosis or treatment is delayed beyond
24 hours.26,53,59 Eloquently stated by Foster in his series of 42 patients
with esophageal injury, however, is that “the cutoff of 24 hours
is arbitrary and any delay in intervention in an ill patient is
hazardous.”60 Wilson’s series in 1971 contained the recommenda-
tion that delay in diagnosis should prompt the surgeon to perform
mediastinal and pleural drainage, and suture repair should be
relegated to patients presenting early.20 Simple debridement and
drainage has been advocated by others if the esophagus adjacent
to the perforation is found to be necrotic.26,61 The debate about
the optimal operative repair after a delay in diagnosis is ongoing.
Advocates for intervention other than suture repair alone contend
that the most common cause of morbidity and mortality is dehis-
cence of the suture with esophageal leak and ongoing mediastinal
sepsis. These authors recommend the use of autologous material to
buttress the repair site, an exclusion and diversion procedure, or
esophagectomy.4,62,63 Despite the diversity of opinions, the major-
ity of case series describe and advocate for direct suture repair
of spontaneous esophageal perforation no matter the length of
time between occurrence and treatment.7,8,11,16,57,60,64-71 Although
the classic approach for treatment of the perforated esophagus
has been the use of the posterolateral thoracotomy, reports of
the management of thoracic perforation via laparotomy exist.72
In addition, minimally invasive techniques such as laparoscopy
and thoracoscopy have been utilized successfully in patients with
Boerhaave’s syndrome.11,73,74
The use of vascularized tissue to reinforce suture repair has
been described as an adjunct for management of esophageal per-
foration. The autologous tissue used to buttress repair include
pleura, pericardial fat, intercostals muscle, diaphragm, fundus
of stomach, aortic adventitia, omentum, rhomboid muscle, and
latissimus muscle.75,76 Fibrin has also been described as an allo-
genic material that can be used to reinforce the esophageal suture
repair.77,78 Richardson and colleagues have also described the
5/21/2012 7:48:25 PM
 30 ■ Surgery: Evidence-Based Practice
use of a diaphragmatic muscle flap as definitive closure of dif-
ficult esophageal defects that were not amenable to primary
suture repair.79 Proponents for the use of a vascularized tissue
flap to reinforce the primary repair report a potential benefit in
decreased esophageal fistula rate as well as an improvement in
mortality.22,71,79-82 However, even with autologous tissue reinforce-
ment, delay in diagnosis and repair can result in esophagocutane-
ous fistula rates as high as 83%.66
Summary: Primary repair of esophageal perforation is appro-
priate even if the intervention is carried out more than 24 hours
after symptoms develop. Consideration may be made for buttress-
ing of the suture line with vascularized tissue but is not manda-
tory. (Grade C recommendation.)
5. Is there a role for an exclusion and diverting procedure after
esophageal perforation?
Drainage or diverting procedures for esophageal perforation first
appeared in the literature in the latter half of the 20th century.
The use of a T-tube inserted into the esophageal defect with pas-
sage of a nasogastric tube through the lumen of the drainage tube
was reported by Abbott and colleagues in 1970.1 Shor-Pinsker and
colleagues used division of the proximal stomach with double gas-
trostomy (one for drainage of the proximal segment, one for enteral
feeding) and reported the technique in 1970.83 Menguy described the
use of the loop cervical esophagostomy for diversion of oral secre-
tions 1 year later.84 Urschel reported his technique of side-cervical
esophagostomy (in continuity) with pleural drainage of the perfo-
rated esophagus, closure of the distal esophagus via an esophageal
band, and feeding gastrostomy in 1974.63 Proponents of diversion/
exclusion procedures site the elimination of continued contamina-
tion of the mediastinum as well as preservation of the esophagus
in situ allowing for later reconstruction as benefits of this manage-
ment technique.1,63 Exclusion/diversion procedures have fallen out
of favor in most recent series except in patients too unstable for a
more definitive repair.11 The review of the management of esoph-
ageal injury from all causes by Wu and Mattox includes an algo-
rithm with the role of T-tube drainage or an exclusion/diversion
procedure relegated to unstable patients who would not tolerate a
more aggressive approach.75 In the series by Attar and colleagues,
of the five patients managed with exclusion and diversion, only one
lived.85 In summary, if primary esophageal repair or resection is
impossible, consideration can be given to wide mediastinal drain-
age with exclusion and diversion (cervical esophagostomy, decom-
pressive gastrostomy, feeding jejunostomy, planned reconstruction
in a delayed fashion) or the creation of a controlled esophagocuta-
neous fistula using the T-tube technique described by Abbott.
Summary: There may be a limited role for a diversion/
exclusion procedure in the setting of significant esophageal
necrosis in a patient with severe physiologic derangements. (Grade
C recommendation.)
6. Is there a role for esophagectomy for esophageal perforation?
Esophagectomy has been advocated in the setting of perforation
when the native esophagus is either involved with malignancy
or nonfunctional. Sarr and colleagues reported their experience
with perforation after instrumentation of the esophagus with a
50% mortality in patients treated with esophagectomy.31 Most case
series support the use of esophagectomy in the setting of malig-
nant perforation, perforation in the setting of severe intrinsic
esophageal disease such as achalasia or stricture, and then only if
PMPH_CH03.indd 30
the patient’s current physiologic state will tolerate such an exten-
sive procedure.26 A more compelling argument for extirpation of
the esophagus can be made in the setting of delayed treatment
of the rupture.5,86 Salo and colleagues reported a 22-year experi-
ence with 90 patients, focusing on the 34 with diagnosis made
over 24 hours after perforation.86 The series included 18 patients
with spontaneous perforation. Nineteen patients had primary
repair with only six survivors (68% mortality) whereas only two
of the fifteen patients undergoing esophagectomy died (mortal-
ity of 13%). The mortality in the primary repair subgroup was
attributed to the high rate of suture dehiscence and subsequent
esophagopleural fistula (the two deaths in the resection group
were due to myocardial infarction). The mortality difference was
statistically significant between the two treatment arms (P = .001).
Gupta and Kaman reported their experience with 11 malignant
esophageal perforations after these patients underwent transhi-
atal resection with only one perioperative mortality.87 In sum-
mary, esophagectomy can be performed with favorable outcomes
in the appropriate patient and should be considered in the setting
of marked mediastinal/esophageal necrosis, malignancy, or dif-
fuse/end-stage esophageal disease.86,88
Summary: Esophagectomy is appropriate for the manage-
ment of esophageal perforation in the setting of malignancy or
end-stage intrinsic esophageal disease. There is no evidence to
support esophagectomy over any other intervention. (Grade C
recommendations.)
7. What is the role of endoluminal therapy for esophageal
perforation?
Endoluminal therapies for esophageal perforation have emerged
for use primarily in patients suffering perforation in the setting
of esophageal malignancy. These approaches evolved as a pal-
liative procedure for perforation of an esophageal malignancy in
the setting of unresectable disease. The most common technique
employed has been the use of the self-expanding metallic stent
(SEMS). Ferri et al. described two cases of spontaneous malignant
esophageal perforation with successful coverage and healing using
SEMS.89 Fischer described a series of 15 patients with esophageal
perforation treated with SEMS and reported excellent outcomes
even in the setting of delayed presentation.90 Most recently, Free-
man et al. reported 19 patients with spontaneous esophageal per-
foration treated with stent placement.91 Only two patients required
operative intervention for a persistent leak. Endoscopic clip appli-
cation is another minimally invasive technique that has been used
for the management of esophageal perforation. Qadeer and col-
leagues reported a single case along with a pooled analysis of cases
treated with endoscopic clip application.92 The report included
17 additional subjects with various etiologies of perforation.
Although the size of perforation ranged from 3 to 25 mm, a total of
only six adjunct procedures were required to achieve healing with
only three patients requiring open operative intervention. This
series included two patients with Boerhaave’s syndrome, one of
whom required exploration and primary closure. As endoluminal
therapies continue to evolve, these modalities may allow for more
rapid control of mediastinal contamination without the physi-
ologic insult of operative intervention, thereby allowing quicker
recovery and potentially better outcomes.
Summary: Not enough evidence currently exists to support
the use of endoluminal techniques for the management of patients
with esophageal perforation. (Grade D recommendation.)
5/21/2012 7:48:25 PM
 Esophageal Perforation ■ 31

Clinical Question Summary

Question
1 What are the most reliable
symptoms and physical findings
for the diagnosis of esophageal
perforation?
2 What are the appropriate
diagnostic studies to evaluate
for esophageal perforation?
3 Is there a role for nonoperative
management of esophageal
perforation?
4 Is there a role for primary repair
of intrathoracic esophageal
perforation?
5 Is there a role for an exclusion/
diversion procedure after
esophageal perforation?
6 Is there a role for
esophagectomy for
management of esophageal
perforation?
7 What is the role of endoluminal
therapy for esophageal
perforation?
Answer Grade of References
Recommendation
Chest pain, fever, a prior history of emesis, C 20, 24-31
and dyspnea. Subcutaneous emphysema
may be considered a finding of delay in
presentation/diagnosis.
Contrast esophagogram, C 24, 29, 34, 37, 41, 42,
esophagogastroduodenoscopy, or computed 44, 45, 46, 47, 49,
tomography. 50, 51
Yes, in the setting of contained perforation C 11, 13, 15, 53, 54
with no significant systemic signs of sepsis.
Yes, including after a delay in presentation or C 7, 8, 11, 16, 57, 60,
diagnosis. Consideration can be made for 64-71, 75-82
vascularized tissue buttress of suture site
but is not mandatory.
There may be a limited role for this type of C 1, 11, 63, 75
procedure in the setting of a moribund
patient with a large defect/extensive
esophageal necrosis not amenable to repair
who would not tolerate esophagectomy.
Yes, in the setting of malignancy or end-stage C 5, 26, 31, 86-88
intrinsic esophageal disease. Not enough
evidence exists to support esophagectomy
over other operative interventions.
There is no conclusive evidence to recommend D 89-92
endoluminal techniques over other
strategies at this time.

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48. Pasricha PJ, Fleischer DE, Kalloo AN. Endoscopic perforation of
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49. Di Maggio EM, Preda L, La Fianza A, et al. Spontaneous rupture
of the esophagus (Boerhaave syndrome): computerized diagno-
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52. Mengoli LR, Klassen KP. Conservative management of esopha-
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54. Vogel SB, Rout WR, Martin TD, Abbitt PL. Esophageal perfora-
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55. Barrett NR. Report of a case of spontaneous perforation of the
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56. Olsen AM, Clagett OT. Spontaneous rupture of the esophagus:
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57. Lawrence DR, Ohri SK, Moxon RE, et al. Primary esophageal
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58. Whyte RI, Iannettoni MD, Orringer MB. Intrathoracic esopha-
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59. Vallbohmer D, Holscher AH, Holscher M, et al. Options in the
management of esophageal perforation: analysis over a 12-year
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60. Foster JH, Jolly PC, Sawyers JL, Daniel RA. Esophageal perfora-
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61. Hardy JD, Tompkins WC Jr, Ching EC, Chavez CM. Esophageal
perforations and fistulas: review of 36 cases with operative clo-
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62. Grillo HC, Wilkins EW Jr. Esophageal repair following late
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387-399.
63. Urschel HC Jr, Razzuk MA, Wood RE, et al. Improved manage-
ment of esophageal perforation: exclusion and diversion in con-
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64. Neel D, Davis EG, Farmer R, Richardson JD. Aggressive opera-
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65. Wang Y, Zhang R, Zhou Y, et al. Our experience on management
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66. Wang N, Razzouk AJ, Safavi A, et al. Delayed primary repair of
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67. Cho S, Jheon S, Ryu KM, Lee EB. Primary esophageal repair in
Boerhaave’s syndrome. Dis Esophagus. 2008;21:660-663.
68. Chao YK, Liu YH, Ko PJ, et al. Treatment of esophageal per-
foration in a referral center in Taiwan. Surg Today. 2005;35:
828-832.
69. Jougon J, Mc Bride T, Delcambre F, et al. Primary esophageal
repair for Boerhaave’s syndrome whatever the free interval
between perforation and treatment. Eur J Cardiothorac Surg.
2004;25:475-479.
70. Keighley MR, Girdwood RW, Wooler GH, Ionescu MI. Morbid-
ity and mortality of oesophageal perforation. Thorax. 1972;27:
353-358.
71. Symbas PN, Hatcher CR Jr, Harlaftis N. Spontaneous rupture of
the esophagus. Ann Surg. 1978;187:634-640.
72. Berne CJ, Shader AE, Doty DB. Treatment of effort rupture of
the esophagus by epigastric celiotomy. Surg Gynecol Obstet.
1969;129:277-280.
73. Landen S, El Nakadi I. Minimally invasive approach to Boer-
haave’s syndrome: a pilot study of three cases. Surg Endosc.
2002;16:1354-1357.
74. Toelen C, Hendrickx L, Van Hee R. Laparoscopic treatment of
Boerhaave’s syndrome: a case report and review of the literature.
Acta Chir Belg. 2007;107:402-404.
75. Wu JT, Mattox KL, Wall MJ. Esophageal perforations: new per-
spectives and treatment. J Trauma. 2007;63:1173-1184.
76. Goldstein LA, Thompson WR. Esophageal perforations: a 15
year experience. Am J Surg. 1982;143:495-503.
77. Bardaxoglou E, Manganas D, Meunier B, et al. New approach
to surgical management of early esophageal thoracic perfora-
tion: primary suture repair reinforced with absorbable mesh and
fibrin glue. World J Surg. 1997;21:618-621.
78. Erdogan A, Gurses G, Keskin H, Demircan A. The sealing effect
of a fibrin tissue patch on the esophageal perforation area in pri-
mary repair. World J Surg. 2007;31:2199-2203.
79. Richardson JD, Tobin GR. Closure of esophageal defects with
muscle flaps. Arch Surg. 1994;129:541-548.
PMPH_CH03.indd 33
Esophageal Perforation ■ 33
80. Gouge TH, Depan HJ, Spencer FC. Experience with the Grillo
pleural wrap procedure in 18 patients with perforation of the
thoracic esophagus. Ann Surg. 1989;209:612-617.
81. Wright CD, Mathisen DJ, Wain JC, et al. Reinforced primary
repair of thoracic esophageal perforation. Ann Thorac Surg. 1995;
60:245-248.
82. Kotsis L, Kostic S, Zubovits K. Multimodality treatment of
esophageal disruptions. Chest. 1997;112:1304-1309.
83. Shor-Pinsky E, Silva-Cuevas A, Franco-Vasquez R, et al. Gastro-
tomy with double gastrostomy in the perforation of the esopha-
gus. Arch Surg. 1970;101:433-435.
84. Menguy R. Near-total esophageal exclusion by cervical esopha-
gostomy and tube gastrostomy in the management of massive
esophageal perforation. Ann Surg. 1971;173:613-616.
85. Attar S, Hankins JR, Suter CM, et al. Esophageal perforation: a
therapeutic challenge. Ann Thorac Surg. 1990;50:45-49.
86. Salo JA, Isolauri JO, Heikkila LJ, et al. Management of delayed
esophageal perforation with mediastinal sepsis. Esophagectomy
or primary repair? J Thorac Cardiovasc Surg. 1993;106:1088-1091.
87. Gupta NM, Kaman L. Personal management of 57 consecutive
patients with esophageal perforation. Am J Surg. 2004;187:58-63.
88. Altorjay A, Kiss J Voros A, Sziranyi E. The role of esophagectomy
in the management of esophageal perforations. Ann Thorac Surg.
1998;65:1433-1436.
89. Ferri L, Lee JK, Law S, et al. Management of spontaneous perfo-
ration of esophageal cancer with covered self expanding metallic
stents. Dis Esophagus. 2005;18:67-69.
90. Fischer A, Thomusch O, Benz S, et al. Nonoperative treatment of
15 benign esophageal perforations with self-expandable covered
metal stents. Ann Thorac Surg. 2008;81:467-472.
91. Freeman RK, Van Woerkom JM, Vyverberg A, Ascioti AJ.
Esophageal stent placement for the treatment of spontaneous
esophageal perforations. Ann Thorac Surg. 2009;88:194-198.
92. Qadeer MA, Dumot JA, Vargo JJ, et al. Endoscopic clips for clos-
ing esophageal perforations: case report and pooled analysis.
Gastrointest Endosc. 2007;66:605-611.
5/21/2012 7:48:25 PM
 Commentaries on
Esophageal Perforation
The chapter entitled “Esophageal Perforation” by Drs Lundy and
Clofton provides an excellent overview and review of the diagnos-
tic modalities and treatment strategies for esophageal perforation
as well as the level of evidence supporting their use. They specifi-
cally address symptoms and physical findings, diagnostic studies,
nonoperative as well as operative treatment strategies to include
primary repair versus exclusion/diversion versus esophagectomy,
as well as stent placement as treatment modalities.
Esophageal perforation continues to have a high morbidity
and mortality regardless of etiology. The development of uniquely
individual patient treatment strategies are necessary to affect
overall success, taking into account underlying disease process,
mode and severity of injury, degree of illness, and overall prog-
nosis. Even though the level of evidence supporting recommen-
dations regarding the optimal diagnostic workup and treatment
of esophageal perforation is generally inadequate to permit firm
conclusions regarding definite recommendations, the authors
have done an excellent job in reviewing the available literature
regarding the preferred strategies in evaluating and treating these
often difficult patients. Despite the lack of solid evidence-based
treatment strategies, several principles of evaluation and manage-
ment have evolved that include the following:
1. The illness severity of the patient is important to consider,
since a patient that is in extremis and in septic shock
must be approached differently than one without systemic
symptoms.
2. Perforated malignancies don’t tend to heal and therefore
resection should be strongly considered.
3. Loop cervical esophagostomy, commonly referred to in many
textbooks, is actually technically difficult (if not impossible)
to perform unless the patient has a long, thin neck.
4. Thin barium should be considered as the initial contrast
medium of choice since it has never been shown to cause
mediastinitis and is a more sensitive contrast agent than its
water soluble counterpart.
5. The decision to perform a primary repair of an esophageal
injury should be based on the quality of the tissues found at
surgery rather than on the length of time from onset of injury
to repair.
6. Esophageal reconstruction is an elective procedure, and can be
done as a delayed procedure following resection if the patient
is septic and in shock. In this case, placement of feeding tubes,
34
PMPH_CH03.indd 34
Scott B. Johnson
esophagectomy, and end-cervical esophagostomy can be done
as a bail-out procedure.
7. When resecting the esophagus from the chest and planning
delayed reconstruction, staple off and resect the esophagus
as far distally near the hiatus as can be safely done but save
as much proximal esophagus as possible to bring out over
the clavicle as an end, cervical esophagostomy—the longer
the proximal length the better the long-term function when
performing a delayed, substernal reconstruction.
8. A gastrostomy tube does NOT necessarily negate the stomach’s
use for later reconstruction, so long as the gastroepiploic
artery is not injured.
9. Esophagoscopy and contrast esophagography are com-
plementary, and one should not be necessarily used to the
exclusion of the other.
10. CT imaging can be helpful in identifying accompanying
abscesses and undrained fluid collections.
11. On table endoscopy performed by the operative surgeon can
be very helpful in determining surgical approach (i.e., collar
incision vs. left neck incision vs. right thoracotomy vs. left
thoracotomy vs. celiotomy).
12. Never prep yourself out of an operation (i.e., will an end-cervical
esophagostomy be necessary? a transhiatal esophagectomy?
feeding tubes? etc.).
13. The native esophagus is always preferred as the conduit of
choice . . . . save it if you can.
14. Exclusionary and diverting procedures (i.e., T-tubes) can be
done, but should be done only as a last resort.
15. If doing a primary repair, make sure the mucosal extent of the
injury is well delineated . . . . often times the muscular defect is
much smaller and the injury underestimated until the entire
mucosal injury is exposed and repaired.
16. The type of suture used (e.g., absorbable vs. nonabsorbable)
and the type of stitch used (e.g., running vs. interrupted) is
NOT as important as delineating and repairing the mucosal
defect and overlying muscular defect.
17. Tissue flaps are not necessary to use and may cause
structuring if wrapped around the circumference of the
esophagus. If used, the Latissimus Dorsi muscle flap can be
a robust, well-vascularized flap that can be brought through
a separate, small thoracotomy incision (but would need to
be spared during performance of the thoracotomy if planned
to use).
5/21/2012 7:48:25 PM

18. A left thoracotomy is best for approaching a distal thoracic
esophageal perforation. In addition, it can allow access to the
belly through a radial diaphragm incision if necessary, as well
as allow exposure of the stomach through the hiatus.
19. A right thoracotomy is best for approaching a proximal or
mid-thoracic esophageal perforation.
20. Esophageal stenting is a viable treatment option to seal
actively leaking esophageal perforations in poor-risk patients.
Drainage of any fluid collections or abscess is an important
adjunct.
“Esophageal Perforation” covers the topic but focuses more on Boer-
haave’s syndrome than necessary. Iatrogenic esophageal perforation
is the most likely etiology accounting for more than 50% of cases.
Boerhaave’s perforation is the etiology in less than 10% in most series
and no more than 15%. We suggest that a general surgeon is much
more likely to be called for an iatrogenic injury than for a Boerhaave’s
syndrome. This knowledge is important since the suspected etiology
of the perforation will alter the workup and management.
Although always a dramatic condition, emetogenic esopha-
geal perforation can be subtle if the patient presents shortly after
the event. This reinforces the importance of a careful history and
physical examination in a patient presenting with chest pain. In
the case of iatrogenic injury, no physical signs may be present at
the time of the procedure. Subcutaneous emphysema will be a late
finding. Therefore, appropriate imaging tests are needed with a
high sensitivity. We agree that CT scanning is the imaging test of
choice since it can give crucial information such as the presence
of mediastinal air, mediastinal mass, small pleural eff usion, and
extravasation of oral contrast.
The Cameron paper from 1979 is from the pre-CT era and
was the first to describe criteria for nonoperative management.
Caution should be used when interpreting this paper since there
were only 8 patients, 5 of which were leaks after an esophageal
operation. In the contemporary literature on esophageal perfora-
tion, post-op leaks are usually not included. We agree with the
authors’ criteria for nonoperative management. Patients in whom
the esophagram shows flow of contrast out of a perforation and
then back into the esophagus without there being any pleural
contamination can be observed. A perforation above the upper
esophageal sphincter will have a higher likelihood of successful
nonoperative management since it is not under pressure and any
saliva that accumulates is swallowed down.
PMPH_CH03.indd 35
Esophageal Perforation ■ 35
In summary, the authors provide a firm knowledge base to
guide the clinician in the diagnosis and treatment of these often
difficult-to-treat patients. Although evidence-based decision
making generally lacks in guiding surgical treatment, several
“Pearls of Wisdom” have emerged as a result of a collective expe-
rience in treating patients with esophageal perforations. It should
be emphasized that optimal critical care of these often very sick
patients is equally important in affecting their successful outcome
as deciding their initial surgical management, but is beyond the
scope of this discussion.
Jeremy S. Juern and John A. Weigelt
The use of endoscopic ultrasound (EUS) is increasing, both for
diagnostic and therapeutic purposes. These echoendoscopes are a
few millimeters wider than normal gastroscopes and the viewing
field is oblique. Thus there is an increased risk of perforation because
the insertion is a partially blind maneuver in addition to the added
bulk. A prospective study of 4894 patients undergoing EUS by a sin-
gle endoscopist had 3 patients with cervical esophageal perforations,
a rate of 0.06%.1 All three patients were octogenarian women with-
out cervical osteophytes, kyphosis, or dysphagia. Symptomatology
in one was chest pain, and in the others was excessive salivation
and sore throat. One had crepitus on exam. In all three, water solu-
ble esophagram showed a leak, which was followed by CT scan. All
three underwent surgical repair via a neck incision with no mortal-
ity. It is important to note that all three perforations happened after
this endoscopist’s first 2500 procedures were performed.
Similar to the rise in the use of EUS is an increase in the use of
transesophageal echocardiography (TEE). Incidence of esophageal
perforation in this group of patients is 0.01%$ to 0.04%.2 Patients
undergoing TEE may be in the operating room or intensive care
unit and hence unable to make their symptoms known. The result
is a late presentation of esophageal perforation. Therefore a high
index of suspicion is needed in patients who have undergone TEE
and subsequently develop postprocedure pneumothorax, pleural
eff usion, or sepsis.
As with most surgical conditions and especially associated
with a gastrointestinal perforation, initial care begins with fluid
resuscitation. Two other principles include nothing by mouth
and broad spectrum antibiotics. Antibiotic choice should cover
the common mouth and upper GI tract organisms and take into
account time from perforation and data obtained from imaging
studies. Initial treatment with clindamycin or an aminopenicil-
lin with β-lactamase inhibitor is appropriate. Depending on the
5/21/2012 7:48:25 PM
 36 ■ Surgery: Evidence-Based Practice
course of treatment, a broader regimen or antifungal coverage
may be needed. If it is a late presentation and an abscess is pre-
sent, antimicrobials are based on culture results. The microbio-
logic data from a recent study of late (≥1 week) presentations of
esophageal perforations after cervical spine surgery showed the
expected microbes: Staphylococcus (including MRSA), Strepto-
coccus, fungi (Candida is common), and gram negatives.3 Further
therapy is determined based on location of perforation, informa-
tion from CT scan, patient symptoms, patient comorbidities, and
a valid assessment of clinician and institution capabilities.
The appropriate therapy for the majority of patients whose
injury is recognized early is primary repair. This is a great option
if our goal of sewing healthy tissue to healthy tissue can be
achieved. This repair should still be covered by a vascularized flap.
Unfortunately, prospective trials documenting this best are just
not available. When healthy tissue is not present, common sense
dictates exclusion and diversion as we do for most gastrointestinal
perforations. Esophagectomy is also a possibility, but reserved for
circumstances where the esophagus is so diseased that any type
of salvage would be unwise. This could occur in cases with late
recognition, advanced malignancy, or achalasia.
Endoluminal therapies with stents and clips finishes the
authors’ management options. There is a recent series from a
specialized European center of 33 patients with benign perfora-
tion treated with esophageal stents.4 Three patients (9%) went on
to esophageal resection. Stent migration happened in 11 patients
(33%), and 12 patients (36%) required a total of 17 additional stents
because of leakage or stent migration. Stent extraction was also a
problem. Of the 10 stent extractions that took place at greater than
6 weeks after insertion, 50% had a complication such as bleeding,
stent fracture, and stent impaction. One patient required gastro-
tomy to remove the stent. The 90-day mortality was 15%. Bear in
PMPH_CH03.indd 36
mind that stenting cannot be used for the cervical esophagus. We
have been unimpressed with clips and stents and they may end up
only being an option for highly specialized centers and in patients
who otherwise would not be candidates for an operation. Endolu-
minal therapy is an interesting concept, but we must remember it
is a Grade D recommendation.
Recognition and diagnosis of esophageal perforation has some
common sense approaches using clinical judgment and existing
diagnostic studies. As usual for surgical conditions, our evidence
for what should be done is weak. All grades of recommendation
on this topic are C or D and the evidence level for the types of
intervention is Grade 4. Better answers may never be available.
However, the authors’ outline is good and allows the reader to fol-
low a logical path for dealing with a patient who has suffered an
esophageal perforation.
REFERENCES
1. Eloubeidi MA, Tamhane A, Lopes TL, Morgan DE, Cerfolio RJ.
Cervical esophageal perforations at the time of endoscopic ultra-
sound: a prospective evaluation of frequency, outcomes, and
patient management. Am J Gastroenterol. 2009;104(1):53-56.
2. Hilberath JN, Oakes DA, Shernan SK, Bulwer BE, D’Ambra MN,
Eltzschig HK. Safety of transesophageal echocardiography. J Am
Soc Echocardiogr. 2010;23(11):1115-1127.
3. Rueth N, Shaw D, Groth S, et al. Management of cervical esoph-
ageal injury after spinal surgery. Ann Thoracic Surg. 2010;90(4):
1128-1133.
4. van Heel NC, Haringsma J, Spaander MC, Bruno MJ, Kuipers EJ.
Short-term esophageal stenting in the management of benign
perforations. Am J Gastroenterol. 2010;105(7):1515-1520.
5/21/2012 7:48:25 PM

Achalasia and Esophageal Spasms
Achalasia and diff use esophageal spasm (DES) are uncommon
esophageal motility disorders in the general population. The inci-
dence of achalasia is 1 in 100,000 in the United States and the
prevalence of diff use esophageal spasm is 0.6% to 2.8% in patients
referred with chest pain.1,2
1. Can a diagnosis be made on clinical presentation of achala-
sia and diff use esophageal spasm?
Achalasia is known to involve any age group but most commonly
presents in patients between the ages of 25 and 60 years. It can be
primary or secondary. Primary achalasia is due to an idiopathic
disorder leading to degeneration of the myenteric plexus. Second-
ary achalasia can be caused by infection with the trypanosomal
disease known as Chagas disease. The diagnosis is often delayed
because of its insidious clinical presentation, which can be mis-
taken with other conditions such as reflux for years. A healthy
index of suspicion and a contrast esophagogram can be the initial
steps in the diagnosis of achalasia.
Dysphagia to solids and liquids (>90%) and regurgitation
(60%) are the two most common symptoms associated with
achalasia. A small subgroup of patients denies the presence of
dysphagia despite having radiographic and manometric features
consistent with achalasia. This may be attributed to impaired vis-
ceral sensation, the absence of primary and secondary peristalsis,
and the adaptation to chronic esophageal dilation.3,4 Other symp-
toms include chest pain (20%–60%), cough or choking, and hali-
tosis.4 Secondary symptoms like weight loss, fever, and respiratory
symptoms from aspiration can also coexist. Unlike achalasia,
chest pain is the most common presenting symptom in patients
with DES. DES can also be associated with dysphagia in some but
it is not as common as in achalasia, and it does not affect the gen-
eral condition of the patient like achalasia.
Even with careful history and physical examination, it can
be challenging to reach a certain diagnosis (Level 2 evidence with
Class B recommendation). This is because symptoms like chest pain
and discomfort should appropriately initiate workup of more severe
conditions such as cardiovascular disease. However, the result is
frequently a delay in the diagnosis of DES that can affect the quality
of life in these patients, even after a cardiac condition is treated.
37
PMPH_CH04.indd 37
CHAPTER 4
Kalyana C. Nandipati and Edward Lin
2. How can we diagnose both achalasia and DES. Is esophageal
function testing mandatory?
The commonly used investigations in the diagnosis are barium
swallow, endoscopy, esophageal manometry, and 24- or 48-hour
pH monitoring. Barium swallow is a good initial test for patients
with dysphagia. Absence of peristalsis or repetitive nonperistaltic
contractions that fail to propel the barium to the distal esophagus
and dilated esophagus are some of the common radiographic fea-
tures of achalasia. The classic “birds beak” (dilated esophagus with
sharp tapering at the Lower Esophageal sphincter [LES]) appear-
ance is seen late in the disease process. Sigmoid esophagus or
dilated and tortuous esophagus is also seen in advanced cases of
achalasia. The upper endoscopy is useful to differentiate between
true and pseudoachalasia. The main role of endoscopy is to exclude
malignant stricture, and biopsy can be obtained from the segment
of esophagus with any mucosal abnormality. In the diagnosis of
achalasia, endoscopy is sensitive in only up to 40% and esophago-
gram in up to 64% to 66%.5 Most of these features on barium swal-
low and endoscopy appear late in the disease process. Most of the
patients will be suffering from symptoms with subtle or no changes
in the prior investigations. Whenever available, esophageal func-
tion tests (EFTs) can help substantiate the diagnosis and initiate
management. The main advantages of manometry over radiogra-
phy are the ability to perform prolonged studies and quantify subtle
motor abnormalities in various regions of the esophagus. The clas-
sic manometric findings in patients with achalasia are absence of
peristalsis in the lower segment of esophagus and failed or incom-
plete relaxation of LES. Several manometric variants can exist in
achalasia. One such variation is vigorous achalasia, which is defined
by the presence of normal to high-amplitude esophageal body con-
tractions in the presence of a nonrelaxing LES. This entity is often
considered an early form of achalasia where some ganglion cells
are still present in the myenteric plexus of the esophagus. These
patients may initially respond well to botulinum injection until the
disease progresses to the more classic form. Other variants include
intact peristalsis with diminutive LES relaxation with degluti-
tion. The introduction of high-resolution manometry (HRM) has
led to more detailed characterization of achalasia, with distinct
manometric features that are beyond the scope of this discussion.6
5/21/2012 8:44:41 PM
 38 ■ Surgery: Evidence-Based Practice
It is unclear whether these unique manometric features and sub-
types of achalasia will eventually be useful to predict response to
surgical management. It is safe to conclude that achalasia can mani-
fest at any point in the disease spectrum.
Key features that differentiate DES from achalasia are the
presence of some peristaltic waveforms, normal LES resting
pressure and LES relaxation on swallowing. A criterion of 30%
or more peristaltic waveforms out of 10 wet swallows has been
used to differentiate DES from vigorous achalasia. The primary
diagnostic feature of DES is the presence of simultaneous con-
tractions of the distal esophageal smooth muscle, manifested as
“synchronous” pressure waves (>8 cm/s propagation) with a mini-
mum amplitude of 30 mmHg.7,8 This should be associated with
normal relaxation of LES at the same time, which is different from
achalasia patients with high LES pressures or nonrelaxing LES.
However, the manometric characteristics of DES can often mimic
or overlap features similar to other conditions. In the diagnosis
of achalasia and DES, it is more prudent to rely on a constellation
of symptoms and tests rather than any one single test. If there is
doubt, repeating studies at a later time may identify a trend and
allow the condition to declare itself. Manometry is essential and
key in the diagnosis of both achalasia and DES (Level 1 evidence
with Class A recommendation).
3. Who should undergo surgery for achalasia and DES?
The goals of treatment for achalasia include relief from dysphagia
and improving emptying of the esophagus by disrupting the LES
muscles as well as averting long-term complications like megae-
sophagus. Young patients respond best to early primary surgical
management of achalasia. However, with the availability of mini-
mally invasive surgery, laparoscopic myotomy has become the
primary treatment option for achalasia.
In contrast, medical management has been the primary treat-
ment for DES. The myotomy is beneficial in patients with hyperten-
sive LES and persistent symptoms despite medical management.
Patti et al. reported that dysphagia was relieved in 80% of DES
patients after thoracoscopic myotomy and in 86% of patients after
laparoscopic myotomy. Chest pain was relieved in 75% and 80%
of these patients, respectively. Regurgitation and heartburn scores
were also significantly improved after operation.9 Subsequent long-
term follow-up studies reported symptomatic improvement in up to
75% of patients after long myotomy for DES.10 Although myotomy
is not the initial treatment of choice for DES, the surgery provides
the best symptomatic improvement in patients with associated
chest pain (Level 2 to 3 evidence with Class B recommendation).
4. What nonsurgical treatment options are there for those with
achalasia and DES?
Medical and endoscopic treatments are commonly used for
nonsurgical treatment of achalasia. Endoscopic options include
pneumatic dilatation (PD) and botox injection. Recent experi-
mental work has been described for endoscopic myotomy as a
treatment for achalasia.
MEDICAL MANAGEMENT
Medical treatment is currently used in patients who are not suitable
for either surgical or endoscopic treatments. Nitrites, nifedipine
(calcium channel blocker), and sildenafi l (phosphodiesterase
PMPH_CH04.indd 38
inhibitor) are the commonly used drugs for medical treatment of
achalasia and DES. Pharmacological agents induce smooth mus-
cle relaxation intended to decrease LES pressure. Nitrites were the
first to be used more than six decades ago, but systemic vasodila-
tory effects and intolerable headaches limited their utility. Nife-
dipine has a better side-effect profi le when compared to nitrates.
Nifedipine is reported to decrease the LES pressure by 30% to
40% in the literature. However, placebo controlled trials reported
little clinical benefit.11 Sildenafil is a phosphodiesterase inhibitor
that is reported to decrease the LES pressure. The desired effect of
sildenafi l was short-lived, and no long-term outcome studies have
been performed to date.12 Medical treatment is associated with
certain side effects and only modest clinical benefit, so their util-
ity is limited to patients who are not suitable candidates for either
endoscopic or surgical intervention.
ENDOSCOPIC MANAGEMENT
Botulinum Toxin
Botulinum toxin (BT, Botox) is a potent inhibitor of acetylcholine
release from the nerve endings. It acts by inhibiting unopposed ace-
tylcholine stimulation at the LES to lower baseline sphincter pres-
sure. A placebo controlled trial reported symptomatic improvement
in 82% of patients who received BT injection compared with 10% of
those who received placebo.13,14 On long-term follow-up, the authors
reported that age greater than 50 years and the presence of vigor-
ous achalasia (esophageal body contractile amplitudes in excess of
40 mm Hg) are the two positive predictors of response to BT injec-
tion.15 Since the initial reports, several studies have been published
in the literature with variable response. The average response rate
with BT at 1 month was 78% (range, 63% to 90%), which later drops
to 58% (range, 25% to 78%) at 6 months and 49% (range, 15% to
64%) by 12 months.16-19 Randomized controlled trials comparing
BT with Heller myotomy reported significantly higher success rate
(34% vs. 87.5%) with myotomy after a 2-year follow-up.20 Studies also
reported that most of the patients required repeated injection and
the response to repeated injections decreases with each treatment.
Repeat injections have been associated with increased incidence of
fibrosis at the gastroesophageal (GE) junction. Surgical interven-
tion after repeated injections is associated with higher incidence of
mucosal injury.21 The adverse effects of BT include mild transient
chest pain and heartburn in up to 5% to 10% of patients.
The current role of BT is reserved for patients who are not
suitable for more invasive treatments with pneumatic dilation or
surgical myotomy. It can also be useful in patients with recurrence
after myotomy or dilatation.
Pneumatic Dilatation
Pneumatic dilatation (PD) is the most commonly used endoscopic
treatment option with reported success rates of 53% to 100%.
Randomized controlled trials comparing PD to botox reported
a significant better response rates with PD that range from 60%
to 95% compared to that of botox (26%–45%).22,23 Dilation can be
performed with endoscopy or under fluoroscopic guidance. The
Rigiflex pneumatic dilator (Boston Scientific, Boston, MA) is the
most widely used system for achalasia. The balloon is placed at
the GE junction and inflated to 8 to 15 pounds per square inch (psi)
and held in place for 15 to 60 s. These balloon dilators expand to
5/21/2012 8:44:42 PM

a 30- or 40-mm diameter. Some perform repeated dilatation over
a period of several weeks to achieve a final resting manometric
pressure below 10 to 15 mm Hg. Studies reported that more than a
third of patients do require repeated dilatations for symptomatic
recurrence over a period of 5 years. Young patients (<40 years),
male sex, and posttreatment LES pressure > 10 to 15 mmHg por-
tend higher incidence of recurrence after PD. This patient popula-
tion responds better with surgical management.
PD is associated with significant complications like perfora-
tion and reflux. The incidence of perforation is reported from 1%
to 8% with a mean of 2.8%. The incidence of perforation increases
in patients with previous botulinum injections, prior myotomy,
and in patients with vigorous achalasia. GE reflux is another sig-
nificant sequelae of pneumatic dilation. Prospective studies using
pH monitoring have diagnosed significant acid reflux in 25% to
35% of patients following dilitation.
PD might be a reasonable option for older patients and
patients with recurrence after myotomy. It may be an alterna-
tive treatment option to myotomy in selected patient population
(Level 1 evidence with Class A recommendation).
5. What is the best surgical approach and technique for Heller
cardiomyotomy?
In 1913, Heller first performed the myotomy through an open
abdominal approach. Over the next several decades, after several
modifications in the technique, Heller’s myotomy has become
the treatment of choice for achalasia. In his initial reports, he
performed an anterior and posterior myotomy through a lapa-
rotomy. Ellis et al. popularized the thoracic approach, in which
distal esophagomyotomy was performed through a left thoraco-
tomy with good success rate (60–94%).24,25 However, the inabil-
ity to extend the myotomy sufficiently onto the stomach, leaving
subhiatal LES intact has been associated with higher recurrence
rates. Therefore, a properly performed thoracic cardiomyotomy
requires delivering the gastric cardia into the chest to complete
the distal extent of the myotomy. The open thoracic approach is
also associated with higher postoperative morbidity. These limita-
tions make the open thoracotomy a less favorable primary surgical
approach. However, it is still useful to have this approach in the
armamentarium of esophageal surgeons, especially for patients
with extensive abdominal surgical history or recurrence after an
abdominal approach. In early 1990s, introduction of the laparo-
scopic approach has revolutionized the treatment of achalasia, and
it rapidly became the treatment of choice. The major advantages of
the laparoscopic approach are elimination of a thoracotomy, faster
recovery, and ability to extend the myotomy adequately onto the
stomach. Long-term studies with the follow-up of 10 years or more
reported success rate ranging from 87% to 93%.26 Studies compar-
ing myotomy with standard endoscopic treatment options report
significantly better long-term success rate with myotomy. Ran-
domized controlled trails reported a significant higher response
rate ranging from 85% to 95% with myotomy compared to the
PD.27,28 (Level 1 evidence with Class A recommendation).
SURGICAL TECHNIQUE
Preoperative Preparation
Presurgical preparations are standard for all patients undergo-
ing foregut surgery. One area that is often overlooked is the need
PMPH_CH04.indd 39
Achalasia and Esophageal Spasms ■ 39
for nutritional optimization in patients who are debilitated or
malnourished. For example, patients with vitamin K depletion
may have more intraoperative bleeding that may hinder visual-
ization during the myotomy. The patient is positioned supine on
the table either with a split leg or straight table. During induc-
tion of general anesthesia, care is taken to prevent aspiration.
Whether a Foley catheter is inserted is the surgeon’s preference.
An atraumatic liver retractor for the left lobe and the reverse
Trendlenburg position is often useful to gain exposure under the
diaphragm. A second generation cephalosporin is given before
the procedure. In addition to standard laparoscopic equipment,
atraumatic gaspers and a mechanical camera holder are helpful
adjuncts to surgery.
Trocar Placement
Trocar placement is variable from surgeon to surgeon. However,
trocar placement should maximize visualization and permit
adequate extension of the myotomy both cephalad and caudally.
We place the camera trocar in the mid epigastrium, with the two
operating trocars on each side of the subcostal margin in order to
form a baseball diamond—the home base being the GE junction
and second base being the camera trocar. An assistant trocar is
placed laterally along the left subcostal margin.
Mobilization of Stomach and Esophagus
The short gastric vessels are divided toward the angle of His
beginning at upper third or half of the greater curvature. Th is
can be accomplished most expeditiously with ultrasonic shears or
bipolar cautery. Once the angle of His is mobilized completely,
we divide the gastrohepatic ligament. The pillar of the right crus
is exposed and a tunnel is made posterior to the GE junction in
order to encircle the entire GE junction with a vessel loop or pen-
rose drain. The penrose drain is used to manipulate the esophagus
without directly handling the esophagus with graspers. We mobi-
lize phrenoesophageal membrane with blunt dissection. Follow-
ing the avascular mediastinal plane, the esophagus is mobilized
circumferentially. The anterior and posterior vagus are identified
and preserved at this point.
Myotomy
The myotomy itself can be made with blunt dissection, low energy
cautery attached to scissors, a hook cautery, ultrasonic shears, or
bipolar device. There is no need to employ multiple devices for a
myotomy and each surgeon uses the instrument that portends
the best outcomes in his or her hands. We use cautery to super-
ficially mark our myotomy path and blunt dissection to perform
the myotomy from the GE junction in a cephalad direction to
extend at least 6 to 9 cm above the squamocolumnar junction
(Z-line). The myotomy starts immediately above the GE junc-
tion on the esophagus because the mucosal layer is easiest to
identify at this level. To disrupt the muscle fibers, graspers are
used to gently elevate the esophageal muscle fibers off the bulg-
ing mucosa beneath. Once the cephalad dissection is completed,
we start our dissection toward squamocolumnar junction and
extend it approximately 3 cm onto the stomach. Oelschlager
and colleagues reported that extending 3 cm onto the stomach
instead of 1.5 cm reduces the lower esophageal sphincter pressure
5/21/2012 8:44:42 PM
 40 ■ Surgery: Evidence-Based Practice

and symptom recurrence without any increase in the incidence of
reflux.29 If an energy source is used to perform the myotomy, cau-
tion should be taken to avoid any energy contact with the muco-
sal aspect of the anterior esophagus or allowing heat to transmit
from a blood vessel down to the mucosal surface. Burn necrosis
may not be apparent at the time of surgery and can manifest as a
perforation 24 to 48 hours later.
Intraoperative endoscopy and manometry are the two differ-
ent techniques reported to be useful to assess the adequacy of a
myotomy. The endoscopic view can identify the squamocolumnar
junction precisely and is useful to assess the proximal and distal
extent of the myotomy. During insufflations, the mucosa is dis-
tended and any remaining circular fibers appearing as a “waist”
formation should be divided. We simply require the lower esoph-
ageal sphincter to open easily with endoscopic air insufflations to
be satisfied with the myotomy. If the GE junction fails to open
with air insufflations, the myotomy should be further extended
onto the stomach.30,31
Intraoperative manometry theoretically offers more func-
tional assessment of the GE junction and was initially used to
assess the adequacy of a fundoplication after myotomy. The
manometry probe is positioned before the operation and the posi-
tion is confirmed by doing intraoperative endoscopy. At the end
of the procedure, residual high-pressure zones are identified and
divided further.32-34 Initial studies were encouraging and showed
that up to 44% to 50% of patients required further myotomy on
the basis of manometry findings. However, there was increased
risk of mucosal injury and one series reported perforation in
three of five patients.35 Chapman et al. suggested that intraopera-
tive manometry is more useful in the initial part of the surgeon’s
experience.36 Studies so far reported that the incidence of postop-
erative dysphagia is comparable to the general literature without
manometry, raising questions regarding its usefulness. Although
intraoperative manometry is useful for research, we believe this
modality is cumbersome to perform, requires an additional setup
of delicate instruments in the operating room, and is time con-
suming compared to endoscopy that has the added advantage of
identifying leaks.
When a rent is identified at the site of the myotomy, repair is
performed with a fine absorbable suture in figure-of-eight fash-
ion. Biologic glues have been used to further buttress a repair but
the efficacies of adhesives are unknown.
With endoscopy, the GE junction is immersed under saline
irrigation and checked for air leaks with insufflation. Endoscopi-
cally, we look for bleeding or mucosal abnormalities that may sug-
gest mucosal injury. We close the hiatal opening posteriorly with
0-silk sutures and bioabsorbable pledgets, but other nonabsorb-
able sutures can also be used. The hiatus is intentionally left wider
than for antireflux surgery to minimize encroachment onto the
dilated esophagus above.
Fundoplication
The literature has divergent views regarding the need for fundopli-
cation after myotomy as well as the type of fundoplication. The
only randomized controlled trial reported that pathologic reflux
disease occurred in 10 of 21 patients (47.6%) after laparoscopic
Heller myotomy alone, but only 2 of 22 patients (9.1%) after Hel-
ler with a Dor fundoplication (P = .005).37 The initial experience
from our institution also revealed that regurgitation is relieved in
95% of the patients with a posterior partial fundoplication (i.e.,
the Toupet 270° fundoplication).38 These studies underscore the
importance of fundoplication after myotomy. The thoracic liter-
ature affirms the need for a fundoplication with the addition of

Table 4.1 Showing Results of Fundoplication after Myotomy

Author/Year Type of Study N F/U Type of Results/ Comments
(Mo) Fundoplication
Richards/200437 RCT 43 6 None (21) vs. Dor (22) GERD—47% (10/21) vs. 9.1%
(2/22) (P < .05)
Anselmino/199739 Prospective case series 38 12 Dor 5.7% (2/38) had abnormal
24-h pH study
Mattioli/2010 40 Database review 60 48 Dor (laparoscopic) 3.3% (2/60) had evidence of
esophagitis
Rebechi/200841 RCT 138 125 Dor (n = 71) vs. Nissen GERD—2.8% vs. 0% (P > .05)
(n = 67) Dysphagia—2.8 % vs. 15%
(P < .001)
Falkenback/200342 RCT 20 40 None (n = 10) vs Nissen GERD—13.1 % (4/10) vs .15%
(n = 10) Nissen group—1 dysphagia
Oelschlager/200329 Database review 110 Standard myotomy + Dysphagia—17 % (9/52) vs. 3%
Dor (n = 52) vs. (2/58) (P < .05)
Extended myotomy +
Toupet (n = 58)
Perrone/2004 43 Retrospective 100 26 Toupet GERD—1/100
Dysphagia—4/100
Ortiz/2008 44 Retrospective 33 10 years Toupet 75% response rate
GERD—24%
RCT—randomized controlled trials; GERD—gastroesophageal reflux disease.

PMPH_CH04.indd 40 5/21/2012 8:44:42 PM


Figure 4.1 Myotomy with Toupet fundoplication.
the Belsey procedure after a cardiomyotomy. Currently, two types
of fundoplications are performed following a Heller myotomy:
anterior Dor fundoplication or posterior Toupet fundoplication.
The Nissen fundoplication is far less commonly performed after a
myotomy to avoid dysphagia (Table 4.1).
In a Dor fundoplication, the fundus was brought over the
myotomy and anchored to the left muscular edge of the myotomy
with 2-0 silk sutures. Then fundus is rotated over the myotomy
toward the right pillar. Two to three sutures are placed on the
right crural pillar in interrupted fashion. The uppermost suture
includes gastric fundus and the right crus. The rest of the sutures
are placed between stomach and edge of myotomy. As an addi-
tional buttress against mucosal disruptions, the Dor fundoplica-
tion is also preferable if a mucosal rent is repaired.
In a Toupet fundoplication, the fundus is delivered pos-
teriorly around the space between the gastric cardia and the
aorta. Interrupted 2-0 silk sutures are placed from the stomach
to the muscular edge of the myotomy on the right and left side
(Figure 4.1). The anterior aspect of the myotomy is exposed.
After the fundoplication is completed, we repeat another
endoscopy to ensure the wrap is in good position and that no inju-
ries are created during the suturing. We routinely use a pedicle of
omental flap to cover the exposed “belly” of the myotomy to mini-
mize any adhesions to the liver surface and serve as an additional
buttress. However, there is no data that an omental patch leads to
better outcomes than leaving the myotomy completely exposed.
6. What is the postsurgical management for patients who have
had cardiomyotomy?
Postoperative Care
Patients typically recover in standard hospital rooms. Pain con-
trol is treated with intravenous narcotic medications as needed.
A gastrograffin swallow study can be performed on postoperative
day 1 at the surgeon’s discretion. The aim of the esophagogram
is primarily to ascertain contrast flow. We find that a contrast
esophagogram may not necessarily identify leaks, and reliance on
signs of early sepsis gives a better prediction of leaks. Clear liquid
diet is started on postoperative day 1. Patients are discharged on
postoperative day 1 if they tolerate clear liquids. Postoperative diet
PMPH_CH04.indd 41
Achalasia and Esophageal Spasms ■ 41
consists of liquids advancing to soft diet for prescribed periods.
How fast diet is advanced is also variable from surgeon to sur-
geon, which can span from 1 to 4 weeks. We generally recommend
an upper endoscopy in 6 to 12 months to examine the esopha-
geal mucosa, which is often difficult to do before surgery when the
lumen is filled with debris.
7. When is esophagectomy indicated for achalasia?
Esophagectomy has been a treatment for long-term achalasia with
severely dilated esophagus also known as sigmoid esophagus.
The University of Michigan reported that 63% of patients with
failed myotomy underwent esophagectomy with good functional
results.45 However, the reported mortality after esophagectomy for
achalasia ranges from 2% to 4%.45,46 Subsequent reports showed
that myotomy relieved dysphagia in a significant portion of
patients with sigmoid esophagus, avoiding an esophagectomy.47-49
For end-stage achalasia, defined as a massively dilated and tortu-
ous esophagus, an esophagectomy may be the only option (Level
2-4 evidence and Class B recommendation). Options for recon-
struction may include a gastric pull-up into the chest, or a colonic
interposition.
8. Treatment options for patients who have failed cardio-
myotomy?
Recurrent dysphagia after cardiomyotomy occurs in 10% to 20%
depending on the length of follow-up. Recurrence after myo-
tomy is a difficult problem if there is no response to additional
dilation therapy. The causes of recurrence includes an incom-
plete myotomy at the time of primary surgery, adhesions, a tight
fundoplication, an esophageal diverticulum, or reflux-induced
strictures.50,51 Failure to extend the myotomy adequately on to
the stomach is the most common cause of recurrent dysphagia.
Mattioli et al. reported that at least 1.5-cm extension onto the
stomach is essential for complete relaxation of the LES.52 Later
reports from Oelschlager et al. recommended that a 3-cm exten-
sion is associated with better symptomatic outcome and lower
recurrence rate.29 Extension on the stomach is difficult due to
the fact that the plane between the submucosa and the muscle
layer is less evident and bleeding is more likely. Patients with
sigmoid esophagus or terminally dilated esophagus preopera-
tively also have higher recurrence of dysphagia after myotomy.
However, this should not deter the surgeons from performing a
myotomy because it is still less invasive a treatment compared to
an esophagectomy. In patients with persistent or recurrent symp-
toms, barium swallow, endoscopy, manometry, and pH monitor-
ing should be repeated.
Treatment options for failed myotomy include endoscopic
dilatation, BT injection, repeat myotomy, and esophagectomy.
The decision to perform a reoperation is influenced by the eti-
ology of recurrence, the patient’s general condition, and time of
recurrence. Early recurrences are better treated with endoscopic
interventions like PD or botox injection.51 PD is reported to have
success rates up to 80% in patients with recurrent dysphagia. PD
for early recurrence should be done with great caution as it has a
higher chance of perforation. Use of low-pressure balloons for ini-
tial dilatation and gradually increasing the pressure in subsequent
dilatations are the key to avoiding complication perforation. Sev-
eral studies show that recurrent achalasia can be treated surgically
with redo myotomy in suitable patients with success rates ranging
from 70% to 85%.53,54
5/21/2012 8:44:42 PM
 42 ■ Surgery: Evidence-Based Practice

In patients who have failed myotomy, a final attempt at promot-
ing esophageal emptying is to perform a longitudinal esophagogas-
trostomy where a linear cutting stapler is deployed intraluminally
at the angle of His, creating a wider aperture at the lower esophageal
sphincter. This is best accomplished laparoscopically by creating an
anterior gastrotomy and passing a laparoscopic cutting stapler into
the GE lumen. This is a nonphysiologic operation and will certainly
worsen reflux. Although this procedure has been described by
Heyrovsky and Barrett several decades earlier, it should be viewed as
an option of last resort. In these patients, who are frequently debili-
tated, a feeding tube and supportive care may be the best options.
PD is the primary and first-line treatment option for patients
with failed myotomy. Other alternative option is botox injec-
tion. Redo myotomy was also reported to have good outcome in
selected patients in experienced hands. (Level 3 to 4 evidence with
Class C recommendation.)

Clinical Question Summary

Question
1 Can diagnosis made on the
clinical presentation of achalasia
and diffuse esophageal spasm?
2 How can we diagnose
both achalasia and DES. Is
esophageal function testing
mandatory?
3 Who should undergo surgery
for achalasia and DES?
4 What nonsurgical treatment
options are there for those
with achalasia and DES?
5 What is the best surgical
approach and technique for
Heller cardiomyotomy?
6 What is the postsurgical
management for patients who
have had cardiomyotomy?
7 When is esophagectomy
indicated for achalasia?
8 What are the treatment options
for patients who have failed
cardiomyotomy?
Answer Levels of Grade of References
Evidence Recommendation
Clinical features are often nonspecific and 2-3 B 1-5
investigations are necessary for the
diagnosis.
Esophagogram, endoscopy, and 1-3 A 6-8
manometry are useful in the diagnosis
of achalasia. Manometry is not only
useful for the diagnosis but also guide
the treatment and follow-up.
Surgery has been the primary 1-3 A 9-10
treatment of choice for achalasia.
All symptomatic patients should be
offered surgical treatment option for
long-term benefit.
Medical and endoscopic treatments 1-2 A 11-23
(botox and dilatation) are two
nonsurgical treatment options for
achalasia. Dilatation reported long-
term symptomatic relief compared
to the botox injections. However,
repeated dilatations are necessary for
long-term relief.
Heller’s myotomy has been the treatment 1-3 A 24-38
of choice for achalasia. Fundoplication
is reported to decrease the incidence
of reflux.
Surveillance endoscopy to check for 3 C 39-44
mucosal abnormality.
Esophagectomy is considered as an 2-3 B 45-49
option in severely dilated and end-
stage achalasia.
Endoscopic treatment options like 3-4 C 50-54
dilatation or botox injections are
main treatment options for patients
who failed or had recurrence after
myotomy. Redo myotomy is also
reported to be successful in selected
series in experienced hands.

PMPH_CH04.indd 42 5/21/2012 8:44:43 PM


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1984;147(1):171-174.
35. Tatum RP, Kahrilas PJ, Manka M, Joehl RJ. Operative manom-
etry and endoscopy during laparoscopic Heller myotomy. An
initial experience. Surg Endosc. 1999;13(10):1015-1020.
36. Chapman JR, Joehl RJ, Murayama KM, Tatum RP, Shi G,
Hirano I, et al. Achalasia treatment: improved outcome of laparo-
scopic myotomy with operative manometry. Arch Surg. 2004;139(5):
508-513; discussion 513.
37. Richards WO, Torquati A, Holzman MD, Khaitan L, Byrne D,
Lutfi R, Sharp KW. Heller myotomy versus Heller myotomy
with Dor fundoplication for achalasia: a prospective random-
ized double-blind clinical trial. Ann Surg. 2004;240(3):405-412;
discussion 412-415.
38. Hunter JG, Trus TL, Branum GD, Waring JP. Laparoscopic
Heller myotomy and fundoplication for achalasia. Ann Surg.
1997;225(6):655-664; discussion 664-665.
39. Anselmino M, Zaninotto G, Costantini M, Rossi M, Boccu C,
Molena D, et al. One-year follow-up after laparoscopic Heller-Dor
operation for esophageal achalasia. Surg Endosc. 1997;11(1):3-7.
40. Mattioli S, Ruffato A, Lugaresi M, Pilotti V, Aramini B,
D’Ovidio F. Long-term results of the Heller-Dor operation with
intraoperative manometry for the treatment of esophageal acha-
lasia. J Thorac Cardiovasc Surg. 2010;140(5):962-969.
5/21/2012 8:44:43 PM
 44 ■ Surgery: Evidence-Based Practice
41. Rebecchi F, Giaccone C, Farinella E, Campaci R, Morino M.
Randomized controlled trial of laparoscopic Heller myotomy
plus Dor fundoplication versus Nissen fundoplication for acha-
lasia: long-term results. Ann Surg. 2008;248(6):1023-1030.
42. Falkenback D, Johansson J, Oberg S, Kjellin A, Wenner J,
Zilling T, et al. Heller’s esophagomyotomy with or without a 360
degrees floppy Nissen fundoplication for achalasia. Long-term
results from a prospective randomized study. Dis Esophagus.
2003;16(4):284-290.
43. Perrone JM, Frisella MM, Desai KM, Soper NJ. Results of lap-
aroscopic Heller-Toupet operation for achalasia. Surg Endosc.
2004;18(11):1565-1571.
44. Ortiz A, de Haro LF, Parrilla P, Lage A, Perez D, Munitiz V,
et al. Very long-term objective evaluation of heller myotomy plus
posterior partial fundoplication in patients with achalasia of the
cardia. Ann Surg. 2008;247(2):258-264.
45. Devaney EJ, Iannettoni MD, Orringer MB, Marshall B. Esophagec-
tomy for achalasia: patient selection and clinical experience. Ann
Thorac Surg. 2001;72(3):854-858.
46. Ellis FH, Jr. Esophagectomy for achalasia: who, when, and how
much? Ann Thorac Surg. 1989;47(3):334-335.
47. Patti MG, Feo CV, Diener U, Tamburini A, Arcerito M, Safadi
B, et al. Laparoscopic Heller myotomy relieves dysphagia in
achalasia when the esophagus is dilated. Surg Endosc. 1999;13(9):
843-847.
PMPH_CH04.indd 44
48. Mineo TC, Ambrogi V. Long-term results and quality of life after
surgery for oesophageal achalasia: one surgeon’s experience. Eur
J Cardiothorac Surg. 2004;25(6):1089-1096.
49. Eldaif SM, Mutrie CJ, Rutledge WC, Lin E, Force SD, Miller JI,
Jr, et al. The risk of esophageal resection after esophagomyotomy
for achalasia. Ann Thorac Surg. 2009;87(5):1558-1562; discussion
1562-1563.
50. Ellis FH, Jr. Failure after esophagomyotomy for esophageal motor
disorders. Causes, prevention, and management. Chest Surg Clin
N Am. 1997;7(3):477-487; discussion 488.
51. Zaninotto G, Costantini M, Portale, G, ZBattaglia G, Molena D,
Carta A, et al. Etiology, diagnosis, and treatment of failures
after laparoscopic Heller myotomy for achalasia. Ann Surg.
2002;235(2):186-192.
52. Mattioli S, Pilotti V, Felice V, Di Simone MP, D’Ovidio F, Goz-
zetti G. Intraoperative study on the relationship between the
lower esophageal sphincter pressure and the muscular compo-
nents of the gastro-esophageal junction in achalasic patients.
Ann Surg. 1993;218(5):635-639.
53. Wang L, Li YM, Li L, Yu CH. A systematic review and meta-
analysis of the Chinese literature for the treatment of achalasia.
World J Gastroenterol. 2008;14(38):5900-5906.
54. Iqbal A, Tierney B, Haider M, Salinas VK, Karu A, Turaqa KK,
et al. Laparoscopic re-operation for failed Heller myotomy. Dis
Esophagus. 2006;19(3):193-199.
5/21/2012 8:44:43 PM

Esophageal Diverticula
G. Travis Clifton and Jonathan B. Lundy
BACKGROUND/OVERVIEW
Esophageal diverticula are outpouchings of the esophagus that
tend to occur in predictable patterns. Esophageal diverticula are
most frequently divided into three subgroups: pharyngoesopha-
geal diverticula, esophageal body pulsion diverticula, and traction
diverticula. Although they are relatively uncommon, these diver-
ticula can cause severe and even life-threatening complications.
Like much of surgery, more recent developments in the treatment
of esophageal diverticula have focused on addressing diverticula
through endoscopic or minimally invasive techniques to lessen
the morbidity (and mortality) associated with treatment in this
often elderly patient population. Controversy remains about what
the optimal surgical techniques are to address pharyngoesopha-
geal diverticula and pulsion diverticula. Unfortunately, because
of the low incidence of these conditions, there is no randomized
data and very little controlled data for the treatment of esopha-
geal diverticula. Fortunately, in spite of controversies, the exist-
ing literature shows that symptomatic esophageal diverticula can
be treated with a high rate of symptomatic improvement and low
morbidity and mortality.
PHARYNGOESOPHOGEAL DIVERTICULA
Overview
Pharyngoesophageal diverticula are relatively rare conditions. The
reported prevalence of Zenker’s diverticula, the most common
pharyngoesophageal diverticula, is between 0.01% and 0.11% in
the general population with an incidence of 2/100,000 people per
year in the United Kingdom.1-4 The ethnic and geographic differ-
ences in pharyngoesophageal diverticula prevalence are not clear.
In all likelihood, the prevalence is increasing as life expectancies
increase and populations age, as the incidence clearly increases with
age. A typical presentation is in the seventh or eighth decades of
life.1 Zenker’s pharyngoesophageal diverticula are more common
in men than women. There is a more than 2:1 ratio (416 men, 153
45
PMPH_CH05.indd 45
CHAPTER 5
women) of men to women in the trials summarized in Table 5.1.5-8
Killian-Jamieson diverticula are rare lateral pharyngoesophageal
diverticula that are distinct from the more common Zenker’s diver-
ticula (ZD). The incidence is not clear, but is much less common
than ZD with only a few case reports in the literature.9-11
Pharyngoesophageal diverticula most commonly refer to ZD.
A ZD, first described in 1769 by Ludow and further character-
ized by Zenker in 1778, is a pseudodiverticular herniation of the
esophageal mucosa through Killean’s triangle, which is a potential
area of weakness in the posterior hypopharynx.12-14 Killean’s tri-
angle is composed of the cricopharyngeus muscle inferiorly and
the inferior pharyngeal constrictor muscles laterally and superiorly.
Although there is some disagreement, the pathogenesis seems to
center on dysfunction of the cricopharyngeus, the key component
of the upper esophageal sphincter (UES), causing high intrabolus
food pressures that result in posterior herniation and progressive
enlargement of the diverticula. This is supported by findings of high
intrabolus pressures in patients with ZD; relief of symptoms and
drop in these pressures after appropriate treatment; and recurrence
or persistence of the diverticulum with persistence of high intra-
bolus UES pressures due to incomplete cricopharyngeal myotomy.
The cause of UES dysfunction is the subject of some controversy
with some reporting mistimed relaxation and contraction of the
UES, cricopharyngeal spasm, or cricopharyngeal hypertrophy.
There are conflicting reports of manometric findings, with some
reporting abnormalities, whereas others have found normal mano-
metric findings; however, mistimed contraction of the cricopha-
ryngeus can be demonstrated with videofluoroscopic studies.20-27
The assertion that the UES abnormalities are caused by refluxing
low pH gastric contents, as suggested by Hunt, has not been dem-
onstrated in subsequent studies.1,8,28 In addition, some people may
have a genetic or anatomic predisposition to developing a ZD, as an
autopsy study demonstrated an anatomic Killean’s triangle present
in 60% (9/15) of men and 34% (11/32) of women, which may explain
the asymmetric increased prevalence in men.14
Killean-Jamieson diverticula occur through an anatomic
weakness inferior to the cricopharyngeus muscle and superior-
lateral to the longitudinal muscle of the esophagus. The etiology of
5/21/2012 8:28:49 PM
PMPH_CH05.indd 46
Table 5.1 Single Institution Retrospective Case-Control Series Comparing Open Surgical Management and Endoscopic Stapled Diverticulotomy
Author, Year (Ref) Method Number of Operative Conversion Complication Leak Recurrence Unsatisfactory Follow-Up Time to Hospital
Patients Time to Open Rate Rate Rate‡ Results (Months) Resumption Stay
of PO (Days) (Days)
Wirth, 2006 (5)† Stapled 20 32 13% (1/23) 10.0% 5.0% 5% 10% 1 5.5
41.5
Open 27 106 - 7.4% 7.4% 3.70% 7.40% 5 12.3
Bonivina, 2007 (8)† Stapled 181 19 4.4% (8/181) 1.1% 0.0% 4.40% 8% 27 1 n/a
Open 116 70 - 1.6% 1.7% 1.70% 6% 48 2 n/a

46
Morse, 2006 (7)†,* Stapled 28 94 14% (4/28) 3.6% 0.0% 0 * 1.3 2.1
17
Open 19 141 - 5.3% 0.0% 0 * 1.3 2.4
Rizetto, 2008 (6)*** Stapled 51 31 3.9% (2/51) 5.8% 0.0% 21.50% 6.50%** n/a 5
40
Open 77 80 10.4% 10.4% 5.50% 4%** n/a 9
† Excluded diverticula <2 to 3 cm from the endoscopic arm of treatment.
‡ Recurrence defined as persistent or recurrence of symptoms or radiographic recurrence of the diverticulum.
* Results reported as mean dysphagia score, pre- and postoperatively. Scores improved significantly in both endoscopic and open groups after surgery
without a significant difference between the groups.
** Reflects long-term dissatisfaction after recurrent or persistent symptoms had been addressed with additional procedures as indicated.
*** Recurrence rate significantly higher in after endoscopic treatment for diverticula ≤3 cm (36%, 9/25) compared to diverticula >3 cm (8%, 2/26), P < .05.

5/21/2012 8:28:49 PM

this diverticulum is not clear and may be congenital or an acquired
pulsion diverticulum.10,11
1. What are the symptoms associated with ZD?
The symptom most commonly experienced by patients with ZD
is dysphagia. In the series listed in Table 5.1 that reported symp-
tom frequencies, virtually all patients experienced some degree
of dysphagia when carefully questioned.5-8 The dysphagia from
Zenker’s diverticulum is thought to be due to dysfunction of the
UES, extrinsic compression of the esophagus from the diverticu-
lum, or both. Additional symptoms associated with ZD include
regurgitation of undigested food, a feeling of a globus in the neck
(particularly with swallowing), cough, aspiration pneumonia,
and weight loss.5-8,18,20,29-34 There is suggestion in some studies that
symptoms other than dysphagia are more likely with larger diver-
ticula.35 Often patients have coped with symptoms for years or
even decades prior to having the diagnosis established.36 Various
degrees of weight loss and cachexia, which can be substantial and
even life threatening, are often present.36 Less commonly, ZD can
present as an acute upper gastrointestinal (GI) bleed due to ulcer-
ation or esophageal varices.37 In addition, there are case reports of
squamous cell carcinoma arising in ZD, so-called Zenker’s car-
cinoma, which is postulated to be due to chronic inflammation
from impacted food within the diverticulum.38 Killiean-Jamieson
diverticula present with symptoms similar to ZD.11
The symptoms associated with Zenker’s diverticulum are
dysphagia, regurgitation of undigested food, globus sensation in
the neck (particularly with swallowing), cough, aspiration, pneu-
monia, and weight loss (Grade C).
2. What workup is necessary for a known or suspected ZD?
When there is concern or suspicion of a ZD based on symptoms,
the workup should include a barium swallow with or without
videofluorographic images that include lateral views. This study
both confirms the presence of the diverticulum and defines the
anatomy that may influence the surgical approach.1 Some experts
recommend upper endoscopy of the diverticulum and esophagus
due to the occasional finding of varices or carcinoma within the
diverticulum and relative frequency of other pathology within
the esophagus.1,5 Endoscopic evaluations should be performed
by an experienced endoscopist given the difficulty intubating the
diverticulum and risk of perforation.38 Upper esophageal manom-
etry is not necessary in the evaluation of a first Zenker’s diver-
ticulum, particularly given that a variety of findings have been
demonstrated.20-27 The possible exception to this is evaluating
recurrent or persistent dysphagia after open or endoscopic cri-
copharyngeal myotomy that may reveal persistently elevated UES
tone or high intrabolus pressures with an incomplete myotomy.6
Zenker’s diverticulum is best evaluated by videofluorographic
contrast swallow study and endoscopy (Grade C). Upper esopha-
geal manometry may be beneficial, although there are divergent
opinions on its importance (Grade D).
3. What are the treatment options for ZD?
The natural history of asymptomatic pharyngoesophageal diver-
ticula is unclear. ZD typically present at an advanced age in
patients who often have multiple comorbidities. It would seem
reasonable to observe a patient without symptoms after a detailed
history and physical examination but this has not been adequately
studied due to the relative infrequency of incidentally discovered
PMPH_CH05.indd 47
Esophageal Diverticula ■ 47
ZD.1 There are multiple procedures described for treating ZD.
These procedures include open cricopharyngeal myotomy alone;
open cricopharyngeal myotomy with diverticulopexy or diverti-
culectomy; rigid endoscopic stapled diverticulotomy; and flexible
endoscopic diverticulotomy though various techniques.
Open surgical management of a ZD through a cervical inci-
sion is safe and effective at relieving dysphagia associated with ZD,
according to available case series and case-control studies.5-8,35,39
The evidence suggests that performing a cricopharyngeal myo-
tomy is a necessary portion of the operation as a diverticulectomy
without myotomy, as had been historically performed, leads to an
unacceptably high rate of recurrence of the diverticulum and or
dysphagia or persistence of dysphagia symptoms.6,35,40-43 Cricopha-
ryngeal mytotomy alone may be sufficient in patients with smaller
diverticula (<2–3 cm) in relieving dysphagia.35 For larger divertic-
ula, a diverticulopexy or diverticulectomy is necessary to elimi-
nate accumulation of food within the diverticulum remnant.35,39
A diverticulopexy is performed by suturing the diverticulum to
the prevertebral fascia so that food does not collect into the diver-
ticulum. Diverticulectomy can be accomplished with a stapler or
a sutured closure in layers.44
Rigid endoscopic management of ZD involves transoral visu-
alization via a rigid endoscope (Weerda diverticuloscope) and
division of the common wall of the esophagus and diverticulum
(posterior wall of the esophagus and anterior wall of the diverticu-
lum; diverticulotomy). In diverticula of sufficient length, division
of this wall also divides the cricopharyngeus muscle allowing for
simultaneous cricopharyngeal myotomy and creation of a common
channel to prevent accumulation of food within the diverticulum.
This technique of dividing the common wall was first described by
Mosher in 1917, although he later abandoned the technique report-
edly after a patient died of mediastinitis which, before the era of
modern antibiotics, was a devastating complication.36,45 Since then,
the technique has been refined with the use of linear cutting staplers
introduced by Collard in 1993.46 Endoscopic linear cutting staplers
have the advantage of reliably sealing the divided esophageal and
diverticular walls together to decrease the risk of leakage. Others
have reported performing the endoscopic diverticulotomy with a
CO2 laser, and, more recently, harmonic scalpel.30,36,47
More recently, there have been several case series report-
ing flexible endoscopic diverticulotomy for the treatment of ZD.
The procedure, in principle, is similar to rigid endoscopic diver-
ticulotomy. Using a flexible endoscope, the common wall of the
posterior esophagus and diverticulum are divided using needle-
knife electrocautery or argon plasma coagulation.48-51 Tang et al.
have reported their experience using endoscopic clips to seal the
divided walls.50
Treatment of Killean-Jamieson diverticula typically consists
of open surgical diverticulectomy with and without esophageal
myotomy, although one case of endoscopic distal diverticulotomy
has been described.9-11 Whichever technique is used, care must be
taken to avoid injury to the recurrent laryngeal nerve that enters
the pharynx adjacent to the base of the diverticulum.
Treatment options for ZD include open surgical management
(cricopharyngeal myotomy, with or without diverticulectomy or
diverticulopexy and rigid or flexible endoscopic diverticulotomy)
(Grade B).
4. What is the optimal intervention for ZD?
Unfortunately, there have not been randomized trials compar-
ing the treatment of ZD using the various techniques described.
5/21/2012 8:28:49 PM
 48 ■ Surgery: Evidence-Based Practice
It is evident from the relatively robust experience reported in
the literature that treatment of ZD, despite being in an elderly
population with significant comorbidities, can be accomplished
safely with generally excellent results; for example, all series in
Table 5.1 report complete resolution of dysphagia or significant
improvement in >80%, and most >90%, of patients. In addition,
serious complication rates and recurrence rates generally remain
low, regardless of the technique used.5-8,18,20,29-36,39,40,46-50
Comparing the risks and benefits of the various treatment
methods for ZD is problematic given the current literature. First,
there is a diverse set of techniques used to treat ZD, which are being
performed at centers with various levels of experience with most
of the experience reported as case series. Next, in published case-
control series, when two procedures are directly compared, there
is naturally some selection bias in these nonrandomized trials, and
often the selection criteria for the different procedures are not clear.
There is also discrepancy among authors regarding what consti-
tutes a complication, as well as the definition of recurrence (recur-
rent dysphagia vs. radiographic recurrence of a diverticulum). In
addition, there is wide variability in the postoperative management
based on institutional or individual experience. Specifically, there is
variability in the need for a postoperative swallow study, the timing
of resumption of oral feeds, and the length of inpatient observation,
if any, needed after treatment.5-8,18,20,29-34,39-40,46-50
Regardless of the technique used, patients have a risk of leak-
age of enteral contents outside of the esophagus, persistence or
recurrence of symptoms, and complications of comorbidities
common in this patient population. Leakage occurs after endo-
scopic management from missed perforation of the diverticulum
by instruments or leakage through the sides of the diverticulo-
tomy incision. The risk of leakage may be increased in techniques
that do not as reliably seal the sides of the diverticulotomy inci-
sion, such as needle-knife palitome or CO2 laser.36,48,52-55 The use of
a harmonic scalpel has promising initial results but needs further
validation.30,47 In open surgery, leakage typically occurs through
the staple or suture line and can lead to a salivary fistula.
Persistence of dysphagia or recurrence of the diverticulum is
often due to incomplete cricopharyngeal myotomy.6,56 This is of
particular concern in patients being considered for endoscopic
management with small diverticula. Many authors consider
a diverticulum of less than 2 to 3 cm a formal contraindication
to endoscopic management because dividing the short common
esophageal-diverticular wall may lead to an inadequate cricopha-
ryngeal myotomy.5,8,57 This high recurrence/persistence rate is
demonstrated in the retrospective case-control series by Rizzetto
et al. and Bonavina et al. (Table 5.1), comparing open and endo-
scopic management and has been seen in other case series as
well.6,58 Rizzetto’s results demonstrated that in patients managed
with rigid endoscopic stapled diverticulotomy, there were persis-
tent symptoms of dysphagia in 36% (9/25) patients with diverticula
<3 cm, compared to 8% (2/26) with diverticula >3 cm.6 Bonavina’s
results demonstrated that 50% (4/8) of patients with diverticula
<3 cm treated with endoscopic stapled diverticulotomy were symp-
tomatic at 5-year follow-up, compared to 6.4% (3/47) with diver-
ticula >3 cm.8 In the other two series in Table 5.1, a diverticulum
of <2 to 3 cm was a contraindication to endoscopic management.5,7
There are reports of using stay sutures to retract the common wall
cephalad, which, in addition to making it easier to seat the stapler
in place, may make the cricopharygeal myotomy more effective in
small diverticula.7,59
Endoscopic techniques have the advantages of no inci-
sion and not requiring a neck dissection. Th is decreases the
PMPH_CH05.indd 48
risk of postoperative wound complications, neck hematoma,
salivary fistula, and laryngeal nerve injury. Th is may be par-
ticularly important in patients with a recurrent ZD after open
surgery or in patients with prior neck surgery or radiation, who
are at higher risk of these complications, particularly recur-
rent laryngeal nerve injury. However, surgeons performing
rigid endoscopic diverticulectomy should be proficient at open
operative management as conversion to open is not uncommon
(4%–13%). 5-8,18,29,31,36,58,59,60 The reasons for converting an endo-
scopic case to open are most frequently inability to adequately
extend the neck, inability to adequately visualize the diverticu-
lum or common wall between the diverticulum and the esoph-
agus, perforation of the diverticulum by the laryngoscope or
stapler, and inability to adequately introduce the stapler into
small diverticula. 5-8,18,29,31,36,58,59,60 In addition, rigid endoscopic
techniques have a risk of dental trauma secondary to passing
instruments through the mouth.8,36,21
One of the more frequently cited benefits of endoscopic man-
agement is decreased operative time with all studies that reported
this data in Table 5.1 taking between 20 and 94 min to complete
the operation on average compared to 70 to 141 min in the open
cases (Table 5.1).5-8 In addition, most authors performing endo-
scopic management reported quicker resumption of oral feeds
and decreased hospital stay (and therefore decreased hospital
costs), with some performing the procedure on an outpatient
basis. However, as previously stated, there is wide variability in the
postoperative management of patients. With endoscopic diver-
ticulotomy, most authors resume a liquid or soft diet the day of
surgery or postoperative day 1 with or without a contrasted swal-
low study.5,7,8,21,29,32,60,61 Most surgeons performing open cricopha-
ryngeal myotomy with diverticulectomy wait longer (2–5 days)
to allow healing of the diverticulectomy suture or staple line.5,8,61
To our knowledge, there is no data to show the postoperative nil-
per-os period, if any, that is appropriate after diverticulectomy.
However, after open cricopharyngeal myotomy alone or with
diverticulopexy, where there is no mucosal violation, it is likely
safe to resume per-os intake shortly after surgery. In Lerut et al.’s
retrospective series of 289 patients treated primarily with open
CP myotomy with diverticulopexy, patients are routinely fed after
a contrasted swallow study on postoperative day 1, and excellent
results were reported.39
Flexible endoscopic techniques have the advantages of allow-
ing endoscopic management in patients who have inadequate
mouth opening or neck extension. In addition, they can be per-
formed under conscious sedation.34,62 Currently, the described
techniques use eletrocautery or plasma argon to seal the divided
walls of the diverticular common wall that may have a higher
rate of leakage.36,48,52-55 There may be a role for flexible endoscopic
therapy in select patients who have a hostile neck and anatomy not
suitable for rigid endoscopic management or patients who are felt
to be unsuitable candidates for general anesthesia.62
For the treatment of ZD, cricopharyngeal myotomy (whether
open or endoscopic) decreases persistence or recurrence of
symptoms compared to open diverticulectomy alone (Grade C).
Open surgical management (cricopharyngeal myotomy with or
without diverticulectomy or diverticulopexy) and rigid endo-
scopic stapling both produce acceptable outcomes (Grade C).
Rigid endoscopic management may allow shorter operative
times compared to open surgical management (Grade B), and
it may allow for quicker resumption of oral feeds and shorter
length of stay compared to open diverticulectomy (Grade D).
Endoscopic diverticulectomy of small diverticula (<3 cm) may
5/21/2012 8:28:49 PM

have higher persistence or recurrence of symptoms compared to
open surgical management (Grade C). Flexible endoscopic (non-
stapled) diverticulostomy can be performed in patients who are
not candidates for rigid endoscopic diverticulostomy but may
have a higher leak rate (Grade C).
EPIPHRENIC DIVERTICU1A
Overview
Thoracic pulsion diverticula, often called epiphrenic diverticula,
are rare conditions. The true prevalence of these diverticula is
unclear as they are often asymptomatic and discovered inciden-
tally on imaging studies. The estimated prevalence varies widely
and has been estimated between 0.015% and 2% of the popula-
tion depending on the population studied.63-65 They are seen in
less than 1% of EGDs but in as many as 3% of EGDs performed for
dysphagia.66 The diverticula have peak incidence in the sixth and
seventh decade and may be more common in men.67
Thoracic pulsion diverticula typically occur within 10 cm of
the gastroesophageal junction and, thus, are commonly referred to
as epiphrenic diverticula.68,69 They can occur more proximally in
the esophagus, although this is rare.70,71 There are multiple diver-
ticula in up to 10% to 15% of cases.72-76 It is generally believed that
an underlying esophageal motility disorder is present in the vast
majority, if not all patients, with an intrathoracic pulsion diverticu-
lum that is not due to a prior esophageal myotomy injury, or distal
of obstruction.75,77-79 The higher intraesophageal pressures experi-
enced proximal to an anatomic or functional (in motility disorders)
obstruction cause the wall of the esophagus to give way creating the
diverticulum that can progressively enlarge over time. Manometry
studies performed on patients with esophageal pulsion diverticula
demonstrate a motility disorder 50% to 100% of the time.65,73,75-77,80-88
More extensive studies, including 24-hour ambulatory manometry,
have been used to characterize motility disorders that are not evi-
dent on a traditional manometric swallow study.78 The motility
disorders associated with esophageal pulsion diverticula include
nonspecific disorders, diffuse esophageal spasm, hypertensive lower
esophageal sphincter (LES), and achalasia.65,75-77,80-86,88 The motility
disorders are typically associated with increased amplitude of con-
tractions, which may explain why diverticula are seen more often in
patients with diffuse esophageal spasm (up to 42%) compared to
patients with achalasia (less than 5%).64,89-91 Causes of mechani-
cal obstruction that have been associated with esophageal pulsion
diverticula include leiomyomas and stricture.73,84,92
5. What are the symptoms associated with esophageal pulsion
diverticula?
Esophageal diverticula are discovered incidentally in patients who
are asymptomatic or with minimal symptoms in up to two thirds of
cases.73 When diverticula are symptomatic, patients’ complaints are
often likely due to an underlying esophageal motility disorder and
include chest pain, dysphagia, and heartburn. Symptoms that may
be due to the diverticulum itself include regurgitation of undigested
food, particularly when lying flat, and aspiration.73,78,91,93 In symp-
tomatic patients, various degrees of weight loss are common and
symptoms have often been present for months to years.78,91,94 Pulmo-
nary complaints may be the sole symptom in up to 25% of patients.95
Less common findings include esophageal obstruction second-
ary to compression from the diverticulum, upper GI bleeding, and
PMPH_CH05.indd 49
Esophageal Diverticula ■ 49
esophagopulmonary fistula.96-99 In addition, there are case reports of
squamous cell carcinoma arising within the diverticulum.100-102
Esophageal pulsion diverticula may be asymptomatic (up to
two thirds of the time). Symptoms associated with the diverticula
include chest pain, dysphagia, heartburn, regurgitation of food,
cough, aspiration, weight loss, bleeding, and obstruction (Grade C).
6. What are the diagnostic tests necessary for pulsion esopha-
geal diverticula?
Esophageal diverticula can be diagnosed on plain chest x-ray as a
mediastinal density with or without an air-fluid level.69 If it is diag-
nosed by other means, imaging of the chest is indicated to evaluate
for pulmonary disease or changes from aspiration.69,73,103 Con-
trasted esophagogram is the single best study to evaluate for an
esophageal diverticulum in that it reliably diagnoses the presence
of the diverticulum as well as defines the number, size, and shape
of the diverticulum and other potential esophageal pathology
including motility disorders.67,77,104 Esophageal endoscopy is rec-
ommended to further evaluate for additional esophageal pathology
and should include attempts to visualize the diverticular mucosa
when possible because of the risk of cancer.100-102,105 There are diver-
gent opinions on the need for esophageal manometry in patients
with esophageal pulsion diverticula. Although most patients will
have abnormal findings, some consider this of academic value only
because they believe that esophageal myotomy above the level of
the diverticulum is indicated even if findings are normal.105 Some,
however, advocate performing a selected esophageal myotomy only
in patients with a demonstrated motility disorder on esophageal
manometry.71 In addition, some surgeons use pH probe findings of
reflux to determine whether an antireflux procedure is necessary,
whereas others perform antireflux procedures routinely.106,107 CT of
the chest has also been used to evaluate esophageal diverticula and
may be of value in defining the surrounding anatomy, particularly in
mid-esophageal diverticula if it is unclear if the diverticula is due
to traction or pulsion physiology.108
Contrasted esophagogram is the best study to evaluate for the
presence of, and characteristics of, esophageal diverticula. Chest
x-ray and/or CT of the chest are indicated to evaluate for signs of
aspiration or pulmonary complication. Esophageal endoscopy is
useful to assess for cancer, dysplasia, and other esophageal disease
(Grade C). Esophageal manometry is useful for defining esopha-
geal motility disorders, although this does not alter the surgical
plan for some surgeons (Grade D). In addition, some advocate for
a 24-hour esophageal pH study to determine the presence of pre-
operative gastroesophageal reflux disease, which influences the
type of antireflux procedure used (Grade D).
7. When is intervention indicated in an esophageal pulsion
diverticula?
Intervention is indicated with esophageal pulsion diverticula in
patients who present with symptoms such as weight loss, pulmonary
complications, significant dysphagia, or pain. In patients with
minimal or no symptoms, most authors favor observation, as the
surgical treatment caries significant risk of morbidity and mor-
tality. Studies following asymptomatic or minimally symptomatic
patients suggest a relatively low rate (~10%) of development of
symptoms over time although the data is not uniform.67,70,73,109 In
contrast, patients with a history of aspiration or pulmonary com-
plaints are at high risk of aspiration and death without a timely
operation.77
5/21/2012 8:28:49 PM
 50 ■ Surgery: Evidence-Based Practice
Asymptomatic or minimally symptomatic diverticula can
be safely observed. Intervention is indicated for symptomatic
diverticula particularly in patients with pulmonary complaints
(Grade C).
8. What treatment is recommended for esophageal pulsion
diverticula?
Endoscopic treatment of patient’s underlying esophageal motility
disorder has been proposed in symptomatic patients who are not
operative candidates, particularly with small epiphrenic diver-
ticula; however, there is limited outcome data to support this.110-112
Proposed treatments include endoscopic dilation and injections
of botulinum toxin (or both), which is largely extrapolated for
experience in treating esophageal motility disorders.70 In motil-
ity disorders, both of these treatments provide temporary relief
in patients with motility disorders affecting the lower esophageal
sphincter; however, the symptoms tend to recur over time. In addi-
tion, dilation carries a 4% to 6% risk of esophageal perforation,
and botulinum toxin causes localized inflammation and scarring
that increase the risk of esophageal mucosal violation should a
myotomy be performed later.95,112
Operative management generally consists of esophageal
mytotomy with or without diverticulectomy although other
approaches have been described. Myotomy is generally accepted
as a necessary component of the operation.105 Although there
is no randomized controlled data to prove this point, the pub-
lished collective experience in case series suggests higher rates
of esophageal leak and recurrence of the diverticulum with
diverticulectomy without myotomy.67,82 Most authors advocate
esophageal myotomy even when no esophageal motility disor-
der can be demonstrated, although this is not uniform.71,113 The
proximal and distal extent of the myotomy are the source of
some controversy. Some feel the distal myotomy should extend
distally 1 to 2 cm onto the gastric cardia to ensure complete
division of the lower esophageal sphincter and, thus, prevent-
ing a functional distal high-pressure zone (whether revealed
by manometry or not).76,77,82,114,115 Others believe that leaving a
manometrically normal LES intact is safe and eliminates the
need for a fundoplication.83,86 The esophageal myotomy should
extend proximally at least to the level of the diverticular neck
to ensure adequate relief of the distal functional obstruction.
Failure to perform adequate proximal myotomy has been associ-
ated with early recurrences in case reports.116,117 Some advocate a
more extensive proximal myotomy to the level of the aortic arch
in all patients or to the level of demonstrated manometric abnor-
malities in patients with symptoms attributed to an esophageal
motility disorder.70,71
Diverticulectomy is likely unnecessary in patients with small,
wide-necked diverticula as they tend to resolve intraoperatively
after an esophageal myotomy is performed. Some surgeons advo-
cate imbrication or pexis of diverticula in selected cases.76,77,79,87,115
By not performing a diverticulectomy, the risk of esophageal leak
is decreased as the esophageal mucosa is not violated. However, if
the diverticulum is large, particularly with a dependent portion, or
has dysplastic changes, a diverticulectomy is necessary.27,75,76,82,85
Most authors advocate the addition of an antireflux pro-
cedure with a partial wrap as part of the operative manage-
ment when an LES myotomy is performed.67,70,71,76,91,94,105-107,118
Although the experience with wraps in patients with esophageal
PMPH_CH05.indd 50
pulsion diverticula is limited to case series, there are randomized
data in patients undergoing a Heller lower esophageal sphincter
myotomy for achalasia that demonstrate significant reduction
in postoperative reflux with the addition of a partial fundoplica-
tion (43% vs. 9%, P = .005).119 A complete (Nissen) fundoplication
may not be advisable as it has been associated with high rates of
dysphagia and progressive esophageal dialation in patients with
achalasia who have undergone esophageal myotomy.120 In addi-
tion, in patients with esophageal diverticula, there is concern
that the higher intraesophageal pressure associated with a com-
plete wrap could cause an esophageal suture line leak or recur-
rence of the diverticulum.95,121 However, others advocate using
manometric data or the preoperative presence of gastroesopha-
geal reflux disease (GERD) to determine the type of wrap to be
performed, and report good results in performing complete
(Nissen) fundoplications in patients with normal esophageal
motility or GERD.70,71,107,121
Classically, esophageal pulsion diverticula are addressed
though a left thoracotomy. There is a growing body of experi-
ence within the literature for minimal invasive management
of esophageal pulsion diverticula.70,71,91,94,107,109,118,122 This can be
accomplished through a laparoscopic transhiatal approach or
thoracoscopic approach. The laparoscopic transhiatal approach
has the advantage of excellent visualization of the hiatus facili-
tating performance of the esophageal myotomy and fundoplica-
tion. In addition, the transhiatal approach allows passage of an
endoscopic stapler in-line with the esophagus to perform the
diverticulectomy.91,118,122,123 However, it may be difficult to per-
form a more proximal esophageal myotomy in patients of the
proximal esophagus or to address mid-thoracic or large diver-
ticula, although all have been successfully accomplished in case
reports.71,124,125 Alternatively, the thoracoscopic approach allows
for greater access to the proximal esophagus but it may be more
technically challenging to perform the myotomy and diverticulec-
tomy given the angle of approach.118,123,126,127
The obvious advantage of the minimally invasive approaches
is avoidance of a thoracotomy in this often elderly patient popula-
tion. This may decrease the morbidity and length of stay associ-
ated with repair compared to open operation. In the reported case
series of minimally invasive treatment, most patients required
inpatient admission of less than 1 week.118 The reported rates of
symptomatic improvement (83%–100%), leak, and recurrence
(0%–20%) appear to be similar to results in published series of
open operative management.107,118,122 However, given the techni-
cal difficulty of the operation and potential pit-falls, this should
only be attempted by surgeons with extensive laparoscopic
experience.106
Endoscopic dilation or botulinum toxin cannot be recom-
mended for symptomatic esophageal pulsion diverticula based
on the existing literature (Grade D). Esophageal myotomy (proxi-
mally to at least above the level of the diverticulum) with or with-
out diverticulectomy is the best operative treatment (Grade C).
A long esophageal myotomy may benefit in patients with diff use
esophageal motility disorders (Grade C). There may be a bene-
fit to extension of the myotomy distally onto the gastric cardia
(Grade D). A partial or complete fundoplication may decrease
postoperative gastroesophageal reflux associated with a lower
esophageal myotomy (Grade C). Minimally invasive approaches
can achieve similar results as open operative techniques without
the morbidity of a laparotomy or thoracotomy (Grade C).
5/21/2012 8:28:50 PM
 Esophageal Diverticula ■ 51

Table 5.2 Evidence-Based Table Based on Intervention for Zenker’s Diverticula

Year, Author, Number of Study Design Findings/Recommendations Level of
Reference # Patients Evidence
2010, Nicholas 7 Retrospective, single-center Using an endostitch to retract the diverticulum 4
et al. #59 case series common wall assists with endoscopic stapled
diverticulotomy in patients with difficult anatomy.
2010, Al-Kadi 18 Retrospective, single-center Flexible endoscopic diverticulotomy with a needle- 4
et al. #48 case series knife papillotome is an effective approach in highly
morbid patients.
2010, Brace 19 Retrospective, single-center Endoscopic stapled diverticulotomy achieves 4
et al. #60 case-control series comparable results to open surgery with shorter
operative times and hospital stay. Methodological
flaws in patient selection.
2010, Repici 58 Retrospective, single-center Similar results between rigid endoscopic stapled 3
et al. #34 case-control series diverticulotomy and flexible needle-knife
diverticulotomy.
2010, Case 22 Retrospective, single-center Flexible endoscopic needle-knife diverticulotomy 4
et al. #62 case series is effective, often without requiring general
anesthesia. Perforation is a common complication.
2009, Sharp 48 Retrospective, single-center Endoscopic stapled and endoscopic harmonic scalpel 3
et al. #30 case-control series diverticulotomy produce similar results with a
higher complication rate for diverticula <2 cm.
2009, Fama 25 Retrospective, single-center Endoscopic diverticulotomy with a harmonic scalpel is 4
et al. #47 case series safe and effective.
2009, 57 Retrospective, single-center Endoscopic stapled diverticulectomy is safe and 4
Wasserzug case series effective.
et al. #31
2009, Harris 31 Retrospective, single-center Endoscopic stapled diverticulectomy is safe and 4
et al. #29 case series effective. Conversion to open is required in some
patients.
2008, Rizzetto 128 Retrospective, single-center Endoscopic stapled diverticulotomy is safe and 3
et al. #6 case-control series effective in diverticula >3 cm. Open surgery has
better long-term results and is recommended in
younger, healthy patients.
2008, Tang 7 Retrospective, single-center Flexible endoscopic clip-assisted diverticulotomy is 4
et al. #50 case series feasible, safe, and effective.
2007, Bonavina 297 Retrospective, single-center Endoscopic stapled diverticulectomy results in similar 3
et al. #8 case series good results as open surgical management except
in patients with diverticula <3 cm.
2007, Palmer 35 Retrospective, single-center Endoscopic stapled diverticulectomy is safe and 4
et al. #57 case series effective. Repeat surgery for persistent or
recurrent dysphagia can be safely performed
endoscopically.
2006, Morse 47 Retrospective, single-center Endoscopic stapled diverticulectomy results in similar 3
et al. #7 case-control series results as open surgery with shorter operative
times.
2006, Lang 63 Prospective, single-center Endoscopic stapled diverticulotomy is safer with 4
et al. #21 case-control series shorter operative times and hospital stays than
open surgical management. Methodological flaws in
patient selection/comparison.
2006, Wirth 47 Retrospective, single-center Both endoscopic stapled diverticulotomy and open 3
et al. #5 case-control series cricopharyngeal myotomy showed good results in
long-term follow-up.

(Continued)

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 52 ■ Surgery: Evidence-Based Practice

Table 5.2 (Continued)

Year, Author, Number of Study Design Findings/Recommendations Level of
Reference # Patients Evidence
2006, Miller 40 Retrospective, single-center Endoscopic stapled diverticulectomy has improved 3
et al. #36 case-control series efficacy and safety compared to flexible endoscopic
CO2 laser diverticulotomy.
2006, Tsikoudas 21 Retrospective, single-center It is possible to predict surgical outcome based on the 4
et al. #58 case series radiographic characteristics of the diverticulum.
2002, Smith 16 Retrospective, single-center Endoscopic stapled diverticulectomy results in 3
et al. #61 case-control series decreased hospital charges secondary to shorter
operative time and hospital stay.
2001, Lerut 325 Retrospective, single-center Open cricopharyngeal myotomy and diverticulopexy 4
et al. #39 case series achieves excellent results with short hospital stay.
2001, Sakai 10 Retrospective, single-center An oblique hood on the end of a flexible 4
et al. #49 case series endoscope simplifies performing a needle-knife
diverticulotomy.
1999, Narne 102 Retrospective, single-center Endoscopic stapled diverticulectomy is safe and 4
et al. #18 case series effective.
1999, Osmote 22 Retrospective, single-center Endoscopic stapled diverticulectomy is effective with 4
et al. #33 case series low risk of complications and a short hospital stay.
1996, Koay 14 Retrospective, single-center Endoscopic stapled diverticulectomy is fast, safe, and 4
et al. #32 case series effective.
1990, Barthlen 43 Retrospective, single-center Recommends cricopharygeal myotomy based on 4
et al. #35 case series manometry findings and treatment results with
open surgical therapy.

Table 5.3 Evidence-Based Table Based on Intervention for Esophageal Pulsion Diverticula
Year, Author, Number of Study Design Findings/Recommendations Level of
Reference # Patients Evidence
2009, Castrucci, 51 Retrospective, single- Recommend tailored approach to treatment of esophageal 4
et al. #83 center case series diverticula based on the patient’s underlying esophageal
motility disorder.
2009, Katsinelos 1 Retrospective, case Effectively treated dysphagia in a patient with a large 4
et al. #110 report epiphrenic diverticulum who was not an operative
candidate with repeat combined dilation and botulinum
toxin injection.
2009, Katsinelos 2 Retrospective, single- Effectively treated dysphagia in two patients with a large 4
et al. #111 center case series epiphrenic diverticulum who was not an operative
candidate with repeat combined botulinum toxin
injections.
2008, Palanivelu 5 Retrospective, single- Laparoscopic transhiatal is the approach of choice. 4
et al. #71 center case series
2008, Zaninotto 41 Retrospective, single- 19 patients with small, mildly symptomatic diverticula were 4
et al. #109 center case series safely followed without surgery. Patients who were
operated on improved symptomatically.
2006, Rosati 11 Retrospective, Laparoscopy offers good access to the distal esophagus 4
et al. #107 single-center case- and inferior mediastinum. Recommend diverticulectomy
control series with myotomy and partial fundoplication.
2005, Fernando 20 Retrospective, Procedures performed laparoscopically and/or with VATS. 4
et al. #106 single-center case- Potential for morbidity is significant. Recommend open
control series surgery except in centers experienced in minimally
invasive esophageal surgery.

(Continued)

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 Esophageal Diverticula ■ 53

Table 5.3 (Continued)

Year, Author, Number of Study Design Findings/Recommendations Level of
Reference # Patients Evidence
2005, Tedesco 21 Retrospective, single- A primary esophageal motility disorder is the cause of most 4
et al. #91 center case series epiphrenic diverticula; laparoscopic treatment should be
the method of choice.
2004, del Genio 13 Retrospective, single- Laparoscopic management of epiphrenic diverticula is safe 4
et al. #122 center case series and effective.
2003, Klaus 17 Retrospective, single- Asymptomatic patients may not require therapy. 4
et al. #70 center case series Laparoscopic approach is the treatment of choice.
A long esophageal myotomy and fundoplication should
be performed.
2003, Matthews 5 Retrospective, single- Laparoscopic or thoracoscopic approaches are feasible, 4
et al. #94 center case series safe, and effective at alleviating dysphagia in patients with
epiphrenic esophageal diverticula.
2002, Nehra 21 Retrospective, single- There is a high prevalence of esophageal motility disorders 4
et al. #78 center case series with esophageal diverticula. Resection of the diverticula
and myotomy of manometrically defined abnormal
segment should be performed.
2002, Nastos 16 Retrospective, Patients with esophageal diverticula had dysfunction 4
et al. #114 single-center case- primarily of the distal esophagus and responded better
control series to esophageal myotomy and fundoplication than patients
with esophageal spastic disorders.
1999, Altorki 102 Retrospective, single- All patients with thoracic esophageal diverticula should 4
et al. #77 center case series undergo operative intervention, regardless of symptoms,
because of the risk of aspiration. This assertion is based
on the high rate of pulmonary complications observed.
1999, Jordan 25 Retrospective, single- Asymptomatic epiphrenic diverticula do not require 4
et al. #79 center case series surgery. Resection or imbrications of the diverticula
are effective. LES myotomy is contraindicated when
gastroesophageal reflux is present or LES pressure is
below normal.
1993, Benacci 112 Retrospective, single- Operation for esophageal diverticula has significant risks 4
et al. #73 center case series and is not warranted in patients with minimal symptoms;
however, it is warranted in patients with incapacitating
symptoms.
1993, Hudspeth 18 Retrospective, single- Diverticulectomy combined with selective myotomy 4
et al. #87 center case series permits excellent operative results.
1992, Fekete 33 Retrospective, Recommend esophageal myotomy distally onto the gastric 4
et al. #82 single-center case- cardia and addition of antireflux procedure.
control series
1992, D’Ugo 19 Retrospective, single- Recommend treatment of the underlying esophageal 4
et al. #85 center case series motility disorder in patients with esophageal pulsion
diverticula with diverticulectomy in selected cases.
1992, Streitz 16 Retrospective, single- Recommend selected esophageal myotomy of areas only 4
et al. #86 center case series with demonstrated manometric abnormalities. Advocate
leaving manometrically normal LES intact.
1986, Evander 8 Retrospective, single- Good results with esophageal myotomy though the 4
et al. #76 center case series LES with or without diverticulectomy and with
fundoplication.
1980, Debas 46 Retrospective, single- Epiphrenic diverticulum is associated with esophageal 4
et al. #84 center case series motility disorders in the majority of patients and
mechanical obstruction in the minority. Surgery should
include diverticulectomy and myotomy or resection of
mechanical obstruction.

PMPH_CH05.indd 53 5/21/2012 8:28:50 PM

 54 ■ Surgery: Evidence-Based Practice

TRACTION DIVERTICULA traction diverticula include granulomatous diseases such as his-

Traction diverticula are true diverticula caused by inflammation
of mediastinal lymph nodes. As the inflammatory process causes
scarring and retraction, it pulls the adjacent esophageal wall, form-
ing a diverticulum. They tend to occur in the mid-thoracic esopha-
gus and are often small and asymptomatic. They are uncommon,
particularly in Western countries. The conditions associated with
toplasmosis, tuberculosis, sarcoidosis although other causes have
been described.128-134 Treatment typically involves medical manage-
ment of the causative inflammatory process. Surgical management
is indicated for complications associated with the diverticulum such
as esophagobronchial fistula or bleeding.44,131 Surgical treatment
typically consists of resection of the inflammatory process with
repair of the esophageal wall or resection of the diverticulum.44,131

Clinical Question Summary

Question
1 What are the symptoms
associated with
Zenker’s diverticulum?
2 What workup is
necessary for a known
or suspected Zenker’s
diverticulum?
3 What are the treatment
options for Zenker’s
diverticulum?
4 Which treatment is
best for Zenker’s
diverticulum?
5 What are the symptoms
associated with
esophageal pulsion
diverticula?
6 What are the diagnostic
tests necessary for
pulsion esophageal
diverticula?
7 When is intervention
indicated in an
esophageal pulsion
diverticula?
8 What treatment is best
for esophageal pulsion
diverticula?
Answer Grade of References
Recommendation
Dysphagia, regurgitation of undigested food, a feeling of C 5-8, 18, 20, 29-34
a globus in the neck (particularly with swallowing),
cough, aspiration pneumonia, and weight loss.
Videofluorographic contrast swallow study; endoscopy. C 1, 5, 38
upper esophageal manometry
D 6, 20-27
Open surgical management (cricopharyngeal myotomy, B 5-8, 18, 20, 21, 29-36,
with or without diverticulectomy or diverticulopexy. 39-43, 52-55, 57,
Rigid or flexible endoscopic diverticulotomy. 60, 61
Cricopharyngeal myotomy (whether open or C 6, 35, 40-43
endoscopic) decreases persistence or recurrence of
symptoms compared to open diverticulectomy alone.
Open (cricopharyngeal myotomy with or without
diverticulectomy or diverticulopexy) and rigid C 5-8, 18, 20, 29-36,
endoscopic stapling both produce acceptable 39, 40
outcomes.
Rigid endoscopic management may allow shorter
operative times compared to open surgical B 5-8
management.
Rigid endoscopic management may allow for quicker
resumption of oral feeds, and shorter length of stay D 5, 7, 8, 21, 29, 32, 60,
compared to open diverticulectomy. 61
Endoscopic diverticulectomy of diverticula <3 cm may
have higher persistence or recurrence of symptoms.
Flexible endoscopic (nonstapled) diverticulotomy can C 5, 8, 57
be performed in patients who are not candidates
for rigid endoscopic diverticulotomy but may have a
higher leak rate. C 36, 48, 52-55
May be asymptomatic (up to two thirds of the time). C 73, 78, 91, 93-99
Chest pain, dysphagia, heartburn, regurgitation of
food, cough, aspiration, weight loss. Less commonly,
bleeding or obstruction.
Contrasted esophagogram. Chest x-ray and/or CT of C 67, 69, 73, 77, 100-
the chest. Esophageal endoscopy. 102, 104, 105
Esophageal manometry. D 70, 71, 83, 86, 105
24-hour esophageal pH study. D 106, 107
Asymptomatic diverticula can be safely watched with D 67, 70, 73, 77
follow-up.
Intervention is indicated for symptomatic diverticula. C 77
Patients with pulmonary complaints have a history
of aspiration.
Endoscopic dilation or botulinum toxin cannot be D 110-112
recommended for symptomatic esophageal pulsion
diverticula based on the existing literature.

(Continued)

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 Esophageal Diverticula ■ 55

(Continued)
Question Answer Grade of References
Recommendation
Esophageal myotomy (proximally to at least above C 27, 67-70, 72-79,
the level of the diverticulum) with or without 82-96 104-109,
diverticulectomy is the best operative treatment. 113-118, 122-126
A long esophageal myotomy may benefit those with
diffuse involvement of esophageal motility disorders. C 70, 71
The myotomy should extend distally onto the gastric
cardia.
A partial or complete fundoplication may decrease D 76, 77, 82, 115, 116
postoperative gastroesophageal reflux associated
with a lower esophageal myotomy. C 67, 70, 71, 91, 94,
Minimally invasive approaches can achieve similar 105-107, 114, 121
results as open operative techniques without the C 70, 71, 91, 94, 107,
morbidity of a laparotomy or thoracotomy. 109, 114, 122-126

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5/21/2012 8:28:50 PM

Gastroesophageal Reflux Disease
INTRODUCTION
Gastroesophageal reflux disease (GERD) is one of the most com-
mon disorders in medical practice, affecting not only Americans
but also becoming a worldwide health problem. Detailed data are
still lacking regarding the incidence and prevalence of GERD in
North America. The fi rst data on GERD incidence came from
a study done in San Diego, California.1 Using a questionnaire,
the authors evaluated the incidence and precipitating factors of
GERD in 446 hospitalized and 558 nonhospitalized subjects.
The authors concluded that 36% of the individuals experienced
heartburn at least once a month and 14% experienced heart-
burn daily. Another interesting study on GERD prevalence in
a North American population was done in Olmsted County,
Minnesota. 2 In this study, the authors surveyed a large, ran-
dom sample of residents aged 25 to 74 years to determine the
prevalence and clinical spectrum of GERD in that community.
The prevalence of heartburn was 42%. Acid regurgitation was
reported by an additional 28% of the individuals. Remarkably,
this population-based study also addressed the occurrence of
other symptoms associated with reflux. For example, dysphagia
was reported by 13.5% of the Olmsted county residents and glo-
bus was reported by 7%.
RISK FACTORS
1. Who is at risk for GERD?
The risk factors of GERD can be divided into four categories:
genetic, demographic, behavioral, and comorbid associations.
Genetic factors: A genetic contribution to the etiology of
GERD has been identified in studies of twins.3,4 Genetic factors
account for 30% to 40% of the liability to GERD.
Demographic factors: Despite the well-known association
between GERD and pregnancy, there is no significant relationship
between sex and GERD.2,5 The effect of increasing age and GERD is
still unclear, with two European studies reporting a slight but sig-
nificant association of GERD with increasing age.3,5,6 Obesity and
59
PMPH_CH06.indd 59
CHAPTER 6
Alejandro F. Sanz and Blair A. Jobe
GERD are clearly related, both from a prevalence and causality asso-
ciation. GERD symptoms increase in severity when a person gains
weight. A meta-analysis confirmed a positive association between
the presence of GERD and increasing body mass index (BMI).7
Another meta-analysis showed a statistically significant increase
in the risk for GERD symptoms, erosive esophagitis, esophageal
adenocarcinoma, with progressively increasing weight.8
Behavioral factors: The most commonly investigated behav-
ioral factors potentially affecting GERD episodes are cigarette
smoking, alcohol consumption, and coffee consumption. Three
cross-sectional studies demonstrated a significant relationship
between GERD symptoms and smoking.3,5,6 On the other hand,
there is not enough data to support or rule out a relationship
between coffee or alcohol consumption and GERD.6
Comorbid factors: In a study using the UK General Practice
Research database, the risk of GERD was significantly increased
in individuals who had visited a general practitioner three times
or more in the preceding year, who had been referred to a special-
ist or hospitalized, or been diagnosed with irritable bowel syn-
drome, ischemic heart disease, peptic ulcer disease, or one of a
range of painful conditions in the year before the index date (the
date they were diagnosed with GERD). The risk of GERD was also
increased among overweight individuals and ex-smokers.6,9
Answer: A number of potential risk factors for GERD have
been identified. However, all of the positive associations have
rather small odds ratios, leaving their clinical implications for
preventive or therapeutic strategies in doubt. Grade of recom-
mendation: B.
DIAGNOSIS OF GERD
2. What is the role and priority of endoscopy in diagnosis of
GERD?
Endoscopy allows direct visualization of the esophageal mucosa.
Endoscopic findings in patients with GERD include esophagi-
tis, erosions and ulcers, strictures, and Barrett’s esophagus. If
moderate-to-severe symptoms of GERD and endoscopic injury
5/21/2012 8:29:59 PM
 60 ■ Surgery: Evidence-Based Practice
are both present, the diagnosis of GERD can be made without
further studies (Level of evidence 4), as this combination has 97%
specificity and 64% sensitivity for accurately diagnosing GERD.10
However, patients with GERD symptoms can have normal endo-
scopic findings, for example, nonerosive reflux disease.
Some data also suggest a role of upper endoscopy in the
evaluation of heartburn in patients in whom once-daily proton
pump inhibitor (PPI) treatment failed compared with those not
receiving any treatment.11 Endoscopy is the first diagnostic test to
consider when medical therapy fails. Endoscopy can also demon-
strate Barrett’s metaplasia, stricture, or an alternative upper gas-
trointestinal diagnosis.
There are a few “alarm features” that can accompany suspected
GERD, which can lead to an alternative diagnosis. Clinically rel-
evant differential diagnoses in the context of GERD include coro-
nary artery disease; gallbladder disease; gastric or esophageal
malignancy; peptic ulcer disease; and eosinophilic, infectious, or
caustic esophagitis. The evidence supporting the utility of “alarm
features” as a diagnostic tool is very limited. However, some of
these features are very characteristic and should lead to suspicion
of a gastric or esophageal malignancy, for example, weight loss,
dysphagia, and epigastric mass on examination. In this clinical
setting, endoscopy is the gold standard for evaluation.
Answer: Any patient with a suspected GERD syndrome, who
has not responded to an empirical trial of twice-daily PPI therapy,
should undergo an endoscopic evaluation with biopsies targeted to
suspected areas of metaplasia, dysplasia, or malignancy.12 (Grade
B recommendation.)
In addition, there is fair evidence that recommends endos-
copy with biopsy for patients with a GERD syndrome with trou-
blesome dysphagia (Level 3 of evidence). Biopsies should target
any areas of suspected metaplasia, dysplasia, or in the absence of
visual abnormalities, normal mucosa. At least five samples should
be collected to evaluate for eosinophilic esophagitis.
3. What is the role of 24-hour esophageal pH monitoring in the
diagnosis of GERD?
Ambulatory 24-hour esophageal pH monitoring is currently
considered the gold standard for diagnosing GERD, with a sen-
sitivity of 79% to 96% and specificity of 85% to 100%.13-16 In addi-
tion, ambulatory 24-hour esophageal pH monitoring is the most
sensitive diagnostic test for identifying acid reflux as the likely
cause for chest pain of noncardiac origin17 and helps to confirm
GERD in patients with persistent symptoms (both typical and
atypical) without evidence of mucosal damage, especially when a
trial of acid suppression has failed. Ambulatory 24-hour esopha-
geal pH monitoring may also be used to monitor the control of
reflux in patients with continued symptoms while on therapy.18
There have been two recent advances in the way we can study
and diagnose GERD. One is combined impedance and acid test-
ing. With this new technology, acid and nonacid reflux can be
recorded. The other development is a wireless method of acid
monitoring. The new wireless device allows a radiotelemetry
capsule to be attached to the esophageal mucosa and monitored
without the discomfort of a nasoesophageal tube. Th is decreases
patient discomfort and allows longer periods of monitoring (48
hours), which may improve accuracy in the measurement of
reflux episodes. In preliminary pH studies performed over peri-
ods > 24 hours, abnormal pH exposure was detected only on the
second day of monitoring in up to one third of subjects. There-
fore, pH monitoring for 48 hours may yield more information
PMPH_CH06.indd 60
about pathological acid reflux in patients being investigated for
GERD (Level 3 of evidence).18
Answer: Ambulatory impedance pH, catheter pH, or wireless
pH monitoring (with the PPI therapy withheld for a period of
7 days) is indicated in patients with a suspected GERD syndrome
who have not responded to a trial of PPI therapy, who have normal
findings on endoscopy, and who have no major abnormalities on
manometry. Wireless pH monitoring has a superior sensitivity to
catheter pH monitoring for detecting pathologic esophageal acid
exposure because of the extended period of recording (48 hours)
and also has superior recording accuracy compared with some
catheter designs. (Grade B recommendation.) There is insufficient
evidence to recommend any type of esophageal impedance or pH
testing (wireless or catheter) while taking PPIs.12
TREATMENT OF GERD
4. What is the mainstay of therapy for GERD?
In the original guidelines for the diagnosis and treatment for GERD,
published by DeVault et al. in 1995, the authors included a review
of 33 randomized trials including over 3000 patients with erosive
esophagitis. They founded symptomatic relief in 27% of placebo-
treated patients, 60% of patients treated with histamine 2 recep-
tor antagonists (H2RAs), and 83% of patients treated with PPIs.
The esophagitis healed in 24% of placebo-treated patients, 50% of
H2RA-treated patients, and 78% of PPI-treated patients. As a result
of this review, the updated guidelines from the American College
of Gastroenterology state that both higher doses and more frequent
doses of H2RAs produce results inferior to those of PPIs. More-
over, the advantages of PPI therapy increase with the severity of the
disease. In addition, randomized and double-blinded studies have
shown the efficacy of PPIs (omeprazole, single and double dose)
over placebo in providing relief of reflux symptoms in patients with
heartburn and improving patients’ general well-being.19
Answer: Acid suppression is the mainstay of therapy for
GERD. PPIs provide the most rapid symptomatic relief and
heal esophagitis in the highest percentage of patients (Level 1 of
evidence).18 There is no statistical difference in the response to
treatment with PPI taken as two daily doses, when compared with
a single daily dose.20,21 (Grade A recommendation.)
5. How does medical treatment of GERD compare with surgical
treatment of GERD?
There is a lot of controversy in the literature defining the best
treatment for GERD, medical or surgical. In the very first articles
that compared both modalities, surgery was much more efficient
than medical treatment. However, those articles usually compare
surgery with medical therapies that are known to be ineffective
today, for example, H2 receptor blockade. With the development
of PPIs, the gap in efficiency between medical and surgical treat-
ment is getting smaller and investigators are following up to eval-
uate long-term outcomes. For example, Lundell et al.22 compared
antireflux surgery with omeprazole therapy for the treatment of
GERD and followed the patients for 5 years. They compared 310
patients with erosive esophagitis, randomized into two groups of
155 patients each and found antireflux surgery to be more effec-
tive than omeprazole. In the study of Lundell and colleagues,
patients were treated with either 20 mg of omeprazole, usually for
4 to 8 weeks, with dose increments to 40 mg in cases of incomplete
5/21/2012 8:29:59 PM
 Gastroesophageal Reflux Disease ■ 61

response in controlling gastroesophageal reflux disease. However,
if the dose of omeprazole was adjusted in cases of relapse, the two
therapeutic strategies displayed levels of efficacy that were not sta-
tistically different.
In an open, parallel-group multicenter, randomized and
controlled trial conducted in 11 European countries called the
LOTUS trial, published by Lundell et al.,23 the authors compared
laparoscopic surgery with medical treatment (esomeprazole 20
mg once daily), and reported initial results for a follow-up period
of 3 years. A total of 554 patients were randomized in the LOTUS
trial. Two hundred eighty-eight underwent laparoscopic surgery
and 260 were treated with PPIs. They concluded that both lap-
aroscopic total fundoplication and continuous esomeprazole
treatment were similarly effective and well-tolerated therapeutic
strategies for providing effective control of GERD. However, post-
fundoplication complaints (e.g., dysphagia) remain a problem
after laparoscopic surgery. The same European group published
a 12-year follow-up study,24 comparing the medical treatment
with omeprazole and antireflux surgery. They found that both
treatment modalities were similarly effective in the treatment of
GERD and well tolerated by the patients. Antireflux surgery was
found to be superior to omeprazole in controlling overall disease
manifestations, but post-fundoplication complaints continue after
surgery.
Mehta et al.25 performed a prospective, randomized study with
a 7-year follow-up to obtain long-term follow-up data. A total of
183 patients were randomized into two groups, 91 to surgery and
92 to optimized PPI therapy (20 mg/day). After 1 year, patients in
the PPI group were offered the opportunity to have surgery. Mehta
and colleague concluded that both optimal PPI therapy and lap-
aroscopic Nissen fundoplication are effective and durable treat-
ments for GERD. Patients who had surgery at the beginning of
the trial and patients who remained on PPIs for the entire course
of the study both had significantly improved symptoms. How-
ever, there was a substantial difference in those patients who had a
moderate response to the medical treatment during the first year
and then decided to undergo surgery. These patients experienced
a significant reduction in symptoms after the laparoscopic Nis-
sen fundoplication. Furthermore, of the patients who remained
on PPIs for the entire duration of the study, only 59% were very
satisfied with symptom control, compared with 80% of patients
who had undergone surgery and were very satisfied.
Answer: Antireflux surgery, performed by an experienced
surgeon, is a maintenance option for the patient with well-
documented GERD.18 (Level 2 of evidence.) There is a decrease in
therapeutic failure of 12% when we compare surgical and medi-
cal treatment for GERD, and these numbers don’t change after an
observational period of 7 years.26 (Grade A recommendation.)
If a patient can benefit from both forms of treatments for
GERD (medical or surgical) with a similar efficacy, PPI therapy
should be recommended first because it is safer and less invasive.
If a patient is diagnosed with a GERD syndrome, but is intolerant
to acid suppression therapy, antireflux surgery should be recom-
mended as an alternative. (Grade A recommendation.)
6. Which is the best fundoplication technique for treatment of
GERD: Total (Nissen) or partial (Toupet)?
Laparoscopic Nissen fundoplication is the most frequently per-
formed operation for GERD in the United States. Laparoscopic
Toupet fundoplication has been proposed as an alternative opera-
tion, due to some adverse events experienced by patients after Nis-
sen fundoplication. Adverse events after laparoscopic Nissen include
dysphagia in 8% to 12%27-30 of patients and gas-related symptoms in
19%.31 In a prospective clinical trial, Lundell et al.32 randomized
137 patients with GERD to either laparoscopic Nissen (65 patients)
or laparoscopic Toupet (72 patients) fundoplication. Both surgical
techniques were equally effective in the resolution of GERD. Dys-
phagia was more common in the early postoperative period after a
360-degree wrap (Nissen), but this difference disappeared with time.
In addition, gas-related symptoms, such as flatulence, were more
frequently seen after laparoscopic Nissen fundoplication (P < .05
at 2 years and P < .01 at 3 years). Even though laparoscopic Toupet
fundoplication appears to be as effective as laparoscopic Nissen fun-
doplication, with fewer side effects, it is not a widely used technique,
probably because there are some studies that report less effective
reflux control using the Toupet, partial-wrap technique.33,34
In two consecutive, prospective, randomized studies per-
formed by the same group, Strate et al.35 and Zornig et al.36 ana-
lyzed patient satisfaction after antireflux surgery during a 2- or
3-year follow-up period. Regardless of the surgical technique
employed (Nissen or Toupet), 85% of patients were satisfied with
the operative result. However, similar to the findings of Lundell
and colleagues, dysphagia was more frequent after Nissen fun-
doplication than after Toupet fundoplication (19 vs. 8, P < .05).
Answer: There is no difference in therapeutic response
between Toupet and Nissen fundoplications performed laparo-
scopically. However, laparoscopic Nissen fundoplication can
cause dysphagia, which is not correlated with esophageal motility.
(Level 1C of evidence; Grade A recommendation.)

Clinical Question Summary

Question
1 Who is at risk for GERD?
2 What is the role and
priority of endoscopy in
GERD?
Answer Level of Grade of References
Evidence Recommendation
Potential risk factors for GERD, including 3 B 2-8
genetic, behavioral, and demographic
factors, have been identified. However, all
of the positive associations have rather
small odds ratios.
Endoscopy with biopsy is recommended in 3 B 12
patients with GERD and dysphagia or in
patients who have not responded to an
empirical trial of PPI therapy.

(Continued)

PMPH_CH06.indd 61 5/21/2012 8:29:59 PM

 62 ■ Surgery: Evidence-Based Practice

(Continued)
Question
3 What is the role of 24-hour
esophageal pH monitoring
in the diagnosis of GERD?
4 What is the mainstay of
therapy for GERD?
5 How does medical
treatment of GERD
compare with surgical
treatment of GERD?
6 Which is the best
fundoplication technique
for treatment of GERD:
total (Nissen) or partial
(Toupet)?
Answer Level of Grade of References
Evidence Recommendation
24-hour esophageal pH monitoring is the 3 B 12-16
gold standard for diagnosing GERD, with a
sensitivity of 79% to 96% and specificity of
85% to 100%.
PPIs provide the most rapid symptomatic 1 A 18, 20, 21
relief and heal esophagitis in the highest
percentage of patients.
Antireflux surgery, performed by an 2 A 18, 25
experienced surgeon, is a maintenance
option for the patient with GERD. In many
patients, medical therapy and surgery
therapy lead to equivalent results.
There is no difference in therapeutic 1C A 26-36
response between the two options.
However, laparoscopic Nissen
fundoplication can cause dysphagia. The
durability of partial fundoplication is
thought to be less than that of Nissen
fundoplication.

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14. Euler AR, Byrne WJ. Twenty-four hour esophageal intralumi-
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15. Richter JE, Castell DO. Gastroesophageal reflux: pathogenesis,
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esophageal pH monitoring: normal values, optimal thresholds,
specificity, sensitivity and reproducibility. Am J Gastroenterol.
1992;87:1102-1111.
17. Hewson EG, Sinclair JW, Dalton CB, et al. Twenty-four hour
esophageal pH monitoring. The most useful test for evaluating
noncardiac chest pain. Am J Med. 1991;90:576-583.
18. DeVault KR, Castell DO; American College of Gastroenterology.
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19. Havelund T, Lind T, Biklund I, et al. Quality of life in patients
with heartburn but without esophagitis: effects of treatment with
omeprazole. Am J Gastroenterol. 1999;94:1782-1789.
20. Johnsson F, Hatlebakk JG, Klintenberg AC, Román J. Symptom
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21. Johnsson F, Hatlebakk JG, Klintenberg AC, et al. One-week
omeprazole treatment: an effective confirmatory test in patients
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and laparoscopy upon hiatal hernia and reflux esophagitis. J Am
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28. Klaus A, Hinder RA, DeVault KR, Achem SR. Bowel dysfunction
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32. Lundell L, Abrahamsson H, Ruth M, et al. Long-term results
of a prospective randomized comparison of total fundic wrap
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oesophageal reflux. Br J Surg. 1996;83:830-835.
33. Fernando HC, Lucketich JD, Christie NA, Ikramuddin S, Schauer
PR. Outcomes of laparoscopic Toupet compared to laparoscopic
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34. Horvath KD, Jobe BA, Herron DM, Swanstrom LL. Laparoscopic
Toupet fundoplication is an inadequate procedure for patients
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35. Strate U, Emmermann A, Fibbe C, Layer P, Zornig C. Laparo-
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5/21/2012 8:29:59 PM
 CHAPTER 7
Inguinal Hernias
George Kasotakis and Marc A. de Moya
INTRODUCTION
Inguinal hernia repair represents the most commonly per-
formed procedure by General Surgeons in the United States with
more than 770,000 repairs performed annually according to the
National Center for Health Statistics.1 These figures have signifi-
cant socioeconomic ramifications, as both the condition and the
operation are associated with significant costs, morbidity, and
affl ict caregivers with a nontrivial burden. Until recently, a belief
commonly held among surgical training programs worldwide
purported that all inguinal hernias be repaired at diagnosis. The
reasoning behind this principle was twofold: early intervention
helped prevent complicating events with unacceptably high mor-
bidity and mortality and allowed a less technically challenging
operation later on. However, a growing body of evidence sug-
gests that the incidence of long-term complications after herni-
orrhaphy might be higher than previously thought, whereas
little is known about the natural history of hernias in men who
elect to not have an operation. Other controversial issues sur-
rounding inguinal hernias include the routine use of mesh and
neurectomies to prevent recurrences and postoperative groin
pain respectively; the role of laparoscopy in unilateral, bilateral,
and recurrent hernias; optimal anesthesia selection for elective
herniorrhaphies; as well as factors predisposing recurrence are
among the topics discussed in this chapter.
1. Should asymptomatic hernias be repaired?
Although the question of whether to intervene in a patient with a
symptomatic hernia is easily answered, defining whether asymp-
tomatic or minimally symptomatic patients warrant hernior-
rhaphy is much more difficult to tackle. The difficulty in this
undertaking lies in estimating the incidence of potentially life-
threatening hernia accidents, which appear to be lower than ini-
tially thought.2,3
Two prospective randomized controlled clinical trials have
been published in the last few years testing the hypothesis that a
strategy of watchful waiting is an acceptable alternative to routine
64
PMPH_CH07.indd 64
repair at diagnosis of an asymptomatic or minimally symptom-
atic hernia in men.4,5
Fitzgibbons and colleagues followed prospectively 720 men
with reducible, minimally symptomatic or asymptomatic ingui-
nal hernias after randomizing them to watchful waiting versus
a Lichtenstein tension-free repair with a prosthetic mesh.4 Pri-
mary outcome measures included worsening pain that inter-
fered with daily activities at 2 years and a change in quality of
life metrics. Both groups developed pain interfering with activ-
ities in equal proportions (5.1% for the watchful waiting group
vs. 2.2% for the surgically treated, P = .52) in the intention-to-
treat analysis. However, 23% of watchful waiting patients had
crossed over to the intervention group by 2 years, citing wors-
ening symptomatology, while 17% of the men assigned to hernia
repair crossed over to watchful waiting. Acute hernia accidents
(bowel obstruction without strangulation) were very rare at a
cumulative accident rate of 0.0018 events per patient-year, and
the patients that presented with those were managed success-
fully with urgent or semielective repairs without significant
complications.
Contrary to popular belief, there appears to be no “penalty”
for delaying operation in the men with minimally symptomatic
or asymptomatic hernias. A follow-up study on the same cohort
of patients assessed a range of objective measures after group-
ing patients in an “immediate” (<6 months) or “delayed” (>6
months) repair group.6 Operative time (64 vs. 67 min, P = .382),
complication (17% vs. 21.5%, P = .375), and recurrence rates
(1% vs. 3.1%), as well as patient satisfaction scores were simi-
lar between the two groups. Watchful waiting also appears to
be a cost-effective approach in managing minimally symptom-
atic patients with hernias7 that does not overburden patients’
caregivers.8
The second trial took place in the United Kingdom and
included 160 males over the age of 55 years with asymptomatic
inguinal hernias.5 The primary outcome was pain at 1 year and
was similar between the two groups. Twenty-three of the 80
observation patients crossed over to repair due to pain or increase
in size. Hernia-related adverse events occurred only in three
5/21/2012 8:45:32 PM

of those, and those were successfully managed with either an
urgent or elective herniorrhaphy after reduction. When the same
cohort of watchful waiting patients were followed for a period of
8 years, more than half (46 out of 80, 57.5%) elected to have their
hernias repaired, with most citing pain or increase in size as an
indication.9 Over the course of the 8 years, only two patients pre-
sented with acute hernia accidents, but neither required bowel
resection.
Given the aforementioned data, it appears that watchful wait-
ing can be safely offered as an option in asymptomatic or mini-
mally symptomatic men with inguinal hernias. (This is a Grade A
recommendation.)
2. Are mesh repairs better than native tissue repairs?
Since the late 19th century, when Bassini introduced the mus-
culoaponeurotic approximation for inguinal hernias,10 the
primary tissue repair dominated the general surgical circles
with multiple variations (Shouldice, McVay) for over a century.
However, it was the unacceptably high recurrence rates of 10%
to 15% that prompted surgeons to look for new approaches.
The concept of “tension-free” repair that was first introduced
by Lichtenstein in the 1980s11 attracted attention early on, as
the addition of a mesh allowed reconstruction without the
need to pull layers of tissue under tension. This technically
easier approach continued to gain ground and multiple pro-
spective randomized trials demonstrated its advantages over
the more traditional native tissue approaches, including a sig-
nificant reduction in recurrence, the ability to perform under
local anesthesia, less pain, and more rapid return to work and
routine physical activities.
In 2001, the Cochrane Collaboration identified 20 prospec-
tive randomized or quasi-randomized clinical trials comparing
open mesh with nonmesh repairs.12 Of those, 17 used a flat mesh,
2 used plug-and-mesh, and 1 used a mesh placed preperitoneally.
The control groups in all studies included a variety of primary
tissue repairs. Despite the marked heterogeneity of the studies
included, it appeared that tension-free approaches required on
average 7 to 10 min less to perform than Shouldice repairs, but
1 to 4 min longer than the Bassini or McVay approach. There was
no statistically significant difference in minor postoperative com-
plications, such as hematoma and seroma formation, or wound
infections. Serious complications, including femoral neurovas-
cular bundle, spermatic cord, and visceral injuries were rare in
both groups. Hospital stay was slightly shorter in the mesh-based
repairs (OR 0.28; 95% CI 0.35–0.22), but significant heterogene-
ity was noted, likely reflecting variability in the local discharge
practices. Return to usual activities/work was also shorter in
the mesh-repair group (OR 0.81; 95% CI 0.73–0.91), and persist-
ing pain or numbness in the genitofemoral area also favored the
tension-free approach (OR 0.68; 95% CI 0.47–0.98 and OR 0.7;
95% CI 0.29–1.72, respectively). Most importantly, recurrence
after mesh repair was consistently less frequently reported and
overall was reduced by between 50% and 75% (OR 0.37; 95% CI
0.26–0.51).
Subsequent prospective trials reported similar findings,
favoring mesh-based repairs over primary herniorrhaphies.13-15
Given the aforementioned data, we conclude that the use of mesh
during open inguinal hernia repair is associated with a significant
reduction in the recurrence risk and may act favorably in reduc-
ing postoperative groin pain and numbness and allowing earlier
PMPH_CH07.indd 65
Inguinal Hernias ■ 65
return to preoperative functioning status. We therefore recom-
mend routine application of mesh-based tension-free inguinal
herniorrhaphy. (This is a Grade A recommendation.)
3. Open or laparoscopic repair for inguinal hernias?
With the improved outcomes and subsequent popularization of
the Lichtenstein herniorrhaphy in the 1980s, and the explosion
of laparoscopic surgery in the 1990s, minimally invasive attempts
at tension-free repairs yielded encouraging results. The dominat-
ing techniques for laparoscopic inguinal hernia repair include the
transabdominal preperitoneal (TAPP) and the totally extraperito-
neal (TEP) approaches.
In an attempt to answer what patient population might benefit
the most from a laparoscopic approach, multiple prospective clin-
ical trials have been conducted. The EU Hernia Trialists Collabo-
ration meta-analysis16 included 41 prospective randomized trials,
comparing laparoscopic to open tension-free herniorrhaphies.
This meta-analysis, that included a total of 7294 patients, demon-
strated no significant difference in recurrence rates between the
laparoscopic and open approach (2.2% vs. 1.7%; OR 1.26; 95% CI
0.76–2.08), but showed a benefit in chronic groin pain in the for-
mer (OR 0.64; 95% CI, 0.52–0.78; P < .001).
Another meta-analysis17 that included 29 prospective ran-
domized trials comprising a total of 5588 patients concluded that
short-term hernia recurrence was higher in the laparoscopically
managed by about 50%, although this result was not statistically
significant (OR 1.51; 95% CI 0.81–2.79). Postoperative compli-
cations were fewer in the laparoscopic group (OR 0.62; 95% CI
0.46–0.84), discharge from the hospital occurred earlier (3.43
hours, 95% CI 0.35–6.5 hours) and patients returned sooner to
normal activity by about 5 days (95% CI 3.51–5.96). The downside
was a slightly longer operative time (15.2 min longer; 95% CI 7.78–
22.63 min).
The Veterans Affairs cooperative trial,18 one of the most
commonly cited trials in the United States, included 1983
patients who were randomized to a tension-free open versus a
laparoscopic repair and had some contradictory fi ndings: Recur-
rence at 2 years was lower in the open group (10.1% vs. 4.9%;
OR 2.2; 95% CI 1.5–3.2), but when the experience of the surgeon
was taken into account (>250 laparoscopic hernia repairs) the
recurrence was low and below 5% with either approach. Com-
plication rate was slightly higher in the laparoscopic group (39%
vs. 33.4%; OR 1.3; 95% CI 1.1–1.3). The laparoscopically treated
patients reported less groin pain at 2 weeks postoperatively and
were able to return to their usual activity 1 day earlier than the
open group.
A more recent meta-analysis from Dedemadi and associates,19
which comprised 1542 patients undergoing laparoscopic versus
Lichtenstein repair, reported similar postoperative complications
and recurrence risk, but noted more recurrences when the TAPP
group was compared with the TEP (RR 3.25; 95% CI 1.32–7.9;
P = .01).
With regard to the optimal approach for managing recurrent
hernias, the Danish Hernia Database analysis,20 which included a
total of 67,306 prospectively recorded herniorrhaphies, demonstrated
a reduced reoperation rate if a laparoscopic approach was used for
the first recurrence (1.3%; 95% CI 0.4–3.0) compared to Lichtenstein
(11.3%; 95% CI 8.2–15.2). Another randomized trial comparing lap-
aroscopic with open repairs for recurrent inguinal hernias21 demon-
strated no difference in operative time or recurrence rates at 5 years
5/21/2012 8:45:32 PM
 66 ■ Surgery: Evidence-Based Practice
(18% for TAPP vs. 19% for Lichtenstein), but postoperative pain and
time to return to work were less with the former.
In summary, laparoscopic repairs offer an equivalent recur-
rence risk and a slightly earlier return to normal activity com-
pared to open repairs, at the expense of longer operative times,
a greater equipment cost, and the need for general anesthesia.
Laparoscopic hernia repairs may offer an advantage for managing
recurrent hernias. (This is a Grade A recommendation.)
4. What are the risk factors for hernia recurrence?
Inguinal hernia recurrence is estimated at <5% with either a
Lichtenstein or laparoscopic repair when performed by experi-
enced surgeons. Using a mesh to reapproximate the tissues in a
tension-free fashion is one of the best known methods employed
to significantly reduce recurrence, however, other risk factors for
hernia recurrence are not clearly delineated.
Mayagoitia et al.22 looked at 551 open hernia repairs per-
formed with either a flat mesh (Lichtenstein), a Prolene Hernia
System or Mesh-Plug and concluded that recurrence was greater
with the latter (2.5%; RR 4.35; 95% CI 0.85–22.23), yet the differ-
ence was not statistically significant. Previous herniorrhaphy, an
internal ring >4.5 cm and postoperative complications were also
found to be predictive of future recurrence.
Data from the Veterans Affairs trial23 demonstrated that
independent predictors of recurrence in the open repair group
were recurrent hernia, lack of a caregiver, and operating time <72
min. Among the patients treated laparoscopically, low surgeon
volume, active lifestyle, and a body mass index (BMI) <25 were
independent predictors.
Although the aforementioned data provide an idea for what
might contribute to a hernia recurrence, larger studies designed to
detect risk factors for recurrence should be performed. (This is a
Grade C recommendation.)
5. Should neurectomy be done routinely for prevention of post-
operative groin pain?
Inguinodynia or chronic groin pain is one of the most dreaded com-
plications following inguinal hernia repair and one that affects qual-
ity of life significantly.24 It is usually attributed to intraoperative nerve
damage or postoperative mesh-related fibrosis. Although traditional
surgical teaching holds that the nerves (ilioinguinal, iliohypogastric,
and genitofemoral) should be identified and preserved during repair,
recent cohort studies demonstrate that routine ilioinguinal nerve
sacrifice is associated with less chronic groin pain, while subjective
paresthesia is usually only temporary.25-27 In addition, ilioinguinal
neurectomy appears to be effective treatment for chronic groin pain
relief after open herniorrhaphy.28,29 However, results of prospec-
tive randomized clinical trials comparing the preservation versus
routine ilioinguinal neurectomy during open tension-free hernior-
rhaphies are conflicting.30-33 In light of the contradictory evidence
and while a Cochrane review is underway, preservation or routine
resection of the inguinal nerves should be left to the discretion of the
treating surgeon. (This is a Grade D recommendation.)
6. What is the optimal approach for bilateral hernias: open or
laparoscopic?
Concurrent repair of bilateral hernias may best be accomplished
laparoscopically. Long-term data demonstrate no difference
in recurrence between bilateral open compared with bilateral
PMPH_CH07.indd 66
laparoscopic repairs,34 and it appears that overall recurrence
(0.63% vs. 0.42%), postoperative complications (1.9% vs. 1.4%),
need for reoperation (0.5% vs. 0.43%), and time to return to previ-
ous activity (14 days vs. 14 days) are the same for unilateral versus
bilateral laparoscopic hernia repair.35
Postoperative complications, operative time, length of stay,
and groin pain appear to favor the laparoscopic approach com-
pared to a Lichtenstein repair in three prospective randomized
trials.36-38 With these data in mind, and given the easier concurrent
access to both groins with the laparoscopic approach, we recom-
mend the TAPP or the TEP for bilateral inguinal hernias. (This is a
Grade B recommendation.)
7. Is a plug necessary for mesh repairs?
Owing to the rising popularity of tension-free herniorrhaphies
over the last few decades, plug-and-patch prostheses, which con-
sist of a “plug” covering the abdominal wall defect and a flat mesh
reinforcing the inguinal canal floor, were developed. The unique
feature of these repairs is that they require minimal dissection,
theoretically allowing for shorter operating times, reducing post-
operative pain and affording earlier recovery. However, these
claims were not confirmed in rigorous clinical trials.
Dalenbäck et al.39 randomized 472 men undergoing tension-
free herniorrhaphy to a Lichtenstein, Prolene Hernia System, or
plug-and-patch repair and followed them for 3 years. Although
operative time was slightly shorter in the latter two groups (40.4
± 1 min vs. 37.4 ± 1 min and 35.5 ± 1 min, respectively), the dif-
ference was not clinically significant. Postoperative complica-
tions, groin pain, return to full functional ability, and incidence
of recurrence did not differ between the groups. Similarly, Nien-
huijs et al.40 randomized 334 patients to the same procedures, and
assessed quality of life and pain with the SF-36 and the visual
analogue scale at 2, 12, and 60 weeks after surgery. There were no
differences noted in either.
Plug-and-patch repair was compared to the Lichentein repair
by Frey et al. In 595 patients undergoing 700 primary or recur-
rent herniorrhaphies there was no differences found in recurrence
rates or postoperative complications.41 Similarly, postoperative
pain and time to recovery did not differ in 141 individuals studied
by Kingsnorth and colleagues.42 Operative time was significantly
shorter in the plug-and-patch group (32 vs. 37.6 min, P = .01), but
the difference was not clinically significant.
On the basis of the above findings, mesh-type selection should be
left to the surgeon’s discretion. (This is a Grade B recommendation.)
8. Local versus general anesthesia: does one confer a better
outcome than the other?
There have been several case series that have described the feasi-
bility and safety of performing inguinal hernia repairs using local
anesthesia.43,44 Other larger database retrospective series have also
suggested that local anesthesia is underutilized as a method for
inguinal hernia repair.45 This has been extended to include lap-
aroscopic hernia repairs,46 as well as open. We focus our question
on the use of local anesthesia versus general anesthesia in open
hernia repairs.
In 2001, Gonullu et al.47 performed a randomized clinical trial
directly comparing the use of local anesthesia to the use of general
anesthesia with a primary outcome of pulmonary effects, postop-
erative pain and fatigue, morbidity, and patient satisfaction. They
demonstrated a significant difference in pain relief but only at one
5/21/2012 8:45:32 PM
 Inguinal Hernias ■ 67

time point (8 hours post-op), but significantly improved CO2 clear-
ance and oxygenation in the local anesthesia group. There was no
significant difference in patient satisfaction. They concluded that
local anesthesia provided slightly better pain control and improved
pulmonary function.
In 2003, O’Dwyer et al. performed a randomized trial compar-
ing local and general anesthesia on 279 patients with ultimately 138
in each group. They found that intraoperative pain led to patient
dissatisfaction but postoperative pain was better at 6 hours than
the general anesthesia group. In addition, they noted that open
repair using general anesthesia was 4% more in cost than local
anesthesia. They concluded that there were no major differences in
patient recovery after local or general anesthesia and patients could
be presented with both options.48
This was followed by a randomized clinical trial compar-
ing local, regional, and general anesthesia in Sweden. There were
approximately 200 patients in each arm of this multi-institutional
trial. The investigators seemed to standardize methods across the
institutions with favorable outcomes for those undergoing local
anesthesia. There was a significant decrease in admission dura-
tion, less immediate postoperative pain, and fewer problems with
urinary retention. However, there was no difference in pain after
the first day and no difference in time to normal activity. This
study suggested that local anesthesia should be used more fre-
quently for open inguinal hernia repairs.49
There is currently a meta-analysis being performed by the
Cochrane Collaboration to evaluate the randomized trials concern-
ing this question. However, after review of the evidence, it appears
as though the use of local anesthesia is safe and effective and in some
patients may be a better alternative to general anesthesia. However,
there is no compelling data that suggest that local anesthesia is supe-
rior to general anesthesia. (This is a Grade B recommendation.)

Clinical Question Summary

Question
1 Should asymptomatic hernias
be repaired?
2 Are mesh repairs better than
native tissue repairs?
3 Does laparoscopy confer
an advantage over open
inguinal herniorrhaphies?
4 What are the risk factors for
hernia recurrence?
5 Should neurectomy for
prevention of postoperative
groin pain be done
routinely?
6 What is the optimal
approach for bilateral
hernias: open or
laparoscopic?
7 Is a plug necessary for mesh
repairs?
8 Local versus general
anesthesia: Does one
confer a better outcome
than the other?
Answer Grade References
Watchful waiting can be safely offered as an option A 4-9
in asymptomatic or minimally asymptomatic men
with inguinal hernias.
Tension-free, mesh-based repairs are associated with A 12-15
decreased recurrences and groin pain, and allow
for earlier return to full activity.
Laparoscopic repairs offer an equivalent recurrence A 16-21
risk and slightly earlier return to normal activity
compared to open herniorrhaphies, at the expense
of longer operating times and the requirement for
general anesthesia.
Native tissue repairs, previous herniorrhaphy, an C 12-15, 22, 23
internal ring >4.5 cm, postoperative complications,
lack of caregiver, and operating time <72 min were
independent predictors for recurrence after open
hernia repair. Low surgeon volume, active lifestyle,
and BMI <25 were predictors of recurrence in
those treated laparoscopically.
Preservation or routine resection of the inguinal D 25-33
nerves should be left to the discretion of the
treating surgeon.
Postoperative complications, operative time, length B 34-38
of stay, inguinal pain, and easier concurrent access
to both groins favor the laparoscopic approach for
bilateral hernia repairs.
The plug-and-patch repair does not offer a clinically B 39-42
significant advantage over flat-mesh repairs in
terms of postoperative complications, chronic
groin pain, return to normal activity, and incidence
of recurrence. Mesh-type selection should be left
to the surgeon’s discretion.
There are no long-term differences between the two. B 46-49
In the short term, there seems to be less pain in
those who undergo local anesthesia.

PMPH_CH07.indd 67 5/21/2012 8:45:32 PM

 68 ■ Surgery: Evidence-Based Practice
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14. Koninger J, Redecke J, Butters M. Chronic pain after hernia
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23. Matthews RD, Anthony T, Kim LT, et al. Factors associated with
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PJ. The measurement of chronic pain and health-related quality
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Hernia. 2008;12:561-569.
25. Zieren J, Tsigris C, Menenakos C. Open tension-free hernia
repair in soccer players: preservation or primary neurectomy of
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inguinal nerve excision in inguinal hernia repairs. Am J Surg.
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27. Tsakayannis DE, Kiriakopoulos AC, Linos DA. Elective neurec-
tomy during open, “tension free” inguinal hernia repair. Hernia.
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28. Loos MJ, Scheltinga MR, Roumen RM. Tailored neurectomy
for treatment of postherniorrhaphy inguinal neuralgia. Surgery.
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30. Malekpour F, Mirhashemi SH, Hajinasrolah E, Salehi N, Kho-
shkar A, Kolahi AA. Ilioinguinal nerve excision in open mesh
repair of inguinal hernia—results of a randomized clinical trial:
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740.
31. Mui WL, Ng CS, Fung TM, et al. Prophylactic ilioinguinal
neurectomy in open inguinal hernia repair: a double-blind ran-
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32. Picchio M, Palimento D, Attanasio U, Matarazzo PF, Bambini
C, Caliendo A. Randomized controlled trial of preservation or
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repair with polypropylene mesh. Arch Surg. 2004;139:755-758;
discussion 9.
33. Ravichandran D, Kalambe BG, Pain JA. Pilot randomized con-
trolled study of preservation or division of ilioinguinal nerve in
open mesh repair of inguinal hernia. Br J Surg. 2000;87:1166-
1167.
34. Kald A, Fridsten S, Nordin P, Nilsson E. Outcome of repair of
bilateral groin hernias: a prospective evaluation of 1,487 patients.
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35. Wauschkuhn CA, Schwarz J, Boekeler U, Bittner R. Laparoscopic
inguinal hernia repair: gold standard in bilateral hernia repair?
Results of more than 2800 patients in comparison to literature.
Surg Endosc. 2010;24:3026-3030.
36. Feliu X, Claveria R, Besora P, et al. Bilateral inguinal hernia
repair: laparoscopic or open approach? Hernia. 2011;15:15-18.
37. Sarli L, Iusco DR, Sansebastiano G, Costi R. Simultaneous repair
of bilateral inguinal hernias: a prospective, randomized study of
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38. Mahon D, Decadt B, Rhodes M. Prospective randomized trial
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39. Dalenbäck J, Andersson C, Anesten B, et al. Prolene Hernia Sys-
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hernia repair: 3-year outcome of a prospective randomised con-
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129; discussion 231.
40. Nienhuijs S, van Oort I, Keeners-Gels M, Strobbe L, Rosman C.
Randomized clinical trial comparing the Prolene Hernia System,
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hernia repair. Br J Surg. 2005;92:33-38.
41. Frey DM, Wildisen A, Hamel CT, Zuber M, Oertli D, Metzger
J. Randomized clinical trial of Lichtenstein’s operation
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5/21/2012 8:45:32 PM
 CHAPTER 8
Esophageal Caustic Injury
Yoram Klein
INTRODUCTION
A caustic substance is defined as a chemical agent that causes tis-
sue injury on contact. Most incidents are due to domestic acci-
dents, affecting mainly children, or suicide attempts among adults.
Approximately 200,000 cases of caustic exposure are reported annu-
ally in the United States, with ingestion being responsible for 5000
of them. This form of exposure carries the highest mortality rate.1
The resulted chemical damage to the upper gastrointestinal tract is
a common problem in acute care surgery that might cause severe
acute and chronic complications. There are three clinical phases of
caustic ingestion: acute, latent, and chronic. In the first few days, the
efforts are focused on stabilizing the patient, establishing the need
for urgent surgical intervention, and an attempt to prevent compli-
cations. In severe cases, those who survived the acute phase will go
into the latent phase that might last for up to 4 weeks. In this phase,
the treatment is focused on maintaining adequate nutritional sta-
tus while dealing with possible systemic complications. The chronic
phase is characterized by the formation of upper gastrointestinal
fibrosis with subsequent strictures. The increased occurrence of
esophageal malignancy among patients who sustained caustic inges-
tion is also considered a late complication of the chronic phase.
Each phase mandates different diagnostic approach and treat-
ment modalities.2
PATHOPHYSIOLOGY
Substances with pH of less than 2 or greater than 12 are considered
to be highly corrosive. Alkali ingestion causes liquefaction necro-
sis of the esophageal wall and lesser damage to the stomach due to
neutralization effect of the gastric acid. In severe cases, the injury
can result in perforation that will cause mediastinitis or peritonitis.
Over the next few days mucosal ulceration will take place. These
processes will lead to intense fibroblastic activity, collagen deposi-
tion, and finally to chronic stricture formation that might appear
after several weeks.3 Acid ingestion causes coagulation necrosis and
tends to affect the stomach more than the esophagus. The severity of
70
PMPH_CH08.indd 70
the damage is determined by the type, quantity, and concentration
of the offensive material together with the time of contact.4 Acid was
believed to cause less severe damage due to the quick eschar for-
mation that prevents further deep penetration, and to its foul taste
and odor that limit incidental ingestion. Nevertheless, studies that
compared the damage potential of acid and alkali found that strong
acid ingestion is more harmful and causes more systemic and local
complications than ingestion of strong alkali substances.5
DIAGNOSIS
1. Can early signs and symptoms predict the severity of the
esophageal or gastric damage?
In most cases anamnesis will make the diagnosis of caustic inges-
tion straight forward, whether it was an accidental or suicidal
event. The extent and location of tissue damage must be evaluated
in a timely fashion in order to plan the treatment and to anticipate
the prognosis. The patient may complain of burning sensation in
the mouth and throat, chest or epigastric pain, nausea and vomit-
ing, odynophagia, or drooling. Respiratory symptoms might sug-
gest exposure by inhalation or aspiration. Most published series
showed that early symptoms may not correlate with the severity of
the tissue damage.6,7 The absence of oropharyngeal signs of injury
upon direct visualization does not rule out significant gastrointes-
tinal tract injury.8,9 It is estimated that around third of the patients
with clinically important esophageal or gastric mucosal injury
will not have signs of oropharengeal burns.
Answer: Although based on low level of evidence (mainly 2b),
the lack of signs and symptoms do not rule out significant esopha-
geal or gastric mucosal injury (Grade B recommendation).
In extreme, rare cases, early laboratory results might show
acute renal failure, acute hepatic insufficiency or disseminated
intravascular coagulation.5 Nevertheless, usually, the laboratory
tests do not contribute to the diagnosis and don’t have an impor-
tant prognostic value.10 Early chest and abdominal plain films are
indicated to exclude pneumoperitoneum or pneumomediasti-
num. Some authors refer to mediastinal or peritoneal free air in
5/21/2012 8:46:17 PM

Table 8.1 Zargar’s Grading Classification of Mucosal
Injury Caused by Ingestion of Caustic Substances
0 Normal examination
1 Edema and hypermia of the mucosa
2a Superficial ulceration, erosions, friability, blisters,
exudates, hemorrhages, whitish membranes
2b Grade 2a plus deep discrete or circumferential ulcerations
3a Small scattered areas of multiple ulceration and areas of
necrosis with brown-black or grayish discoloration
3b Extensive necrosis
the plain fi lms as the most important indication for emergency
operation in the acute phase.11 On the other hand, plain fi lms were
shown to have low diagnostic value.12 In cases where perforation
was not excluded by plain films, an oral contrast enhanced comput-
erized tomography (CT) of the chest and abdomen is indicated.13
Evidence for severe damage in early CT scan, can also predict the
development of late complications in the chronic phase.14 The CT
has replaced the contrast swallow fluoroscopy, which are seldom
used today in the early management of caustic ingestion.
There is a consensus that the most valuable diagnostic tool
in the initial management of caustic ingestion is upper gastroin-
testinal endoscopy. As mentioned before, both lack of symptoms
and the absence of findings in the physical oropharyngeal exami-
nation do not exclude important gastrointestinal mucosal burn.
This makes the endoscopy an obligatory diagnostic study in every
case as stated by most authors. Still, few series reported selective
endoscopy, only for symptomatic patients, as a safe approach espe-
cially in the pediatric population.15,16 The upper endoscopy is used
to diagnose the presence of mucosal damage and to evaluate its
extent. The most commonly used endoscopic grading system for
early caustic gastrointestinal burns was established by Zargar in
1992 (Table 8.1). Grades I and IIA burns will heal most of the time
without any sequelae.3 However, strictures will develop in 70%
to 100% of patients with Grade IIB injury, with circumferential
ulceration, and Grade III injury, with necrosis. High grade inju-
ries will also increase the likelihood of systemic complications in
the acute phase.17 Mortality that was directly related to the caustic
injury was reported mostly for patients with Grade 3 burns.
2. What is the proper timing for endoscopy in the acute phase
of caustic injury?
If perforation is not suspected, endoscopy should be done within
the first 24 hours as stated by most authors.17-19 Few others used
96 hours as the target for early endoscopy.20 No study that spe-
cifically examined the correct timing for endoscopy was found till
date (Level of evidence 3).
Answer: Endoscopy is mandatory and safe after the initial
stabilization of the patient. It should be done within the fi rst
24 hours after admission to the emergency department. (Grade of
recommendation C.)
MEDICAL TREATMENT
If no signs of injury were found in endoscopy, oral feeding can
be resumed as soon as the patient can swallow saliva, and the
patient can be safely discharged from the hospital. In more
PMPH_CH08.indd 71
Esophageal Caustic Injury ■ 71
severe burns the fi rst priority is to maintain a patent airway.
Any sign of oropharyngeal, glotic edema or upper airway burn
should be addressed as a pending airway obstruction and prompt
tracheal intubation is indicated. If the patient is showing signs
of hemodynamic compromise, rapid fluid resuscitation should
be started. Early consultation with the regional toxicology con-
sulting service is also warranted. An attempt to clear the stom-
ach from the offending corrosive agent by inducing vomiting is
strictly contraindicated to avoid the risk of repeated esophageal
exposure. Despite being practiced in several centers, irrigation
of the stomach with neutralizing agents was found to be inef-
fective.21 As mentioned before, any sign of perforation man-
dates immediate surgical exploration. Patients in whom such a
catastrophe was ruled-out are candidates for medical supportive
care. The patient should be on a nothing per os order. Insertion
of nasogastric tube (NGT) should be placed. Nevertheless, no
conclusive data to support this doctrine can be found in the lit-
erature. Except for one retrospective study from the 1980s, no
other studies have challenged the need for NGT. Th is study actu-
ally attributed the low occurrence of late stricture formation to
early insertion of NGT.22 In the acute and latent phase of patients
with severe esophageal burn (Grade 2B and 3), the NGT can be
an important channel for enteral feeding. In cases where gas-
tric injury prevents using the NGT for nutrition support, either
intravenous total parenteral nutrition or enteral nutrition via
surgically inserted feeding jejeunostomy is indicated.
3. Should prophylactic antibiotic therapy be used?
Prophylactic antibiotic is used in several series in order to reduce
occurrence of systemic infection. Like in other clinical scenarios,
prophylactic antibiotic was never found to have any benefit.23,24
(Level of evidence 2B.)
Answer: according to the current evidence, the use of pro-
phylactic antibiotic therapy is not recommended (Grade B).
4. Should corticosteroids be used?
The most common late sequel of caustic ingestion is the formation
of esophageal stricture. Up to third of the patients will develop
this complication between 2 weeks and several years after the
exposure.3 The use of corticosteroids in an attempt to attenuate
the formation of stricture was suggested. Prospective controlled
study of this intervention in the pediatric population failed to
show any benefit.25 In a pooled review of 572 patients, the use
of corticosteroids in Grade 2 and 3 esophageal burns was found
to be ineffective. Th is review also found evidence for increased
morbidity in patients who received corticosteroids therapy.26
Repeated pooled analysis on a larger database showed the same
results.27 (Level of evidence 2C.) There are also scattered reports
on the use of local injection of corticosteroids directly into the
stenotic lesion as an adjuvant to endoscopic dilation. One study
showed the potential of this technically challenging procedure
to reduce the severity of future stenosis.28 Anyhow this interven-
tion never gained popularity and it is rarely used in the clinical
setting.
Answer: The use of corticosteroids for prevention of late
esophageal stricture is not recommended (Grade of recom-
mendation B).
The topical application of the anti fibroblastic agent mitomy-
cin C was investigated in the past several years with inconclusive
results, and continued future investigation is needed.29
5/21/2012 8:46:17 PM
 72 ■ Surgery: Evidence-Based Practice

Endoscopic interventions offer the most effective treat-
ment for esophageal stricture. This can be achieved with
bougienage, balloon dilatation of stent placement. Endoscopic
procedure is considered to be dangerous in days 7 to 21 due
to the increased fragility of the damaged esophageal wall and
the increased risk of perforation. 30 Despite this, there were few
reports on earlier endoscopic dilatation as a safe and effective
preventive measure. 31,32 In a later stage, when fibrotic strictures
are already formed in the esophagus, repeated dilatation is
the treatment of choice. Successful and safe repeated self-
bougienage by the patients in their home was also described. 33,34
The use of endoluminal stents to prevent stricture formation
was described anecdotally in the literature since the late seven-
ties, with various successes. 35,36 No recommendations can be
made in this stage regarding this intervention due to the pau-
city of data.
SURGERY
In the acute and latent phases, signs of perforation or intractable
severe sepsis are indications for immediate surgical intervention.
The main objective is source control of the sepsis, which is achieved
in most instances by esophagectomy with wide debridement and
drainage of necrotic tissue in the mediastinum and/or peritoneal
cavity. Usually, the patient’s systemic and local condition precludes
definitive reconstruction of the upper gastrointestinal tract, and
cervical esophagostomy with feeding jejeunostomy are indicated.
According to the authors experience, the transhiatal esophagectomy
is the most appropriate and safe procedure in this circumstances.
5. What is the indication for surgery in the chronic phase?
In the chronic stage the most common indication for surgery
are strictures that are resistant to repeated endoscopic dilatation
attempts. Lately a defi nition for failed endoscopic dilatation
was introduced. Resistant stricture was defi ned as inability to
reach a minimal luminal diameter of 14 mm during 2 weeks
of endoscopy attempts. Recurrent stricture was defi ned as fail-
ure to maintain this diameter for more than 4 weeks after it
was achieved. 37 It is estimated that approximately half of the
patients with established esophageal stricture will need an
esophagectomy due to failed endoscopic dilatations. 38 (Level of
evidence 3)
Answer: Failed endoscopic dilatation to reach or maintain a
minimal esophageal luminal diameter of 14 mm, together with
clinical incapacitating dysphagia, is an indication for surgery for
esophageal replacement (Grade C).
6. What is the proper timing for definitive surgical interven-
tion in the chronic phase?
Animal studies and physiology research have shown that col-
lagen deposition and fibrotic changes are concluded at least 6
months after the injury. 39 Th is fact suggests that defi nitive recon-
struction should be attempted at least 6 months after the pri-
mary insult, in order to prevent restenosis after the operation.40
Th is is our policy as well, despite reports of earlier successful
esophageal replacement after as early as 2 months postinjury.41
(Level of evidence 3.)
Answer: Definitive surgical procedure for chronic esophageal
stricture after a caustic injury should be attempted after at least 6
months after the incident (Grade C).
Another possible indication for late surgical intervention is
iatrogenic esophageal perforation that can complicate endoscopic
dilatation in up to 0.8% in this setting. Lastly, surgery might be
indicated for the development of esophageal malignancy, which
affected postcaustic ingestion patients 1000 times more frequently
than the general population.42

Clinical Question Summary

Question Answer Grade of References
Recommendation
1 Can early signs and symptoms predict the The lack of signs and symptoms do not B 6, 7, 8, 9
severity of caustic injury? rule out significant esophageal or
gastric mucosal injury.
2 What is the proper timing for endoscopy in Endoscopy should be done within the first C 17-20
the acute phase of caustic injury? 24 hours after caustic ingestion.
3 Should prophylactic antibiotic therapy be The use of prophylactic antibiotic therapy B 23, 24
used? is not recommended.
4 Should corticosteroids be used? The use of corticosteroids for prevention B 25-27
of late esophageal stricture is not
recommended.
5 What is the indication for surgery in the Failed endoscopic dilatation is an C 37
chronic phase? indication for surgery for esophageal
replacement.
6 What is the proper timing for definitive Definitive surgical procedure should be C 39, 40
surgical intervention in the chronic phase? attempted at least 6 months after the
incident.

PMPH_CH08.indd 72 5/21/2012 8:46:17 PM


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10. Chen TY, Ko SF, Chuang JH, et al. Predictors of esophageal stric-
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14. Ryu HH, Jeung KW, Lee BK, et al. Caustic injury: can CT grad-
ing system enable prediction of esophageal stricture? Clin Toxi-
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15. Crain EF, Gershel JC, Mezey AP. Caustic ingestions. Symptoms
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16. Gupta SK, Croffie JM, Fitzgerald JF. Is esophagogastroduodenos-
copy necessary in all caustic ingestions? J Pediatr Gastroenterol
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17. Cheng HT, Cheng CL, Lin CH, et al. Caustic ingestion in adults:
the role of endoscopic classification in predicting outcome. BMC
Gastroenterol. 2008;8:31.
18. Poley JW, Steyerberg EW, Kuipers EJ, et al. Ingestion of acid and
alkaline agents: outcome and prognostic value of early upper
endoscopy. Gastrointest Endosc. 2004;60(3):372-377.
19. Tohda G, Sugawa C, Gayer C, Chino A, McGuire TW, Lucas
CE. Clinical evaluation and management of caustic injury in
the upper gastrointestinal tract in 95 adult patients in an urban
medical center. Surg Endosc. 2008;22(4):1119-1125. Epub 2007
Oct 27.
20. Zargar SA, Kochhar R, Mehta S, Mehta SK. The role of fiberop-
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21. Kirsh MM, Peterson A, Brown JW, et al. Treatment of caus-
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22. Wijburg FA, Beukers MM, Heymans HS, Bartelsman JF, den Har-
tog Jager FC. Nasogastric intubation as sole treatment of caustic
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bined use of steroid, antibiotics and early bougienage against
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diovasc Surg (Torino). 1999;40(2):307-310.
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25. Pelclová D, Navrátil T. Do corticosteroids prevent oesophageal
stricture after corrosive ingestion? Toxicol Rev. 2005;24:125-129.
26. Anderson KD, Rouse TM, Randolph JG. A controlled trial of
corticosteroids in children with corrosive injury of the esopha-
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27. Fulton JA, Hoff man RS. Steroids in second degree caustic burns
of the esophagus: a systematic pooled analysis of fift y years of
human data: 1956–2006. Clin Toxicol. 2007;45:402-408.
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ment the effects of endoscopic dilation in corrosive esophageal
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29. Pace F, Antinori S, Repici A. What is new in esophageal injury
(infection, drug-induced, caustic, stricture, perforation)? Curr
Opin Gastroenterol. 2009;25(4):372-379.
30. Katzka DA. Caustic injury to the esophagus. Curr Treat Options
Gastroenterol. 2001;4(1):59-66.
31. Tiryaki T, Livanelioglu Z, Atayurt H. Early bougienage for relief
of stricture formation following caustic esophageal burns. Pedi-
atr Surg Int. 2005;21(2):78-80.
32. Kochhar R, Poornachandra KS, Dutta U, Agrawal A, Singh K.
Early endoscopic balloon dilation in caustic-induced gastric
injury. Gastrointest Endosc. 2010;71(4):737-744.
33. Bapat RD, Bakhshi GD, Kantharia CV, et al. Self-bougienage:
long-term relief of corrosive esophageal strictures. Indian J Gas-
troenterol 2001;20(5):180-182.
34. Lee HJ, Lee JH, Seo JM, Lee SK, Choe YH. A single center experience
of self-bougienage on stricture recurrence after surgery for corrosive
esophageal strictures in children. Yonsei Med J. 2010;51(2):202-205.
35. Mills LJ, Estrera AS, Platt MR. Avoidance of esophageal stric-
ture following severe caustic burns by the use of an intraluminal
stent. Ann Thorac Surg. 1979;28:60-65.
36. Wang RW, Zhou JH, Jiang YG, et al. Prevention of stricture with
intraluminal stenting through laparotomy after corrosive esoph-
ageal burns. Eur J Cardiothorac Surg. 2006;30(2):207-211.
37. Kochman ML, McClave SA, Boyce HW. The refractory and the
recurrent esophageal stricture: a definition. Gastrointest Endosc.
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38. Adegboye VO, Brimmo A, Adebo OA. Transhiatal esophagec-
tomy in children with corrosive esophageal stricture. Afr J Med
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39. Demirbilek S, Aydin G, Yucesan S, Vural H, Bitiren M. Polyunsatu-
rated phosphatidylcholine lowers collagen deposition in a rat model
of corrosive esophageal burn. Eur J Pediatr Surg. 2002;12:8-12.
40. Han Y, Cheng QS, Li XF, Wang XP. Surgical management of
esophageal strictures after caustic burns: a 30 years of experi-
ence. World J Gastroenterol. 2004;10(19):2846-2849.
41. Munoz-Bongrand N, Gornet JM, Sarfati E. Diagnostic and therapeu-
tic management of digestive caustic burns. J Chir. 2002;139:72-76.
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Crit Care Med. 2002;165(8):1037-1040.
5/21/2012 8:46:17 PM
 CHAPTER 9

Esophageal Tumors
Daniel S. Oh and Steven R. DeMeester

BACKGROUND 1. How should esophageal cancer be clinically staged?

Clinical staging is accomplished through imaging modalities,
Cancer of the esophagus represents 1.1% of cancers in the
and it allows for the rational selection of appropriate therapy
United States, with 16,640 new cases of esophageal cancer in
while minimizing the risk of performing unnecessary surgery in
this country in 2010.1 Despite being a relatively uncommon
patients with systemic disease. It should be noted that in 2010, the
cancer in the population at large, it is highly lethal, and has
7th edition of the American Joint Committee on Cancer (AJCC)
the worst 5-year survival of all malignancies after pancreatic
TNM staging system was published with significant changes, par-
cancer and lung cancer, respectively.1 Moreover, the incidence
ticularly with regard to N staging.4 Rather than being a binary
of esophageal cancer in the Western world is growing faster
staging system of nodal metastases (yes versus no), the new stag-
than all other solid organ malignancies combined, with a 600%
ing system stresses the number of involved nodes as being impor-
rise in incidence between 1975 and 2001. 2 This rapid rise in
tant for outcome, similar to gastric cancer. Further, celiac nodal
incidence has been accompanied by a shift in the histologic
involvement is no longer considered synonymous with systemic
type of esophageal cancers, with squamous cell carcinoma on
metastases or M1 disease, and the location of the involved nodes
the decline and adenocarcinoma on the rise such that in the
is not considered important in the new system.
United States adenocarcinoma has represented the majority of
Over the past decade, two imaging modalities have emerged as
esophageal tumors since 1990. 3 It is well established that the
the mainstays of clinical staging of esophageal cancer, endoscopic
primary risk factor for esophageal adenocarcinoma is chronic
ultrasound (EUS) and integrated PET/CT scans. Combined, these
gastroesophageal reflux disease, a condition that has reached
complementary modalities have been the most reliable and infor-
epidemic proportions in the United States. Caucasian men are
mative ways to assess the depth of primary tumor invasion (T),
the demographic group at the highest risk for this disease, and
the extent of nodal metastases (N), and systemic metastases (M).
esophageal cancer is the fifth leading cause of cancer deaths
For assessment of the T stage of the esophageal lesion, EUS has
in American men aged 40 to 79.1 In the setting of severe gas-
been shown to be the most accurate imaging modality currently
troesophageal reflux disease, a well-characterized sequence of
available. The inherent difficulty of assessing the T stage is primar-
reflux induces mucosal injury such that the damaged squamous
ily due to the thin nature of the esophagus, where the difference
mucosa of the distal esophagus is replaced with columnar
between T1 and T3 is a matter of a few millimeters. Endoscopic
mucosa that can eventually result in intestinal metaplasia or
ultrasound is the only modality with the resolution that allows
Barrett’s esophagus. With further progression of disease, Bar-
such a fine distinction to be made, as the resolution of CT scans
rett’s esophagus can become dysplastic, and ultimately prog-
and MRI cannot distinguish the different layers of the esophagus.
ress to invasive adenocarcinoma.
At the typical 7.5-Mhz frequency, the modality gives a depth of
As with all gastrointestinal malignancies, complete surgical
field of approximately 5 cm. At this time, the best available data
extirpation represents the cornerstone of therapy, but this can
examining the performance of EUS in tumor staging comes from a
only have a benefit when the disease is locoregional. Unfortu-
recent meta-analysis of 43 published studies.5 The pooled sensitiv-
nately, only 23% of newly diagnosed esophageal cancer patients
ity of EUS for T stage ranged from 81.4% to 92.4% and the pooled
present with localized disease, eliminating the possibility of cura-
specificity ranged from 94.4% to 99.4%, depending on the T stage
tive resection in the majority of patients.1 Patients with distant
examined (Table 9.1). EUS is still somewhat limited in sensitiv-
metastases have a poor prognosis, with a 5-year survival of 3%.1
ity for earlier stage tumors, especially distinguishing between T1
Thus, in the evaluation of the newly diagnosed patient with esoph-
and T2 tumors, with equal chances of under- or over-staging intra-
ageal cancer, staging becomes the first priority.
mural disease. Further, with the possibility of using nonsurgical
74

PMPH_CH09.indd 74 5/21/2012 8:47:46 PM


Table 9.1 Summary of Imaging Modalities Used in the Clinical Staging of Esophageal Cancer
Stage Modality Number of Studies Pooled Sensitivity
(95% CI)
T1 EUS 43
T2 EUS 43
T3 EUS 43
T4 EUS 43
N EUS 44
N EUS-FNA 4 0.97 (0.92–0.99)
N CT 17
N PET 10
M CT 7 0.52 (0.33–0.71)
M PET 9 0.71 (0.62–0.79)
options for intramucosal or T1a disease, it is critical to note that
EUS does not have reliable results in accurately assessing these
early tumors despite using higher frequencies of up to 20 MHz.6
As an alternative, an endoscopic mucosal resection with resection
of both the mucosa and submucosa is the most accurate method of
assessing the depth of invasion of a superficial lesion.7 In reviewing
the data on EUS, it should also be noted that like any ultrasound
based modality, the results are highly operator dependent. Finally,
an additional limitation of EUS is that in up to one third of patients
with newly diagnosed esophageal cancer, the tumor is too bulky to
allow passage of the EUS endoscope, although in these scenarios
dilatation to allow accommodation of the EUS instrument may be
considered.
EUS is also the best imaging modality available for assess-
ment of the N stage (Table 9.1). Since the majority of potential
lymph node metastases are located in the region of the esopha-
gus, EUS provides a clear image of the area directly surrounding
the esophagus to assess lymph nodes in the mediastinum and the
abdomen. The best available data on the performance of EUS on
N staging comes from a recent meta-analysis of 44 publications,
which showed a pooled sensitivity of 84.7% and a specificity of
84.6%.5 The inferior performance of EUS in assessing N status
compared to its performance in assessing T status is primarily
due to reliance on the visible characteristics of the nodes. Reli-
ance on visible characteristics such as size greater than 1 cm or
a homogeneous appearing lymph node are not highly reliable in
predicting the pathologic presence of microscopic tumor cells in
a lymph node. More information is achieved when EUS is com-
bined with fine needle aspiration (FNA) to biopsy the node of
interest under real-time ultrasound guidance. On the basis of
a meta-analysis of four publications specifically examining the
performance of EUS-FNA, the pooled sensitivity and specificity
of EUS-FNA to detect metastatic nodes rose to 96.7% and 95.5%,
respectively.5 A major limitation for FNA, however, is that the
needle may potentially have to traverse the tumor to access the
lymph node of interest, which can produce a false positive result,
and therefore FNA is not possible in these circumstances. The use
of a protected needle may be considered to minimize this risk of
contamination.
Perhaps the most important aspect of clinical staging for the
surgeon is to detect systemic metastases or determine the M stage,
since the presence of such disease will preclude curative resection.
PMPH_CH09.indd 75
Esophageal Tumors ■ 75
Pooled Specificity Reference
(95% CI)
0.82 (0.78–0.85) 0.99 (0.99–1.0) 5
0.81 (0.78–0.85) 0.96 (0.95–0.97) 5
0.91 (0.89–0.93) 0.94 (0.93–0.95) 5
0.92 (0.89–0.95) 0.97 (0.97–0.98) 5
0.85 (0.83–0.86) 0.85 (0.83–0.86) 5
0.96 (0.91–0.98) 5
0.5 (0.41–0.60) 0.83 (0.77–0.89) 8
0.57 (0.43–0.70) 0.85 (0.76–0.95) 8
0.91 (0.86–0.96) 8
0.93 (0.89–0.97) 8
The modality that has shown to be best suited for this purpose is
the FDG-PET scan. As evident from a recent meta-analysis of nine
publications, PET scans have improved the sensitivity of detecting
systemic metastases compared to CT scans, although they have com-
parable specificity (Table 9.1).8 More recently, integrated PET-CT
scans have become commonplace due to the convenience of having
the patient undergo both scans in the same setting. Further, this
allows accurate coregistration of the PET and CT data for improved
interpretation of the images. Due to this convenience, integrated
PET-CT has gained popularity as the preferred modality of assess-
ing for distant metastases. Two retrospective single-institutional
studies have demonstrated improved sensitivity and specificity of
integrated PET-CT compared to separate PET and CT scans.9,10
2. Is transthoracic esophagectomy superior to transhiatal
esophagectomy and does extended lymphadenectomy improve
survival?
There is possibly no other area of alimentary tract surgery with
more debate than the subject of the esophagectomy. There are
several different techniques of esophagectomy that are performed
by esophageal surgeons around the world, and the fundamental
argument has centered on whether there is any oncologic benefit
of the more extensive lymphadenectomy that can be achieved in
a transthoracic approach compared to a transhiatal approach.
Proponents of the transthoracic approach argue that it is inher-
ently safer to dissect the esophagus under direct visualization in
the chest and allows for an extended lymph node dissection in
the mediastinum that is beneficial in patients with locoregional
esophageal cancer. Opponents to the transthoracic approach
believe the benefits are outweighed by the additional morbidity
introduced by a thoracotomy, with its attendant pain and pulmo-
nary compromise. In addition, the concept of extended lymph-
adenectomy to improve survival remains controversial.
To date, there have been four prospective, randomized trials
published from 1993 to 2007 comparing the outcomes of transhiatal
and transthoracic resections.11-15 Three of these studies are of
suboptimal quality due to the inclusion of patients who received
adjuvant therapy and a mixture of squamous cell and adenocar-
cinoma pathology. Although no difference in overall survival was
demonstrated in the three studies by Goldminc et al., Chu et al.,
and Jacobi et al., there is a concern for a type II error given the
5/21/2012 8:47:47 PM
 76 ■ Surgery: Evidence-Based Practice
small sample sizes, with a mean of only 23 patients in each arm
in these trials. The best data on this issue comes from Hulscher
and colleagues in the Netherlands.14,15 This prospective, random-
ized control trial was conducted in patients with esophageal
adenocarcinoma and were treated by primary surgical resection
alone without neoadjuvant or adjuvant chemotherapy or radia-
tion. A total of 220 patients were randomized to either transhiatal
or transthoracic esophagectomy with a minimum follow-up of
5 years. All patients had adenocarcinoma of the distal esophagus
or the gastroesophageal junction. The transhiatal resection
removed a mean of 16 nodes compared to 31 nodes with a tran-
sthoracic en bloc resection. After a minimum of 5 years of
follow-up, it was observed that while survival was similar between
the two approaches overall (34% vs. 36%, P = .71), when outcome
was assessed in patients with locoregional disease, defined as hav-
ing 1 to 8 metastatic nodes in the specimen, there was a significant
improvement in disease-free and overall survival with the transt-
horacic approach and its more extensive lymphadenectomy. These
patients, who represented the majority of patients in the trial,
benefited from an absolute improvement in survival of 20% at
5 years (19% vs. 39% for transhiatal and transthoracic resections,
respectively). To place this in context, there have been few innova-
tions in the treatment of esophageal cancer that have resulted in a
20% absolute improvement in 5-year survival in the current era,
either by the introduction of induction chemotherapy or the addi-
tion of adjuvant therapy. Importantly, there was no difference in
in-hospital mortality between the two groups, although the com-
plication rate was higher with the transthoracic approach.
Of interest is the observation that no survival advantage was
observed in the remaining patients based on the transthoracic
approach, in the patients without any nodal involvement, or in the
patients who had more than eight metastatic nodes present. The
finding that transthoracic esophagectomy with extended lymph-
adenectomy benefited only patients with one to eight metastatic
nodes is likely due to the risk of systemic disease that is reflected
by the extent of nodal metastases. When more than eight nodes are
present, systemic disease is nearly always present, and the type of
resection does not matter since locoregional control with an exten-
sive operation is outweighed by the burden of systemic disease. At
the other extreme, when the tumor is early such that there are no
nodal metastases, there is little advantage in removing more nodes
because the disease is confined to the esophagus. This observa-
tion has been noted in the surgical experience with intramucosal
tumors, in which lymphadenectomy does not provide any benefit
to reducing risk or recurrence or survival.16,17 Thus, the survival
benefit of the transthoracic approach in patients with locoregional
disease, which is reflected by the presence of one to eight involved
nodes, is due to the superior locoregional control with the more
extensive lymphadenectomy. In this trial, locoregional recurrence
was 25% in those who underwent transthoracic resection com-
pared to 42% in those who had a transhiatal resection.
Underlying the improved survival associated with the tran-
sthoracic approach to esophagectomy is the principle of extended
lymphadenectomy. Although transthoracic esophagectomy has been
shown to be superior to transhiatal resection, not all transthoracic
operations are equivalent. There is convincing data from around
the world indicating that the more lymph nodes removed allows for
both accurate staging as well as a therapeutic benefit. An analysis of
SEER data from the United States between 1973 and 2003 included
3568 patients who underwent surgical resection for esophageal can-
cer.18 In this epidemiologic study, the number of nodes removed as a
PMPH_CH09.indd 76
continuous variable was an independent predictor of survival,
with the greater number of nodes removed being associated with
improved survival. The optimal number of nodes to be removed was
observed to be ≥ 30 lymph nodes. This benefit on overall survival
was observed in both N0 patients as well as in N1 patients with met-
astatic lymph nodes (6th AJCC Staging System). The survival advan-
tage gained even among N1 patients is evidence that the improved
survival is not a function of stage cleansing or stage migration.
Two recent publications have examined the optimal number
of nodes to remove during esophagectomy using large multi-
institutional, international databases.19,20 Combined, these two pub-
lications encompass nearly 7000 patients with esophageal cancer
who were treated with surgery alone at 21 high-volume academic
centers from North America, Europe, and Asia. The exclusion of
patients who received neoadjuvant and adjuvant therapy allows
for a reliable estimate of the effect of surgery alone on the natural
history of the disease, and the effect of various degrees of lymph-
adenectomy on outcomes. Similar to the SEER data from the United
States, these international studies showed that the number of nodes
removed was indeed an independent predictor of outcome, with
improved survival following more extensive lymphadenectomy. In
one study, the optimal cutoff was found to be 23 to 29 nodes and
in the other study the cutoff was 30 nodes. Each study used differ-
ent statistical modeling in different patient populations, but both
came to a similar conclusion, that a minimum of between 23 and 30
nodes are required to maximize the benefit of surgery, and this is in
line with the conclusions from the SEER data. Interestingly, there
continued to be a benefit with increasing number of nodes removed
above the threshold, and there was no number at which there was
no additional benefit on survival.19 Notably, only the transthoracic
en bloc or modified McKeown esophagectomy allowed for the reli-
able removal of this minimum threshold compared to a simple Ivor
Lewis esophagectomy or transhiatal approach.
3. Does a pyloric drainage procedure improve outcomes of
esophagectomy?
Another issue related to esophagectomy that generates heated
debate is whether or not to perform a pyloroplasty or pyloromyo-
tomy at the time of operation. Since a truncal vagotomy is unavoid-
able for most types of esophageal resection, it was extrapolated
from the historical experience of treating peptic ulcer disease
that a significant proportion of patients would have delayed gas-
tric emptying. However, debate persists as to whether esophagec-
tomy patients really benefit to the same extent as do peptic ulcer
patients from a pyloric drainage procedure. Proponents of routine
pyloric drainage argue that the two primary reasons to perform
such a procedure is to prevent gastric stasis with its attendant risk
of aspiration and to allow for improved gastrointestinal function
and return to regular eating. Those who omit pyloric drainage
argue that the concerns of performing a vagotomy in this setting
are overestimated (particularly with the construction of a narrow
gastric tube), that the procedure introduces unnecessary periop-
erative complications, and that it increases bile reflux and dump-
ing. Moreover, delayed gastric emptying in the current era may be
addressed postoperatively through the use of endoscopic balloon
dilatation or botulinum toxin injection of the pylorus.
In the published literature there have been nine randomized
control trials investigating the effect of a pyloric drainage proce-
dure at the time of esophagectomy and reconstruction. These trials
were compiled in a recent meta-analysis by Urschel and colleagues
5/21/2012 8:47:47 PM

with outcomes combined from 553 patients.21 Over 90% of the
pyloric drainage procedures in the studies were pyloroplasties, but
notably there was a heterogeneous mix of methods of esophagec-
tomy, routes of reconstruction, and technical specifics to the con-
struction of the gastric conduit.21 In particular, it is difficult to
discern the effect of gastric tube width on this issue, since a thin
gastric tube without pyloroplasty may actually function better than
a large remnant stomach with a pyloromyotomy. In these nine stud-
ies, half used a whole stomach, whereas the other half used a gastric
tube. In addition, there was a mix of posterior and anterior (subster-
nal) position of the gastric conduit. Given these differences and the
heterogeneous nature of these surgical methodologies even within
the same trial, the data must be interpreted with caution.
Three of the nine trials reported early postoperative out-
comes with and without a pyloroplasty.22-24 In the meta-analysis,
the only statistically significant difference was a lower rate of
early gastric outlet obstruction in the postoperative period with
a pyloroplasty compared to those who did not have a pyloroplasty
(3.5% vs. 18.3%, respectively; relative risk 0.18; 95% CI 0.03–0.97;
P = .046).21 There was no difference in operative mortality, anasto-
motic leak, or pulmonary morbidity. However, five patients or 3%
who did not have a pyloroplasty suffered a fatal aspiration event
compared to none of the patients who did have a pyloroplasty.
Although this did not reach statistical significance (P = .14), it is
possibly due to the underpowered nature of the study. To place a
3% fatal aspiration rate in perspective, the overall perioperative
mortality of esophagectomy of all causes in high-volume centers
is approximately 3% to 5%. In fact, fatal aspiration events in one
of these trials accounted for all of the postoperative mortalities.22
Complications directly related to the pyloroplasty were uncom-
mon, occurring in 1.7% of the sum of patients from three trials
reporting this data.21 There were no instances of injury to the gas-
troepiploic pedicle or issues reported with conduit shortening.
With regards to the long-term outcomes of pyloric drainage
beyond the immediate postoperative period, the meta-analysis of
the nine randomized control studies showed that while there was
a trend for shorter gastric emptying time, increased intake of food,
and less obstructive symptoms in patients who underwent pyloric
drainage, this did not reach statistical significance.21 Moreover,
there was no difference in dumping or diarrhea between the two
groups. However, there was also a trend for more bile reflux in
the pyloric drainage patients, but again this did not reach statisti-
cal significance. On the basis of the data from these trials, it was
observed that all of these differences between patients with and
without pyloroplasty became less evident as time passed. Thus,
the long-term outcomes between the patients who did and did not
have a pyloric drainage procedure appear to be similar, and the
most beneficial effect of the procedure is protecting against imme-
diate postoperative complications.
DOES CHEMOTHERAPY OR RADIATION
IMPROVE OUTCOME IN SURGICALLY
RESECTABLE PATIENTS?
4. What is the outcome of surgery alone?
Complete surgical resection is the cornerstone of therapy for
locoregional esophageal cancer. However, esophagectomy has
historically been associated with a high perioperative mortality
rate of 10% to 20% compounded by poor survival, especially in
PMPH_CH09.indd 77
Esophageal Tumors ■ 77
the era when the majority of patients were high-risk individuals
with squamous cell carcinoma who had significant smoking and
drinking backgrounds, and presented for surgery severely mal-
nourished. As a consequence, chemotherapy and radiation were
widely adopted as adjuvant therapies to improve outcome. When
interpreting the published data on this issue, however, it is useful
to understand what can realistically be accomplished with surgery
alone in the current era, given the changes in patient demograph-
ics, refinements in surgical technique, and improvement in the
postoperative care of patients. Such data on the baseline results
of surgery alone can place in context the results from trials evalu-
ating the effect of adding chemotherapy and/or radiation to the
treatment of surgical patients.
There have been several retrospective single institution cohort
series reporting outcomes after esophagectomy. At the authors’
own institution, a review of 100 consecutive esophageal adeno-
carcinoma patients treated with transthoracic en bloc esophagec-
tomy provides unique insights into the effect of radical surgical
resection, since none of these patients received neoadjuvant or
adjuvant therapy.25 This series reviewed the experience from 1982
to 2000, when the perioperative mortality rate was 6% overall,
although the rate dropped to 2.5% in the latter time period of the
study. All patients had an R0 resection and 5-year overall survival
was 52.2%, with 1% developing an anastomotic local recurrence,
9% developing regional recurrence, and 31% developing systemic
disease. Thus, in patients who are well staged and resected with
a transthoracic esophagectomy with a removal of a median of 48
lymph nodes, surgery alone can result in much better outcomes
than what was assumed based on historical experience.
The only prospective data on the outcome of surgery alone
comes from the randomized control trial of Hulscher and col-
leagues, in which patients with esophageal adenocarcinoma had
either transthoracic or transhiatal esophagectomy between 1994
and 2000 without any chemotherapy or radiation.14,15 In this series
of 220 patients representing stage I-III of disease, in-hospital mor-
tality for the whole group was 3.2%, and esophagectomy alone
resulted in an overall 5-year survival of approximately 35% (tran-
sthoracic 36% vs. transhiatal 34%). It is important to recognize
that nearly one third of the patients had residual tumor left behind
with either an R1 or R2 resection in both surgical arms, and this
undoubtedly effected the overall survival in a negative manner.
Nevertheless, this prospective trial demonstrates the natural
history of the disease treated with surgery alone at high-volume
esophageal centers in the contemporary era.
5. What is the outcome of adjuvant therapy?
Adjuvant chemotherapy for esophageal adenocarcinoma patients
who have undergone esophagectomy appears to be associated with
slightly improved survival, but the data is sparse and applicability
to esophageal adenocarcinoma must be extrapolated from more
robust gastric cancer data. There has been only one prospective ran-
domized control trial evaluating the role of adjuvant chemotherapy
in patients with esophageal cancer who have undergone resection
with curative intent, reported by Ando and colleagues for the Japa-
nese Clinical Oncology Group.26 All 242 patients had squamous cell
carcinoma, and were randomized into surgery alone versus surgery
followed by two cycles of cisplatin and fluorouracil. Despite 24% of
patients in the adjuvant arm not completing the intended proto-
col, there was an improvement in disease-free 5-year survival in the
adjuvant chemotherapy arm, from 45% to 55% (P = .037).
5/21/2012 8:47:47 PM
 78 ■ Surgery: Evidence-Based Practice

Regarding patients with adenocarcinoma, the best data on
adjuvant chemotherapy in these patients is from a phase II trial
from the Eastern Cooperative Oncology Group (E8296), reported
by Armanios and colleagues.27 This study comprised 59 patients
with tumors of the distal esophagus (16%), gastroesophageal junc-
tion (62%), and gastric cardia (22%). Following surgery with R0
resection at 20 different centers, the protocol consisted of four
cycles of paclitaxel and cisplatin. Eighty-four percent of patients
completed the protocol, and 3-year disease-free survival was 42%.
Since this was not a phase III prospective randomized trial, the
authors used a historical control arm to conclude that this protocol
improved survival compared to surgery alone. This specific his-
torical surgical control arm survival data was extrapolated from
another Intergroup trial28 that had an aberrantly low 2-year sur-
vival rate of 38%. These poor surgical outcomes are not representa-
tive of what can be accomplished with surgery alone in the current
era with an R0 resection, where 5-year survival can be 50%.25
The addition of radiotherapy in an adjuvant setting for
patients with esophageal adenocarcinoma has not been studied in
a prospective fashion. However, data can be extrapolated from the
Southwest Oncology Group (SWOG-9008) trial reported by Mac-
donald and colleagues.29 This trial was a prospective, randomized
control study investigating the effect of adjuvant fluorouracil and
leukovorin with 45 Gy of radiation after gastrectomy compared
to surgery alone. Approximately 20% of the patients had adeno-
carcinoma of the gastric cardia, which is commonly assumed
to be applicable for distal esophageal adenocarcinoma. Notably,
heterogeneity of treatment effect was not performed in this study
to determine if the outcome differed based on tumor location.
There was improved relapse-free 3-year survival in the adjuvant
chemoradiation arm (48% vs. 31%), and the hazard ratio for death
with surgery alone was 1.35 (95% CI 1.09–1.66; P = 0.05). The
applicability of this trial to distal esophageal adenocarcinoma is
speculative and must be interpreted with caution.
6. What is the outcome of neoadjuvant therapy?
In contrast to adjuvant therapy administered in the postoperative
setting, neoadjuvant or induction therapy has several theoreti-
cal advantages. It is assumed to have better tolerability since the
patient does not need to recover from a major operation and subse-
quently could increase the chances of successful completion of the
intended therapy. Further, it is possible that the ability to obtain an
R0 resection is increased due to shrinkage of the tumor. Finally,
the response of the tumor to the therapy can give a good indicator
of the biology of the disease, and its response to the given therapy
may be informative in future management. Neoadjuvant therapy
with chemotherapy alone or in combination with radiation has
been studied for esophageal adenocarcinoma through several pro-
spective trials, in contrast to the investigation of adjuvant therapy.
Neoadjuvant chemotherapy alone followed by surgical resec-
tion for esophageal cancer has been investigated by four phase III
prospective randomized control trials, although one remains in
abstract form (Table 9.2). Three studies concluded that neoadjuvant
chemotherapy improved survival, whereas one study concluded that
there was no difference. The largest published trial is the Medi-
cal Research Council (MRC) OEO2 trial, which randomized 802
patients with esophageal and cardia cancer, of whom two thirds had

Table 9.2 Phase III Randomized Trials in Neoadjuvant Chemotherapy for Esophageal Adenocarcinoma
Study Tumor Adeno- Protocol Patients Curative Survival HR
Location carcinoma Resection (95% CI)
MRC OEO2 Esophagus and 66% Pre-op Post-Op 802 Total R0 Overall HR death
GE junction 5-year
Cis + 5-FU x2 - 400 60% 23.00% 0.84
then surgery (0.72-0.98,
P = 0.03)
Surgery alone - 402 54% 17.00% -
Intergroup Esophagus and 54% Pre-op Post-op 440 Total R0 Overall HR death
113 GE junction 3-year
Cis + 5-FU x3 - 213 62% 23% 1.07
then surgery (0.89–1.32)
Surgery alone - 227 59% 26% -
MAGIC Distal 100% Pre-op Post-op 503 Total R0 Overall HR death
esophagus, 5-year
GE junction, ECF x3 then ECF x3 250 69.30% 36.30% 0.75
stomach surgery (0.60–0.93,
P = .009)
Surgery alone - 253 66.40% 23.00% -
FFCD 9703 Distal 100% Pre-op Post-op 224 Total R0 Overall HR death
esophagus, 5-year
GE junction, Cis + 5-FU x2 or Cis + 5-FU 113 84% 38% 0.69
stomach 3 then surgery in 47.8% (0.50–0.95,
P = .02)
Surgery alone - 111 73%
GE junction = gastroesophageal junction; Cis = cisplatin; 5-FU = 5-fluorouracil; ECF = epirubicin, cisplatin, fluorouracil; HR = hazard ratio.

PMPH_CH09.indd 78 5/21/2012 8:47:47 PM

 Esophageal Tumors ■ 79

adenocarcinoma.30 The neoadjuvant arm consisted of two cycles of
cisplatin and fluorouracil, which was completed by 90% of partici-
pants. After a median follow-up of 6 years, the neoadjuvant chemo-
therapy arm had improved survival compared to the surgery alone
arm with a hazard ratio of 0.84 (95% CI 0.72–0.98; P = .03). Abso-
lute 5-year survival was 23% in the chemotherapy arm compared to
17.1% in the surgery alone arm. However, this trial has been criti-
cized for numerous issues, including a 10% perioperative mortality
rate, a significantly lower complete resection (R0) rate in the surgery
alone arm, and the inclusion of 9% of patients who received con-
current radiation. These issues appear to place the surgical arm at a
disadvantage despite randomization, and could have influenced the
outcome of this trial. In contrast to this study, the Intergroup 8911
trial from the United States, using three cycles of neoadjuvant cispla-
tin and fluorouracil, did not show any survival advantage compared
to surgery alone in a total study population of 443 patients.28
More recently, a prospective, randomized perioperative che-
motherapy trial was reported by Cunningham and colleagues
(the MRC Adjuvant Gastric Infusional Chemotherapy or MAGIC
trial).31 This trial is unique in that it consisted of both a periopera-
tive as well as postoperative chemotherapy regimen, consisting of
surgical resection sandwiched between three cycles of epirubicin,
cisplatin, and fluorouracil (ECF) before and after surgery for a
total of six cycles. This study comprised 503 patients who were
randomized to surgery alone or the perioperative chemotherapy
and surgery protocol. All patients had adenocarcinoma, although
the majority had gastric cancer (74%), with the remainder consist-
ing of gastroesophageal and distal esophageal tumors. Whereas
86% of patients assigned to the chemotherapy and surgery arm
completed the preoperative three cycles of ECF, only 41.6% com-
pleted all six pre- and postoperative cycles. At 4 years of median
follow-up, the group who had perioperative chemotherapy had
a significantly higher likelihood of disease-free survival with a
hazard ratio of 0.66 (95% CI 0.53–0.81; P < .001). Both the local
and distant recurrence rates were lower in the perioperative che-
motherapy group. Overall 5-year survival was 36.3% with che-
motherapy compared to 23.0% with surgery alone. There was no
evidence of heterogeneity of treatment effect when tested accord-
ing to the site of tumor, indicating reliable applicability to patients
with lower esophageal and gastroesophageal adenocarcinomas.
The addition of radiation therapy to chemotherapy in the
neoadjuvant setting followed by surgical resection has been inves-
tigated by five phase III prospective randomized control trials in
esophageal adenocarcinoma (Table 9.3).32-36 The theoretical advan-
tages of adding radiation are to induce greater complete response
rates, improve complete resection rates, and to maintain local
control during systemic treatment with chemotherapy while await-
ing surgery. Of the published trials, only the Walsh trial was limited

Table 9.3 Phase III Randomized Trials in Neoadjuvant Chemoradiation for Esophageal Adenocarcinoma
Study Tumor Adeno- Protocol Patients Curative Survival HR
Location carcinoma Resection (95% CI)
Australia Esophagus 63% Pre-op Post-Op 256 Total R0 Overall HR Death
Cis + 5-FU x1 + 35 - 128 80% NA 0.89
Gy radiation then (0.67-1.19)
surgery
Surgery alone - 128 59% NA -
Michigan Esophagus 76% Pre-op Post-Op 100 Total R0 Overall HR Death
3-year
Cis + 5-FU + - 50 45% 30% 0.73
vinblastine + 45 (0.48-1.12)
Gy radiation then
surgery
Surgery alone - 50 45% 16% -
Ireland Esophagus, 100% Pre-op Post-Op 113 Total R0 Overall HR Death
cardia 3-year
Cis + 5-FU x2 + 40 - 58 NA 32% NA
Gy radiation then (P = 0.01)
surgery
Surgery alone - 55 NA 6% -
CALGB Esophagus, 75% Pre-op Post-Op 56 Total R0 Overall HR Death
9781 cardia 5-year
Cis + 5-FU x2 + - 30 NA 39% NA
50.4 Gy radiation (1.46-5.69)
then surgery
Surgery alone - 26 NA 16% -
CROSS Esophagus, GE 75.20% Pre-Op Post-Op 363 Total R0 Overall HR Death
junction 3-Year
Paclitaxel + - 175 92.30% 59% 0.67
carboplatin x5 + (0.50-0.92)
41.4 Gy radiation
then surgery
Surgery alone - 188 64.90% 48% -

PMPH_CH09.indd 79 5/21/2012 8:47:47 PM

 80 ■ Surgery: Evidence-Based Practice

to adenocarcinoma, with the remaining studies having a mixture
of squamous cell carcinoma and adenocarcinoma. It is apparent
that these trials are significantly smaller than trials examining the
impact of induction chemotherapy alone. Two of these published
trials have shown improved survival with induction chemoradia-
tion: the Irish trial reported by Walsh et al. and the CALGB 9781
trial reported by Tepper et al.32,37 Both of these studies have been
severely criticized and require cautious analysis of the data.
The Irish trial comprised 113 patients with esophageal adenocar-
cinoma who were randomized to either surgery alone or two cycles
of fluorouracil and cisplatin with 40 Gy of radiation followed by sur-
gical resection.32 Complete pathologic response occurred in 25% of
the chemoradiation arm. Median follow-up was only 10 months, and
survival was significantly improved with induction chemoradiation.
The 3-year survival rate was 32% in those who received chemoradia-
tion compared to 6% in those had surgery alone (P = .01). Criticisms
of this study include an unacceptable survival rate for the surgical
arm in the context of what is accomplished with surgery alone in the
current era; the suboptimal preoperative staging that is performed
resulting in incomplete resections; and the short follow-up.
The CALGB 9781 trial also showed a significant improvement
in survival with induction chemoradiation that comprised two
cycles of cisplatin and fluorouracil with 50.4 Gy of radiation.37 This
trial was closed prematurely after 3 years due to poor accrual, with
only 56 total patients enrolled from 18 centers. The majority (75%)
of these patients had adenocarcinoma, and after a median follow-up
of 6 years, improved survival was noted in the neoadjuvant therapy
arm compared to the surgery alone arm. Five-year overall sur-
vival was 39% for 30 patients in the neoadjuvant arm and 16% for
26 patients in the surgery arm. The most significant criticism of
this trial is its lack of power, as it was originally designed to include
475 patients. Such a trial is subject to publication bias given its posi-
tive result and must be interpreted with caution.
The largest neoadjuvant chemoradiation trial to date for
esophageal cancer has been completed in the Netherlands and has
been reported in abstract form.36 This study included 363 patients
who were randomized to five cycles of preoperative paclitaxel and
carboplatin with 41.4 Gy of radiation followed by surgery or sur-
gery alone. Seventy-five percent of patients had adenocarcinoma
and the complete pathologic response was 32.6%. There were sig-
nificantly more R0 resections with neoadjuvant therapy than in
the surgery alone group. Median follow-up was 32 months and
there was improved survival with neoadjuvant therapy compared
to surgery alone, with a hazard ratio of 0.67 (95% CI 0.50–0.92;
P = .011). Three-year survival was 59% in the neoadjuvant arm
compared to 48% in the surgery only arm.
SUMMARY
The surgical management of esophageal cancer is complex, but
there is Level 1 evidence to guide the decision-making process
in the care of patients with this disease (see the following table).
Initial clinical staging of esophageal cancer should be performed
with EUS to determine the T and N stage, and integrated PET/
CT for the M stage (Level 1a). If locoregional disease is present,
there appears to be improved survival with neoadjuvant therapy
followed by surgical resection in many patients (Level 1b). There is
significant variability in the precise protocol of chemotherapy and
radiation used in published trials, and the selection of patients for
neoadjuvant therapy as well as the specific protocol can only be
guided by individual clinician and institutional preference at this
time. If surgical resection is performed, a transthoracic esophagec-
tomy with radical lymphadenectomy results in superior survival
(Level 1b), and a minimum of 23 to 30 lymph nodes should be
removed for both accurate staging and maximal curative effect
(Level 1b). A pyloric drainage procedure is recommended to pre-
vent gastric outlet obstruction that may lead to fatal aspiration in
the early postoperative period, but long-term functional outcomes
do not appear to be different (Level 1a).

Clinical Question Summary

Question Answer Level of Evidence Grade of
Recommendation
1 How should esophageal cancer be EUS is used for T and N staging, and PET/CT Level 1a A
clinically staged? is used for M staging.
2 Is transthoracic esophagectomy Transthoracic esophagectomy results in Level 1b A
superior to transhiatal improved survival compared to transhiatal
esophagectomy? esophagectomy when locoregional disease
(1 to 8 involved nodes) is present.
3 Does extended lymphadenectomy Extended lymphadenectomy improves Level 1b B
improve survival? survival when a minimum of 23 to 30
nodes is removed.
4 Does a pyloric drainage Routine pyloric drainage procedure reduces Level 1a B
procedure improve outcomes of aspiration events in the postoperative
esophagectomy? setting.
5 Does chemotherapy or radiation Neoadjuvant therapy improves survival Level 1b A
improve outcome in surgically in selected patients. Patient selection,
resectable esophageal cancer? specific chemotherapy agents, and the
addition of radiation have not been
standardized.

PMPH_CH09.indd 80 5/21/2012 8:47:47 PM


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27. Armanios M, Xu R, Forastiere AA, et al. Adjuvant chemotherapy
for resected adenocarcinoma of the esophagus, gastro-esophageal
junction, and cardia: phase II trial (E8296) of the Eastern Coop-
erative Oncology Group [erratum appears in J Clin Oncol.
2008;26(22):3819]. J Clin Oncol. 2004;22:4495-4499.
28. Kelsen DP, Winter KA, Gunderson LL, et al. Long-term results
of RTOG trial 8911 (USA Intergroup 113): a random assignment
trial comparison of chemotherapy followed by surgery com-
pared with surgery alone for esophageal cancer. J Clin Oncol.
2007;25:3719-3725.
29. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy
after surgery compared with surgery alone for adenocarcinoma
of the stomach or gastroesophageal junction. N Engl J Med.
2001;345:725-730.
30. Allum WH, Stenning SP, Bancewicz J, Clark PI, Langley RE.
Long-term results of a randomized trial of surgery with or with-
out preoperative chemotherapy in esophageal cancer. J Clin
Oncol. 2009;27:5062-5067.
31. Cunningham D, Allum WH, Stenning SP, et al. Perioperative
chemotherapy versus surgery alone for resectable gastroesopha-
geal cancer. N Engl J Med. 2006;355:11-20.
32. Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N,
Hennessy TP. A comparison of multimodal therapy and sur-
gery for esophageal adenocarcinoma [see comment][erra-
tum appears in N Engl J Med 1999;341(5):384]. N Engl J Med.
1996;335:462-467.
33. Urba SG, Orringer MB, Turrisi A, Iannettoni M, Forastiere A,
Strawderman M. Randomized trial of preoperative chemoradia-
tion versus surgery alone in patients with locoregional esopha-
geal carcinoma [see comment]. J Clin Oncol. 2001;19:305-313.
34. Burmeister BH, Smithers BM, Gebski V, et al. Surgery alone ver-
sus chemoradiotherapy followed by surgery for resectable cancer
of the oesophagus: a randomised controlled phase III trial. Lan-
cet Oncol. 2005;6:659-668.
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 82 ■ Surgery: Evidence-Based Practice
35. Boige V, Pignon J, Saint-Aubert B, et al. Final results of a ran-
domized trial comparing preoperative 5-fluorouracil/cispla-
tin to surgery alone in adenocarcinoma of stomach and lower
esophagus: FNLCC ACCORD07-FFCD 9703 trial. J Clin Oncol.
2007;25:Abstr 4510.
36. Gaast AV, Hagen Pv, Hulshof M, et al. Effect of preoperative
concurrent chemoradiotherapy on survival of patients with
PMPH_CH09.indd 82
resectable esophageal or esophagogastric junction cancer: results
from a multicenter randomized phase III study. J Clin Oncol.
2010;28:Abstr 4004.
37. Tepper J, Krasna MJ, Niedzwiecki D, et al. Phase III trial of tri-
modality therapy with cisplatin, fluorouracil, radiotherapy, and
surgery compared with surgery alone for esophageal cancer:
CALGB 9781. J Clin Oncol. 2008;26:1086-1092.
5/21/2012 8:47:47 PM

The Use of Esophageal Stents
Esophageal cancer is the eighth most common cancer and is the
sixth leading cause of cancer-related death worldwide.1 In the
USA, in 2010, esophageal cancer was diagnosed in 16,640 new
patients and 14,500 esophageal cancer death were recorded2 with
an overall annual incidence of approximately 5.4 cases per 100,000
population.3 The advancement in diagnostic technology, surgical
equipment, and intensive care did not change significantly the
grim overall prognosis.
Most patients (>60%) with esophageal cancer are presenting
with unresectable or inoperable esophageal cancer due to local
invasion, distant metastases, or medical comorbidities. Qua lity of
life takes precedence over long-term prognosis. Several options
exist for esophageal cancer palliation, including best supportive
care, chemotherapy and/or radiation therapy, esophagectomy,
retrosternal bypass, as well as endoluminal therapy, neodymium:
yttrium-aluminum garnet (Nd:YAG) laser, photodynamic ther-
apy, brachytherapy, and stents.4
According to the National Comprehensive Cancer Network
(NCCN) Guidelines for esophageal cancer, the primary objectives
for best supportive care are centered on the restoration and mainte-
nance of the ability to swallow, as well as control of pain and bleed-
ing. The patient’s nutritional status is optimized, and the patient’s
sense of well-being and quality of life are preserved. Endoscopic
stent placement is a well-accepted and effective treatment option
for dysphagia, but it is associated with recurrent dysphagia due
to tumor and tissue in-growth, stent migration, food impaction,
bleeding, perforation, and aspiration pneumonia.
The first successful insertion of an esophageal tube was
reported by Sir Charles Symonds in 1887 and was followed by the
development of plastic esophageal tubes. In 1983, Frimbbeger ini-
tially used expanding spiral metallic stents for the treatment of
malignant esophageal stricture and dysphagia, and their use has
now been well established for palliation of malignant dysphagia.5
1. What are the indications for esophageal stents: Is it only for
palliation?
The safety and efficacy of the self-expending metal stents for the
palliation of malignant dysphagia have been shown in multiple
83
PMPH_CH10.indd 83
CHAPTER 10
Yaron Perry and Robert Jones
studies. In 1993, Knyrim et al. published a controlled prospec-
tive randomized study in the New England Journal of Medicine
comparing metal with plastic stents, and observed 95% to 100%
technical success in using metal stents. In the metal stents group,
they had not reported any complications such as perforation, aspi-
ration or migration, and stent mortality.6
The advancement in the stents’ design and delivery systems
led to their use for other indications in addition to intra-luminal
esophageal cancer and dysphagia. Oral and enteric nutrition are
key to the support of esophageal cancer patients. Stenting the
esophagus early in the stage of concentric narrowing will lead
to better nutrition options such as oral intake of semisolids and
puree diet, and increase the calorie support and quality of life.7
Palliative treatment of malignant esophagopulmonary fistula
has been explored in two major studies discussed below.
Kim et al. reported a prospective analysis of 14 patients with
esophagopulmonary fistula caused by esophageal and broncho-
genic carcinoma. Palliative treatment was done successfully in 12
patients who had complete sealing of the fistula resulting in reso-
lution of aspiration symptoms. A mean survival of 100.9 days was
reported.8
Shin et al. reported the long-term outcomes of 61 patients
with esophagorespiratory fistula after palliative treatment with
covered expandable metallic stents. The clinical success was
80% with mean survival of 93.8 days. In patients with malignant
esophagorespiratory fistula, the option of covered stents prevents
ongoing aspiration and it is used in patients with dismal progno-
sis with an average of 90 to 100 days from stent placement. The
surgical alternative for palliative resection and repair of the fistula
has perioperative mortality of 29% to 47%.9
The initial concern about migration and the older genera-
tion design made palliative treatment underutilized for the relief
of malignant dysphagia due to extrinsic compression. Recently,
Van Heel et al. conducted a prospective single-center study of
50 consecutive patients with extrinsic compression, mostly by
obstructive lung cancer, mediastinal metastases, or extrinsic
local recurrence after esophagectomy. They demonstrated tech-
nical insertion success in all patients. They used self-expandable
5/21/2012 8:46:59 PM
 84 ■ Surgery: Evidence-Based Practice

metallic stents with 10% complication rate, which included hem-

orrhage (6%) and perforation due to prestent dilation (4%). The
median survival was 44 days with median patency of 46 days.10
Until the past few years, it was generally believed that dysphagia
due to extrinsic compression should be treated with an uncov-
ered stent to prevent stent migration.11-13 This will obviate the side
effects of the permanent uncovered stent such as tissue in-growth,
reflux, and risk of aspiration. In the study by Peter D. Siersema on
the use of covered stents, dysphagia improvement and the occur-
rence of complications and recurrent dysphagia were no differ-
ent in patients with extrinsic compression of the esophagus and A B C
in patients with primary esophageal cancer. Only one (3%) stent
migrated to the stomach. These positive results need to be balanced
with the poor overall prognosis of this patient group, with one-
third dying from progressive disease within 30 days after treat-
ment.14 The associated complications that were described with the
early generations of esophageal stents, such as tumor and
tissue in-growth, migration, bleeding, perforation, aspiration and
gastroesophageal reflux, prevented their use in benign esophageal D E
stricture. The new-generation covered stents and the option of
simple retrieval led to a new interest of treating benign strictures
with esophageal stents (Figure 10.1).
Treatment of achalasia with self-expending metal stents
was fi rst described by De Palma in 1998 for patients who failed
medical therapy or pneumatic dilation, or who were poor sur-
gical candidates.15 Only a few reports followed this study.16-19
A recent prospective study by Cheng et al. was published in
World Journal of Gastroenterology, which includes 90 achala-
sia patients who were treated with a temporary self-expanding
metallic stents. Stent retrieval was performed by gastroscopy
4 to 5 days after placement. Treatment success was achieved in
all patients with a patency of the lower esophageal sphincter at F G H
1 month after stent removal, and the dysphagia scores signifi-
cantly improved for all patients. Clinical remission rate in the Figure 10.1 The variety of stents described and stent position-
patient who received 3-cm diameter stent declined slowly from ing. A—Nitinol fully covered stent.** B—Nitinol covered stent
100% at 6 months to 83.3% at the 10 years assessment. 20 The with traction loop.*** C—Plastic covered stents.** D—The Ella
results are encouraging, but still not comparable with the cur- stent is composed of the biodegradable polymer polydioxanone.*
rent long-term success rates of laparoscopic Heller myotomy, E—Introduction systems for the self-expandable stents.**/***
which is a valid option for inoperable patients or patient with F—Fluoroscopic Guidance insertion of esophageal stents; Bar-
multiple comorbidities. ium swallow delineate the stricture. G—Fluoroscopic position-
Apart from palliation of malignant dysphagia, stents are ing and patency proven with oral contrast. H—Final position.
proven to benefit benign stricture and obstruction in the settings *doi:10.1016/j.gie.2010.07.031. How to Cite or Link Using DOI
of achalasia, anastomotic stricture, and esophagopulmonary fis- Copyright © 2010 American Society for Gastrointestinal Endos-
tula (Level 2b evidence; Grade C recommendation). copy Published by Mosby, Inc. **With permission from Boston
Scientific Corporation. ***With permission from Merit EndoTek,
Merit Medical Systems.
2. What are the stents options: Metal versus plastic? Covered or
uncovered? Removable or Permanent?
cardia cancer were randomly allocated to have one of three com-
More than 130 patient series have reported on stent placement for monly used stent types placed (see Figure 10.1): the UltraflexTM
the palliation of malignant dysphagia caused by mid- or distal- stent (UltraflexTM Esophageal NG Stent System, Boston Scientific,
esophageal cancer. These studies have mainly dealt with one Natick, MA), the Flamingo Wallstent (Boston Scientific, MA),
stent type only and cannot be used to compare the effectiveness or the Z-stent (Wilson-Cook Medical, Winston-Salem, NC). 25
of different stent types. A few retrospective studies have com- Both the UltraflexTM stent and Flamingo Wallstent are made of
pared different stent types.21-23 In these studies uncovered stents nitinol and covered at their midsections with a polyester cover.
were used, and it has been convincingly shown that partially or The Z-stent is made of stainless steel and covered with polyethyl-
fully covered stents give better long-term palliation of malignant ene over its entire length. No statistically significant differences
dysphagia than uncovered stents.24 There have been few pro- were found between the stents for dysphagia improvement,
spective studies that have directly compared stent types for the the occurrence of complications, such as perforation or hem-
palliation of malignant esophageal strictures. In one study 100 orrhage, and the occurrence of recurrent dysphagia, as deter-
patients with inoperable mid- and distal-esophageal or gastric mined by stent migration or tissue overgrowth and in-growth.

PMPH_CH10.indd 84 5/21/2012 8:47:00 PM


A trend toward more complications with Z-stents was, however,
observed; this difference would have been statistically signifi-
cant if 150 patients instead of 100 patients had been randomized.
Similar fi ndings with regard to dysphagia improvement and
complications were observed in another study, which was a ran-
domized trial performed in the UK, in which UltraflexTM stents
(n = 31) and Flamingo Wallstents (n = 22) were compared in
patients with malignant dysphagia caused by distal-esophageal
cancer.26 An ongoing issue with stents is the occurrence of recur-
rent dysphagia because of stent migration, tumoral or nontu-
moral tissue growth and food obstruction. Recurrent dysphagia
occurs in 30% to 40% of patients after a mean follow-up of
2 to 3 months.27 Reintervention for stent-related recurrent dys-
phagia is effective in more than 90% of patients.28 According to
Homs group experience, 28 the most effective treatment strategy
for tissue overgrowth or in-growth and stent migration is the
placement of a second stent, or, in some cases of migration, stent
repositioning. For cases of food obstruction, endoscopic stent
clearance is an easy and effective strategy to employ. After treat-
ment for recurrent dysphagia, the median survival of patients
has been shown to be longer than 2 months.28 Reintervention is
expensive because in many cases endoscopy, a new stent, or even
admissions to the hospital is required. To reduce the need for
reinterventions, two new stent designs, the Polyflex® stent (Bos-
ton Scientific) and the Niti-S double stent (Taewoong Medical,
Seoul, Korea), have been developed. Polyflex® stents are made
of silicone and polyester, fully covered, and were designed to
reduce nontumoral tissue overgrowth and in-growth, which is
mostly seen after the placement of partially covered stents made
of nitinol because of hyperplastic tissue growth. By contrast, the
Niti-S double stent was developed to reduce stent migration. It
combines a flare at both ends and a double layer configuration,
with an inner cover and an outer uncovered nitinol wire tube
to allow the mesh of the stent to embed itself in the esophageal
wall. The Polyflex® stent, the Niti-S double stent and the Ultraf-
lexTM stent (the most commonly used stent type worldwide) were
recently compared in a randomized trial including 125 patients
with esophageal or gastric cardia cancer.29 The improvement of
dysphagia and complications was similar for the three stents,
but, overall, it was found that recurrent dysphagia occurred more
frequently with UltraflexTM stents (n = 22 [52%]) than with Poly-
flex® stents (n = 15 [37%]) or Niti-S stents (n = 13 [31%]; P = 0.03).
Of the main causes of recurrent dysphagia, stent migration was
most commonly seen with Polyflex® stents (n = 12 [29%] vs.
UltraflexTM stents n = 7 [17%] and Niti-S stents n = 5 [12%]). Tis-
sue in-growth and overgrowth were more frequent with Ultra-
flexTM stents (n = 13 [31%] and, to a lesser degree, Niti-S stents
n = 10 [24%] vs. Polyflex® stents n = 4 [10%]). Food obstruc-
tion occurred frequently with UltraflexTM stents (n = 10 [24%])
vs. Polyflex® stents n = 2 [5%] and Niti-S stents n = 1 [2%]). In
conclusion, Flamingo Wallstents and Niti-S stents are both
appropriate for the palliation of dysphagia from esophageal can-
cer. The same is probably true for UltraflexTM stents, although
recurrent dysphagia caused by tissue in-growth and overgrowth
or food obstruction occurs more frequently with this stent
design. By contrast, Z-stents and Polyflex® stents seem less pref-
erable in these patients, because, compared with the other stents,
Z-stents are likely to be associated with a higher risk of com-
plications, and Polyflex® stents are more prone to migrate. Also
placement of Polyflex® is technically demanding.
PMPH_CH10.indd 85
The Use of Esophageal Stents ■ 85
Randomized controlled studies have proven the advantage of
metal expandable covered stents from patency rate, migration, and
reintervention rate (Level 2b evidence; Grade B recommendation).
3. What is the optimal insertion technique?
The surgeon must become well acquainted with the stents charac-
teristics, as these devices should not only be able to palliate dys-
phagia from primary esophageal cancer, but also from extrinsic
malignant compression. In this regard, it is important to realize
that various stents differ in characteristics such as radial force,
buckling characteristics, shortening or no shortening on deploy-
ment, and releasing proximally or distally. The selection of stent
type is also influenced by stricture characteristics, such as being
straight or angulated, fully or semi-circumferential, intrinsic or
extrinsic, and location in the esophagus. To predict which types
of strictures are most likely to recur, it is important to differentiate
between esophageal strictures that are simple (i.e., focal, straight
strictures with a diameter that allows endoscope passage) and
those that are more complex (i.e., long [>2 cm], tortuous stric-
tures with a narrow diameter). Complex strictures are considered
refractory when they cannot be dilated to an adequate diameter.
Upper endoscopy is the diagnostic procedure of choice for the
detection of an esophageal stricture and its underlying cause. It
is mandatory that biopsy samples are taken to confi rm whether
the stricture is benign or malignant in nature, particularly if the
suspicion of malignancy is high. We perform all our stent place-
ment procedures in the operating room or in the endoscopy suite
with anesthesia support. The procedures are performed with the
patients under sedation with midazolam, propofol, or general
anesthesia in case we expect prolonged procedure, technical dif-
ficulty and a need for intubation for airway protection. Flouros-
copy is advisable because most of our stent placements are done
under fluoroscopic guidance, before insertion, the proximal
margin of the stricture is marked by radiopaque markers (paper
clip attached to adhesive band can be used as well). Savary dila-
tion over a guide-wire under fluoroscopic guidance is performed
to facilitate the introduction of the stent applicator, in cases of
smaller lumen than the pediatric scope diameter (18F). Subse-
quently the applicator with the uploaded stent was advanced over
the guide-wire and positioned with the proximal radiopaque
marker approximately 2 cm proximal to the marker site. One has
to measure the total length of the stricture and has to select the
correct stent length accordingly. The stent is released under fluo-
roscopic control by withdrawing the transparent external sleeve
while holding the internal pusher stationary. The introducing
systems are unique to each stent’s brand, although these prin-
cipals are universal. Endoscopy is performed immediately after
stent release to confirm the correct positioning and stent expan-
sion across the stricture.
In case of malpositioning or a need to readjust the position of
the stent, most of the current commercial expanded covered stents
have a mechanism. Loop, starts, or side wires facilitate grasping
and pull/push reposition under direct endoscopic vision. We use
the side channel of the adult endoscope to insert biopsy forceps or
endograsper to hold on the stent and reposition it.
Most of the current commercial stents can be repositioned
especially after the initial deployment. Coming back a couple of
days later may result in more technical difficulties, due to full
expansion of the stent, scarring, tissue in-growth, and edema.
5/21/2012 8:47:01 PM
 86 ■ Surgery: Evidence-Based Practice
Occasionally, removal of the stent or repositioning of it in a sig-
nificant distance from its original faulty position has to be done
using an endo-loop or a snare, which grasp the stent circum-
ferentially and can facilitate a distal migration issues. Ingestion
of liquids is usually allowed immediately after stent insertion.
Patients are instructed to progressively resume a puree diet
without any specific restriction. Routine follow-up is 1, 2, 3,
and 6 months. Patients are questioned about relief of dysphagia,
pain, heartburn, or any other symptoms potentially related to
the stent. In any case of dysphagia or significant symptoms, con-
trast radiography is performed, occasionally followed by upper
endoscopy according to presenting symptoms and radiographic
fi ndings.
Proximal Esophageal Cancer
Esophageal cancer that is located close to the upper esophageal
sphincter (i.e., 7% to 10% of all esophageal cancers) has tradi-
tionally been regarded as too difficult to manage with stents. The
reason for this belief is that placing stents at this location was
thought to be associated with a high risk of complications, such
as perforation, aspiration pneumonia, proximal migration, and
patient intolerance caused by pain and foreign body sensation.
Over the last few years, this view has begun to change. Two stud-
ies that included 22 and 104 patients, respectively, reported the
results of stent placement in the proximal esophagus.30,31 In the
latter study, 44 patients had a malignant stricture within 4 cm of
the upper esophageal sphincter. 30 Endoscopic visualization and/
or fluoroscopic monitoring were used to control for precise posi-
tioning of the proximal stent end just below the upper esopha-
geal sphincter. Dysphagia improved in most patients, and the
occurrence of complications and recurrent dysphagia was com-
parable with that in patients who underwent stent placement in
the mid and distal esophagus. In total, 5% to 15% of patients
had foreign body sensation; however, in none of the patients
was stent removal indicated. A recommended technique of stent
removal is to grasp the nylon loop that is attached to the proxi-
mal end of most stents. Th is decreases the stent diameter and
facilitates pulling the stent out. Yoon et al. 31 designed a special
hook to grasp this loop and to remove the stent under fluoro-
scopic control. Although they reported that this technique was
successful in the removal of 127 of 130 stents (98%), the caveat of
this technique is that these loops quite often break during stent
removal. Grasping the proximal end of the stent with a snare or
a rat-toothed forceps can be easily done in the same technique
of repositioning.
Fluoroscopic guidance and endoscopic grasping mecha-
nism (loop, string, etc.) have been proven to be safe and repro-
ducible way to position the esophageal stent (Level 3a evidence;
Grade C recommendation).
4. What is the role of stents in benign esophageal stricture and
anastomotic leak?
The most common causes of benign esophageal strictures include
peptic injury, Schatzki’s ring, esophageal web, radiation injury,
caustic injury and anastomotic strictures. Strictures caused by
radiation or caustic injury and anastomotic strictures are the
most resistant to endoscopic dilation, which is the custom-
ary treatment modality. 32 Although dilation usually results in
PMPH_CH10.indd 86
symptomatic relief, recurrent strictures do occur. To predict
which types of strictures are most likely to recur, it is impor-
tant to differentiate between esophageal strictures that are simple
and those that are more complex.32 In most patients with sim-
ple esophageal strictures, 1 to 3 dilations are required to relieve
symptoms, with an additional 25% to 35% of patients requiring
repeat dilations.33
Strictures that are long (>2 cm), tortuous, or associated with
a diameter that precludes passage of a normal diameter endo-
scope are defined as complex esophageal strictures.31 The most
common causes include radiation injury, anastomotic stricture, 34
caustic ingestion, 35 photodynamic therapy-related stricture, and
severe peptic injury. Severe peptic injury can occur in patients
in the intensive care unit or in mentally disabled people. Com-
plex esophageal strictures are more difficult to treat than simple
esophageal strictures, require at least three dilation sessions to
relieve symptoms, and are associated with high recurrence rates.
If complex strictures cannot be dilated to an adequate diameter
allowing passage of solid food, it will recur within a time interval
of 2 to 4 weeks or require ongoing (more than 7 to 10) dilation
sessions.31 Novel treatment modalities for refractory strictures
include temporary stent placement and incisional therapy. To
prevent recurrence due to in-growth of granulation tissue, the
completely covered Polyflex® stent made of silicone and poly-
ester was evaluated in three retrospective series.36-37 In the first
two series, 36,37 the experience was favorable. In one series, relief
of dysphagia occurred in 17 of 21 patients (81%) after a median
follow-up of 21 months, especially in those with caustic and
hyperplastic (due to partially covered stent placement) stric-
tures.36 In the other series, relief occurred in 12 of 15 patients
(80%) with caustic, post-radiation, anastomotic, or peptic stric-
tures after a median follow-up of 22.7 months.37 No complica-
tions were mentioned in the fi rst series, 36 but in the other study
recurrent dysphagia was seen in 33% of patients, which was
due to mucosal hyperproliferation in four patients and stent
migration in one patient.37 Less optimistic results on Polyflex®
stents have been reported since. Holm et al.38 placed 84 Polyflex®
stents in 20 patients, most with benign or anastomotic strictures.
Migration was the most frequent complication, noted in 18 of 29
patients (62%) and for 53 of 83 stent placements (64%). Hyper-
plastic tissue growth and stricture formation around the stent
were seen in 5 patients (17%) after 15 procedures (18%). Remark-
ably, only 5 of 83 procedures (6%) resulted in long-term symptom
relief after stent removal, which is in line with the experience at
my institution. The management of patients who have refractory
hypopharyngeal strictures after chemoradiation and/or surgery
can be unsatisfactory as normal diameter stents placed in this
location can cause a foreign body sensation, severe pain, fistula
formation, or perforation. Patients with refractory hypopharyn-
geal strictures who have undergone stent placement sometimes
need a feeding tube, but experience difficulties in saliva control.
To prevent the need for a feeding tube and to allow patients to
eat, a cervical Niti-S stent was developed that has a body diam-
eter of 10, 12, or 14 mm. Th is stent is available with or without a
flare that is 2 mm wider than the body diameter and is covered or
uncovered. Th is stent effectively improved dysphagia in a small
series of seven patients.39 As six of the seven patients developed
stent migration and/or granulation tissue in-growth or over-
growth, additional new stents were placed a median of 3 months
after the previous stent placement. Hypopharyngeal strictures
5/21/2012 8:47:01 PM

have a high recurrence rate, and prolonged stent placement with
periodic stent exchanges at intervals of 6 weeks to 3 months is,
therefore, indicated.
In conclusion, Polyflex® stents (plastic stents) have originally
been advocated to be a promising stent type for the treatment of
complex benign strictures. However, recent experience has ques-
tioned this optimistic view and further studies are required to
select the most optimal patient population. In addition to stent
migration, another disadvantage of using Polyflex® stents is that
the stent applicator is large and stiff compared with the applica-
tors used for metallic stents. Dilation before stent placement is
often required. For these reasons, metal stents, particularly par-
tially covered UltraflexTM stents, are recommended to treat benign
esophageal strictures and it is advisable to retrieve the stents 4 to 6
weeks after placement. UltraflexTM stents have the advantage that
they are less likely to migrate than Polyflex® stents. For patients
with complex hypopharyngeal strictures, the use of the modi-
fied Niti-S stents may be beneficial.39 In this study, the best results
obtained with the 10- or 12-mm cervical Niti-S stent types that
are flared and fully covered. The use of covered self-expanding
stents have additionally been used for management of spontane-
ous perforations,40-42 iatrogenic perforations,43 and anastomotic
leaks.44
Freeman et al.40 reported on the use of silicone-coated stents
in 21 patients with spontaneous esophageal perforation all were
placed endoscopically using general anesthesia and fluoroscopy.
Adequate drainage of infected areas was achieved, Leak occlu-
sion occurred in 17 patients (89%). Fifteen patients (79%) were
able to initiate oral nutrition within 72 h of stent placement.
Two patients (10%) with a perforation extending across the gas-
troesophageal junction experienced a continued leak after stent
placement and underwent operative repair. Leak occlusion was
confirmed by esophagram. Stent migration was documented in
four patients (21%) requiring repositioning or replacement. Stents
were removed at a mean of 20 ± 15 days after placement. Hospital
length of stay was 9 ± 12 days.
A recent prospective study,44 one from Germany, included
30 patients with postoperative anastomotic leaks, all were treated
by endoscopic insertion of self-expanding covered plastic stents.
Complete leak healing was obtained in 27 of 30 patients (90%).
The mean healing time was 30 days. In-hospital mortality after
treatment of esophageal leaks with stents was 3% (1 patient). The
second study by Blackmon et al.45 from the department of sur-
gery in the Methodist hospital in Huston Texas reported a mean
follow-up of 15 months, 23 of the 25 patients with esophageal
or gastric leaks during a 15-month period were managed with
endoscopic stenting as primary treatment. Healing occurred in
patients who were stented for anastomotic leakage after gastric
bypass or sleeve gastrectomy (n = 10). One patient with three
esophageal iatrogenic perforations healed with stenting. Eight
patients successfully avoided esophageal diversion and healed
with stenting and adjunctive therapy. Two of the four patients
with tracheoesophageal fistulas sealed, one patient with an upper
esophageal perforation treated successfully with stent place-
ment. These studies imply that stenting is a viable option for the
treatment of esophageal anastomotic leaks and perforations.
PMPH_CH10.indd 87
The Use of Esophageal Stents ■ 87
This treatment modality includes adequate drainage and stents
placement in selected patients. When done selectively it resulted
in rapid leak occlusion, provided the opportunity for early oral
nutrition, while future studies may give more information on
hospital length of stay and comparing its outcomes and morbid-
ity to operative repair.
Multiple reports and prospective nonrandomized study sup-
port the use of removable covered stents in anastomotic leak and
benign strictures (Level 3b evidence; Grade C recommendation).
WHAT IS THE FUTURE?
Future developments in stent design include the development of
biodegradable stents for benign stenoses,46 but another possible
application could be the treatment of malignant dysphagia in
patients undergoing palliative chemotherapy.
Biodegradable stents theoretically represent an ideal treat-
ment approach for refractory benign esophageal stricture patients
because it may provide prolonged temporary patency in associa-
tion with stricture remodeling. The potential efficacy of biode-
gradable stents relies on the simple concept that a stricture that
needs repeat dilation will respond to prolonged dilation with an
endoprosthesis left in situ for several weeks or months. This tem-
porary remodeling of the fibrotic stenosis is obtained with a stent
made of highly biocompatible material that should not induce
mechanical or irritative damage with growth of granulation tis-
sue, new stricture formation, or fistula development. Until now,
few studies have reported the use of biodegradable stents for the
treatment of benign esophageal conditions that could potentially
decrease the need for reinterventions for stent removal.47 In a sin-
gle case series from Japan, 13 patients (2 with caustic strictures,
4 with anastomotic strictures, 7 with esophageal cancer after
endoscopic mucosal dissection) were treated with a biodegrad-
able stent constructed of poly-l-lactic acid monofilaments. Stent
migrations were seen in 10 patients (77%) within 10 to 21 days of
placement, whereas the stent remained in position in 3 patients
(23%). No symptoms of restenosis were observed and further
endoscopic therapies were not required. The same investigators
reported encouraging results in two other patients with posten-
doscopic submucosal dissection, stent placement with the intent
to reduce the risk of esophageal stricture.48
Other developments for malignant esophageal strictures
include the incorporation of Beta-emitting agents49 and cyto-
toxic agents in esophageal stents, which may prevent recurrent
tumor overgrowth at both ends of the stent. An exciting option
for refractory benign esophageal strictures is the possibility of
resecting these strictures with a circular stapling device through
a minimally invasive endoscopic and transgastric approach.50
Finally, it can be anticipated that new devices for endoscopic sur-
gery will be developed, which might provide additional tools for
use in patients with refractory benign strictures.51
Thoracic and esophageal surgeons must be familiar with the
stents options to treat esophageal pathology. They should master
endoscopic skills and have the stenting procedure available as part
of the growing field of esophageal surgery.
5/21/2012 8:47:01 PM
 88 ■ Surgery: Evidence-Based Practice

Clinical Question Summary

Question Answer Levels of Grade of References
Evidence Recommendation
1 What are the Esophageal stents are very useful in providing 2b C 8-14
indications for immediate relief of dysphagia and
esophageal stents: Is represent the treatment of choice in cases
it only for palliation? involving a fistula between the esophagus
and the airway.
2 What are the stents Most of the recent study support the 2b B 23-30
options: Metal versus advantage of metal covered stents over
plastic? Covered the over products, in patency, less
or uncovered? reintervention, and better outcome. Most
Removable or of these type of stents can be removed in
permanent? the initial couple of weeks.
3 What is the optimal Fluroscopic control placement with 3a C 31-33
insertion technique? endoscopic assistance for direct
visualization has been described in most of
the studies to give optimal results.
4 What is the role of Endoscopic insertion of self-expanding 3b C 41-45
stents in benign covered plastic stents in benign stricture
esophageal stricture and in anastomotic leak have been
and anastomotic described in couple prospective studies
leak? with limited recommendation of treatment
in highly selective patient.

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13. De Palma GD, Catanzano C. Removable self expending metal
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20. Ying-Sheng Cheng, Fang Ma, Yong-Dong Li, Ni-Wei Chen, Wei-
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21. May A, et al. Self-expanding metal stents for palliation of malig-
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22. Dorta G, et al. Comparison between esophageal Wallstent and
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Am J Gastroenterol. 1997;92:400-406.
24. Vakil N, et al. A prospective, randomized, controlled trial of
covered expandable metal stents in the palliation of malignant
esophageal obstruction at the gastroesophageal junction. Am J
Gastroenterol. 2001;96:1791-1796.
25. Siersema PD, et al. A comparison of 3 types of covered metal
stents for the palliation of patients with dysphagia caused by
esophagogastric carcinoma: A prospective, randomized study.
Gastrointest Endosc. 2001;54:145-153.
26. Sabharwal T, et al. A randomized prospective comparison of
the Flamingo Wallstent and Ultraflex stent for palliation of dys-
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27. Homs MY, et al. Causes and treatment for recurrent dysphagia
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28. Verschuur EM, et al. New design esophageal stents for the pal-
liation of dysphagia from esophageal or gastric cardia cancer:
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0241.2007.01542.x
29. Dumonceau JM, et al. Esophageal fistula sealing: choice of stent,
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70-78.
30. Verschuur EM, et al. Esophageal stents for malignant strictures
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31. Yoon CJ, et al. Removal of retrievable esophageal and gastroin-
testinal stents: experience in 113 patients. AJR Am J Roentgenol.
2004;183:1437-1444.
32. Lew RJ, et al. A review of endoscopic methods of esophageal
dilation. J Clin Gastroenterol. 2002;35:117-126.
33. Pereira-Lima JC, et al. Endoscopic dilation of benign esopha-
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34. Honkoop P, et al. Benign anastomotic strictures after transhiatal
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35. Poley JW, et al. Ingestion of acid and alkaline agents: outcome
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The Use of Esophageal Stents ■ 89
36. Evrard S, et al. Self-expanding plastic stents for benign esopha-
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37. Repici A, et al. Temporary placement of an expandable polyester
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38. Holm AN, et al. Self-expanding plastic stents in treatment of
benign esophageal conditions. Gastrointest Endosc. [doi: 10.1016/
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39. Conio M, et al. A modified self-expanding Niti-S stent for the
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40. Freeman RK, Van Woerkom JM, Ascioti AJ. Esophageal stent
placement for the treatment of iatrogenic intrathoracic esopha-
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stenting as a new concept of “stent-guided regeneration and re-
epithelialization.” Gastrointest Endosc. 2009;69:1282-1287.
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now and where can we go? World J Gastroenterol. 2008;14:3798-
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43. Salminen P, Gullichsen R, Laine S. Use of self-expandable metal
stents for the treatment of esophageal perforations and anasto-
motic leaks. Surg Endosc. 2009;23:1526-1530.
44. Sandha GS, et al. Expandable metal stents for benign esophageal
obstruction. Gastrointest Endosc Clin N Am. 1999;9:437-446.
45. Blackmon SH, Santora R, Schwarz P, et al. Utility of removable
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46. Fry SW, Fleischer DE. Management of a refractory benign
esophageal stricture with a new biodegradable stent. Gastroin-
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47. Repici A, Vleggaar FP, Hassan C, van Boeckel PG, et al. Efficacy
and safety of biodegradable stents for refractory benign esoph-
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48. Saito Y, Tanaka T, Andoh A, et al. Novel biodegradable stents for
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dissection. Dig Dis Sci. 2008;53:330-333.
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5/21/2012 8:47:01 PM
 Commentary on
The Use of Esophageal Stents
The chapter entitled “The Use of Esophageal Stents” by Drs. Perry
and Jones provides an excellent literature review on the history, use,
and types of esophageal stents. It also provides an excellent sum-
mary of their use in: (1) malignant obstructions, including both
intrinsic strictures and extrinsic compression; (2) esophagorespi-
ratory fistulas; (3) achalasia; (4) benign strictures; and (5) esopha-
geal leaks, both from anastomotic disruptions and perforations. It
also provides what I consider to be a detailed description of the dif-
ferent types of stents available, their indications, the pros and cons
concerning their use, and the future of esophageal stenting.
Esophageal stenting has emerged as an important adjunc-
tive tool in treatment of esophageal diseases. As is common with
many new and emerging technologies, esophageal stenting was
initially met with some skepticism, especially when considered
as treatment for historically difficult-to-treat problems such as
tracheoesophageal fistulas and anastomotic leaks, which had
up until relatively recently either been treated nonoperatively—
providing little to no palliation—or alternatively with large-scale
operations associated with significant morbidity and mortality.
However, as the use of esophageal stents for treating such difficult
problems have been studied and experience gained, indications
for their use has generally increased in popularity, and skepticism
for their use lessened. Although esophageal stenting has been
around a relatively long time for the treatment and palliation of
malignant strictures, their use was always tempered by tissue and
tumor in-growth, as well as their inability (or at best, difficulty)
to remove due to the fact that they were uncovered, exposing the
metal interstices as a lattice to the in-growth of tissue and tumor.
However, with the advent of covered stents a whole new range of
esophageal pathology is now able to be palliated and definitively
treated with esophageal stenting. In addition, their placement
and removal can be done with relative ease even in the endos-
copy suite under moderate sedation as an outpatient procedure.
As their use increases for palliation of terminal disease however,
an inevitable increase in the emergence of “stent-related compli-
cations” will occur, altering terminal events and time frames.
One example of this is stenting of a tracheoesophageal fistula that
results after treatment of a bulky, inoperable cervical esophageal
cancer treated with combined chemoradiotherapy. Such a fistula
is doomed to heal, yet placement of a stent can provide additional
survival benefit preventing both fatal aspiration as well as what
would otherwise be nutritionally depleting dysphagia. Although
placement of a stent in this situation can actually prolong life, it
90
PMPH_CH10.indd 90
Scott B. Johnson
does so modestly and the ultimate outcome remains poor. How-
ever, instead of the terminal event being aspiration or malnutri-
tion, the immediate cause of death may shift to aortic erosion and
bleeding, or, alternatively, mediastinal sepsis. Often patients get
such good palliation that they forget the severity of their disease.
One such example is a patient that had an inoperable esophageal
cancer causing both obstruction and airway fistulization that was
treated with a total of three stents in his esophagus, placed one
inside the others. His esophagus essentially ended up being a lead
pipe, although he continued to swallow without significant signs
or symptoms of aspiration or dysphagia for a prolonged period of
time. He kept returning expecting additional palliation and suc-
cess until no further stents could be placed, at which time a diffi-
cult discussion was had with the patient and his family. However,
it is without question that without the stents the patient would
have died several months earlier although from a different termi-
nal event.
Covered esophageal stents are relatively easy to deploy, easy
to remove, and usually only cause relatively minor, if any compli-
cations when initially inserted. Most complications are secondary
to stent migration or obstruction and only cause minor problems
such as abdominal pain or dysphagia, usually easily treated with
stent removal and when necessary, replacement. Serious compli-
cations are relatively rare but do occur, and include erosion into
the adjacent aorta, as well as fistulous erosion into the trachea
possibly secondary to pressure necrosis, although the underlying
disease process and its primary treatment continue to be contrib-
utory factors.
Even though the level of evidence supporting recommenda-
tions regarding using esophageal stenting is generally inadequate
to permit firm conclusions regarding definite indications and
contraindications for their use, the authors have done an excel-
lent job in reviewing the available literature regarding the clinical
applications of esophageal stents. Despite their potential draw-
backs, esophageal stents can successfully treat esophageal leaks,
anastomotic dehiscence, airway fistulas, undilatable strictures,
and iatrogenic injuries that would have otherwise been devastat-
ing complications to either palliate or definitively treat, requiring
either long-term hospitalizations at best, or extensive, comman-
do-type operations to correct when more conservative treatment
has failed. As such, they have become an invaluable and an indis-
pensible tool that every esophageal surgeon should be comfort-
able and facile to use and deploy.
5/21/2012 8:47:01 PM

Neoadjuvant and Adjuvant
Treatment of Esophageal Cancer
J. Camilo Barreto and Mitchell C. Posner
INTRODUCTION
Esophageal cancer is a highly lethal tumor. Despite continued
attempts to improve outcomes with adjuvant or neoadjuvant ther-
apy, long-term survival remains poor. There has been significant
progress in reducing perioperative morbidity and mortality in
the past decades as a result of improved surgical techniques and
perioperative management. However, the oncologic outcomes of
surgical resection alone are unacceptably low, yielding 5-year sur-
vival rates in the range of 10% to 30%.1-3 The majority of patients
succumb to metastatic disease, underscoring the need for sys-
temic treatment. The fact that most patients are diagnosed at a
locally advanced stage has stimulated the use of combined modal-
ity therapy, especially in the neoadjuvant setting, in an effort to
improve outcome. Numerous regimens and combinations have
been evaluated in clinical trials in the past decades, including che-
motherapy and radiation therapy (RT), alone or in combination in
the perioperative setting. Other studies have suggested a role for
definitive chemoradiotherapy (CRT) without surgical resection.
Despite multiple published trials and some progress achieved in
treatment outcomes, there is still significant room for improve-
ment and many questions remain unanswered regarding the best
approach to treat esophageal cancer. The pathology and treatment
of cervical esophageal cancer (usually with squamous cell histol-
ogy) is more similar to that of other head and neck cancers. For
this reason, this chapter will be more focused on adjuvant and
neoadjuvant treatment of carcinoma of the thoracic esophagus
and GE junction.
1. What are the proper diagnostic and imaging studies prior to
and during treatment of esophageal cancer?
ANSWER: The initial diagnosis of esophageal cancer is achieved
with upper endoscopy and tissue biopsies to obtain histologic
confirmation. In addition, histologic diagnosis is a prerequisite
if either RT and/or chemotherapy is being planned. Since tumor
91
PMPH_CH11.indd 91
CHAPTER 11
stage influences therapeutic decisions, the next step to define
further treatment consists of the imaging workup to adequately
characterize the tumor, nodal and metastatic (TNM) extent of the
disease. For this purpose, imaging studies can be broadly catego-
rized according to whether they are used for local, regional, or
systemic staging.
Endoscopic ultrasound (EUS) is most commonly used for
local tumor staging and for regional lymph node assessment. Ret-
rospective studies have shown higher accuracy of EUS (76%–89%)
compared with computed tomography (CT) scan (50%) for pri-
mary tumor staging.4 For lymph node staging, the accuracy of EUS
ranges from 70% to 80% compared with 50% for CT scan.4 Based
on morphology alone, EUS may not be capable to discriminate
between metastatic and enlarged benign lymph nodes. However,
EUS-guided fine needle biopsy (FNA) can improve the accuracy
for nodal staging up to 90%.5 EUS has also demonstrated to be
superior to magnetic resonance imaging (MRI) and 18fluorodeox-
yglucose (FDG) positron emission tomography (PET) in local and
regional staging.6,7 An analysis by Lowe et al.7 showed an accuracy
of 71% for EUS in local tumor staging, compared with 42% for CT
or PET. However, the sensitivity and specificity between the three
modalities was not different for lymph node staging. In addition
to these reports, a meta-analysis by Van Vliet et al.6 showed that
EUS has higher sensitivity (80%) than CT (50%) and FDG-PET
(57%) for detection of regional lymph node metastases, although
lower specificity (70%, 80%, and 83%, respectively). The same
study also demonstrated the superiority of EUS to detect celiac
lymph node involvement.
CT scan of the chest and abdomen is currently used routinely
in most centers to assess local tumor extent but most importantly
to rule out disseminated disease. However, PET has been added
recently to the staging armamentarium of esophageal cancer as
it can change the treatment plan in up to 20% of patients.8-10 In
the aforementioned meta-analysis by Van Vliet et al.,6 FDG-PET
showed an increased sensitivity for distant metastases (71%),
when compared with CT scan (52%), and both imaging modalities
5/21/2012 8:49:05 PM
 92 ■ Surgery: Evidence-Based Practice
demonstrated high specificity (>90%). In a prospective study of
74 patients, Flamen et al.8 showed that PET had a higher accu-
racy to diagnose stage IV disease compared with CT scan and
EUS combined (82% vs. 64%). Although it was less sensitive than
EUS for nodal staging, its specificity was higher (98%) than CT
and EUS combined (90%). Another retrospective analysis by van
Westreenen et al.9 found that the number of unnecessary explora-
tions due to metastatic disease could be reduced from 44% when
patients were staged with CT scan alone to 21% if patients had
a preoperative FDG-PET scan. The ACOSOG trial Z0060 was
designed to define the role of FDG-PET in the detection of meta-
static disease after patients had completed conventional staging
with CT scan. FDG-PET identified unsuspected metastatic disease
that was subsequently confirmed by biopsy or further work up in
4.8% of patients, with an additional 3.7% histologically uncon-
firmed cases.10 More recently, FDG-PET has been combined with
CT images (PET-CT) to complement the functional and anatomic
information provided by both modalities.
PET scan has shown another potential role in assessing tumor
response during systemic treatment for esophageal cancer. An
objective metabolic response, manifested by a decrease in the FDG
standard uptake value (SUV) in the primary tumor, correlates with
improved histopathologic response and survival compared with
patients who do not respond,11,12 and can help to tailor treatment
depending on response.11 In addition, the proportional decrease in
SUV seems to correlate with the survival outcome after treatment,
and higher preoperative SUV has been correlated with decreased
survival.13 It should be noted that in these reports, a PET response
was not an accurate predictor of pathologic complete response.
2. Should adenocarcinoma and squamous cell carcinoma (SCC)
of the esophagus be treated differently?
ANSWER: Adenocarcinoma and SCC of the esophagus are dis-
tinct histologic entities that should be studied and managed as
such. Although some risk factors are common for both tumor
types, such as smoking and previous RT to the mediastinum,
other factors are more histologic-type specific (i.e., chronic irri-
tation conditions and alcohol abuse predispose to SCC, whereas
gastroesophageal reflux disease, Barrett’s metaplasia, and obe-
sity are risk factors for adenocarcinoma). In addition, while SCC
tends to be more common in endemic areas of the world, in the
USA adenocarcinoma has become more prevalent in the last three
decades. This is a germane consideration when examining the
published literature on therapeutic approaches, since older stud-
ies usually included a higher proportion of patients with SCC, and
still a significant proportion of recent studies have included mixed
populations with both histologic types. However, a more careful
analysis of the current evidence can provide some clues to the
value of a tailored therapeutic approach to each tumor type.
Due to the significant morbidity and mortality associated
with esophagectomy, and level 1 evidence of improved outcomes
with CRT compared with RT alone without surgery, some inves-
tigators have suggested that patients with esophageal cancer may
derive an equivalent benefit from definitive CRT alone. Two trials
have directly addressed this question in patients with SCC of the
esophagus. The German Esophageal Cancer Study Group14 ran-
domized 172 patients with locally advanced (T3 and T4) SCC of
upper- and mid-third esophagus to CRT followed by surgery ver-
sus CRT alone. Sixty-six percent of the patients in the surgery arm
group ultimately underwent resection. In the intention-to-treat
PMPH_CH11.indd 92
analysis, the trial demonstrated comparable 2-year overall sur-
vival (OS) in both treatment groups (39.9% vs. 35.4% respectively),
although the group that underwent surgery had better 2-year local
progression-free survival (64.3% vs. 40.7%). Notably, patients in
the surgical group also had a lower rate of cancer-related mortal-
ity, but this was offset by an increase in treatment-related mor-
tality (12.8% in the surgical group vs. 3.5% in the definitive CRT
group). The FFCD 9102 trial,15 in which 90% of the patients had
a diagnosis of SCC, included 259 patients with T3 tumors. The
main difference with the German trial was that only patients who
responded to initial CRT were then randomized to definitive CRT
or resection. In a similar fashion to the German trial, there was
no significant difference in 2-year OS (40% vs. 34%, respectively),
although there was a higher frequency of locoregional recurrence
in the group without surgery. The 3-month mortality was 9.3%
in the surgical group, compared with 0.8% in the definitive CRT
group. From these two trials it can be concluded that in patients
with SCC tumor, response correlates with a better prognosis, and
that in patients who respond, definitive CRT is an acceptable
alternative to resection, with lower treatment-related mortality
although with a higher risk of local recurrence. Non-responders
have a worse prognosis, but salvage surgery may play a role if an
R0 resection is accomplished.14 These trials provide high-level evi-
dence favoring definitive CRT for patients with SCC histology, but
suggest that if perioperative mortality is minimized, that onco-
logic outcome may be enhanced with the addition of resection.
In patients with adenocarcinoma histology, the available
literature has focused more on the value of combining chemo-
therapy and/or RT with surgery, rather than assessing the role of
surgery. Many randomized trials have been conducted to compare
multimodality therapy including surgery with surgery alone.16-19
Despite the fact that most centers routinely use combined therapy
as the standard of care, the available literature has shown confl ict-
ing results, and based on evidence, its role in improving the out-
comes of surgical treatment remains under investigation. For this
reason, surgery remains the cornerstone of therapy in patients
with adenocarcinoma and is the preferred option, generally in the
context of multimodality therapy. The trials comparing multimo-
dality therapy with surgery alone will be addressed in more detail
in the following sections.
3. What is the role of adjuvant or neoadjuvant RT alone in
esophageal cancer?
ANSWER: RT has the theoretical advantage of increasing local
control rates either by decreasing the tumor size before resection
thereby maximizing the chance for an R0 resection or by treat-
ing residual microscopic disease when administered after surgery.
However, it is also associated with a higher risk of complications
due to fibrosis and impaired healing. There have been five ran-
domized trials evaluating RT alone in the adjuvant setting and
another five trials for neoadjuvant RT with varying patient num-
bers. None has demonstrated a benefit in OS. The two largest tri-
als were conducted by French and Chinese investigators. Ténière
et al.20 randomized over 200 patients with SCC of the esophagus
after curative resection to 45 to 55 Gy versus observation. Post-
operative irradiation did not improve survival, although there
were fewer recurrences in the radiation group. In the only study
to show more favorable results, Xiao et al.21 randomized almost
500 patients to doses of 50 to 60 Gy postoperatively. In this study,
there was no OS benefit with the addition of RT (32% vs. 41%;
5/21/2012 8:49:05 PM

P = 0.44). In the subgroup of patients with lymph node metastases
and stage III, they found a survival benefit. Other trials22-24 have
failed to show a survival advantage, and although they were gen-
erally associated with better local control rates, there were also
increased complication rates in the group treated with radiation.
Five randomized trials have assessed the value of neoadjuvant RT
and none have demonstrated a significant benefit with the use of
RT alone;25-29 a meta-analysis from the Cochrane collaboration
did not find clear evidence of a benefit from neoadjuvant RT.30
Although not a trial of adjuvant or neoadjuvant therapy, the
RTOG 850131 was a landmark trial to establish the superiority of
CRT over RT alone for definitive treatment of esophageal cancer.
One hundred and twenty-three patients, most with SCC, were ran-
domized to either CRT or RT, without surgery, and even though
the CRT group received a lower dose of radiation, there was a ben-
efit with combined therapy with regard to OS, local recurrence
and distant metastases rates.
Given these results and considering that generally better
outcome has been reported with combined modality therapy, RT
alone is not usually indicated in the adjuvant or neoadjuvant set-
ting. Its main role is for palliation of symptoms in patients who
are deemed not candidates for surgery.
4. Is preoperative CRT better than preoperative chemotherapy
alone for esophageal cancer?
ANSWER: In North America, most cancer centers use neoad-
juvant CRT as the standard of care as opposed to neoadjuvant
chemotherapy alone for patients with esophageal cancer. Current
evidence suggests that the advantages of CRT over chemotherapy
include higher rates of R0 resection, complete pathologic response,
and local tumor control. However, no consistent improvements in
OS have been demonstrated.
The trials examining preoperative chemotherapy versus
surgery alone have shown conflicting results. Older studies
included, in the main, patients with SCC who were underpowered
and did not demonstrate a significant benefit with preoperative
chemotherapy.29,32,33
More recent and larger trials, including patients with both
histologies have reported inconsistent results.1,34,35 The Intergroup
trial 113,1 which included 452 patients, did not demonstrate a ben-
efit from preoperative chemotherapy when compared with surgery
alone, although most patients did not complete the intended regi-
men. In contrast, a similar trial from the British Medical Research
Council34 enrolled 802 patients, most of who had adenocarcinoma,
and showed a significant improvement in OS for both tumor his-
tologies (43% in the neoadjuvant chemotherapy group vs. 34% in
the surgery alone group at 2 years). The Medical Research Council
(MRC) also conducted the MAGIC trial35 in patients with gastric
and gastroesophageal junction adenocarcinoma, in which one-
fourth of the patients had adenocarcinoma of the distal esophagus.
It compared pre- and postoperative chemotherapy with resection
alone. There was a significant benefit in 5-year survival favoring
the perioperative chemotherapy group (36% vs. 23%), although it
was not specifically powered for patients with esophageal cancer.
There have been several trials conducted evaluating concur-
rent preoperative CRT versus surgery alone. Five of these trials
have included 5-fluorouracil (5-FU)- and cisplatin-based CRT reg-
imens. Walsh et al.17 reported improved OS with CRT (32% vs. 6%
at 3 years) in patients with adenocarcinoma, as well as increased
median survival (16 months vs. 11 months). The much lower than
PMPH_CH11.indd 93
Neoadjuvant and Adjuvant Treatment of Esophageal Cancer ■ 93
expected survival in the surgery-only arm (6% 5-year survival)
raises a cautionary note in this trial. Following this report, three
other randomized trials2,16,18 failed to demonstrate a benefit in OS
with the use of preoperative CRT. The EORTC trial,2 designed
for patients with SCC, showed improved DFS in the combination
group, but an OS benefit may have been potentially compromised
by a high postoperative mortality rate. The trials from the Uni-
versity of Michigan16 and the Australasian Group18 did not show
an improvement in OS. The former was underpowered to demon-
strate an OS benefit while the latter delivered lower than standard
doses of both chemotherapy and RT. Finally, although the Cancer
and Leukemia Group B (CALGB) 9871 trial19 demonstrated an
impressive improvement in OS in the combined treatment group
(39%) versus the surgery-only group (16%), this trial was closed
early after accruing only 56 of 500 planned patients with adeno-
carcinoma of the esophagus and therefore the results are suspect.
Only one trial compared directly preoperative chemotherapy
with preoperative CRT.36 One hundred and twenty-six patients
with locally advanced adenocarcinomas of the GE junction were
randomly assigned to either treatment, followed by surgery. Again,
accrual goals were not achieved, although a trend toward improved
3-year survival (47.4% vs. 17.7%) and higher rates of pathologic
complete response were observed in the trimodality group.
A recent report provides the best evidence to date of the
potential value of preoperative CRT. The phase III CROSS study
compared a more modern regimen of carboplatin, paclitaxel, and
concurrent RT with surgery alone in resectable esophageal or
EG junction cancers.37 The combined treatment group had sig-
nificantly improved OS (HR 0.67) and R0 resection rates (92% vs.
65%). Importantly operative mortality was low in both groups sug-
gesting that if excellent surgical results are achieved and consistent
with what is reported in high-volume centers, neoadjuvant therapy
may prove to be of value.
Due to the inconsistent results reported in clinical trials of
neoadjuvant CRT, there have been several meta-analyses that have
attempted to address the shortcomings of single small, heteroge-
neous trials that were designed to test the worth of preoperative
CRT.38-40 These meta-analyses have reported results in favor of CRT
and a significant proportion of patients were downstaged prior to
surgery. The most recent meta-analysis40 identified a 19% decrease in
the HR for death, which was significant for both tumor histologies. It
should be noted that in this meta-analysis, they separately analyzed
the role of neoadjuvant chemotherapy without radiation and a sur-
vival benefit was also identified, although of a lesser degree.
In the USA, preoperative CRT followed by surgery is the most
common approach for patients with resectable disease, although
it remains investigational. In summary, although there are con-
flicting results, the available data suggests that neoadjuvant CRT
improves local control and can modestly improve survival, com-
pared with surgery alone.
5. What is the role of surgery in the combined modality therapy
of esophageal cancer?
ANSWER: As described above, there is evidence to support a regi-
men of definitive CRT in patients with SCC, in whom the addition of
surgery may not improve survival. Briefly, the German Esophageal
Cancer Study Group14 comparing patients with locally advanced
SCC treated with a regimen of CRT plus surgery versus definitive
CRT, found similar 2-year OS between the two groups, even though
there was better local control and cancer-related mortality in the
5/21/2012 8:49:05 PM
 94 ■ Surgery: Evidence-Based Practice

surgical group. These findings suggest that any potential benefit in
cancer outcome from preoperative CRT combined with surgery
were potentially abrogated due to the high treatment-related mor-
tality associated with surgery. The FFCD 9102 trial,15 which ran-
domized responders to initial CRT to definitive CRT versus surgery
also did not find an OS benefit with preoperative CRT, but did dem-
onstrate a lower rate of disease- specific deaths. Again preoperative
CRT was associated with significant treatment mortality. Patients
with SCC that do not respond to CRT may derive a benefit from
salvage surgery. Based on these trials, either definitive CRT with-
out surgery or trimodality treatment including resection is a viable
treatment option for patients with esophageal SCC.
No such trials have been conducted to compare combined
treatment with and without surgery exclusively in patients with
adenocarcinoma of the esophagus. In the FFCD 9102 trial,15 only
11% of 259 patients had this histology, and although no difference
between SCC and adenocarcinoma outcomes was observed in a
multivariate analysis, the authors acknowledged that their results
were applicable mainly for patients with SCC. As detailed earlier,
CRT trials have often shown conflicting results.2,16-19 Thus, surgical
resection has been the standard of care for patients with adeno-
carcinoma, and the trials that have assessed combined modality
therapy in this subset of patients have always included surgery in
both treatment arms.
Even in patients with SCC, based in the aforementioned
trials,14,15 surgery appears to enhance locoregional control. Patients
who obtain a complete pathological response to CRT derive no
benefit from resection, whereas those with residual local disease
following CRT would likely fail without surgery. Unfortunately,
current imaging methods are not accurate enough to discrimi-
nate between these two groups of patients. One can reasonably
conclude that esophagectomy is a critical component of multimo-
dality therapy, but only contributes to improved outcome if the
mortality associated with resection is minimized.
6. What is the optimal neoadjuvant regimen for esophageal
cancer?
ANSWER: The optimal treatment strategy for esophageal can-
cer is still under investigation. From the trials described above,
and despite many of them failing to demonstrate a clear improve-
ment in survival, in most cancer centers combined neoadjuvant
chemotherapy and RT is considered the standard approach for
patients with resectable disease. The recommended regimens used
in trials that have shown a survival benefit include cisplatin plus
5-FU.17,19,40 Based on the most recent multicenter phase III CROSS
trial,37 paclitaxel- and carboplatin-based CRT can prolong median
survival from 26 to 49 months with a HR for death of 0.67 in the
CRT group and should be now considered as an acceptable stan-
dard regimen. In the specific subset of patients with distal third
or GE junction adenocarcinoma, the chemotherapy regimen of
epirubicin, cisplatin, and 5-FU before and after surgery, based on
the results of the MAGIC trial,35 which showed improved 5-year
survival from 23% to 36% and a HR for death of 0.75, is a viable
option if radiation is not a component of the combined modality
approach. Current trials are under investigation to examine the
role of targeted therapy for esophageal cancer.

Clinical Question Summary

Question
1 What are the proper diagnostic
and imaging studies prior
to and during treatment of
esophageal cancer?
2 Should adenocarcinoma and
squamous cell carcinoma
(SCC) of the esophagus be
treated differently?
3 What is the role of adjuvant
or neoadjuvant RT alone in
esophageal cancer?
4 Is preoperative CRT better than
preoperative chemotherapy
alone for esophageal cancer?
5 What is the role of surgery in
the combined modality therapy
of esophageal cancer?
6 What is the optimal neoadjuvant
regimen for esophageal cancer?
ECF: epirubicin, cisplatin, 5-FU; pCR: pathologic complete response.
Answer Levels of Grade of References
Evidence Recommendation
Upper endoscopy and biopsy for 1b A 5-13
diagnosis. EUS for local and regional
staging. CT and PET for systemic
staging.
Surgery with combined therapy is 1b A 14, 15
preferred for adenocarcinoma.
Definitive chemoradiation can be
considered for SCC.
RT alone has not demonstrated a survival 1a A 20-31
benefit either in the adjuvant or in the
neoadjuvant setting.
Most centers prefer CRT over 1a A 2, 17, 19, 34,
chemotherapy alone. CRT can improve 36-40
rates of pCR, R0 resection and local
recurrence. Improved OS was shown
in a meta-analysis.
Surgery improves local control and disease- 1b A 2, 14-19
specific mortality, although with higher
treatment-related mortality. Selected
patients with SCC do not obtain a
survival benefit from it after CRT.
Cisplatin- and 5-FU-based CRT or 1b A 17, 19, 37, 40
paclitaxel- and 5-FU-based CRT. In
distal or GE junction adenocarcinoma,
ECF pre- and postoperatively.

PMPH_CH11.indd 94 5/21/2012 8:49:05 PM


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32. Roth JA, Pass HI, Flanagan MM, et al. Randomized clinical trial
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33. Schlag PM. Randomized trial of preoperative chemotherapy
for squamous cell cancer of the esophagus. The Chirurgische
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34. Medical Research Council Oesophageal Cancer Working Group.
Surgical resection with and without chemotherapy in oesopha-
geal cancer. Lancet. 2002;359:1727-1733.
35. Cunningham D, Allum WH, Stenning SP, et al. Perioperative
chemotherapy versus surgery alone for resectable gastroesopha-
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agogastric junction. J Clin Oncol. 2009;27:851-856.
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39. Urschel JD, Vasan H. A meta-analysis of randomized controlled
trials that compared neoadjuvant chemoradiation and surgery
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5/21/2012 8:49:05 PM
 CHAPTER 12

Esophageal Atresia and

Tracheoesophageal Fistula
Miller C. Hamrick, David E. Carney, and William C. Boswell

INTRODUCTION associated defects. It is generally accepted that 50% to 70% of

patients with EA/TEF have associated anomalies, with 35% hav-
Esophageal atresia and tracheoesophageal fistula (EA/TEF) incor- ing cardiac defects and another 25% having genitourinary or gas-
porate a range of congenital anomalies wherein maldevelopment of trointestinal anomalies.6-8 Leonard et al. reported that the 1-year
the foregut presents clinically with discontinuity of the esophagus survival rate of infants with congenital heart disease and EA/TEF
and/or a fistula between the esophagus and trachea. EA/TEF is an was 67% versus 95% for those with isolated EA/TEF.8 Of the con-
uncommon anomaly, occurring in 1 out of every 3000 to 5000 live genital heart defects, the most common single defects were ventric-
births. This congenital anomaly is identified with a slightly greater ular septal defect (VSD) in 19%, atrial septal defect (ASD) in 20%,
incidence in Caucasian and male patients. As compared to the gen- patent ductus artery (PDA) in 13%, and tetralogy of fallot in 5%.8
eral population, there is a slight increased risk of development in
twins (2.5%) and siblings of a previously affected child (1%).
Esophageal atresia with tracheoesophageal fistula has been
described with great interest throughout the surgical literature
since its original description in 1670 by Dr William Durston,
who identified a blind-ending upper esophagus in one of a set of
conjoined twins.1 Although attempts at operative repair began as
early as the late 1800s, mortality remained lethal. Ultimately, pri-
mary repair was abandoned and management included a cervical
esophagostomy and gastrostomy tube. The first successful pri-
mary repair of esophageal atresia with tracheoesophageal fistula
was performed in 1941 by Dr Cameron Haight.2
Numerous varieties of this anomaly have been described, Type A (8%) Type B (1%) Type C (86%)
with five subtypes commonly illustrated. The three most frequent
anomalies incorporate 98% of all cases (Fig. 12.1). The most com-
mon anomaly is Type C that presents with esophageal atresia and a
fistula between the distal trachea and the lower esophageal pouch
(86% of cases). Isolated esophageal atresia without a fistula (Type
A) occurs in 8% of cases, whereas an “H-type” tracheoesophageal
fistula without esophageal atresia (Type E) occurs in 4%.
In nearly one half of all cases of esophageal atresia, there
are malformations of other organ systems, most commonly the
cardiovascular system.3,4 The most well-defined cluster of mal-
formations is the VACTERL association, which comprises ver-
Type D (1%) Type E (4%)
tebral, anorectal, cardiac, tracheoesophageal, renal, and limb
anomalies.5 Typically, for a patient to be classified as having Figure 12.1 Types of esophageal atresia and tracheoe-
the VACTERL association, he or she must have two or more sophageal fistula.
97

PMPH_CH12.indd 97 5/21/2012 8:50:05 PM

 98 ■ Surgery: Evidence-Based Practice
Pertinent when considering the operative approach, 4% of patients
were found to have a right-sided aortic arch.
Additional anomalies are more common in the setting of Type
A atresia (proximal atresia with no fistula), and least common in
Type E (esophageal continuity with a cervical H-Type fistula).6-8
Dr de Jong and colleagues reported that 107 of the 463 patients
(23.1%) with EA or TEF qualified to have VACTERL anomaly.
Thirty percent of that cohort had only VACTERL-type defects
whereas 70% had VACTERL defects in association with other
structural defects. The additional structural defects included single
umbilical artery (20%), genital anomalies (23%), duodenal atresia
(8.9%), and cleft lip/palate (4.4%).9 Recently a VACTERL-H associ-
ation has been described that includes congenital hydrocephalus.10
In addition, multiple chromosomal anomalies, genetic disorders,
and somatic syndromes are associated with EA and TEF.11-20
The initial workup of patients carrying a diagnosis of EA
or TEF must include evaluation for other anomalies. A complete
physical exam must be followed by a chest and pelvic radiograph,
echocardiogram, renal ultrasound, and spinal ultrasound. As
previously described, complex congenital heart defects are respon-
sible for the majority of deaths in this patient population.8
Unfortunately, the rarity of congenital anomalies and the
limited number of clinical cases at any given institution makes
prospective treatment studies difficult. Unless otherwise noted,
the data referenced below are almost exclusively opinions of
respected authorities (Oxford Centre Level 3-5). Most categorical
recommendations are Grade C or D, based on the results of case
series from varied, international institutions that demonstrate
similar and reproducible outcomes.
RISK FACTORS
1. What are environmental and/or genetic risk factors that
predispose to the development of esophageal atresia and
tracheoesophageal fistula?
For years, lack of clarity has surrounded the mechanisms responsible
for normal embryogenesis of the trachea and esophagus. A rudimen-
tary consensus is that the esophagus and trachea develop as a primi-
tive tube that ultimately becomes a separate trachea and esophagus.
The mechanism by which this process occurs is still unclear though
theories include propagation of the respiratory system,22,23 septal
formation,24-27 or elongation and proliferation of the foregut.28,29
In part, the abnormal morphogenesis associated with EA
and TEF remains poorly understood due to limited availability
of human embryos for investigation, and the absence of satisfac-
tory in vitro or computer-generated models. Attempts to recreate
the congenital malformation led to manipulation of environ-
mental factors, yet consistent reproduction of this lesion was not
observed. Finally in the late 1970s, Thompson and coworkers gen-
erated malformations in rat and rabbit fetuses in response to the
chemotherapeutic agent methimazole (Adriamycin).30 Though the
anomalies produced by Adriamycin in rat models cause tracheoe-
sophageal defects similar to those seen in humans, true investi-
gation remains limited since the Adriamycin-induced anomalies
are predicated on interfering with DNA and RNA synthesis.23,31,32
Likewise, other environmental factors and genetic abnormalities
have been implicated in the development of EA/TEF.3,9,23,30-39
Answer: Although associated with many genetic disorders
and syndromes, methimazole is the only known causative factor
PMPH_CH12.indd 98
to have a reproducible association with tracheoesophageal anom-
alies. Level 2c evidence.
DIAGNOSIS
2. What is the safest and most accurate method to confirm the
diagnosis of EA with TEF?
With expanded prenatal screening, antenatal diagnosis of EA/TEF
is possible; however, the positive predictive value of a prenatal ultra-
sound is only 20% to 40%.40 In these cases, diagnosis relies on a small
or absent stomach bubble in the setting of maternal polyhydram-
nios. After birth, infants typically manifest symptoms with the first
feeding demonstrated by gagging, choking, and excessive drooling.
The diagnosis is initially suspected based on these symptoms and an
inability to pass an orogastric tube. Often an air-filled, dilated, proxi-
mal esophagus is visualized on plain radiographic imaging. Air in the
stomach and lower intestine suggests the presence of a distal fistula.
As with most esophageal lesions confirmation is obtained
through direct visualization, radiographic imaging, or both.
When the diagnosis of EA is unclear or if there is concern for a
proximal cervical fistula, a small amount of dilute, nonionic con-
trast material may be used for an upper pouch study under fluoro-
scopic guidance. Ideally, this should be performed at a center that
has both experience with pediatric care and has full resuscitative
capability in the event of aspiration. It remains imperative to use
isosomotic contrast as hyperosmolar contrast such as Gastrograf-
fin, if aspirated, may result in severe pulmonary edema, respiratory
distress, and chemical pneumonitis.41 The benefits of bronchoscopy
over contrast esophagram include a higher rate of diagnosis, the
ability to evaluate for associated laryngotracheal and esophageal
anomalies, and safety.42 For the “H-type” fistula, the two methods
may prove complementary and repeated attempts at endoscopy
and imaging are often necessary to confirm the diagnosis.43
Answer: The diagnosis of a TEF requires a high index of
suspicion. Bronchoscopy/esophagoscopy is considered the best
method for safe, accurate diagnosis of common lesions (Level 3b
evidence—Grade D recommendation).
TREATMENT
The surgical treatment of EA/TEF will center on management as
it relates to short-gap and long-gap atresia. The most common pre-
sentation in the current era is a presumptive diagnosis of short-gap
atresia based on the clinical scenario and initial imaging. Rarely
is an attempt at primary repair hindered by insufficient length.
The alternative scenario is a presumptive diagnosis of long-gap
atresia at birth, wherein the surgeon needs to decide when and
how to reconstruct the esophagus. Once a patient has been appro-
priately screened for associated anomalies, there are three specific
concerns to consider. First the surgeon must be aware of options
to manage a high-output fistula in the unstable patient. Next it
is paramount to understand safe options to obtain sufficient
length in order to perform primary repair in the management of
short-gap esophageal atresia. Finally the management of long-gap,
Type A, esophageal atresia requires the broad understanding of
alternative conduits when esophageal replacement is mandated.
The inherent risk of fistulas communicating the distal trachea
and gastrointestinal tract include respiratory distress as a result
5/21/2012 8:50:05 PM

of ineffective ventilation and/or reflux with subsequent aspiration
and chemical pneumonitis. Elevated airway pressure of the new-
born allows passive ventilation into the stomach leading to abdom-
inal distention, elevated diaphragms, hypercarbia, and even gastric
perforation.44 Premature infants are at greatest risk of this compli-
cation and it is this scenario that requires emergent intervention.
3. What is the best method to stabilize the patient with a high-
output fistula?
Emergent treatment of a patient suffering respiratory or hemody-
namic compromise secondary to a high-output tracheoesophageal
fistula can be managed in several ways. Passing a fogerty catheter
through or adjacent to the endotracheal tube, through the fistula,
with subsequent balloon occlusion of the distal esophagus has
been described in the emergent setting.45 Similarly, the creation
of a gastrostomy and retrograde passage of a balloon may effec-
tively occlude the fistula.44 High-frequency jet ventilation has also
been offered as a method to stabilize a high-output fistula.46 Addi-
tional management options including gastrostomy “waterseal,”47
gastric division,48 and banding of the gastroesophageal junc-
tion49 have been described in the literature but are not commonly
recommended secondary to excess morbidity. Finally, a rapid
transpleural thorocotomy and ligation of the distal fistula along
with subsequent gastrostomy is a reliable temporizing measure.50
Answer: Of the numerous techniques described, the most
reliable technique employed by the general surgeon would be
transpleural ligation of the fistula combined with placement of a
gastrostomy tube (Level 5 evidence—Grade D recommendation).
Primary repair of the esophageal atresia in this setting is not rou-
tinely recommended, particularly in the preterm infant (Level 3b
evidence—Grade D recommendation).
4. What is the best method to obtain length for primary repair
in the setting of short-gap esophageal atresia?
Type C lesions (proximal atresia with distal TEF) are by far the most
common esophageal malformation and rarely require emergent
intervention as described above. Surgery may be delayed for several
days while a full assessment of the infant is completed. Formal repair
involves a right posterolateral thoracotomy employing an extrapleu-
ral dissection, exposing the posterior mediastinum. The tracheal fis-
tula should be controlled early in the operation with suture ligation
close to the trachea, carefully avoiding compromise of the tracheal
lumen. The proximal esophagus should be extensively mobilized
into the thoracic inlet, which increases length of the proximal pouch
and allows assessment for a fistula from the proximal esophageal
pouch to the trachea. After patency is assured, the distal esophagus
is mobilized in a limited manner sufficient to facilitate the anastomo-
sis, yet avoiding disruption of the tenuous blood supply. Most often
the proximal and distal ends may be mobilized to allow for primary
repair under mild to moderate tension. At times, additional length is
required to minimize tension on the esophageal anastomosis.
Numerous techniques have been described when it is antici-
pated that extensive mobilization will not yield sufficient length to
allow for primary repair.51-64 Most of the reported procedures are of
historical significance only. Preservation of the native esophagus is
always the best option in the setting of short-gap atresia and efforts
should be made to perform a primary repair even in the setting of
moderate tension.65 This notion is best supported when comparing
rates of stricture and anastomotic leak in patients with short- and
PMPH_CH12.indd 99
Esophageal Atresia and Tracheoesophageal Fistula ■ 99
long-gap atresia who had primary repair without additional length-
ening procedures. Bagolan et al. report 71 consecutive cases repaired
primarily without the need for esophageal replacement with no sig-
nificant difference in regards to leak rate, stenosis, fistula formation,
and postoperative reflux for long- versus short-gap atresia.66
Answer: The best method to allow primary repair in short-
gap esophageal atresia remains extensive mobilization with
primary closure under tension. (Level 3b evidence—Grade C
recommendation)
Treatment of long-gap, Type A, esophageal atresia presents a
major challenge for the general and pediatric surgeon. Typically,
this is defined as a gap of 2 or more centimeters or, two or more ver-
tebral bodies. Historically, attempts at primary repair when the gap
exceeds 3 cm are associated with more frequent complications.67-69
5. What is the best timing for surgical repair of long-gap
atresia?
As techniques to deal with this formidable problem have evolved,
controversy still surrounds the timing of intervention and the
selection of an esophageal substitute. The timing of the surgical
intervention has been debated; many experts suggest that imme-
diate repair in the first 72 hours after birth can be accomplished,66
whereas others suggest that a better outcome can be gained by
delaying repair for weeks to months.70 It is widely believed that
in long-gap atresia, the lower esophagus and stomach are hypo-
plastic, and delayed repair is favored when large bolus gastros-
tomy tube feeds can be used to create reflux and distention of the
blind-ending lower pouch allowing for spontaneous growth.66,71
Some groups are strong proponents of waiting at least 3 months
to repair all cases of long-gap atresia citing greater longitudinal
growth of the esophagus as compared to the thoracic vertebral
column, facilitating anastomosis.65 This longitudinal growth is
hypothesized to evolve secondary to the swallowing reflex in the
upper pouch, and reflux into the lower pouch.72 Obviously, this
requires periodic suctioning of the upper pouch, which may be
accomplished in the outpatient setting.73
Answer: Despite the theoretical advantages of time, there is
no firm data to support delaying repair past the neonatal period
in near-term infants devoid of additional anomalies (Level 3
evidence—Grade D recommendation) Preterm, low-birth-weight
infants clearly benefit from staged or delayed repair of esophageal
atresia (Level 2c evidence—Grade B recommendation).
6. What is the best conduit for creation of a neoesophagus?
The discussion regarding esophageal conduits is broad but often
centers on the type of conduit and best anatomic location for
placement of the neoesophagus. Esophageal conduits are used for
many reasons including esophageal atresia, esophageal injury due
to caustic ingestion, trauma, infectious conditions, and congenital
absence of the stomach. Although it is generally well accepted that a
child’s native esophagus should be preserved, this is not often pos-
sible, especially when the defect extends multiple vertebral bodies
in length. There are many described methods for creating a neoe-
sophagus, including the use of stomach, colon, or small intestine.
Preoperative considerations are paramount when anticipating that
a child may require an esophageal conduit. Many of these infants
have other associated anomalies and careful attention to detail
increases a surgeon’s options at the time of esophageal reconstruc-
tion. For example, a child that initially required a gastrostomy
5/21/2012 8:50:05 PM
 100 ■ Surgery: Evidence-Based Practice

Table 12.1 Acute Morbidity and Mortality from Case Series Employing Various Conduits for the Treatment of
Esophageal Atresia
Year Author Conduit Patients (n) Mortality (n) Stricture n (%) Anastomotic
Leak n (%)
2009 Spitz Gastric transposition 192 9 34 (19.6) 21 (12)
2002 Hirschl Gastric transposition 41 0 20 (49) 15 (36)
1998 Ein Gastric tube 11 0 8 (72) 9 (81)
1985 Goon Gastric tube 46 1 27 (59) 35 (76)
2003 Hamza Colonic interposition 475 5 25 (5) 47 (10)
2000 Erdogan Colonic interposition 18 4 3 (17) 11 (61)
1993 Cusick Jejunal interposition 6 2 2 (33) 1 (17)
1988 Saeki Jejunal interposition 19 2 2 (10) 3 (15)
1994 Bax Jejunal free graft 4 0 1 (25) 0

tube must have the location carefully considered should a gastric
conduit be considered for reconstruction. Likewise, a colostomy
created for an associated anorectal malformation can damage the
blood supply and limit options for a future colonic transposition
if great care is not exercised. Obviously, any congenital anatomic
abnormality may limit the availability of certain conduits.
The technical aspects regarding harvesting and placement
of the neoesophageal conduits are beyond the scope of this dis-
cussion. The inherent advantages and disadvantages are well
documented elsewhere.75 A comparison of acute morbidity and
mortality across varied case series yields no discernable difference
in complications (Table 12.1).
Answer: There is no data to support the use of any specific
conduit for the creation of a neoesophagus. Initial rates of stric-
ture and leak are similar as is the incidence of late dysphagia. Gas-
tric conduits appear to have fewer late complications that require
operative correction (Level 3 evidence). The best conduit is dictated
by the comorbidity and anatomic limitations of the patient along
with the clinical experience of the operating surgeon (Grade D
recommendation).
POSTOPERATIVE MANAGEMENT
The most common acute complications following repair of EA/
TEF are anastomotic leak and stricture. Long-term complications
are related to gastroesophageal reflux and esophageal dysmotil-
ity. Anastomotic leak following repair of EA occurs in 15% of all
cases. Most leaks can be managed with drainage and nutritional
support. The rate of spontaneous resolution of an anastomotic leak
approaches 95% when a retropleural dissection plane was used at
the time of the original repair.75 In the minority of cases (3–5%),
the leaks are uncontrolled with drainage and antibiotics alone,
leading to clinical deterioration and sepsis. These major leaks are
often identified in the initial 48 h after surgery and reoperation
is critical to control drainage and attempt repair. In this setting,
the repair should be buttressed with a pleural or pericardial flap
to assist in vascularization and healing. Most surgeons advocate
7 days without feeding following index repair of the esophagus.
An upper gastrointestinal swallow study to evaluate for leak is
performed on day 7. A leak identified by this study, in the absence
of clinical deterioration, can be managed conservatively. The
consensus opinion advocates a repeat study the following week to
confirm closure prior to initiating oral feeding.
Esophageal stricture is a common complication following
repair of EA. Quoted incidence ranges from 30% to 80% of all
patients. Many factors have been implicated in stricture formation
including ischemia, tension, anastomotic leak, and poor operative
technique. Once a clinically symptomatic stricture is diagnosed
on esophagram, bougienage is typically performed over a wire.
Some studies quote 90% success with operative.
7. Do all children with EA/TEF require antireflux therapy with
medication and/or surgical procedures?
With improved survival and a marked decrease in acute compli-
cations following repair of esophageal atresia, late complications
including tracheomalacia, stricture, and reflux have required
increased attention.78 In children who have undergone repair of
esophageal atresia, 40% to 50% suffer from clinically relevant reflux
with an even greater percentage noted in patients with a history
of long-gap atresia.79,80 Many patients develop symptoms months
to years after the original repair.81 Greater than of 30% of patients
have severe reflux, refractory to acid suppression therapy, and
require surgery to relieve symptoms.81,82 These findings result from
inherent esophageal dysmotility and anatomic distortion where
the cardia anchors to the diaphragmatic crura and pleuroperito-
neal membrane. Manometric study reveals that it is the character-
istic dysmotility of the disrupted esophagus and not nerve injury
that contributes to the development of advanced reflux.83 Despite
structural and functional abnormalities, half of all neonates will
not manifest clinically significant reflux following repair.
Short- and long-term morbidity from reflux can be very
significant in this patient population and most surgeons would
provide empiric, medical treatment for reflux following repair of
esophageal atresia.84 Absolute indications for operative interven-
tion include recurrent stricture following dilation, severe dysmo-
tility, presence of a paraesophageal or sliding hiatal hernia, or
endoscopic findings of severe esophagitis. As children grow and
develop clinical symptoms of reflux, they should be evaluated and
managed similar to any other child. When an antireflux proce-
dure is warranted, authors are divided, advocating either a Nissen
fundoplication or Thal procedure in patients with previous repair
of esophageal atresia. Those proponents of the Thal procedure feel

PMPH_CH12.indd 100 5/21/2012 8:50:05 PM

 Esophageal Atresia and Tracheoesophageal Fistula ■ 101

a Nissen may exacerbate the inherent esophageal dysmotility and
increase the risk of dysphagia and aspiration.
Operative treatment for reflux in patients with a history of
esophageal atresia should take into account the potential for signifi-
cant scarring at the hiatus secondary to the previous dissection and
ongoing esophagitis. Patients with a history of repair for esophageal
atresia have an increase in wound complications and postoperative
pneumonia following an antireflux operation, as compared to those
without previous surgery for atresia.85 Recurrent or persistent reflux
following antireflux surgery approaches 15% for patients with pre-
vious repair of esophageal atresia compared to 6.5% for all other
patients.86 In an attempt to limit recurrent symptoms in this group
of patients, some authors advocate long-term use of proton pump
inhibitors for recurrent reflux following antireflux surgery. As with
any procedure for reflux, the best method to prevent recurrence is
proper surgical technique at the index operation.87
Answer: All patients should be treated with acid suppression
therapy following repair of esophageal atresia until it is clear there
are no symptoms of stricture or pathologic reflux. Recurrent stric-
ture following dilation and sudden death spells remain absolute
indications for antireflux surgery (Level 3 evidence—Grade C
recommendation).

Clinical Question Summary

Question
1 What are environmental
and/or genetic risk
factors that predispose
to the development of
esophageal atresia and
tracheoesophageal fistula?
2 What is the safest and
most accurate method to
confirm the diagnosis of
esophageal atresia with
tracheoesophageal fistula?
3 What is the best method to
stabilize the patient with a
high-output fistula?
4 What is the best method to
obtain length for primary
repair in the setting of
short-gap esophageal
atresia?
5 What is the best timing for
surgical repair of long-gap
atresia?
6 What is the best conduit
for creation of a
neoesophagus?
7 Do all children with
esophageal atresia and
tracheoesophageal fistula
require antireflux therapy
with medication and/or
surgical procedures?
Answer Level of Grade of References
Evidence Recommendation
Methimazole is the only known causative 2c N/A 30
factor to have a reproducible
association with tracheoesophageal
anomalies.
Bronchoscopy/esophagoscopy is 3b C 42, 43
considered the best method for safe,
accurate diagnosis of common lesions.
The most reliable method is transpleural 5 C 44-50
ligation of the fistula combined with
gastrostomy tube.
The best method for primary repair 3b C 65, 66
in short-gap esophageal atresia is
extensive mobilization with primary
closure under tension.
There is no data to support delaying 3/2c D/B 66, 70
repair past the neonatal period in
near-term infants devoid of additional
anomalies. / Preterm, low-birth-weight
infants clearly benefit from staged or
delayed repair of esophageal atresia.
The best conduit is dictated by the 4 D 71, 72, 74, 75
comorbidity and anatomic limitations
of the patient along with the clinical
experience of the operating surgeon.
All patients should be treated with acid 3 D 79-82, 86, 87
suppression therapy following repair of
esophageal atresia. Recurrent stricture
following dilation and sudden death
spells are absolute indications for
antireflux surgery.

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73. Aziz D, Schiller D, Gerstle JT, et al. Can ‘long-gap’ esophageal
atresia be safely managed at home while awaiting anastomosis?
J Pediatr Surg. 2003;38:705-708.
74. Spitz L., Hitchcock R. Oesophageal atresia and trachea-esophageal
fistula. In: Om Freeman, NV et al., eds. Surgery of the Newborn.
New York: Churchill Livingstone; 1994.
75. Manning PB, Morgan RA, Coran AG, et al. Fift y year’s expe-
rience with esophageal atresia and tracheoesophageal fistula.
Beginning with Cameron Haight’s first operation in 1935. Ann
Surg. 1986;204:446.
76. Serhal L, Gottrand F, Sfeir R, et al. Anastomotic stricture after
surgical repair of esophageal atresia: frequency, risk factors,
and efficacy of esophageal bougie dilatations. J Pediatr Surg.
2010;45:1459-1462.
77. Said M, Mekki M, Golli M, et al. Balloon dilation of anastomotic
strictures secondary to surgical repair of oesophageal atreasia.
Br J Radiol. 2003;76:26.
78. Okada A, Usui N, Inoue M, et al. Esophageal atresia in Osaka: a
review of 39 years’ experience. J Pediatr Surg. 1997;32:1570-1574.
79. Guo W, Fonkalsrud E, Swaniker F, et al. Relationship of esopha-
geal anastomotic tension to the development of gastroesophageal
reflux. J Pediatr Surg. 1997;32:1337-1340.
80. Jolley SG, Johnson DG, Roberts CC, et al. Patterns of gastro-
esophageal reflux in children following repair of esophageal
atresia and distal tracheoesophageal fistula. J Pediatr Surg.
1980;15(6):857-862.
81. Koivusalo A, Pakarinen MP, Rintala RJ. The cumulative inci-
dence of significant gastrooesophageal reflux in patients with
oesophageal atresia with a distal fistula—a systematic clini-
cal, pH-metric, and endoscopic follow-up study. J Pediatr Surg.
2007;42:370-374.
82. Little DC, Rescorla FJ, Grosfeld JL, et al. Long-term analysis of
children with esophageal atresia and tracheoesophageal fistula.
J Pediatr Surg. 2003;38:852-856.
83. Kawahara H, Kubota A, Hasegawa T, et al. Lack of distal esoph-
ageal contractions is a key determinant of gastroesophageal
reflux disease after repair of esophageal atresia. J Pediatr Surg.
2007;42:2017-2021.
84. Burjonrappa SC, Youssef S, St-Vil D. What is the incidence of
Barrett’s and gastric metaplasia in esophageal atresia/trache-
oesophageal fistula (EA/TEF) patients? Eur J Pediatr Surg.
2011;21(1):25-29.
85. Holschneider P, Dubbers M, Engelskirchen, et al. Results of the
operative treatment of gastroesophageal reflux in childhood
with particular focus on patients with esophageal atresia. Eur J
Pediatr Surg. 2007;17(3):16.
86. Holschneider P, Dubbers M, Engelskirchen R, et al. Results of
the operative treatment of gastroesophageal reflux in childhood
with particular focus on patients with esophageal atresia. Eur J
Pediatr Surg. 2007;17:163-175.
87. Pashankar D, Blair GK, Israel DM. Omeprazole maintenance
therapy for gastroesophageal reflux disease after failure of fun-
doplication. J Pediatr Gastroenterol Nutr. 2001;32:145-149.
5/21/2012 8:50:05 PM
 Commentary on
Esophageal Atresia and
Tracheoesophageal Fistula
The chapter entitled “Esophageal Atresia and Tracheoesophageal
Fistula” by Miller C. Hamrick, David E. Carney, and William C.
Boswell does an excellent job of summarizing the surgical history
of the approach to this difficult congenital anomaly. Prior to Cam-
eron Haight’s successful repair of a tracheoesophageal fistula (TEF)
in a newborn in 1939, this uniformly lethal anomaly seemed des-
tined to be a postmortem finding only. Over the ensuing 70 years,
huge strides in the perinatal, neonatal, and pediatric surgical care
of these infants have led to a survival of approximately 95%. The
chapter addresses seven major questions about the pathophysiol-
ogy and surgical management of infants with esophageal atresia/
tracheoesophageal fistula (EA/TEF). I will provide commentary
on all seven questions but in general must state at the outset that
the difficulty in pediatric surgical evidence-based treatises is
that the relatively infrequent nature of any one anomaly deprives
authors of the critical numbers needed to give the recommenda-
tions/conclusions that offer the necessary weight. Nonetheless,
multiple small studies from reputable pediatric surgical centers
unfortunately have to substitute for randomized, prospective,
double-blinded studies that other medical conundrums organize
to promote consensus for best practice guidelines.
Question 1 addressed the environmental/genetic factors
associated with TEF. Adriamycin has been the only drug iden-
tified in an animal model to cause similar birth anomalies in
rats. The RNA/DNA damage that this drug causes has led to the
conclusion that there is likely chromosomal damage that leads to
this anomaly. The fact that there is an overall 50% to 70% asso-
ciated anomaly rate would imply that in utero organogenesis is
commonly adversely affected in multiple systems when EA/TEF
babies are born. It should be noted that the table showing the five
common varieties of TEF has been changed in many textbooks
to provide new classifications based on frequency rather that the
older labels used by the authors.Thus, Type C that is seen in 86% of
TEF cases is now called Type 1, Type A seen in 7% of the anoma-
lies is called Type 2, Type E seen in 5% of the cases is called Type
3, with Type B (approx. 1%) being Type 4 and Type D (<1%) being
Type 5 in the new nomenclature.
Question 2 tried to address the question of how best to clas-
sify the TEF/EA anomaly facing the pediatric surgeon. Proximal
fistulae (Type B and D) and H-type fistula are notoriously diffi-
cult to diagnose. Though we would agree with the authors that
bronchoscopy is the most likely test to ascertain with certainty
the presence of these fistulae, pediatric surgeons have long argued
104
PMPH_CH12.indd 104
Michael Hirsch
that the type of mobilization of the proximal pouch that needs
to be done to achieve “tension-free” anastamosis will reveal the
presence of the proximal fistulae in the overwhelming majority
of cases. Only in the H-type (E) fistulae cases is bronchoscopy
imperative; it can also be used to cannulate the fistula with small
tubing that can greatly facilitate the intraoperative repair.
Question 3: The “high output fistula” described in section
is fortunately a relatively rare occurrence. More commonly, the
problem with instability in a pre-repaired TEF patient is the gas-
eous dilatation of the GI tract that cannot be decompressed. This
rarely becomes so critical that ligation of the TEF is necessary
as a stabilizing technique, but ligation is clearly the most defini-
tive management modality. The other less invasive temporizing
methods described by the authors, including tube placement with
water seal drainage and balloon occlusion of the fistula either ret-
rograde through the gastrostomy or antegrade next to the endo-
tracheal tube, are more commonly used.
Question 4 suggests that OR mobilization of the two esopha-
geal segments and intraoperative repair of the short gap TEF/EA
anomaly is usually sufficient to solve the problem. The authors
are correct in emphasizing that most of this mobilization must
be derived from the proximal segment of esophagus, as the dis-
tal segment’s segmental blood supply will be compromised if it is
extensively dissected.
Question 5 addresses the thorny dilemma of how to handle
the “long-gap” EA. The authors conclude that there is no advan-
tage in delaying the repair during the newborn period, but instead
preparing for esophageal replacement if necessary, if the native
esophagus cannot be used. Despite their citations, we believe
there have been many descriptions over the last few years, of tech-
niques to stimulate the linear growth of the native esophageal seg-
ments (the Foker technique or serial dilatations) that can promote
delayed primary repair.1 With the very discouraging data pointed
to in the Question 6 discussion of the optimal mode of esophageal
replacement, with high leak, stricture rates in all modalities, we
believe that native esophageal preservation must be a tantamount
goal. In addition, we feel that it is important to add the increas-
ing use of minimally invasive approach to esophageal atresia
repair.2,3
The subject of Question 7 is the need for antireflux surgery
in repaired TEF/EA patients with gastroesophageal reflux disease
(GERD). We agree with the authors’ conclusions that this surgery
should be reserved for children with near sudden infant death
5/21/2012 8:50:06 PM

syndrome (SIDS) experiences from reflux or from clear peptic
stricture complications of GERD. It must also be recognized that
the gold-standard antireflux procedure, the Nissen fundoplication,
has been implicated in causing the dysmotile repaired esophagus
or esophageal replacements to develop an achalasia-like emptying
problem. This points to the potential advantage of a less than 360-
degree circumferential fundoplication such as the Toupet, Thal, or
Boix-Ochoa approaches.
Overall, we congratulate the authors for their thorough yet
concise description of this very challenging anomaly complex and
its surgical management.
PMPH_CH12.indd 105
Esophageal Atresia and Tracheoesophageal Fistula ■ 105
REFERENCES
1. Foker JE, Linden BC, Boyle EM, et al. Development of a true pri-
mary repair for the full spectrum of esophageal atresia. Ann Surg.
1997;226(4):533-541; discussion 541-543.
2. Szavay PO, Zundel S, Blumenstock G, Kirschner HJ, Luithle T,
Girisch M, et al. Perioperative outcome of patients with esopha-
geal atresia and tracheo-esophageal fistula undergoing open
versus thoracoscopic surgery. J Laparoendosc Adv Surg Tech A.
3. MacKinlay GA. Esophageal atresia surgery in the 21st century.
Seminars in Pediatric Surgery, 2009;18(1):20-22.
5/21/2012 8:50:06 PM
PMPH_CH12.indd 106 5/21/2012 8:50:06 PM
 PART 1I

THE STOMACH

PMPH_CH13.indd 107 5/21/2012 8:50:52 PM

PMPH_CH13.indd 108 5/21/2012 8:50:53 PM

Peptic Ulcer Disease
1. How has the surgery of peptic ulcer disease (PUD) changed
over time?
Few diseases in western society have been so dramatically trans-
formed over time as PUD. Although rarely described in the early
medical literature, its incidence reached epidemic proportions by
the mid-1900s then slowly began to decline, a trend that continues
to this day.1,2 From the beginning, operative therapy served as an
important cornerstone in the management of PUD since the avail-
able medical measures were often ineffective. Landmark investi-
gations by Beaumont, Pavlov, Dragsted, and Edkins among others
served as the pathophysiologic foundation on which many new
surgical strategies for the management of PUD were developed.3
While these operations appeared to be very effective at controlling
both intractable and complicated PUD, they could be associated
with significant short term and long-term consequences.4
Simultaneously, major progress was also being made with two
different nonoperative approaches to the management of PUD:
pharmacotherapy and flexible endoscopy. Antisecretory drugs,
introduced in 1977, largely replaced both the Sippy diet and antacid
therapy and a decade later they were superseded by the introduction
of the first proton pump inhibitor. Moreover, a specific infectious eti-
ology for PUD was suggested by Warren and Marshall in 1983; within
a decade, more than 1500 scientific articles were being published on
the topic annually.5 Soon, specific antimicrobial drug regimens were
validated as a primary method of treating and curing PUD.
As a result of these pharamacologic advances and evolving
endoscopic techniques, the operative approach to PUD has dra-
matically changed. Since 1960, multiple investigators have noted a
significant reduction in total surgical volume.6-8
A personal survey of a 20-year experience in two major Texas
teaching hospitals demonstrated an 80% decrease in the overall
number of operations for PUD.9 Currently, the most common
indications for surgery are perforation and bleeding while intrac-
tability has become nearly obsolete.
Patient demographics are also continuing to change. Indi-
viduals hospitalized with PUD are now older, more frequently
female, and more likely to have major comorbid conditions.10,11
109
PMPH_CH13.indd 109
CHAPTER 13
Wayne H. Schwesinger
They are also more likely to require an emergency operation.12
(Evidence Grade B)
2. What are the major risk factors for PUD?
By the mid-20th century, it was generally agreed that gastric
hyperacidity was the primary cause of PUD. Thus, the oft quoted
aphorism: “no acid, no ulcer.”13 Early speculations on the specific
pathogenetic factors causing hyperacidity focused on the relative
contributions of stress, smoking, familial predisposition, hor-
monal changes, aspirin intake, and dietary indiscretions.
A paradigm shift occurred when it was recognized that either
Helicobacter pylori infection or NSAID use could be implicated
in most cases of peptic ulceration albeit through entirely differ-
ent mechanisms.14-16 With H. pylori infection, a complex interac-
tion occurs between bacterial virulence factors (cagA, cagPAI,
vacA), host factors (interleukins, TNF-α, chemokines), and envi-
ronmental factors (smoking, high salt intake).17,18 The result is a
persistent chronic gastritis. The location of the infection in the
stomach helps to determine the clinical course. Antral-dominant
infections result in reduced somatostatin levels, hypergastrinemia
and gastric acid hypersecretion and can produce duodenal ulcers.
Gastric body-dominant infections are associated with mucosal
atrophy and hypochlorhydria; this pattern may result in either
benign or malignant gastric ulcers.
In contrast, the gastric mucosal injury caused by NSAIDs
(including aspirin) results mostly from inhibition of the consti-
tutive enzyme cyclo-oxygenase-1 (COX-1) a major product of
arachidonic acid metabolism in the gastric mucosa. COX-1 is
responsible for the release of prostacyclin a potent cytoprotectant.
When release is inhibited, gastric acid and other irritants can
more easily damage the gastric mucosa. Another isoform, COX-2,
is induced by inflammatory stimuli and has significant antiin-
flammatory activity, but fewer gastric side effects.19
Importantly, a synergism can develop between the two major
risk factors. In a meta-analysis of 25 related studies, the presence
of H. pylori infection was found to increase the risk of PUD in
NSAID users 3.5-fold compared with non-infected patients.20
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 110 ■ Surgery: Evidence-Based Practice
The special category of idiopathic PUD (non-NSAID and
non-H. pylori) can be accounted for by severely altered gastric
physiology, inaccurate H. pylori testing, or covert NSAID use.
Overall, non-NSAID and non-H. pylori ulcers tend to occur in
older and sicker patients and are associated with a higher recur-
rence rate.21 Rare causes of ulceration include Zollinger–Ellison
syndrome, G-cell hyperplasia, Crohn’s disease, cocaine abuse,
and systemic mastocytosis.22 (Evidence Grade A)
3. What is the appropriate therapy for H. pylori positive PUD?
In patients with PUD who are H. pylori positive, eradication of the
organism is crucial. In a Cochrane analysis of over 3900 patients in
34 trials, the ulcer healing rate after therapy was 75% to 85% and
the recurrence rate was 12% to 14%.23 First-line therapy as recom-
mended in the Maastricht Consensus Report 2-2000 combines a
PPI with clarithromycin and amoxicillin or metronidazole twice
daily for 1 to 2 weeks.24 Eradication rates with initial treatment of
75% to 90% have been reported, but are declining in most countries
because of antibiotic resistance.25 The Helicobacter Antimicrobial
Resistance Monitoring Program (HARP) studied 347 clinical iso-
lates and found that the highest rate of resistant strains occurred
with metronidazole (25.1%) and clarithromycin (12.9%), while
amoxicillin resistance was uncommon (0.9%).26
Second-line rescue treatment with quadruple therapy typi-
cally combines a PPI with bismuth, metronidazole, and tetracy-
cline. Eradication should always be confirmed with either a urea
breath test or a stool antigen. Alternative therapeutic approaches
are desperately needed. Studies are ongoing with new antibiotics
(e.g., levofloxacin) and with a sequential regimen involving a PPI
plus amoxicillin for 5 days followed by a PPI plus clarithromycin
and tinidazole for another 5 days.27 (Evidence Grade A)
4. How can the risk of PUD be minimized in patients requiring
regular NSAID therapy?
Several options are available for reducing the risk of peptic ulcers
in patients receiving NSAIDs. In NSAID-naïve patients who are
infected with H. pylori, eradication of the organism before begin-
ning NSAID therapy is associated with a significant reduction in
the risk of ulcer.28 Even in patients taking low-dose aspirin (80 mg),
eradication of H. pylori can provide significant protection from
PUD and its complications. Proton pump inhibitors, the prostaglan-
din analogue Misoprostol, and high doses of histamine-2-receptor
antagonists are also effective in reducing the prevalence of NSAID-
induced ulcers.29,30 Misoprostol usage is limited, however, by its fre-
quent association with dose-related abdominal pain and diarrhea.
(Evidence Grade A)
5. In a patient suspected of having a bleeding peptic ulcer, what
should the initial approach be?
Optimal management depends on a timely and accurate diagno-
sis and an adequate resuscitation, processes which should proceed
concurrently. The initial clinical approach should be determined,
in large part, by the patient’s presentation. A history of red blood
or dark “coffee ground” emesis nearly always indicates an upper
gastrointestinal (UGI) source. The rectal passage of black, digested
blood (melanic stool) is also indicative of a lesion proximal to the
ligament of Trietz.31 The passage of bright red blood per rectum
usually suggests a primary colorectal source, but can also occur in
patients with upper tract lesions if the rate of bleeding is torrential
and the transit time is brief.
PMPH_CH13.indd 110
A rapid assessment of the patient’s hemodynamic and physi-
cal status should guide early therapy and appropriate triage. The
presence of hemorrhagic shock, either compensated or decompen-
sated, mandates aggressive fluid management with blood products
and/or crystalloid. In addition, preexisting comorbities such as
cardiac disease or hepatic or renal dysfunction must be addressed
since most deaths are related to nonbleeding causes.32 Specific
coagulation abnormalities must also be rapidly corrected.
End-points for resuscitation include (1) normalization of
blood pressure, (2) restoration of hemoglobin concentration, (3)
correction of coagulopathies, and (4) correction of end-organ
dysfunction.33 Such an aggressive and multifaceted approach is
supported in the controlled study of Baradarian et al., in which
intensive monitoring and early hemodynamic stabilization were
provided by a specialized resuscitation group.34 This resulted in a
significant reduction in the associated mortality when compared
with routine floor management.
During resuscitation, nasogastric tube placement is used
to sample the contents of the stomach. In patients who present
with a history of hematemesis, nasogastric aspiration of fresh, red
blood indicates the presence of ongoing bleeding and is an inde-
pendent predictor of poor clinical outcome when compared with
aspiration of either clear or “coffee ground” material.35 In bleed-
ing patients who present with melena but without hematemesis, a
bloody nasogastric aspirate provides strong evidence for a lesion
in the UGI tract.36 The finding of a negative aspirate is less reliable
as it may fail to detect duodenal lesions.
Nasogastric tubes can also used for gastric lavage prior to
endoscopy, but success is limited by the size of the tube and the pres-
ence of clots. Alternatively, prokinetic agents are able to effectively
clear the stomach. Several randomized, controlled clinical trials
have documented that a preendoscopic bolus or infusion of eryth-
romycin improves the quality of the subsequent endoscopic exami-
nation and reduces the need for repeat endoscopic procedures.37,38
This approach appears to be cost-effective.39 (Evidence Grade A)
6. In patients with bleeding ulcers, what is the current role of
endoscopy?
Endoscopy is the definitive diagnostic study for UGI bleeding. In
a multicenter study of 11,160 patients with nonvariceal UGI bleed-
ing, endoscopy identified the bleeding site in 83% of cases. The
most common finding was peptic ulcers (32%) with gastric ulcers
more common than duodenal ulcers (54% vs. 37%).40
Risk stratification is another important function of endoscopy
as it guides early management.41 Patients with a clean-based ulcer
or a nonprotruding pigmented spot are at low risk of rebleeding
and generally require no further endoscopic interventions. Con-
versely, high-risk stigmata such as an actively bleeding ulcer or
an ulcer with a visible vessel forecast a poor outcome and indi-
cate the need for aggressive endoscopic therapy. Another subset of
patients who have an ulcer with an adherent clot also appears to
be at high risk for rebleeding and benefits from removal of the clot
and directed endoscopic therapy.42
The optimal timing for endoscopy continues to be debated.
It is generally agreed that patients who are actively bleeding or
who are unstable require urgent endoscopy to prevent further
deterioration. In the remaining patients, the recommended tim-
ing ranges from urgent to elective. Recent data appear to support
the use of early endoscopy to identify low risk patients who will
require only brief or no hospitalization.43 It has been argued that
5/21/2012 8:50:53 PM

such an approach improves resource utilization. However, two
randomized trials addressing this issue differ in their conclusions
with only one showing significant cost-savings.44,45 Presumably,
this disparity results from differences in practice patterns.
Ulcer bleeding stops spontaneously in the majority of patients
(80–85%).46 In the remainder, endoscopic therapy has proven
efficacious and cost-effective.43,47 By 1992, a meta-analysis of 30
randomized clinical trials was reported, in which a variety of endo-
scopic hemostatic techniques were compared with medical therapy
alone.48 The endoscopically treated group demonstrated significant
reductions in further bleeding (odds ratio (OR), 0.38; 95% confi-
dence interval (CI), 0.32–0.45), need for surgery (OR, 0.36; 95% CI,
0.28–0.45), and mortality (OR, 0.55; 95% CI, 0.40–0.76). Serious
complications directly related to endoscopy were infrequent and
included induced rebleeding (0.4%) and perforation (0–0.9%).
Numerous studies have been conducted comparing the wide
variety of available hemostatic techniques: injection, thermal, and
mechanical. Overall, initial hemostasis rates range from 85% to
100% for all methods.49 However, injection therapy alone, whether
with dilute epinephrine, thrombin, polidocanol, or cyanoacrylate, is
associated with a higher rebleeding rate and a more frequent need
for surgery than when combined with any other therapy.50 A recent
Cockrane systematic review of 17 randomized studies has confirmed
that dual therapy with epinephrine injection and any other tech-
nique reduces the rebleeding rate from 18.8% to 10.4%, emergency
surgeries from 10.8% to 7.1%, and mortality from 5% to 2.5% without
increasing the complication rate.51 Interestingly, evidence is emerg-
ing that monotherapy with thermal or mechanical methods may
be as effective as epinephrine-based combination therapy except in
those patients with profound bleeding.52,53 (Evidence Grade A)
7. What is the role of pharmacotherapy in the management of
a bleeding peptic ulcer?
Pharmacotherapy in patients with bleeding PUD significantly
impacts outcome. Proton pump inhibitor (PPI) infusion, when
used as an adjunct to endoscopic therapy, reduces the risk of fur-
ther bleeding (OR, 0.49; 95% CI, 0.37–0.65) and decreases the need
for surgery (OR, 0.61; 95% CI, 0.48–0.78).54 Such therapy should be
initiated as early as possible. In a recent randomized study, preen-
doscopic PPI was found to facilitate clot formation at the bleed-
ing site and to reduce the need for endoscopic therapy.55 A recent
international consensus recommendation proscribed the use of an
intravenous bolus of PPI followed by a continuous PPI infusion to
reduce rebleeding and mortality in patients with high-risk endo-
scopic stigmata.56 The optimal dosage of PPI is still debated. A con-
temporary meta-analysis has suggested that high-dose regimens
do not further reduce the rate of rebleeding or the need for surgical
intervention when compared with nonhigh dose regimens.57
All patients who are found to be infected with H. pylori should
receive oral eradication therapy as soon as practicable because the
continued long-term presence of H. pylori predicts rebleeding.58
Thus, in a meta-analysis of seven studies, successful eradication
therapy was found to reduce rebleeding rates to 2.9% compared with
20% in the noneradicated group (OR, 0.17; 95% CI, 0.10–0.32).59
In the absence of H. pylori infection, NSAID usage is often
found to be a major contributing cause of ulcer bleeding and may
actually have more severe consequences. A single case–control
study of this issue has demonstrated that NSAID-related bleeding
when compared with matched H. pylori positive cases is associated
with an increased risk of rebleeding (32.4% vs. 13.3%, p = 0.001), an
PMPH_CH13.indd 111
Peptic Ulcer Disease ■ 111
increased need for surgical therapy (15.2% vs. 4.8%, p = 0.01), and
an increased mortality (15.2% vs. 3.8%, p = 0.005).60 All NSAIDs,
including low-dose aspirin, should be immediately stopped in
bleeding patients. (Evidence Grade A)
8. Under what circumstances is an operation indicated for a
bleeding peptic ulcer? What surgical techniques are associated
with the lowest rate of UGI rebleeding?
Surgical therapy is indicated in patients whose bleeding is not con-
trolled by nonoperative measures.61,62 The presence of exsanguinat-
ing hemorrhage or the lack of endoscopic support are self-evident
indications for emergency operation. Recurrent bleeding after
endoscopy is a more common; albeit, less precise indication. In 5%
to 20% of patients who undergo endoscopic hemostasis, bleeding
continues or recurs, a finding that is associated with an increase in
mortality of 5- to 16-fold over controls.63 Risk factors identified by
two separate logistic regression analyses as independent predictors
of rebleeding or mortality include advanced age, shock, comorbidi-
ties, size of ulcer, and presence of major stigmata of hemorrhage.64,65
Most patients with rebleeding can benefit from a second-
look endoscopy performed to provide additional hemostatic
therapy if necessary. In a randomized trial comparing endoscopic
retreatment with surgery, control of bleeding was achieved endo-
scopically in 35 of 48 patients (72.9%) with fewer complications
experienced than in the surgery alone group (7 vs. 16).66 Another
randomized trial compared a scheduled second therapeutic
endoscopy within 16 to 24 h after the initial endoscopy with a
control group without a routine second endoscopy. The rate of
recurrent bleeding was significantly lower in the second-look
group (5% vs. 13.8%, p = 0.03) and a trend toward fewer opera-
tions for rebleeding was identified.67 Further controlled studies
are clearly necessary, but both selective and routine second-look
endoscopy appear capable of favorably influencing the outcome
of peptic ulcer bleeding.
Unsuccessful endoscopic retreatment manifest as persistent or
recurrent bleeding should be addressed by endovascular emboliza-
tion or operation. The choice of a specific procedure depends on the
availability of resources and expertise and, to some degree, usually
reflects specific local preferences. Embolization can achieve high
clinical success rates with a low morbidity rate when performed in
specialized centers. However, no controlled studies are available
that directly compare the two strategies, angiography and surgery,
in bleeding patients.68,69
In the case of surgery, the choice of the most appropriate opera-
tion remains problematic because relevant, high-grade surgical evi-
dence is rare. To this point, only two controlled, randomized trials
comparing various operative approaches have been published since
1990; one from France and a second from England (Table 13.1).70,71
A small, retrospective, multicenter study from Scotland and a large
audit from the Department of Veterans Affairs National Surgical
Quality Improvement Program (NSQIP) database have also been
reported.72,73 The former studies by Poxon et al. and Kubba et al.
compare conservative operations (ulcer oversewing or excision)
with more advanced procedures (vagotomy plus pyloroplasty or
resection). The latter studies by Millat et al. and de la Fuente et al.
compare two different advanced therapies (vagotomy, pyloroplasty
and ulcer oversewing vs. vagotomy and resection).
Notably, all operative techniques described in these studies
resulted in a similar, relatively high mortality rate. In two of the
four studies, the least aggressive forms of therapy were associated
5/21/2012 8:50:53 PM
 112 ■ Surgery: Evidence-Based Practice

Table 13.1 Selected Trials of Surgical Management of Bleeding Peptic Ulcer

Author (Ref) Study Type n Operation Rebleeding (%) Mortality (%)
Poxon (71) CRT 62 Oversewing/excision 7 (11.3)* 16 (26)
67 TV/P or TV/A 4 (5.0)* 13 (19)
Milatt (70) CRT 58 Oversewing/TV/P 10 (17) 13 (22.4)
60 Resection 2 (3) 14 (23.3)
Kubba (72) NRT 31 Oversewing 7 (23)* 7 (23)
36 TV/P or TV/A 1 (2.7)* 5 (14)
de la Fuente (73) NSQIP audit 518 TV and drainage 57 (11.0) 93 (18.0)
389 TV and resection 46 (11.8) 70 (17.22)
CRT: controlled randomized trial; NRT: nonrandomized trial; TV: truncal vagotomy; P: pyloroplasty; A: antrectomy; *p < 0.05.

with a significantly higher rate of rebleeding. Taken together, such
sparse data provides little evidence-based guidance for the surgeon
faced with treating a patient who presents with hemorrhage refrac-
tory to nonoperative therapies. Based on the available literature
and personal experience, the author prefers to oversew the bleed-
ing vessel in duodenal ulcers with the addition of pyloroplasty and/
or a truncal vagotomy. Bleeding gastric ulcers are managed with
partial gastric resection but without vagotomy. In each situation,
the patient should be tested for H. pylori infection and treated, if
positive. As noted before, eradication of the organism should be
documented. (Evidence Grade A)
9. What approach is preferred for the management of perforated
PUD?
Perforation is a potentially catastrophic complication of PUD that
is usually heralded by the abrupt and dramatic onset of severe,
midepigastric or generalized abdominal pain. Since the large
majority of perforations occur on the anterior aspect of the stom-
ach or duodenum, pneumoperitoneum is present in 80% to 90%
of cases and is readily detectable on plain abdominal fi lms or CT
scan.74 Posterior perforations are rare (2%) and have a more insidi-
ous presentation and a worse outcome.
The therapy of ulcer perforation should address three sepa-
rate but related issues: the perforation itself, its underlying cause,
and the resultant peritonitis and sepsis. In regards to the last issue,
initial management commonly includes rapid fluid resuscitation,
nasogastric tube drainage, and systemic antibiotic administra-
tion. There is less certainty about the respective roles of operative
and nonoperative therapies for the actual perforation and its asso-
ciated pathogenetic factors.
Peptic ulcer perforation remains a highly morbid condition
with a reported mortality of 8% to 30%.75,76 Based on a number of
multifactorial analyses, several predictors of postoperative com-
plications and death have been consistently identified, includ-
ing treatment delay, circulatory shock, and major concurrent
illness.77,78 Moreover, it has been suggested that these predictors
can be used to stratify patients and can help to plan initial ther-
apy. Using such an approach, Rahman et al. identified 84 high-
risk patients in a cohort of 626 patients with perforated ulcer and
managed them nonoperatively with peritoneal tube drainage.79
They found a significant decrease in overall mortality compared
with historical controls who had undergone conventional opera-
tive treatment (9.5% vs. 3.9%; p < 0.0001).
The use of nonoperative therapy for ulcer perforation remains
controversial, but appears to be gaining wider acceptance. As
early as 1961, contrast studies documented that more than 40%
of perforations were sealed by the time of clinical presentation.80
Subsequently, multiple nonrandomized studies indicated that
nonoperative treatment of sealed perforations can result in a
lower morbidity and mortality than conventional surgical ther-
apy (Table 13.2).81-84 However, nonoperative treatment fails in 16%
to 32% of perforated patients necessitating emergency operation.
In the only controlled, randomized trial published to date, Crofts
et al. compared initial nonoperative therapy with early opera-
tion in 83 patients with perforation.85 No difference was noted
in mortality (4.7% vs. 5.0%), but the hospital stay was 35% longer
in the nonoperative group. The mixed results with nonopera-
tive therapy suggest that such an approach cannot be universally
applied; however, its selective use especially in high-risk patients
may be appropriate if a strict protocol and close follow-up can be
assured.86
Specific operative strategies for the management of ulcer
perforation have continued to evolve. Prior to recognition of the
pathogenic roles of H. pylori and NSAIDs, numerous studies com-
paring simple closure with definitive operations (vagotomy with
or without resection) appeared to demonstrate a lower recurrence
rate following the more aggressive approach (Table 13.3).87-89 Sub-
sequently, excellent long-term results were observed in 107 care-
fully selected patients followed for 2 to 20 years after patch closure
and parietal cell vagotomy.90 The authors reported an operative
mortality of only 0.9% and a recurrence rate of 7.4%. However, a
more recent controlled randomized study comparing simple clo-
sure with vagotomy and pyloroplasty in over 200 patients failed to
demonstrate an advantage in mortality or recurrence compared
with the more definitive procedure.91
In the current Helicobacter era, pharmacotherapy has fur-
ther confused the role of definitive surgery in the management
of perforation. Worldwide, the prevalence of H. pylori infection
in patients with perforated PUD is reported to range from 47%
to 100%.92 Persistence of the infection after perforation predicts
recurrence of the ulcer, while successful eradication of the organ-
ism results in a significant reduction in recurrence rates.93,94 In a
related study of patients followed for 18 months, ulcer recurrence
was noted in 70% of patients with persistent infection but in only
19% of those in whom H. pylori was eradicated.95 In a controlled,
randomized trial comparing PPI therapy with anti-Helicobacter
therapy following simple closure of the ulcer, the relapse rate was

PMPH_CH13.indd 112 5/21/2012 8:50:53 PM

 Peptic Ulcer Disease ■ 113

Table 13.2 Selected Trials of Nonoperative Management of Perforated Peptic Ulcer

Author (Ref) Study Type n Treatment Recurrent, % Mortality, %
Marshall (84) NRT 49 Nonoperative 16.3 6.1
21 Operative 0 14.3
Crofts (85) CRT 40 Nonoperative 27.5 5.0
43 Operative 0 4.7
Berne (82) NRT 35 Nonoperative 0 3.0
294 Operative NA 6.2
CRT: controlled randomized trial; NRT: nonrandomized trial; *p < 0.05.

Table 13.3 Selected Trials of Surgical Management of Perforated Peptic Ulcer

Author (Ref) Study Type n Treatment Recurrent, % Mortality, %
Boey (87) CRT 41 Closure 36.6* 0
37 Closure/PCV 10.6 0
Tsugawa (88) NRT 15 Closure 63.6* 26.7*
24 Closure/TV 38.1 12.5
Jordan (89) NRT 306 Closure 35.9 10.4
208 Antrectomy/TV 24.4 2.5
Gutierrez de La Pena (91) CRT 117 Closure 7.1 4.3
90 V/P 4.4 4.4
CRT: controlled randomized trial; NRT: nonrandomized trial; TV: truncal vagotomy; PCV: parietal cell vagotomy; *p < 0.05.

found to be significantly reduced in the anti-Helicobacter group
after 1 year (4.8% vs. 38.1%; p < 0.001).96
These data suggest that the majority of patients with perfo-
rated peptic ulcers can be treated with simple closure of the ulcer
when the procedure is combined with appropriate medical mea-
sures such as anti-Helicobacter therapy, PPI administration, or
NSAID modulation. More definitive surgical approaches may be
reserved for patients with recurrent ulcer disease or for perfora-
tions that are associated with hemorrhage or obstruction.
Successful closure of perforations can be achieved with either
open or laparoscopic techniques. In addition, a hybrid approach
has recently been described, in which intraoperative endoscopy is
used with laparoscopy to plug the perforation with omentum.97 A
meta-analysis of 1113 patients from 15 selected studies found that
the purely laparoscopic approach required longer operating times,
but was associated with less postoperative analgesic use, a shorter
hospital stay, and fewer wound infections.98 To date, three random-
ized studies have confirmed that laparoscopic and open repairs are
equally safe and effective and have confirmed that postoperative pain
is improved in the laparoscopic group.99-101 However, not all patients
are candidates for laparoscopy. In particular, age over 70 years and
the persistence of symptoms longer than 24 h are associated with
increased morbidity and mortality and are considered relative con-
traindications to the laparoscopic approach.102 (Evidence Grade B)

Clinical Question Summary

Question
1 How has the surgery of peptic ulcer
disease (PUD) changed over time?
2 What are the major risk factors for
PUD?
Answer Grade References
The number of operations performed for PUD has declined B 7-10
by >80% over the past two decades. The most common
indications are perforation and bleeding. Operations for
intractability are rare. Patients are generally older, sicker,
and more often female.
In western countries, PUD is primarily caused by H. pylori A 18-21
infection and NSAID use. Idiopathic causes include ZES,
G-cell hyperplasia, Crohn’s disease, cocaine abuse, and
systemic mastocytosis.

(Continued)

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 114 ■ Surgery: Evidence-Based Practice

(Continued)
Question
3 What is the appropriate therapy for
H. pylori positive PUD?
4 How can the risk of PUD be minimized
in patients requiring regular NSAID
therapy?
5 In a patient suspected of having a
bleeding peptic ulcer, what should the
initial approach be?
6 In patients with bleeding ulcers, what is
the current role of endoscopy?
7 What is the role of pharmacotherapy in
the management of a bleeding peptic
ulcer?
8a Under what circumstances is an
operation indicated for a bleeding
peptic ulcer?
8b What surgical techniques are associated
with the lowest rate of UGI rebleeding?
9 What approach is preferred for the
management of perforated PUD?
Answer Grade References
First-line therapy combines PPI + clarithromycin + A 23-25
amoxicillin or metrinidazole and has a successful
eradication rate of 78–90%. Rescue therapies are
available for nonresponders.
If found, H. pylori should be eradicated before NSAID A 27-30
therapy is initiated. Misoprostol, PPI therapy, and
double-dose H2RA therapy are all effective in reducing
the risk of NSAID-induced gastrointestinal complications.
A rapid and accurate diagnosis and aggressive resuscitation A 33-34
should proceed simultaneously in patients thought to be
bleeding from an UGI source.
Endoscopy is the definitive diagnostic and prognostic A 43-53
study. It is also an effective therapeutic tool with initial
hemostasis rates of 85–100%.
When used as an adjunct to endoscopic therapy, PPIs reduce A 54, 55
the risk of further bleeding and the need for surgery.
Surgery is indicated for peptic ulcer hemorrhage that is not A 61-63
controlled by endoscopic therapy or recurs following
apparently successful endoscopic therapy (5–20%).
When used for peptic ulcer bleeding, combined partial A 83, 85, 86
gastric resection and vagotomy is associated with the
lowest recurrence rate. However, this approach also has
a higher rate of short term and long-term postoperative
complications. Vagotomy with oversewing of the ulcer is
effective when combined with anti-H. pylori therapy in
H. pylori + patients.
Nonoperative therapy can be used in selected patients B 92-99
who are found to have a sealed perforation on contrast
study. Patch closure is indicated in most patients.
H. pylori should be eradicated when infection is present.
The laparoscopic approach is being used with increased
frequency.

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ulcer perforation. Ann Surg. 2000;231:153-158.
97. Lunevicius R, Morkevicius M. Comparison of laparoscopic
vs open repair for perforated duodenal ulcers. Surg Endosc.
2005;19:1565-1571.
PMPH_CH13.indd 117
Peptic Ulcer Disease ■ 117
98. Siu W, Leong H, Law B, et al. Laparoscopic repair for perforated
peptic ulcer: A randomized controlled trial. Ann Surg. 2002;
235:313-319.
99. Lau WY, Leung KL, Kwong KH, et al. A Randomized Study
Comparing Laparoscopic Versus Open Repair of Perforated
Peptic Ulcer Using Suture or Sutureless Technique. Ann Surg.
1996;224:131-138.
100. Malkov I, Zaynutdinov A, Veliyev N, et al. Laparoscopic and
endoscopic management of perforated duodenal ulcer. J Am
Coll Surg. 2004;198:352-355.
101. Bertleff M, Halm J, Bemelman W, et al. Randomized clinical
trial of laparoscopic versus open repair of the perforated peptic
ulcer: The LAMA trial. World J Surg. 2009;33:1368-1373.
102. Bertleff M, Lange J. Laparoscopic correction of perforated
peptic ulcer: First choice. A review of the literature. Surg Endosc.
2010;24:1231-1239.
5/21/2012 8:50:53 PM
 Commentary on
Peptic Ulcer Disease
Management of peptic ulcer disease (PUD) has changed drasti-
cally over the course of my career. For a young surgeon at Denver
General Hospital in the late 1980s, elective operations for intracta-
ble PUD and gastric outlet obstruction as well as emergency opera-
tions for bleeding and perforation were surprisingly common. We
debated the optimal role of various procedures (including subtotal
resection, vagotomy and antrectomy, vagotomy with pyloroplasty
or gastroenterostomy and highly selective vagotomy) based the
indication and patient stability. We fretted over how to close the
“difficult duodenal stump” and when to use a lateral duodenos-
tomy tube. On teaching rounds we discussed (1) different types of
pyloroplasty (e.g., Heineke-Mikulicz, Finney, and Jaboulay), (2)
different ways to reconstruct after gastric resection (e.g., Billroth
I, Billroth II, Hofmeister, Roux-en-y, and Polya) and their relative
advantages/disadvantages, (3) giant duodenal ulcer, (e) classic pre-
sentation of a “blown duodenal stump”, (f) the Zollinger–Ellison
syndrome, and (6) different types postgastrectomy syndromes
(e.g., dumping, bile gastritis, afferent loop, and efferent loop) and
how they would be managed surgically. We were diligent in these
discussions because we were certain that there would be questions
related to PUD on the in-service exams as well as the written and
oral board exams. These operations and the associated discussions
are now largely irrelevant in my practice as an Acute Care Sur-
geon. I occasionally operate for perforation, rarely for bleeding or
obstruction and never for intractability. Occasionally, I am called
to assist my junior partners, because they have done so few of these
operations. The manuscript nicely outlines the reasons for these
changes including (1) the wide spread use of new pharmacother-
apy, (2) the expanded role of interventional endoscopy, and (3) the
changing epidemiology of PUD where pathologic hyperacidity has
been replaced by the Helicobacter pylori infection and nonsteroidal
anti-inflammatory drug (NSAID) use as prime inciting events.
SO WHAT DOES A SURGEON REALLY
NEED TO KNOW ABOUT PUD?
1. The H. pylori story: Most patients (above 90%) with PUD
have an H. pylori infection and/or recent use of NSAIDs. The
location of the H. pylori infection helps determine the clinical
presentation. Antral-dominant infection causes hyperacidity
with duodenal ulcer while body-dominant infection causes
mucosal atrophy with hypochlorhydria and gastric ulcers.
NSAIDs can aggravate this pathophysiology by inhibiting
constitutive COX-1, which decreases the local production
cytoprotective prostacyline. The treatment of H. pylori
includes a combination of a proton pump inhibitor (PPI)
118
PMPH_CH13.indd 118
Frederick A. Moore
with clarithromycin (500 mg bid) and amoxicillin (1 gm bid)
or metronidazole (500 mg bid) for 10 to 14 days. Second-line
rescue therapy treatment includes quadruple therapy which
combines a PPI with bismuth subsalicycle (2 tablets daily),
metronidazole (250 mg qid) and tetracycline (500 mg qid) for
14 days. Eradication should always be confirmed with either a
urea breath test or a stool antigen. Eradication rates with either
regimen range from 75% to 90%.
2. Management of Upper Gastrointestinal Bleeding: This has
shifted to more aggressive endoscopy for risk stratification
and therapeutic interventions. Resuscitation and correction of
coagulopathy are key early interventions prior to endoscopy.
PPI infusions should be started as early as possible. Stop
NSAIDs and aspirin. Do not forget the H. pylori story.
If rebleeding occurs after endoscopic intervention, repeat
endoscopy (not surgery) is indicated. If bleeding cannot be
controlled, interventional radiology embolization is an option
in specialized centers. If you have to operate, what procedure
should be performed is debatable. I agree with the author—be a
minimalist: (1) wedge resection of gastric ulcers (if feasible) with
no truncal vagotomy and (2) oversew the bleeding vessel within
the duodenal ulcers with pyloroplasty and a truncal vagotomy.
Again do not forget the H. pylori story.
3. Treatment of Perforated Duodenal Ulcer: In this era of H. pylori,
the treatment of a perforated PUD has been simplified. After
volume resuscitation and antibiotic administration, go to the OR
and perform open or laparoscopic repair with peritoneal washout.
Usually, the perforation is on the anterior surface of the postpyloric
duodenum and is <5 mm in diameter. This is best closed with an
omental patch. Attempts to close the hole directly can result in a
bigger hole, when the sutures pull through the inflamed tissue. Do
not forget the H. pylori story. For patients who have clearly failed
medical management or those who cannot afford, tolerate or
comply with medical management, a highly selective vagotomy is
reasonably definitive ulcer operation. Nonoperative management
of perforated PUD in selected patients is an option supported by
the literature, but I rarely pursue this.
4. Management of a Perforated Gastric Ulcer: These are
commonly associated with NSAID use. In a stable patient, with
a perforated ulcer on the greater curvature or in the body of the
stomach are frequently amenable to wedge resection and this is
a reasonable option. Perforated ulcers on the lesser curvature of
the stomach, distal gastrectomy including the ulcer is usually
required. Billroth I reconstruction is preferred and a vagotomy
is not required. In the unstable patient, biopsy and omental
patch closure can be life-saving. Do not forget the H. pylori
story.
5/21/2012 8:50:53 PM
 CHAPTER 14

Zollinger–Ellison Syndrome
Geoffrey W. Krampitz and Jeffrey A. Norton

INTRODUCTION Stomach distension, vagal Stomach lumen

stimulation, GRP, intraluminal
peptides, and hypercalcemia
Zollinger–Ellison Syndrome (ZES) is a syndrome of severe pep- +
tic ulcer disease caused by gastrin hypersecretion by a functional
neuroendocrine tumor called gastrinoma. In 1955, Zollinger and Stomach pH below 3, –
somatostatin, secretin, GIP, G-cell
Ellison reported cases of islet cell tumors of the pancreas and gas- VIP, glucagon and calcitonin
tric acid hypersecretionin association with unusual occurrences of
Gastrin
jejunal peptic ulcer disease. These recurrent ulcers were refractory
to conventional acid-reduction surgery and ultimately required CCK2R Gastrin-R

total gastrectomy for symptomatic control.1 Zollinger and Elli- Pl

son theorized that the associated pancreatic tumors were the cause ECL cell Ca2+
H-K-ATPase
of the severe peptic ulcer disease in these patients. We now know
PK H+
that these tumors first described by Zollinger and Ellison are in fact
Histamine Histamine-R
gastrinomas that produce unregulated amounts of the hormone AC cAMP
gastrin that in turn stimulates excessive gastric acid secretion, lead- Parietal cell
ing to intractable peptic ulcer disease.

PATHOPHYSIOLOGY Figure 14.1 Effect of gastrin on oxyntic parietal cells. AC:

Parietal cells of the oxyntic mucosa of the stomach secrete hydro-
chloric acid into the stomach lumen in response to histamine from
mast cells and enterochromaffin-like (ECL) cells, acetylcholine
from vagal innervations, and the linear peptide hormone gastrin
from G cells of the duodenum, antro-pyloric mucosa, and pancreas.
Gastrin is central to the pathophysiology of ZES. Gastrin release
is stimulated by stomach distension, vagal stimulation mediated
by gastrin-releasing peptide, intraluminal peptides, and hypercal-
cemia. It is inhibited by stomach acidity (pH < 3) via a negative
feedback mechanism mediated by the release of somatostatin by
delta cells, secretin, gastroinhibitory peptide, vasoactive intesti-
nal peptide, glucagon, and calcitonin. Gastrin exerts its effects on
the oxyntic mucosa of the stomach via two independent pathways,
directly on parietal cells and indirectly via ECL cells (Fig. 14.1).
In the indirect pathway, gastrin binds the cholecystokinin-2
receptor on ECL cells, potentiating the release of histamine, that
in turn interacts with histamine-2 receptors on parietal cells to
activate adenylatecyclase to increase intracellular cyclic AMP
adenylatecyclase, cAMP: cyclic adenosine monophosphate, Ca2+:
calcium ion, CCK2R: cholecystokinin-2 receptor, ECL: entero-
chromaffin-like, gastrin-R: gastrin receptor, H+: hydrogen ion,
histamine-R: histamine receptor, H-K-ATPase: hydrogen potas-
sium adenosine triphosphatase, PI: phosphatidyl inositol, and PK:
protein kinase.
(cAMP).2 In the direct pathway, gastrin binds receptors on the
parietal cells that increase intracellular calcium levels via the
phosphatidyl inositol pathway. Both cAMP and calcium act via
protein kinases to activate the hydrogen potassium ATPase (H-K-
ATPase) on the apical membrane of parietal cells, thereby increas-
ing gastric acid production.3
In summary, gastric acid production is stimulated by three
mechanisms mediated by gastrin, histamine, and acetylcholine.
Gastrin is the principal effector in the gastrin pathway and plays
a major role in the histamine pathway. Although conventional
acid-reduction surgery eliminates the cholinergic stimulus for

119

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 120 ■ Surgery: Evidence-Based Practice

gastric acid production, it does not address the effects of gastrin.

Thus, it becomes clear why the sentinel cases of peptic ulcer dis-
ease in the setting of gastrinoma that so intrigued Zollinger and
Ellison were refractory to conventional acid-reduction surgery.

EPIDEMIOLOGY

Incidence
Gastrinoma is the second most common neuroendocrine tumor
with a yearly incidence of approximately 0.1 to 3 cases per million
people. ZES is the underlying cause in approximately 0.1% to 1% of
patients with peptic ulcer disease.4 Because of an increased aware-
ness of ZES and the widespread availability of accurate immu- Figure 14.2 Distribution of gastrinomas within the duode-
noassays to measure serum concentrations of gastrin, gastrinoma num and pancreas. Within the duodenum, 57% of gastrinomas
is increasingly diagnosed and treated at an early stage of disease. are found in the first portion, 33% in the second portion, 8.5%
However, the mean time from symptoms to diagnosis is 8 years in in the third portion, and only 3% in the fourth portion. Within
many studies, so that improvements in detection are needed. the pancreas, 48% of gastrinomas are found in the tail, 30% in the
head, and 22% in the body.

ASSOCIATION WITH MULTIPLE

ENDOCRINE NEOPLASIA TYPE 1
ZES occurs in both sporadic and familial forms. In 80% of
cases, ZES occurs sporadically. However, approximately 20%
of patients with ZES have the familial form associated with mul-
tiple endocrine neoplasia type 1 (MEN1). Fift y percent of patients
with MEN1 have ZES making gastrinoma the most common
functional neuroendocrine in MEN1. Thus, during the workup
for ZES, MEN1 must always be excluded. Figure 14.3 Duodenal gastrinoma. (A) Endoscopic view of duo-
denal gastrinoma. (B) Pathology specimen of a solitary duodenal
gastrinoma.
CHARACTERISTICS

Size and Location 176 Patients

with ZES
Approximately 80% of gastrinomas are found within the gastri-
noma triangle, the apices of which are bounded by the junction 82 (47%) 45 (26%) 36 (20%) 11 (6%) 11 (6%)
Duodenal tumor Lymph node Pancreatic Primary in other No tumor found
of the cystic and common bile ducts superiorly, the junction of only tumor location
the second and third portions of the duodenum laterally, and
Possible
the neck of the pancreas medially. Primary gastrinomas have 19 (11%) 26 (15%)
LN Primary
Not disease-free Disease-free
been reported in a number of ectopic anatomical sites includ-
ing the jejunum, stomach, liver, spleen, mesentery, ovary, heart, F/U – 10.4 ± 1.2 yrs
and lymph nodes.5 Gastrinomas are three times more likely to
occur in the duodenum than in the pancreas, with the highest 18 (10%) 8 (5%)
Remained Relapsed
proportion in the fi rst portion of the duodenum and becoming disease-free 3 = Duod. tumor
progressively less common in the distal duodenum (Fig. 14.2).6 LN Primary
4/8 Reop
1 = Unknown primary
Duodenal gastrinomas (Fig. 14.3) are often smaller compared
with pancreatic tumors (0.95 vs. 2.1 cm) that are larger and usu- Figure 14.4 Distribution of patients with ZES dependent on
ally solitary.7 In MEN1, both pancreatic and duodenal gastrino- surgical results. Of the 176 patients with ZES undergoing explor-
mas are multiple (Fig. 14.4). Gastrinomas have been found in atory laparotomy, 45 had an LN only removed, and 26 of the 45
extrapancreatic, extraintestinal lymph nodes with no identifi- patients (15%) were disease-free postresection and had a pos-
able primary pancreatic or duodenal tumor.8-10 Whether these sible LN primary. By permission.8
represent lymph node primary tumors or metastases from occult
pancreatic or intestinal primary tumors is controversial. In one
series of 138 patients who underwent exploration for gastrinoma, ery that neuroendocrine cells may be found within abdominal
10% of patients with sporadic ZES achieved long-term cure after lymph nodes offers a possible explanation for the origin of these
resection of a lymph node only. These patients were followed tumors.11,12 The characteristics of gastrinomas are summarized
for a mean of 10 years, suggesting that these tumors represent in Table 14.1.
true lymph node primary gastrinoma (Fig. 14.5). 8 The discov-

PMPH_CH14.indd 120 5/21/2012 8:51:36 PM


Table 14.1 Characteristics of Gastrinoma
Tumor Incidence Hormone Signs or
(people/ secreted symptoms
million/year)
Gastrinoma 0.1–3 Gastrin Epigastric pain,
diarrhea,
esophagitis
Figure 14.5 Specimens from Patient 7. Panel A shows the
bisected duodenum (D), common bile duct (C), and head of
the pancreas (P). A small gastrinoma is present in the duodenal
mucosa (arrow). Panel B shows a histologic section of a duodenal
gastrinoma (solid arrow). The size of the tumor barely exceeds
the size of a normal mucosal fold (open arrow). (Hematoxylin
and eosin, x10.) By permission. 52
METASTATIC POTENTIAL AND SURVIVAL
Gastrinomas are slow growing, but approximately 60% to 90% are
malignant, with patients having lymph node, liver, or distant meta-
static disease at the time of diagnosis. In 25% of cases, the tumor may
pursue a particularly aggressive course. Gastrinoma is associated
with lymph node involvement in 50% to 80% of patients and, unlike
many other types of cancers, lymph node involvement alone without
hepatic or distant metastases does not decrease survival.13-15 Pancre-
atic gastrinomas appear to have a higher incidence of liver metastases
compared with duodenal tumors (50% vs. 10%), whereas duodenal
tumors have a higher incidence of lymph node metastases (40–70%).
In addition, tumors in the distal pancreas are more likely to metasta-
size to the liver than are tumors arising within the gastrinoma trian-
gle.16 Overall, however, gastrinomas of the duodenum and pancreas
appear to have a similar incidence of metastases. Because liver metas-
tases have a direct affect on survival, pancreatic gastrinomas have
a decreased long-term survival compared with duodenal primary
tumors. Patients without any liver metastases had a 95% 20-year
survival, whereas patients with diffuse bilobar liver metastases had
a 10-year survival of only 15%. Patients who had a solitary liver
metastasis or fewer than five discrete metastases in both liver lobes
had an intermediate survival (60% at 15 years).17 The extent of liver
involvementneuroendocrine tumor is therefore the most impor-
tant predictor of survival in neuroendocrine tumors (Fig. 14.6).
CLINICAL PRESENTATION
Patients with ZES most often present with symptoms of pep-
tic ulcer disease. Gastrinomas secrete excessive amounts of the
PMPH_CH14.indd 121
Zollinger–Ellison Syndrome ■ 121
Location (%) Malignant (%) MEN1
(%)
Duodenum Pancreas Lymph Node
60 20 10 60–90 20
Figure 14.6 Multiple duodenal gastrinomas in MEN1 with ZES.
hormone gastrin, and thus the gastric parietal cells are under con-
stant stimulation to produce acid, which causes peptic ulceration
and epigastric abdominal pain in 80% of patients with ZES.
Diarrhea, caused by gastrin-induced acid hypersecretion and
increased bowel motility, is the second most common symptom
and may be the only manifestation of ZES in 20% of patients.
Esophagitis with or without stricture occurs with more severe
forms of the syndrome.
As mentioned previously, approximately 20% of patients with
ZES will have it as part of MEN1, and this syndrome must always
be excluded. A significant family history of ulcers and peptic ulcer-
ation occurring at a young age are clues to familial gastrinoma. In
addition, peptic ulcers in association with hyperparathyroidism
and/or nephrolithiasis, pituitary tumors or prolactinomas, benign
thyroid tumors, benign and malignant adrenocortical tumors,
lipomas, and cutaneous angiofibromas all may be indicative of
MEN1.
Patients with ZES usually have a solitary ulcer in the proxi-
mal duodenum much like patients with peptic ulcer disease
unrelated to gastrinoma. However, “atypical” presentations con-
sisting of peptic ulceration in multiple locations or in unusual
locations such as distal duodenum or jejunum should raise
concern for ZES. In addition, recurrent ulceration refractory
to appropriate medical treatment, or after acid-reducing surgi-
cal procedures, should raise suspicion of ZES. All patients with
peptic ulcer disease severe enough to require surgery should be
screened preoperatively for gastrinoma. Furthermore, patients
with peptic ulcer disease in the presence of persistent diarrhea
or the absence of Helicobacter pylori infection should be investi-
gated. However, not all patients with ZES have peptic ulcer dis-
ease, and 20% of patients with ZES have no evidence of peptic
ulceration at the time of presentation.
Because ZES is rare and few clinicians have seen many cases,
there may be a failure to include ZES in the differential diagnosis.
ZES should be considered in all patients who present with one or
5/21/2012 8:51:37 PM
 122 ■ Surgery: Evidence-Based Practice
more symptoms referable to the upper gastrointestinal tract or in
those with peptic ulcer disease and primary hyperparathyroidism
and nephrolithiasis or family history suspicious for MEN1.
DIFFERENTIAL DIAGNOSIS
Hypergastrinemia may occur as a manifestation of many dis-
eases or conditions apart from ZES. Ulcerogenic conditions with
excessive gastric acid secretion include gastric outlet obstruc-
tion, retained gastric antrum after Bilroth II reconstruction, and
G-cell hyperplasia. Nonulcerogenic conditions without excessive
gastric acid secretion include postvagotomy, postgastric bypass,
pernicious anemia, atrophic gastritis, short gut syndrome after
significant intestinal resection, and renal failure, Helicobacter
pylori infection, VIPoma, and stomach irradiation. Many of
these conditions are associated with achlorohydria, in which
stomach acid production is absent, resulting in hypergastrinemia
and mimicking ZES.
DIAGNOSIS
Laboratory Studies
Table 14.2 summarizes the laboratory values for the diagnosis of
ZES.
Fasting Serum Gastrin
The evaluation of a patient in whom ZES is suspected begins by
obtaining a fasting serum concentration of gastrin. Hypergas-
trinemia occurs in almost all patients with ZES and is defined as
a serum gastrin concentration >100 pg/mL. Therefore, a normal
fasting serum gastrin concentration effectively excludes ZES.
Antacid medications like histamine receptor antagonists or pro-
ton pump inhibitors may cause a false-positive increase in serum
gastrin concentration, and those medicines should be withheld
for at least 1 week before measurement of the serum gastrin
concentration.
Basal Acid Output
Achlorhydria is a common cause of hypergastrinemia, and gas-
tric acid secretion is measured to exclude this condition. A nor-
mal adult basal acid output (BAO) is approximately 2 to 5 mEq/h.
Table 14.2 Diagnosis of Gastrinoma
Blood Measurement Fasting Normal Range
Gastrin <100 pg/mL
BAO 2 to 5 mEq/hr
Fasting gastric acid concentration
Secretin stimulation test <200 pg/mL increase of gastrin
concentration above baseline
PMPH_CH14.indd 122
A BAO greater than 15 mEq/h (>5 mEq/h in patients who have
undergone previous acid-reducing operations) is abnormal and
occurs in 98% of patients with ZES. Measurement of gastric pH
is a simpler, but less accurate, indicator of gastric acid hypersecre-
tion. A gastric pH > 3 essentially excludes ZES, whereas a pH ≤ 2
is consistent with ZES.
Postsecretin Challenge
An increased fasting serum gastrin concentration (>100 pg/mL)
and abnormally elevated BAO (>15 mEq/L) establish the diagnosis
of ZES. Many patients with ZES have gastric acid hypersecretion
and minimally increased fasting serum gastrin concentrations
(100–1000 pg/mL). For these patients, the secretin stimulation
test is the provocative test of choice. After an overnight fast, secre-
tin is administered intravenously (2 U/kg), and blood samples
are collected immediately before and at 2, 5, 10, and 15 min after
giving the secretin. Secretin normally inhibits gastrin produc-
tion; however, in the setting of a gastrinoma, secretin produces a
paradoxical increase in gastrin secretion. An increase in gastrin
concentration of 200 pg/mL above baseline is diagnostic of ZES.
The test sensitivity is not 100%, and approximately 15% of patients
with gastrinoma may have a negative secretin test.
Serum Calcium and Parathyroid Hormone
All patients undergoing an initial workup for ZES should be
screened for hyperparathyroidism associated with MEN1. ZES
was the initial clinical manifestation in 40% of patients with
MEN1, and the onset of ZES symptoms preceded the diagnosis
of hyperparathyroidism in 45% of patients.18 The initial screen
should include a serum calcium measurement, which exploits the
high penetrance of hyperparathyroidism in MEN1. If hypercalce-
mia is detected, parathyroid hormone levels should be measured
in order to confirm the diagnosis of hyperparathyroidism. Hyper-
calcemia resulting from hyperparathyroidism can significantly
exacerbate the symptoms of ZES and further elevate serum gas-
trin levels due to the underlying gastrinoma. As such, the diag-
nosis of hyperparathyroidism coexistent with ZES may alter the
surgical management of the associated conditions.
LOCALIZATION
The diagnosis of ZES can be achieved by clinical symptoms and
biochemical analysis. However, locating the primary tumor and
Result with Gastrinoma Test Sensitivity (%)
>100 pg/mL 99
>15 mEq/h 98
(>5 mEq/h in patients who have
undergone previous acid-
reducing operations)
pH ≤ 2
≥200 pg/mL increase of gastrin 85
concentration above baseline
5/21/2012 8:51:39 PM
 Zollinger–Ellison Syndrome ■ 123

Table 14.3 Sensitivities of Tumor Localization Modalities

Study % of Tumors Localized

Overall Pancreas Duodenum Liver Metastases

PREOPERATIVE
Noninvasive
Transabdominal ultrasonography 20–30 14
Abdominal computed tomography 50 80 35 50
Abdominal magnetic resonance imaging 25 83
Somatostatin receptor scintigraphy 71–90 50
Invasive
Endoscopic ultrasonography 85 75–100 28–57
Selective arterial secretin injection test 90

INTRAOPERATIVE
Palpation 65 91 60
Intraoperative ultrasonography 83 95 58
Duodenotomy – – 100

identifying any evidence of metastases is critical to developing

appropriate treatment strategies. Localization of gastrinomas
should begin with noninvasive imaging to assess the extent of
tumor spread and exclude unresectable disease. Invasive modali-
ties can then be used to localize the primary tumor prior to sur-
gery because accurate localization of gastrinomas offers the best
chance at curative resection. The sensitivities of various tumor
localization modalities are summarized in Table 14.3.

Ultrasound
Transabdominal ultrasonography is often the initial imaging
study obtained during the workup of abdominal symptoms. It
is noninvasive, relatively inexpensive, and readily available. On
ultrasound, gastrinomas appear as well-defined, homogeneous
hypo- or iso-echogenic mass lesion. However, transabdominal
ultrasound is of limited use in identifying gastrinomas, as its sen-
sitivity is less than 30%.19
Endoscopic ultrasound (EUS) is an invasive procedure that
combines endoscopy and ultrasound to produce high quality, Figure 14.7 Computed tomography scan of gastrinoma.
detailed, cost-effective, images of the walls of the hollow gas- (A) Duodenal gastrinoma. (B, C) Pancreatic head gastrinoma.
trointestinal tract and adjacent organs during surveillance for (D) Hepatic metastases.
gastrinoma (Fig. 14.7). EUS has a sensitivity of 85% for detect-
ing pancreatic gastrinomas, but only 43% for detecting duodenal as small as 5 mm and is therefore a powerful adjunct for detecting
gastrinomas.20 There was great variability in the sensitivities for tumors not identified during preoperative imaging.22,23 However,
EUS localization of pancreatic (75–100%) and duodenal (28–57%) IOUS is poor at detecting duodenal gastrinomas, 24 and thus is no
tumors among a number of studies reviewed. Whether the dif- substitute for duodenotomy with direct palpation.
ferences in sensitivities are due to operator-dependence, patient
populations, or instrumentation is unclear. Nevertheless, the low Duodenotomy
sensitivity of EUS for duodenal tumor given the frequency of
small duodenal gastrinomas is a significant limitation.21 Duodenotomy is necessary to allow direct inspection and explo-
Intraoperative ultrasound (IOUS) is very useful for localizing ration of the duodenal mucosa. A recent prospective study of
intrapancreatic gastrinomas. IOUS can localize pancreatic tumors patients with sporadic ZES who underwent surgical exploration

PMPH_CH14.indd 123 5/21/2012 8:51:39 PM

 124 ■ Surgery: Evidence-Based Practice
revealed a significantly higher cure rate following duodenotomy,
both immediately and long term.25 Duodenotomy was particularly
important in the detection of small duodenal tumors, allowing
localization of 90% of tumors <1 cm versus only 50% discovered
on preoperative imaging. Duodenotomy is the intraoperative
procedure of choice for detection of gastrinoma and should be
performed in all surgical explorations for gastrinoma. Duodenal
wall gastrinomas occur in greatest density more proximally in
the duodenum. Regional lymph nodes should be systematically
sampled, as lymph node metastases may be inapparent at explora-
tion and will be found in 55% of patients with duodenal tumours.
Gastrinomas can ultimately be found by an experienced surgeon
in nearly all patients.26-28
Computed Tomography
Due to their relative hypervascularity, gastrinomas appear
as hyperattenuating lesions in the arterial phase on contrast-
enhanced computed tomography (CT) (Fig. 14.8). Overall, abdom-
inal CT detects approximately 50% of gastrinomas. However, the
sensitivity of CT depends greatly on tumor size, tumor location,
and the presence of metastases.29 CT reliably detects gastrinomas
larger than 3 cm in diameter, whereas tumors smaller than 1 cm
in diameter are rarely detected. Intermediate tumors between 1
and 3 cm are identified in 30% of cases. Primary gastrinomas that
arise within the pancreas are identified much more reliably than
those in extrapancreatic, extrahepatic locations (80% vs. 35%). In
addition, CT scanning identifies only 50% of liver metastases.
Magnetic Resonance Imaging
Gastrinomas are relatively hypervascular when compared with
normal intraabdominal tissues, and therefore gastrinomas have
lower signal intensity on T1 imaging and higher signal intensity
on T2 imaging compared with surrounding organs. Although,
Figure 14.8 SPECT/SRS of duodenal gastrinoma.
PMPH_CH14.indd 124
abdominal magnetic resonance imaging (MRI) has a low sensi-
tivity (25%) in localizing primary gastrinomas, it is particularly
useful in detecting hepatic metastases (sensitivity of 83%). Gastri-
noma metastases in the liver appear bright with distinct periph-
eral enhancement on dynamic T2-weighted images. In addition,
MRI is especially useful to differentiate gastrinoma metastases
within the liver from hemangiomas.
Somatostatin Receptor Scintigraphy
Somatostatin receptor scintigraphy (SRS), also called octreoscan,
is the study of choice for localizing both primary and metastatic
gastrinoma (Fig. 14.9). During SRS, patients suspected of harbor-
ing gastrinoma are administered 6 mCi of 111In-labeled octreotide
by intravenous injection. The compound identifies gastrinomas
because the vast majority of these tumors avidly express type 2
somatostatin receptors to which octreotide has a high affi nity.
Gamma recorders estimate tracer uptake at particular time points
(usually 4 hours, and if necessary 24 and 48 h) after administra-
tion of the radioactive compound.
One prospective study using SRS in 146 patients found a sen-
sitivity of 71%, specificity of 86%, positive predictive value of 85%
and a negative predictive value of 52%.30 With a high pretest prob-
ability, as in the setting of ZES, SRS has an overall sensitivity of
approximately 90%, specificity approaching 100%, and positive
predictive value near 100%.30,31 The sensitivity of SRS for gastri-
noma exceeds all other imaging modalities combined (angiogra-
phy, MRI, CT, ultrasonography).
In the study of gastrinoma, SRS altered clinical management
in almost 50% of patients, reflecting the ability of SRS not only
to identify the primary tumor location, but also clarify equivocal
results generated by conventional imaging studies.32 The accuracy
of SRS can be further improved by the application of anatomi-
cal imaging by single photon emission computed tomography
(SPECT).33,34 SRS/SPECT enables convenient whole body imaging
to detect the presence of gastrinomas throughout the body.
Like CT, however, the sensitivity of SRS correlates directly
with the size of tumors. SRS was able to detect 96% of gastrinomas
larger than 2.2 cm, but only 30% of tumors smaller than 1.1 cm.
Figure 14.9 Endoscopic ultrasound of extraduodenal gastrinoma.
5/21/2012 8:51:40 PM

100 No liver metastases (n = 158)
90
Probability of survival (percent)
80 p = 0.028
70
60
50
40 p = 0.0004
30
20
Diffuse liver metastases (n = 27)
10
0
0 5 10 15
Years since diagnosis
Figure 14.10 Survival of patients with liver metastases from
gastrinoma. By permission.20
SRS had a sensitivity of 64% for intermediate tumors sized
between 1.1 and 2.2 cm. Because duodenal gastrinomas are usu-
ally subcentimeter in size (Fig. 14.10), SRS fails to detect about
50% of these tumors.7,20,22
A positive SRS study strongly predicts the presence of tumor,
but the inconsistent negative predictive value (33–100%) cau-
tions against excluding a tumor on the basis of a negative study.
SRS has a false-positive localization rate of about 12%. Extra-
abdominal false-positives localization scans were more common
than intraabdominal false-positive scans and were attributed
to thyroid, breast or granulomatous lung disease. 35 The most
common cause of false-positive intraabdominal SRS scans was
accessory spleens, localization to prior operative sites and renal
parapelvic cysts. Only 2.7% of these false-positive studies actu-
ally altered management, suggesting the importance of a high
awareness of other potential causes for a positive SRS scan in the
clinical setting.
Selective Arterial Secret Injection Test
Selective arterial secretin injection test (SASI) evolved from ear-
lier invasive localization techniques, namely selective angiography
and portal venous sampling, with increasing degrees of overall
sensitivity (60% and 80%, respectively). SAIS can demonstrate
the artery supplying a gastrinoma by exploiting the paradoxical
stimulating effect of secretin on gastrinomas to produce gastrin.36
By using catheter directed injection, 30 U of secretin is infused
sequentially into the tributaries of the splenic, gastroduodenal,
and the superior mesenteric arteries. A blood-sampling catheter
is placed in the right hepatic vein to collect blood samples for
gastrin measurement following each injection. At different time
points, the hepatic venous serum immunoreactive gastrin level is
measured. An increase in gastrin greater than 80 pg/mL and more
than 20% above the basal levels is considered a positive result.
By identifying the vessel that supplies the gastrinoma, SASI
localizes the tumor to the vascular distribution attributed to that
particular vessel. SASI can localize gastrinomas smaller than
5 mm in diameter with 90% sensitivity.22 However, SASI is an
invasive procedure, does not directly image the lesion, requires
specialized expertise, and cannot locate occult gastrinomas
PMPH_CH14.indd 125
Zollinger–Ellison Syndrome ■ 125
outside the vascular distribution of the infused vessels. Further,
in patients with nonimaged tumors, SASI always seems to local-
ize the tumor to the gastrinoma triangle limiting its utility.
Developed liver
metastases
(n = 13)
TREATMENT
Single liver lobe
metastases
(n = 14) Medical Management
Proton Pump Inhibitors
The introduction of proton pump inhibitors (PPIs) in the 1980s
has made medical management of gastric acid hypersecretion
possible in patients with ZES. PPIs are the most potent inhibi-
20 25 tors of gastric acid secretion and function by targeting the
H-K-ATPase on the apical membrane of parietal cells. PPIs are weak
protonatable pyridines that undergo acid catalyzed conversion to
thiophilic sulfonamides. These permanent cations then form dis-
ulfide bonds with cysteine residues within the alpha-subunit of
the H-K-ATPase.37 By irreversibly and covalently altering chemi-
cal structures critical to proton transport, PPIs provide potent,
specific, and durable inhibition of gastric acid production.38
Oral omeprazole39 and intravenous pantoprazole must be
dose adjusted in patients with ZES in order to normalize BAO lev-
els to less than 15 mEq/h (less than 5 mEq/h in patients who have
reflux esophagitis or who have had prior operations to reduce acid
secretion, such as subtotal gastrectomy). Measuring BAO after
initiating drug therapy is necessary because relief of symptoms
alone is not a reliable indicator of effective acid control.40,41 Con-
versely, if acid hypersecretion is controlled, epigastric discomfort
resolves and ulcers heal in virtually all patients.42,43 Because of the
recent advances in the effective medical treatment of ZES, total
gastrectomy is no longer indicated in patients with gastrinoma.
Surgical Management
MEN1 and ZES
Table 14.4 shows outcomes of surgical management of gastrinomas.
Neck Exploration
Hypercalcemia resulting from hyperparathyroidism can sig-
nificantly exacerbate the symptoms of ZES and further elevate
serum gastrin levels due to the underlying gastrinoma. Thus, in
ZES patients with coexistent hyperparathyroidism, neck explora-
tion for resection of parathyroid hyperplasia should be performed
prior to embarking on removal of gastrinomas. In these patients,
subtotal parathyroidectomy (3 and ½ glands with the cervical
thymus) can significantly decrease end-organ effects of hypergas-
trinemia allowing for better medical control of ZES symptoms.
Gastrinoma Resection
Gastrinomas associated with MEN1 tend to be multiple, small,
usually originate in the duodenum, and frequently develop
lymph node metastases; however, these tumors may be more
indolent than sporadic tumors and may have a more favorable
long-term prognosis.43 In patients with MEN1 and ZES, surgi-
cal resection is seldom curative (0–10%), but may be effective
to prevent or decrease the development of liver metastases.6
Tumor size correlates with progression to liver metastasis, which
5/21/2012 8:51:43 PM
 126

PMPH_CH14.indd 126
■
Surgery: Evidence-Based Practice

Table 14.4 Outcome of Surgical Management of Gastrinoma

Series Level of N Median With With Tumor Metastases Disease-free Disease- Overall
Evidence Follow Up MEN1 (%) Malignancy Resected (%) Survival (%) related Mortality
(Years) (%) (%) Mortality (%) (%)
Mortellaro III 12 (12 surgery) 18 100 8 92 NR 8 at 3 yrs, 0 33
et al. 0 at last
(2009) follow-up
(57)
Norton et al. II 81 (48 surgerya, 6.9 100 5 vs. 24 NR 6 vs. 24 19 immediately, 2 vs. 50 0 vs. 3 at
(2001) 33 no 0 at 5 yrs 10 yrs
(53) surgeryb)
Thompson III 40 (40 surgery) 15 100 43 NR 3 68 0 97 at 5 yrs
(1998) 94 at 10 yrs
(58) 94 at 15 yrs
Norton et al. III 195 (160 12 21 vs. 26 54 94 5 vs. 29 51 immediately, 1 vs. 23 21 vs. 54
(2006) surgery, 35 41 at last
(45) no surgery) follow-up
Norton et al. III 151 (151 8 19 8 (7 sporadic 93 NR 51 vs. 16 (45) 0 at 5 yrs 14
(1999) surgery) vs. 14 immediately (sporadic &
(27) MEN1) (sporadic vs. MEN1)
MEN1) 5 vs. 14 at
40 vs. 4 at 5 yrs 10 yrs
(sporadic vs. (sporadic
MEN1) vs. MEN1)
34 vs. 0 at
10 years
(sporadic vs.
MEN1)

5/21/2012 8:51:43 PM
PMPH_CH14.indd 127
MacFarlane II 10 NR 100 60 70 NR NR NR 0
et al.
(1995)
(56)
McArthur II 22 16 14 44 41 NR 14 NR 19 at 10 yrs
et al.
(1996)
(54)
Jaskowiak II 17 2.3 13 94 100 NR 35 6 12
et al.
(1996)
(55)
Kisker et al. II 25 5.2 8 48 96 NR 44 0 w/o liver NR
(1998) mets at 5
(14) years vs.
72 w liver
mets
a
Group 2A (n = 17; single PET 2.5–6 cm) and group 2B (n = 31; two or more lesions, 2.5 cm in diameter or larger, or one lesion larger than 6 cm) underwent laparotomy.
b
Group 1 (n = 17) (all PETs smaller than 2.5 cm) and group 3 (n = 8) (diffuse liver metastases) did not undergo surgery.
Zollinger–Ellison Syndrome
■
127

5/21/2012 8:51:43 PM
 128 ■ Surgery: Evidence-Based Practice

One or more symptoms related to upper GI tract (diarrhea, epigastric abdominal

pain), PUD (refractory, recurrent, atypical, requiring surgery, without H. pylori)
nonconstricting closure of the remaining duodenum and special
+/– hyperparathyroidism/nephrolithiasis/family history of MEN1 attention is paid to avoid injury to the ampulla of Vater. Regional
lymph nodes should be systematically sampled and excised, as lymph
ZES excluded,
reevaluate 3-6
No Serum gastrin >
100 ng/dl?
node metastases may be unapparent at exploration and will be found
months

No Yes
in 55% of patients with duodenal tumors. Resection of a single duo-
denal gastrinoma and regional lymph node dissection resulted in a
BAO > 15 mEq/hr
Secretin stim test
with serum gastrin >
200 ng/gl?
No
(5 if prior surgery) or
gastric pH < 2?
cure in 60% of patients with sporadic gastrinoma.22 Multiple duo-
Yes
denal gastrinomas localized to either the upper or the lower aspects
Yes
Diagnosis of ZES of the duodenum may undergo partial resection of the duodenum.
For patients with large tumors or ampullary involvement, a pylorus-
Sporatic ZES
No Hypercalcemia, Yes
Familial ZES/MEN1
preserving pancreaticoduodenectomy may be indicated.22
hyperparathyroid
? Patients with pancreatic disease should undergo mobilization
of the pancreas and palpation with intraoperative ultrasound. For
Treatment with PPI
(titrate to BAO < 10
mEq/hr)
disease in the body and tail of the pancreas, the patient should
Resection with
adequate margins undergo a distal pancreatectomy with lymph node excision. Pan-
Palliative medical and regional lymph
management SRS/SPECT, CT, MRI node resection creatic head and neck tumors not involving major ductal or vascu-
No No
lar structures are enucleated. For bulky large tumors localized to
Cytoreductive surgery,
TACE/RFA
Yes Extent of disease
(90% tumor may be
safely removed)?
Yes
Metastases?
Whipple
pancreaticoduodenectomy
Yes Ampullary
involvement?
the pancreatic head, a pylorus-preserving pancreaticoduodenec-
No
tomy may be necessary.49
Yes

Subtotal Yes No Exploratory laparotomy Localized to

parathyroidectomy
Familial ZES/MEN1?
and duodenotomy duodenum? Advanced Disease
No

Reimage in 3–6 No Yes Mobilization of

Gastrinoma > 2 cm?
months
Whipple
pancreaticoduodenectomy
Figure 14.11 Summary algorithm.
in turn is the strongest predictor of survival. Consequently, in
patients who have MEN1, surgery is recommended only if there
is an identifiable tumor greater than 2 cm in size. The opera-
tion should include resection of body and tail pancreatic NETs,
enucleation of palpable pancreatic head tumors, duodenotomy
with excision of duodenal tumors, and peripancreatic lymph
node sampling.45 The goal of such an operation is to prevent
liver metastases and thus decrease tumor-related mortality, not
to cure ZES.6 However, some studies have documented cure of
ZES in MEN1 patients by performing Whipple pancreaticodu-
odenectomy. We do not favor that approach because the long-
term survival is excellent with the surgical approach described
above and the morbidity is less.
Sporadic Gastrinomas
All patients with sporadic gastrinoma who do not have unresec-
table metastatic disease should undergo exploratory laparotomy
for potential cure of ZES.46 A recent study followed 160 ZES
patients for a mean of 12 years and demonstrated that routine sur-
gical removal of gastrinoma increased survival (54% vs. 21%) by
increasing disease-related survival (23% vs. 1%) and decreasing the
development of distant disease (rate of metastasis 29% vs. 5%).47
Surgical exploration and duodenotomy should be performed even
in patients without an identifiable tumor on preoperative imaging,
but with clear biochemical evidence of sporadic ZES because of
the high probability of an occult duodenal gastrinoma.45
Gastrinomas localized to the duodenum may be locally
resected with adequate margins.48 Resection should allow for
Yes Involving major
ductal/vascular
Yes
structures or bulky?
No
Tumor enucleation
with lymph node
resection
Because 60% to 90% of gastrinomas are malignant, management
pancreas with
palpation/IOS of advanced disease is a significant problem. At the time of diag-
Yes
nosis of ZES, 25% to 33% of patients have liver metastases5 with
Localized to
pancreatic
5% to 15% limited to one lobe of the liver.20,50 In these patients,
head/neck?
cytoreductive surgery should be considered if more than 90% of
No
the visible tumor can be safely removed.5 Other cytoreductive
Distal pancreatectomy
with lymph node
resection
strategies, such as transarterial chemo-embolization (TACE) and
radiofrequency ablation (RFA), may be performed preoperatively
or in lieu of an operation in the case of liver metastases. Surgery
remains the primary option for patients, as alternative therapies,
including chemotherapy, radiofrequency ablation, transarterial
chemoembolization, biotherapy, polypeptide radionuclide recep-
tor therapy, antiangiogenic therapy, and selective internal radio-
therapy, have failed to demonstrate a long-term survival benefit.51
SUMMARY AND RECOMMENDATIONS
In summary, ZES is a syndrome caused by gastrinoma usually
located within the gastrinoma triangle and associated with symp-
toms of peptic ulcer disease and diarrhea. The diagnosis of ZES is
achieved by measuring fasting levels of serum gastrin, BAO, and
postsecretin challenge testing. Due to the high association of ZES
with MEN1, hyperparathyroidism must be excluded by obtaining a
serum calcium and parathyroid hormone level. Treatment of ZES
consists of medical control of symptoms with PPIs and evaluation
for potentially curative surgical intervention. Noninvasive imaging
studies including SRS, CT, and MRI should be performed initially
to evaluate for metastases and identify resectable disease. Invasive
imaging modalities, such as EUS may be performed to further
evaluate primary tumors. IOUS, palpation, and duodenotomy are
used for intraoperative localization of gastrinomas. In patients with
MEN1, surgical resection should be pursued only if there is an iden-
tifiable tumor larger than 2 cm. All patients with resectable spo-
radic gastrinoma should undergo surgical exploration. In patients
with liver metastases, cytoreductive surgery should be performed if
more than 90% of the visible tumor can be safely removed. Figure
14.11 summarizes the workup, medical management, and surgical
approach to ZES.

PMPH_CH14.indd 128 5/21/2012 8:51:43 PM

 Zollinger–Ellison Syndrome ■ 129

Clinical Question Summary

Question Answer Levels of Grade of References
Evidence Recommendation
What percent of patients Surgical cure rate in patients with MEN1 is low II-III B 27, 28, 59,
with MEN1 are (0–10%) without pancreaticoduodenectomy. 60
surgically cured? Some have reported cures, but they did not
demonstrate negative postoperative secretin
stimulation test and normal fasting gastrin
and the follow-up was short. The role of
pancreaticoduodenectomy remains controversial.
What percent of patients Cure rates are variable due to studies with small III B 27, 61, 62
without MEN1 are number of patients and short or incomplete
surgically cured? follow-up. The largest analysis involving 123
patients with a mean follow-up of 8 years showed
a postoperative cure rate of 60%, 40% at 5 years,
and 34% at 10 years.
What is the biological Both locations are equally malignant. Pancreatic III B 16, 27, 50,
behavior of duodenal gastrinomas tend to be larger and have a higher 63-67
and pancreatic incidence of liver metastases. Duodenal tumors
gastrinomas? are smaller and tend to metastasize to the lymph
nodes. As a result, pancreatic lesions tend to
have a worse prognosis. Gastrinomas pursue a
particularly aggressive course in 24% of cases
that is more common in women and patients
without MEN1; it has shorter disease duration,
higher serum gastrin levels, large pancreatic
tumors, liver metastasis, and a long-term
survival rate of 30% compared with 95% for the
nonaggressive form.
What is the best SRS is more sensitive than all other imaging II B 31, 33, 34,
noninvasive imaging modalities combined, the accuracy of which 68-70
modality to localize can be further improved by the application of
tumors? anatomical imaging such as CT. CT is usually
the first study performed, but is limited by its
inability to resolve small tumors. MRI has a poor
sensitivity for primary tumors but is useful in
evaluating hepatic lesions.
Can primary gastrinoma In one series of 138 patients who underwent IV C 8, 11, 12
tumors arise from exploration for gastrinoma with a mean
lymph nodes? follow-up of 10 years, 10% of patients with
sporadic ZES achieved long-term cure after
resection of a lymph node only. The notion
of lymph node primary gastrinoma is further
supported by reports of neuroendocrine cells
within abdominal lymph nodes.
What are the most The presence and extent of liver metastases are I A 17, 50, 63,
important predictors of the most important determinants of survival in 71, 72
survival? patients with gastrinoma.
Should surgical All patients with sporadic tumors and biochemical III B 26-28, 46,
exploration be evidence of gastrinoma should undergo surgical 47
undertaken in patients exploration, even without image localization.
without MEN1 Because small duodenal tumors are the most
with biochemical common and most difficult to localize on
evidence of ZES but preoperative imaging, duodenotomy and lymph
without definitive node sampling should be performed in all surgical
tumor localization by explorations for gastrinoma. Using this approach,
preoperative imaging? gastrinomas can ultimately be found by an
experienced surgeon in nearly all patients.

(Continued)

PMPH_CH14.indd 129 5/21/2012 8:51:44 PM

 130 ■ Surgery: Evidence-Based Practice

(Continued)
Question
When should surgery be
performed in patients
with ZES and MEN1?
Should surgical
interventions be
attempted in patients
with liver metastases?
Answer Levels of Grade of References
Evidence Recommendation
In patients with MEN1, surgery is recommended II-III B 27, 45, 73
only if there is an identifiable tumor greater
than 2 cm in size, as even with advanced disease,
long-term survival is common. The goal of
such an operation is not to affect a cure, since
surgery is seldom curative in these patients, but
rather to ameliorate symptoms and prevent liver
metastases.
Cytoreductive surgery should be considered if III-IV C 5, 51, 71,
the tumor could be safely removed. Other 72, 74
cytoreductive strategies, such as transarterial
chemo-embolization (TACE) and radiofrequency
ablation (RFA), may be performed preoperatively.
TACE, RFA, polypeptide radionuclide receptor
therapy, antiangiogenic therapy, and selective
internal radiotherapy may be performed in cases
with unresectable disease in order to relieve
symptoms, but they have failed to consistently
demonstrate a long-term survival benefit. Liver
transplantation may be considered in selected
patients.

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Oncol. 1999;17(2):615-630.
51. Ehehalt F, Saeger HD, Schmidt CM, Grützmann R. Neuroendo-
crine tumors of the pancreas. Oncologist. 2009;14(5):456-467.
52. Pipeleers-Marichal M, Somers G, Willems G, et al. Gastrinomas
in the duodenums of patients with multiple endocrine neoplasia
type 1. N Engl J Med. 1990;322(11):723-727.
53. Mortellaro VE, Hochwald SN, McGuigan JE, Copeland EM,
Vogel SB, Grobmyer SR. Long-term results of a selective surgi-
cal approach to management of Zollinger–Ellison syndrome in
patients with MEN1. Am Surg. 2009;75(8):730-733.
54. Norton JA, Alexander HR, Fraker DL, Venzon DJ, Gibril F, Jensen
RT. Comparison of surgical results in patients with advanced
and limited disease with multiple endocrine neoplasia type 1 and
Zollinger–Ellison syndrome. Ann Surg. 2001;234(4):495-505.
55. Thompson NW. Current concepts in the surgical management
of multiple endocrine neoplasia type 1 pancreatic-duodenal
disease. Results in the treatment of 40 patients with Zollinger–
Ellison syndrome, hypoglycaemia or both. J Intern Med. 1998;
243(6):495-500.
56. MacFarlane MP, Fraker DL, Alexander HR, Norton JA, Lubensky
I, Jensen RT. Prospective study of surgical resection of duodenal
and pancreatic gastrinomas in multiple endocrine neoplasia type
1. Surgery. 1995;118(6):973-979; discussion 979-980.
57. McArthur KE, Richardson CT, Barnett CC, et al. Laparotomy
and proximal gastric vagotomy in Zollinger–Ellison syndrome:
results of a 16-year prospective study. Am J Gastroenterol. 1996;
91(6):1104-1111.
58. Jaskowiak NT, Fraker DL, Alexander HR, Norton JA, Doppman
JL, Jensen RT. Is reoperation for gastrinoma excision indicated
in Zollinger–Ellison syndrome? Surgery. 1996;120(6):1055-1062;
discussion 1062-1063.
5/21/2012 8:51:44 PM
 CHAPTER 15
Evidence-Based Bariatric Surgery
Amir H. Shariff and Robert L. Bell
1. What is the magnitude and impact of the global obesity
epidemic?
Obesity is an increasingly serious health problem globally and in
the Western world in particular. The World Health Organization
(WHO) estimated that globally in 2008 approximately 1.5 billion
adults (age ≥ 20 years) were overweight; of these, more than
200 million men and nearly 300 million women were obese. WHO
further projects that by 2015, approximately 2.3 billion adults will
be overweight and more than 700 million will be obese. Nearly
43 million children under the age of 5 were overweight globally in
2010. Once considered a problem only in high-income countries,
overweight and obesity are now dramatically on the rise in low- and
middle-income countries, particularly in urban settings.1
The definition and classification of obesity is based primar-
ily on the body mass index (BMI), calculated as weight divided by
the square of height with kilograms per square meter as the unit
of measurement. WHO classifies a BMI of greater than 25 kg/m2
as overweight with obesity being a BMI of greater than 30 kg/m2.
Obesity is more specifically defined as a BMI of 30 to 35 kg/m2 fall-
ing in the category of class I obesity, a BMI of 35 to 40 kg/m2 as class
II and a BMI of over 40 kg/m2 as class III obesity.2
Obesity is associated with premature mortality and other
adverse health consequences. It has been estimated that obesity-
related illnesses are responsible for an estimated 3% to 6% of total
health care costs.3,4 Most of these related illnesses can be improved
or reversed with weight loss.5
It is these increases in the prevalence of severe obesity that
have continued to fuel demand for weight loss surgery (WLS).
Accordingly, the number of bariatric operations being performed
is increasing every year, with a 22-fold increase from 1996 to
2008.6 Controlled trials and observational studies demonstrate
that WLS produces significant and sustained weight loss com-
pared with alternative forms of treatment.7,8 The mortality rates
of severely obese patients who underwent WLS has been found
to be lower than those of severely obese patients who had not.9,10
Landmark findings from the Swedish Obese Subjects study show
an estimated 28% reduction in the adjusted overall mortality
rate in the surgical groups compared with conventionally treated
132
PMPH_CH15.indd 132
controls.11 Decreased mortality in the surgical groups was primar-
ily due to fewer deaths from cardiovascular disease (especially
myocardial infarction [MI]) and cancer. A study of 7925 gastric
bypass patients in Utah12 similarly showed significant reductions
in mortality linked to fewer deaths from coronary artery disease,
diabetes, and cancer.
As WLS continues to increase, patients are getting both older
and heavier; however, at the same time, the hospital length of
stay is becoming shorter and the laparoscopic approach is almost
exclusively being used.13,14 Since the early 2000s, WLS has been
integrated into accredited general surgical training programs in
the United States; this has helped shorten the learning curve for
laparoscopic procedures.15
2. What are the indications for WLS?
Traditionally, obesity surgery is considered appropriate for adult
patients with a BMI greater than 40 kg/m2, with or without comor-
bidites, or a BMI between 35 and 40 kg/m2 with obesity-related
comorbidity. These selection criteria were suggested in March
1991 by the National Institutes of Health Consensus Development
Panel16-18 and have been subsequently adopted by all major surgical
and nonsurgical societies. In the near future, the selection criteria
are likely to expand to include patients with a BMI between 25 and
35 kg/m2, with obesity-related comorbidities, though this remains
to be validated. In a prospective randomized trial by Dixon
et al.,19 an operative method, gastric banding, was compared with
a conservative therapy (encouragement to lifestyle changes plus,
if accepted, hypocaloric diet) in diabetic patients with a BMI of
30 to 40 kg/m2. The excessive weight loss was 62.5% in 2 years after
gastric banding compared with 4.3% in the conservative control,
and the remission rate of diabetes was 73% after gastric banding
compared with 13% with conservative therapy.
A complex issue in the National Institutes of Health (NIH)
selection criteria is the proper definition of comorbidities, which
warrant WLS due to their seriousness and potential alleviation
through weight loss. Comorbidities may be divided into medical,
physical, and psychological categories. In this respect, medi-
cal conditions such as sleep apnea and other hypoventilation
5/21/2012 8:52:38 PM

syndromes,20 type II diabetes mellitus,21 obesity-related cardiomy-
opathy and hypertension,22 hyperlipidemia,23 asthma,23 pseudo-
tumor cerebri,24 knee osteoarthritis,25 low-back pain,26 female
urinary incontinence,25 and infertility27 are well-documented
indications for WLS.
Additionally, physical, social, and psychological problems are
important factors in the quality of life of obese persons and play a
leading role in deciding on conservative or surgical treatment of
obesity. Studies have shown improvements in quality of life indi-
cators following WLS compared with nonsurgical controls.28,29
Thus, deliberation on WLS options must incorporate an assess-
ment of the patient’s current physical, social, and psychological
status as well as the expected effects of therapy on these indices.
Prior to considering WLS, it is advisable that all patients have
tried alternative methods of weight loss. The following indicate
components of conservative methods for weight loss:30
• Nutrition: Energy-reduced diet in addition to another
nutritional intervention (such as a liquid diet or other energy-
reduced form of a mixed diet).
• Physical exercise: Implementation of a cardiovascular and/or
strength endurance sport with at least 2 h per week, if no barri-
ers exist (such as osteoarthritis of the knee for walking).
• Psychotherapy: Implementation of an inpatient or outpatient
psychotherapy (behavioral therapy or depth psychology) in
cases of an eating disorder (binge-eating, night-eating) or psy-
chopathology (e.g., depression, anxiety).
• Group therapy: Modification of life style should be conducted
and supervised within a group, if possible.
Surgical therapy should be considered not only in the setting of
the failure of conservative multimodal therapy, but also in the
case of futility of efforts. This can occur when the chances of suc-
cess of conservative therapy appear remote due to the nature and/
or severity of the disease or due to psychosocial factors. Primary
surgery may also be indicated if radical weight loss should not be
postponed for medical reasons.
Special consideration is given to women of reproductive age
and obese adolescents. Women who wish to have children after
WLS should not be denied an operation, because the course of
pregnancy and the health of the baby are usually unaffected by
previous obesity surgery.27,31-33 Furthermore, the risks of pregnancy
after WLS are far less than the risks of pregnancy in the setting
of uncontrolled obesity.34 Patients are generally advised to avoid
getting pregnant within 1 year after WLS, and once pregnancy
is confirmed, special consideration must be given to nutritional
counseling. In addition to primary obstetrical care, WLS patients
should have continued follow-up with the bariatric surgical team
during the pregnancy.
As previously stated, the prevalence of childhood obesity is
steadily rising. Careful consideration should be given before offer-
ing WLS to adolescents who have yet to reach skeletal maturity.
However, recent studies on adolescents (12–19 years old) suggest
that surgery in this age group is as effective as in adults.35-37
Various contraindications must also be taken into account.
As patients’ noncompliance with follow-up schedules can lead
to potentially life-threatening complications, all candidates for
obesity surgery must hold a realistic view of the operation and
the necessity for lifelong aftercare. Severe mental or cognitive
retardation and malignant hyperphagia are therefore generally
considered absolute contraindications, because such patients will
PMPH_CH15.indd 133
Evidence-Based Bariatric Surgery ■ 133
be unable to eat or exercise as required postoperatively.38 That
being stated, minor and major mental and personality disorders
are highly prevalent in the severely obese patients.39 Surgery is
contraindicated only in the cases of severe mental disease not
responding to treatment.
3. What factors must be considered prior to WLS?
Some patients may pursue WLS without fully understanding the
procedures or their implications. Preoperative teaching by a multi-
disciplinary team improves patient selection, and enables patients
to choose the surgical procedure most appropriate for them.
However, Orth et al. have shown that preoperative knowledge, as
assessed by a test, did not predict success after laparoscopic gastric
bypass surgery.40 Therefore, patients who do not, at first, have full
knowledge of bariatric surgery should not be discriminated against
undergoing surgery if they are eventually properly educated.
Gupta et al.41 used the American College of Surgeons’ National
Surgical Quality Improvement Program (NSQIP) dataset to study
patients undergoing WLS. In 11,023 patients, they found the
30-day morbidity and mortality to be 4.2% and 0.19%, respectively.
This mortality rate compares very well with commonly performed
operations, such as aortic aneurysms (mortality 3.9%), coronary
artery bypass graft (3.5%), craniotomy (10.7%), and pancreatectomy
(8.3%).42 The incidence of specific complications including super-
ficial incisional infection (1.8%), sepsis (0.7%), pneumonia (0.6%),
reintubation (0.5%), failure to wean from ventilator (0.4%), renal
insufficiency (0.2%), and MI (<0.1%) was very low given the degree
of illness that accompanies these patients. Risk factors associated
with increased risk of postoperative morbidity included recent MI/
angina, dependent functional status, stroke, bleeding disorder,
hypertension, BMI, and type of bariatric surgery. Interestingly,
patients with a BMI of 35 to <45 and >60 kg/m2 had significantly
higher risks compared with patients with BMI of 45 to 60 kg/m2.
Although at first these findings seem counterintuitive, they tend to
match the patients who have the most weight-related comorbidities.
Patients with the lower BMI cannot have the surgery unless they
have a life-threatening comorbidity such as diabetes, hypertension,
cardiac failure, or sleep apnea while patients with the higher BMI
(>60 kg/m2) more likely to have weight-related comorbidities.
In view of these data, there must be an individual assessment
of risk factors relative to potential reduction in long-term dis-
ease risk and burden. For instance, though coronary artery dis-
ease remains a risk factor for morbidity and mortality after WLS,
this risk factor reduces significantly after weight reduction from
WLS.43,44 Patients with a history of coronary artery disease should
undergo preoperative assessment of their cardiovascular status
and undergo medical optimization and stabilization as indicated.
Smoking has been shown in studies to be a risk factor for postop-
erative complications, for example, thromboembolic and pulmo-
nary complications.45 Smoking also significantly increases the risk
of postoperative marginal ulceration.46,47 Therefore, weight loss
surgeons should strongly encourage their patients to quit smoking
prior to surgical intervention.
Patients referred for bariatric surgery are more likely than
the overall population to have psychopathology such as somati-
zation, social phobia, obsessive–compulsive disorder, substance
abuse/dependency, binge-eating disorder, posttraumatic stress
disorder, generalized anxiety disorder, and depression.48 Patients
with poorly controlled psychiatric disorders may have a subop-
timal outcome after bariatric surgery. However, no consensus
5/21/2012 8:52:38 PM
 134 ■ Surgery: Evidence-Based Practice
recommendations exist regarding preoperative psychological
evaluation.49 Approximately 88% of US bariatric programs use
some form of preoperative psychological evaluation, with half
requiring a formal standardized assessment.49 Many insurance
companies require such psychological evaluations before grant-
ing precertification for a bariatric procedure. Nevertheless, the
bulk of evidence shows no relationship between preexisting axis
1 psychiatric diagnoses or axis 2 personality disorders and post-
operative weight loss.49,50
The nutrition professional is an integral part of multidisci-
plinary bariatric care.51 They are charged with the preoperative
nutritional assessment and weight loss efforts as well as postopera-
tive diet education and eating behaviors.52 Despite the wide use of
preoperative nutritional education and the requirement by many
insurance companies for dietary counseling, data still are needed
to prove an association with postoperative weight loss or dietary
compliance.53
The management of cholelithiasis at the time of WLS remains
controversial with some advocating routine cholecystectomy dur-
ing WLS and others advocating cholecystectomy only if the patient
is symptomatic.54 Performing a cholecystectomy at the time of WLS
has not been shown to significantly increase the operative times,
morbidity or length of stay.55 In postoperative patients with no
prior history of cholelithiasis, the overall rate of symptomatic gall-
stone formation was found to be approximately 8% and the mean
time for its development was 10.2 (range 2–37) months. Logistic
regression analysis showed that only postoperative weight loss of
more than 25% of original weight was associated with symptom-
atic gallstones formation.56
Immediate preoperative considerations include the use of
antibiotic prophylaxis. This was first studied by Pories et al.57 who
observed a reduction in wound infections in gastric bypass patients
who received cefazolin compared with those who received a pla-
cebo, thus making antibiotic administration routine. Prophylaxis
of thromboembolic complications is also an essential part of WLS.
The use of low molecular weight heparin and intermittent pneu-
matic compression stockings at the time of surgery has reduced
the incidence of thromboembolic events to near 0%.58
4. What are the most common bariatric surgery procedures?
There are several competing aims in WLS, including weight loss,
adjustability, reversibility, and safety. WLS reduces caloric intake
by modifying the anatomy of the gastrointestinal tract via restric-
tion, malabsorption or a combination of the two techniques. Ensu-
ing changes in the gut–brain axis alter peptides that may regulate
appetite and satiety (e.g., ghrelin, glucagon-like peptide-1, and
peptide YY3-36).59 For all types of surgery, there is overwhelming
evidence on safety, efficacy, and effectiveness in terms of weight
loss. Therefore, the decision about the specific type of WLS must
be taken with the patient’s individual situation and the surgeon’s
expertise in mind. Figure 15.1 demonstrates the most commonly
performed WLS procedures.
JEJUNOILEAL BYPASS
The jejunoileal bypass (JIB) arose as the forerunner to modern
bariatric surgical techniques in the late 1950s.60 At that time, it
was the most effective surgical intervention for achieving and
maintaining weight loss. Several variations existed, but typically,
PMPH_CH15.indd 134
(a) (b) (c) (d)
Figure 15.1 Weight loss surgical procedures: (a) Roux-en-Y
gastric bypass; (b) adjustable gastric band; (c) sleeve gastrectomy;
and (d) biliopancreatic diversion.
35 centimeters of proximal jejunum was anastomosed, end-to-
side or end-to-end, to the terminal 10 cm of ileum. The weight loss
would be accomplished through malabsorption.61
However, JIB was associated with severe complications such
as renal failure (37%), diarrhea (29%) and consequent electrolyte
imbalances, calcium oxalate nephrolithiasis (29%), liver disease
(10%), acute fulminant liver failure (7%), fat-soluble vitamin defi-
ciencies, malnutrition, and death.62 It is now well established that
JIB is devastating because of its dramatic complications, and is no
longer used for the management of morbid obesity. Most patients
who underwent this procedure have either died or have undergone
a conversion to a different bariatric procedure.
LAPAROSCOPIC ROUX-Y
GASTRIC BYPASS
The Roux-Y gastric bypass (RYGB) was first described by Mason
and Ito63,64 in 1967 and laparoscopic gastric bypass (LRYGB) is cur-
rently the most commonly performed WLS in the United States.
LRYGB involves the creation of a small (20–30 mL) gastric pouch,
which is anastomosed to a 60 to 150 cm Roux limb (Figure 15.1a).
In this way, a portion of the alimentary tract is rerouted to bypass
the distal stomach and the proximal small bowel. Typically, the
small bowel is transected just distal to the ligament of Treitz and
the Roux limb is elevated and anastomosed to the gastric pouch
in an antecolic, antegastric fashion using a linear or circular sta-
pler.65 The proximal bowel segment, also called the biliopancreatic
limb, usually is connected to the alimentary limb 60 to 150 cm
distal to the gastrojejunostomy and this jejuno-jejunostomy is
constructed using a linear stapler. The ensuing mesenteric defect
at the jejuno-jejunostomy and the Petersen’s defect (between the
transverse mesocolon and the Roux limb) are closed to prevent
internal herniation.66,67
Modifications to the LRYGB can be performed, the so-called
“long limb” or “distal gastric bypass” variations, where the length
of the Roux limb is increased to enhance malabsorption. The Roux
limb can be lengthened up to 300 cm, creating a common channel
of only about 100 cm. In addition, the gastric pouch can be made
smaller. A recent study compared patients who had undergone
LRYGB with a 150-cm Roux limb to patients who underwent a
distal gastric bypass. Although the distal gastric bypass patients
had a significantly greater percentage of excess weight loss after
5 years, they also had significantly lower albumin, hemoglobin,
iron, and calcium levels.68 Thus, although these variations afford
superior long-term weight loss, they do cause protein-calorie
5/21/2012 8:52:38 PM

malnutrition requiring frequent revision, and should not be the
primary operation for obese or super-obese patients.
Close, long-term follow-up is recommended after LRYGB.
A typical follow-up schedule after LRYGB would be evaluation at
1 to 3 weeks, followed by quarterly visits during the 1st year and
annually thereafter to assess weight loss, resolution of comorbidi-
ties, long-term complications, and need for continuing education
and support. Patients are counseled to eat small, frequent meals
of high-protein and low-carbohydrate content. They should take
long-term vitamin supplements (multivitamins, vitamin B12, and
calcium, with some patients requiring iron supplementation) and
undergo periodic blood testing to identify and treat deficiencies
accordingly. Patients should be encouraged to develop regular
exercise practices.69
The mortality rate after LRYGB ranges from 0.3% to 1%.7 The
most frequently reported perioperative complications associated
with laparoscopic RGB are wound infection (2.98%), anastomotic
leak (2.05%), gastrointestinal tract hemorrhage (1.93%), bowel
obstruction (1.73%), and pulmonary embolus (0.41%), whereas the
most frequently reported late complications are stomal stenosis
(4.73%), bowel obstruction (3.15%), and incisional hernia (0.47%).70
Anastomotic leak is probably the most feared of all the early
postoperative complications. An anastomotic leak occurs in 1%
to 2% of patients after RYGB and usually becomes evident in
the first 2 weeks postoperatively.71 The leak can occur at the site
of the gastrojejunostomy, the staple line of the bypassed gastric
remnant, the staple line of the gastric pouch itself or the jejuno-
jejunostomy. Tachycardia, dyspnea, abdominal pain, peritonitis,
or unexplained oliguria can be the predominant symptoms of an
anastomotic leak. These patients will most likely require surgical
intervention.
The possibility of intestinal obstruction is the second, major
postoperative concern. Patients can present with an obstruction
of any of the three limbs of the LRYGB.72,73 Potential origins for
obstruction include internal hernias, external hernias (abdomi-
nal wall) associated with the incision or trocar site, intestino-
intestinal intussusception (albeit rare), acute gastric distension or
iatrogenic problems related to surgical error in the formation of
the Roux limbs or anastomoses.
The LRYGB has established long-term effectiveness for sus-
tained weight loss, reduction of comorbidities, and a low risk for
long-term nutritional sequelae in comparison with other options
for WLS.74,75
LAPAROSCOPIC ADJUSTABLE
GASTRIC BANDING
Laparoscopic adjustable gastric banding (LAGB) is the most com-
mon restrictive WLS performed globally69 (Figure 15.1b). The
original technique was described by Belachew76 and by Favretti.77
It involves no bowel transaction, is reversible, and has lower oper-
ative mortality and morbidity compared with combination weight
loss procedures.78 In systematic reviews, mortality has occurred in
1 in 2000 to 1 in 3000 patients.7,79
Placement of the gastric band via the pars flaccida approach
has become the consensus choice for better handling of instru-
ments and band, low complexity in dissection maneuvers, and low
complication rate.80 Dissection starts near the angle of His above
the greater curvature of the stomach. Then the lesser omentum
PMPH_CH15.indd 135
Evidence-Based Bariatric Surgery ■ 135
is opened through the pars flaccida component to provide expo-
sure of the right crus of the diaphragm. A point along the anterior
border of this muscle, at its lowermost aspect, is selected, and the
peritoneum is opened. The band placer is then passed along this
path until it appears on the greater curvature of the stomach at the
site of prior dissection at the angle of His. Using the band placer,
the band is drawn along this pathway and then locked around the
stomach. A subcutaneous reservoir, or port, is connected to the
band tubing, which allows adjustability of the band circumfer-
ence. The port is usually secured to the anterior rectus fascia.
All patients undergo follow-up following LAGB to optimize
weight loss, detect postoperative complications, and perform band
volume adjustment. In the early days of LAGB, band fills were
performed almost always under radiologic guidance.81 This was
necessary as the exact volume requirements were unknown and
the mechanisms of band restriction less understood.82 However,
as experience has increased with both the duration of follow-up
and the number of patients, decisions on the quantity of band fi lls
can be safely made clinically.
Long-term complications after LAGB include band slippage,
gastric pouch dilatation, and gastric erosion. Rates of slippage in
the literature have ranged from less than 1% to over 20%. Pos-
terior slippage of the band is almost exclusively seen in those
patients whose gastric band was placed using the perigastric
technique. Opening of the lesser sac during this technique is
thought to be the predominant factor predisposing to posterior
slip. This complication has become far less common following the
introduction of the pars flaccida technique.80 Anterior slippage of
the band is more controversial. It has been postulated that inad-
equate anterior fi xation of the band is a major etiological factor.83
The technique employed for anterior fi xation is highly variable,
with the majority of proponents for fi xation using between two
and five interrupted gastrogastric imbrication sutures to cre-
ate an anterior wrap, or “gastrogastric tunnel” around the band.
Variations on this include the use of a continuous running suture,
mesh pledgets to reinforce suture fi xations, and the use of fundo-
crural suture fi xation.84-86 Despite these measures, there are
reports of similar slippage rates with and without the use of imbri-
cation sutures.87 Other factors potentially associated with slippage
include size of the gastric pouch, premature band inflation, hia-
tus hernia, and recurrent vomiting.88,89 Conservative treatment
such as band deflation is certain to fail in a definitive slip. Surgi-
cal options for slippage include reduction of the gastric prolapse
with refastening of the primary band, band repositioning, band
removal and replacement with a new band either immediately or
at a subsequent operation, and band removal with conversion to
an alternative bariatric procedure.90
Gastric pouch dilation is often confused with slippage, but
can be differentiated radiologically. If the band has not slipped,
the band remains in its normal oblique lie. Gastric pouch dilation
is thought to be a result of the high pressures generated within the
proximal gastric pouch from excessive or inappropriate eating.91
Patients often report a lack of restriction, and present seeking fur-
ther fi lls when paradoxically, band deflation is indicated.92 Once
pouch dilatation has resolved, the band can then be reinflated in
the future. If pouch dilation persists, band repositioning or con-
version to other procedures may be necessary.
Intragastric erosion of the gastric band is reported with a
frequency of 0.5% to 3.8%.93 Different hypotheses have been sug-
gested to explain this complication: (1) damage of the gastric wall
5/21/2012 8:52:38 PM
 136 ■ Surgery: Evidence-Based Practice
during band implantation;94 (2) infection of the band-site;95 (3)
overfi lling the band;96 and (4) abnormal reaction of the peripros-
thesic tissue to the presence of the band.96 The gastric band must
then be removed, typically via laparoscopy. However, an endo-
scopic approach has been used, especially when the band has
nearly completely migrated into the stomach.93,97
LAPAROSCOPIC SLEEVE GASTRECTOMY
Laparoscopic sleeve gastrectomy (LSG) originally proved to be a
beneficial procedure for interval weight loss as the first stage of a
two-staged bypass procedure98 (Figure 15.1c). More recently, LSG
is showing promise as a primary bariatric procedure for appropri-
ate candidates.99,100 Currently, LSG comprises only about 2% of all
bariatric operations in the United States.99
The technique of LSG follows the transoral placement of 34
to 60 Fr bougie, which is advanced into the gastric antrum and
pylorus. Starting approximately 4 cm proximal to the pylorus,
the stomach is transected, initially transversely, and subsequently
longitudinally. The stomach is then divided proximally using the
sequential firings of 4.8 and 3.5 mm linear staplers. This results
in a narrow, tubular, stomach. The greater curvature vessels and
short gastrics can be divided using endoscopic staplers, thermal
ligature devices, or ultrascission.101,102 The resected portion of
stomach is then removed.
LSG appears to be a safe and effective procedure with low
morbidity and mortality. It is important to remember that the sta-
ple line is long, with potential for leakage and bleeding. The inci-
dence of staple-line leakage after LSG ranges from 0% to 5.5%102,103
and with overall complication rates ranging from 0% to 24%.103 It
has been suggested that staple-line reinforcement can decrease the
incidence of leaks and different techniques have be implemented to
reinforce the staple line, including buttressing and oversewing.103,104
The efficacy of these techniques has been contested. A recent report
of 529 LSG performed without the use of staple-line reinforcement
demonstrated a 0% incidence of gastric leak and 0.19% mortality
rate.102 The authors contend that there are two main tenets to adopt
to minimize leaks. First, and of utmost importance, is to avoid cre-
ating a physiologic stricture at the incisura angularis and second,
to avoid stapling too close to the esophagus in the area of the car-
dia. A recent meta-analysis concluded that despite several draw-
backs in the study, staple-line reinforcement did not seem to have
any clear benefit, at least concerning leak rate.105
Although classified as a restrictive procedure, LSG appears to
be more than just a gastric restrictive operation. With the removal
of the gastric corpus and fundus, the number of orexigenic cells
that produce the hormone ghrelin is significantly reduced.106 Thus,
LSG is not only a multipurpose operation, but also a multifacto-
rial one, with a restrictive aspect and a complex neurohormonal
aspect, not yet fully elucidated.107,108
BILIOPANCREATIC DIVERSION WITH
DUODENAL SWITCH
Biliopancreatic diversion (BPD) was first described by
Scopinaro109,110 (Figure 15.1d). This was later modified with
the additions of a duodenal switch and a sleeve gastrectomy
PMPH_CH15.indd 136
to create the biliopancreatic diversion with duodenal switch
(BPD-DS).111,112
The standard BPD-DS technique involves dividing the small
bowel 250 cm above the ileocecal valve with a stapler, and then
forming a biliopancreatic limb by connecting the bowel proximal
to the transection to a point 100 cm above the ileocecal valve. The
bowel distal to the transection is elevated as an alimentary limb
to the upper abdomen. Gastric sleeve resection creates a tubular-
ized stomach of approximately 100 cm3. The duodenum is divided
3 cm distal to the pylorus, and duodenoileostomy establishes con-
tinuity of the alimentary limb. Limb lengths determine weight
loss and complications. A common limb that is too long provides
inadequate weight loss, whereas one that is too short causes debili-
tating diarrhea and nutritional deficiencies. The gastric remnant
size should provide some restriction, but not prevent initiation of
protein digestion.
Close follow-up evaluation in the postoperative period is
recommended. Typical postoperative follow-up includes visits at
2 and 6 weeks, then quarterly for the 1st year, biannually for the
2nd year, and annually thereafter.113,114 Assessments are made by
both the surgeon and the nutritionist, and biochemical surveil-
lance by complete blood count, chemical metabolic profi le, and
parathyroid hormone level is performed at regularly scheduled
intervals. An exercise program is helpful, as are multivitamin,
iron, vitamin D, and calcium supplements.
The 30-day mortality of early laparoscopic BPD series ranges
from 2.6% to 7.6%.115,116 Major complications, which occur in up to
25% of cases, may include early occurrence of anastomotic leak,
duodenal stump leak, intraabdominal infection, hemorrhage,
and venous thromboembolism.116,117 Late complications include
stomal ulceration, bowel obstruction, incarceration, or stricture.118
Diarrhea is a frequent chronic complication of BPD. Iron defi-
ciency is common, with 6% of patients experiencing serious iron
deficiency anemia (hemoglobin <10 mg/dL).119 Surveillance of
biochemical and hematologic markers of iron deficiency should
drive replacement. Calcium and vitamin D malabsorption also
are common, manifesting as secondary hyperparathyroidism.120
The high incidence of stomal ulceration, severe protein-calorie
malnutrition, and diarrhea have limited its broad acceptance.121
VERTICAL BANDED GASTOPLASTY
In 1982, Mason introduced the vertical banded gastroplasty
(VBG).122 A transgastric window is created using a circular stapler.
A gastric pouch of approximately 20 mL is fashioned after a ver-
tical gastric division is performed using a linear stapler through
the transgastric window. By using a mesh band (polypropylene
or polytetrafluoroethylene) or, less commonly, a silastic ring, the
gastric pouch outlet can be calibrated and reinforced.123
VBG was a very popular restrictive procedure in the United
States in the 1980s, but with time, it became clear that gas-
troesophageal reflux, complications associated with the band
(penetration, infection, bleeding, and obstruction) and unsatisfac-
tory weight loss124 were too frequent and the procedure has since
been almost completely abandoned. As many as 25% to 54% of
VBG patients ultimately seek revisional surgery125,126 with the goal
being to reverse the complications of VBG and to induce weight
loss. Options include conversion to a RYGB123 or VBG reversal via
gastrogastrostomy.
5/21/2012 8:52:38 PM

REVISIONAL BARIATRIC SURGERY
When patients are unsatisfied with their weight loss or develop
complications after their initial procedure, they frequently seek
revisional bariatric surgery (RBS). Approximately 5% of bar-
iatric surgery patients have been estimated to require RBS. The
RBS population could be quite heterogeneous, depending on
their initial procedure, the indications for surgical revision, and
the revisional procedure performed.127 For instance, as previ-
ously discussed, patients might seek RBS after VBG because of
dysphagia due to esophageal dysmotility, intractable vomiting,
gastroesophageal reflux caused by stricture or gastroparesis of
the distal stomach, symptomatic erosion of the band into the gas-
tric lumen, or, most commonly, weight regain due to staple line
or band disruption.125,128 Complications after LRYGB that might
require surgical revision include intractable stricture, nonheal-
ing marginal ulcers, and metabolic complications.129 Failure of
weight loss after RYGB is commonly attributed to eating behav-
iors, staple line dehiscence with gastrogastric fistulas, and gas-
tric pouch and gastrojejunal anastomosis dilation, resulting in a
“loss of restriction.” Regardless of the initial procedure, RBS is
commonly associated with an increased incidence of complica-
tions quoted as high as 22% to50%, with a reported mortality rate
of 1% to 2%.129,130 It is vital that the surgeon make every effort,
using medical record review as well as preoperative radiographic
and/or endoscopic assessment, to define the prior procedure or
procedures performed and understand the anatomy.
Patients who never lose weight may have had a technical
complication such as incomplete stapling131,132 or an inappropriate
operation. Those who regain weight after years may have experi-
enced staple line recanalization or behavioral failure.130 Reopera-
tion on a previous gastroplasty usually involves creating a Roux-Y
to a newly stapled proximal stomach pouch cephalad to the prior
gastric alteration.128 Likewise, most authors advocate LRYGB for
revision of LAGB because of complications or insufficient weight
loss.133 Finally, in cases of failed BPD-DS, some have advocated
the use of a pouch reduction procedure,134 and in cases of failed
LRYGB, either LAGB to improve the restrictive component135
or lengthening the Roux limb to improve the malabsorptive
component.136
Revisional bariatric operations may be performed
laparoscopically137,138 or via open techniques.139,140 Surgeons may
prefer an open approach to address severe adhesions or to per-
mit tactile localization of prior partitions in the stomach to avoid
creation of undrained or ischemic segments during restapling.141
5. How do the different WLS procedures compare?
LRYGB, LAGB, LSG, and BPD-DS remain the popular WLS
options. Meta-analyses of studies comparing the different
surgical procedures have several limitations, such as lack of
randomization, heterogeneity of study populations, lack of
consistent control populations, variations in patient follow-up
and the reporting of comorbidities, and patients that are lost to
follow-up.105
Garb et al. performed a meta-analysis of studies comparing
LRYGB and LAGB between 2003 and 2007, encompassing 7383
patients.142 They found a composite percentage excess weight loss
(%EWL) of 49.4% for LAGB versus 62.6% for LRYGB and found
%EWL outcomes for LRYGB significantly superior to those for
LAGB at the three time points examined (1, 2, and >3 years). The
PMPH_CH15.indd 137
Evidence-Based Bariatric Surgery ■ 137
improvement in %EWL for LRYGB over LAGB was approximately
19% at 1 year and 16% at >3 years.
Three large meta-analyses were performed by Buchwald et
al. Mean weight loss was 47.5% after LAGB, 61.6% after LRYGB,
and 70.1% after BPD (with or without duodenal switch).143 The
postoperative 30-day mortality was 0.07% for all laparoscopic
restrictive procedures, 0.16% for LRYGB and 1.11% for the lap-
aroscopic malabsorptive procedures.144 When focusing on diabe-
tes, 79.3% of diabetic patients had resolution of their clinical and
laboratory manifestations of diabetes and 98.9% had resolution
or improvement after WLS. They observed greater resolution for
BPD-DS followed by LRYGB and then LAGB.145
Since LSG is a fairly new WLS technique, there are fewer
studies comparing its efficacy. Benedix et al. found that patients
who had undergone LSG experienced a greater %EWL (41.5%)
than those who had undergone LAGB (28.9%), but similar to the
%EWL in those patients that underwent a LRYGB (45%).146 Simi-
larly, in a randomized study from Belgium, LSG achieved a higher
weight loss than LAGB.147 However, further trials are needed to
document the benefits of LSG over other forms of WLS.
6. Are there endoscopic techniques to effect weight loss?
Greater focus has turned toward minimally invasive endoscopic
therapies in the management of obesity. Most of these therapies,
however, are cumbersome and unlikely to be practical in an outpa-
tient endoscopy setting. Several transoral endoluminal procedures
that avoid permanent surgical modification of the gastrointestinal
tract are under investigation in the United States.148
The primary endoscopic treatment modalities for obesity are
restrictive interventions, including intragastric balloons, tran-
soral gastroplasty, and endoluminal vertical gastroplasty. The
duodenojejunal bypass sleeve is the only malabsorptive endolu-
minal device that has been studied in humans. Electrical stimu-
lation to delay gastric emptying is also under investigation, with
some early experience in humans.149
By far, the most widely studied of the minimally invasive
endoscopic therapies for obesity is the gastric balloon. In 1985,
the first widely used intragastric balloon, the Garren–Edwards
gastric bubble (GEGB), was approved for use in the United States.
Approved as an adjunctive modality to a multifaceted approach
to obesity, the GEGB was a polyurethane cylindrical device with
a self-sealing valve through which a removable air-insufflation
catheter was inserted. The bubble was insufflated with 220 mL of
air and detached. The bubble was then left to float freely in the
stomach and could be removed endoscopically after being punc-
tured with a forceps. Several studies were published showing that
diet and behavior modification were equally as efficacious as the
GEGB in producing weight loss.150,151 Complications of the GEGB
were significant and included gastric erosions, gastric ulcers,
small bowel obstruction, Mallory–Weiss tears, and esophageal
lacerations due to the use of a cumbersome overtube during bal-
loon placement.152,153 As a result, the GEGB is no longer used or
available in the United States. Research continues in developing
the ideal gastric balloon.154
7. What are the important aspects of postoperative care
following WLS?
Obesity is a “chronic disorder that requires a continuous care
model of treatment.”155 Bariatric surgery is not a guarantee of
5/21/2012 8:52:38 PM
 138 ■ Surgery: Evidence-Based Practice
success, and patients require ongoing postoperative care. To
reduce the likelihood of weight regain and to ensure that comorbid
conditions are adequately managed, all patients should receive
careful medical follow-up postoperatively. To guide patients
through the transition to life after bariatric surgery, a multidisci-
plinary team that includes an experienced primary care physician,
endocrinologist, or gastroenterologist is needed. Patients should
consider enrolling postoperatively in a comprehensive program
for nutrition and lifestyle management. Such support can ease the
transition to life after bariatric surgery.156
EXERCISE AND PHYSICAL ACTIVITY
After WLS, patients experience a rapid loss of body weight, 14.1%
to 48.5% of which may include lean body mass.157 Postopera-
tive patients that exercise were shown to lose 28% more fat and
retained 8% more lean body mass compared with those who did
not exercise.158 The American College of Sports Medicine recom-
mendations on healthy exercise levels are a minimum of 150 min
(2.5 h) of moderate intensity exercise per week, stating that there
may be advantages to increasing exercise to as much as 3.5 h a
week for maintaining long-term weight loss.159 The activity type,
duration, and intensity of exercise in post-WLS patients are quite
distinct from the exercise habits of young, physically fit, controls.
Successful WLS patients typically exercise longer, but at lower-
level intensity.160 Aerobic physical activity positively influences
weight loss, body composition, and comorbidity resolution after
LRYGB for obesity.160
NUTRITIONAL MANAGEMENT
Protein malnutrition, defined by hypoalbuminemia (albumin <
3.5 mg/dL), remains the most severe macronutrient complication
associated with malabsorptive surgical procedures. Protein mal-
nutrition causes an annual hospitalization rate of 1% per year after
malabsorptive procedures and leads to significant morbidity.161,162
When it occurs, protein malnutrition is generally observed at 3 to
6 months after surgery and is largely attributed to the development
of food intolerance to protein-rich foods.163 Prevention of protein
malnutrition requires regular assessment of protein intake and
counseling regarding ingestion of protein from protein-rich foods
and modular protein supplements. To maintain lean body mass
during weight loss, roughly 60 g of protein should be consumed
per day.164
The anatomic changes imposed by malabsorptive surgery
increase the risk for various vitamin and mineral deficiencies.161
After LRYGB, screening and supplementation of deficiencies
with a multivitamin-mineral, iron, vitamin B12, or calcium with
vitamin D is routinely conducted, and prophylactic supplementa-
tion should be considered in all patients.165 A daily multivitamin
and calcium supplementation with added vitamin D is recom-
mended for all WLS patients.166 Recommended doses of elemen-
tal calcium after bariatric surgery range from 1200 to 2000 mg
daily, and these usually contain vitamin D as well.161 Patients
must be instructed to take calcium carbonate preparations with
meals to enhance intestinal absorption. Calcium citrate prepa-
rations are preferred because this salt is better absorbed in the
absence of gastric acid production.167 A rise in serum parathyroid
PMPH_CH15.indd 138
hormone indicates negative calcium balance and/or a vitamin D
deficiency and this can serve as a screening tool for metabolic
bone disease.168
Vitamin B12 deficiencies can occur after bariatric surgery
procedures that bypass the lower stomach. In the absence of vita-
min B12 supplementation in post-LRYGB patients, the incidence
of vitamin B12 deficiency is 33% to 40% at the first postoperative
year169 and 8 to 37% by 2 to 4 years161,170. Anemias as a result of vita-
min B12 deficiency have been reported to occur in more than 30%
of patients 1 to 9 years after LRYGB.165 The initiation of vitamin
B12 supplementation within 6 months postoperatively is recom-
mended for all LRYGB, LSG, and BPD-DS patients.
Steatorrhea induced by malabsorptive surgical procedures can
lead to deficiencies in fat-soluble vitamins.165 Vitamin A deficiency
after bariatric surgery results from poor nutritional intake, mal-
digestion, malabsorption, and impaired hepatic release of vitamin
A. The incidence of vitamin A deficiency was 61% to 69% at 2 to
4 years after BPD (with or without duodenal switch).113,171 Vitamin
K levels have also been found to be low in 50% to 60% of patients
who underwent BPD (with or without duodenal switch).167,172
The extent of metabolic and nutritional evaluations necessary
after bariatric surgery should be guided by the surgical procedure
performed. Purely gastric restrictive procedures are not associated
with alterations in intestinal continuity and do not alter normal
digestive physiology. As a result, selective nutritional deficiencies
are uncommon. Nutritional intake assessments and laboratory
surveillance of vitamin and mineral levels are key to ensuring the
adequacy of nutrition after WLS. Both are recommended after all
bariatric surgeries, even if patients tolerate their diet well, with no
vomiting or diarrhea, to detect subclinical nutritional deficiencies
and prevent development of frank deficiencies.173-175 Malabsorp-
tive procedures can be associated with micronutrient and macro-
nutrient deficiencies and require lifelong supplementation and
monitoring of laboratory data by a team familiar with possible
deficiencies.173,174
TYPE 2 DIABETES MELLITUS
Type 2 diabetes mellitus (T2DM) is a common morbidity asso-
ciated with obesity and can improve to the point that little or
no medication is necessary in patients after WLS.21 After com-
bination or malabsorptive procedures, insulin-treated patients
experience a significant decrease in insulin requirements; the
majority of patients can discontinue insulin therapy by 6 weeks
after surgery,176 and some may even be able to discontinue insulin
before hospital discharge. The long-term effects of these bypass
operations on T2DM appear to include both fat-loss-dependent
and hormonal mechanisms.177 By contrast, purely restrictive
operations appear to improve T2DM as a result of fat loss alone.19
Though not fully elucidated, improvements in insulin resistance
are observed almost immediately after LRYGB and are, in part,
due to increased levels of GLP-1 seen after LRYGB.21,178
Due to the rapid resolution of T2DM after LRYGB, oral hypo-
glycemic agents and long-acting insulins should be avoided in the
immediate postoperative period as changes in GLP-1 and other
incretins increase insulin sensitivity. Consequently, administra-
tion of these medications in the postoperative period increases the
risk of hypoglycemia. These agents should be reintroduced later
only if clinically indicated.
5/21/2012 8:52:39 PM

LIPID DISORDERS
Triglyceride and low-density lipoprotein (LDL)-cholesterol decrease
and high-density lipoprotein-cholesterol increases after WLS.179-181
The improvement in dyslipidemia appears to be related not only to
the percentage of excess weight loss, and more specifically adipocyte
mass loss, but also to the decrease in insulin resistance.179 Given the
improvement in cardiovascular mortality after bariatric surgery,
these changes have likely led to a decreased risk of cardiovascular
disease.12,182 Lipid-lowering therapy for LDL-cholesterol and triglyc-
eride values that remain above desired goals after surgery should be
continued. Due to the dramatic reductions in lipid levels, the doses
of lipid-lowering drugs should be periodically reevaluated.
DUMPING SYNDROME
Abdominal pain and cramping, nausea, diarrhea, lightheadedness,
flushing, tachycardia, and syncope are all indicative of dumping.
These symptoms are reported frequently after the intake of simple
sugars and may serve to discourage the intake of energy-dense
foods and beverages.183 Gastric dumping occurs initially in 70% to
76% of patients who have had a RYGB.184,185 Historically, dumping
was thought to be the result of the hyperosmolarity of intestinal
contents, which resulted in an influx of fluid into the intestinal
lumen with subsequent intestinal distention, fluid sequestration in
the intestinal lumen, decreased intravascular volume, and hypoten-
sion. More recent data suggest that food bypassing the stomach and
entering the small intestine leads to the release of gut peptides that
are responsible for dumping symptoms.186 Dumping symptoms tend
to become less prominent with time183 and can usually be controlled
with certain nutritional changes, such as (1) eating small meals; (2)
avoiding ingestion of liquids within 30 min of a solid-food meal; (3)
avoiding simple sugars and increasing intake of fiber and complex
carbohydrates; and (4) increasing protein intake.187
8. Does accreditation of WLS centers improve outcomes?
It is generally accepted that surgical outcomes are related to the
volume of procedures performed per year by a surgeon or at a
hospital.188,189 Consequently, several policy-generating bodies have
recommended limiting the conduct of several technically complex
operations to high-volume centers. This philosophy was adopted
by the accrediting bodies for bariatric surgery centers of excel-
lence. The American College of Surgeons Bariatric Surgery Cen-
ter Network Program (ACS/BSCNP)190 and the American Society
of Metabolic and Bariatric Surgery’s Surgical Review Corpora-
tion (ASMBS/SRC)191 have published guidelines for requirements
for hospitals seeking designation as accredited WLS centers or
Clinical Question Summary
Questions Answers
1 What is the magnitude and impact of Obesity is a burgeoning health problem with
the global obesity epidemic? significant associated comorbidities. Weight
reduction can result in improved survival.
2 What are the indications for WLS? A BMI of more than 40 kg/m2 or a BMI of more than
35 kg/m2 with obesity-related comorbidity meets
current NIH criteria for WLS.
PMPH_CH15.indd 139
Evidence-Based Bariatric Surgery ■ 139
“Centers of Excellence” (COE). Both of these accrediting bodies
require that at least 125 bariatric operations be performed annu-
ally to achieve this designation. In 2006, Medicare required that
hospitals providing WLS services for its beneficiaries must be
accredited by one of these organizations.192
Multidisciplinary care is generally considered essential in the
management of clinically complex and high-risk WLS patients.
Such care involves the creation of a WLS team with a dedicated and
appropriately credentialed director. It also includes appropriately
trained surgical, medical, psychiatric, nutrition, and nursing per-
sonnel. Such staffing is now required by both the ACS/BSCNP190 as
well as the ASMBS/SRC.191 It is necessary not only in the immedi-
ate postoperative period, but also in the long run as patients adjust
medically and psychosocially to the results of WLS.
To achieve accreditation, the onus has been put on facilities to
adequately outfit their hospitals in ways that accommodate WLS
patients at all points of care. Extended-size gowns, pants, and robes
must be routinely available, as well as respiratory support with
Continuous Positive Airway Pressure and Bilevel Positive Airway
Pressure therapy. Pneumatic, size-appropriate lower extremity
compression sleeves should also be available. The center of excel-
lence accrediting bodies recommend that CT or MRI scanners
have a weight capacity 400 lbs or greater. The American Institute
of Architects has established guidelines for planning and design-
ing WLS healthcare facilities.193 These specify a barrier-free envi-
ronment that avoids stairs and provides ramp access when possible.
They set minimal clearances for rooms that will accommodate WLS
patients, including operating rooms, and address appropriate-sized
inpatient rooms, and postanesthesia care units. The guidelines set
clearance for a floor-mounted toilet at 5 ft, and weight ratings for
toilets and sinks at 700 lb and 300 lb, respectively.
Challenges have been made to the concept of COEs. Liv-
ingston194 contends that the major difference between COEs and
non-COEs was the higher procedure volume in the COEs. Despite
the higher procedure volume requirements and the rigorous stan-
dards imposed on COEs, their outcomes were equivalent to non-
COEs. When analyzing data from 102,069 bariatric operations
and adjusting for comorbidities, Kohn et al. found that greater
bariatric case volume was associated with improvements in the
incidence of total complications.195 Their findings supported the
concept of volume-dependent COE programs, though they dem-
onstrated no differences on the basis of actual accreditation status
per ACS/BSCN or ASMBS/SRC.
Certification systems need to evolve and should continue to
emphasize the value of higher-volume centers, especially for higher-
risk patients, but should not restrict provision of care at lower-
volume centers to the point that patients cannot achieve access
and therefore suffer disproportionately from untreated obesity.196
Grade References
B 3, 8-12
B 16, 17
(Continued)
5/21/2012 8:52:39 PM
 140 ■ Surgery: Evidence-Based Practice

(Continued)
Questions Answers Grade References
3 What factors must be considered Factors associated with increased postoperative B 41, 54, 55, 58
prior to WLS? morbidity and mortality include recent MI,
hypertension, stroke, dependent functional
status, smoking, and poorly controlled
psychiatric disorders. Management of preexisting
cholelithiasis remains controversial. Prophylaxis
against thromboembolic complications is
indicated.
4 What are the common bariatric These are the laparoscopic Roux-en-Y gastric B 69, 74, 75, 99, 100, 118
surgery procedures? bypass, laparoscopic adjustable gastric banding,
LSG, and BPD. JIB remains of historical
significance. Revisonal bariatric surgery for
unsatisfactory weight loss is associated with
increased morbidity and mortality.
5 How do the different WLS Large meta-analyses comparing the WLS procedures B 142-146
procedures compare? have suffered from many limitations. LRYGB
remains the current gold standard for bariatric
surgery.
6 Are there endoscopic techniques to There does exist an endoscopically deployed A 150
effect weight loss? intragastric balloon though is currently not used
secondary to its complication profile. Research
continues in the search for endoscopic therapies.
7 What are the important aspects of WLS necessitates undergoing a lifestyle change with B 17, 158, 161, 173, 177,
postoperative care following WLS? focus on exercise and nutritional management to 178
monitor caloric intake and prevent micronutrient
and vitamin deficiencies. Diabetes mellitus and
dyslipidemias show dramatic improvement, thus
medication adjustments are necessary.
8 Does accreditation of WLS centers It is recommended that all bariatric surgeries D 194-196
improve outcomes? be performed at accredited centers, though
outcomes may be equivalent.

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enteroinsular axis and the recovery from type 2 diabetes after
bariatric surgery. Obes Surg. 2004;14:840-848.
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Evidence-Based Bariatric Surgery ■ 145
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5/21/2012 8:52:39 PM
 CHAPTER 16
Gastric Adenocarcinoma
Antonio I. Picon and Martin S. Karpeh
INTRODUCTION
Gastric adenocarcinoma constitutes a major health problem in
many countries around the world. According to World Health
Organization’s (WHO) report, gastric cancer is the second most
common cause of cancer mortality. It is estimated that in United
States, 27,000 new gastric cancer cases were diagnosed in 2010
and 10,570 deaths from this disease.1 There has been a progres-
sive decrease in the incidence of gastric cancer around the world
largely due to eradication of Helicobacter pylori and other risk fac-
tors that are not completely understood.2,3 There has been a dra-
matic increase of proximal gastric and gastroesophageal junction
(GEJ) cancers along with changes in histology, with the diff use-
type adenocarcinoma increasing in prevalence.4 Across the globe
and particularly in Asia, gastric cancer remains the most com-
mon cancer among men and the most common cause of cancer-
related deaths in countries such as Japan. In Japan and other
parts of the Asia, noncardiac tumors continue to be more com-
mon compared with the West. In the United States and in many
other western countries, gastric cancer is typically diagnosed at
an advanced stage.5,6 In countries with a high incidence of gas-
tric cancer such as Japan and Korea, there is widespread aware-
ness of the disease, and screening programs are more widely
available, consequently, early gastric cancer (EGC) is diagnosed
more frequently in these countries.7 EGC is defined as a cancer
confined to the mucosa and submucosa independently of the
nodal status. In many cases, patients are asymptomatic and diag-
nosed incidentally by experienced endoscopist. The incidence of
EGC in countries where there is mass screening for gastric can-
cer is around 53% and 5-year survival rates are above 90% in
well-differentiated, mucosal lesions without nodal involvement.8
Environmental risk factors include H. pylori infection, high salt
intake, smoking, and other dietary factors. Patients with a fam-
ily history of nonhereditary gastric cancer have a higher risk of
developing gastric cancer. E-cadherin mutations occur in approx-
imately 25% of families with the autosomal dominant form of
hereditary diff use gastric cancer (HDGC). Pathologically, all
the gastric cancers with CDH1 mutations have shown invasive,
146
PMPH_CH16.indd 146
poorly differentiated, diffuse gastric cancer (DGC) and display
signet-ring cell features. The estimated cumulative risk for gastric
cancer by the age of 80 in HDGC families is 67% for men and 83%
for women.9 Prophylactic gastrectomy should be considered in this
high-risk group of young and asymptomatic carriers with germline
truncating CDH1 mutations, after appropriate genetic counseling
is obtained.10,11 The majority of gastric tumors are adenocarcinoma,
and histopathologically divided into two major subtypes.12 The
intestinal-type or well-differentiated tumor that originates from
gastric mucosa. This histotype is often associated with cancers of
the distal stomach, older-age patients, H. pylori infection, and a
propensity for liver metastases. The diffuse type or poorly differen-
tiated is believed to originate from the lamina propria of the stom-
ach, it grows along the submucosa and it has more of an infiltrative
pattern. The diffuse type is seen in younger patients, associated with
familial cancers, early metastases, and lymphatic spread.
DIAGNOSIS AND STAGING
1. What is the ideal diagnostic and staging work-up for gastric
adenocarcinoma?
Gastric adenocarcinoma is usually associated with vague and
nonspecific gastrointestinal symptoms. In countries with high
incidence of gastric cancer and massive screening after the age of
40, the prevalence of early and asymptomatic lesion is high. In the
United States the majority of patients present with locoregional or
systemic disease that may preclude curative treatment. The diag-
nostic modality of choice is upper gastrointestinal endoscopy. The
identification of early lesions will depend on the experience of the
endoscopist and systematic evaluation of the stomach to detect
subtle changes in color, vascularity, or texture.8 Endoscopic ultra-
sound, as an adjunct to endoscopy, is used selectively.13 In insti-
tutions where endoscopist are experienced in the techniques of
endoscopic mucosal resection (EMR) or endoscopic submucosal
dissection (ESD), EUS is helpful in selecting tumors for endoscopic
removal. EUS plays an important role in determining the depth
of invasion and nodal status of the tumor that will determine the
5/21/2012 8:54:03 PM

subsequent treatment.14,15 It can aide in identifying locally advanced
disease that would be appropriate for neoadjuvant therapy proto-
cols and can guide the surgeon to determine the extent of resection
and lymphadenectomy.16 It also plays a role in the surveillance of
patients after EMR or ESD.
Computed tomography (CT) of the chest and abdomen with
contrast has a long track record in the detection of metastatic dis-
ease. The sensitivity for determining nodal status has typically been
a weakness, but recently multislice CT was shown to be accurate in
detecting paraaortic nodal metastases.17 Attempts have been made
to compare CT with magnetic resonance imaging (MRI) of the
stomach for staging, no significant advantage was noted for either
modality.18 Positron emission tomography-computed tomography
(PET-CT) should be used selectively when there is high suspicious
of metastatic disease that is not evident with other modalities, and
in proximal and GEJ tumors.19 There is no role of PET-CT in the
work-up of T1 lesions where the sensitivity is just 10%.20 Mucinous
and signet-ring cell tumors may have low standardized uptake
value (SUV) in the presence of metastatic disease. Tumor mark-
ers (CEA and CA-19-9) are elevated in approximately one-third
of patients. They are useful to assess response to adjuvant therapy
and assess recurrence in those patients with elevated levels before
treatment.21,22 Tumor markers should not be used to change the
surgical treatment. Laparoscopy should be used for staging in
selective group of patients. Many have shown that laparoscopy can
change patient management in 20% to 30%.23-25 The yield from lap-
aroscopy increases with increasing stages of disease and hence it
should be considered in patients with advanced (deep T2, T3, and
T4) tumors more than 8 cm in size, and locally advanced tumors
with or without locoregional disease on preoperative imaging.26
Laparoscopic peritoneal lavage cytology is an important prog-
nostic factor. Patients with positive cytology behave like stage IV
gastric cancer with dismal survival in 5 years.21,27,28 The finding of
positive cytology or carcinomatosis will identify patients with a
very poor prognosis and will change the treatment algorithm of
those patients.25
ANSWER: The ideal work-up should include esophagoduo-
denoscopy with biopsy. EUS is used selectively when considering
endoscopic resection for selected T1 cancers or when the T stage is
needed to help choosing treatment. Chest imaging and multislice
CT of the abdomen and pelvis have a long track record for ruling
out metastatic disease and is performed in all cases. PET-CT can
be informative in cases of advanced disease and especially in GE
junction and proximal tumors, but is not helpful in staging T1
cancers. Tumor markers (CEA and CA-19-9) are of value during
surveillance, if elevated at presentation. Staging laparoscopy with
peritoneal cytology for locally advanced cancers plays an impor-
tant role in detecting clinical and radiologic occult disease.
Table 16.1 EGC: Criteria for Curative Endoscopic Resection
Mucosal Cancer
No ulceration Ulcerated
Size (mm) ≤20 >20 ≤30 >30
Intestinal EMR ESD ESD Gastrectomy + LN
dissection
Diffuse Consider Gastrectomy + LN dissection
Surgery
PMPH_CH16.indd 147
Gastric Adenocarcinoma ■ 147
TREATMENT OF EGC
2. What are the treatment options in the treatment of EGC?
EGC is defined as tumors confined to the mucosa or submucosa
independently of the nodal status. Radical surgery had always been
considered the standard of care for EGC. In Japan, Korea, and other
countries with high incidence of EGCs, EMR and ESD are well
accepted techniques in the hands of experienced endoscopist, and
they have been recognized as definitive therapy in selected group
of patients.29 The selection criteria came from the paper published
by the National Cancer Center in Tokyo, Japan.30,31 The results of
this large retrospective analysis of prospectively collected data
revealed that none of the well-differentiated intramucosal can-
cers of less than 30 mm in diameter, regardless of the presence of
ulceration; intramucosal cancers without ulceration, regardless of
size, and well-differentiated adenocarcinomas of less than 30 mm,
without lymphovascular invasion were associated with lymph node
metastases. Of note, tumors invading the submucosa, but less than
0.5 cm in size were also all free of lymph node metastases. The
selection criteria for EMR or ESD are listed in Table 16.1.
ESD is considered curative for patients that meet the follow-
ing criteria: well-to-moderately differentiated histopathology;
negative vertical margin (intramucosal lesion or extension into the
submucosa for less than 500 μm); negative lateral margin; and no
lymphatic or vascular invasion. If these guidelines are followed,
published data suggests that patients will be at minimal or no risk
of nodal metastases and results will be comparable to radical sur-
gery. If after EMR or ESD the above criteria are not met, patient
should undergo radical surgery. The exception to the rule is a posi-
tive lateral margin that may undergo repeat ESD, if the endoscopist
and pathologist are comfortable repeating the procedure. The most
common complication after EMR–ESD is delayed bleeding with an
incidence up to 7% to 8% and perforation in about 4% of cases.31
Follow-up after ESD consists of repeating EGD at 3 months and
annually thereafter. CT scan should be obtained at 1 year for dis-
tant metastases and EUS in 3 to 6 months for nodal disease in the
selected group of patients who refused radical surgery. For patients
who have EGC, but refuse or do not meet the criteria for endoscopic
resections, subtotal gastrectomy with a D1 dissection or modified
D1 lymphadenectomy,32 pylorus preserving gastrectomy,33 or prox-
imal gastrectomy with or without jejunal interposition is an option
supported by Level II-3 evidence.34
ANSWER: EMR and ESD are comparable techniques to radi-
cal surgery in the treatment of EGC that meet the strict criteria
for endoscopic treatments based on large Level II-3 data sources.
There are no randomized trials comparing EMR and gastrec-
tomy. Radical surgery with limited lymphadenectomy (modified
Submucosal Cancer
SM1 (<500 μm) SM2 (>500 μm)
≤30 Any size
ESD Gastrectomy + LN
dissection
5/21/2012 8:54:04 PM
 148 ■ Surgery: Evidence-Based Practice
gastrectomy type A [MGA] or type B [MGB]) for EGC that do not
meet the criteria for endoscopic procedures should be offered as
the standard of care.
TREATMENT OF ADVANCE
GASTRIC CANCER
3. When should neoadjuvant therapy be considered?
The rational for using neoadjuvant therapy is based on the assump-
tion that occult systemic disease will be best treated early before
resecting the primary tumor thus avoiding the immunosuppres-
sive and debilitating effects of surgery and increasing treatment
efficacy. The primary goal of this therapy is to improve progres-
sion-free survival (PFS) and overall survival (OS). Potential ben-
efits of neoadjuvant therapy are that it is better tolerated prior to
surgery, patients tend to get more of the intended treatment, the
tumors can be downstaged, response to therapy can be assessed,
and surgery can be avoided in patient that progress.16
The British Medical Research Council provided the first
level I evidence for a conclusive survival benefit for R0 resection
following the use of preoperative chemotherapy in patients
with resectable gastric, gastroesophageal, and distal esophageal
adenocarcinomas over surgical resection alone.35 The MAGIC
trial used preoperative and postoperative epirubicin, cisplatin,
and 5-fluorouracil (ECF) combination chemotherapy. Criticisms
of this trial included the lack of optimal preoperative staging and
subgroup analysis by stage, but the selection criteria were consis-
tent with established treatment the study was powered to show a
survival benefit for the entire treatment cohort rather than a select
subgroup. There was no difference in the postoperative complica-
tions or operative mortality between the groups. The response
rate as assessed by tumor size was significantly improved in the
group randomized to chemotherapy. The study demonstrated
improved resectability, PFS, and OS. Assessment of response
to neoadjuvant therapy by PET-CT is not only used as a guide
in the treatment of these patients, but also metabolic as well as
pathologic response has been correlated with better outcome.36,37
The role of neoadjuvant chemoradiation therapy in patients with
potentially resectable esophageal and cardia adenocarcinomas
was supported in a sentinel study by Walsh et al.38 This study was
criticized for the lack of rigid preoperative staging measures and
for the poor survival results of the surgery alone group, but the
randomization was sound and the selection criteria reflected the
standards used at the time. The multimodality treated group had
a 25% complete response rate and a significant improvement in
3-year survival over surgery alone. Other phase II and III trials
have shown improved pathologic response and survival advan-
tages when preoperative chemoradiation therapy was used.39-42 In
a phase III trial of 126 patients with locally advanced adenocar-
cinoma of the lower esophagus or gastric cardia, patients were
randomized to chemotherapy followed by surgery or chemora-
diation therapy followed by surgery. In patients receiving chemo-
radiation therapy, there was a significant probability of showing
a complete response or tumor-free lymph nodes at resection.
Operative mortality was not significantly increased in the chemo-
radiation group. Preoperative chemoradiation therapy improved
3-year survival rate, but was not statistically significant.39 There
is no large prospective randomized trial assessing the role of pre-
operative chemoradiation in gastric cancer. Its value has yet to be
PMPH_CH16.indd 148
determined as most studies have been limited to proximal gastric
and GEJ tumors.
ANSWER: Neoadjuvant chemotherapy should be recom-
mended for patients at risk of systemic failure. Tumors with radio-
logic and endoscopic evidence of locally advanced disease (>T3
or N positive) in patients without symptoms requiring palliative
therapy, and without evidence of distant disease or positive peri-
toneal cytology should be considered for neoadjuvant treatment.
The goal is to treat micrometastatic disease, improve the R0 resec-
tion rate, and prolong survival.
4. What is the ideal extent of resection and lymphadenectomy?
The type and extent of resection and the lymphadenectomy to
be performed will depend on the location and the clinical stage
of the tumor. Treatment should be tailored according to the biol-
ogy of the tumor to avoid under- or overtreatment of the disease.
The controversy regarding the extent of resection, total versus
subtotal gastrectomy, was answered in three prospective random-
ized trial comparing both techniques.43-45 There was no difference
in survival after R0 resection. An analysis of a large prospective
database found proximal subtotal gastrectomy to have similar
survival results compared with total gastrectomy in the treatment
of early proximal gastric cancers.46 Proximal gastrectomy is an
option in the treatment of early proximal gastric cancers, but it
has been associated with acid reflux and esophagitis.47 Proximal
gastrectomy has been associated with few long-term complications
when performed with jejunal interposition and with excellent
outcome.34,48 Gastric adenocarcinoma, especially the diffuse type,
tends to spread submucosally several centimeters from the primary
tumor, the duodenal margin should be at least 3 cm and proximal
margin should be at least 6 cm, if possible, to minimize the risk of
leaving a positive margin.49 The management of R1 resection (posi-
tive macroscopic margin) should be addressed taking into account
the surgical risk to the patient and the biology of the tumor. In one
retrospective study, patients with five or more positive nodes had
the same poor survival regardless of margin status.50 The goal of
surgery is to achieve an R0 resection with minimal morbidity and
mortality to maximize the probability of cure. When faced with a
positive margin, the presence of positive cytology and/or N2-N3
disease, reresection may not make a difference in survival.51
The extent of lymphadenectomy should be tailored according
to the clinical stage of the disease.52 D0 lymphadenectomy is done
when no attempt is made to harvest perigastric lymph nodes and is
done when resection is performed only when palliation is the goal.
D1 lymphadenectomy is done when the perigastric lymph nodes
(stations 1–6 in the Japanese nomenclature), and a D2 lymphadenec-
tomy is done when D1 nodes are included with lymph nodes along
the left gastric artery, splenic artery, and the celiac axis. A modified
lymphadenectomy has been advocated for treating EGC patients.
MGA includes 2/3 subtotal gastrectomy and a D1 lymphadenectomy
plus the left gastric artery nodes (station 7) and it should include
celiac axis nodes (station 8a) for lower third cancers. MGA is indi-
cated for tumors confined to the mucosa, but not eligible for endo-
scopic removal. MGB includes 2/3 subtotal gastrectomy, D1 plus
station 7, 8a, and 9 (common hepatic artery nodes). MGB is indi-
cated for deeper T1 tumors confined to the submucosa. Extended
D3 and D4 lymphadenectomies have been shown not to increase
survival, therefore they are not currently recommended.53,54
The ideal extent of the lymphadenectomy has been debated
for decades. There are no Japanese randomized control trials
5/21/2012 8:54:04 PM

(RCT) comparing D1 and D2 dissections. The advantage of D2
compared with D1 was reported by the Japanese in large retro-
spective analysis.55,56 Two well-designed prosective randomized
western trials did not show a survival advantage for routine use
of the D2 lymphadenectomy versus the D1 and demonstrated an
increase in morbidity and mortality.57,58 Much has been written
extolling the positives and negatives of these trials, the morbidity
and mortality was higher than expected, patients had less exten-
sive disease and better OS than expected raising questions about
the power of these trials to show a difference.59
Routine distal pancreatectomy and splenectomy in the D2
lymphadectomy group was associated with increased morbidity
and mortality in both the MRC and Dutch trials. Distal pancre-
atectomy and/or splenectomy should be performed selectively
when there is direct organ involvement.58,60,61 It has been shown
that the number of positive lymph nodes, and not the location, is a
more reliable measure of prognosis. The current recommendation
is to harvest at least 15 lymph nodes to optimize staging.62
ANSWER: The extent of gastrectomy and lymphadenectomy
should be tailored according to the stage of the tumor. A subto-
tal gastrectomy should be sufficient provided that an R0 resection
can be achieved. An MGA or MGB is recommended for EGC.
For advanced gastric cancers expert opinion would favor radical
gastectomy with a D2 lymphadenectomy, but the best evidence
currently supports gastrectomy with D1 lymphadenectomy in
western patients. Extended lymphadenectomy (D3-D4) and rou-
tine pancreatectomy and/or splenectomy are not supported by
the data. A minimum of 15 lymph nodes should be harvested for
adequate staging of advanced gastric cancers.
5. When should adjuvant therapy be considered?
A number of meta-analyses of RCT have examined the impact
of postoperative chemotherapy in the treatment of gastric cancer
compared with surgery alone. A recent study looked at individual
patient data from 17 trials (3838 patients) representing 60% of the
targeted data with more than 7 years of median follow-up. Adjuvant
5-fluorouracil-based chemotherapy was associated with a signifi-
cant OS benefit (hazard ratio [HR], 0.82; 95% confidence interval
[CI], 0.76–0.90; P < 0.001) and disease-free survival (HR, 0.82; 95%
CI, 0.75–0.90; P < 0.001).63 A large phase III Japanese trial random-
ized patients with stages II and III gastric cancer who underwent
gastrectomy with D2 or more extensive lymphadenectomy, with R0
resection and no hepatic, peritoneal or distant metastasis. Patients
were randomly assigned to undergo surgery followed by S-1 che-
motherapy or surgery alone. S-1 chemotherapy showed superiority
to surgery alone with improved 3-year OS rate.64
The results of the intergroup 0116 prospective randomized trial
comparing 5-fluorouracil and leucovorin and external beam radia-
tion therapy with observation set the standard for adjuvant chemo-
radiation therapy after surgery in the United States. This trial has
been criticized for poor quality control of surgical therapy.65 The
trial contained a large percentage of T3 and node-positive tumors
and reanalysis of the data suggested that the degree of residual dis-
ease post resection was not insignificant.66,67 There were no T1N0,
and just 35 stage-IB patients were randomized leaving open ques-
tions regarding suitability of this regimen for early-stage tumors.
ANSWER: There is insufficient data to recommended adju-
vant therapy for node negative T1 and T2 gastric cancers. In node-
positive and advanced gastric cancers, adjuvant chemoradiation
therapy should be offered due to the high locoregional and systemic
PMPH_CH16.indd 149
Gastric Adenocarcinoma ■ 149
recurrence rate.63,68 An acceptable minimal alternative after ade-
quate R0 resection of advanced gastric cancers would be 5-fluorou-
racil or S-1 based chemotherapy. The high incidence of recurrence
after R0 resection of advanced gastric cancer makes it imperative to
recommend adjuvant therapy to optimize survival probability.
6. What is the ideal surgical management of stage IV disease?
Treatment options in the management of stage IV gastric cancer
are and have been controversial in part due to historic data sup-
porting the limited option of surgery alone for palliation. There is a
distinct lack of prospective randomized and adequate prospective
studies evaluating surgical treatment in these patients. With cur-
rent refinements, chemotherapy patients with metastatic disease
have been shown to improve their quality of life compared with
best supportive care. The patients should be offered chemotherapy
and there is no standard regimen currently recommended. In a
recent Cochrane review of chemotherapy versus best supportive
care, both single agent and combination chemotherapy regimen
resulted in superior palliation and improved survival.69 There is
a trend to use combination of drugs and oral fluoropyrimidines
in combination with other drugs have shown to be effective.70-72
In HER2-positive disease addition of trastuzumab to chemother-
apy improves survival for patients with locally advanced disease,
recurrent or metastatic gastric cancer.73
In a recent retrospective review of stage IV gastric cancer
diagnoses using the SEER database, the authors analyzed three
subgroups divided on the basis on whether cancer-directed ther-
apy was recommended but not performed, recommended and
performed, or not recommended. Patients who had recommended
cancer-directed surgery had significantly improved survival. They
concluded that highly selected group of stage IV gastric cancer
patients who undergo surgery have significantly greater survival
than unresected patients, including those patients that surgery was
recommended but not performed.74 This retrospective review sug-
gests that surgeons were able to select those of stage IV patients
that could tolerate and benefit from surgical resection. It is of inter-
est that Asian race and age less than 60 years were associated with
prolonged survival. The authors concluded that surgery should be
considered in highly selected stage IV patients with acceptable sur-
gical risk.75 Palliative gastrectomy for incurable disease has been
associated with significant morbidity and mortality.76 The majority
of patients with stage IV cancer can have their symptoms palliated
without surgery. Despite these facts, a poorly defined group of stage
IV patients undergoing surgery had longer survival compared with
patients undergoing other types of intervention.77-79 Prospective
randomized trials of defined stage IV patients are needed to clearly
identify which patients will benefit most from resection.
In a multicenter randomized trial comparing surgical gas-
trojejunostomy (GJJ) and endoscopic stent placement for the pal-
liation of malignant gastric outlet obstruction in unresectable or
metastatic, GJJ was associated with better long-term results and
is the treatment of choice in patients with a life expectancy of
2 months or longer. For those patients with a life expectancy of
less than 2 months, they favored stent placement.80
ANSWER: Stage IV gastric patients should be offered chemo-
therapy as first-line therapy to prolong survival and palliation of
symptoms. In highly selected group of patients, with good perfor-
mance status surgery can be considered. In the presence of gastric
outlet obstruction, GJJ should be offered in patients with a life
expectancy of 2 months or longer.
5/21/2012 8:54:04 PM
 150 ■ Surgery: Evidence-Based Practice
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advanced gastric cancer. J Surg Oncol. 2010;101(4):305-314.
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23. Conlon KC, Karpeh MS, Jr. Laparoscopy and laparoscopic
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24. Burke EC, et al. Laparoscopy in the management of gastric ade-
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31. Gotoda T. Endoscopic resection of early gastric cancer. Gastric
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32. Shimada Y. JGCA (The Japan Gastric Cancer Association). Gas-
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33. Shibata C, et al. Outcomes after pylorus-preserving gastrectomy
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34. Katai H, et al. Long-term outcome after proximal gastrectomy
with jejunal interposition for suspected early cancer in the upper
third of the stomach. Br J Surg. 2010;97(4):558-562.
35. Cunningham D, et al. Perioperative chemotherapy versus sur-
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42. Ajani JA, et al. Phase II trial of preoperative chemoradiation in
patients with localized gastric adenocarcinoma (RTOG 9904):
Quality of combined modality therapy and pathologic response.
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44. Robertson CS, et al. A prospective randomized trial comparing
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45. Gouzi JL, et al. Total versus subtotal gastrectomy for adenocar-
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46. Harrison LE, Karpeh MS, Brennan MF. Total gastrectomy is not
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47. Hsu CP, et al. Esophageal reflux after total or proximal gastrec-
tomy in patients with adenocarcinoma of the gastric cardia. Am
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48. Katai H, et al. Prospective study of proximal gastrectomy for
early gastric cancer in the upper third of the stomach. Br J Surg.
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49. Bozzetti F, et al. Adequacy of margins of resection in gastrec-
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50. Kim SH, et al. Effect of microscopic resection line disease on gas-
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51. Sun Z, Xu HM. Stage and microscopic positive margins in
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52. Nakajima T. Gastric cancer treatment guidelines in Japan. Gas-
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53. Yonemura Y, et al. Randomized clinical trial of D2 and extended
paraaortic lymphadenectomy in patients with gastric cancer. Int
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54. Sasako M, et al. D2 lymphadenectomy alone or with para-aortic
nodal dissection for gastric cancer. N Engl J Med. 2008;359(5):
453-462.
55. Sano T, et al. Recurrence of early gastric cancer. Follow-up of
1475 patients and review of the Japanese literature. Cancer.
1993;72(11):3174-3178.
56. Maruyama K, et al. Lymph node metastases of gastric cancer.
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57. Bonenkamp JJ, et al. Extended lymph-node dissection for gastric
cancer. N Engl J Med. 1999.340(12):908-914.
58. Cuschieri A, et al. Patient survival after D1 and D2 resections
for gastric cancer: long-term results of the MRC random-
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1999;79(9–10):1522-1530.
59. Fayers PM, et al. Sample size calculation for clinical trials: the
impact of clinician beliefs. Br J Cancer. 2000;82(1):213-219.
60. Otsuji E, et al. Total gastrectomy with simultaneous pancreati-
cosplenectomy or splenectomy in patients with advanced gastric
carcinoma. Br J Cancer. 1999;79(11–12):1789-1793.
61. Takeuchi K., et al. Total gastrectomy with distal pancreatec-
tomy and splenectomy for advanced gastric cancer. J Surg Res.
2001;101(2):196-201.
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62. Karpeh MS, et al. Lymph node staging in gastric cancer: Is loca-
tion more important than Number? An analysis of 1,038 patients.
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63. Paoletti X, et al. Benefit of adjuvant chemotherapy for resectable
gastric cancer: a meta-analysis. JAMA. 2010;303(17):1729-1737.
64. Sakuramoto S, et al. Adjuvant chemotherapy for gastric
cancer with S-1, an oral fluoropyrimidine. N Engl J Med.
2007;357(18):1810-1820.
65. Macdonald JS, et al. Chemoradiotherapy after surgery compared
with surgery alone for adenocarcinoma of the stomach or gas-
troesophageal junction. N Engl J Med. 2001;345(10):725-730.
66. Hundahl SA, et al. Improved regional control and sur-
vival with “low Maruyama Index” surgery in gastric cancer:
Autopsy findings from the Dutch D1-D2 Trial. Gastric Cancer.
2007;10(2):84-86.
67. Douglass HO, Jr., et al. Gastric cancer: D2 dissection or low Mar-
uyama Index-based surgery—a debate. Surg Oncol Clin N Am.
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68. Panzini I, et al. Adjuvant chemotherapy in gastric cancer: A
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vious meta-analyses. Tumori. 2002;88(1):21-27.
69. Wagner AD, et al. Chemotherapy for advanced gastric cancer.
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70. Cunningham D, et al. Capecitabine and oxaliplatin for advanced
esophagogastric cancer. N Engl J Med. 2008;358(1):36-46.
71. Kang YK, et al. Capecitabine/cisplatin versus 5-fluorouracil/
cisplatin as first-line therapy in patients with advanced gastric
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2009;20(4):666-673.
72. Ajani JA, et al. Multicenter phase III comparison of cisplatin/S-1
with cisplatin/infusional fluorouracil in advanced gastric or gas-
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73 . Roukos DH. Targeting gastric cancer with trastuzumab: New
clinical practice and innovative developments to overcome resis-
tance. Ann Surg Oncol. 2010;17(1):14-17.
74. Smith JK, et al. Potential benefit of resection for stage IV gastric
cancer: A national survey. J Gastrointest Surg. 2010;14(11):1660-
1668.
75. Lim S, et al. Results following resection for stage IV gastric can-
cer; Are better outcomes observed in selected patient subgroups?
J Surg Oncol. 2007;95(2):118-122.
76. Wanebo HJ, et al. Cancer of the stomach. A patient care study
by the American College of Surgeons. Ann Surg. 1993;218(5):
583-592.
77. Doglietto GB, et al. Surgery: Independent prognostic fac-
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2000;24(4):459-463; discussion 464.
78. Hanazaki K, et al. Palliative gastrectomy for advanced gastric
cancer. Hepatogastroenterology. 2001;48(37):285-289.
79. Meijer S, De Bakker OJ, Hoitsma HF. Palliative resection in gas-
tric cancer. J Surg Oncol. 1983;23(2):77-80.
80. Jeurnink SM, et al. Surgical gastrojejunostomy or endoscopic
stent placement for the palliation of malignant gastric outlet
obstruction (SUSTENT study): a multicenter randomized trial.
Gastrointest Endosc. 2010;71(3):490-499.
5/21/2012 8:54:04 PM
 Commentary on Gastric
Adenocarcinoma
With a slightly different “lumper” view of epidemiology, one
can discern three broad categories of nonhereditary gastric car-
cinoma, with the first two closely linked to Heliobacter pylori
infection1: (1) Intestinal-type tumors arising in long-standing
(H. pylori–related) intestinal metaplasia. These often arise near
the antrum-corpus junction along the lesser curvature. This type
of disease typifies the pattern seen in epidemic areas, especially
in Asia. (2) Diff use-type tumors arising in the body, typically
associated with intense, H. pylori–related gastritis, but with negli-
gible intestinal metaplasia. (3) Gastroesophageal junction tumors
whose incidence continues to increase in the United States and
in most “Western” countries. These tumors are associated with
obesity and reflux, but not with H. pylori infection.
With respect to staging, readers should be aware that current
seventh edition AJCC/UICC staging, to be used for all cases after
January 1, 2010, represents a major departure from previous ver-
sions. For example, tumors arising from the proximal 5 cm of
the stomach and extending to the gastroesophageal junction, as
well as all EG junction tumors, are now classified, for staging pur-
poses, as esophageal cancer (i.e., not stomach).2 This, combined
with other changes, has created substantial migration of site and
stage from previous editions. The authors have, perhaps diplo-
matically, skipped over the potentially impact of these changes on
treatment (e.g., teams, paradigms).
A second staging issue should be highlighted. Japanese
Gastric Cancer Association (JGCA) staging (a.k.a. the “General
Rules”) represents an internationally popular alternative staging
system used throughout Asia. This system has also undergone
considerable revision over years.3 For example, the “N4” desig-
nation was eliminated, and, with it, the term “D4 lymphadenec-
tomy.” And given the redefinition of N2 nodes, a modern “D2”
operation approximates the D3 of former years. The reshuffling
of nodal designations has created confusion among non-Japanese
surgeons. To clarify current definitions, an updated “third Eng-
lish version” has recently been published.4
The authors appropriately highlight the revolution in early
gastric cancer (EGC) management represented by endoscopic
resection techniques. The selection criteria in Table 1 are largely
based on nodal analysis from a 5,265-patient cohort of surgically
treated EGC patients treated at the two major cancer centers in
Tokyo.5 This classic 2000 paper highlighted subgroups with zero
nodal involvement and merits close study.
The section on neoadjuvant treatment emphasizes a key find-
ing, but one which still generates controversy: neoadjuvant treat-
152
PMPH_CH16.indd 152
Scott A. Hundahl
ment can be delivered with no increase in surgical mortality. And
because neoadjuvant protocols allow surgeons to deselect those
with rapid progression/metastases, results for those completing
surgical treatment generally appear enhanced.
The section on surgical resection and lymphadenectomy suc-
cinctly covers a truly vast surgical controversy. Some additional
trials and reports deserve mention. They include the following:
1. A Taiwanese prospective randomized single-institution trail
by Wu et al.6 In a setting of 0% postoperative mortality, the
investigators observed a 5.9% survival advantage to “D3”
lymphadenectomy over “D1” lymphadenectomy (59.5% vs.
53.6%, p = .04). A related 10.3% difference in recurrence
at 5 years was reported, but this did not reach significance
(p = .197). Because of changes in JGCA definitions, what
was, at the time of trials’ initiation, a “D3” operation actually
approximates a modern “D2” lymphadenectomy.
2. Dutch D1-D2 Trial updates with 10- and 15-year follow-up and
are available.7,8 Songun et al. reported that at 15 years, death
from gastric cancer was 48% for D1 versus 37% for D2 (p = .01),
but, as noted, the death from “toxicity of treatment” was 4% for
the D1 cohort and 10% for the D2 cohort. Overall survival was
21% for D1 and 29% for D2 (p = n.s.).
3. Proof that modern pancreas-preserving D2 surgery, as
advocated by Maruyama,9 can be safely performed in a
European population is provided by a well-done 191-patient
Italian study by Deguili et al. in which in-hospital mortality
was only 3.1%.10,11 Thus, many gastric cancer experts continue
to favor pancreas-preserving D2 surgery for patients with local-
regional T2-or-greater disease.
An alternative method of customizing a lymphadenectomy
involves use of the “Maruyama Program”12,13 to guide surgeons to
an operation which does not leave regional nodal disease behind.
The concept of “low Maruyama Index” gastric cancer surgery was
developed by the author (S.H.) for the Intergroup 0116 “Macdon-
ald” chemoradiation trial to prospectively analyze the survival
impact of variation in surgical lymphadenectomy. The Maruyama
Index is simply the sum of Maruyama Program predictions of dis-
ease in regional node stations #1 through #12, which the surgeon
leaves in the patient. In the Macdonald chemoradiation study,
with T and N as covariates, Maruyama Index proved to be an
independent predictor of survival overall and for both treatment
groups.14 A retrospective blinded analysis of Maruyama Index in
the Dutch D1 versus D2 trial was subsequently performed. Again,
5/21/2012 8:54:04 PM

Maruyama Index proved to be an independent predictor of sur-
vival, and compelling “dose–response” was noted.15 Autopsy anal-
ysis among Dutch Trial patients expiring within 10 years indicated
that “low Maruyama Index surgery” was associated with lower
local-regional failure.16
The authors summarize the importance of properly selecting
gastric cancer patients who may benefit from surgical palliation
in the face of unresectable or disseminated disease. Selection of
appropriate candidates might also be guided by results of a non-
randomized analysis of 285 ineligible Dutch Trial cases with good
performance status who had Stage IV disease.17 Overall survival
time was greater if a resection was performed (8.1 vs. 5.4 months;
p < .001). For patients aged above 70 years, a survival advantage of
about 3 months with resection was observed, but morbidity and
perioperative mortality in such patients was very high at 50% and
20%, respectively. Patients with only one metastatic site benefitted
form resection (survival 10.5 vs. 6.7 months; p = .034). For patients
with two or more metastatic sites, however, resection carried no
significant survival advantage (5.7 vs. 4.6 months; p = .084). Hart-
grink et al. concluded that patients with good performance status
aged below 70 years with one metastatic site appear reasonable
candidates for palliative resection.
REFERENCES
1. Stemmermann G, Fenoglio-Preiser C. Gastric cancer: epidemiol-
ogy. In: Kelsen D, Daly J, Kern S, Levin B, Tepper J, eds. Gastroin-
testinal Oncology: Principles and Practice. Philadelphia: Lippincott
Williams & Wilkins; 2002:p. 311-324.
2. Edge SBB, DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC
Cancer Staging Manual. 7th ed. New York: Springer; 2009.
3. Sayegh ME, Sano T, Dexter S, Katai H, Fukagawa T, Sasako M.
TNM and Japanese staging systems for gastric cancer: How do
they coexist? Gastric Cancer. 2004;7(3):140-148.
4. Sano T KYe. Japanese classification of gastric carcinoma: 3rd Eng-
lish edition. Gastric Cancer. 2011;14(2):101-112.
5. Gotoda T, Yanagisawa A, Sasako M, Ono H, Nakanishi Y, Shi-
moda T, et al. Incidence of lymph node metastasis from early gas-
tric cancer: estimation with a large number of cases at two large
centers. Gastric Cancer. 2000;3(4):219-225.
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Gastric Adenocarcinoma ■ 153
6. Wu CW, Hsiung CA, Lo SS, Hsieh MC, Chen JH, Li AF, et al.
Nodal dissection for patients with gastric cancer: A randomised
controlled trial. Lancet Oncol. 2006;7(4):309-315.
7. Hartgrink HH, van de Velde CJ. Status of extended lymph node
dissection: Locoregional control is the only way to survive gas-
tric cancer. J Surg Oncol. 2005;90(3):153-165.
8. Songun I, Putter H, Kranenbarg EM, Sasako M, van de Velde CJ.
Surgical treatment of gastric cancer: 15-year follow-up results
of the randomised nationwide Dutch D1D2 trial. Lancet Oncol.
2010;11(5):439-449.
9. Maruyama K, Sasako M, Kinoshita T, Sano T, Katai H, Okajima
K. Pancreas-preserving total gastrectomy for proximal gastric
cancer. World J Surg. 1995;19(4):532-536.
10. Degiuli M, Sasako M, Ponti A, Calvo F. Survival results of a mul-
ticentre phase II study to evaluate D2 gastrectomy for gastric
cancer. Br J Cancer 2004;90(9):1727-1732.
11. Degiuli M, Sasako M, Ponti A, Soldati T, Danese F, Calvo F.
Morbidity and mortality after D2 gastrectomy for gastric cancer:
Results of the Italian Gastric Cancer Study Group prospective
multicenter surgical study. J Clin Oncol. 1998;16(4):1490-1493.
12. Kampschoer GH, Maruyama K, van de Velde CJ, Sasako M,
Kinoshita T, Okabayashi K. Computer analysis in making pre-
operative decisions: a rational approach to lymph node dissec-
tion in gastric cancer patients. Br J Surg. 1989;76(9):905-908.
13. Siewert JR, Kelsen D, Maruyama K, Feussner H, Omote K, Etter
M, et al. Gastric Cancer Diagnosis and Treatment – An Interac-
tive Training Program. 1 ed. Berlin, Germany: Spinger Electronic
Media; 2000.
14. Hundahl SA, Macdonald JS, Benedetti J, Fitzsimmons T.
Surgical treatment variation in a prospective, randomized trial
of chemoradiotherapy in gastric cancer: The effect of undertreat-
ment. Ann Surg Oncol. 2002;9(3):278-286.
15. Peeters KCMJ, Hundahl SA, Kranenbarg EK, Hartgrink H,
van de Velde CJH. “Low-Maruyama-Index” surgery for gastric
cancer – A blinded re-analysis of the Dutch D1-D2 Trial. World
J Surg. 2005;29:1576-1584.
16. Hundahl SA, Peeters KC, Kranenbarg EK, Hartgrink H, van
de Velde CJ. Improved regional control and survival with “low
Maruyama Index” surgery in gastric cancer: Autopsy findings
from the Dutch D1-D2 Trial. Gastric Cancer. 2007;10(2):84-86.
17. Hartgrink HH, Putter H, Klein Kranenbarg E, Bonenkamp JJ,
van de Velde CJ. Value of palliative resection in gastric cancer.
Br J Surg. 2002;89(11):1438-1443.
5/21/2012 8:54:04 PM
 CHAPTER 17
Management of Upper GI Bleeding
Bruce A. Crookes
INTRODUCTION
Upper gastrointestinal (UGI) bleeding is a common cause for
admission to the intensive care unit (ICU) and accounts for over
300,000 admissions in the United States.1,2 Optimal outcomes
depend on rapid identification of the etiology of the hemorrhage,
and the implementation of appropriate pharmacologic and proce-
dural therapies.
Ulcer disease accounts for the majority of these cases. Other
etiologies include varices, Mallory-Weiss syndrome, vascular
lesions, and inflammatory states of the UGI tract. Despite advances
in pharmacology and endoscopic therapies over the last several
decades, all causes of mortality have remained constant, ranging
from 4.5% to 10%,1-4 and up to 50% for variceal bleeding.5 Medi-
cal comorbidities and the use of anticoagulants complicate treat-
ment.4 Fortunately, over 80% of UGI bleeds stop spontaneously,
and only 2% require surgical intervention.6 Prompt and decisive
management is required, particularly in patients in whom arterial
bleeding cannot be controlled by endoscopy,7 when bleeding con-
tinues despite endoscopic therapy, or for high-risk patients. Best
practices should be used to prevent further episodes.
Initial guidelines for the management of UGI bleeding
were published almost 20 years ago. Over this period significant
advancements in treatment have developed. The purpose of this
chapter is to review the current evidence, including recent practice
guidelines, for the prevention and management of UGI bleeding.
1. What is the role of medical therapy in the prevention of UGI
bleeds and how successful is it?
The use of medical prophylaxis is highly dependent on the poten-
tial etiology of the bleeding. In some cases this is primary preven-
tion, whereas in others secondary prevention is the goal. Because
ulcer disease is the primary cause of many UGI bleeds, provid-
ers must identify the reason for ulceration. There are three prin-
cipal causes of ulcer disease: (1) stress-related mucosal damage
(SRMD), (2) nonsteroidal anti-inflammatory drug (NSAID) use,
and (3) Helicobacter pylori infection.
154
PMPH_CH17.indd 154
Patients who are critically ill have a number of causes for
ulcer formation including decreased mucous secretion, altered
GI motility, and mucosal ischemia.8 These factors are especially
prevalent in patients with large burns, head injury, coagulopathy,
or in patients who require mechanical ventilation. Traditionally,
antacids, sucralfate, or histamine-2 receptor antagonists (H2RA)
have been used,8 which were all able to reduce bleeding epi-
sodes, but none was clearly superior. More recently, proton pump
inhibitors (PPIs) have been studied for stress ulcer prophylaxis.
These agents are able to keep gastric pH > 4 by suppressing acid
secretion.8
Cook et al. found that ranitidine had lower bleeding rates
than sucralfate.9 However, several other studies showed decreased
mortality and pneumonia rates with sucralfate.8,10 Conrad et al.,11
in a randomized, double-blind study, found omeprazole to be
more effective than cimetidine in preventing GI bleeding in
critically ill patients. Omeprazole was able to reduce the rate of
bleeding from 6.8% to 4.5%, but neither pneumonia nor mortal-
ity rates had improved. Most recently, Somberg et al.12 examined
the concept of tolerance to pantoprazole, and found that iv pan-
toprazol controlled gastric pH well, whereas the administration
of cimetidine seemed to show decreases in gastric pH the lon-
ger it was administered. There was no significant increase in the
incidence of UGI bleeding or pneumonia, however. The lack of
difference between PPIs and H2 receptor agonists with respect
to ICU mortality, UGI bleeding prophylaxis, and pneumonia is
consistent across multiple studies, a finding that was confirmed
in a meta-analysis by Lin et al.13 Note that the preventative effects
of stress ulcer prophylaxis with omeprazole has not been shown
to hold in non-ICU patients, probably because the incidence of
UGI bleeding is so low.14
Similarly, pharmacotherapy is beneficial for preventing bleed-
ing related to NSAIDs used for pain relief or cardiovascular dis-
ease. Some have suggested changing from aspirin to clopidogrel
for cardio- or cerebrovascular disease. Chan et al.15 found in a
randomized placebo-controlled study that patients with a history
of bleeding ulcers have less frequent bleeding when esomeprazole
was added to aspirin as opposed to a change to clopidogrel, by a
5/21/2012 8:55:00 PM

rate of 0.7% as compared with 8.6%. In a large, prospective, ran-
domized controlled trial of 3873 patients taking clopidogrel with
omeprazole or placebo, the event rate of UGI bleeding was sig-
nificantly less with omeprazole, with no difference in the rate of
cardiovascular events.16 Alternative drugs, such as COX-2 inhibi-
tors, also can be used when NSAIDs are used for pain control in
arthritis. Another study by Chan et al.17 found that in patients who
were H. pylori negative and taking non-aspirin NSAIDs there was
additional reduction in UGI bleeding from 8.8% to 0% with the
addition of esomeprazole after they were changed to celecoxib. In
another study by Chan et al. that focused on patients on who were
H. pylori negative and taking a non-aspirin NSAID (celecoxib) the
incidence of UGI bleeding was reduced from 8.8% to 0% when
esomeprazole was administered. Lai et al.18 studied patients who
were taking aspirin and who were H. pylori positive. After eradica-
tion therapy, patients were randomized to lansoprazole or placebo
while continuing aspirin. The PPI group had an ulcer complication
rate of 1.6% compared with 14.8% with placebo. Udd et al. 19 found
that regular- and high-dose omeprazole are equally effective for
preventing peptic ulcer bleeding.
Whereas acid suppression is the hallmark of prevention for
ulcer-related bleeding, reduction of portal venous pressure is most
effective for preventing esophageal bleeding. β-Blockers are the
main class of drugs that are used to accomplish this goal. They
were first used in this role in the 1980s after introduction by Leb-
rec20 and others. Lebrec et al. found that patients with large varices
were significantly less likely to bleed when nadolol was adminis-
tered instead of a placebo.21 Kiire similarly found that propranolol
significantly reduced bleeding from varices as compared to pla-
cebo.22 Other drugs, such as isosorbide mononitrate (IM), have
also been investigated to prevent variceal bleeding. Angelico et
al.23 found that propranolol and IM provided similar protection
against variceal bleeding. However, long-term use of nitrates has
been linked to increased mortality. A recent review by Talwalkar
and Kamath showed that β-blockers provide a 9% absolute risk
reduction for primary prophylaxis and a 21% reduction for second-
ary prevention. They also note that no individual trial has linked
β-blocker prophylaxis to improved survival, but this has been
demonstrated in meta-analysis.24 Some authors have investigated
a combination of β-blockers and nitrates. Merkel et al.25 demon-
strated a decreased bleeding risk from 29% to 12% with a combi-
nation treatment. However, some studies have shown an increased
rate of adverse events with these combination therapies.24 Other
authors have investigated the use of β-blockers to prevent the for-
mation of growth of varices. Merkel and colleagues26 found that
the risk of variceal growth decreased from 21% to 7% and 51% to
20%, at the 1- and 5-year follow-up, respectively. However, Grosz-
mann et al. 27 studied patients with cirrhosis and portal hyperten-
sion and were unable to show that β-blockers prevented variceal
formation. In addition, recent studies have compared the use of
β-blockers and endoscopic ligation for primary prophylaxis.
RECOMMENDATIONS
1. PPIs or H2RAs should be used as stress ulcer prophylaxis in
critically ill patients to prevent GI bleeding.
2. Risk of ulcer formation for patients taking NSAIDs is
significantly reduced when a PPI or H2RA prophylaxis is
utilized.
PMPH_CH17.indd 155
Management of Upper GI Bleeding ■ 155
3. In patients taking clopidogrel in the setting of coronary
artery disease, UGI bleeding risk is reduced in patients taking
omeprazole.
4. β-Βlockers can be used safely for primary prophylaxis from
variceal bleeding and may slow the growth rate of small varices.
Strength of Recommendations: 1. A, 2. A, 3. A, 4. B.
2. What is the role of medical therapy in treating UGI bleeds
and how effective is it?
As mentioned in the introduction, most UGI bleeds stop spon-
taneously. However, clinicians can optimize patient outcomes
through both pharmacologic and procedural interventions. UGI
bleeds caused by ulcer disease are frequently treated with acid
suppression. Initially H2RAs were used, and a review by Collins
and Langman28 in the mid-1980s found that these drugs decreased
rates of surgery and death in certain populations. Over the next
decade, however, PPIs were introduced, opening new avenues of
therapy. Lanas et al.29 found that omeprazole was superior to ran-
itidine in decreasing rebleeding episodes, a finding that has since
be reaffirmed.30 No differences were found, however, in mortality
or units of blood transfused. Khuroo and colleagues31 found that
PPIs reduced ongoing bleeding from 36.4% to 10.9% and reduced
the need for surgery as compared to placebo. In nonvariceal
bleeding, pre-endoscopy proton pump therapy has been shown to
downstage UGI bleeding lesions, and iv PPI administration after
successful endoscopy may decrease both mortality and rebleed-
ing events, although the data is conflicting.32,33 For example,
Lau et al.34 found that PPI treatment was superior in preventing
rebleeding after endoscopic treatment of ulcer bleeding. Danesh-
mend et al.,35 however, did not find omeprazole to reduce mortal-
ity, rebleeding, or transfusion requirements, but that it was only
able to demonstrate a decrease in the endoscopic signs of bleeding
with PPI treatment. Regional differences in patient populations
may account for these differences as one study was conducted
in Europe and the other in Asia. Lau et al.36 similarly found a
decrease in the signs of recent bleeding with PPI treatment, and
also demonstrated a decreased need for endoscopic therapy.
In addition to acid suppression, treating ulcer etiology is
imperative. This includes managing critical illness, limiting NSAID
use, and treating H. pylori when appropriate. In H. pylori positive
patients, Riemann et al.37 demonstrated that curative triple therapy
with PPI was superior to maintenance therapy with H2RAs.
Sung et al.38 showed that medical therapy should not stand
alone: their study found that patients treated with both endoscopy
and PPI were much less likely to rebleed than patients treated with
PPI alone (1.1% compared with 11.6%). Intravenous administration
of prokinetic agents (i.e., erythromycin or metoclopramide) prior
to esophagogastroduodenoscopy (EGD) in the setting of acute
UGI bleeding also decreases the need for repeat endoscopy.39
Medical treatment of variceal bleeding differs from ulcer
bleeding in that therapeutic agents are different than those used for
prophylaxis. The mainstays of active variceal bleeding pharmaco-
logic treatment are vasoconstrictive and vasoactive drugs. Vaso-
pressin and terlipressin are vasoconstrictive agents that have been
shown to decrease active variceal bleeding. However, these drugs
can have significant side effects including headache, pulmonary
edema, and coronary vasoconstriction.40 Octreotide is the main
vasoactive drug used to treat variceal bleeding. It is a hormone ana-
logue of somatostatin that alters GI hormone signaling, decreases
5/21/2012 8:55:01 PM
 156 ■ Surgery: Evidence-Based Practice
gastric and pancreatic secretions, and alters splanchnic blood flow.
Multiple studies have demonstrated the superior efficacy of oct-
reotide over vasopressin40-42 for stopping active bleeding and pre-
venting rebleeds. It appears, however, that terlipressin is not inferior
to octreotide in the control of variceal hemorrhage.43 Despite this,
no mortality benefit is gained. The recent meta-analysis by Gross
et al.44 found that vasoconstrictive therapy was only 68.7% success-
ful as compared to vasoactive therapy, which was 75.9% successful.
Banding ligation, however, is the most effective therapy and should
be the primary intervention for stopping variceal bleeding.44
The role of transfusion does deserve special mention.
Although restrictive transfusion practices have been shown to
decrease mortality in ICU patients,45 transfusion in the setting of
UGI bleeding has been less well studied. A recent Cochrane review
of red cell transfusion in the setting of UGI bleeding showed that
more deaths and rebleeding occurred in patients receiving trans-
fusions, although the paucity of patients in the included trials did
not allow for the development of any useful conclusions.46
RECOMMENDATIONS
1. PPIs should be preferentially used over H2RAs to reduce
rebleeding episodes after successful endoscopic therapy.
2. Octreotide should be used to slow the rate of variceal bleeding,
until definitive endoscopic therapy can be implemented.
3. Pre-endoscopy PPI therapy should be utilized to downstage the
grade of the lesion in nonvariceal bleeds
4. Intravenous PPI therapy decreases mortality and rebleeding in
nonvariceal UGI bleeds after successful endoscopic therapy.
Strength of Recommendations: 1. A, 2. B, 3. A, 4. A.
3. What is the role of endoscopy in treating, or for prophylaxis
of, UGI bleeds and how successful is it?
Endoscopy is beneficial in UGI bleeds because it can be simulta-
neously diagnostic and therapeutic, particularly in patients with
no prior history of bleeding. Ulcer bleeding can be stopped or
reduced with medical treatment as previously discussed. Multiple
studies, however, have shown that endoscopy confers further pre-
vention of rebleeding.38,47 Endoscopic findings of active bleeding or
a visible vessel require treatment due to their high rates of rebleed-
ing. Ulcers with adherent clots are more controversial: Bini and
Cohen47 directly compared endoscopy with medical treatment in
patients with adherent clots. They found that recurrent bleeding
episodes mean hospital stay, and transfusion requirements were
significantly reduced with endoscopy.
Several methods are available to achieve endoscopic hemo-
stasis, including adrenaline injection, laser, and heater probes. No
significant differences have been found among individual injec-
tion or thermal coagulation therapies.2 Chung et al.48 found that
initial hemostasis was achieved equally by injection and heater
probe. Injection monotherapy, however, has been associated
with higher rates of repeat endoscopy.49 For ulcers with spurting
vessels, combination treatment with injection and heater probe
reduced the rate of surgery from 29.6% to 6.5%. There continue
to be patients who fail endoscopic treatments. Lau et al.50 studied
patients who had undergone successful initial endoscopic treat-
ment and randomized them to surgery or repeat endoscopy if
they rebled. Over one-quarter of patients who were randomized
to have repeat endoscopy still required salvage surgery.50
PMPH_CH17.indd 156
While endoscopy is used solely for the treatment of ulcer dis-
ease, this intervention can be used for both treatment of active
bleeding and prophylaxis for patients with varices. Options for
endoscopic management of varices include injection sclerother-
apy and banding ligation. Both techniques have been used for
the control of acute hemorrhage, but multiple studies have found
that ligation is superior to sclerotherapy.5,51,52 Banding has a lower
rebleeding rate and reduced complications. Stiegmann et al.53 also
showed a higher mortality rate in patients who used sclerotherapy
for the control of hemorrhage. In addition, the recent meta-analysis
by Gross et al.44 demonstrated the superiority of endoscopic band-
ing ligation over medical therapy in the treatment of acute variceal
bleeding. The combination of banding and sclerotherapy has been
evaluated as well. Neither Laine54 nor Saeed55 was able to dem-
onstrate additional benefit to combination therapy, with Saeed’s
study showing an increased complication rate with dual treatment.
Although endoscopic banding is superior for the treatment
of acute variceal bleeding, the role of endoscopy and the optimal
type of treatment for prophylaxis of variceal bleeding remains
controversial. Van Buuren et al.56 found that there was no differ-
ence in the number of episodes of bleeding when sclerotherapy was
compared with cases where no treatment was given. Villanueva
et al.,57 however, found that combination medical therapy was
more successful in preventing variceal bleeding. In addition, other
trials have shown increased mortality rates with sclerotherapy,
and this practice is not recommended.5 Endoscopic banding has
been widely studied for prophylaxis of variceal bleeding. Th is
technique is often compared with medical prophylaxis with
β-blockers alone or in combination with IM. A recent study by
Wang et al.58 found that combined medical (β-blocker plus IM)
and procedural therapies were equally effective for primary pro-
phylaxis. Conversely, Sarin et al.59 showed that banding reduced
the initial bleeding risk from 43% to 15%, as compared to
β-blockers alone. Villanueva et al.60 showed that combined medi-
cal therapy was superior for secondary prophylaxis without an
all cause mortality benefit. Lo et al.61 recently found that band-
ing was better for secondary prevention, but that combined medi-
cal therapy improved overall survival. A meta-analysis by Gluud
et al.62 showed that banding ligation reduced bleeding episodes
as compared to β-blockers without any difference in morality.
RECOMMENDATIONS
1. Endoscopic treatment should be used to stop active hemorrhage
from ulcer disease, as it confers additional prevention of
rebleeding episodes. Injection monotherapy should be
avoided.
2. Endoscopic banding ligation is the treatment of choice for
acute variceal hemorrhage and should be undertaken as soon
as possible.
3. Banding ligation is an effective means of preventing variceal
bleeding and can be used when medical prophylaxis cannot be
tolerated.
Strength of Evidence: 1. A, 2. A, 3. B.
4. What is the role of interventional radiology in treating UGI
bleeds?
Angiography has been established as the primary therapy for
many lower GI bleeds. Its role in UGI bleeding, however, is not
5/21/2012 8:55:01 PM
 Management of Upper GI Bleeding ■ 157

as well defined. Angiography has been used since the 1970s for
control of GI hemorrhage for both diagnosis and therapy.63
Defreyne et al.64 published a study about a series of patients with
GI bleeding treated with angio-embolization, which showed that
patients with an upper GI source had higher rates of rebleeding
and lower success rate when compared to patients with lower GI
sources. Carreira,65 however, showed that embolization was suc-
cessful 90% of the time in a study with predominately UGI bleeds.
Other studies have found similar success rates.66,67 Poultsides
et al.68 recently published an article on a series of patients with
gastroduodenal hemorrhage that underwent embolization with a
94% technical and 51% clinical success rate. Most of these studies
indicate that embolization should be used in patients with massive
ongoing hemorrhage who cannot tolerate surgery due to medical
comorbidities.69
Eriksson et al. recently published a retrospective study of
patients undergoing transcatheter arterial embolization (TAE) or
surgery for patients with recurrent UGI bleeding after endoscopy.
The authors found that despite a higher-risk profi le in the patients
undergoing TAE, the 30-day mortality was lower in the TAE
group (3% vs. 14%), although the results did not reach statistical
significance.70
RECOMMENDATION
Angiography should be used in patients with massive hemorrhage
who are too ill to undergo an operation.
Strength of Recommendation: C.

Clinical Question Summary

Question
1 What is the role of medical therapy
in prevention of UGI bleeds?
2 What is the role of medical therapy
in treating active UGI bleeds?
3 What is the role of endoscopy for
treating or preventing UGI bleeds?
4 What is the role for interventional
radiology in treating UGI bleeds?
Answer Grade References
(1) PPI or H2RA should be used as stress ulcer prophylaxis A 11, 13
in critically ill patients.
(2) Risk of ulcer formation is significantly reduced with A 15, 17, 18
maintenance PPI or H2RA for patients who take
NSAIDs regularly.
(3) In patients taking clopidogrel in the setting of coronary A 16
artery disease, UGI bleeding risk is reduced in patients
taking omeprazole.
(4) β-Blockers can be used safely for primary prophylaxis B 21, 22, 24, 26
of variceal bleeding.
(1) PPI should be preferentially used over H2RAs to reduce A 29, 31-34, 36
bleeding episodes after successful endoscopy.
(2) Octreotide should be used to slow the rate of variceal B 40-42, 44
bleeding until definitive endoscopy is performed.
(1) Endoscopic treatment should be used to stop A 38, 47, 49
active hemorrhage from ulcer disease, as it confers
additional prevention of rebleeding episodes. Injection
monotherapy should be avoided.
(2) Endoscopic banding ligation is the treatment of choice A 5, 44, 51, 52
for acute variceal bleeding and should be undertaken as
soon as possible.
(3) Banding ligation is effective for preventing variceal B 58-61
bleeding and should be used when medical prophylaxis
cannot be tolerated.
(1) Angiography is safe and should be used in patients with C 64, 66, 67
massive UGI bleeding who are too ill to undergo an
operation.

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term experience. Rev Esp Enferm Dig. 1999;91:684-692.
66. Toyoda H, Nakano S, Takeda I, et al. Transcatheter arterial
embolization for massive bleeding from duodenal ulcers not
controlled by endoscopic hemostasis. Endoscopy. 1995;27:304-
307.
67. Park MH, Park GS, Park SW, et al. [Clinical effectiveness of
transcatheter arterial embolization for acute upper and lower
non-variceal gastrointestinal bleeding]. Korean J Gastroenterol.
2005;46:262-268.
68. Poultsides GA, Kim CJ, Orlando R, 3rd, Peros G, Hallisey MJ,
Vignati PV. Angiographic embolization for gastroduodenal
hemorrhage: safety, efficacy, and predictors of outcome. Arch
Surg. 2008;143:457-461.
69. Loff roy R, Guiu B. Role of transcatheter arterial embolization for
massive bleeding from gastroduodenal ulcers. World J Gastroen-
terol. 2009;15:5889-5897.
70. Eriksson LG, Ljungdahl M, Sundbom M, Nyman R. Transcath-
eter arterial embolization versus surgery in the treatment of
upper gastrointestinal bleeding after therapeutic endoscopy fail-
ure. J Vasc Interv Radiol. 2008;19:1413-1418.
5/21/2012 8:55:01 PM
 Commentary on Management of
Upper GI Bleeding
This chapter addresses four important questions in the manage-
ment of upper gastrointestinal (UGI) bleeding. For long a chal-
lenge to surgeons and gastroenterologists alike, the management
of bleeding from the UGI tract begins with determining the
source. This is often a challenge in itself, since patients can present
with hypotension and no obvious source, blood from the rectum,
melena, or the most dramatic hemetemesis (vomiting of blood).
Interrogating the stomach via a nasogastric tube and looking
for blood is usually the first step, concomitant with intravenous
access and resuscitation. When blood is found, UGI endoscopy
is mandatory, as there is no alternative method of distinguishing
variceal, gastric ulcer, duodenal ulcer, gastritits/duodenitis, or the
rarer hemobilia as the source.
Once the source is determined, the following four questions
illustrate the management dilemmas facing the clinician:
1. What is the role of medical therapy in prevention of
UGI bleeds?
2. What is the role of medical therapy in treating active UGI
bleeds?
3. What is the role of endoscopy for treating or preventing UGI
bleeds?
4. What is the role for interventional radiology in treating
UGI bleeds?
What is missing from this chapter is the question “What is
the role of surgery in the management of UGI bleeds?” As this
chapter illustrates, surgery has been relegated to secondary, ter-
tiary, or even quaternary management strategy for UGI bleeding.
Medical management, endoscopic interventions, and even angio-
embolization are currently all thought to have advantages over
surgical interventions in the management of UGI bleeding. Th is
chapter highlights the literature supporting this radical change
in management strategy. Surgical textbooks from the end of
the 20th century routinely advised surgical approach to GI
bleeding if greater than 6 units of blood transfusion were
required.While this chapter succinctly outlines new therapies
to control hemorrhage (drugs, endoscopy, angio-embolization),
the adage that mortality increases with increasing requirement
of blood transfusion still holds, as evidenced by the Cochrane
review.1 Th is is common sense. However, at what point in an
extended trial of repeated endoscopies or medical management
is the surgeon called? The answer to this question, in the early
part of the 21st century, is often “too late.” It often appears that
160
PMPH_CH17.indd 160
Gregory J. Jurkovich
calling the surgeon is seen as a sign of defeat, rather than an
acknowledgment that a stitch in a bleeding vessel might be a
wise option.
With less experience in the surgical management of acute
GI bleeding, and the undeniable frequent success noted in this
chapter with medical management and endoscopic control of
bleeding, many surgeons are inexperienced or unskilled in the
surgical approach to GI bleeding. Th is can lead to further delays
in surgical management, more blood loss and transfusions, and
a self-fulfi lling worse outcome for surgical therapy. The key
question for surgeons is when to intervene. When medications,
endoscopic coagulation, or angio-embolization fail to stop the
bleeding, what is the surgical approach? When is an operation
indicated? What is the operation of choice for the variety of
causes of GI bleeding? These questions go well beyond the content
of this chapter, as there are perhaps as many surgical technical
options for the management of GI bleeding as there are alterna-
tive therapies. Nonetheless, the single defi ning concept should be
clear: stop the bleeding. That is the fundamental key to the man-
agement of GI bleeding. Resuscitation strategies should focus on
an earlier and more balanced use of red blood cells, plasma, and
platelet transfusions and a relatively more restricted use of crys-
talloids. Although this approach has been considered beneficial
primarily in the context of traumatic hemorrhage requiring mas-
sive resuscitation, it seems applicable to patients with GI bleed-
ing who also require multiple units of packed red blood cells. It
is particularly important to correct measured coagulopathy and
thrombocytopenia.2,3
Although surgical therapy is generally reserved for patients
with life-threatening hemorrhage who have failed the manage-
ment options highlighted in this chapter, perhaps the great-
est challenge is the timely, early identification of those patients
who require surgical therapy. Recognizing this select group of
patients prior to inflicting delays will avoid unnecessary blood
transfusion, prolonged hemodynamic instability, and the subse-
quent risk of complications. The historical surgical recommen-
dations (shock, >6 units of blood transfused) reflected a concern
and respect for the severity and temporal sequence of shock, but
they are also currently supported by a concern for the deleteri-
ous immunosuppressive effects of blood transfusions. Balancing
this long-held surgical adage is the new recognition that bleed-
ing from peptic ulcer disease can be effectively and efficiently
controlled by endoscopic techniques, including retreatment
5/21/2012 8:55:01 PM

after initial control of bleeding, which has shown to decrease
the need for surgery and results in fewer complications than
surgical management, even in the presence of large volumes of
blood transfusion.4
Surgical management retains a role for the giant duodenal
or gastric ulcer, the posterior penetrating duodenal ulcer into
the gastroduodenal artery, the failed recurrent bleeding peptic
ulcer of any location and size, and, rarely, diff use stress or drug-
induced gastritis. Not included in this discussion is the role of
surgery for GI tract tumors and malignancy. The management of
bleeding esophageal varices has almost entirely been relegated to
endoscopic control and/or endovascular TIPS (transjugular intra-
hepatic portosystemic shunt), although the rare patient—and
perhaps even rarer surgeons—could be identified for acute portal
decompression via surgical methods.5
In all cases, multiple factors including the source of hemor-
rhage, the appearance of the bleeding site at the time of endoscopy,
and patient comorbidities must be considered. The decision to
proceed with medications, endoscopy, angio-embolization,
or surgery ultimately depends on clinical judgment, but surgical
PMPH_CH17.indd 161
Management of Upper GI Bleeding ■ 161
options remain important tools in the management of GI
bleeding.
REFERENCES
1. Jairath V, Hearnshaw S, Brunskill SJ, et al. Red cell transfusion for
the management of upper gastrointestinal haemorrhage. Cochrane
Database Syst Rev. 2010:CD006613.
2. Kwok A, Faigel DO. Management of anticoagulation before
and after gastrointestinal endoscopy. Am J Gastroenterol. 2009;
104(12):3085-3097; quiz 3098.
3. Anderson MA, Ben-Menachem T, Gan SI, et al. Management of
antithrombotic agents for endoscopic procedures. Gastrointest
Endosc. 2009;70(6):1060-1070.
4. Lau JY, Sung JJ, Lam YH, et al. Endoscopic retreatment compared
with surgery in patients with recurrent bleeding after initial endo-
scopic control of bleeding ulcers. N Engl J Med. 1999;340:751-756.
5. Henderson JM. Surgery versus transjugular intrahepatic portal
systemic shunt in the treatment of severe variceal bleeding. Clin
Liver Dis. 2006;10(3):599-612.
5/21/2012 8:55:01 PM
PMPH_CH17.indd 162 5/21/2012 8:55:01 PM
 PART 111

SMALL BOWEL

PMPH_CH18.indd 163 5/21/2012 8:55:43 PM

PMPH_CH18.indd 164 5/21/2012 8:55:43 PM

CHAPTER
Small1Bowel
James H. Lee, John J. Hong, Dale Dangleben, and
POSTOPERATIVE ILEUS
The historical definition of ileus is the functional inhibition of
propulsive bowel activity irrespective of cause. Postoperative
ileus (POI) is an uncomplicated ileus which occurs following sur-
gery, and generally resolves spontaneously in approximately 2 to
3 days. A paralytic POI is any POI lasting longer than 3 days.1
POI increases hospital length of stay (LOS) by hindering patient
mobility, delaying enteral feeding, and contributing to postopera-
tive patient discomfort.2
The extent and duration of POI in patients undergoing elective
abdominal surgery was examined by Artinyan et al.3 The median
duration of POI was 5 days, with the duration of POI 10 days or
less in 96.6% of the 88 patients in the study. Variables such as age,
body mass index, anesthesia time, surgery time, estimated blood
loss (EBL), and total opioid dose were analyzed to determine the
presence of a correlation between duration of POI and any of the
aforementioned factors. The only statistically significant factors
that were independently associated with duration of POI were EBL
and total opioid dose. The initiation of unrestricted clear liquids
took a mean number of 1.6 days, with 22.7% of patients tolerating
a solid diet by the 6th postoperative day.3
POI features the impairment of gastrointestinal motility after
abdominal, or other surgical procedures, leading to the accumu-
lation of gas and fluids in the bowel, with the resultant delay in
defecation and passage of flatus.4 Patients can present in variable
ways; some patients are essentially asymptomatic, whereas others
present with absent bowel sounds, diet intolerance, nausea and
vomiting, and abdominal pain and distention. All portions of
the gastrointestinal tract are affected by POI, with the recovery
of each occurring at different rates. Typically, return of function
of the small intestine is seen within 4 to 24 h after surgery, fol-
lowed by the stomach in 24 to 48 h, and ends with the return of
large intestine function within 48 to 72 h.5
Several physiologic mechanisms control gastrointestinal
motility. These mechanisms include the autonomic nervous system,
inflammation, GI hormones, acid/base status, electrolyte imbal-
ances, and various other metabolic disturbances. These factors
165
PMPH_CH18.indd 165
CHAPTER 18
Surgery
Michael M. Badellino
can be altered by surgery and anesthetic agents, including opioid
medications, to effect bowel motility.6
The diagnosis of POI cannot be defi nitively excluded or con-
fi rmed by any diagnostic test. Abdominal radiographs may dem-
onstrate nonspecific dilated loops of small and large bowels. The
utilization of upper GI series and abdominal computerized axial
tomography (CAT) scans may be required to differentiate an
ileus from a bowel obstruction. The recognition of POI is based
on the usual signs and symptoms in the proper postoperative
setting.
Typically the resolution of POI is marked with the passage
of flatus or defecation. The return of bowel sounds, decreasing
amounts of bile in the nasogastric tube (NGT) drainage, decrease
in NGT output, and the tolerance of oral intake are other mea-
sures that can demonstrate the resolution of POI.
1. Are there other agents and/or techniques that can be used to
improve the duration of POI?
A variety of management approaches can be utilized to reduce the
prevalence of POI. Minimally invasive surgical techniques, such
as laparoscopy, have been shown to have advantages over tradi-
tional open procedures. These include improved cosmesis, faster
recovery, fewer surgery-related complications such as adhesions
or hernias, diminished pain, shorter LOS, and faster resolution
of POI. A reduced duration of POI and an associated reduction in
LOS has been documented in a number of controlled studies. Lacy-
randomized patients with colon cancer to either laparoscopic-
assisted colectomy or open colectomy. Patients randomized to
the laparoscopic group had a quicker time to oral intake, lower
requirement for NGT insertion, and a quicker mean time to recov-
ery of POI (36 h) compared with the open group (55 h). The lap-
aroscopic group also had a shorter mean LOS (5.2 days) than the
open group (7.9 days).7 Salimath et al. performed a retrospective
review of all consecutive patients who underwent either laparo-
scopic-assisted colectomy or open colectomy. Out of 247 patients,
the laparoscopic group had an earlier first passage of flatus
(2.9 days), an earlier first bowel movement (3.7 days), and a shorter
5/21/2012 8:55:43 PM
 166 ■ Surgery: Evidence-Based Practice
LOS (4.4 days) compared with the open group (first passage of
flatus 3.6 days; first bowel movement 4.4 days; LOS 8 days).8
The profound impact that opioid analgesia has on GI motility
and length of POI is well established.9 The gastrointestinal effects
of opioids are observed with systemic opioid administration with
intravenous patient controlled analgesia, intramuscular opioid
injection, or epidural opioid administration.10 An improved affect
of epidural local anesthetics on the duration of POI was demon-
strated by a literature review encompassing multiple studies.11
Epidural local anesthetics reduced the duration of POI by 36 h
when compared with systemic opioids and by 24 h when com-
pared with epidural opioids in a recent review.12 No statistical
difference exists when comparing epidural local anesthetic with
epidural combination local and opioid.
Numerous methods have been implemented to decrease opioid
usage in providing analgesia, based on the information that opi-
oids inhibit GI motility and prolong POI. The use of nonsteroidal
anti-inflammatory (NSAID) medications is the most-established
technique of opioid-sparing analgesia. The administration of
NSAIDs results in a shortening of POI, improved GI motility, and
less postoperative nausea and vomiting in experimental and clini-
cal studies.13,14
Despite popular belief, use of the NGT may potentially exacer-
bate POI.15 Complications such as pharyngitis, maxillary sinusitis,
and rhinitis may result from prolonged NGT usage. The current
recommendation is routine NGT removal after surgery to help
avoid the complications associated with prolonged NGT usage.16
Postoperative NGT use was shown to be a major risk factor for
pulmonary complications, including atelectasis, pneumonia, or
respiratory failure requiring mechanical ventilation in a study
of 1055 patients undergoing nonthoracic surgery by McAlister
et al.17 An odds ratio of 7.7 in causing pulmonary complications is
seen with the perioperative use of an NGT. Nelson et al. showed
that the use of an NGT delayed the return of bowel function in
abdominal operations of any type in a recent meta-analysis.18 This
review encompassed 28 studies and fulfi lled the eligibility criteria
of patients having abdominal operations of any type, emergency or
elective. The patients were randomized before completion of the
operation for selective NGT use with early removal or to receive
an NGT and have it remain in place until intestinal function had
returned. The data showed an earlier return of bowel function in
postsurgical patients not having an NGT routinely inserted.
Early resumption of enteral feedings have now been shown
to be safe and beneficial for the patient, allowing earlier tolerance
of a solid diet and return of bowel function.19 Han-Guerts et al.
conducted a randomized prospective study using 128 patients
undergoing open abdominal colorectal or vascular procedures.
Patients were assigned to either a conventional return to regular
diet group or a group that resumed a diet as soon as tolerated. A
shortened LOS was observed in the “as tolerated” group because
a normal diet was tolerated after a median of 2 days compared
with 5 days in the conventional group. An earlier passage of fla-
tus, a bowel movement of approximately 1 day sooner, the ability
to tolerate a regular diet 3 days earlier, and a hospital discharge 2
days before controls was seen in patients started on clear liquids
4 h after elective colorectal surgery in a prospective randomized
study by Stewart et al.20
Recommendation: Earlier resolution of POI and decreased
hospital LOS is associated with minimally invasive surgical tech-
niques, the use of local epidural anesthetic anesthesia, avoidance
PMPH_CH18.indd 166
of NGT usage and early enteral feedings. When these strategies
are utilized in patients after surgery, they lead to a faster recovery
time from POI and as a result a clinically significant shortened
hospital LOS. (Grade A recommendation)
2. Does chewing gum shorten the duration of POI?
Asao et al., based on the evidence that early enteral feedings
lessened the extent of POI, examined an alternative approach
of using gum chewing to stimulate bowel function in the post-
operative period. It is postulated that gum increases vagal tone
and increases the release of GI hormones associated with bowel
motility. In this small series of 19 patients who underwent lap-
aroscopic colon resection for cancer, an earlier return of bowel
function was seen in patients prospectively randomized to the
gum-chewing group compared with controls. The gum-chewing
group experienced passage of flatus about 24 h sooner and first
defecation approximately 2.7 days earlier than controls.21 A meta-
analysis and systematic review of the literature conducted by
Chan showed that when combined with usual postoperative care,
surgical patients randomized to gum chewing passed flatus 24.3%
earlier, had bowel movements 32.7% sooner, and were discharged
from the hospital 17.6% faster than those with standard postop-
erative care alone.22
Recommendation: Gum chewing shortens the duration of
POI and may be utilized in postoperative patients, according to
prospective studies in the colorectal literature. Although statisti-
cally significant, the reduction in time to return of bowel func-
tion is not necessarily clinically meaningful. Conversely, the use
of chewing gum does not appear to have any associated morbidity.
(Grade C recommendation)
3. Does the use of selective opiate receptor inhibitors decrease
duration of POI?
A novel approach for the management of POI recently has been
the development of a selective opioid receptor antagonist. The
μ, κ, and δ opioid receptor subtypes are involved in the regula-
tion of GI tract function.23 The most important subtype involved
in GI motility, transit time, and central pain management is the
μ receptor.24 Alvimopan (Entereg) is a synthetic, peripherally act-
ing μ opioid antagonist with limited GI absorption that does not
cross the blood–brain barrier.25 The use of alvimopan to acceler-
ate GI recovery in the management of POI has been supported by
clinical trials. Alvimopan 6 mg shortened the length of POI as
measured by the median time to first flatus which decreased from
70 to 49 h, median time to fi rst bowel movement which decreased
from 111 to 70 h, and median time until readiness to hospital dis-
charge which decreased from 91 to 68 h compared with placebo in
the first published study of 78 patients undergoing partial colec-
tomy or total abdominal hysterectomy.28
Wolff et al. prospectively randomized 500 patients undergo-
ing bowel resection or radical hysterectomy to receive either alvi-
mopan or placebo. They found an improved time to GI recovery by
15 to 20 h following alvimopan 6 mg and by 22 to 28 h following
alvimopan 12 mg. The mean time to hospital discharge was 13 h
sooner for the alvimopan 6 mg group and 20 h sooner for the alvi-
mopan 12 mg group.27 Delaney also observed an earlier return
of bowel function in patients given postoperative alvimopan in
a study of approximately 400 patients undergoing bowel resec-
tion, simple hysterectomy, or radical hysterectomy. The mean
5/21/2012 8:55:43 PM

return of GI function for all patients was improved by 14.1 h
after doses of Alvimopan 6 mg and by 7.5 hours after Alvimo-
pan 12 mg. Patients given Alvimopan 6 mg were discharged from
the hospital a mean of 14 h earlier when compared with patients
given placebo.28 Viscusi found GI recovery, as measured by toler-
ance of solid diet, passage of flatus, and defecation, accelerated by
7.5 h for patients given 6 mg alvimopan versus 9.9 h for patients
given alvimopan 12 mg dose in approximately 600 patients who
underwent open laparotomy for bowel resection, simple hysterec-
tomy, or radical hysterectomy. The mean time to discharge order
was reduced by 14.2 h for the 6 mg dose and by 15.2 h for the
12 mg dose.29 No differences between placebo and alvimopan
were observed in regards to postoperative opioid consumption
and POI related morbidity as shown by a higher postoperative
NGT insertion, increased LOS, or readmission rate in these tri-
als. Using pooled data from alvimopan trials, Wolff et al. showed
that overall POI morbidity is lower in groups treated with alvi-
mopan (6.6–11.2%) versus placebo (14.1–19.7%).30 Two percent of
patients in the alvimopan groups complications of POI resulting
in increased LOS compared with approximately 7% of patients in
the placebo groups. Furthermore, patients treated with alvimopan
are less likely to undergo readmission (4.9% alvimopan, 8.3% pla-
cebo) for POI complications at 10 days, whereas those readmitted
at 7 days were comparable between groups.30
Recommendation: Although sponsored by the manufacturer,
prospective randomized studies demonstrate improvement in the
duration of POI and hospital LOS with the use of alvimopan, a
selective opiate receptor inhibitor. These differences, while statis-
tically significant, do not consistently translate into clinical rel-
evance. Data on cost effectiveness of alvimopan are needed prior
to adopting its use. (Grade C recommendation)
INTRAABDOMINAL ADHESIONS
The most frequent complication of abdominal surgery is intraab-
dominal adhesions which develop in over 93% of patients undergo-
ing laparotomy. 31 In patients operated on once for adhesive small
bowel obstruction (ASBO), the cumulative recurrence rate and
need for hospital admission for ASBO is 18% and 29% at 10 years
and 30 years, respectively.32
The peritoneal cavity is a closed sac in males or an open sac
through the gynecological tract in females that lies in the space
between the visceral and parietal peritoneum. The peritoneum
consists of a connective tissue layer covered by a mesothelium.
The peritoneal cavity contains approximately 10 mL of serous fluid
under normal conditions. This fluid circulates within the abdomi-
nal cavity through well-defined routes and joins with the vascular
system via the lymphatics.
Peritoneal trauma and inflammation leads to in a decrease
of blood flow and local angiogenesis which then results in the
formation of intraabdominal adhesions.33 Vascular permeability
increases and inflammatory cells are released. A fibrin gel then
forms from actived fibrinogen at the site of peritoneal injury
which acts to connect the two damaged layers of peritoneum. A
fibrinolytic process is then initiated by plasmin, an active protease
formed by the action of plasminogen activators on its precursor,
plasminogen, that attempts to control fibrin formation by hydro-
lyzing fibrin to fibrin split products. The theory of adhesion for-
mation is a pathologic alteration in fibrinolysis resulting from a
PMPH_CH18.indd 167
Small Bowel Surgery ■ 167
decrease in the plasminogen activator activity, largely mediated
through tissue plasminogen activator.34 The regeneration pro-
cess leads to the organization of non degraded fibrin matrix and
causes the apposition of two damaged peritoneal surfaces result-
ing in adhesion development.35 Inflammatory cells such as mac-
rophages, mast cells, fibroblasts, eosinophils, red blood cells, and
tissue debris are contained in adhesions. Adhesions mature into
fibrous collagen bands covered by mesothelium with decreasing
amounts of cells.
Small bowel obstruction (SBO) is the most frequently encoun-
tered clinical manifestation of abdominal adhesions, with 74%
of cases being related to previous surgery.36 A mortality rate of
almost 10% has been identified in reviews of hospital admissions
for adhesional SBO,37 which increases to approximately 15% in
patients undergoing small bowel resection.38 There is a 33% risk of
inadvertent enterotomy when surgery is required for adhesional
SBO and a 19% risk of inadvertent enterotomy with the pres-
ence of adhesions during a reoperative laparotomy.39 Adhesions
from previous surgery significantly increased operative time by a
median time of 18 min, in a study that examined effects of previ-
ous surgery on operative times.40 The mortality rate ranges from
20% to 50% in patients who have an undetected bowel injury after
undergoing operation for adhesional SBO.41 Although adhesions
reform in approximately 85% of patients, adhesiolysis remains the
treatment for adhesions.42
4. Are there any techniques/agents that have been shown to
decrease intraabdominal adhesion formation following lapa-
rotomy?
A variety of technical methods have been employed in an attempt
to minimize postoperative abdominal adhesion formation. Com-
pared with other means of transection, sharp mechanical transec-
tion of tissue is followed by the least amount of tissue reaction
and necrosis in one study.43 Peritoneal inflammation results from
the presence of foreign material or debris that may arise from
gauze, sponges, starch powder, suture, surgical drapes, gowns,
masks, and many other items that are found in postoperative
adhesions, inferring a causal relationship between the forma-
tion of adhesions and the presence of foreign material.44 In a
prospective study by Tulandi et al. analyzing patients undergo-
ing laparotomy for gynecological procedures, peritoneal closure
offered no benefit in reducing postoperative adhesion forma-
tion. A comparison between the incidence of adhesion formation
between patients with separate closure of the peritoneum and
fascia to patients with closure of the fascia only was made. No
statistical difference was seen in the incidence of adhesion forma-
tion in patients with peritoneal closure (22.2%) and those without
peritoneal closure (15.8%).45 Another prospective study random-
ized patients to a separate layer closure of the peritoneum ver-
sus a single layer closure of the fascia. There was no difference in
wound complications including infection, incisional hernia, or
dehiscence between the two groups.46 Nonclosure of the perito-
neum reduces operative time and is safer, allowing the underlying
viscera to remain under direct visualization during closure.
A lower rate of postoperative adhesions is observed in studies
evaluating laparoscopic to open surgery. Polymeneas et al. found
that 100% of all open cholecystectomy patients had thick and exten-
sive adhesions to the operative site compared with a rate of 44%
of loose, easily separable adhesions between the gallbladder liver
5/21/2012 8:55:43 PM
 168 ■ Surgery: Evidence-Based Practice
bed and omentum or duodenum after laparoscopic cholecystec-
tomy.47 One hundred and twenty-five patients with different prior
laparoscopic procedures were compared with 131 patients with
previous horizontal suprapubic laparotomy and 89 patients
with previous midline laparotomy in a study conducted by Aude-
bert et al. The rates of umbilical adhesions were highest in those
with a midline laparotomy (51.7%), were intermediate in those with
horizontal suprapubic laparotomy (19.8%), and lowest in those
after laparoscopy (1.6%).48 Studies show that fewer adhesions form
between the incision and the operative site with a laparoscopic
approach. Research has also demonstrated a lower rate of refor-
mation of adhesions after laparoscopic adhesiolysis.49 Milingos
et al. assessed adhesion reformation as a secondary endpoint in
his clinical study regarding pregnancy rates after open micro-
surgical and laparoscopic adhesiolysis for periadnexal adhesions.
Initial adhesion scores were calculated and compared with adhe-
sion scores obtained on the same patients after open adhesiolysis
through laparotomy or laparoscopic adhesiolysis. Although scores
were similar before adhesiolysis, there was a greater reduction in
the adhesion scores in the laparoscopic group on second-look lap-
aroscopy performed 3 to 6 months after the operation compared
with the group that underwent laparotomy.50
NSAIDs and corticosteroids have shown an ability to reduce
postoperative adhesions in animal models and a correlation has
been sought with human subjects.51-55 Other studies have exam-
ined agents that may interfere with the pathways of fibrin degra-
dation and deposition. Anticoagulants such as heparin and low
molecular weight heparins (LMWH) have also demonstrated a
decrease in adhesion formation in animal studies.56,57 Recombi-
nant tissue plasminogen activator, a fibrinolytic agent, has also
showed promise in animal models in reduction of postoperative
adhesions.58-60 Unfortunately, similar results in human investi-
gations is lacking and the majority of studies that have reported
success in using these various agents to prevent postoperative
adhesions are limited to animals.
The premise of barrier devices is to provide protection from
adhesion formation by separating the layers of the peritoneum.
An ideal barrier device should provide unrestricted coverage of
the affected peritoneum, be easily applied by both laparoscopic
and open surgical methods, and remain effective throughout the
healing process.61 Various forms of barriers have been developed,
which include solid membranes and polymer solutions of polysac-
charides such as cellulose, dextran, hyaluronic acid, and chitosan.
Viscous gels may form when these solutions are applied at the
end of the procedure. Membranes are placed directly on poten-
tial sites of adhesions. FDA-approved barriers currently include
hyaluronic acid-carboxymethylcellulose (Seprafi lm®), polylac-
tide membrane (Surgiwrap®), regenerated cellulose (Interceed®),
expanded polytetrafluoroethylene (Preclude®), and icodextrin
solution (Adept®). Seprafilm® was designed as a nontoxic, nonim-
munogenic, biocompatible material that reduces postoperative
abdominal adhesion formation by forming a hydrophilic gel that
provides a protective coating around traumatized tissues for up to
7 days during remesothelialization approximately 24 h after place-
ment. A recent meta-analysis of eight randomized controlled tri-
als, studied the efficacy of Seprafi lm® in 4203 patients. Adhesions
were classified as grade 0: no adhesions; grade 1: least severe and
filmy, avascular, and translucent; grade 2: moderately severe and
medium thickness and limited vascularity; and grade 3: very
severe and dense and highly vascularized. There was a statistically
PMPH_CH18.indd 168
higher incidence of grade 0 adhesions in patients treated with
Seprafi lm® compared with controls. The severity of grade 2 and 3
adhesions among Seprafi lm®-treated patients was also signifi-
cantly less than observed for the control group. The incidence
of grade 1 adhesions was statistically insignificant between Sep-
rafi lm® and control groups. According to this meta-analysis,
Seprafi lm® decreases abdominal adhesions following surgery.62
However, there are studies that demonstrate no difference in the
overall incidence of postoperative SBO between patients treated
with Seprafim® and controls.63 Although not statistically signifi-
cant, there is a slightly higher frequency of abdominal abscesses
and a more frequent incidence of fistulas, sepsis, and peritonitis
with the use of Seprafim® compared with controls (2% vs. <1%)
and a higher frequency of anastomotic leaks (4% vs. 2%) when
wrapped around a fresh anastomosis.64
Recommendation: A variety of methods have been utilized
to decrease the formation of postoperative abdominal adhe-
sions. These include sharp dissection and minimization of tissue
trauma, the reduction of foreign body contamination within the
surgical field, and the application of minimally invasive surgical
techniques when indicated. Although the use of barriers between
the peritoneal layers has shown a decreased incidence and severity
of postoperative abdominal adhesions, there has been no impact
on the rate of postoperative SBO. (Grade A recommendation)
ADHESIONAL SBO
With clinical evidence of strangulation, patients with adhesional
SBO may require immediate operative intervention to minimize
the risk of necrotic bowel and perforation.65 A trial of nonopera-
tive management is acceptable for patients without this clinical
picture.66 The conventional approach allows 48 h of nonoperative
management as the majority of adhesional SBO resolve during
this time period.67
5. Is the early use of water-soluble contrast indicated in the
diagnosis/management of SBO?
Recently, the role of water-soluble contrast medium in predict-
ing the need for surgery after the failure of conservative man-
agement in the setting of adhesive small bowel obstruction has
been evaluated. The most commonly used water-soluble contrast
agent is meglumine amidotrizoate (Gastrografin®) is which has an
osmolarity of 1900 mosm/L and is a mixture of sodium diatri-
zoate and meglumine diatrizoate. Bowel wall edema contributes
to proximal bowel distention and increases the pressure gradient
across an obstructing region. Gastrografin® causes water to enter
the bowel lumen thereby decreasing bowel wall edema through
the process of osmosis.68
The use of Gastrografin® has been studied for its possible ther-
apeutic function in the resolution of SBO and its potential ability to
predict successful nonoperative management of SBO. Abbas et al.
conducted a recent meta-analysis to investigate the diagnostic
use of Gastrografin® in determining the successful conservative
management of SBO. Patients with SBO without indications for
immediate surgery were evaluated with 100 mL of Gastrografin®,
orally or by NGT, and followed by abdominal imaging in 4 to
24 h. A partial SBO was indicated by the presence of contrast in
the colon which indicated a higher probability of resolution with
5/21/2012 8:55:43 PM

conservative management. On the other hand, a complete SBO is
signified when contrast does not reach the colon and is unlikely to
resolve without surgical intervention. There were six prospective
randomized studies that addressed whether Gastrografin® has a
therapeutic role in the treatment of SBO. In patients who would
require surgery, there was no observed difference in resolution of
SBO in patients treated with Gastrografin® versus placebo. Based
on the meta-analysis, Gastrografin® is useful in the prediction of
successful conservative management of SBO but has no therapeu-
tic benefit in patients with SBO.
Recommendation: Water-soluble contrast agents such as Gas-
trografin® have been able to predict successful conservative man-
agement in patients with SBO without clinical indications for
operation. However treatment with Gastrografin® has not been
shown to reduce the need for surgical intervention in patients
with postoperative SBO. (Grade A recommendation)
6. Can computed tomography (CT) predict the need for opera-
tion in patients with incomplete SBO?
The diagnosis of SBO can be made on plain abdominal radio-
graphs in only 67 to 80% of patients.70 Patients with complete,
closed-loop obstruction or strangulation associated with obstruc-
tion may demonstrate abdominal radiographs that are entirely
normal.71 CT scan is well established in the diagnosis of small
bowel obstruction since the first large published series show-
ing its utility and efficacy.72 Findings indicative of a SBO on CT
include air-fluid levels, collapsed loops distal to distended bowel
loops, and a possible transition point. CT has a sensitivity of
94% to 100% and an accuracy of 90% to 95% in confirming the
diagnosis and revealing the cause of small bowel obstruction.73
Reviews have also shown CT to be highly accurate for diagnos-
ing ischemic bowel with a sensitivity of 83%, specificity of 92%,
positive predictive value of 79%, and a negative predictive value of
93%.74 Potential signs of reversible or early small bowel strangula-
tion on CT include mesenteric edema, engorgement of the mes-
enteric vasculature, slight thickening of the bowel wall, and the
“target sign.” The CT findings of high attenuation of the bowel
wall, pneumatosis, hemorrhagic changes in the mesentery, gas in
the portal vein, and poor or no enhancement portend bowel wall
bowel infarction or gangrene. 85% of patients with strangulated
SBO were correctly identified when investigators used of a com-
bination of five highly specific findings on CT, which included a
large amount of ascites, diff use engorgement of the mesenteric
vasculature or mesenteric haziness, an unusual course of the
mesenteric vasculature, poor enhancement of the bowel wall, and
a serrated beak.75
Recommendation: Specific CT scan findings have the ability
to identify SBO and in conjunction with other specific findings
may diagnose bowel ischemia and allow for surgical interven-
tion. If clinically indicated, patients presenting with SBO should
be evaluated with CT scan of the abdomen following obstruction
series. (Grade A recommendation)
7. Is there any difference between stapled or handsewn tech-
niques for bowel anastomosis?
Handsewn and stapled anastomosis in colon and rectal surgery
were compared in a meta-analysis combining data from 13 ran-
domized controlled trials. No significant differences in wound
infection rate, cancer recurrence rate, mortality, or total, clinical,
PMPH_CH18.indd 169
Small Bowel Surgery ■ 169
and radiological leak rates between handsewn and stapled tech-
niques. However, there was a statistically higher rate of strictures
and intraoperative technical problems with a stapled anastomo-
sis.76 The increased stricture rate with stapled anastomoses may
result from higher collagen levels and an overactive inflammatory
response.77
Recommendation: Prospective randomized trials have shown
no differences between handsewn and stapled anastomoses in
regards to wound infection, leak rate, mortality, and cancer
recurrence. However, the rate of postoperative stricture forma-
tion may be higher with stapled anastamoses. The type of anas-
tomosis that is performed, whether handsewn or stapled, should
be based on the surgeon’s comfortability and preference. (Grade A
recommendation)
8. Are there any techniques to predict outcome of a small bowel
anastomosis (i.e. flourescein, doppler, surface oximetry)?
There has been interest in investigating the usefulness of floures-
cein, doppler, and even surface oximetry measurements for the
intraoperative determination of small bowel viability dating
back to 1980. Bulkley et al. conducted a prospective, controlled
trial comparing Doppler and fluoroscein techniques with stan-
dard clinical judgement in the intraoperative determination of
small intestinal viability following acute intestinal ischemic dis-
ease.78 Seventy-one ischemic bowel segments were independently
assessed with doppler, fluoroscein, and clinical judgement 15 min
after surgical correction of the underlying lesion in 28 consecutive
patients operated on for acute intestinal ischemia. The resected
segments were evaluated by a pathologist, “blinded” with respect
to specific viability assessment technique, in areas with the great-
est concern for viability as indicated by any of the three assessment
techniques. A sensitivity of 100%, specificity of 100%, predictive
value of 100%, and overall accuracy of 100% was observed in the
assessment of viability of determinant segments with the fluores-
cein method. The differences, favoring the fluorescein method,
in specificity, predictive value, and overall accuracy were all sta-
tistically significant when compared with the Doppler method.
Although the overall accuracy of standard clinical judgment was
relatively high at 89%, the predictive value was relatively low at
64%. Although not statistically significant, the Doppler method
was less reliable than clinical judgment in the assessment of small
intestinal viability.
Locke et al. conducted a study on 11 mongrel dogs to evalu-
ate the utility of surface oximetry to assess bowel viability.79 A
baseline surface oxygen tension tension (Pso2) was determined
through the placement of miniaturized oxygen electrodes placed
on stomach serosa and several sites along the antimesenteric bor-
der of small intestine. The small intestine was then sequentially
devascularized to a specific Pso2. Both high and low Pso2 anasto-
moses were performed on each dog with reexploration 48 h after
the first operation. The researchers found that all anastomoses
healed when Pso2 exceeded 50% of the initial normal value, that
1/3 of anastomoses leaked when Pso2 ranged from 30% to 50%
of the initial value, and that anastomoses necrosed when created
with Pso2 below 30% predevascularization. However, in a recent
similar investigation in rats by Posma et al. blood flow was signifi-
cantly decreased to even less that 10% of baseline as measured by
near-infrared spectroscopy but had no significant effect on anas-
tomotic wound strength.78
5/21/2012 8:55:44 PM
 170 ■ Surgery: Evidence-Based Practice

Although there are numerous techniques that have been
implemented for the intraoperative determination of small bowel
viability, there have been no reported studies to date using these
techniques to predict small bowel anastomotic failure in humans.
Recommendation: There is currently a lack of literature
regarding the use of techniques such as fluorescein, Doppler, and
surface oxygen tension to predict the probability of anastomotic
failure in human populations. Fluorescein has been shown to be a
useful adjunct in the determination of intestinal viability, whereas
Doppler flowmeter appears to add little to clinical judgement of
intestinal viability. (Grade C recommendation)
9. Are there any predictors of ischemia in patients with partial
SBO?
There are a multitude of studies regarding the use of CT scan
to predict the need for an operation to prevent strangulation in
patients with PSBO. There are no published prospective studies
to date that identify clinical features or CT scan findings that pre-
dict small bowel ischemia alone in patients with PSBO. Although
indicators such as leukocytosis, fever, tachycardia, focal tender-
ness, and elevated lactate levels suggest the intestinal ischemia,
they are not very specific.80 However, it is useful to identify the
factors associated with strangulating obstruction. Zielinski et al.
performed a recent retrospective review in 100 consecutive SBO
patients treated both operatively and nonoperatively to identify pre-
operative risk factors associated with strangulating SBO.81 The
clinical findings of vomiting, absence of “small bowel feces sign,”
mesenteric edema, and free intraperitoneal fluid were signifi-
cantly associated with the need for operative intervention on mul-
tivariate analysis. Mesenteric edema and free intraperitoneal fluid
increased the risk of the need for operative intervention by 3.6-
and 3.8-fold, respectively. Patients with “small bowel feces sign”
were 5-fold less likely to require operation whereas patients with
vomiting were 4.7 times more likely to require operation. When
patients presented with all of these clinical features they were 16
times more likely to require operation.
Recommendation: There are currently no reliable clinical or
radiographic indicators that predict ischemia in patients with PSBO.
The creation of a multivariate model incorporating laboratory stud-
ies, CT findings, and features of the clinical scenario may predict
which patients may need operative intervention to prevent delayed
recognition of infarcted bowel. (Grade C recommendation)

Clinical Question Summary

Question
1 Are there other agents and/or
techniques that can be used to
improve the duration of POI?
2 Does chewing gum shorten the
duration of POI?
3 Does the use of selective opiate
receptor inhibitors decrease duration
of POI?
4 Are there any techniques/agents
that have been shown to decrease
intraabdominal adhesion formation
following laparotomy?
5 Is the early use of water-soluble
contrast indicated in the diagnosis/
management of SBO?
6 Can computer tomography (CT)
predict the need for operation in
patients with incomplete SBO?
7 Is there any difference between stapled
or handsewn techniques for bowel
anstamosis?
8 Are there any techniques to predict
outcome of a small bowel anastomosis
(i.e. flourescein, doppler, surface
oximetry)?
9 Are there any predictors of ischemia in
patients with partial SBO?
Answer Grade References
Minimally invasive surgical techniques, local epidural A 7-20
anesthetics, avoidance of NGT, and early enteric
feedings.
Yes, chewing gum has been shown to decrease length of C 21, 22
POI and LOS, but not to a clinically meaningful degree.
Yes, it has an impact of both the duration of POI, C 23-30
tolerance of solid diet, and LOS, but not to a clinically
meaningful degree. The cost/benefit ratio is unclear.
Sharp dissection, minimizing tissue trauma, decreasing A 43-64
foreign bodies in surgical field, barrier devices.
The use of water-soluble contrast has shown to predict A 69
the success of conservative management, but has not
shown to decrease the need for operation.
CT scan can diagnose SBO and SBO with associated A 70-75
ischemia requiring surgical intervention.
There has been no difference shown between the two, A 76, 77
however, stapled anastomoses have a higher rate of
stricture.
There is currently a lack of literature regarding the C 78, 79
use of techniques such as fluorescein, Doppler, and
surface oxygen tension to predict the probability of
anastomotic failure in human populations.
There are currently no reliable clinical or radiographic C 80, 81
indicators that predict ischemia in patients with PSBO.

PMPH_CH18.indd 170 5/21/2012 8:55:44 PM


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5/21/2012 8:55:44 PM
 Commentary on
Small Bowel Surgery
Ronald M. Stewart
Lee, Hong, Dangleben, and Badellino have written a lucid sum-
mary of the evidence concerning the management of a number of
clinically relevant issues concerning surgery of the small bowel. On
the whole, I agree with their assessment and would commend this
chapter to the practicing surgeon. The authors and their editors
seem to have imposed a measure on the grading scale that is not
listed in the Oxford Centre criteria: criteria of clinical relevance
and cost utility, as they downgrade some evidence based on these
criteria.
1. The authors conclude minimally invasive surgical techniques,
local epidural anesthetics, avoidance of nasogastric tubes, and
early enteric feedings result in a shortened duration of adynamic
ileus. They believe the evidence supporting this deserves a grade
of A. Although this is a broad sweeping number of techniques,
their conclusions are sensible and seem well supported by
modern evidence. These techniques and approaches also are
sensible and plausible; therefore, it seems prudent that we should
adopt these measures to shorten the recovery time following
abdominal procedures.
2. Concerning the question of does chewing gum reduce the
duration of postoperative ileus, the authors conclude that it
does, but not to a clinically significant degree. They give this
evidence a grade of C. Chewing gum is an extremely low-cost
measure that has been shown in at least two randomized trials
to reduce the duration of ileus, so I believe Lee et al. should
have graded the evidence for its use higher. Given the fact that
it is very low cost, very low risk, may reduce the risk of parotitis
and is probably more comfortable for the patient, I would
recommend its use in patients with normal mental status.
3. The authors conclude that postoperative use of selective opiate
antagonists do reduce the duration of ileus and length of stay,
but not to a clinically significant degree. I believe the level
of evidence is higher than a C grade, but share the author’s
skepticism and their concern regarding cost–benefit concerns.
These assessments are broader than the Oxford criteria. It seems
that there is the need for a large scale, nonindustry sponsored
clinical trial for these agents.
173
PMPH_CH18.indd 173
4. Regarding the risk of adhesion formation the authors conclude
sharp dissection, minimizing tissue trauma, decreasing foreign
bodies in surgical field and the use of barrier devices lead to fewer
adhesions, although the extrapolation to reduced risk of small
bowel obstruction is largely lacking. This seems sensible. Although
the authors do not explicitly state this it seems to me that the use
of barriers (hyaluronic acid-carboxymethylcellulose [Seprafilm®],
polylactide membrane [Surgiwrap®], regenerated cellulose
[Interceed®], expanded polytetrafluoroethylene [Preclude®], and
icodextrin solution [Adept®]) should be selectively used based on
the clinical situation.
5. Concerning the use of water-soluble contrast and computed
tomography scan the authors conclude that these options are
helpful in the diagnosis of small bowel obstruction. This fits
with my clinical experience. These two options can be combined
and seem to have significant utility in situations where it is not
clear that there is a complete bowel obstruction.
6. Concerning whether there are any differences between hand
sewn and stapled anastomoses the authors conclude that there is
no difference; however, stapled anastomoses have a higher rate
of stricture. I do not believe that there is a difference between
the two techniques including stricture formation, except the
circular EEA anastomoses, which would hardly ever be used
on the small bowel. I cannot recall ever seeing a stricture from
the side-side stapled anastomoses (functional end-to-end) with
the GIA type staplers. The weight of evidence supports there is
no difference, including stricture formation.
7. There are no reliable techniques to determine the outcome of
a small bowel anastomosis and the authors conclude this in
their review; however, it is known that patients who have shock,
immunocompromise, a systemic inflammatory state or exposed
small bowel have a greater risk of anastomotic failure.
8. The authors conclude there are no reliable predictors of small
bowel ischemia in patients with small bowel obstruction; however,
they cite papers that at least add improved predictive ability for
complete bowel obstruction. I believe traditional clinical findings,
combined with CT scan criteria are helpful at predicting those at
risk for dead bowel or ultimate need for operation.
5/21/2012 8:55:44 PM
 CHAPTER 19

Crohn’s Disease of the

Small Bowel
Thomas Donkar, Andrea Bafford, and Randolph M. Steinhagen

INTRODUCTION usually for complications related to either fibrostenosis (obstruc-

tion) of perforation (abscess/fistula), which occur when the disease
Inflammatory bowel disease (IBD) is comprised of two major becomes refractory to medical therapy. Other intractable symp-
groups of disorders: Crohn’s disease (CD) and ulcerative colitis toms or complications that may lead to surgery include major hem-
(UC). Both are chronic, relapsing inflammatory disorders of the orrhage, failure to thrive, cancer, and extraintestinal symptoms.5,6
gastrointestinal (GI) system, with unclear etiology. CD can affect Typically surgery for small bowel CD involves some combi-
the entire GI tract from mouth to anus, but most commonly affects nation of bowel resection, strictureplasty, or drainage of abscess.
the ileum and the colon.1 It is not uncommon for CD to affect mul-
tiple sites in the intestinal tract simultaneously and in discontin-
uous fashion, that is “skip lesions.” Its incidence and prevalence
INTESTINAL OBSTRUCTION
within the United States is 5/100,000 and 100/100,000, respectively.
Intestinal obstruction is a common complication which is the result
CD is most commonly diagnosed in adolescence and early adult-
of inflammation, fibrosis, thickening of the wall, and narrowing of
hood, but there is also a second peak in age of onset during the
the lumen with resultant stricture formation. Patients present with
fifth and sixth decades of life. CD is more prevalent in certain eth-
abdominal pain, cramping, nausea, vomiting, and abdominal dis-
nic groups, including those with Jewish backgrounds from Europe
tention. While it is possible for the patient to present with acute
and the United States and also in those from Scandanavia, when
obstruction, in most cases obstructive symptoms are chronic and
compared with those from Asia and Africa.2
the patients learn to restrict their diet, lose weight, and often develop
Clinically, patients with CD present with symptoms of abdom-
significant abdominal distension. Acute obstruction can usually be
inal pain, diarrhea, weight loss, fever, or rectal bleeding, depend-
managed nonoperatively with bowel rest and medications designed
ing on the region of the GI tract involved. Patients with CD of the
to reduce the inflammation and edema. Surgery is indicated only if
small bowel typically follow one of the two distinct forms: fibros-
there is a failure to respond or if the clinical picture worsens.5,6
tenotic and perforating disease. The fibrostenotic form results from
Chronic obstruction results from the presence of fibrostenotic
chronic inflammation and produces fibrosis in the bowel wall and
strictures, which restrict passage of intestinal contents but do
narrowing of the lumen, which can lead to bowel obstruction. The
not stop it completely. Crohn’s patients with chronic obstruction
perforating form results from transmural inflammation which can
report an impaired quality of life, are afraid to eat, and frequently
lead to abscess formation and subsequent fistulazation, or rarely,
lose weight. Once the fibrosis becomes established, there is little
free perforation. As there is no definitive cure, treatment of CD is
that medical management can do to reverse it and without surgi-
directed toward symptomatic relief and improving overall qual-
cal intervention these patients can become severely malnourished
ity of life. While medical management is important for induction
and debilitated.5-7
and maintenance of remission and amelioration of symptoms,
surgery, when indicated, has been shown to alleviate symptoms
and improve overall quality of life.3,4 INTRAABDOMINAL ABSCESSES
1. What are the indications for surgery in small bowel CD?
Approximately 10% to 30% of patients affected with CD are expected
CD typically produces a clinical course characterized by remission to develop an intraabdominal abscess during the course of their life-
and exacerbation. Most patients do not require surgery during the time.8 Patients present clinically with fever, generalized malaise, and
first 8 to 10 years of their disease.5 When surgery is indicated, it is abdominal pain. Primary treatment for intraabdominal abscess is

174

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drainage, either percutaneously or operatively, which generally will
result in control of systemic sepsis and allow time for the patient
to be repleated prior to resection of the diseased bowel. Percutane-
ous drainage may serve as a viable alternative to surgical interven-
tion, with success dependent upon abscess complexity and patient
clinical characteristics.9 Gutierrez found no significant difference
between time to abscess resolution when comparing percutaneous
and surgical drainage, and noted that approximately 1/3 of per-
cutaneously drained abscesses needed definitive surgery within
1 year following drainage.10 Garcia reported that percutaneous
drainage was successful about 50% of the time, but concluded that
surgical drainage was superior to both medical management and a
percutaneous approach, with regards to abscess recurrence.11
FISTULA
Fistula formation in CD is common, occurring in approximately
30% of patients. The most common enteric fistula observed is
enteroenteric, between two portions of small intestine. Th is may be
asymptomatic; however, if the communication is very distal in the
intestinal tract, this may result in the bypass of a large segment of
bowel leading to diarrhea and malabsorption, thus requiring sur-
gical intervention. Symptomatic fistulas require resection of the
fistula source, usually with reanastomosis; if the secondary loop
is normal and is just an “innocent bystander” it may be treated by
simple wedge resection and closure. If however, it is also involved
with CD, it also will need to be resected.5,6
Enterocolic fistulas are typically found between ileum and
sigmoid colon. This communication can allow for rapid transit of
enteric contents and thus can cause metabolic abnormalities and a
hypovolemic state, if there is a large amount of diarrhea. Repair of
ileo-sigmoid fistulas involves resection of the involved ileum, and
primary repair or resection of the sigmoid colon.5,6 If CD is evident
in the sigmoid colon, or if the location of the opening precludes safe
primary closure, then a sigmoid resection should be undertaken.12
An enterovesical fistula is a connection between the small
bowel and bladder that typically presents with pneumaturia,
fecaluria, or most characteristically, a urinary tract infection con-
taining multiple organisms. This is treated with surgical resection
of the involved small bowel and closure of the hole in the blad-
der, if it can be identified. Often there is so much inflammation
involving the bladder wall that the opening cannot be accurately
seen. Since the bladder is intrinsically normal, it is important not
to debride the fibrotic, inflamed tissue as reduced bladder capac-
ity may result. Whether the hole is closed or not, an indwelling
urinary catheter should be left in place for 7 to 10 days, with the
expectation that the bladder will heal. To be on the safe side,
cystography may be done prior to removal of the catheter.
Enterocutaneous (EC) fistulas are communications between
the small intestine and the abdominal wall, usually communicat-
ing through the skin at the site of a previous incision. This type of
fistula is most often seen from postoperative anastomotic break-
down or from bowel with recurrent disease. The etiology of the EC
fistula dictates the most effective management strategy. Patients
with EC fistulas secondary to anastomotic breakdown are usually
managed initially nonoperatively. If the fistula fails to heal with
a regimen of bowel rest, total parenteral nutrition and adequate
control of sepsis in a period of about 6 weeks, then resection of
PMPH_CH19.indd 175
Crohn’s Disease of the Small Bowel ■ 175
the involved small bowel is necessary. Closure rates with surgical
intervention are approximately 60% to 80%.13
Medical management has been shown to frequently be effec-
tive, particular in those patients with EC fistula secondary to
recurrent disease. In a randomized clinical trial, Present showed
a closure rate of 55% with use of a 3-dose regiment of infliximab,
an anti-TNFα monoclonal antibody. It should be noted however,
that the best overall success was seen in patients with fistulizing
perianal disease.14 Other nonsurgical approaches include the use
of immunomodulators such as 6-mercaptopurine, which also has
been shown to aid in spontaneous closure; however, recurrence is
common after the medication is discontinued.13,14
FREE PERFORATION
Free perforation is a rare complication of CD and has been reported
at 1% to 3% lifetime risk.6 However, Werbin reported rates as high
as 8%, and concluded that a more conservative approach to therapy
and delayed surgery increases this risk.15 Patients who clinically
present with signs of an acute abdomen, indicative of free perfo-
ration, should be taken emergently for surgery. Resection of the
perforated segment results in a 10-fold reduction in mortality, as
compared with simple closure of the perforated site.16
MALIGNANCY
The annual incidence of small bowel carcinoma in the general
population is small, approximately 2%. Although uncommon in
the Crohn’s population as well, a meta-analysis by Jess estimated
that patients with CD have a 27-fold increase in overall risk for
developing small bowel cancer.17 A literature review by Dossett
showed that patients with CD who develop small bowel adeno-
carcinoma are younger, and more likely male, when compared
with patients without Crohn’s.18 CD patients were also found to
have a poorer prognosis, as the cancer was usually found at a more
advanced stage and was more likely to be poorly differentiated.
Small bowel adenocarcinoma in CD occurs predominantly in the
ileum. The clinical presentation is likely to be obstruction, hemor-
rhage, fistula, or perforation. Unfortunately, the diagnosis is most
often made during postoperative histological examination of the
resected specimen.
FAILED MEDICAL MANAGEMENT
(INTRACTABILITY)
The initial management of CD is medical. Failure of medical man-
agement is defined as uncontrolled symptoms on maximal doses of
medication; disease progression while on maximum medical ther-
apy; significant side effects of the medication; or noncompliance.
2. What is the etiology of CD?
Although no single factor has been identified as the precipitat-
ing insult leading to the development of CD, research has concen-
trated on four main areas: environmental, immunologic, genetic,
and microbiologic.19
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 176 ■ Surgery: Evidence-Based Practice
ENVIRONMENTAL
As documented by Ouyang, the number of cases of CD and UC
continues to rise in once low-incidence areas of Southern Europe
and Asia.19 The new influx of reported cases in these areas has
given rise to the hypothesis of an association between IBD and
social and economic progress. The “hygiene hypothesis” proposes
that the increase in incidence of IBD in these regions is due to
a dramatic change from a “dirty” lifestyle, with high microbial
exposure, to a “clean” lifestyle, with low microbial exposure and
overall improvement in hygiene and sanitation.20 This lifestyle
change is a result of safer food and water, and better access to
antibiotics, vaccines, contributing to fewer infections. Thus, with
deceased microbial exposure so early in life, the body’s immune
system has faced fewer challenges and is less prepared, therefore
setting the stage for a surge in allergic, autoimmune, and chronic
inflammatory diseases.20,21
A meta-analysis by Mahid confirmed that smoking remains
the strongest environmental risk factor for IBD, specifically CD.22
A multicenter Japanese study showed that dietary factors, specifi-
cally an increased consumption of sugars and sweeteners, fats,
fish, and shellfish, have a positive association with an increased
risk of CD.23 Studies of environmental triggers such as adverse live
events, that is, stress-inducing events, have been inconclusive in
showing a direct relationship between stress and IBD.24
MICROBIOLOGIC
Recent studies have determined that the role of infectious agents
in the etiology of IBD is less likely. Newer research has discredited
the proposal that the measles vaccine was a factor in the etiology of
CD. Mycobacterium paratuberculosis has also been shown to be a
noncontributor to CD, as studies of patients who received a 2-year
course of a combination of clarithromycin, rifabutin, and clofaz-
imine antituberculous therapy showed no clinical improvement.25
However, adherent-invasive Escherichia coli has been shown to
colonize the ileal mucosa of CD patients, and has the ability to
adhere to and invade the intestinal epithelial cells.26 Although it is
unclear as to whether this bacteria directly causes ileal CD or if it
is a secondary invader of the previously inflamed mucosa.
The loss of immunologic tolerance against intestinal flora
remains an active theory of the etiology of the development of
IBD.27 Animal studies involving mice show that intestinal flora
exacerbate the colitis rather than directly causing the disease.28
However, studies comparing the intestinal flora of IBD and those
of healthy patients, in an attempt to establish a connection, have
been inconclusive.20
GENETIC
Genetic information pertaining to IBD etiology includes the iden-
tification of the IBD1 region on chromosome 16, and the discovery
of the NOD2/CARD15 gene, regarded as the first susceptibility
gene in CD.29-32 A mutation in the NOD2 gene leads to the acti-
vation of nuclear factor (NF) κB,33 a factor in the inflammatory
response, and as shown by Hampe et al., substantially increases a
patient’s susceptibility to developing CD.34 Other potential genetic
associations include the DLG5 gene and the IL23R gene, which
encode for a scaffolding protein involved in maintaining epithe-
PMPH_CH19.indd 176
lial integrity, and a subunit of the receptor for the cytokine IL-23,
respectively.35-37
There is a vast amount of information that has been developed
in recent years that demonstrates the important role of genetic
factors in the etiology of IBD. Only a tiny fraction of this material
is touched upon in this discussion. Regardless, this area of study
presents a wealth of untapped knowledge concerning the suscep-
tibility to and the underlying mechanisms of these diseases. It is
an area that warrants continued study and one that will heavily
influence the future of clinical management.
IMMUNOLOGIC
The role of immunologic factors in the etiology of CD has been
studied extensively, with the major focus on adaptive immu-
nity. Studies have attempted to distinguish CD from UC based
on immunologic characteristics of adaptive immunity and T-cell
lineage, with CD being associated with Th-1 and production of
IFN-γ, and UC with Th-2 and production of IL-13.38-40 Recent
studies have reported a third addition to the Th lineage, Th-17,
which produces mainly IL-17 as well as IL-6 and TNF-α.40 Like
Th-1, Th-17 plays a role in mediation of immunity and inflam-
mation in autoimmune and inflammatory conditions.41 Further-
more, IL-17+ cells have been detected by immunohistochemical
staining, along with Th-17 cells in the inflamed mucosa of CD
patients, suggesting that Th-17 may have a possible immunologic
role in the etiology of CD.42,43
As immunologic therapy continues to be a promising treat-
ment for Crohn’s patients, a better understanding of the immuno-
logic and genetic factors in the pathogenesis of CD are important
to help tailor future clinical therapies.
3. What is the role of strictureplasty in the surgical treatment
of CD?
Approximately 30% to 50% of patients who require surgical inter-
vention for CD will develop recurrent disease that requires addi-
tional surgery in the future.44,45 Patients that undergo multiple
surgical resections are at significant risk for the development of
short bowel syndrome. Thus, a surgical policy of bowel preser-
vation is warranted to reduce this risk. This topic was addressed
in 1982 by Lee and Papaioannou, who published results on the
use of strictureplasty to relieve obstructive symptoms in Crohn’s
patients.46 A bowel conservation approach, via strictureplasty, has
become the accepted means of treating obstructive CD, especially
in those patients with multiple strictures who would otherwise
require multiple resections or resection of a very significant length
of intestine to extirpate the disease. Patients treated with repeated
strictureplasty operations are less likely to develop short bowel
syndrome than those treated with multiple resections.47
A meta-analysis by Yamamoto et al. looked at 1112 patients
in 23 studies. They found that patients treated by strictureplasty
most commonly presented with obstruction secondary to fibrotic
stenosis. In this review of more than 3000 strictureplasties, the
most common areas of small bowel involvement were jejunum
and/or ileum;48 a finding further substantiated by a meta-analysis
by Tichanskly et al.49 Both studies confirmed that the majority of
patients who undergo strictureplasty, do so by one of two tech-
niques, Heineke–Mikulicz or Finney. The length of affected bowel
usually determines the technique used, as the Heineke–Mikulicz
strictureplasty is used with strictures less than 10 cm in length
5/21/2012 8:56:32 PM

and the Finney strictureplasty is used for strictures between 10
and 20 cm in length. The Finney technique involves making a
U-shaped incision over the stricture site and then closing the oppos-
ing surfaces of bowel. When strictured bowel segments are greater
than 20 cm in length, a side-to-side isoperistaltic strictureplasty, as
reported by Michelassi may be used as Finney or other techniques
may not be technically feasible in such long segments.50
Yamamoto found that the overall recurrence rates follow-
ing strictureplasty at 5- and 10-year follow-up were 41% and 51%,
respectively. Several other studies in this analysis also reported no
difference in recurrence rates when comparing the two most com-
mon strictureplasty techniques, Heineke–Mikulicz and Finney.48
A prospective study by Tonelli51 comparing recurrence rates fol-
lowing ileocolic strictureplasty with those following resection con-
cluded that there was difference between the two groups. However,
this study included only 28 patients, and therefore larger studies
are needed to confirm the results. Comparison of recurrence rates
between strictureplasty and bowel resection have proved difficult
and currently there are no other randomized trials on which to base
any conclusions. However, it is clear that strictureplasty remains
an important option for bowel preservation in CD when surgery is
indicated for the treatment of obstructive complications.
4. Does the type of anastomosis affect outcome or recurrence?
While medical management is the mainstay of initial therapy
for CD, it has been estimated that 70% of patients will undergo
surgery by 10 to 15 years following diagnosis.44 However, surgery
is not curative and recurrence of disease is common. A Cochran
review by Doherty found endoscopic recurrence rates of approxi-
mately 70% to 80%, and reoperative rates of nearly 25% to 30%,
5 years after surgical intervention.45 Several studies have attempted
to determine whether surgical technique can impact these high
rates of recurrence.
In a multicenter, randomized control trial, McLeod looked at
the effect of anastomotic construction on recurrence of CD fol-
lowing ileocolic resection.52 The types of anastomosis evaluated
included end-to-end hand-sewn anastomosis and side-to-side
stapled anastomosis. After a mean follow-up of 11.9 months, an
endoscopic recurrence rate was 42.5% in the former compared
with 37.9% in the latter (p = 0.55), thus showing no statistical dif-
ference. Symptomatic recurrence was also found to not be signifi-
cantly different at 21.9% and 22.7% (p = 0.92), respectively. This
study also reported no difference in complication rates between
the anastomotic types and showed rates that were similar to other
studies. Another meta-analysis performed by Simillis, which
included a total of 661 patients in eight studies, also reported
similar results with regards to the effect of anastomotic technique
on Crohn’s recurrence rates, finding no significant difference
between end-to-end and side-to-side anastomoses.53
5. How is CD differentiated from UC?
Distinguishing CD from UC is an important clinical deci-
sion when the disease is limited to the colon. It is a process that
requires reviewing findings across multiple diagnostic modali-
ties. It is combination of medical history, clinical evaluation, and
endoscopic and histological findings that help make the determi-
nation. Additionally recent studies have shown a possible use of
serologic markers, pANCA and ASCA, as a way of differentiating
between CD and UC.54-56 A definitive diagnosis is not always clear
PMPH_CH19.indd 177
Crohn’s Disease of the Small Bowel ■ 177
resulting in a diagnosis of indeterminate colitis (IC) in approxi-
mately 10% of patients.57,58
Patients afflicted with either of the IBDs may present with
abdominal pain, diarrhea, weight loss, and fever. A large major-
ity of UC patients will also present with blood in their stool and
at times, may have symptomatic anemia. Although bloody stool
is present in almost all patients with UC, patients with CD may
also experience bleeding, making a clear distinction based on
bleeding alone, difficult. Since CD can involve any portion of the
intestinal tract, while UC affects only the large intestine, involve-
ment of any portion of the intestine other than the large intestine
will favor the diagnosis of CD. Other features that point to the
diagnosis of CD are rectal sparing, the presence of strictures or
fistulas, skip lesions, perianal disease, transmural inflammation,
and granulomas, which are features that can be seen on histologic
examination. In particular, perianal suppuration with abscesses
and fistulae, is a hallmark of CD. It must be emphasized, however,
that none of these distinctions can make either diagnosis with
absolute certainty (except perhaps granulomas, which are found
in a relatively small percentage of patients with CD) and in some
cases clear and certain determination is not possible.
Colonoscopic evaluation with biopsies can be very useful in
differentiating CD from UC.59 As CD often involves the terminal
ileum, while UC generally does not, a full colonoscopy with evalu-
ation of this region is essential. Grossly, CD has been described as
inflammation with discrete ulcers, known as aphthous ulcers, that
can appear throughout the colon or small bowel in noncontigu-
ous fashion, referred to as “skip lesions”.60,61 These aphthous ulcers
sometimes combine to form a larger network of longitudinal ulcer-
ation, creating an appearance known as “cobblestoning.”61 While
colonoscopy is useful for examining the TI and colon, additional
modalities such as upper GI X-rays with small bowel follow through,
esophagogastroduodenoscopy, and capsule endoscopy may be use-
ful for diagnosing and evaluating CD proximal to the terminal
ileum. In comparison, UC is limited to the large intestine (with the
exception of occasional “backwash ileitis” which can produce ileal
inflammation), always involves the rectum and extends proximally
for a variable distance, but always in a contiguous fashion.60,61 No
skip lesions are present and during active disease superficial ulcers,
pseudopolyps, and mucosa that is erythematous and friable can be
observed.60,61 Specimens from Crohn’s patients show transmural
inflammation and lymphocytic aggregates evident in all layers of
bowel wall. In addition, noncaseating granulomas are sometimes
found. In comparison, UC specimens show inflammation limited
to the mucosa and submucosa. In areas of active inflammation,
superficial erosions and or ulcerations can also be found, as well as
a decrease in mucin producing goblet cells.61
Serological markers, such as pANCA and ASCA, have recently
been described as having utility for distinguishing CD from UC.
pANCA has been found in about 60% to 80% of UC patients,54,55 and
also in a subgroup of CD patients described by Vasiliauskas as hav-
ing “UC-like Crohn’s”’ that is, those CD patients who present with
left-sided colitis, abdominal pain, urgency, and hematochezia.56
A prospective study performed by Joosens found that patients diag-
nosed with IC who had a positive serology were more likely, over
time to eventually be given a definitive diagnosis then those with
negative serology; specifically ASCA+/pANCA– was predictive of
CD and ASCA–/pANCA+ was predictive of UC or UC-like CD.62
While biological markers have not yet been able to make a clear
distinction between CD and UC in all cases, they may provide a
window into future diagnosis and treatment.
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 178 ■ Surgery: Evidence-Based Practice

6. When is fecal diversion necessary in the surgical treatment demonstrated an incidence of carcinoma arising within bypassed
of CD? segments.86,87 For these reasons and because of equivalent safety
profi les, resection has come to replace bypass as the surgical tech-
Fecal diversion has been shown to decrease the incidence of and
nique of choice for the treatment of intestinal CD complications.
increase the time interval to CD recurrence.63-65 However, res-
Nevertheless, the rate of recurrence and reoperation after surgery
toration of GI tract continuity is preferred by both patients and
for CD remains high, with one study demonstrating a 31% chance
surgeons and therefore permanent stoma is avoided whenever
of needing a second operation within 10 years and a 28% likeli-
possible. Nevertheless, certain conditions, including severe fistu-
hood of needing a third procedure within another 10 years fol-
lizing perianal CD and uncontrolled colitis or proctitis, are best
lowing initial surgery.88 When CD does recur, it most frequently
managed with stoma creation, possibly on a temporary basis.
occurs at the site of previous anastomosis.89-92 When deciding upon
The frequency of perianal involvement in patients with CD
length of resection, surgeons must therefore balance the need to
has been reported to range from 13% to 38%.66 Manifestations of
relieve symptoms, prevent anastomotic complications, and avoid
perianal CD include anal skin tags, perianal abscesses and fistu-
recurrence with the need to preserve bowel length.
lae, anal fissures, anorectal strictures and rectovaginal fistulae.67
Clearance of all macroscopic disease during intestinal resec-
Local treatment of these conditions is frequently unsuccess-
tion for CD is necessary to prevent unacceptably high recurrence
ful.68 Studies have demonstrated both effective symptom control
rates and possibly also an increased risk of anastomotic compli-
and improved healing rates when stomas are used in the treat-
cations.93 The need to obtain microscopically negative margins,
ment of perianal CD.69-71
however, is more controversial. In a retrospective study published
Rehg et al. compared outcomes of patients with perianal CD
in 1977, Bergman and Krause found that patients with CD who
who were treated with local surgical therapy and fecal diversion
underwent intestinal resections with a 10 cm or greater margin
to those who underwent local surgical therapy alone. Eighty-
of microscopically normal bowel had significantly lower rates
five percent of patients treated with fecal diversion had complete
of disease recurrence than those who did not; 29% versus 84%,
resolution of their fistulae compared with only 19% of patients
respectively.94 Additional reports have also favored wide surgical
treated with local surgery alone. Intestinal continuity was reestab-
margins.95-100
lished in 46% of diverted patients, of which 50% remained disease
In contrast, other studies have demonstrated no association
free.70 In another study, fecal diversion led to temporary symp-
between disease recurrence and presence of histologic abnor-
tom improvement in 29% of patients, initial improvement with
malities at resection margins. Pennington et al. compared rates of
later plateau in 33% of patients, and healing in 19% of patients.
clinical recurrence, suture line recurrence, and need for reopera-
The remaining 19% of patients had no effect.71 Makowiec et al.
tion between patients with positive and negative histologic surgi-
prospectively evaluated 90 Crohn’s patients with perianal fistu-
cal margins and found no difference.91 Further, the incidences of
lae and found that fecal diversion significantly increased healing
postoperative leak, fistula, abscess, and obstruction were identical
rates and decreased recurrence rates.72 Other studies have simi-
(6%) in both groups. Additional retrospective studies have also
larly demonstrated improved healing with the creation of divert-
demonstrated no relationship between rate of clinical recurrence
ing stomas.73,74
and presence of microscopic disease at resection margins.64,101-106
Fecal diversion has also been shown to induce remission in
Kotanagi et al. categorized pathologic margin appearance as histo-
patients with Crohn’s coloproctitis. In an early study by Oberhel-
logically normal, showing nonspecific changes, showing changes
man et al., diverting ileostomy performed in 13 patients with CD
suggestive of CD, and showing changes diagnostic of CD. These
of the colon led to immediate and persistent symptom relief in
authors found no association between histologic changes at
all patients.75 Similarly, Edwards et al. found that defunctioning
the resection margin and anastomotic recurrence in 100 patients
stomas led to acute remission in 48 of 55 (87%) of patients with
with CD.107
refractory Crohn’s colitis.76
The potential relationship between histologic changes at the
Finally, as with other disease processes, diverting stomas
resection margin and disease recurrence has led authors to evalu-
are used in Crohn’s surgery to protect high-risk anastomoses or
ate the role of intraoperative frozen section. Hamilton et al. com-
delay anastomosis construction until risk factors are minimized.
pared patients who had resection margins determined by frozen
Known risk factors for anastomotic complication include prior
section with those with margins chosen on the basis of visual
radiation, poor nutrition, bowel obstruction, sepsis, immunosup-
inspection alone.108 Frozen section was found to be a poor pre-
pressive medications, and low rectal anastomosis.77
dictor of actual margin involvement. Further, the incidences of
A 12% to 49% rate of permanent stoma is reported in patients
postoperative anastomotic leakage, clinical recurrence, and reop-
with perianal CD.78-83 Predictors of permanent stoma include
eration were similar whether or not intraoperative frozen section
anorectal strictures, complex perianal fistulae, rectovaginal fis-
was utilized. Two earlier studies also demonstrated the low reli-
tulae, colonic disease, rectal disease, subtotal, left-sided, or rec-
ability of frozen section in predicting disease recurrence.109,110
tal resection, history of temporary fecal diversion, and fecal
Only one study has addressed the effect of histologic disease
incontinence.78,82-84
at surgical margins in a prospective manner. Fazio et al. ran-
domly assigned 152 patients undergoing ileocolic resection for
7. How much small bowel should be resected at the time of
CD to either 2 cm or 12 cm macroscopically negative margins.111
surgery (i.e., do macroscopically or microscopically involved
Follow-up data was available in 131 patients. The authors found
margins make a difference)?
no difference in disease recurrence between the two groups. In
In the early days of surgical therapy for CD surgical bypass or addition, recurrence was unrelated to the presence or absence of
exclusion procedures were advocated. However, the frequency of microscopic disease at the resection margin. Interestingly, in this
persistent symptoms and need for reoperation following bypass study, extended resection did not predict achievement of micro-
procedures led to concern over their efficacy.85,86 Further, studies scopically disease-free margins.

PMPH_CH19.indd 178 5/21/2012 8:56:32 PM

 Crohn’s Disease of the Small Bowel ■ 179

In summary, although early studies seemed to favor wide
resection of bowel involved with CD, more contemporary reports
and the only randomized controlled trial to address this subject
matter have shown no association between residual microscopic
disease and disease recurrence. Given this data, conservative
resection margins should be utilized in Crohn’s intestinal surgery
to preserve bowel length.
8. What is the role of laparoscopy in small bowel CD?
Laparoscopy in colon and rectal surgery has been shown to
decrease postoperative pain and narcotic usage,112 duration of
hospital stay,113 and time to first bowel function.113 Because of the
technical challenge posed by acute bowel wall and mesenteric
inflammation as well as fistulizing and phlegmonous processes,
CD was initially considered a contraindication to laparoscopic
surgery. Further, the ability to assess for diff use disease and skip
lesions via laparoscopy has been questioned given the diminished
tactile feedback and potentially, decreased exposure associated
with this surgical technique. Multiple studies, however, have dem-
onstrated the safety and efficacy of laparoscopy in CD.114-119
Two large meta-analyses address the topic of laparoscopy in
CD. Tan et al. pooled the results of 14 studies, published between
1990 and 2006, which compared laparoscopic with open bowel
resection for CD.114 The majority of these reports focused on ileo-
colic resections. Two prospective, randomized, controlled trials
and two case-matched studies were included. The remaining
10 studies were retrospective, single institution reviews. An 11.2%
rate of conversion from laparoscopy to open surgery was found.
Laparoscopy was associated with significantly shorter time to first
bowel function and oral intake, decreased duration of hospital
stay, decreased cost, and decreased operative morbidity. Opera-
tive time was longer for laparoscopic cases. There was no differ-
ence in rate of disease recurrence, whether surgery was performed
laparoscopically or in open fashion.
Lesperance et al. utilized the 2000–2004 Nationwide Inpa-
tient Sample to identify 49,609 bowel resections performed for
CD. Laparoscopic surgery was associated with improved out-
comes compared with open surgery with respect to cost, length of
hospital stay, discharge disposition, postoperative GI, pulmonary
and cardiovascular complication, and mortality. There was no dif-
ference between the two groups in intraoperative, wound or infec-
tious complications.115
Other studies have similarly demonstrated decreased nar-
cotic usage, time to first bowel function and length of hospital stay
with laparoscopy compared with open surgery for CD.116-118,120,121
Operative time, however, is typically longer with laparoscopy.120,121
Mortality and recurrence have consistently been found to be
similar regardless of surgical technique.116-120 In conclusion, lap-
aroscopy has led to improved surgical outcomes in CD without
negatively impacting mortality or rate of recurrence. Although
operative time is increased with laparoscopy, overall cost appears
to be reduced.

Clinical Question Summary

Question
1 What are the indications for surgery in
small bowel CD?
2 What is the etiology of CD?
3 What is the role of strictureplasty in
the surgical treatment of CD?
4 Does the type of anastomosis affect
outcome or recurrence?
5 How is CD differentiated from UC?
Answer Grade of References
Recommendation
Acute bowel obstruction that fails to resolve; A 14, 16
perforation leading to abscess, fistula or B 8-12, 15, 17
peritonitis; malignancy; failed medical therapy;
and intolerance to the medications.
Some combination of environmental, A 21, 24
immunologic, genetic, and microbiologic B 22, 25, 28-30
factors. B 34-37, 41
Strictureplasty is a safe alternative to bowel A 44, 48, 49
resection for the treatment of fibrostenotic B 52
obstructing CD; it is especially useful in C 47, 50
recurrent disease, when long and/or multiple
segments of small intestine are involved,
and any situation in which preservation of
intestinal length is of paramount concern.
The type of anastomosis used for restoration A 44-46
of intestinal continuity following resection B 43
for CD does not affect the outcome or
recurrence rates.
A combination of factors including clinical B 54-57, 59, 62
presentation, endoscopic and radiographic
appearance, histologic examination, and
serologic markers can be used to try to
differentiate UC from Crohn’s colitis; in some
cases the distinction is not possible.
(Continued)

PMPH_CH19.indd 179 5/21/2012 8:56:32 PM

 180 ■ Surgery: Evidence-Based Practice

(Continued)
Question
6 When is fecal diversion necessary in
CD?
7 How much small bowel should be
resected at the time of surgery (i.e.,
do macroscopically or microscopically
involved margins make a difference)?
8 What is the role of laparoscopy
in CD?
Answer Grade of References
Recommendation
Fecal diversion is used primarily in patients B 69-76
with fulminant proctocolitis; in patients with
high operative risk; in patients with severe
fistulizing perianal disease; and in the presence
of high-risk anastomoses.
The incidence of surgical complications and B 64, 91, 93-111
subsequent recurrence rates are lower
when the surgical resection margins are
macroscopically free of disease; whether or
not the margins are microscopically involved
does not affect the surgical outcome or the
long-term recurrence rate.
Laparoscopy in CD is associated with decreased B 114-120
postoperative pain and narcotic use, shorter
time to resumption of bowel function, shorter
hospital lengths of stay, and decreased
cost when compared with open surgery.
Laparoscopy does not appear to affect
operative mortality or disease recurrence.

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107. Kotanagi H, Kramer K, Fazio VW, Petras RE. Do microscopic
abnormalities at resection margins correlate with increased
anastomotic recurrence in Crohn’s disease? Retrospective
analysis of 100 cases. Dis Colon Rectum. 1991;34:909-916.
108. Hamilton SR, Reese J, Pennington L, Boitnott JK, Bayless TM,
Cameron JL. The role of resection margin frozen section in the
surgical management of Crohn’s disease. Surg Gynecol Obstet.
1985;160:57-62.
109. Krause U, Bergman L, Norlén BJ. Crohn’s disease. A clinical study
based on 186 patients. Scand J Gastroenterol. 1971;6:97-108.
110. Holmes SJ, Richter HM, 3rd, Garberoglio CA, Block GE, Moossa
AR. The surgical treatment of Crohn’s disease. Br J Clin Pract.
1981;35:5-12.
111. Fazio VW, Marchetti F, Church M, Goldblum JR, Lavery C,
Hull TL, Milsom JW, Strong SA, Oakley JR, Secic M. Effect
of resection margins on the recurrence of Crohn’s disease in
the small bowel. A randomized controlled trial. Ann Surg.
1996;224:563-571; discussion 571-573.
112. Weeks JC, Nelson H, Gelber S, Sargent D, Schroeder G; Clinical
Outcomes of Surgical Therapy (COST) Study Group. Short-
term quality-of-life outcomes following laparoscopic-assisted
colectomy vs open colectomy for colon cancer: A randomized
trial. JAMA. 2002;287:321-328.
113. Milsom JW, Böhm B, Hammerhofer KA, Fazio V, Steiger E,
Elson P. A prospective, randomized trial comparing laparos-
copic versus conventional techniques in colorectal cancer
surgery: a preliminary report. J Am Coll Surg. 1998;187:46-54;
discussion 54-55.
PMPH_CH19.indd 183
Crohn’s Disease of the Small Bowel ■ 183
114. Tan JJ, Tjandra JJ. Laparoscopic surgery for Crohn’s disease:
A meta-analysis. Dis Colon Rectum. 2007;50:576-585.
115. Lesperance K, Martin MJ, Lehmann R, Brounts L, Steele SR.
National trends and outcomes for the surgical therapy of
ileocolonic Crohn’s disease: A population-based analysis of
laparoscopic vs. open approaches. J Gastrointest Surg. 2009;
13:1251-1259.
116. Fichera A, Peng SL, Elisseou NM, Rubin MA, Hurst RD.
Laparoscopy or conventional open surgery for patients with
ileocolonic Crohn’s disease? A prospective study. Surgery.
2007;142:566-571; discussion 571.e1.
117. Stocchi L, Milsom JW, Fazio VW. Long-term outcomes of
laparoscopic versus open ileocolic resection for Crohn’s
disease: follow-up of a prospective randomized trial. Surgery.
2008;144:622-627; discussion 627-628.
118. Umanskiy K, Malhotra G, Chase A, Rubin MA, Hurst RD,
Fichera A. Laparoscopic colectomy for Crohn’s colitis. A large
prospective comparative study. J Gastrointest Surg. 2010;14:658-
663.
119. Lowney JK, Dietz DW, Birnbaum EH, Kodner IJ, Mutch MG,
Fleshman JW. Is there any difference in recurrence rates in
laparoscopic ileocolic resection for Crohn’s disease compared
with conventional surgery? A long-term, follow-up study. Dis
Colon Rectum. 2006;49:58-63.
120. Alessandroni L, Bertolini R, Campanelli A, Di Castro A, Natuzzi
G, Saraco E, Scotti A, Tersigni R. Video-assisted versus open
ileocolic resection in primary Crohn’s disease: A comparative
case-matched study. Updates Surg. 2010;62:35-40.
121. da Luz Moreira A, Stocchi L, Remzi FH, Geisler D, Hammel J,
Fazio VW. Laparoscopic surgery for patients with Crohn’s colitis:
A case-matched study. J Gastrointest Surg. 2007;11:1529-1533.
5/21/2012 8:56:32 PM
 Commentary on Crohn’s Disease
of the Small Bowel
This is an excellent review of the current state of our knowledge
of Crohn’s disease. Since its first description by Crohn, Oppen-
heimer and Ginsburg at Mount Sinai in 1932, we have made great
strides in the manipulation of the immune system and control of
symptoms, but we still have only a rudimentary understanding of
the etiology of this disease. With the recent advent of biological
drugs that allow immune modulation, the surgical treatment of
many of our patients has changed. In the last 10 years, the need for
proctectomy in patients with severe perianal disease has decreased
drastically and most can now be managed with local surgical
treatment of the fistulas using setons, and maintenance medical
treatment with biologic agents that are able to keep the perianal
disease under control. This treatment is effective for both patients
with Crohn’s disease and patients with indeterminate colitis that
have undergone restorative proctocolectomy and subsequently
develop severe pouchitis with perianal fistulas and behave like
Crohn’s disease. This combination treatment has been very effec-
tive and has decreased the excision of J-pouches to a minimum
in a group of patients that were very difficult to treat in the past.
In patients that still require abdominoperineal resection, healing
problems in the perineal wound seem to respond to the addition
of topical growth factors if the perineal wound remains unhealed
after 3 months, thereby decreasing the need for surgical wound
revisions and addition of gracilis or rectus muscle flaps.1
Surgical treatment of Crohn’s disease can be classified in
different ways. One method that has been previously described
is to divide the patients into obstructing and fistulizing disease.
Patients with obstruction tend to be easier to treat both medically
and surgically while those with fistulizing disease tend to have
more complications and need surgery more frequently. Another
classification which I find useful from a surgical point of view is to
classify Crohn’s disease patients requiring surgical treatment by
degree of difficulty.2 Patients with localized short segment disease
in the terminal ileum undergoing a limited resection can often
be done laparoscopically with a single resection and anastomo-
sis. I prefer a side-to-side ileocolic anastomosis performed with a
long linear stapler instead of an end-side since anastomosis which
has a smaller surface area and may develop a symptomatic stric-
ture sooner and therefore may shorten the symptom free interval.
Reoperations for recurrent disease and more complex resections
with fistulas and abscesses are more difficult to perform laparo-
scopically and often open surgery becomes necessary. These cases
range from relatively straight forward resections if there are few
adhesions, to very difficult procedures if the recurrent disease
involves multiple sites, severe adhesions and internal fistulas and
184
PMPH_CH19.indd 184
Tomas M. Heimann
abscesses. I feel very strongly that these cases should be done by
an experienced gastrointestinal (GI) surgeon, able to perform dif-
ficult GI surgery to minimize the risk of complications, anasto-
motic leaks, and ureteral injury. In the final category, are patients
with short length residual small bowel, with multiple sites of
recurrent disease, often with internal or enterocutaneous fistulas
and abdominal wall issues which result from incisional hernias
caused by previous surgeries. These cases can be very challenging.
Reopening the abdominal cavity and sorting out the various loops
of bowel can take several hours and avoidance of enterotomies
is crucial to preserve bowel length and reduce the risk of creat-
ing new fistulas and abscesses, which may produce catastrophic
results. Bowel preservation is of utmost importance and closure
of the incision can be challenging if the abdominal wall is thinned
out from previous wound infections and the presence of large ven-
tral hernias where the bowel may be covered only with skin. In
these situations, reinforcing the closure with acellular dermis may
be the best way to obtain a reliable closure especially in the face
of significant wound contamination. Although great progress has
been made in the area of small bowel transplant, it is always better
to be able to preserve sufficient small bowel to allow the patient to
rely on his own intestines for nutrition, preferably with minimal
or no need for long-term intravenous nutrition. Septic patients
with multiple fistulas and abscesses and an empty abdominal cav-
ity with only a few remaining loops of small bowel are not the best
candidates for good outcomes after intestinal transplant as it is
difficult to eradicate the infection which is necessary before the
transplant may be performed.
The distinction between Crohn’s disease and ulcerative coli-
tis is of critical importance in determining surgical treatment in
patients with colitis. Performance of restorative proctocolectomy,
in a patient who is subsequently is found to have Crohn’s disease,
can lead to failure of the operation and permanent ileostomy. In
most instances, colonoscopy and multiple biopsies can differenti-
ate Crohn’s disease from ulcerative colitis. When necessary, small
bowel study may also be helpful to rule out the presence of small
bowel disease. If considerable doubt exists, a subtotal colectomy
may be performed with and end ileostomy and rectal preserva-
tion. The final decision about the next operative procedure can be
made after the colon is examined by pathology and a diagnosis is
made. If the colon shows ulcerative colitis then a restorative proc-
tocolectomy can be performed. If the diagnosis is Crohn’s disease
and the rectal segment is spared, an ileorectal anastomosis is per-
formed instead. Some patients may opt to keep the ileostomy and
undergo completion proctectomy at a later date. A major problem
5/21/2012 8:56:32 PM

may occur when the colitis is diagnosed as ulcerative colitis and
the patient undergoes restorative proctocolectomy and years later
he/she develops severe pouchitis with intractable stricture of the
inflow tract, recurrent pelvic abscesses or severe perianal disease
with multiple fistulas and the diagnosis of Crohn’s disease becomes
obvious, yet a review of the colonic pathology still shows ulcerative
colitis. A significant percentage of these patients will require pouch
excision and permanent ileostomy.
The need for permanent diversion versus temporary diversion
in Crohn’s disease differs depending on the extent and location of
the disease and the difficulty of the operative procedure being per-
formed. Patients with intractable perianal disease, rectal inflam-
mation with strictures and rectal cancer will need proctectomy
with a permanent stoma, most likely an ileostomy. Temporary
stomas are used when the surgeon feels that multiple anastomosis
need protection or when multiple enterotomies in a difficult case
require proximal diversion to avoid extensive bowel resection.
These stomas are usually loop ileostomies although occasionally
may be proximal jejunostomies and then the patient will require
supplementation with parenteral nutrition.
Regarding the question about the amount of bowel resection,
there are several factors that must be considered. The amount of
residual small bowel and colon after surgical resection is of major
importance. If the colon is normal, about 4′-5′ of normal small
intestine constitutes the minimum needed for adequate nutrition.
If the patient has an ileostomy, a longer length, usually over 8′ is
necessary. Strictureplasty may be used to preserve bowel length, but
it cannot be used in fistulizing disease where a resection is neces-
sary. As far as resection margins and anastomosis are concerned,
grossly visible disease should be resected if a resection is planned,
because anastomosis between grossly diseased bowel may result in
a leak with life threatening consequences. In general, it is better to
take a slightly longer segment of bowel and perform a safe anasto-
mosis than to compromise the surgical outcome to save a few inches
of diseased small bowel. The more complicated the operation, with
multiple sites of recurrent disease, the more likely it is that there will
be microscopic inflammation in the resected margins.
Recurrence after surgical resection for Crohn’s disease remains
a major problem.3 Postoperative prophylaxis is rapidly changing
from antiinflammatory drugs such as 6-mercaptopurine to biologi-
cal immunomodulators such as infliximab, especially in high-risk
patients with extensive disease, residual disease after surgery, or
previous early postoperative recurrence. The postoperative period
offers an ideal opportunity to control recurrence of the disease
because in the majority of patients all visible disease is removed and
this may be the only opportunity to treat normal appearing bowel
with immunomodulators that may be able to delay the reactivation
of the immune process that causes recurrent disease.
PMPH_CH19.indd 185
Crohn’s Disease of the Small Bowel ■ 185
The problem of carcinoma in Crohn’s disease occurs with some
frequency and must always be kept in mind when treating these
patients. Small bowel tumors usually present as a site of obstruc-
tion, especially in patients with longstanding disease.4 These tumors
may be difficult to distinguish from benign strictures and often
only biopsy or resection reveals the true nature of the obstructing
lesion. Another group at high-risk to develop anorectal cancer is
patients with perianal disease that require subtotal colectomy and
ileostomy. As the perianal disease becomes quiescent after diver-
sion, many patients delay the completion proctectomy. This is inad-
visable because development of an anal squamous cell carcinoma or
rectal adenocarcinoma often does not produce any new symptoms
until the lesion is advanced and then the outcome is poor. Except
in rare instances, we always recommend completion proctectomy
within a year of colectomy if restoration of intestinal continuity is
not contemplated.
In summary, recent advances in medical treatment have had
some beneficial effects mainly in decreasing the rate of proctec-
tomy for patients with perianal disease. Patients with significant
strictures causing obstruction and patients with abscesses and
enteric fistulas still require surgical resection or strictureplasty
as the biological drugs are unable to control severe advanced
disease. Hopefully, as we continue to learn to understand the
mechanism of immunomodulation better and perhaps learn
the etiology of Crohn’s disease, we will be able to treat this
disease earlier and diminish the need for repeated surgical
intervention.
REFERENCES
1. Kurtz MP, Svensson E, Heimann TM. Use of platelet-derived
growth factor for delayed perineal wound healing in patients with
inflammatory bowel disease: A case series. Ostomy Wound Manag.
2011;57:24-31.
2. Heimann TM, Greenstein AJ, Lewis B, Kaufman D, Heimann DM,
Aufses AH, Jr. Comparison of primary and reoperative surgery in
patients with Crohn’s disease. Ann Surg. 1998;227:492-495.
3. Heimann TM, Greenstein AJ, Lewis B, Kaufman D, Heimann
DM, Aufses AH, Jr. Prediction of early symptomatic recurrence
after intestinal resection in Crohn’s disease. Ann Surg. 1993;218:
294-298; discussion 298-299.
4. Ribeiro MB, Greenstein AJ, Heimann TM, Aufses AH, Jr. Adeno-
carcinoma of the small intestine in Crohn’s disease. Surg Gynecol
Obstet. 1991;173:343-349.
5. Ribeiro MB, Greenstein AJ, Sachar DB, Barth J, Balasubramanian S,
Harpaz N, Heimann TM, Aufses AH, Jr. Colorectal adenocarci-
noma in Crohn’s disease. Ann Surg. 1996;223:186-193.
5/21/2012 8:56:32 PM
 CHAPTER 20

Small Bowel Tumors and

Diverticular Disease of SB
John D. Cunningham and Akintunde Akinleye

INTRODUCTION classified as gastrointestinal stromal tumors (GIST). It had previ-

There are approximately 7000 small bowel malignant tumors
diagnosed each year in the United States.1 The small number of
cases per year allows for little information related to their presen-
tation, natural history, surgical treatment, adjuvant therapy, and
outcomes. There are currently no randomized studies concern-
ing surgical management of small bowel tumors because of their
vague presentation, difficult diagnostic workup, and due to the
fact that diagnosis is often made at the time of laparotomy. There
are some trials regarding the use of adjuvant therapy for small
bowel tumors but these trials contain few patients, often are not
randomized, and contain patients with similar tumor histology in
other gastrointestinal sites. This chapter has been written based
on retrospective reviews from major medical centers and from
national cancer databases. This is the best data that is currently
available. The likelihood of there being randomized trials regard-
ing treatment of small bowel tumors that have enough patients
to reach statistical significance is unlikely. The evidence-based
medicine for this chapter is C level at best.
Although the small bowel mucosa accounts for over 70% of
the length and over 90% of the surface area of the intestine, only
1% to 3% of all gastrointestinal tumors arise there.2,3 A number
of reasons have been given for this finding. Small bowel contents
have a rapid transit time through the small bowel and the mucosa
is not exposed to possible carcinogens for long periods of time
and the liquid nature of the contents that may be less irritating to
the small bowel. Other reasons that prevent the transformation of
small bowel mucosa to malignancy include the decreased bacte-
rial count in the small bowel compared to the colon, increased
amount of lymphoid tissue, alkaline pH, and the presence of the
enzyme benzyprene hydoxylase that helps to detoxify potential
carcinogens. The true explanation most likely is a result of many
of these factors.
1. What are the most common types of small bowel cancer?
The most common types of small bowel cancer are carcinoid,
adenocarcinoma, lymphoma, and sarcoma. Sarcomas are now
ously been believed that mesenchymal gastrointestinal tumors
were of smooth muscle origin but with the advent of immunohis-
tochemical staining and electron microscopy that was shown not to
be the case. Most evidence now suggests that most sarcomas actu-
ally originate from the interstitial cells of Cajal and small bowel
sarcomas are now referred to as GIST. The use of the term GIST
became widespread in the late 1990s and is currently the appropri-
ate nomenclature for mesenchymal tumors of the small bowel.
ADENOCARCINOMA
Adenocarcinomas of the small bowel are most commonly found
in males in their sixth decade of life.2-6 Over half of the lesions are
found in the duodenum while a quarter is found in the jejunum
and the rest in the ileum.2-7 The most common presenting symp-
toms are pain, nausea and vomiting, and bleeding.2-5
CARCINOID
Carcinoids arise from the Kulchitsky cells in the crypts of Lie-
berkühn. Men are slightly more likely to get carcinoids than
women.8,9 The median age of onset is 66 years.8 The most common
site for carcinoid tumors is in the ileum.2,3,7-9 The most common
presenting symptom is abdominal pain while nausea, vomiting,
and bleeding are less common complaints.3,7,8 The carcinoid syn-
drome is found in patients whose disease has spread to the liver.
LYMPHOMA
The gastrointestinal tract is the most common site of extran-
odal lymphoma. Men are more likely to have lymphoma than
women.2,10 Patients present at a median age of 62 years.10 The jeju-
num and ileum account for the vast majority of lymphomas.2,3,7,10
The most common presenting symptoms in order are pain, fever,
weight loss, and anemia.3,10

186

PMPH_CH20.indd 186 5/21/2012 8:57:15 PM


SARCOMA/GIST
Men are more likely to be diagnosed with sarcomas/GIST than
women.11-13 The majority of these tumors are found in the jejunum
and ileum and the remainder in the duodenum.2,3,7,11,13 Abdomi-
nal pain, an abdominal mass, gastrointestinal bleeding, fever, and
weight loss are the most common presenting symptoms.3,13
2. Has the incidence, histology, or location of small bowel
tumors changed over the last 20 years?
A recent review of the National Cancer Data Base (NCDB) from
1985 to 2005, the SEER database from 1973 to 2004, and the Con-
necticut Tumor Registry from 1980 to 2000 has shown that there has
been changes in the incidence of small bowel tumors over the last 30
years.2,7 The incidence has risen from 11.8 to 22.7 cases per million
persons from 1973 to 2004.2 The Connecticut tumor registry showed
an increase from 10.5 to 14.9 cases/100,000 over 20 years.7 There has
also been a significant change in the location of tumors in the small
bowel over the last 20 years. Duodenal tumors have increased dramat-
ically while the number of jejunal and ileal tumors has decreased.2
ADENOCARCINOMA
The incidence of adenocarcinomas increased from 5.7 to 7.3 cases per
million from 1973 to 2004.2 This is an annual increase of 1.3% and
an overall increase of 26%.2 The proportion of small bowel tumors
that are adenocarcinomas decreased from 42.1% to 32.6% from 1985
to 2005.1 There were no changes in patient or tumor characteristics
during this time period.2 Adenocarcinomas were more frequently
found in the duodenum over this same time period while there was
a concomitant decrease in jejunal and ileal adenocarcinomas.1,2
CARCINOID
Carcinoid tumors increased in incidence dramatically from 2.1 to
9.3 cases per million over the same time period.2 The annual inci-
dence increased by 3.6% per year while the overall percent change
was 341% from 1973 to 2004.2 This increased incidence accounts
for carcinoids becoming the most common type of small bowel
tumor with an increase in proportion from 27.5% to 44.3%.2 There
was an increase in the number of carcinoids found in the duo-
denum also. From 1973 to 2005, the rate of duodenal carcinoids
increased from 10.9% to 22.3%.2
LYMPHOMA
The rate of increase of lymphomas averaged 2.3% per year and
totaled 94.3%.2 This calculates to a rate of 4.4 cases per million up
from 2.2 cases per million.2 The proportion of small bowel cancers
being lymphomas did not change over 30 years of study.2 Lym-
phomas also showed a change in location with more tumors being
found in the duodenum and less in the jejunum and ileum.2
SARCOMA/GIST
The incidence and proportion of small bowel tumors that are
sarcomas/GIST did not change over the last 30 years.2 However,
PMPH_CH20.indd 187
Small Bowel Tumors and Diverticular Disease of SB ■ 187
there was a slight increase in incidence of duodenal sarcoma/GIST
tumors over the same time period.2
3. What is the most sensitive test for diagnosing small bowel
tumors?
Small bowel tumors usually present with vague, nonspecific symp-
toms that could be attributed to a large number of other possible
diagnoses. This accounts for a delay in the diagnosis of most tumors
and the late stage seen with small bowel tumors at the time of diag-
nosis. The nonspecific complaints lead to the ordering of multiple
tests to try to make the diagnosis. Most tests are ordered based on the
presenting symptoms. The most common symptoms that patients
present with are abdominal pain, nausea and vomiting, bleeding,
anemia, obstruction, and an acute abdomen. Imaging of the small
intestine is the most difficult of all the areas of the gastrointestinal
tract to evaluate. As one might have guessed the use of diagnostic
imaging tests have changed dramatically over the last 30 years. The
last 20 years has seen a significant increase in the use of computed
tomography (CT) and endoscopy. Prior to this, an upper gastroin-
testinal study with a small bowel follow through (UGISBFT) was
the most common test to evaluate the nonspecific symptoms asso-
ciated with small bowel tumors.3,14
UGISBFT
This test requires the patient to swallow barium and the barium
is followed through the small bowel with serial abdominal X-rays.
The sensitivity of the test is limited because the images are not
obtained continuously and overlapping bowel loops can obscure
small mucosal defects. This test found direct evidence of small
bowel tumors in less than 30% of cases.14 This test is used infre-
quently today because of its poor accuracy and the advent of upper
endoscopy and CT imaging.
UPPER ENDOSCOPY
The passage of an endoscope through the stomach into the duode-
num is a very accurate test for finding lesions in the duodenum up
to the ligament of Treitz. The advantage of this technique is that it
visualizes the lesion and allows one to biopsy the lesion to make
the diagnosis. Many centers today use endoscopic ultrasound to
evaluate tumor depth of penetration and to evaluate nodal disease
for patients with duodenal, pancreatic, and gastric lesions.
Colonoscopy can be used in some instances to visualize the distal
10 to 60 cm of the ileum. This is often patient and user dependent.
ENTEROCLYSIS
If one suspects a small bowel tumor in the jejunum or ileum, entero-
clysis can be performed; and this has replaced UGISBFT.14 Entero-
clysis is a double contrast study of the small bowel that requires the
placement of a tube into the proximal small bowel. The patient is
then injected with methylcellulose and contrast to image the small
bowel. This test is useful to delineate mucosal defects associated
with jejunal and ileal tumors. Although this test is more accurate
than a UGISBFT, it requires a skilled radiologist to perform, there
is significant patient discomfort, it requires sedation, there is a
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 188 ■ Surgery: Evidence-Based Practice
significant amount of radiation, and it is expensive and very time
consuming.14 Therefore, it is used infrequently.
COMPUTED TOMOGRAPHY (CT)
CT imaging for delineating small intraluminal lesions in the small
bowel is not very accurate. CT imaging for small bowel lesions is
more likely to identify lymph node metastases, mesenteric strand-
ing, abdominal masses, and distant disease. However, due to the
vague presentation and nonspecific symptoms seen with small
bowel tumors, most patients will have a CT done during their
diagnostic evaluation. CT imaging may be performed following
the presumed diagnosis of a small bowel tumor by another diag-
nostic test to determine the extent of disease.
CAPSULE ENDOSCOPY
Capsule endoscopy has become a much more common diagnostic
test for patients with suspected small bowel pathology. The test
involves the ingestion of a small video camera in a capsule. It is
most commonly used for patients who have occult gastrointestinal
bleeding with repeatedly normal endoscopy and colonoscopy. It
can be used to visualize mucosal disease, angiodysplasias, ulcers,
polyps, and cancer. Its main advantage is that it can visualize the
entire small bowel. As it is usually performed for occult bleeding,
only few small bowel cancers are found with this test.14
Since the preoperative diagnosis of a small bowel tumor may
be made in up to 50% of cases, surgery appears to be the best diag-
nostic test for small bowel tumors.2-4,7 Surgery allows for evaluation
of the entire small bowel and it allows the surgeon to evaluate any
abnormal findings found on preoperative imaging. Although most
studies were done before the widespread use of diagnostic laparos-
copy, this would seem to be the perfect test to evaluate patients
for a presumed small bowel pathology not found on preoperative
imaging. Surgery also allows the surgeon to therapeutically treat
the tumor. In a series of 217 small bowel adenocarcinomas, surgery
made the diagnosis in 30% of patients, CT 14%, UGISBFT 26%,
upper endoscopy 24%, physical exam 4%, and ultrasound 2%.4
4. What are the risk factors for developing small bowel cancer?
It is difficult to determine patient risks for small bowel tumors
due to the small number of cases. There appears to be a slight
sexual predilection with males being more likely to develop a
small bowel tumor than women.2,4,6,7,9-13 Age appears to be a factor
related to small bowel tumors with the median age of diagnosis
being between 55 and 65 years.2-13
Adenocarcinomas of the small bowel are associated with
Crohn’s disease and are usually found in the distal ileum.3 Famil-
ial polyposis has been associated with an increased risk of adeno-
carcinoma of the periampullary area and this area needs to be
followed closely in patients who have had their colon removed for
disease. Lymphoma has been associated with celiac sprue disease,
parasitic infections, and in the immuno-compromised patient.
Meckel’s diverticulum has been found to be a risk factor for the
development of carcinoid tumors in the ileum.15
5. What is the principal treatment for small bowel cancer?
Surgery is the mainstay of treatment for small bowel cancer. The
optimal surgical resection has not been as well delineated for
PMPH_CH20.indd 188
small bowel cancer as it has been for colonic cancer. The recom-
mendations for resection include the primary tumor with grossly
clear margins and a wedge of mesentery to include lymph nodes
for evaluation. The exception to this rule is for sarcomas/GIST
that can be resected without a lymphadenectomy because these
tumors rarely spread to lymph nodes.
ADENOCARCINOMA
Surgical resection for cure for adenocarcinoma is possible in up to
67% of patients.2-5 This may reach as high as 80% for nonmetastatic
disease.2 Patients who present with duodenal lesions will need to
undergo pancreaticoduodenectomy. Jejunal and ileal resections
can be performed with wedge resections.
CARCINOID
The majority of carcinoids are located in the ileum. The surgical
procedure of choice is a wedge resection. One must evaluate the
rest of the gastrointestinal tract as carcinoids can present with syn-
chronous lesions. Carcinoids can also have a desmoplastic reaction
in the mesentery that may make them difficult to resect. Resection
for cure can be accomplished in up to 84% of patients.2,9,10
LYMPHOMA
The most common site of small bowel lymphomas are in the
jejunum and the ileum and therefore the optimal treatment is a
wedge resection.2,3,10 Resection for cure can be achieved in over
two-thirds of patients.10 Surgical treatment of this disease has not
changed in the last 30 years.2
SARCOMA/GIST
Sarcomas/GIST are most commonly found in the duodenum and
jejunum and rarely spread to lymph nodes. Surgical resection
should include the primary tumor, but an extensive lymphadenec-
tomy need not be performed. Avoidance of tumor rupture during
surgery is imperative to prevent tumor spread. The goal of surgery
is macroscopic negative margins with an intact pseudocapsule. The
primary tumor can be resected in up to 88% of cases.2,11,12 Although
a large number of patients can be resected, surgery is usually not
curative in the majority of patients.11-13,16
6. What is the role of adjuvant therapy in small bowel cancer?
A number of different chemotherapy regimens have been used
to treat small bowel cancer. For the most part, none have been
shown to be effective with the recent exception of the use of
imatinib for GIST. There is very little evidence-based medicine
regarding these drugs. There is no role for radiotherapy in the
treatment of small bowel cancer as the entire abdominal cavity
would need to be treated because of the mobility of the small
bowel. In addition, the small bowel is the most sensitive organ to
radiotherapy in the abdomen and complications would be very
common.
5/21/2012 8:57:15 PM

ADENOCARCINOMA
Two-thirds of adenocarcinomas will present with nodal or distant
metastases.2-6 Patients with full thickness bowel involvement and
nodal disease are candidates for adjuvant therapy. If the distant
disease is resected, stage IV patients can also receive chemother-
apy in an adjuvant setting. There has been an increase in the use
of adjuvant therapy for patients with adenocarcinoma from 8% to
22% over the last 20 years.2 Despite the use of adjuvant therapy, no
survival advantage has ever been demonstrated.2-6 The use of che-
motherapy in a palliative setting for small bowel adenocarcino-
mas has resulted in a median survival of 8 months and no overall
improvement in survival.5
CARCINOID
Carcinoids tend to be diagnosed late with nodal involvement or
distant disease found in the majority of patients at the time of
presentation.2,3,9 The risk of nodal and distant disease increases
with the size of the primary tumor and multicentric disease is a
common finding. The use of chemotherapy in the adjuvant setting
has been shown to be of no benefit.2,3,9 There is no role for the use
of palliative chemotherapy if surgical resection can be performed
for metastatic disease.2,3,9 Octreotide has been used in the pallia-
tive setting to control symptoms of the carcinoid syndrome. There
has been some data to suggest it may keep disease from progress-
ing for short periods of time.
LYMPHOMA
Lymphoma is a very chemo-sensitive type of tumor. Unfortu-
nately, lymphoma of the small bowel is usually diagnosed at the
time of laparotomy and the final pathology is not available for
several days precluding the use of chemotherapy as the primary
treatment. If the patients are rendered free of disease from sur-
gery, most patients are not given chemotherapy.2,3 There has been
no change in the adjuvant treatment pattern of small bowel lym-
phoma over the past 20 years.2 Patients with metastatic disease are
all treated with chemotherapy.
SARCOMA/GIST
With the discovery that most sarcomas of the small bowel actually
arise from the interstitial cells of Cajal and not smooth muscle
cells, the role of adjuvant chemotherapy has changed dramatically.
The use of adjuvant therapy for sarcomas did not alter survival.2,3,11
However, the discovery that GIST has a mutation in the c-KIT
oncogene resulting in the activation of the KIT receptor tyrosine
kinase has made them susceptible to imatinib. Imatinib exerts its
influence in GIST by blocking the adenosine triphosphate bind-
ing site of KIT to the transmembrane receptor. Thereby, imatinib
inhibits the proliferation and promotes apoptosis of GIST cells by
interrupting the tyrosine kinase mediated intracellular signaling.
The use of chemotherapy for GIST has increased dramatically
from 2001 to 2005 because of this finding.2
The use of imatinib started in patients with metastatic disease
and the majority of patients were shown to have rapid and sustained
PMPH_CH20.indd 189
Small Bowel Tumors and Diverticular Disease of SB ■ 189
responses. These findings coupled with the high rate of recurrence
after curative resection has led to the use of imatinib in an adju-
vant setting for patients with GIST. The ACOSOG Z9001 trial used
imatinib for patients with resected tumors larger than 3 cm for
1 year versus placebo.17 The study was stopped after 1 year due to
the recurrence free survival advantage seen in the imatinib arm.17
There was no difference in overall survival and it was thought that
the use of imatinib in this setting only delayed the time to recur-
rence.17 One has to ask the question, would it be better to wait until
the recurrence occurs and then treat the patient?
GIST often presents with advanced disease and the use of
imatinib in a neoadjuvant setting has been studied. The RTOG
0312 trial treated patients with unresectable disease for 8 to 12
weeks and found that over 90% had an objective response and
most of them went on to be resected for cure.18
Patients with GIST that have metastatic disease to the liver or
peritoneum are treated with imatinib until progression of disease.
There is now a second line drug, sunitinib, for use in patients with
refractory GIST to imatinib.
The low toxicity profile of imatinib along with its oral dosing
and significant efficacy has altered the natural history of this dis-
ease. Currently, there is not enough data to accurately address the
correct dosing, timing of treatment, and length of treatment for
patients receiving imatinib to define the subset(s) of patients who
will most likely benefit from treatment.
7. What are the prognostic factors for survival for small bowel
tumors?
The two most important prognostic factors for survival in small
bowel cancer are tumor stage at the time of presentation and the
ability to completely resect the tumor.2-6,9-13
ADENOCARCINOMA
The median survival for patients with small bowel adenocarci-
noma is less than 20 months.2-5 The 5-year survival for all com-
ers is about 30%.2-5 Improvements in survival have been seen in
patients with early stage disease, complete surgical resections, and
duodenal lesions.2-5 Poor prognostic findings include age greater
than 55 years, ileal or jejunal location, Afro-American descent,
poorly differentiated tumors, and microscopic positive margins.2-5
There has been no change in survival over the past 20 years for
patients with adenocarcinoma of the small bowel.2
CARCINOID
Carcinoid tumors have the longest survival of all small bowel
tumors. The median survival for all patients with carcinoid
tumors is greater than 10 years.2,3,8,9 Stage was the most important
predictor of survival in this group.2,3,8,9 Other favorable prognostic
indicators included tumors less than 1 cm, incidentally found
lesions, duodenal location, age less than 50 years, and female
sex.8,9 There had been no change in survival for patients with car-
cinoid over the past 20 years.2 The majority of patients with carci-
noid tumors eventually die from progression of disease. This fact
coupled with the increasing incidence of carcinoid tumors war-
rant the need for the development of adjuvant trials to treat this
disease.
5/21/2012 8:57:15 PM
 190 ■ Surgery: Evidence-Based Practice
LYMPHOMA
The 5-year survival for patients with small bowel lymphoma is
approximately 50%.2 There has been no change in survival over
the past 20 years.2 Survival is based on stage of disease and resec-
tion for cure.2,3,10 Poor prognostic findings include male sex, age
greater than 75 years, and non-Caucasian ethnicity.2,3,10
SARCOMA/GIST
The median survival for patients with sarcomas prior to the new
nomenclature and treatment with imatinib was up to 34 months
with a 5-year survival of 39%.2,3,11 Survival was improved for
patients with smaller tumors, less mitotic activity, complete resec-
tions, and age less than 75 years.2,3,11 Despite the increased use of
imatinib for GIST, the median survival is only 40% at 5 years.19
The long-term effects of imatinib on the survival of GIST patients
may not be seen for several more years as the use of the drug has
only recently become more widespread.
Tumor size less than 10 cm, gross residual disease after resec-
tion, high mitotic activity, and male sex have also been implicated
as poor prognostic findings for survival in GIST patients.11,12,16
8. What is the optimal treatment for small bowel tumor
recurrence?
The most common location for recurrence of small bowel cancer
is the abdominal cavity followed by the liver and omentum. The
majority of patients are not resectable at the time of recurrence
and palliative surgery, chemotherapy, or pain management are the
main treatment options.2-6,9-13,19
ADENOCARCINOMA
The most common site of recurrence is in the peritoneum or omen-
tum. Most patients will develop liver metastases also. If the recur-
rence is isolated which it rarely is, surgical resection would be the
treatment of choice. There is no surgical approach for widely meta-
static adenocarcinoma and these patients are treated with palliative
intent. The survival following recurrence is less than 6 months.5
CARCINOID
The most common site of recurrence for carcinoid tumors is the
liver. Intraabdominal spread is also common. There is a role for
debulking disease for carcinoid tumors because there is no effec-
tive chemotherapy, and the tumors often become symptomatic
before they are life threatening.19 Liver metastases that cause car-
cinoid syndrome can be treated with surgery or octreotide. Both
modalities have been shown to reduce symptoms, but disease
progression is the rule. Complete surgical resection of disease can
improve long-term outcomes and surgery is also very important
in relieving symptoms from recurrent disease.19
LYMPHOMA
Recurrence following surgical resection for lymphoma occurs in
up to one-third of patients.3 Treatment is chemotherapy and may
PMPH_CH20.indd 190
include radiation therapy in certain instances. Gastrointestinal
complications during treatment of intestinal lymphomas are well
documented and must be watched for.
SARCOMA/GIST
Recurrence following curative resection is the rule rather than the
exception for sarcomas/GIST.2,3,11-13 The most common locations
for recurrence are the peritoneum, omentum, and the liver.2,11-13
If the patient has resectable disease, the patient should undergo
resection.11-13 Survival following complete surgical excision of a
recurrence can be as good as for an initial resection for cure.11-13,16
Five-year survivals are up to 40% following a second complete
resection.12 Patients with unresectable disease should be treated
with imatinib and patients with rapid and sustained responses may
become candidates for exploration.12,16
SMALL BOWEL DIVERTICULAR DISEASE
There are two main types of small bowel diverticular disease. There
are true diverticula of the small bowel and the most common of
these is a Meckel’s diverticulum. False diverticula of the small
bowel can happen throughout the small intestine and they resemble
their colonic counterparts. The mean age at the time of diagnosis is
68 years and women are more likely to be diagnosed than males.20
The incidence of small bowel diverticulosis is estimated to be less
than 1% with the most common location being in the duodenum.20
This most likely represents an increased incidence due to the wide-
spread use of upper endoscopy. The most common explanation for
the development of small bowel false diverticula is an underlying
abnormality in intestinal peristalsis.20
The vast majority of diverticula are asymptomatic.20 Compli-
cations from diverticula include pain, rupture, abscess formation,
and peritonitis; and occur in 10% to 20% of patients.20 Surgical
treatment is usually required for patients who present with symp-
tomatic disease.20
The majority of small bowel diverticula are diagnosed dur-
ing upper endoscopy or laparotomy for another indication.20 Over
three-quarters of the diverticula are found in the duodenum while
the rest are dispersed between the jejunum and the ileum.20 There
is no role for prophylactic surgical resection of the false divertic-
ula because they are often multiple and they are found throughout
the length of the small bowel.20
9. Is there a role for surgery to remove a Meckel’s diverticulum
found incidentally at the time of surgery for another reason?
Meckel’s diverticula are usually remembered by the rule of twos.
They are found within 2 ft of the ileocecal valve, they are 2-in.
long, they have two possible types of mucosa, and they are too bad
if you have one. Symptoms can include inflammation that mimics
appendicitis, peritonitis from rupture, bleeding, obstruction, and
abscess formation.15 These complications are usually corrected
surgically because the diagnosis is rarely made preoperatively.15
Meckel’s diverticula are usually asymptomatic and are found
most commonly at the time of laparotomy for another indication.
A recent study15 recommends that incidental Meckel’s diverticula
should be removed to prevent possible complications and to decrease
the risk of developing cancer in the Meckel’s diverticula.15
5/21/2012 8:57:15 PM
 Small Bowel Tumors and Diverticular Disease of SB ■ 191

Summary Table
Adenocarcinoma Carcinoid Lymphoma Sarcoma/GIST
Mean age (years) 65 51 62 59
Symptoms Pain, bleeding, Pain, bleeding, nausea, Pain, fever, weight loss, Bleeding, pain
nausea, vomiting, vomiting
obstruction
Location Duodenum Distal ileum Jej-ileal Jejunal
Diagnostic Test Upper endoscopy Laparotomy, CT Laparotomy CT, capsule endoscopy
Surgery
Med survival (months) 13 182 13 22
Overall survival 23 Not reached 15 66
(months)
Curative resection (%) 65 73 67 85
Poor prognosis Advanced stage, age Size, liver metastases, Age > 75 years, Tumor size, positive
> 55 years, ileal age < 50 years, nonwhites margins
location jejunal location
Adjuvant therapy No benefit No benefit No benefit Beneficial, imatinib
Time to recurrence 23 25 14 25
(months)
Sites of recurrence Peritoneum, liver, Mesentery, liver Peritoneum, bone Abdominal, omentum,
omentum marrow liver

REFERENCES
1. Jemel A, Siegel R, Xu J, Ward E. Cancer Statistics 2010. CA Can-
cer J Clin. 2010;60:277-300.
2. Bilimora KY, Bentrem DJ, Wayne JD, et al. Small bowel cancer in
the United States: Changes in epidemiology, treatment and sur-
vival over the last 20 years. Ann Surg. 2009;249:63-71.
3. Cunningham JD, Aleali R, Brower ST, et al. Malignant small
bowel neoplasms: Histopathologic determinants of recurrence
and survival. Ann Surg. 1997;225:300-306.
4. Dabaja BS, Suki D, Pro B, et al. Adenocarcinoma of the small
bowel: Presentation, prognostic factors, and outcome in 217
patients. Cancer. 2004;101:518-526.
5. Hong SH, Koh YH, Rho SY, et al. Primary adenocarcinoma of
the small intestine: presentation prognostic factors and clinical
outcome. Jpn J Clin Oncol. 2008;39:54-61.
6. Nicholl MB, Ahuja V, Conway C, et al. Small bowel adeno-
carcinoma: Under staged and undertreated? Ann Surg Oncol.
2010;17:2728-2732.
7. Hatzarras I, Plaesty JA, Abir F, et al. Small-bowel tumors: epide-
miologic and clinical characteristics of 1260 cases from the Con-
necticut tumor registry. Arch Surg. 2007;142:229-235.
8. Landry CS, Brock G, Scoggins CR, et al. A proposed system
for small bowel carcinoid tumors based on an analysis of 6380
patients. Amer J Surg. 2008;196:896-903.
9. Shebani KO, Souba WW, Finkelstein DM, et al. Prognosis and
survival in patients with gastrointestinal tract carcinoid tumors.
Ann Surg. 1999;229:815-823.
10. Fischbach W, Kestel W, Kirchner T, et al. Malignant lympho-
mas of the upper gastrointestinal tract. Cancer 1992;70:1075-
1080.
11. Howe JR, Karnell LH, Scott-Conner C. Small bowel sarcoma:
Analysis of survival from the National Cancer Data Base. Ann
Surg Onco. 2001;8:496-508.
12. Dematteo RP, Lewis JJ, Leung D, et al. Two hundred gastrointes-
tinal stromal tumors: Recurrence patterns and prognostic fac-
tors for survival. Ann Surg. 2000;231:51-58.
13. Crosby JA, Catton CN, Davis A, et al. Malignant gastrointestinal
stromal tumors of the small intestine: A review of 50 cases from
a prospective database. Ann Surg Oncol. 2001;8:50-59.
14. Hara AK, Leighton JA, Sharma VK, et al. Imaging of small bowel
disease: Comparison of capsule endoscopy, standard endoscopy,
barium examination and CT. Radiographics. 2005;25:697-711.
15. Thirunavukarasu P, Sathaiah M, Sukumar S, et al. Meckel’s
diverticulum: A high risk region for malignancy in the ileum.
Ann Surg. 2011;253:223-230.
16. Eisenberg BL, Judson I. Surgery and imatinib in the manage-
ment of GIST: Emerging approaches to adjuvant and neoadju-
vant therapy. Ann Surg Oncol. 2004;11:465-475.
17. DeMatteo R, Owzar K, Maki R, et al. Adjuvant imatinib mesy-
late increases recurrence free survival (RFS) in patients with
completely localized primary gastrointestinal stromal tumor
(GIST): North American Intergroup Phase III trial ACOSOG
Z9001. Proc Am Soc Clin Oncol. 2007:Abstract 10079.
18. DeMatteo RP, Maki RG, Singer S, et al. Results of tyrosine kinase
inhibitor therapy followed by surgical resection for metastatic
gastrointestinal stromal tumor. Ann Surg. 2007;245:347-352.
19. Bourdeaux JP, Putty B, Frey DJ, et al. Surgical treatment of
advanced-stage carcinoid tumors. Lessons learned. Ann Surg.
2005;241:839-846.
20. Akhrass R, Yaffe MB, Fischer C, et al. Small bowel diverticulosis:
perceptions and reality. J Amer Coll Surg. 1996;184:383-388.

PMPH_CH20.indd 191 5/21/2012 8:57:15 PM

 CHAPTER 21
Enterocutaneous Fistula
Peter A. Learn
Enterocutaneous fistula (ECF) remains one of the most challeng-
ing surgical problems in alimentary tract surgery with continued
high rates of associated morbidity and mortality. The difficulty
of fistula management can be compounded by the interplay of
the underlying pathology, ongoing sepsis, and the physiologic
derangements caused by the fistula itself. The heterogeneity of
the etiology, location, and behavior of ECF further complicates
the study of interventions for ECF. The treatment of patients with
ECF remains in large part guided by fundamental principles of
resuscitation, control of sepsis, aggressive wound care and con-
trol of effluent, nutritional support, and appropriately timed
surgical intervention. Although many of these principles of man-
agement still rely heavily on historical experience and expert
opinion, adequate data exists on some aspects of care to provide
an evidence-based framework for ECF management. This chap-
ter will specifically address the nonacute management of exter-
nal intestinal fistulas. Studies limited to pancreatic, anorectal, or
inflammatory bowel disease (IBD) fistulas are excluded.
1. What factors predict mortality in ECF?
While many studies on ECF report mortality and associated factors,
almost none have rigorously evaluated models to predict mortality.
One exception is a study by Altomare et al. in which a predictive
model was derived from logistic regression analysis on a retrospec-
tive cohort of 70 consecutive patients from 1981 to 1986.1 The model,
incorporating only the APACHE II score and serum albumin at
time of diagnosis was then prospectively evaluated in a subsequent
17 patients and demonstrated an accuracy of 94% in predicting mor-
tality (Level 1b evidence).
Answer: A reasonably accurate estimation of mortality can be
calculated using a model incorporating APACHE II score and serum
albumin, although the model would benefit from further validation
in other cohorts (Level 1b evidence, Grade B recommendation).
2. What is the optimal nutritional strategy in ECF?
The significant nutritional demands of ECF are well-recognized
and result from the interplay of several factors including premorbid
192
PMPH_CH21.indd 192
malnutrition, intestinal failure resulting from fistula diversion,
fistula-related sepsis, and persisting underlying pathology. Ensur-
ing adequate nutritional support is a fundamental principal in
fistula management, and both enteral and parenteral approaches
have been evaluated to varying degrees.
Total parenteral nutrition (TPN) reached widespread avail-
ability in the 1970s and was quickly applied to the nutritional sup-
port of patients with ECFs. The best data available supporting its
use are obtained from prospective cohort studies performed in
that decade using historical controls (Level 4 evidence). In these
early studies, patients receiving TPN had approximately twice the
ECF closure rate and at least half to one-quarter the mortality.2,3
While significant methodological flaws make the exact degree of
improvement attributable strictly to TPN difficult to ascertain, the
clear benefits of TPN in modern management preclude the ability
to subject the intervention to placebo-controlled study.
Enteral nutrition has also been advocated as a viable means
of supporting patients with ECF, and published case series reports
have demonstrated the ability to meet nutritional requirements
with various forms of enteral nutrition in select populations (Level
4 evidence).4,5 Additionally recognized benefits of enteral nutrition
are lower costs compared to TPN. However, a trial comparing enteral
versus parenteral nutrition strategies has not been performed.
Answer: TPN can be used to provide complete nutritional sup-
port to patients with ECF and potentially increase rates of fistula
closure (Level 4 evidence, Grade C recommendation). Enteral nutri-
tion is attractive for its potential benefits over long-term TPN and
deserves further evaluation against TPN in controlled studies. As
enteral nutrition has been observed to meet the nutrition needs of
some patients, it can be considered for use on a selective basis, in the
setting of a clinical study, or as an adjunct to TPN; it remains unclear
if rates of fistula closure or time to closure are positively affected rel-
ative to TPN alone (Level 4 evidence, Grade C recommendation).
3. What is the role of somatostatin analogs in the management
of ECF?
Early case series reporting the use of somatostatin and its analogs
in the treatment of ECF fostered optimism about the potential for
5/21/2012 8:58:35 PM

this therapy and ultimately led to the reporting of several clinical
trials, making this question the most rigorously studied aspect of
ECF management. The ability to combine the results of the trials,
however, is limited by their usage of different analogs and doses
for different lengths of time in heterogeneous populations.
The most recently published of these trials evaluated the use
of the long-acting somatostatin analog, lanreotide PR (prolonged
release), in both pancreatic and ECF.6 In this multicenter, ran-
domized, double-blind, placebo-controlled trial, patients were
included based on clear definitions for pancreatic and EC fistulae.
The primary endpoint was reduction in fistula output by 50% at
72 h after the first injection. Nonresponders at this first assessment
were unblinded and permitted to cross over. Secondary analyses
included time to fistula closure. The study met its power require-
ments after enrolling 111 patients, among whom there were 18
duodenal and 18 nonduodenal small bowel ECFs. Overall, 64.8%
of patients receiving lanreotide met the primary endpoint com-
pared to only 37.7% of patients on placebo (OR 3.07, p = 0.006),
a trend that was preserved in the subset of patients with ECF. A
shorter time to fistula closure was suggested in the analysis of
patients who remained on lanreotide in the blinded group, but
the study was not powered to evaluate this outcome. Although
the study makes a strong argument for the ability of lanreotide to
decrease fistula output (Level 1b evidence), conclusions regarding
time to closure are limited by the trial design to educated specula-
tion and extrapolation.
A smaller but well-designed study by Sancho et al. reported
the results of a randomized, double-blind, placebo-controlled
trial of octreotide therapy in the early treatment of postoperative
ECF (Level 1b evidence).7 The study population included patients
with gastric, intestinal, and a small number of pancreatic fistulae
diagnosed within 8 days of enrollment, stratified into two groups
by daily volume of output and regardless of presence of ongoing
sepsis. Patients received standardized support therapy, includ-
ing TPN and the trial treatment: either subcutaneous octreotide
100 mcg three times a day (14 patients) or saline placebo admin-
istered identically (17 patients). The trial treatment was adminis-
tered either for 20 days of continuous treatment or until fistula
closure. Randomization scheme and postrandomization exclu-
sion events were reported, and the trial was powered to detect a
decrease of fistula output of 50% or greater. In this trial, admin-
istration of octreotide failed to reduce fistula output better than
placebo. Spontaneous closure events occurred in each arm, but
neither the incidence nor the mean time to closure reached sta-
tistical significance, although the study was not powered to study
these endpoints.
These results contrasted somewhat with the same group’s
prior results published in 1987.8 In this randomized, placebo-
controlled, double-blind, crossover study (Level 1b evidence),
14 patients with postoperative small bowel ECF underwent
standardized treatment with TPN for 7 days. The patients then
received either octreotide (225–300 mcg daily divided into three
doses) or saline placebo for 2 days. After 2 days, the groups were
crossed over to the other treatment. After the 4 days of the cross-
over portion of the trial, all patients were treated indefinitely with
octreotide to the point of fistula closure or surgical intervention.
While a power analysis and other important information were not
reported as in the later trial, octreotide in this trial clearly reduced
fistula output volume by at least half with a rebound in output
following interruption of octreotide therapy by placebo. The dif-
ferences in the results of these two studies by the same group are
PMPH_CH21.indd 193
Enterocutaneous Fistula ■ 193
attributed by study authors to a possible effect of the timing of
octreotide administration after stabilization of the ECF, noting
that control of sepsis was not required in the later study.
Two further randomized-controlled trials have been published
on this specific topic. In 1992, Torres et al. published the results
of a multicenter, randomized (scheme unreported), single-blind,
placebo-controlled trial of continuous intravenous somatostatin
infusion (Level 2b evidence).9 The study results demonstrated no
difference in the frequency of fistula closure, although it appeared
that fistula output and time to closure was decreased in the somato-
statin group. However, absence of information on the age of the
fistulas, crossover of three patients from the placebo arm to the
somatostatin arm, and intergroup differences in pretreatment fis-
tula output complicates the interpretation of the results. In addi-
tion, the evaluation of time to closure would have benefited from
a more sophisticated event analysis technique (i.e., Kaplan–Meier
analysis). In 1993, Scott et al. published results of their random-
ized, double-blind, placebo-controlled trial of octreotide (Level 2b
evidence).10 As they did not observe significant reductions in fistula
losses or increased rates of spontaneous closure, a high dropout
rate and small sample size impair the interpretation of the results.
Answer: No evidence from controlled trials definitively sup-
ports the use of somatostatin analogs to increase the frequency of
spontaneous ECF closure (Level 1b evidence, Grade A recommen-
dation). Somatostatin may decrease fistula output and time to clo-
sure but would benefit from further well-designed confirmatory
studies (Level 2b evidence, Grade B recommendation). Octreotide
has not been consistently demonstrated to decrease fistula out-
put or time to closure and support for its use must be considered
limited (Conflicting results from Level 1b and 2b studies, Grade
D recommendation). Prolonged release lanreotide can be used to
reduce fistula output volume, but its effect on time to fistula clo-
sure or frequency of closure has not been definitively answered
(Level 1b evidence, Grade A recommendation).
4. When is the optimal timing for elective surgical interven-
tion for ECF?
The subject of optimal timing for elective surgical intervention
has not been prospectively evaluated. In retrospective studies,
the data is mixed. In a cohort of 205 patients undergoing surgical
treatment of ECF, among whom more than half had IBD, Lynch
et al. noted higher rates of recurrence in patients undergoing sur-
gery 2 to 12 weeks after their last operations (28% vs. 20% within
2 weeks and 15% greater than 12 weeks), although this finding
did not achieve statistical significance (Level 4 evidence).11 Some-
what contradictory results were observed by Brenner et al. in their
cohort of 135 patients undergoing surgery for ECF repair, among
whom a quarter had IBD. In this study, ECF recurrence was 12%
when operation was performed within 36 weeks of fistula forma-
tion compared to 36% for those undergoing operation after 36
weeks.12 Although the method by which this interval was identi-
fied is only partially addressed in the paper, this dichotomized
factor was independently associated with recurrence on multi-
variate logistic regression (Level 4 evidence).
When discussing the timing of surgery, it is also instructive to
consider the findings of the Gayral’s lanreotide study: even in the
placebo treated arm, spontaneous fistula closure occurred within
17 days in half the patients (Level 1b evidence). Thus, planning for
surgical repair of ECF should account for the natural history of
the disease which favors spontaneous closure.
5/21/2012 8:58:36 PM
 194 ■ Surgery: Evidence-Based Practice

Answer: The optimal timing for fistula repair remains
unknown. As about half of fistulae will spontaneously close within
3 weeks, this seems the minimum reasonable period for observa-
tion (conflicting Level 4 evidence, Grade D recommendation).
5. Is surgical closure of the fistula best accomplished by
resectional or nonresectional approaches?
The choice between resectional (i.e., small bowel resection) and
nonresectional (i.e., oversewing or wedge repair) techniques
to address the originating bowel segment has not been stud-
ied prospectively. In the previously mentioned study by Lynch
et al., fistula recurrence occurred in 32.7% of patients treated
with nonresectional techniques compared with 18.4% of patients
undergoing segmental resection of the fistulous origin.11 The
association of nonresectional techniques with recurrence of the
fistula was significant on multivariate analysis (Level 4 evidence).
Similarly, the multivariate analysis by Brenner et al. for factors
associated with recurrence after surgery appeared to favor resec-
tion with a hand-sewn anastomosis over resection with a stapled
anastomosis or nonresectional repair (Level 4 evidence).12 While
these results have been interpreted to suggest a superiority of
resectional approaches, it is very easy to postulate on factors that
could have confounded recurrence and the inability to resect a
fistula.
Answer: Resection of the segment of bowel from which the
fistula originates might be preferable to nonresectional techniques
when feasible (Level 4 evidence, Grade C recommendation).

Clinical Question Summary

Question
1 What factors predict
mortality in ECF?
2 What is the optimal
nutritional strategy in
ECF?
3 What is the role of
somatostatin analogs in
the management of ECF?
4 What is the optimal timing
for elective surgical
intervention for ECF?
5 Is surgical closure of the
fistula best accomplished
by resectional or
nonresectional
approaches?
Answer Grade of Level of References
Recommendation Evidence
A model incorporating APACHE II B 1b 1
scoring and serum albumin is highly
accurate in predicting mortality.
TPN can not only provide complete C 4 2, 3
nutritional support to patients, but
may also increase rates of closure.
Enteral nutrition should be considered C 4 4, 5
on a selective basis.
Somatostatin analogs do not A 1b, 2b 6-10
significantly increase the frequency
of spontaneous ECF closure.
Somatostatin may decrease both B 2b 9
fistula output and time to
spontaneous closure.
Octreotide is inconsistently D 1b, 2b 7, 8, 10
demonstrated to decrease fistula
output.
Prolonged release lanreotide can be A 1b 6
used to decrease fistula output.
Inadequate data exists to endorse a D 4 11, 12
strong recommendation on timing.
Resection of the originating segment C 4 11, 12
of bowel may decrease likelihood of
recurrence.

REFERENCES
1. Altomare DF, Serio G, Pannarale OC, Lupo L, Palasciano N. Pre-
diction of mortality by logistic regression analysis in patients with
postoperative enterocutaneous fistulae. Br J Surg. 1990;77(4):450.
2. Deitel M. Nutritional management of external gastrointestinal fis-
tulas. Can J Surg. 1976;19(6):505-509.
3. Thomas RJ. The response of patients with fistulas of the gas-
trointestinal tract to parenteral nutrition. Surg Gynecol Obstet.
1981;153(1):77-80.
4. Levy E, Frileux P, Cugnenc PH, Honiger J, Ollivier JM. High-out-
put external fistulae of the small bowel: management with con-
tinuous enteral nutrition. Br J Surg. 1989;76(7):676.
5. Teubner A, Morrison K, Ravishankar HR, Anderson ID, Scott
NA, Carlson GL. Fistuloclysis can successfully replace parenteral

PMPH_CH21.indd 194 5/21/2012 8:58:36 PM


feeding in the nutritional support of patients with enterocutane-
ous fistula. Br J Surg. 2004;91(5):625-631.
6. Gayral F, Campion JP, Regimbeau JM, Blumberg J, Maisonobe P,
Topart P, et al. Randomized, placebo-controlled, double-blind study
of the efficacy of lanreotide 30 mg PR in the treatment of pancreatic
and enterocutaneous fistulae. Ann Surg. 2009;250(6):872-877.
7. Sancho JJ, di Costanzo J, Nubiola P, Larrad A, Beguiristain A.
Randomized double-blind placebo-controlled trial of early oct-
reotide in patients with postoperative enterocutaneous fistula.
Br J Surg. 1995;82(5):638.
8. Nubiola C, Nubiola-Calonge P, Badia JM, Sancho J, Gil MJ, Segura M.
Blind evaluation of the effect of octreotide (SMS 201-995), a somatosta-
tin analogue, on small-bowel fistula output. Lancet. 1987;2(8560):672.
PMPH_CH21.indd 195
Enterocutaneous Fistula ■ 195
9. Torres AJ, Landa JI, Moreno-Azcoita M, Arguello JM, Silecchia
G. Somatostatin in the management of gastrointestinal fistulas.
A multicenter trial. Arch Surg. 1992;127(1):97.
10. Scott NA, Finnegan S, Irving MH. Octreotide and postoperative
enterocutaneous fistulae: A controlled prospective study. Acta
Gastroenterologica Belgica. 1993;56(3-4):266.
11. Lynch AC, Delaney CP, Senagore AJ, Connor JT, Remzi FH,
Fazio VW. Clinical outcome and factors predictive of recurrence
after enterocutaneous fistula surgery. Ann Surg. 2004;240(5):
825-831.
12. Brenner M, Clayton JL, Tillou A, Hiatt JR, Cryer HG. Risk fac-
tors for recurrence after repair of enterocutaneous fistula. Arch
Surg. 2009;144(6):500-505.
5/21/2012 8:58:36 PM
 CHAPTER 22
Short Bowel Syndrome
Andrea MacNeill and S. Morad Hameed
INTRODUCTION
The decision to undertake a massive intestinal resection is among
the most difficult and dreaded in surgery. Unfortunately, condi-
tions such as Crohn’s disease, radiation enteritis, neoplasms (such
as desmoid tumors), and abdominal catastrophes (including mes-
enteric ischemia, closed loop obstruction or intestinal volvulus)
sometimes leave no other options.1 Massive resection can lead to
short bowel syndrome (SBS), a state of nutrient malabsorption,
or ultimately to intestinal failure (IF), a situation where adequate
nutrition and hydration cannot be maintained without nutritional
supplementation.2 These conditions, once considered uniformly
fatal, have tested the limits of medical and surgical innovation
and care, and have prompted exciting advances and promising
new strategies.
The emergence of parenteral nutrition (PN) in the 1960s, a
landmark event in surgical history,3 changed the course of IF, sud-
denly making it survivable in the short-term.3 Recently, intesti-
nal rehabilitation efforts have sought to capitalize on improved
understanding of intestinal adaptation to achieve enteral auton-
omy. Advances in surgical reconstruction have expanded the
nontransplant armamentarium against SBS at the same time as
survival rates from intestinal transplantation (IT) are improving.
1. What is a massive resection and who is at risk of Intestinal
Failure?
Enteral nutrition (EN) is dependent on the highly integrated func-
tion of the stomach, pancreas, liver, small intestine, and colon.
Resection or dysfunction of any combination of these organs con-
fers a unique IF risk. The small intestine is typically 800 cm long
and sees about 8 to 9 L of fluid per day.4 Macronutrients (proteins,
carbohydrates) are preferentially absorbed in the jejunum, while
the ileum is primarily responsible for the absorption of fluid, bile
salts, and vitamin B12. The colon absorbs residual water, and gen-
erates and absorbs short chain fatty acids. Together, the ileum and
colon act to slow intestinal transit through neurohumoral mecha-
nisms (ileocolic brake), coordinated peristalsis, and the action of
the ileocecal valve.
In general, patients with 200 cm of healthy small intestine
and an intact ileocecal valve and colon have a high likelihood of
achieving nutritional independence after massive resection. How-
196
PMPH_CH22.indd 196
ever, patients with less than 100 cm of jejunum and no colon (or
less than 50 to 60 cm of jejunum with an intact colon) and those
with pathology in the residual small intestine (Crohn’s disease,
radiation enteritis, pseudo-obstruction) are at high risk of IF and
long-term PN dependence.1,2 Preservation of the ileocecal valve
can protect the small intestinal remnant by preventing reflux
of colonic material and resultant bacterial overgrowth. These
thresholds are important to consider intraoperatively, and may
influence decisions regarding resection versus stricturoplasty in
Crohn’s disease, or resection versus temporary closure, resuscita-
tion and reevaluation in cases of borderline viability in the con-
text of obstruction or ischemia.
Postoperatively, plasma levels of citrulline (a non-protein
amino acid produced in the intestinal mucosa, and a marker of
viable intestinal mass) have some prognostic value: levels less than
20 mmol/L have been shown to be highly predictive of permanent
IF.5 Interestingly, the postresection phase is far from static: intes-
tinal adaptation, which has been the subject of intense scientific
investigation, may ultimately make the difference between life-
long dependence on PN and enteral autonomy.
2. What is the optimal nutrition support strategy in SBS?
INITIAL CONSIDERATIONS
An aggressive approach to rehydration, correction of electrolyte
abnormalities, and provision of macro- and micronutrients must
be taken in intestinal resection patients considered to be at high
risk of IF. Fluid balance and serum electrolyte levels should ini-
tially be monitored every few hours, and replaced proactively. Diar-
rhea, which is often due to a combination of low-absorptive surface
area, gastric hypersecretion, and the osmotic effects of bile salts in
patients with ileal resections, can be addressed initially by limiting
oral intake and administering antidiarrheals such as loperamide
or codeine, proton pump inhibitors, or cholestyramine to bind bile
salts. Low-dose broad-spectrum antibiotics can be administered if
there is suspicion that small bowel bacterial overgrowth may be a
contributing factor, but this is more common later in the disease
process. Interestingly, in patients with less than 60 cm of small intes-
tine, the initiation of enteral feeds can have a net secretory effect on
5/21/2012 8:59:13 PM

the gut and actually lead to increased fluid losses. The effects of oral
intake should be carefully monitored in these patients.
PN
For patients with less than 100 cm of jejunum remaining, the early
initiation of PN has been lifesaving. PN should be started within
a few days postoperatively and continued until EN can be ramped
up to 80% of goal. Priorities for PN administration include ade-
quate provision of macronutrients (protein, carbohydrate, lipid),
replacement of electrolytes including magnesium (which is par-
ticularly prone to depletion), and replacement of micronutrients
such as zinc, which is often depleted. Patients with ileal resections
are prone to deficiencies of vitamin B12 and fat-soluble vitamins
(A, D, E, K). Levels should be monitored and vitamins should
be replaced accordingly. Transition to EN should be gradually
attempted in these patients as adaptation proceeds.
Patients with less than 60 cm of small intestine remaining
will require long-term or home PN. These patients are at high risk
of complications such as line sepsis, venous thrombosis, steatosis,
cholestasis, and hepatic cirrhosis. Among these complications,
end-stage liver disease is among the most feared and is a lead-
ing cause of PN-related mortality. Cholestasis may benefit from
reductions of PN dose or PN cycling. Although the mechanisms of
PN-associated liver disease (PNALD) are still unclear, vegetable-
or soy-based lipid emulsions may promote cholestasis through the
generation of inflammatory mediators. Recent studies have pro-
vided early evidence to suggest that omega 3 fatty acid prepara-
tions (omegaven) may reduce the effect of PNALD in children.6,7
TRANSITION TO EN
In animal studies, EN, has been shown to limit mucosal atrophy and
preserve surface area, promote endocrine function, and enhance
mucosal immunity.8 Besides these advantages, EN is more physi-
ologic, safe, and cost-effective than PN. For these reasons, numer-
ous experts have promoted a stepwise transition to EN over days
and weeks.2 Based on small trials, various authors have argued that
carbohydrate-to-fat ratios may determine diarrhea volumes: high-
carbohydrate diet may favor diarrhea in patients with jejunostomy,
while reducing output in patients with intact colons.9,10
ANSWER: Early efforts in nutrition support in IF should focus
on parenteral administration of macronutrients and maintenance
of euvolemia and electrolyte balance. Pharmacologic interventions
may be needed to reduce GI losses. For patients with favorable prog-
nosis for nutritional independence, a graded escalation of enteral
feeds with weaning from PN should be initiated. For patients with
less than 50 cm of small intestine, preparations should be made for
long-term PN. All patients should be monitored closely for vitamin
and micronutrient deficiencies, with special emphasis on vulner-
abilities due to specific gastrointestinal anatomy (e.g., vitamin B12
deficiencies with ileal resection) (Grade D recommendation).
3. What pharmacologic strategies can promote intestinal
adaptation?
In the immediate postoperative phase, the intestinal remnant under-
goes both structural and functional adaptation to compensate for
the loss of absorptive and digestive capacity. Whether or not these
PMPH_CH22.indd 197
Short Bowel Syndrome ■ 197
measures will be sufficient to achieve enteral autonomy is depen-
dent upon the length, location, and quality of remaining bowel, with
the presence of a colon of particular importance. The majority of
the adaptive response occurs within the first few months following
resection, but the process may continue beyond 2 years.
Following ileal resection, the jejunum undergoes morphologic
changes in villus height and crypt depth, along with increased
enzymatic activity. The ileum has relatively greater adaptive capac-
ity, responding to jejunal loss by increasing in overall length and
diameter, in addition to histologic alterations, to maximize absorp-
tive surface area.
EN
Intestinal adaptation is contingent upon enteral stimulation, and
will not occur in the fasted state. In particular, enteral fat stimu-
lates the release of trophic hormones important to the adaptive
process. Continuous enteral feeding has been shown to be supe-
rior to bolus feeds in inducing adaptation, as mucosal receptors
and transporters remain maximally saturated.11
GROWTH HORMONE AND GLUTAMINE
Recent years have witnessed a surge of interest in pharmacologic
manipulation of the trophic hormones involved in intestinal adap-
tation, with some promising results. Growth hormone (GH) is
known to induce structural and functional adaptation in animal
models12,13 and has been studied in combination with the amino acid
glutamine, which is believed to be the primary fuel of enterocytes.14
Early case series of GH + glutamine in conjunction with a high-
carbohydrate diet generated considerable optimism of improved
intestinal absorption,15,16 but the results of larger, more rigorous
trials have been mixed. A 2010 Cochrane Collaboration systematic
review analyzed five double-blind, placebo-controlled, randomized
trials from 1997 to 2005(Level 1a evidence).17 These studies consis-
tently demonstrated that treatment with GH resulted in significant
increases in body weight and lean body mass (with or without glu-
tamine), as well as the absorptive capacities of energy, nitrogen, and
fat, although these latter findings displayed considerable heteroge-
neity. Although PN requirements declined for some patients during
the treatment period, the benefits of GH + glutamine were not sus-
tained after cessation of therapy. Concern regarding the neoplastic
risk of ongoing treatment with growth factors calls into question
the utility of this therapy. These trials provided little evidence of
synergy with glutamine, and are insufficient to recommend the
routine use of GH in SBS patients at present.
It has been suggested that the observed increases in body
weight may simply reflect extracellular fluid retention, and that
altered fluid balance may be secondary to renal-modulating effects
of GH, rather than actions on the gastrointestinal tract.18 The over-
whelming incidence of peripheral edema documented in the trials
described above (77% overall) would support the notion that GH-
induced weight gain may not reflect enhanced nutrient absorption.
In addition to peripheral edema, GH is associated with a variety of
adverse effects including carpal tunnel syndrome (32%), arthral-
gias (10%), and gynecomastia, which are thought to result from the
nonspecific nature of GH.17
5/21/2012 8:59:13 PM
 198 ■ Surgery: Evidence-Based Practice
Future studies investigating the effect of exogenous GH
administration during the early postoperative phase, rather than
after a period of homeostatic IF, might help elucidate the thera-
peutic potential of this intervention.
GLUCAGON-LIKE PEPTIDE 2
Glucagon-like peptide 2 (GLP-2) is another growth factor whose
potential role in the treatment of SBS has been extensively inves-
tigated. In addition to being intestinotrophic, GLP-2 slows gastric
emptying, inhibits gastric acid secretion, enhances mesenteric
blood flow, and may exert a protective effect against inflammatory
states. In vivo, GLP-2 is quickly inactivated by dipeptidyl peptidase
IV, prompting the development of a degradation-resistant synthetic
analog, teduglutide.
GLP-2 is synthesized in the distal ileum and proximal colon.
Patients with end jejunostomies therefore display a markedly reduced
postprandial rise in GLP-2, and benefit most from supplementation.
The first human study of GLP-2 involved eight SBS patients with end
jejunostomies, and demonstrated significant improvement in nutri-
ent absorption, with histologic evidence of adaptation, and increased
body weight.19 Phase II trials of teduglutide20 yielded similar results,
with increased absorption, decreased fecal weight and increased
urine output. In a Phase III RCT of 83 PN-dependent patients, low-
dose teduglutide resulted in >20% reduction in PN requirements,
with three patients able to discontinue PN altogether.21 A separate
trial examined the effects of continued GLP-2 administration over a
2-year period, and found a significant reduction in fecal wet weight
(from 3.0 to 2.0 kg/day) with improved renal function.22 While
jejunostomy patients derive maximal benefit from GLP-2 supple-
mentation, patients with intact colons exhibit similar responses, sug-
gesting that GLP-2 remains advantageous even at supraphysiologic
levels. In contrast to GH, GLP-2 is generally well tolerated (Level 1b
evidence).
FUTURE DIRECTIONS
A number of other hormonal agents are under investigation for
possible intestinotrophic roles in SBS. Thyroid hormone supple-
mentation has been shown to enhance intestinal adaptation dur-
ing the phase of transient hypothyroidism following massive small
bowel resection.23 EGF, IGF-1, and leptin have all demonstrated
promise in animal studies, but have yet to be trialed in humans.
A ROLE FOR OCTREOTIDE?
Care must be taken to avoid substances which may interfere with
the adaptation process. Octreotide is a potent antisecretory agent
which may be beneficial in the setting of high volume intestinal
losses, but it is also antitrophic. Therefore, current recommenda-
tions are to avoid administration of octreotide in the early adap-
tive phase, and to employ it judiciously thereafter if high intestinal
outputs render fluid and electrolyte balance problematic.
ANSWER: Enteral feeding is a necessary prerequisite for
intestinal adaptation. Administration of GH, with or without glu-
tamine, can stimulate a short-term increase in body weight. GLP-2
increases fluid and nutrient absorption, with significant reductions
PMPH_CH22.indd 198
in PN requirements. Both hormonal therapies are currently only
recommended for use within the context of clinical trials (Grade B
recommendation).
4. What is the role of autologous intestinal reconstruction sur-
gery in adults?
The goals of surgical intervention for SBS are three-fold: to slow
intestinal transit, improve peristaltic function, and enhance
mucosal absorption.24 In general, intestinal continuity should
be restored whenever possible, but other techniques to decrease
transit time (artificial valves, antiperistaltic segments, colonic
interposition) have fallen out of favor. Peristaltic function can be
impaired by strictured segments or excessive bowel dilatation.
Stricturoplasty and serosal patching are preferred over recurrent
resection to preserve absorptive surface area. Historically, dilated
bowel at risk of stasis and bacterial overgrowth was rectified using
tapering enteroplasty or intestinal plication techniques. These have
been largely supplanted by two intestinal lengthening procedures,
which also serve to enhance mucosal absorption and have emerged
as the mainstays of autologous intestinal reconstructive surgery.
Bianchi’s eponymous longitudinal intestinal lengthening
and tailoring (LILT) procedure was first described in 1980. This
technique involves separation of the two leaves of mesentery, with
transection of the bowel along its long axis and subsequent anas-
tomosis in continuity. To date there are more than 130 reported
cases in the literature, with an overall survival rate of 80%, a mean
increase in intestinal length of 40% to 53% and enteral autonomy
achieved in 54%.25-27
Serial transverse enteroplasty (STEP) was first performed in
2003, and there are now more than 60 reported cases, the vast
majority in children.25,28-32
By sequentially partially transecting the small bowel using
alternate fi rings of the linear stapler along the mesenteric and
antimesenteric borders, this technique is eclipsing the Bianchi
procedure as a fi rst-line intervention due to its relative techni-
cal simplicity. Survival and enteral autonomy are comparable
to the Bianchi procedure to date (92% and 49%, respectively),
but STEP offers the added benefit of being able to more than
double initial remnant length, and it can be repeated if neces-
sary in the event of bowel redilatation. Andres and colleagues33
report the largest single-center experience with repeat STEP
(reSTEP) involving 16 procedures in 14 patients (including two
adults) after previous Bianchi or STEP. At median follow-up of
14.5 months, survival was 100% with 43% weaned from PN;
36% were referred for IT, with good outcomes and no addi-
tional technical difficulty encountered as a result of the previ-
ous lengthening procedures.
Sudan et al.25 report the single largest experience with intes-
tinal lengthening, comparing results with both Bianchi and
STEP procedures over a 24-year period, taking into account the
belated introduction of STEP. They performed 77 procedures (43
Bianchi vs 34 STEP) in 64 patients, including 14 adults. At median
follow-up of 3.8 years, there was no difference in survival (91%
overall) and comparable rates of enteral autonomy (58% overall).
There was, however, a nonsignificant trend toward longer time
to complete discontinuation of PN after the Bianchi procedure
(8.4 vs. 4.8 months after STEP, p = 0.07). STEP achieved margin-
ally superior lengthening (52% vs. 48% with Bianchi, p = 0.01) and
complication rates were approximately 10% in both groups. Early
reported complications with both procedures include anastomotic
5/21/2012 8:59:13 PM

and staple line leaks, mechanical obstruction, and vascular injury
resulting in small bowel necrosis. Late complications documented
after Bianchi procedure include interloop fistulae and anasto-
motic stricture.
The efficacy of these procedures has led to many SBS patients
being liberated from the complications of PN-dependence. Although
data in adults are lacking, autologous intestinal reconstruction has
been postulated to be an effective bridge to transplantation.
ANSWER: The STEP and Bianchi procedures are two intes-
tinal lengthening procedures whose safety and efficacy have been
demonstrated in the cumulative international experience in chil-
dren. The literature in adults with SBS is meager, but there are case
reports of progression to enteral autonomy. Autologous intestinal
reconstruction may be sufficient to enable long-term survival after
SBS, or may be employed as a bridge to transplantation (Grade D
recommendation).
5. What is the role of IT in the management of SBS?
Despite ongoing refinements in technical aspects of IT and immu-
nosuppression, including the use of tacrolimus-based regimens, as
well as steady improvements in clinical outcomes and postoperative
quality of life, the decision to pursue transplantation as a therapeutic
option must be made with careful consideration of its risks and ben-
efits. The procedure is risky, with up to 50% of patients experiencing
complications such as mesenteric ischemia from vascular occlusion,
anastamotic leaks, intestinal perforation, stricture, line sepsis and
other nosocomial infections, opportunistic infections, and lym-
phoproliferative disease. The small intestine is highly immunogenic
and prone to rejection. During episodes of rejection, its mucosal
defenses may weaken, subjecting the recipient to sepsis risk at a time
when escalation of immunosuppression is often required. This com-
bination of immunosuppression and bacterial colonization of the
graft leaves IT recipients vulnerable to rapid deterioration.34
Indications for transplantation were considered in a pro-
spective study of 389 patients on home PN, which compared out-
comes in patients with IF who remained on PN against those who
received IT. The study confirmed higher survival rates among PN
patients than IT patients, and supported it as a primary treatment
for IF. IT was still considered to be indicated for patients with des-
moid tumors and PN-related liver failure, where hazard ratios for
death were high, and possibly for patients with recurrent catheter-
related complications and ultra short bowel.35
Because of the potential for morbidity and mortality, ITs have
mainly been performed in situations where no other therapeutic
options are available.36Therefore, no randomized trials and very
few cohort studies have been done to evaluate their efficacy and
safety in comparison to nontransplant alternatives. Most of our
insights about the role of IT are derived from national and inter-
national registries. These databases suggest that IF patients who
progress to end-stage liver disease (ESLD) due to PN-associated
cholestasis have the highest mortality among all patients on solid
organ waiting lists. The standard approach to these patients is com-
bined hepatic and IT, as hepatic transplantation alone often leads
to recurrent liver failure if the IF is not addressed. Patients under-
going IT alone (no ESLD) have better prognosis than those with
multivisceral transplants, likely because of more stable physiology
at the time of the operation. Overall patient and graft survival at 1
year is about 80% and 65%, respectively for IT, and 50% and 49%
for combined intestinal and hepatic transplants. Survival figures
have improved over time.36 In recent years, living-related donor
PMPH_CH22.indd 199
Short Bowel Syndrome ■ 199
liver and IT has been advanced to address high waiting list mor-
tality among patients with combined organ failures. Outcomes
have been similar to those in conventional transplantation.39
ANSWER: Outcomes after IT are steadily improving. Com-
bined intestinal and liver transplantation is indicated for IF patients
with ESLD. IT may also be indicated for those with high predicted
mortality due to conditions such as recurrent catheter-related
complications and ultra short bowel. The treatment of uncom-
plicated IF with PN and multidisciplinary care is associated with
high survival and favorable quality of life. PN therefore remains
the primary treatment for IF (Grade C recommendation).
6. What is the evidence for specialized centers of intestinal
rehabilitation?
The complexity of SBS and the rapid evolution of both medical
and surgical treatment strategies have prompted regional con-
centration of SBS management to specialized centers. Over the
past decade, intestinal rehabilitation programs (IRPs) have been
established at tertiary-care institutions offering comprehensive,
multidisciplinary therapy to promote intestinal adaptation with
the goal of eventual enteral autonomy. They provide aggressive
nutritional management with precise metabolic control, optimi-
zation of pharmacologic therapies with access to investigational
agents, prompt recognition and treatment of complications,
effective use of surgical rehabilitation techniques, and early refer-
ral for transplantation when indicated. The localization of IRPs
to centers with transplant programs facilitates and expedites the
referral process and may contribute to the high survival rates
after transplantation in these centers.
IRPs have demonstrated excellent outcomes in terms of survival
and enteral independence. To date, they have been predominantly
localized within pediatric medical centers, and the majority of the
literature regarding outcomes of multidisciplinary care reflects the
pediatric experience. The Center for Advanced Intestinal Rehabili-
tation at Children’s Hospital Boston compared the first 6 years of
their experience with historical controls, and found significantly
improved survival with comprehensive, multidisciplinary care
(89% cf 70%) and significant gains in enteral tolerance.38 Likewise,
Seattle Children’s Hospital documented an 88% survival rate over
the first four years of its Intestinal Failure Program, with 45%
enteral autonomy and a decrease in PN caloric requirements from
100% to 41% (p < 0.01).39
A common theme, and important feature of these referral
programs, is the successful rehabilitation of patients with pre-
existing liver disease. Torres et al.40 report the 4-year experience
of the University of Nebraska Medical Center, which includes an
adult SBS population. The majority of patients referred to their
program had hyperbilirubinemia and evidence of chronic liver
disease on pretreatment biopsy. Of these patients, 82% experi-
enced normalization of liver enzymes with multidisciplinary
treatment. Another regional IRP reported a dramatic reversal of
IF-associated liver disease with aggressive rehabilitation. Of these
patients, 75% with evidence of liver disease treated over a 6-year
period experienced complete resolution, prompting the authors to
conclude that hepatic dysfunction within this population is often
reversible and may be rescued by referral to a specialized center.41
The preliminary results of a Canadian multidisciplinary IF unit
corroborate this finding. Although overall survival rates remain
unchanged compared to historical controls, mortality from liver
failure has declined significantly (from 90% to 46%).42
5/21/2012 8:59:13 PM
 200 ■ Surgery: Evidence-Based Practice

The success of these programs has been attributed to the exper-
tise of dedicated practitioners delivered via a multimodal approach
with meticulous attention to detail. In addition, improved com-
munication between care providers and family members allows for
expeditious decision-making. Close collaboration with transplant
teams enables early assessment and ensures continuity of care
throughout the entirety of the rehabilitation process.
The concentration of SBS care to dedicated centers has given
rise to the Pediatric Intestinal Failure Consortium—a multidisci-
plinary collaboration of pediatric hospitals in the U.S. and Canada
that plans to review current practices to better define the optimal
management of SBS in this population. Although much can be
extrapolated to the adult SBS patient from this body of knowledge,
a similar collaborative approach to the management of adult SBS
would undoubtedly be of great benefit.
ANSWER: Dedicated IRPs offering comprehensive, multi-
disciplinary treatment of SBS may offer some advantage in terms
of survival, enteral autonomy, and reversal of liver disease over
the care of patients in nonspecialized institutions (Grade C
recommendation).
CONCLUSIONS
Prompt surgical care for intestinal catastrophes, followed by judi-
cious resection of small bowel and aggressive perioperative nutri-
tional support are turning the tide in the management of SBS.
PN has permitted survival with high quality of life and low PN-
associate mortality (0% to 22%). A new emphasis on intestinal
adaptation, selective use of autologous surgical reconstruction,
selective intestinal or multivisceral transplantation, and metic-
ulous perioperative care at high volume centers has resulted in
4-year survival as high as 90%40 for a condition that, until recently,
was considered to be uniformly fatal. Dedicated clinical care and
more research are needed to continue to make advances in this
complex and inspiring area.43

Clinical Question Summary

Question
1 What is the role of PN in SBS?
2 What is the evidence for GH in the
treatment of SBS?
3 What is the evidence for
teduglutide in the treatment of
SBS?
4 What is the role of autologous
intestinal reconstruction surgery
in adults with SBS?
5 What is the current role for IT in
SBS?
6 Do IRPs offer any benefit in the
treatment of SBS?
Recommendation Level of Evidence References
Early PN should focus closely on D 1
administration of macronutrients, careful
control of fluid and electrolyte balance,
and correction of micronutrient and
vitamin deficiencies. Patients should
be carefully transitioned to EN at the
earliest opportunity.
GH can lead to short-term weight gain B 17
with some evidence of increased
nutrient absorption, but the literature
does not support its routine use in the
management of SBS.
The safety and efficacy of GLP-2 have been B 20-22
demonstrated in clinical trials, which are
ongoing at present. GLP-2 administration
increases intestinal absorption,
decreases fecal output, and improves
renal function. Its use remains restricted
to an experimental context.
Both STEP and Bianchi procedures are D 25, 27, 32, 33
effective in increasing intestinal length 44
and decreasing PN requirements in
children. There is a paucity of experience
in the adult SBS population, with case
reports of improved enteral tolerance
and autonomy.
IT is a good strategy in situations where C 36
no other therapeutic options are viable
(e.g., PNALD with ESLD, catheter-
related complications).
Multidisciplinary IRPs have demonstrated C 38-42
excellent outcomes in terms of survival,
increased enteral tolerance, and reversal
of hepatic dysfunction. They may offer
some advantage over nonspecialized
centers in the treatment of SBS.

PMPH_CH22.indd 200 5/21/2012 8:59:14 PM


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with parenteral nutrition-associated liver disease. Arch Surg.
2010;145(6):547-551.
7. Fallon EM, Le HD, Puder M. Prevention of parenteral nutrition-
associated liver disease: Role of omega-3 fish oil. Curr Opin Org
Transplant. 2010;15(3):334-340.
8. Sigalet DL, Mackenzie SL, Hameed SM. Enteral nutrition and
mucosal immunity: implications for feeding strategies in surgery
and trauma. Can J Surg. 2004;47(2):109-116.
9. Nordgaard I, Hansen BS, Mortensen PB. Colon as a digestive organ
in patients with short bowel. Lancet. 1994;343(8894):373-376.
10. Matarese LE, O’Keefe SJ, Kandil HM, et al. Short bowel syn-
drome: Clinical guidelines for nutrition management. Nutr Clin
Prac. 2005;20(5):493-502.
11. Joly F, Mayeur C, Messing B, et al. Morphological adaptation
with preserved proliferation/transporter content in the colon of
patients with short bowel syndrome. Am J Physiol Gastrointest
Liver Physiol. 2009;297(1):G116-G123.
12. Shulman DI, Hu CS, Duckett G, Lavallee-Grey M. Effects of short-
term growth hormone therapy in rats undergoing 75% small
intestinal resection. J Pediatr Gastroenterol Nutr. 1992;14(1):3-11.
13. Inoue Y, Copeland EM, Souba WW. Growth hormone enhances
amino acid uptake by the human small intestine. Ann Surg.
1994;219(6):715-722; discussion 722-724.
14. van der Hulst RR, van Kreel BK, Meyenfeldt von MF, et al.
Glutamine and the preservation of gut integrity. Lancet.
1993;341(8857):1363-1365.
15. Byrne TA, Persinger RL, Young LS, Ziegler TR, Wilmore DW. A new
treatment for patients with short-bowel syndrome. Growth hor-
mone, glutamine, and a modified diet. Ann Surg. 1995;222(3):243-
254; discussion 254-255.
16. Byrne TA, Morrissey TB, Nattakom TV, Ziegler TR, Wilmore
DW. Growth hormone, glutamine, and a modified diet enhance
nutrient absorption in patients with severe short bowel syn-
drome. JPEN J Parenter Enteral Nutr. 1995;19(4):296-302.
17. Wales PW, Nasr A, de Silva N, Yamada J. Human growth hor-
mone and glutamine for patients with short bowel syndrome.
Cochrane Database Syst Rev. 2010;16(6):CD006321.
18. Jeppesen P. Growth factors in short-bowel syndrome patients.
Gastroenterol Clin N Am. 2007;36(1):109-121.
19. Jeppesen P, Hartmann B, Thulesen J, et al. Glucagon-like peptide 2
improves nutrient absorption and nutritional status in short-bowel
patients with no colon4. Gastroenterol. 2001;120(4):806-815.
20. Jeppesen PB. Teduglutide (ALX-0600), a dipeptidyl peptidase
IV resistant glucagon-like peptide 2 analogue, improves intesti-
nal function in short bowel syndrome patients. Gut. 2005;54(9):
1224-1231.
PMPH_CH22.indd 201
Short Bowel Syndrome ■ 201
21. Jeppesen PB, Gilroy R, Pertkiewicz M, et al. Randomised placebo-
controlled trial of teduglutide in reducing parenteral nutrition and/
or intravenous fluid requirements in patients with short bowel syn-
drome. Gut. 2011.
22. Jeppesen PB, Lund P, Gottschalck IB, et al. Short bowel patients
treated for two years with glucagon-like Peptide 2: effects on
intestinal morphology and absorption, renal function, bone and
body composition, and muscle function. Gastroenterol Res Prac.
2009;2009:Article ID 616054.
23. Yuksel O, Tatlicioglu E, Poyraz A, et al. Effects of thyroid hor-
mone on the adaptation in short bowel syndrome. J Surg Res.
2009;155(1):116-124.
24. Petty JK, Ziegler MM. Operative strategies for necrotizing entero-
colitis: The prevention and treatment of short-bowel syndrome.
Semin Pediatr Surg. 2005;14(3):191-198.
25. Sudan D, Thompson J, Botha J, et al. Comparison of intestinal
lengthening procedures for patients with short bowel syndrome.
Ann Surg. 2007;246(4):593-601; discussion 601-604.
26. Hosie S, Loff S, Wirth H, et al. Experience of 49 longitudinal
intestinal lengthening procedures for short bowel syndrome.
Eur J Pediatr Surg: official journal of Austrian Association of
Pediatric Surgery ... [et al] = Zeitschrift für Kinderchirurgie. 2006;
16(3):171-175.
27. Reinshagen K, Kabs C, Wirth H, et al. Long-term outcome in patients
with short bowel syndrome after longitudinal intestinal lengthen-
ing and tailoring. J Pediatr Gastroenterol Nutr. 2008;47(5):573-578.
28. Kim HB, Lee PW, Garza J, et al. Serial transverse enteroplasty
for short bowel syndrome: a case report. J Pediatr Surg. 2003;
38(6):881-885.
29. Ismail A, Alkadhi A, Alnagaar O, Khirate A. Serial transverse
enteroplasty in intestinal atresia management. J Pediatr Surg.
2005;40(2):E5-E6.
30. Javid PJ, Kim HB, Duggan CP, Jaksic T. Serial transverse entero-
plasty is associated with successful short-term outcomes in infants
with short bowel syndrome. J Pediatr Surg. 2005;40(6):1019-1023;
discussion 1023-1024.
31. Wales PW, Dutta S. Serial transverse enteroplasty as primary
therapy for neonates with proximal jejunal atresia. J Pediatr Surg.
2005;40(3):E31-E34.
32. Modi B, Javid P, Jaksic T, et al. First Report of the International
Serial Transverse Enteroplasty Data Registry: Indications, Effi-
cacy, and Complications. J Am Coll Surg. 2007;204(3):365-371.
33. Andres AM, Thompson J, Grant W, et al. Repeat surgical
bowel lengthening with the STEP procedure. Transplantation.
2008;85(9):1294-1299.
34. Gilroy R, Sudan D. Liver and small bowel transplantation: Ther-
apeutic alternatives for the treatment of liver disease and intesti-
nal failure. Semin Liver Dis. 2000;20(4):437-450.
35. Pironi L, Joly F, Forbes A, et al. Long-term follow-up of patients
on home parenteral nutrition in Europe: Implications for intesti-
nal transplantation. Gut. 2010;60(1):17-25.
36. American Gastroenterological Association. American Gastro-
enterological Association medical position statement: Short
bowel syndrome and intestinal transplantation. Gastroenterol-
ogy. 2003;124(4):1105-1110.
37. Tzvetanov IG, Oberholzer J, Benedetti E. Current status of living
donor small bowel transplantation. Curr Opin Organ Transplant.
2010;15(3):346-348.
38. Modi BP, Langer M, Ching YA, et al. Improved survival in a
multidisciplinary short bowel syndrome program. J Pediatr Surg.
2008;43(1):20-24.
39. Javid PJ, Malone FR, Reyes J, Healey PJ, Horslen SP. The experi-
ence of a regional pediatric intestinal failure program: Successful
5/21/2012 8:59:14 PM
 202 ■ Surgery: Evidence-Based Practice
outcomes from intestinal rehabilitation. Am J Surg. 2010;
199(5):676-679.
40. Torres C, Sudan D, Vanderhoof J, et al. Role of an intestinal
rehabilitation program in the treatment of advanced intestinal
failure. J Pediatr Gastroenterol Nutr. 2007;45(2):204-212.
41. Cowles RA, Ventura KA, Martinez M, et al. Reversal of intestinal
failure-associated liver disease in infants and children on paren-
teral nutrition: experience with 93 patients at a referral center for
intestinal rehabilitation. J Pediatr Surg. 2010;45(1):84-87; discus-
sion 87-88.
PMPH_CH22.indd 202
42. Diamond IR, de Silva N, Pencharz PB, et al. Neonatal short bowel
syndrome outcomes after the establishment of the first Canadian
multidisciplinary intestinal rehabilitation program: preliminary
experience. J Pediatr Surg. 2007;42(5):806-811.
43. Nightingale J. Guidelines for management of patients with a
short bowel. Gut. 2006;55(Suppl 4):iv1-iv12.
44. Wales PW, Brindle M, Sauer CJ, Patel S, de Silva N, Chait P.
Percutaneous cholangiography for the treatment of parenteral
nutrition-associated cholestasis in surgical neonates: prelimi-
nary experience. J Pediatr Surg. 2007;42(11):1913-1918.
5/21/2012 8:59:14 PM
 Commentary on Short
Bowel Syndrome
James Davis
The chapter “Short Bowel Syndrome and Intestinal Failure” pro-
vides insight and recommendations based on level of evidence
supporting decision-making in five areas associated with manage-
ment of patients with short bowel syndrome (SBS). The questions
addressed are (1) What is the optimal nutrition support strategy
in SBS? (2) What pharmacologic strategies can promote intestinal
adaptation? (3) What is the role of autologous intestinal recon-
struction surgery in adults? (4) What is the role of IT (intestinal
transplantation) in the management of SBS? (5) What is the evi-
dence of specialized centers of intestinal rehabilitation?
With regards to the nutrition support strategy, optimizing
nutritional support for these patients is crucial, starting with
parenteral nutrition in the early postoperative stages and mov-
ing toward enteral nutrition (EN). There has been a general trend
toward early feeding of patients that have undergone gastroin-
testinal surgery. The advantages of EN over parenteral nutri-
tion include maintenance of intestinal barriers and better stress
hormone responses. EN has also been reported to preserve gut
structure and function as well as enhance gut mediated immu-
nity.1 More recently, a meta-analysis on early feeding versus late
feeding in patients with gastrointestinal surgery showed that
there was no difference in complications between the two groups
and in fact a decrease in mortality in the early feeding group.2
With regards to what pharmacologic strategies can promote
intestinal adaptation, this area appears to have immense potential
for research. The level of evidence used to support the recommen-
dations is mostly based on expert opinion or case studies, which
makes it difficult to obtain a firm conclusion. The exception to this
is seen in question (2) on glutamine and growth hormone, as well
as glucagon-like peptide (GL-2) which provided level 1a and 1b
evidence. Glutamine has been shown to be crucial in maintaining
intestinal health. Not only is it the primary energy source for the
small intestine, it also helps in maintaining the gut mucosal bar-
rier, as well as plays a major role in the maintenance of metabo-
lism and function.3,4 However, growth hormone has not shown a
consistent beneficial effect. Currently, GL-2, as well as epidermal
growth factor (EGF), has shown promise in promoting intestinal
growth and enhancing absorption. GL-2 is produced in the distal
intestine and colon and has a role in stimulating mucosal growth
and absorption. EGF functions to increase absorption as well as
203
PMPH_CH22.indd 203
stimulates intestinal adaptation. Both are currently in clinic trials
and show real potential for the future.
With regards to the role of autologous intestinal reconstruc-
tion in adults, experience has been in the pediatric population. As
stated by the author, literature in the adult population is scarce at
best. There is a recent study of 20 adult patients, 6 who underwent
the Biachi procedure and 14 who underwent the STEP procedure,
looking at outcome of intestinal lengthening.5 Their results of a
90% survival rate with mean follow-up of 4.1 years and 59% enteral
autonomy were comparable to the published data in the pediatric
population. Given the paucity of data it is difficult to ascertain
the safety and efficacy in the adult population. It appears to be an
option in adults who have no further progression in enteral toler-
ance and are dependent on parenteral nutrition.
Patients who develop life-threatening complications from
parenteral nutrition are candidates for IT. There have been approx-
imately 2000 cases reported in the United States with majority of
patients below 18 years old. Looking at IT in the United States
between 1999 and 2008, there has been an improvement in time
to transplant as well as waiting list mortality.6 Short-term results
have improved although the difficulty still lies in preventing rejec-
tion in this population. As more experience is gained in this field
and long-term data are gathered, a better understanding of the
role for transplant may be seen.
There is a lack of evidence supporting specialized center in
intestinal rehabilitation. However, there is extensive experience
and evidence of the importance of specialized centers in the car-
diac population7 as well as the trauma population.8 In both areas,
it has been shown that regionalization led to improved outcomes
as well as cost-effectiveness. Extrapolating this evidence to the
short bowel population, we could make an argument for devel-
oping specialized centers for intestinal rehabilitation in order to
improve outcome as well as providing a comprehensive data base
for further research.
These questions, as important as they are, are difficult to
answer due to the rarity of this disease. Most of our understand-
ing is extrapolated from the neonatal population. Given the diffi-
culty of this subject and the level of evidence available, the author
has done an excellent review of the literature to obtain recommen-
dation to these difficult questions.
5/21/2012 8:59:14 PM
 204 ■ Surgery: Evidence-Based Practice
REFERENCES
1. Winter TA, O’Keefe SJ, Callanan M, Marks T. Effect of severe
undernutrition and subsequent refeeding on gut mucosal protein
fractional synthesis in human subject. Nutrition. 2007;23:29-35.
2. Lewis SJ, Andersen HK, Thomas S. Early enteral nutrition within
24 h of intestinal surgery versus later commencement of feed-
ing: a systematic review and meta-analysis. J Gastrointest Surg.
2009;13(3):569-575.
3. van der Hulst RR, van Kreel BK, von Meyenfeldt MF, Brummer RJ,
Arends JW, Deutz NE, et al. Glutamine and the preservation of
gut integrity. Lancet. 1993;341:1363-1365.
PMPH_CH22.indd 204
4. Souba WW, Klimberg VS, Plumley DA, Salloum RM, Flynn TC,
Bland KI, et al. The role of glutamine in maintaining a healthy gut
and supporting the metabolic response to injury and infection.
J Surg Res. 1990;48(4):383-391.
5. Yannam GR, et al. Intestinal lengthening in adult patients with
short bowel syndrome. J Gastrointest Surg. 2010;14(12):1931-1936.
6. Mazariegos GV, et al. Intestinal transplantation in the United
States 1999–2008. Am J Transplant. 2010;10:1020-1034.
7. Kereiakes DJ. Specialized center sand systems for heart attack
care. Am Heart Hosp J 2008;6(1):14-20.
8. MacKenzie EJ et al. The value of trauma center care. J Trauma.
2010;69(1):1-10.
5/21/2012 8:59:14 PM
 PART IV

LARGE BOWEL

PMPH_CH23.indd 205 5/21/2012 9:01:17 PM

PMPH_CH23.indd 206 5/21/2012 9:01:18 PM

Diverticular Disease of the Colon
Diverticular disease of the colon is considered as a disease of “mod-
ern times,” prevalent principally in Western Societies. The appear-
ance of colonic diverticulosis in postmortem specimens paralleled
both industrialization and the widespread use of refined wheat
products.1 The incidence of colonic diverticular disease, particu-
larly its acute manifestations, has continued to increase.2,3 Along
with its ensuing complications, diverticular disease is estimated to
result in at least USD 2.4 billion in direct health-care costs annu-
ally in the United States.4
Acute diverticulitis is the most frequent complication aris-
ing from the presence of colonic diverticula. The sigmoid colon
is affected in 95% of cases. Patients may present initially with
complications such as perforation requiring immediate operative
intervention. Most patients, however, recover following conser-
vative medical management with appropriate antibiotic therapy.
Up to 85% of cases of acute diverticulitis can be managed non-
operatively.5 Improvements in antibiotic therapy, better imaging
diagnostic modalities, and the use of appropriate percutaneous
drainage techniques have aided the prevalence of nonoperative
therapy in the acute setting.6,7
The methods of management of diverticulitis in the acute
setting and following discharge from the hospital have evolved
over the past few decades. Several of the longstanding commonly
accepted dogmas and guidelines have been based on a small col-
lection of studies generally with lower-level evidence. Many of
these “standards” have been challenged in recent years.
Pertinent areas of interest and controversy in the manage-
ment of patients with colonic diverticular disease include the
indications and timing for operative management, the relevance
of age in operative decision-making, the appropriate methods
and techniques of operative management, the place of laparos-
copy, and strategies for preventing recurrent attacks. The relevant
recent literature pertaining to these areas will be discussed, exam-
ined, and reviewed below.
1. What is the optimal operation for patients requiring surgery
for complicated acute diverticulitis? Is performing a primary
anastomosis an option?
Hinchey in his 1978 paper on the treatment of diverticulitis
divided acute diverticulitis into four stages, now referred to as
207
PMPH_CH23.indd 207
CHAPTER
CHAPTER 23
1
Brent Izu and A. Peter Ekeh
the Hinchey Stages I–IV, with worse clinical features and mortal-
ity with each successive stage. Stage IV disease involves feculent
peritonitis and was described to be accompanied with a high
mortality.8 This staging system has been widely adopted to pro-
vide a standard for comparison of the severity of acute diverticu-
litis. The Hinchey classification has also been used as a basis for
decision-making with regards to specific surgical therapy in the
acute setting.
The operative management of complicated acute diverticu-
litis has evolved over time. Fortunately, surgical management is
necessary in less than 10% of patients admitted to the hospital
with an attack of diverticulitis.9 Historically, staged operations
were commonly performed involving the initial closure of the
perforation with a proximal diversion (ileostomy or transverse
colostomy) and then a subsequent delayed resection of the dis-
eased portion and anastomosis. This approach has been largely
supplanted by the Hartmann operation—resection of the acutely
inflamed bowel including the perforated portion of colon and a
proximal end colostomy.
In one of the very few randomized prospective trials that
have been performed relating to management of diverticulitis,
Zeitoun et al. compared primary resection with suture drain-
age with proximal colostomy followed by secondary resection. In
this study, most of the patients in the primary resection group
had Hartmann operations with a small minority (5%) undergoing
primary anastomoses. They found a lower incidence of postopera-
tive peritonitis; fewer reoperations and a shorter hospital stay in
the primary resection group.10 (Level 1 evidence) This study only
included patients with Hinchley Stages III and IV. There was no
difference in mortality between the two groups. This confirmed
prior retrospective cohort studies which had arrived at similar
conclusions. Finlay et al. compared outcomes in patients under-
going primary resection with proximal drainage and diversion.
Morbidity was significantly higher in patients undergoing diver-
sion without resection, including a higher incidence of fistula for-
mation in the patients with staged operations.11
More recently, other authors have published data on the use
of primary resection and anastomosis in patients with perforated
sigmoid diverticulitis. This has been described in some instances
with extra measures like proximal protective ileostomies and
intraoperative on-table colonic lavage. The reports involving
5/21/2012 9:01:18 PM
 208 ■ Surgery: Evidence-Based Practice
primary anastomosis in the acute setting are all retrospective.
Stumpf et al. found 19 of 36 patients considered low risk (Hinchey
Stages I and II) had no complications following primary resection
and anastomosis. They concluded that this method of manage-
ment be considered in low risk patients with acute diverticulitis.
(Level 2b evidence)12 Similarly, a small retrospective series from
Australia comparing 33 patients who had a primary anastomosis
with 64 who had Hartmann procedures revealed no marked dif-
ference in morbidity, and no increased mortality. They also con-
cluded that primary anastomosis has an acceptable morbidity and
mortality. (Level 2 evidence) The patients in the primary anas-
tomosis group were in earlier Hinchey stages.13 These two stud-
ies mentioned are representative of several other reports in the
literature with similar findings and similar levels of evidence.14-17
Protective ileostomies and colonic lavage were utilized in some
of these studies, but no recommendation can be made on these
practices based on their irregular and random use.
Overall, the literature regarding primary anastomosis of
acute complicated diverticulitis involves heterogeneous popula-
tions, differing methods (e.g., the use of protective ileostomy and
intraoperative colonic lavage), and possess problems of selection
bias. Two recent systemic reviews of the retrospective literature on
this topic highlighted this observation, recognizing that patients
selected for primary resection and anastomosis have a lower mor-
tality than those treated by Hartmann’s procedure. These factors
limit clinically sound conclusions and demonstrate the need for
prospective randomized studies in this area.18,19
In recent years, a novel approach in the operative manage-
ment of acute diverticular perforations with the use of laparoscopy
has been reported. This involves laparoscopy with intraperitoneal
irrigation and drain placement in lieu of the standard operative
procedures. The goal in this approach is to avoid a Hartmann pro-
cedure and delay the resection of the diseased colon to an elective
setting. A number of case series have described there experiences
with this technique, generally with favorable results (Level 4
evidence).20-23 A small retrospective study comparing laparoscopic
peritoneal lavage with primary anastomosis with a defunction-
ing stoma for Hinchey Stage III complicated diverticulitis demon-
strated a shorter hospital stay in the laparoscopic cohort. Most of
the patients in the laparoscopic group eventually underwent elec-
tive surgical resection laparoscopically.24 (Level 2 evidence)
Summary: Primary resection of the inflamed colon (with or
without primary anastomosis) is the optimal method of treating
complicated sigmoid diverticulitis. (Grade A recommendation)
Primary anastomosis of the colon at the initial operation can be
considered in Hinchey Stage I and II patients. (Grade B recommen-
dation) Laparoscopic intraperitoneal lavage may be considered in
perforated diverticulitis but more studies addressing this technique
are needed to validate this practice. (Grade B recommendation)
2. What are appropriate indications for elective sigmoid resection
after uncomplicated diverticulitis?
There is little controversy with regard to the utility of operative
intervention for complications arising from diverticular disease in
the acute period or in the long term. The appropriate indications
for surgical intervention after uncomplicated acute diverticulitis,
that is, disease in the absence of the complications of fistulas, stric-
tures, abscess or free perforation, have been subject to much debate.
The primary purpose of surgical intervention after acute attacks of
diverticulitis is the prevention of recurrence and the accompanying
PMPH_CH23.indd 208
morbidity. Consequently, recommendations are generally based on
the risk of recurrence and the severity of subsequent attacks. Most
studies assessing the risk of repeat attacks are retrospective studies
and have very wide variability of follow-up, making it difficult to
establish an accurate recurrence rate.
Clinical practice patterns and recommended guidelines have
proposed elective colon resection after two or more acute attacks
of diverticulitis successfully treated medically, or after a single
attack requiring in a patient below 40 years of age. (Grade C rec-
ommendation) Although these recommendations are currently
considered to be dated, their origins are of importance to gain
a balanced historical perspective and understanding of the man-
agement of this disease process.5
The recommendation for surgery following two attacks in older
patients is based primarily on case series data indicating signifi-
cant recurrence rates after medically managed acute diverticulitis.
(Level 4 evidence) Parks, in 1969, published a review of 455 patients
admitted with acute diverticulitis. Of the patients treated medically,
24.6% subsequently had a second attack and 3.8% a third. Further-
more, the paper suggested that medical management was less effec-
tive for symptom control with subsequent bouts.25 Makela et al.26
similarly showed recurrences of 22% of patients with diverticulitis
managed medically and complications seen in 50% of patients who
presented with a second attack (Level 4 evidence).
Recent series have challenged the true incidence of the recur-
rence of acute diverticulitis as well as the severity of subsequent
attacks stated in the older literature. Addressing the incidence
of recurrence, a large retrospective cohort series involving over
3000 patients admitted for episodes of acute diverticulitis showed
that 9.4% of patients had a single recurrence and 3.9% had a sec-
ond episode.27 This is lower than has reported in the older studies
and has a longer follow-up period than any of the prior reports
(8.9 years). (Level 2 evidence) Another retrospective review showed
that only 2.7% of patients who presented emergently with acute
diverticulitis and required surgery had a prior history of medi-
cal management. The majority of the cases were initial presenta-
tions.28 (Level 4 evidence) Other contemporary series on the other
hand have identified high recurrence rates after a single episode
of diverticulitis, although the recurrences were not necessarily
complicated presentations and could be typically treated medi-
cally. A study from the Lahey Clinic in Massachusetts involving
over 600 patients demonstrated a recurrence rate of 36% after
an initial attack although only 3.9% of these presentations were
complicated.29 (Level 2 evidence) Similarly, a series from the
Netherlands demonstrated a 48% recurrence rate in noncompli-
cated diverticulitis treated medically.30
Regarding the severity of further subsequent attacks of diver-
ticulitis, a retrospective study by Chapman et al. found that multi-
ple episodes of diverticulitis are not associated with increased risk
of mortality or poor outcomes from complicated diverticulitis.31
(Level 2 evidence) Salem and others used a state-wide database to
construct a Markov model to evaluate lifetime risks of death and
colostomy, care costs, and quality of life associated with elective
colectomy after subsequent episodes of diverticulitis using hypo-
thetical cohorts of 35- and 50-year-old patients who recovered
from a nonsurgically treated diverticulitis episode. They found
that performing a colectomy after the fourth rather than the sec-
ond episode in patients older than 50 years resulted in 0.5% fewer
deaths, 0.7% fewer colostomies, and saved USD 1035 per patient.
They concluded that expectant medical management after uncom-
plicated diverticulitis was associated with lower rates of death and
5/21/2012 9:01:18 PM
 Diverticular Disease of the Colon ■ 209

colostomy, and was cost saving compared with a strategy of elec- 4. Are there any evidence-based dietary recommendations to
tive prophylactic colectomy. (Level 2 evidence)32 prevent the recurrence of acute uncomplicated diverticulitis? Is
To date, there are no randomized controlled trials pitting the practice of prohibiting the intake of “seeds,” popcorn, etc.
observation against elective sigmoid resection following recur- after an acute episode valid?
rent episodes of uncomplicated diverticular disease of the colon.
In conjunction with standard antibiotic therapy for uncomplicated
A multicenter randomized clinical trial is currently underway in
diverticulitis, patients are often given dietary recommendations.
Europe, which intends to compare elective colon resection with
Fiber intake is the most significant dietary factor in preventing
conservative therapy in patients with recurrent diverticulitis or
and reducing recurrence of diverticulitis. The progression of
continuing symptoms after an attack.33
colonic diverticular disease has paralleled the drop in dietary
Summary: Though elective sigmoid resection has been tradi-
fiber consumption in the United States, Europe, and Asia.1
tionally recommended after two attacks of uncomplicated divertic-
A number of studies have highlighted the benefits of fiber intake
ulitis, a case-by-case determination made to establish the need for
in the prevention and recurrence of diverticular disease. Burkitt,
operative management is necessary. (Grade C recommendation)
based on his experiences in rural Africa, published the original
Waiting until at least the fourth episode attack of diverticuli-
observations of the effect of fiber, over 30 years ago. He compared
tis before elective surgery can result in lower colostomy and lower
colonic transit times and stool weight in three populations with low,
death rates. (Grade B recommendation)
mixed, and high residue diets. Colonic transit time was decreased
Given the strength of these recommendations, there is no
and stool weight was increased in patients with high residue diets.
strong basis for the conventional decision to routinely proceed to
He further obtained epidemiological data from various countries,
a colectomy after two episodes of uncomplicated diverticulitis.
noting the very low prevalence of diverticular disease in populations
with high residue diets compared with those with low and mixed res-
3. Should younger patients (<40–50 years) undergo elective sigmoid idue diets.1 A cohort study from Greece demonstrated that patients
colon resection after a single attack of acute diverticulitis? with radiologically confirmed diverticulitis were demonstrated to
have a lower intake of fiber and higher intake of red meat.42
Traditional clinical practice and expert guidelines have advocated
A prospective questionnaire-based study with a 4-year
elective sigmoid colectomy after the first attack of uncomplicated
follow-up by Aldoori et al. evaluated the effect of various diets on
diverticulitis in patients below 40 years of age. Th is recommen-
the incidence of diverticular disease in a prospective longitudinal
dation is based on multiple case series and retrospective studies
cohort study involving over 40,000 men. The participants reporting
from the 1960s and 70s demonstrating more “virulent” presen-
diets high in fruit and vegetable fiber had a significantly lower inci-
tation and more recurrences in patients below 40 years of age.
dence of symptomatic diverticulitis. Diets high in fat and red meat
Studies confirming this notion and others challenging this are
were also noted to “augment the risk”.43 (Level 2b evidence) The same
continuously presented in the literature—all similarly retrospec-
group of investigators recently updated this study, 18 years after its
tive. There are no prospective studies comparing observation to
commencement, focusing specifically on the relationship between
elective surgery in patients below 40 years of age.
the incidence of diverticular disease and nut, corn, and popcorn
Multiple retrospective cohort studies have compared rates
consumption. They noted no associations between the intake of
of complication and operation in younger patients with those of
these foods and the incidence of diverticulitis or diverticular bleed-
older patients. Some reports show that younger patients develop
ing. There was in fact an inverse association between the consump-
more subsequent complications, have more recurrences, and that
tion of these foods and diverticulitis.44 (Level 2b evidence)
the disease displays a more aggressive course compared with older
There is some good evidence that supports the clinical recom-
patients (Level 2b evidence).34-37 Other studies of comparable
mendation given to patients to increase the fiber intake after acute
quality draw different conclusions disputing the claim of a more
attacks of diverticulitis as a means to lower recurrence rates. Bro-
“virulent” disease process in younger patients.38-40
dribb demonstrated in a randomized controlled trial with fiber
A recent retrospective review comparing patients older than
versus placebo that fiber improved symptoms of dyspepsia, bowel
and younger than 50 years of age demonstrated more sever com-
dysfunction, and pain in patients with symptomatic diverticular
plications in the older group, although there were more recur-
disease.45 (Level 1 evidence) This is in line with another randomized
rences in the group younger than 50 years of age.41
controlled crossover trial by Taylor who performed in the 1970s,
The decision tree analysis model described above by Salem
comparing bran tablets (18 g/day) with a high-roughage diet and a
et al. specifically addressing younger patients concluded that per-
laxative. The bran group was found to have better results in improv-
forming colectomy after the fourth episode compared with the
ing symptom score, stool weight, transit time, and motility.46
first episode resulted in 0.1% fewer deaths, 2% fewer colostomies,
The advice given against the consumption of popcorn, seeds,
and saved US$5429 per patient (Level 2 evidence).32
and nuts in an attempt to prevent obstruction of diverticula and
Summary: Given the conflicting conclusions based on evi-
subsequent inflammation has no basis in the medical literature.
dence of similar quality (Level 2) and studies of varying quality,
Summary: Dietary fiber can play a role in both the prevention
no definite evidence-based recommendations can be made with
of initial and recurrent attacks of diverticulitis. Patients should be
regard to the indication for surgery after an uncomplicated attack
advised to increase their fiber content in their diet after a bout of
of acute diverticulitis in younger patients. Individualized deci-
uncomplicated diverticulitis. (Grade A recommendation)
sions based on patient’s circumstance will need to be made prior
to proceeding with surgery. (Grade C recommendation)
5. Is laparoscopic colectomy equivalent or superior to open
However, as in older patients, there is a reduction in the num-
colectomy for diverticular disease? Is the overall cost different?
ber of colostomies and death rate associated with holding elec-
tive surgery until after the fourth attack—it ever occurs. (Grade B A multi-institutional randomized prospective trial published in the
recommendation) New England Journal of Medicine in 2004 demonstrated a clear

PMPH_CH23.indd 209 5/21/2012 9:01:18 PM

 210 ■ Surgery: Evidence-Based Practice

role for laparoscopy in colon surgery. This study, however, focused
specifically on colon cancer and demonstrated noninferiority in
recurrence rates, a shorter length of stay, and a decreased use of par-
enteral narcotics in the laparoscopic group. A recently concluded
prospective multicenter, randomized controlled study specifically
compared laparoscopic sigmoid colon resection with the open pro-
cedure in patients with diverticular disease. This European trial,
which ran over a 4-year period and included 104 patients, showed
a reduction in complications in the laparoscopic cohort of patients
compared with the open group (9.6% vs. 25.0%; p = .038). The lap-
aroscopic group also had statistically significant decreases in post-
operative pain, less systemic analgesic needs, and shorter hospital
stays. The operative time was longer in the laparoscopic group.47
A 6-month follow-up of this study further showed a reduction of
major complications in the laparoscopic group.48 (Level 1 evidence)
There are a number of other retrospective cohort and case con-
trolled studies offering Level 2 and 3 evidence on a range of outcome
measures comparing laparoscopic sigmoid colectomy for diverticu-
lar disease with the traditional open procedure.
Comparing laparoscopic colon resection with the open pro-
cedure, a number of these studies found no difference in compli-
cation rates or mortality.49 A quicker return to diet, shorter time to
first bowel movement, reduced length of hospital stay, and reduced
estimated blood loss have, however, been consistently reported to
be associated with laparoscopy.50-54 (Level 2b evidence)
Laparoscopic sigmoidectomy in most series had longer oper-
ative time but typically a shorter length of stay and increased hos-
pital charges.51,52 (Level 2 evidence)
A single study from France comparing laparoscopic with open
approaches in elderly patients concluded based on their findings that
laparoscopic colectomy could be safely applied to older patients with
a reduction in complications, less pain, and a shorter hospital stay.55
(Level 2 evidence)
Two studies examining the cost per case report an overall
reduction with laparoscopic sigmoid colectomies possibly related
to the reduced length of stay.53,55,56
Summary: Laparoscopic colon resection is a safe and effective
approach for the elective treatment of patients with diverticular
disease and is associated with fewer complications, less operative
pain, and a shorter postoperative hospital stay. (Grade A recom-
mendation) Laparoscopic colon resection is furthermore associ-
ated with a quicker resumption of bowel function and reduced
intraoperative blood loss. It is appropriate for elderly patients.
(Grade B recommendation)

Clinical Question Summary

Question
1 Is laparoscopic colectomy
equivalent or superior to open
colectomy for diverticular
disease? Is the overall cost
different?
2 What are appropriate
indications for elective sigmoid
resection after uncomplicated
diverticulitis?
3 Should younger patients
(<40–50 years) undergo
elective sigmoid colon
resection after a single attack
of acute diverticulitis?
4 Are there any evidence-based
dietary recommendations
to prevent the recurrence
of acute uncomplicated
diverticulitis? Is the practice
of prohibiting the intake of
“seeds,” popcorn, etc. after an
acute episode valid?
5 What is the optimal operation
for patients requiring surgery
for complicated acute
diverticulitis? Is performing
a primary anastomosis an
option?
Answer Grade of References
Recommendation
Laparoscopic colon resection is a BA 47-56
safe and effective approach for the
elective treatment of patients with
diverticular disease. Laparoscopic
colon resection is associated with
a lower anastomotic leak rate and
morbidity rate.
A case-by-case determination of the C 27, 31, 32
need for operative management is
necessary.
Individualized decisions based on C 32, 34-38
patients’ circumstance will need to
be made prior to proceeding with
surgery.
Dietary fiber can play a role in both A 44-46
the prevention of initial and
recurrent attacks of uncomplicated
diverticulitis.
Primary resection of the inflamed AB 10-17
colon (with or without primary
anastomosis). Primary anastomosis of
the colon at the initial operation can
be considered in Hinchey Stage I and
II patients.

PMPH_CH23.indd 210 5/21/2012 9:01:18 PM

 Diverticular Disease of the Colon ■ 211

Summary Table
Subject Year References Level of Strength of Findings
Evidence Recommendation
Indication for elective 2004 32 2 B Expectant medical management
colectomy after after uncomplicated diverticulitis
uncomplicated with lower cost, fewer deaths,
diverticulitis. and fewer colostomies.
Elective colectomy in 2004 32 2 B Colectomy after the fourth episode
younger patients is associated with lower rates of
following a single death and colostomy.
episode
Dietary fiber intake and 1994 43 2 B Diets high in fruit and vegetable
risk of diverticulitis fiber had a significantly lower
incidence of symptomatic
diverticulitis.
Primary anastomosis for 2007 12 2 B Primary resection and anastomosis
sigmoid diverticulitis can be considered in low risk
patients (Hinchey Stages I and II)
with acute diverticulitis.
Laparoscopy for 2005 2009 50 47 48 2I BA Laparoscopy associated with quicker
diverticular disease 2010 return to diet, shorter time, and
reduced length of hospital stay.
Laparoscopic sigmoid colectomy
is associated with a lower
anastomotic leak rate and a
lower postoperative morbidity.

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 Commentary on
Diverticular Disease of the Colon
Surgeons who manage patients with colonic diverticulitis encounter
a spectrum of clinical problems and they must select a therapy from
an array of therapies, which they conclude is optimal for an individ-
ual patient. Drs Izu and Ekeh provide an informative review of the
options available to surgeons who manage patients with diverticu-
lar disease of the colon. The authors emphasize several key points,
which they characterize in terms of available supporting evidence.
The majority of surgeons use an abdominal computed tomog-
raphy (CT) scan to evaluate a patient with suspected diverticulitis.
Surgeons categorize the patient into four categories of severity, pri-
marily based on the CT images. Drs Izu and Ekeh endorse the value
of the Hinchey scoring paradigm. Patients with minimal divertic-
ulitis, Hinchey Stage I or II, are usually successfully treated with
antibiotics and procedural interventions are not required as the
majority of patients make an uneventful and permanent recovery.
Patients with a Hinchey Stage III or IV usually require an interven-
tion to assist them in their recovery, and the surgeon should expect
a more complex problem and a prolonged recovery.
Drs Izu and Ekeh identify a study published in 2000 by
Zeitoun et al. as providing high-quality evidence. The Zeitoun et
al. paper concludes that outcome is superior in Hinchey Stage III
and IV diverticulitis if a Hartmann procedure is performed, pre-
sumably because with resection of the infected colon, the source
of sepsis is eliminated. However the authors point out that there is
a substantial body of lower-level evidence that supports the thera-
peutic value of percutaneous drainage of abscess. This procedure
has the obvious benefit of being performed by an interventional
radiologist using local anesthesia. Drs Izu and Ekeh reference sev-
eral studies which report that series of patients acutely ill with
diverticulitis have been cured of their sepsis syndrome without
emergency surgery on their colon.
214
PMPH_CH23.indd 214
Richard J. Mullins
Drs Izu and Ekeh highlight that a surgeon planning emergency
surgery on a patient can select from several options. While surgeons
have used a formal laparotomy for decades as the means of control-
ling complicated acute diverticulitis, the authors of this chapter point
to a growing body of evidence that skilled laparoscopic surgeons
can manage the patient with Henchey Stage III or even IV diver-
ticulitis with minimally invasive methods. Another treatment trend
supported by observational series of patients in high-volume colon
surgery centers is resection and primary anastamosis of disease-free
ends of the colon in patients having an emergency operation.
There is wide spread agreement among surgeons that antibi-
otics are usually an effective treatment for acute uncomplicated
colonic diverticulitis. Successful treatment leads to the question
should the patient have an elective colon resection, performed by
laparotomy or laparoscopy, combined with a primary colonic anas-
tomosis. Drs Izu and Ekeh report favorable results that patients
who have one episode of acute uncomplicated diverticulitis can be
followed through two, three, or even four additional bouts before
elective surgical resection is needed. This recommendation is based
on the clinical experience published in manuscripts by many colon
surgeons that only a small minority of patients with diverticulosis
of the colon have recurrent bouts of infection. The authors of the
chapter prudently point out there is room for considerable clinical
judgment when deciding when to recommend surgical resection.
Operations on patients with diverticulitis can be a daunting task.
Surgeons planning to attempt resection of complicated diverticulitis
of the colon, or surgeons planning to take down a Hartmann proce-
dure colostomy and perform an anastamosis should expect that they
may encounter a densely inflamed, scarred surgical field, where con-
ventional dissection planes do not exist, and shortened mesenteries
severely restrict the ability to achieve a tension-free anastamosis.
5/21/2012 9:01:18 PM

Crohn’s Colitis and
Ulcerative Colitis
INTRODUCTION
Inflammatory bowel disease (IBD) includes Crohn’s disease (CD)
and ulcerative colitis (UC). Although there is a small percentage
of overlap in the clinical and pathologic manifestations of these
diseases, they tend to be clinically separate and distinct. The etiol-
ogy of both CD and UC is unknown. UC involves the colon and
rectum, whereas CD can involve any portion of the gastrointes-
tinal tract from the mouth to the anus. UC tends to involve the
rectum and spread proximally in the vast majority of the cases,
although relative rectal sparing does occur. It tends to be a con-
tinuous disease without skip areas. UC is a mucosal disease unless
it presents in a fulminant manner, at which time all layers of the
bowel wall can be involved. CD is a transmural inflammatory
disease that begins in the mucosa, but rapidly involves all layers
of the bowel wall. This explains the clinical manifestations of the
pathophysiologic process in which fistulas, abscesses, and fibro-
stenotic disease are commonly seen. To complicate matters even
more, in about 6% of the pathologic specimens (post op), features
of both CD and UC can be found. This has been termed as inde-
terminate colitis, and it has implications in terms of clinical man-
agement later.
1. How do patients with IBD colitis present?
Patients with CD can manifest with one or more different symp-
toms such as abdominal pain, bleeding, abscess, and fistulas.
Patients can have symptoms sometimes for many years prior to
the diagnosis.1-3 This was illustrated in a series that included 66
patients with IBD of whom 45 had CD and 21 had UC.2 Nonspe-
cific digestive symptoms resembling irritable bowel syndrome
were present for an average of 7.7 years prior to the diagnosis of
CD, which was significantly longer than for UC (average 1.2 years).
Symptoms were present for the longest amount of time in patients
with disease limited to the colon compared with the small bowel
(average 11.4 vs. 4.9 years).2
Physical examination will frequently demonstrate an inflam-
matory mass most commonly in the right lower quadrant. It has
215
PMPH_CH24.indd 215
CHAPTER
CHAPTER 24
1
Kervin Arroyo and Barry Salky
been estimated in population-based cohort studies that 20% to
40% of individuals with CD will develop fistulas over the lifetime
of their disease.4 Fistulas occur in 17% to 43% of the patients with
CD.5 According to a study in Minnesota, the risk of developing a
fistula is 33% at 10 years and 50% at 20 years.6
The clinical presentation of CD can be varied depending on
the pathophysiology of the disease. Diarrhea secondary to inflam-
mation is the most common presentation followed by obstruction
secondary to fibro-stenotic disease. Fistulas can present in any
form, but internal fistulas are most common. Perianal disease is
common, and it is not seen in UC.
Mucosal ulceration, rectal bleeding, diarrhea, and abdomi-
nal pain characterize UC. Patients frequently have symptoms for
many months prior to the diagnosis. Obstruction and fistulas are
not part of the clinical presentation of UC. Unless fulminant coli-
tis is present, fever is not a common presentation of UC.
2. What is the optimal medical management of patients
with CD?
Since the presentation of CD can be so varied, it is important to
compare treatments with similar manifestations of the disease.
Therefore, the Crohn’s Disease Activity Index (CDAI) was devel-
oped. The CDAI is based on the symptoms and is divided into four
different categories.7,8 A CDAI of <150 corresponds to patients who
are asymptomatic. A CDAI between 150 and 220 (mild to moderate
CD) corresponds to patients that ambulate and are able to toler-
ate an oral diet without dehydration. A CDAI between 220 and 450
(moderated to severe) corresponds to patients who have failed treat-
ment or with symptoms such as fever, weight loss, abdominal pain,
and nausea or vomiting. The last category is the severe or fulminant
form (CDAI > 450). These patients have symptoms despite conven-
tional treatment. They can present with high fevers, persistent vom-
iting, intestinal obstruction, or evidence of an abscess.8 Selected
trials of medical management of IBD are presented in Table 24.1.
Corticosteroids are effective for the induction of remission
in CD, but approximately 20% of patients are refractory to ste-
roid therapy,9 particularly when used for more than 15 weeks.10
5/21/2012 9:09:06 PM
 216 ■ Surgery: Evidence-Based Practice
However, other studies have shown that corticosteroids are not
effective for maintenance of remission in CD.11
Sulfasalazine is commonly used in CD but the efficacy is
not well supported by randomized controlled trials (RCTs).12,13 A
meta-analysis of three double-blind RTCs of mesalamine (Pentasa®
4 g daily) in active CD found that there was an overall mean
reduction in the CDAI of 67 points, about 25 points better than
with placebo. However, this decrease in the CDAI represents only
a modest clinical benefit and is mainly seen after 4 weeks of treat-
ment.13 A meta-analysis published by Hanauer et al. failed to dem-
onstrate a significant benefit of these drugs.13 Also, mesalamine
reduces the risk of clinical recurrence of CD.46
Azathioprine is an immunosuppressant that inhibits T lym-
phocytes. Several RCTs have demonstrated the efficacy of aza-
thioprine and mercaptopurine as induction treatment of CD.
This Cochrane review reported an overall response rate of 54%
for active CD compared with a placebo response rate of approxi-
mately 33%.14 Azathioprine reduces the risk of clinical recurrence
of CD.46
Methotrexate is a dihydrofolate reductase inhibitor that sup-
presses the body’s natural immune responses.17 A review per-
formed by Cochrane collaboration in 2009 included three RCTs.16
Of the three studies, one study demonstrated that intramuscu-
lar methotrexate at doses of 15 mg/week was more effective than
placebo for the maintenance of remission of CD. Another one
demonstrated no difference between methotrexate and 6-MP for
maintenance of remission in CD.16 A randomized, double-blind
study by Feagan et al.17 showed that relapse was more frequent
in the placebo group versus the methotrexate group, 61% ver-
sus 35%, respectively. Maté and Jiménez published a study of 28
patients with CD who achieved remission in about 80% of the
patients taking methotrexate.16 Feagan et al. published a series of
CD patients in 2000. In 35 of 40 patients, the remission was main-
tained at 40 weeks of treatment.16,17 He concluded that in Crohn’s
patients who had been induced into remission with methotrexate,
more patients remained in remission while taking intramuscular
methotrexate compared with placebo.17 The Maté–Jiménez et al.
and Oren et al. studies suggest that methotrexate is safe, but failed
to show a benefit for lower doses given orally.16,18 Methotrexate at a
dose of 25 mg intramuscularly every weekly was linked to induce
remission and complete withdrawal from steroids in patients with
refractory CD. There is evidence that methotrexate reduces the
need for steroid treatment (steroid sparing effect).15
The chimeric monoclonal antibody (cA2) was supported in
this study of 108 patients with CD resistant to treatment.1 A single
infusion of cA2 was an effective short-term treatment in many
patients with moderate to severe, treatment-resistant CD.1
Infliximab is a chimeric IgG1 monoclonal antibody that acts
against tumor necrosis factor alpha (TNF-α). This medication is
effective and has played a significant role in the treatment of CD.4
This RCT evaluated the effects of maintenance with infliximab
and compared the reduction in hospitalizations, surgeries, and
procedures. They randomized a total of 282 patients at week 14
as responders. The 5 mg/kg infliximab group had a reduction of
>50% in hospitalizations when compared with the placebo group.
In terms of surgeries, the 5 mg/kg infliximab group had a reduc-
tion of >50% in surgeries when compared with the placebo group,
60 versus 118 patients, respectively.4
An analysis of patients from the ACCENT phase III clini-
cal trial demonstrated that when patients entered in remission
with infliximab, they had fewer hospitalizations, surgeries, and
PMPH_CH24.indd 216
improved quality of life.19 Patients with CD who respond to an ini-
tial dose of infliximab are more likely to be in remission at weeks
30 and 54 if infliximab treatment is maintained every 8 weeks.19
In another study, Sands et al. performed an RCT of 306 patients
with CD and draining fistulas. Of the 306 patients, 195 responded
to the drug and 87 patients did not. All the patients were random-
ized to receive placebo or infliximab every 8 weeks and followed
up at week 54. The time to loss response was longer for patients
who received infliximab maintenance therapy than the placebo
group. Nineteen percent of the patients in the placebo group and
36% in the treatment group had a complete absence of draining
fistulas.20
In another study by Present et al., 58% to 68% of patients
achieved the reduction of 50% or more from base line in the num-
ber of draining fistulas observed at two or more consecutive study
visits. During the same period of time, this was achieved in 26%
of the patients in the placebo group. Closure of the fistulas was
achieved in 55% and 38% of the patients who received infliximab
5 and 10 mg/kg, respectively. These fistulas remained closed for
a mean time of 3 months.21 According to all these reviews, there
is extensive evidence supporting the utility of infliximab as an
induction agent for CD.
Adalimumab is a subcutaneously administered immuno-
globulin G1 monoclonal antibody that binds with high affinity to
human TNF and modulates its biologic drug. Adalimumab was
significantly more effective than placebo in maintaining remission
in moderate to severe CD through 56 weeks.2 The fistula closure
was higher and the exacerbation of CD was lower.2 Adalimumab
was superior to placebo for induction of remission in patients with
moderate to severe CD naive to anti-TNF therapy. The optimal
dose regimen for adalimumab in this study was 160 mg.3
Natalizumab is an IgG4 monoclonal antibody and a selec-
tive adhesion molecule (SAM) inhibitor.22 The data of this review
showed that natalizumab was effective for induction of clinical
response and remission in patients with moderately to severely
active CD.22 The dose of natalizumab used in this study was 300
mg or 3 to 4 mg/kg. These studies also support the results that
natalizumab may be an effective treatment for active CD.23,25
Certolizumab pegol is a monoclonal antibody that has a bind-
ing affinity for TNF-α, which does not induce apoptosis of T cells
or monocytes. A RCT study26 of 668 patients at 147 centers, the
induction therapy of 400 mg of certolizumab pegol was admin-
istered at 0, 2, and 4 weeks. Sixty-four percent of the patients
responded to induction therapy, and the response was maintained
through week 26 in 62% of the patients. At the end of the study,
the patients that responded to induction therapy were more likely
to maintain response and remission at week 26.26 Another RCT
performed by Sandborn et al.6 included 662 patients with at least 3
months with moderate to severe CD in 171 centers. The treatment
with certolizumab was associated with a modest benefit in the
response at weeks 6 and 26, but the rate of remission was not.6
3. When is surgical intervention required in the management
of CD?
Surgery is necessary to treat some complications of the disease.
Selected trials of surgical management of IBD are presented in
Table 24.2. A prospective study evaluating the natural history of CD
showed that 33% of patients with chronically or intermittently active
disease developed complications requiring hospitalization and sur-
gery in the first year after diagnosis, 13% in the second year, and 3%
5/21/2012 9:09:07 PM
 Crohn’s Colitis and Ulcerative Colitis ■ 217

in each subsequent year.27 Surgical treatment is required in approxi-
mately 70% of patients.28 The need for operation is determined by the
interaction among the gastroenterologist, surgeon, and the patient.
Patients have better outcome when they are well-prepared medically,
psychologically, and had surgery in a timely fashion.
4. What are the advantages of laparoscopic approach in CD
An early case comparison feasibility study in 1999 demonstrated a
significant decrease in the length of stay (LOS) with less complica-
tions in the laparoscopic group compared with the open group.31
There is a clear advantage to decreased adhesions and smaller
incisions in these patients with laparoscopic surgery.29,30 This RCT
followed up 60 patients after elective ileocolic resection for refrac-
tory, noncomplicated CD. They concluded that laparoscopic tech-
niques offered a faster recovery of pulmonary function, fewer
complications, and shorter LOS compared with conventional
surgery in these patients. These were all statistically significant.32
A 10-year follow-up study confirmed that laparoscopic ileocolic
equals open ileocolic resection with the same incidence of recur-
rent disease. There were significantly less incisional hernias in the
laparoscopic group.33 This meta-analysis study published in 2008
showed statistically significant benefit in return of bowel function,
oral intake, LOS, morbidity, and equal recurrence in the laparo-
scopic groups.35 This Cochrane review demonstrates that the lap-
aroscopic approach reduces the operative blood loss, allows quicker
return of bowel function, and shorter LOS.47
We need to do a better job at training surgeons to use laparo-
scopic surgery for CD. In a population-based analysis of laparo-
scopic versus open approaches to CD, there were 396,911 admissions
for CD and 49,609 surgeries from 2000 to 2004. Only 2826 surger-
ies (6%) were performed laparoscopically even though there was a
statistically significant lower complication rate, shorter LOS, lower
charges, and lower mortality.36 Yet, the vast majority of surgeries for
CD are being performed in an open manner.

TABLE 24.1 Selected trials of medical management of IBD

Author (ref) Study n Treatment Clinical Response Comments
Type
Colombel (2) RCT 261 Placebo adalimumab 40 mg, 28 (16.5%) Clinical response;
260 eowadalimumab 40 mg 71 (41.3%) decrease CDAI Score
257 weekly 75 (47.8%) ≥100 at week 56
Hanauer (3) RCT 74 Placebo adalimumab 80 mg, 9/74 (12%) remission Clinical response;
75 adalimumab 160 mg 18/75 (24%) remission remission rates
76 27/76 (36%) remission
Lichtenstein (4) RCT 143 Placebo infliximab 5mg/kg 45/143 (31%) Number of
139 19/139 (14%) hospitalizations
Hanauer (19) RCT 110 Placebo infliximab 5 mg/kg, 23/110 (21%) Clinical response;
113 Infliximab 10 mg/kg 44/113 (39%) remission at 2 weeks
112 50/112 (45%)
Sands (20) RCT 143 Placebo infliximab 5 mg/kg 27/143 (19%) Clinical response;
139 50/139 (36%) complete absent of
draining fistulas
Ghosh (23) NRCT 63 Placebo infusion Remission rate 27% Clinical remission; score
68 natalizumab 3 mg/kg2 response 43% of <150 on the CDAI
66 infusions natalizumab Remission rate 28%
51 3 mg/kg2 infusions response 50%
natalizumab 6 mg/kg Remission rate 42%
response 61%
Remission rate 39%
response 65%
Sandborn (25) NRCT 18 Placebo 300 mg of Remission rate 26% Response; decrease
17 natalizumab response 28% (CDAI) score of at
24 Remission rate 44% least 70 points
response 61%
Rutgeerts (27) RCT ACT Placebo infliximab 37% clinical response Clinical Response;
1121121122 5mg/kg Infliximab UC69% clinical decrease in the
ACT 10 mg/kg Placebo response UC61% Mayo score of at
2123121120 infliximab 5mg/kg clinical response least 3 points and
Infliximab 10 mg/kg UC29% clinical at least 30%
response UC64%
clinical response
UC69% clinical
response UC
NRCT = no randomized control trial.

PMPH_CH24.indd 217 5/21/2012 9:09:07 PM

 218 ■ Surgery: Evidence-Based Practice

TABLE 24.2 Selected Trials of Surgical Management of IBD

Author (ref) Study n Treatment Clinical Response
Ali (28) NRCT 253354 Laparoscopic IPAA Open IPAA Lap Group had a longer OR time with
higher cosmesis scores.
Milsom (32) NRCT 29 31 Open ileocolic for CD Laparoscopic Lap group had a faster recovery
ileocolic for CD of pulmonary function, fewer
complications, and shorter LOS.
Stocchi (33) NRCT 2927 Open ileocolic for CD Laparoscopic Lap ileocolic is at least comparable to
ileocolic for Crohn’s OC in the treatment of ileocolic
CD.
Wu (34) MA 16 Trials 396527 Laparoscopic surgery for UC Open Lap surgery for UC had a better
surgery for UC postoperative fasting time,
postoperative hospital stay, and
overall complication rate.
TAN (35) MA 286595 Laparoscopic Surgery for CD Open Laparoscopic surgery for CD takes
Surgery for CD longer to perform and lower
morbidity.
Maartense (42) NRCT 3030 Lap hand-assisted Restorative Quality of life questionnaires were
Proctocolectomy with IPAA Open comparable for lap hand-assisted
Restorative Proctocolectomy With laparoscopic vs open restorative
IPAA proctocolectomy with IPAA.
Polle (43) NRCT 3030 Lap hand-assisted proctocolectomy Open proctocolectomy has a negative
Open restorative proctocolectomy impact on body image and cosmesis.
Lap group had longer operating
times and higher costs.
NRCT = no randomized control trial, MA = meta-analysis.

5. What is the optimal medical management of patients with UC?
The medical management of UC has been mainly 5-aminosalicylates,
corticosteroids, and immunosuppressants. High-dose intrave-
nous steroid therapy forms the basis of pharmacologic treatment
for acute UC.37 If this fails, immunosuppressive medications can
be used. The second line of treatment consists of cyclosporine A,
with a switch to azathioprine for maintenance of therapy.37
Infliximab is a chimeric IgG1 monoclonal antibody that acts
against TNF-α.. Two RCTs in the treatment of UC were presented
in this paper.27 There were 364 patients in each group with moder-
ate to severe active UC. They divided the patients into two groups,
placebo and infliximab. The infliximab group was subdivided into
two groups based on 5 and 10 mg/kg of body weight dose. They
administered the medication at 0, 2, 6, and 8 weeks. In the first
trial, 69% of the patients who received 5 mg of infliximab and
61% of those who received 10 mg had a clinical response at week 8
compared with 37% of those who received placebo.27 In the second
RCT, 64% of the patients who received 5 mg of infliximab and
69% of those who received 10 mg had a clinical response at week 8
compared with 29% of those who received placebo.27 The response
of treatment at week 54 was 45% for the infliximab group versus
20% for the placebo group.
This multicenter RCT of 45 patients demonstrated that inf-
liximab reduced the need for colectomy compared with placebo
(29% vs. 67%).38 The ACT Trials published that infliximab was
associated with improved health-related quality of life scores.38
Does infliximab affect the surgical outcome after operation? This
case-matched study compared only 13 patients; the study showed
no adverse impact from the previous infliximab therapy on the
laparoscopic ileal pouch anal anastomosis (IPAA) postoperative
course; that is, mean operative time (353 vs. 355 min), complica-
tion rate (23% vs. 38%), and mean hospital stay (22 vs. 25 days).37
6. What are the advantages of laparoscopic approach in UC?
The open approach has been the standard of care for the surgical
treatment of the UC. All newer laparoscopic approaches have to
judge against the open approach. The transformation to laparo-
scopic surgery for UC has been slow. However, with the development
of newer energy devices and the extensive experience being gained
with the laparoscopic approach to UC, more and more patients are
being offered this type of surgery.39 Elective laparoscopic procto-
colectomy for UC is safe and provides many short-term benefits in
both the acute and chronic setting.39-41 The reasons why it is not
being used more frequently are multiple, and they include technical
expertise, complicated intestinal surgery in “sick” patients, multi-
ple quadrant surgery, and time constraints. High-dose steroids and
other immunosuppressant medications make for technically chal-
lenging surgery as well. While short-term advantage has been dem-
onstrated (decreased LOS and cosmetics), long-term postoperative
quality of life has been comparable to open cohorts.42
In terms of urgent cases, there are only a small number of reports
that have studied the laparoscopic approach in the setting of severe
colitis. This study demonstrated that in the urgent setting, the lap-
aroscopic approach is associated with the short-term benefits of faster
return of bowel function, decreased inpatient narcotic requirement,
and shorter LOS compared with the open approach.39 The patients

PMPH_CH24.indd 218 5/21/2012 9:09:07 PM

 Crohn’s Colitis and Ulcerative Colitis ■ 219

that underwent a laparoscopic colectomy progress to the second and
third operative stages of restorative proctocolectomy faster than those
patients who underwent open colectomy.39 The short- and long-term
results of the laparoscopic approach were compared in this study of
73 patients. They concluded that laparoscopic IPAA offers significant
advantages over the open conventional procedure in terms of body
image and cosmesis.43,44 The postoperative return of bowel function
and analgesic requirements after laparoscopic IPAA has been less
concordant. They observed a faster return of bowel function; that is,
passing flatus and tolerating liquid diet, in the laparoscopic group.45
In this meta-analysis, they evaluated 16 controlled trials that
include 923 patients. They found that laparoscopic surgery com-
pared with open surgery (39.3% vs. 54.8%) had a longer operative
time (weighted mean difference 69.29 min). As to recovery of bowel
function, peritoneal abscess, anastomotic leakage, postoperative
bowel obstruction, wound infection, blood loss, and mortality, lap-
aroscopic surgery did not show any superiority over open surgery.
They concluded that further evaluation with more well-designed
and long-term follow-up studies is required.34
This Cochrane study evaluated the effects of laparoscopic ver-
sus open ileal pouch anal anastomosis for patients with UC and
familial adenomatous polyposis. They included 11 trials for a total
of 607 patients. No significant differences were found in mortality,
complications, reoperation, and readmission. The operative time
was significantly longer in the laparoscopic group. The cosmesis
scores were higher in the laparoscopic group.28

Clinical Question Summary

Question
1 How do patients with IBD
colitis present?
2 What is the optimal medical
management of patients
with CD?
3 When is surgical intervention
required in the management
of CD?
4 What are the advantages of
laparoscopic approach in CD?
5 What is the optimal medical
management of patients
with UC?
6 What are the advantages of
laparoscopic approach in UC?
Answer Grade References
Symptoms such as abdominal pain, bleeding, abscess, and C 1-3
fistulas in CD. Mucosal ulceration, rectal bleeding, diarrhea,
and abdominal pain characterize UC.
Corticosteroids can induct remission, but 20% of patients A 2-4, 10, 11,
exhibit refractoriness to therapy. Infliximab reduced by 19-23, 25
>50% the need for surgery and improved QOL. Patients
achieved the reduction of 50% or more from base line in
the number of draining fistulas. Natalizumab is effective for
induction of clinical response and remission in patients with
moderately to severely active CD. Adalimumab is effective
in maintaining remission in moderate to severe CD. The
optimal dose regimen for adalimumab was 160 mg.
Surgery is necessary to treat some complications in patients B 28
with chronically or intermittently active disease.
With the laparoscopic approach, the patients have a faster B 32, 33, 35
recovery of pulmonary function, faster return of bowel
function, shorter LOS, less adhesions, and less incisional
hernias.
Infliximab is an effective treatment for UC. About 69% of the B 27, 38
patients who are treated had a clinical response. Reduced
the need for colectomy compared with placebo. It was
associated with improved health-related quality of life
scores.
Short-term advantage has been demonstrated to have a faster A 28, 34, 42, 43
return of bowel function, decreased inpatient narcotic
requirement, and better body image.

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5/21/2012 9:09:07 PM

Large Bowel Obstruction
Ryan A. Lawless, Dale A. Dangleben, and Michael M. Badellino
INTRODUCTION
Large bowel obstructions are a diagnostic as well as management
challenge for even the most experienced surgeon. This is due to
the multitude of possible diagnoses and physiologic derangements
with which these patients present. Maneuvering through the
anatomy, diagnosis, management, and operative technique with
care and due diligence will allow the surgeon to adequately man-
agement this most challenging entity. There remains a paucity of
Level 1 evidence in the literature to assist with surgical decision-
making even today. Recent articles were reviewed to support the
recommendations made in the discussion to follow.
Clinical Questions
How do patients with large bowel obstruction present?
What are the most common causes of large bowel obstruction?
What is the proper diagnostic evaluation?
What is the preferred operative approach?
What is the role of laparoscopy in the treatment of large bowel
obstruction?
What is the role of colonic stenting?
Clinical Presentation
1. How do patients with large bowel obstruction present?
The presentation of large bowel obstruction depends on the degree of
intestinal luminal narrowing and the duration of obstruction. There
is very little evidence in the reviewed literature to characterize the
presenting symptoms of acute large bowel obstruction. The under-
lying etiology of the obstruction often dictates the presentation. In a
prospective observational study of 150 patients admitted with acute
mechanical bowel obstruction, it was reported that 36 patients
(24%) had a large bowel obstruction. Presenting symptoms and
physical examination findings most commonly included absence of
221
PMPH_CH25.indd 221
CHAPTER
CHAPTER 25
1
the passage of flatus (90%) and/or feces (80.6%) and abdominal dis-
tention (65.3%). The most common etiologies noted for both small
and large bowel obstructions were adhesions, incarcerated hernias,
and large bowel malignancy (64.8%, 14.8%, and 13.4%, respectively).
The most common causes for large bowel obstruction were large
bowel malignancy, adhesions, retroperitoneal tumors, and hernias
in 47.4%, 36.3%, 5.5%, and 2.7%, respectively.1
COLON CANCER
In approximately 10% of patients, colon cancer presents as a large
bowel obstruction.2 Obstruction is most likely to present in the sig-
moid colon (75%), followed by ascending colon (10%), transverse
colon (5%), and descending colon (5%). Of patients who presented
with obstruction, 20% had ischemia, 15% had necrosis, and 10% had
perforation. In this subset of patients with mechanical large bowel
obstruction, 16.6% were intraoperatively diagnosed with ischemia,
16.6% with necrosis, and 11.1% with perforation. The incidence of
necrosis and perforation was significantly greater in patients with
large bowel obstruction than with small bowel obstruction.1
HERNIAS
Hernias cause <3% of large bowel obstructions. Although infre-
quent, large bowel obstruction caused by hernia is more likely to
be associated with ischemia, necrosis, and perforation.1 The pres-
ence of skin erythema or laboratory data to suggest bowel ische-
mia, including leukocytosis, lactic acidosis, or metabolic acidosis
suggest bowel compromise and should prompt early operative
intervention.
COLONIC VOLVULUS
Colonic volvulus is responsible for 10% to 15% of large bowel
obstructions. In a recent review, it was noted that 76% of cases
occurred in the sigmoid colon and in older patients. Risk
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 222 ■ Surgery: Evidence-Based Practice
factors for sigmoid volvulus are high fiber diet, African American
heritage, institutionalization, laxative abuse, previous abdominal
surgery, pregnancy, Chagas disease, Hirschsprung’s disease, and
Parkinsonism.2
Cecal volvulus accounts for approximately 22% of cases.
Overall, cecal volvulus tends to occur in younger patients that
may suggest a congenital and abnormal attachment of the right
colon to the abdominal wall.2
ACUTE COLONIC
PSEUDO-OBSTRUCTION
(OGILVIE’S SYNDROME)
Acute colonic pseudo-obstruction (ACPO) is secondary to a
number of metabolic and physiologic causes. It is characterized
by abdominal distention, pain (80%), nausea with or without
vomiting (60%), and obstipation (40%) in the absence of mechani-
cal obstruction. Synonyms include adynamic ileus, acute colonic
ileus, and Ogilvie’s Syndrome.3-6 The pathophysiologic basis of
ACPO is multifactoral.
INFREQUENT CAUSES
Other, less frequent, causes of large bowel obstruction include
stool impaction, strictures from inflammatory bowel disease, or
chronic diverticulitis, and acute diverticulitis with extracolonic
abscesses.
In summary, the most common clinical symptoms associated
with large bowel obstruction are the absence of flatus and/or feces,
and abdominal distention. A significant number of patients with
large bowel obstruction will also have colonic ischemia, necrosis,
and/or perforation.1 (Grade C recommendation)
Differential Diagnosis
2. What are the most common causes of large bowel obstruction?
There was no Level 1 evidence identified to establish succinct diag-
nostic or treatment algorithms. There are a wide range of etiologies
of large bowel obstruction. Thus, evaluation and treatment algo-
rithms can be complex.
In 2000, Jenkins et al. retrospectively reviewed 73 patients
with secondary causes of small and large bowel obstruction. The
etiology of obstruction was metastatic neoplastic process (19%),
colonic volvulus (17%), Crohn’s disease (14%), hernia (11%), and
diverticular disease (7%).7 A comprehensive outline classification
scheme is illustrated in Current Therapy in Colon and Rectal Sur-
gery.8 This simple outline divides the causes into extrinsic to the
bowel wall, intrinsic to the bowel wall, and intraluminal lesions.
EXTRINSIC TO THE BOWEL WALL
Lesions extrinsic to the bowel wall lead to external compression
of the colonic lumen. Possible extrinsic lesions include neoplastic
growth from an adjacent organ or, more frequently, a retroperito-
neal tumor.1 As with small bowel obstruction, the two other main
extrinsic causes are hernias and adhesions.
PMPH_CH25.indd 222
INTRINSIC TO THE BOWEL WALL
Neoplasms within the colonic wall account for around 47% of cas-
es.1 Other intrinsic causes include strictures secondary to Crohn’s
colitis, ulcerative colitis, chronic ischemia, diverticular disease,
or external radiation. Endometriosis has also been implicated as
being an intrinsic cause of large bowel obstruction.9
INTRALUMINAL LESIONS
Intraluminal lesions come in the form of iatrogenic causes and
physiologic derangements. Iatrogenic lesions include foreign bod-
ies introduced by several routes that become misplaced and lead
to colonic obstruction. Biliary stents or colonic stents may migrate
from their intended position and become lodged in the colon
leading to obstruction.10,11 Small et al.12 evaluated 23 patients who
underwent colonic stenting for left colon obstruction secondary
to benign obstruction. Thirty-eight percent of the patients have a
major morbidity including stent migration (n = 2) and reobstruc-
tion (n = 4). Seymour et al.13 reviewed another series of 18 patients
and observed that only 1 of the 18 patients had stent migration
when placed for left-sided colon cancer. The stent migration in
this patient did not lead to obstruction. Other intraluminal causes
of colonic obstruction include phytobezoars, large gallstones, and
rectal foreign bodies.14
Diagnostic Evaluation
3. What is the proper diagnostic modality?
Options for confirming a radiographic diagnosis of large bowel
obstruction are limited and frequently require a multidisciplinary
approach. Often, large bowel obstruction is diagnosed by clinical
presentation, plain abdominal radiograph, and specialized radio-
logic tests. Plain abdominal radiographs have 84% sensitivity and
72% specificity for diagnosing large bowel obstruction.2
A water-soluble contrast enema may be used in many cases to
establish the diagnosis with 96% sensitivity and 98% specificity.2
Computed tomography (CT) scanners are now readily available
in most hospital settings. In a 7-year, single-institutional review, it
was noted that multidetector CT imaging was more accurate than
contrast enema in diagnosing large bowel obstruction and allowed
for the evaluation of other disease process.15 In a recent literature
review by Finan et al., CT imaging of the abdomen and pelvis with
contrast was recommended in the evaluation of patients with sus-
pected large bowel obstruction as Level 3 evidence. CT scans allow
for the evaluation of the primary process as well as possible meta-
static disease.16 It is the opinion of the authors that although CT
imaging and water-soluble enema have comparable diagnostic
capability, CT is preferable due to its ability to further evaluate the
abdomen and pelvis for other disease. Also, the ready availability of
CT imaging machines makes this imaging modality preferable.
As stated earlier, a full laboratory evaluation is needed in the
diagnosis of large bowel obstruction. It is useful in the determi-
nation of the patient’s overall clinical status and may indicate the
presence of intestinal ischemia, necrosis, and perforation. No Level
1 evidence could be found to support obtaining specific laboratory
tests. However, it is known that patients with a large bowel obstruc-
tion can present with multiple metabolic derangements that must
be corrected prior to operative intervention. Initial laboratory
5/22/2012 6:30:53 PM

evaluation should include a complete metabolic count to evaluate
for leukocytosis and anemia. Also, a complete metabolic profi le
to include liver function tests as well as a lactate level, coagula-
tion profile, and arterial blood gas analysis should be obtained. As
previously noted, the most common cause of colonic obstruction is
colon cancer. Given this observation, a baseline carcinoembrionic
antigen (CEA) level should be obtained.
In addition to the routine hematologic testing discussed
above, it is the option of the authors that CT imaging of the abdo-
men and pelvis with intravenous and oral contrast is preferable
for diagnosing a large bowel obstruction. CT imaging lends itself
to being readily available, quickly interpreted, and allows for eval-
uation of the extent of the primary process and possible metastatic
disease. If necessary, water-soluble contrast can be given rectally
for further evaluation.15 (Grade C recommendation)
Surgical Treatment
4. What is the preferred operative approach?
Operative therapy of acute large bowel obstruction begins with the
correction of fluid status, electrolytes, and acid/base disturbances.
Insertion of a Foley catheter, nasogastric tube, and possibly cen-
tral venous pressure monitoring catheter should be considered.
Careful attention to antibiotic and prophylactic (venous throm-
boembolism and gastrointestinal) regimens is necessary.2 Finan
et al. in 2007 published recommendations regarding placement
of self-expanding metallic stents (SEMS) for acute large bowel
obstruction in the absence of signs of peritonitis/perforation. The
authors also provided Level 3 evidence for the efficacy of SEMS for
conversion of an emergent/urgent situation into an elective one.16
If there is concern over ischemia or perforation, and the patient
has not clinically improved, or cecal diameter is increasing, laparot-
omy should be performed.17 Because most cases of colonic obstruc-
tion are due to colon cancer, it is incumbent on the operating surgeon
to thoroughly evaluate the remaining colon for synchronous lesions.
OPERATIVE MANAGEMENT OF
OBSTRUCTING COLON CANCER
The debate over management in obstructing colorectal cancer cen-
ters on three main options: complete nonoperative management
using stents, performing resection with primary anastamosis ver-
sus colostomy/ileostomy, and initial nonoperative management
with stent decompression followed by interval laparoscopic resec-
tion and anastamosis.
In right-sided colon cancer, a right hemicolectomy should
be performed.2 The distal resection margin may include the right
branch of the middle colic artery, especially if the lesion is located
at the hepatic flexure.8 In patients who are hemodynamically sta-
ble, this can be accomplished with a primary anastamosis at the
time of resection. The lack of bowel preparation in these patients
is not a contraindication to primary anastomosis.16 However, in
patients who are hemodynamically compromised, with perfo-
rated peritonitis, or with distended, edematous bowel, a resection
with end ileostomy should be performed.2 In a 1998 review of 232
cases of obstructing colon cancer requiring urgent surgical inter-
vention, in 160 patients, lesions were located in the colon, and the
remainder being in the rectum. In this group, there was a 25%
mortality rate. Further analysis of the group who died revealed a
PMPH_CH25.indd 223
Large Bowel Obstruction ■ 223
slightly higher mortality rate associated with primary anastamo-
sis in the setting of urgent operative intervention.18
In 2002, de Aguilar-Nascimento et al. reviewed 23 patients with
obstructing lesions of the left colon. The patients underwent two
different surgical treatments: (1) 14 underwent one-stage colonic
resection with colonic lavage (n = 10) or a subtotal colectomy (n = 4)
with primary anastamosis and (2) nine patients underwent staged
resection with either Hartmann’s or loop colostomy. There was one
case of anastomotic dehiscence in the resection and primary anas-
tamosis group and two cases in the staged resection group. These
authors concluded that one-stage resection and primary anasta-
mosis are safe and may be indicated for the management of the
majority of cases.19 Finan et al. found that mortality of one-stage
procedures was similar to that for a staged approach, and hospital
length of stay was longer for a staged resection. They concluded
that primary resection and anastomosis are the preferred option
for uncomplicated malignant left-sided large bowel obstruction.16
For those patients who present with disseminated disease, a pallia-
tive resection should be performed. For recurrent disease, a bypass
procedure or proximal stoma is the preferred approach.2
Subtotal colectomy and segmental resection have been deter-
mined to be equally safe procedures. The choice between the two pro-
cedures should be based on certain characteristics of the individual
case. Cecal ischemia, perforation, or serosal tearing favors subtotal
colectomy. Patients with synchronous lesions should also undergo
subtotal colectomy. A segmental resection is favored if a rectal anas-
tomosis is to be performed. Known preoperative continence distur-
bance favors segmental resection.16 (Grade C recommendation)
Role of Laparoscopy
5. What is the role of laparoscopy in the treatment of large bowel
obstruction?
A Cochrane review, updated in 2008, reported that laparoscopic
colon resection for colon cancer is a safe procedure. Survival rates
are equivalent to open resection. Although there was a trend toward
a lower number of lymph nodes harvested with laparoscopic resec-
tion, this did not translate to an increased development of distant
metastasis, tumor recurrence, or any difference in 5-year disease-
free survival compared with the open technique.20,21
OPERATIVE MANAGEMENT OF
COLONIC VOLVULUS
Sigmoid Volvulus
In hemodynamically unstable patients or those with peritonitis,
early operative intervention is indicated. In stable patients, endoscopic
decompression should be attempted. If endoscopic reduction is unsuc-
cessful, or gangrenous mucosa is encountered during endoscopy,
emergent surgery should be performed. If the volvulus is reduced
endoscopically, elective sigmoid resection is strongly advised as there
is a 60% recurrence rate. Sigmoid resection with end-colostomy
(Hartmann’s procedure) should be performed in the setting of gan-
grene, hemodynamic compromise, or free perforation. In cases ame-
nable to resection and primary anastomosis, a subtotal colectomy
with ileorectal anastomosis may be needed if there is a large size dis-
crepancy between the proximal and distal resection margins.2
Two retrospective reviews, one in patients undergoing emer-
gency resection and primary anastomosis with or without colon
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 224 ■ Surgery: Evidence-Based Practice
lavage, and a second comparing one- and two-stage operations,
concluded that one-stage resection without on-table lavage or
cecostomy is a safe and acceptable treatment option. Despite the
higher rate of shock in patients with gangrenous bowel, overall
anastomotic leak and mortality rates did not differ significantly.22
Single-stage operations resulted in shorter hospital stays com-
pared with two-stage operations.23
Cecal Vovulus
Nonoperative approaches to cecal volvulus are rarely successful.
Although cecopexy and cecostomy are acceptable treatment alter-
natives in high-risk patients and have a lower operative mortality,
the long-term morbidity and mortality are higher. Patients with
viable bowel should undergo right hemicolectomy with primary
anastomosis; those with nonviable bowel require end ileostomy
and proximal colostomy.2
OPERATIVE MANAGEMENT OF
OTHER CAUSES
The treatment of benign stricture is segmental resection. In
Crohn’s disease, stricturoplasty may be more desirable. Preopera-
tive screening colonoscopy is warranted to rule out primary malig-
nancy. Strong consideration must be given to diverting colostomy
in the presence of radiation-induced stricture. However, radiation
does not preclude resection with primary anastamosis.2
Nonoperative management
6. What is the role of colonic stenting?
The role of colonic stenting as a primary treatment modality has
recently been a topic of debate in the literature with respect to
efficacy and safety. Endoluminal stenting has made a significant
impact on the nonoperative treatment of large bowel obstruction.
Given that patients with large bowel obstruction have a significant
morbidity and mortality from diverting colostomy (16% and 5%,
respectively), SEMS have become an acceptable treatment option
for those patients with inoperable disease and for those who are
poor surgical candidates.9
The minimally invasive nature of colonic stents offers an accept-
able alternative therapy for the treatment of large bowel obstruction
in patients who are poor surgical candidates or those with inoper-
able malignant lesions.4,24 Benign strictures caused by diverticulitis,
inflammatory bowel disease, radiation, or ischemic colitis can also
be treated minimally invasively.4 Digital dilation; balloon, or rigid
dilation; steroid injection; electroincision; tube decompression; and
SEMS are all potential minimally invasive treatments.
In 2010, the American Association for Gastrointestinal Endos-
copy (ASGE) published a review of the current literature and recom-
mendations for the use of endoscopy in the management of colonic
obstruction. SEMS were successfully placed in 91% of patients with
malignant colonic obstruction. When placed successfully, 90% of
patients had relief of obstructive symptoms.4 SEMS can be used in
both palliative and preoperative settings. Poor surgical candidates
with malignant colonic obstruction can receive relief with palliative
colonic stenting. The ASGE group supported favorable outcomes
in this group with a clinical success rate of 90% to 93%. SEMS can
also be used as a bridge to surgery. Colonic decompression prior
PMPH_CH25.indd 224
to surgical resection has resulted in fewer complications, shorter
hospital stays, and decreased need for colostomy with a higher
rate of primary anastomosis when compared with urgent surgery.4
Complications associated with placement of colonic stents include
intestinal perforation, stent occlusion, and migration.24
Colonic stenting is the most widely accepted method of
nonoperative treatment. Its use is limited by the small number
of adequately trained physicians and centers performing the pro-
cedure. Small et al.24 reported that endoscopists experienced in
pancreaticobiliary endoscopy had a lower complication rate com-
pared with endoscopists without the same experience. The major-
ity of literature regarding SEMS involves the treatment of rectal,
sigmoid, left, and distal transverse colon lesions. Placement of
SEMS allows for the relief of obstruction, full evaluation of the
primary process by diminishing the urgency of the situation, and
creating the possibility of a one-staged procedure.
Other options available for nonoperative management
include photodynamic therapy, electrocoagulation, laser coagu-
lation, and balloon dilation. A recent Cochrane review demon-
strated that these other modalities have little role in relieving
acute obstruction but may be of value in subsequent treatment.5
(Grade C recommendation)
ACUTE COLONIC PSEUDO-OBSTRUCTION
The prevalence of ACPO is not known; however, it has been postulated
to be responsible for 20% of cases of large bowel obstruction, occur-
ring in 1% of hospitalized patients undergoing orthopedic procedures
and 0.3% of patients with major burns. Predisposing factors include
myocardial infarction, neurologic disease, severe infection, electrolyte
imbalance, surgery, and trauma. The most common causes found in
large retrospective evaluations included operative (23%) and nonop-
erative (11%) trauma, cardiac disease (10–18%), and infection (10%).3
The most significant complications of ACPO are intesti-
nal ischemia and colonic perforation. The rate of perforation in
ACPO has been reported between 3% and 15%. Cecal diameter
determines the rate of intestinal ischemia with rapid increasing
rates at diameters >0–12 cm for more than 6 days.
Initial management of ACPO is evaluation of potential cor-
rectable causes such as electrolyte imbalance and narcotic or anti-
cholinergic medication use. Conservative management includes
nothing by mouth, gastric decompression as necessary, body posi-
tioning, and placement of a rectal tube. This conservative approach
is a reasonable approach for up to 48 h with serial abdominal
examination, laboratory testing, and abdominal radiographs. The
reported success rate is between 20% and 92%.4
A variety of pharmacologic agents have been investigated for the
treatment of ACPO. Neostigmine, an anticholinesterase parasym-
pathomimetic agent, has been shown in multiple studies in a review
by ASGE to have consistently positive results. There are many poten-
tial anticholinergic side effects with neostigmine administration.4,6,26
A patient that is to be treated with neostigmine must be under a
cardiac monitor with atropine readily available.4 A randomized
controlled trial published in the New England Journal of Medicine
in 1999 showed that 10 of 11 patients who failed 24 h of conserva-
tive therapy given neostigmine had prompt colonic decompression.
The one patient who failed initial therapy had decompression fol-
lowing a second dose. Two patients relapsed requiring colonoscopic
decompression with one eventually requiring subtotal colectomy.26
None of the patients in the control group decompressed with
5/22/2012 6:30:53 PM
 Large Bowel Obstruction ■ 225

administration of a placebo. Furthermore, seven patients in the pla- CONCLUSION

cebo group received open-label treatment with neostigmine and had
prompt colonic decompression. The use of neostigmine is supported
by Level 2 data and has changed primary surgical management for
colonic pseudo-obstruction. Contraindications include mechanical
urinary and intestinal obstruction.
Endoscopic decompression of ACPO has a reported success
rate of 80%, with approximately 20% of patients requiring fur-
ther colonoscopic decompression secondary to recurrence. Two
nonrandomized studies have shown that there is a decreased
recurrence rate when a tube is placed during colonoscopy. Other
procedures described for the treatment of ACPO include percuta-
neous endoscopic colostomy in either the cecum or the left colon
and CT-guided transperitoneal percutaneous cecostomy.3
Surgical intervention is indicated for patients who have failed
conservative management or who have progressed to colonic per-
foration. Mortality rates from 30% to 60% have been reported
for patients requiring surgical intervention for ACPO. Surgical
options include a venting stoma, cecostomy, colostomy, or colonic
tube placement.3 There are a paucity of clinical trials comparing
these different surgical interventions. It is our opinion that surgi-
cal intervention should be reserved for the subset of patients with
either a complication secondary to ACPO or those who fail con-
servative management.
The outcomes for patients presenting with large bowel obstruc-
tion vary depending on the cause of obstruction and the pres-
ence of compromised bowel at the time of operation. Mortality
rates for patients with large bowel obstruction from colon
cancer range from 5% to 25%. The mortality rate increases
with findings of necrosis or perforation.1,27 A study by Zorcolo
et al. 28 retrospectively reviewed records of 323 patients who
presented with obstruction from left-sided colorectal cancer
and diverticular disease and underwent urgent surgery. Pri-
mary anastomosis was performed in 176 (55.7%) patients with
a 30-day mortality of 5.7%. Nine patients (5.1%) had anasto-
motic breakdown. Hartmann’s resection was associated with
a higher incidence of systemic and surgical morbidity (39.5%
and 24.3%, respectively). Mortality from primary anastomosis
(5.7%) compared favorably with those undergoing Hartmann’s
resections (20.4%).
As mentioned, colonic stenting has the ability to convert an
emergent/urgent procedure to an elective procedure allowing for
adequate colonic preparation and preoperative evaluation/opti-
mization of the patient. The reviewed studies reveal a lower mor-
bidity and mortality when colonic stents were used as a bridge to
a one-stage procedure.

Clinical Question Summary

Question
1 How do patients with large bowel
obstruction present?
2 What are the most common causes
of large bowel obstruction?
3 What is the proper diagnostic
modality?
4 What is the preferred operative
approach?
5 What is the role of laparoscopy
in the treatment of large bowel
obstruction?
6 What is the role of colonic
stenting?
Answer Grade of References
Recommendation
Absence of passage of flatus (905) and/or feces C 1
(80.6%) and abdominal distension (65.3%) were
the most common symptoms and physical finding.
Large bowel cancer, adhesions, retroperitoneal C 4, 5, 7-11
tumors, and hernias were the most common
causes of large bowel obstruction. Hernias,
adhesions, strictures, endometriosis, ingested
foreign bodies, phytobezoars, gallstones, and
rectal foreign bodies have all been found to cause
large bowel obstruction.
CT imaging is more accurate for the diagnosis of C 2, 12
large bowel obstruction than contrast enema. CT
imaging in conjunction with contrast enema may
yield superior results.
Stomas are preferred for patients with recurrent C 2, 4, 14, 15
disease or palliative resection. A primary
anastomosis can be safely performed for
obstructing colon lesions.
Laparoscopic colon resection is a safe and feasible C 20, 21
treatment option. Colonic stenting is a safe and
effective bridge to subsequent minimally invasive
left colectomy.
Colonic stenting can be used as a bridge to a C 4, 5, 9, 24
one-stage procedure or as a palliative option.
The success rate for relieving obstruction is
approximately 90%. Three-quarters of patients
in which colonic stents are placed as a bridge to
surgery undergo elective resection.

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 226 ■ Surgery: Evidence-Based Practice
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2010;71(3):560-572.
25. Baraza W, Lee F, Brown S, Hurlstone DP. Combination endo-
radiological colorectal stenting: A prospective 5-year clinical
evaluation. Ann Surg Oncol. 2002;9:574-579.
26. Ponec RJ, Saunders MD, Kimmey MB. Neostigmine for the
treatment of acute colonic pseudo-obstruction. N Engl J Med.
1999;341(3):137-141.
27. Hennekine-Mucci S, Tuech JJ, Brehant O, et al. Management
of obstructed left colon carcinoma. Hepatogastroenterology.
2007;54:1098-1101.
28. Zorcolo L, Covotta L, Carlomagno N, et al. Safety of primary
anastomosis in emergency colo-rectal surgery. Colorectal Dis.
2003;5:262-269.
5/22/2012 6:30:53 PM
 Commentary on
Large Bowel Obstruction
Martin A. Schreiber
The authors of the chapter “Large Bowel Obstruction, Ogilvie’s
and Volvulus” have performed an evidenced-based review sum-
marizing the diagnosis, management and outcomes of patients
with large bowel obstruction. The review highlights the fact that
the literature does not contain Level 1 evidence or support Grade A
recommendations in this field. The authors provide a nice descrip-
tion of the differential diagnosis of large bowel obstruction and
they conclude based on the literature that computed tomography
is the best modality available to establish a diagnosis. The authors
outline the indications for operative management of large bowel
obstruction and options for therapy that include open exploration,
laparoscopic exploration, primary anastomosis, damage control
techniques, and the creation of diverting ostomies. The indica-
tions for each of the modalities are well-described. The authors
focus on the fact that colonic stenting is a viable option to either
establish colonic continuity prior to definitive therapy or palliate
patients who are not candidates for resection.
In general, the review is well-balanced and it touches on the
critical elements of the topic. However, the review only superfi-
cially addresses diverticulitis as a cause of large bowel obstruction
classifying it as a “less frequent cause” of large bowel obstruction.
In fact, diverticulitis is frequently cited as the third most common
cause of large bowel obstruction following neoplasm and volvu-
lus.1 Complete large bowel obstruction secondary to diverticulitis
has traditionally been treated with sigmoid resection and proxi-
mal colostomy. Resection with on-table preparation followed by
primary anastomosis with or without proximal diversion has also
been reported.2,3 Although the use of stents for benign disease
remains controversial, stent placement followed by semi-elective
one-stage resection has been reported.2
The authors correctly identify colonic pseudo-obstruction or
Ogilvie’s Syndrome as an important element in the differential
diagnosis of large bowel obstruction. They briefly mention that
227
PMPH_CH25.indd 227
mechanical obstruction is a contraindication to the use of neo-
stigmine. This important point requires additional discussion.
The use of neostigmine in patients with mechanical obstruction
may result in life threatening perforation. Mechanical obstruction
should be definitively excluded prior to prescribing neostigmine
in these patients. Appropriate imaging modalities include com-
puted tomography or water-soluble contrast enema.4,5 Colonos-
copy can also be used to rule out distal obstruction and, as the
authors point out, it has the potential to be a therapeutic inter-
vention. Side effects of the administration of neostigmine include
bronchospasm, bradycardia, and hypotension, potentially leading
to syncope. The incidence of these complications can be reduced
by giving the drug as a continuous infusion as opposed to bolus
administration and reducing the dose from 2 to 1 mg.6
REFERENCES
1. Webb AL, Fink AS. Large Bowel Obstruction; Current Surgical
Therapy. 10th ed. Philadelphia, PA: Elsevier; 2011: 154-157.
2. McCafferty MH, Roth L, Jorden J. Current management of diver-
ticulitis. Am Surg. 2008;74:1041-1049.
3. Edward CL, Murray JJ, Coller JA, et al. Intraoperative colonic
lavage in nonelective surgery for diverticulitis. Dis Colon Rect.
1997;40:669-674.
4. Chapmann AH, McNamara M, Porter G. The acute contrast
enema in suspected large bowel obstruction: Value and technique.
Clin Radiol. 1992;46:273-278.
5. Beattie GC, Peters RT, Guy S, Mendelson RM. Computed tomog-
raphy in the assessment of suspected large bowel obstruction.
ANZ J Surg. 2007;77:160-165.
6. Delgado-Aros S, Camilleri M. Pseudo-obsruction in the critically
ill. Best Prac Res Clin Gastroenterol. 2003;17:427-444.
5/22/2012 6:30:53 PM
 CHAPTER 26
Radiation Injury to the
Small and Large Bowel
Ali Y. Mejaddam and David R. King
The first report of radiation-induced injury to the gastrointesti-
nal tract occurred 2 years after the discovery of x-rays in 1897, in
a scientist who developed colic and diarrhea after daily experi-
mental exposure of his stomach to x-rays.1 Radiotherapy has since
become an essential part of the multimodal treatment of various
neoplasms. Expectedly, the increasing number of patients treated
with radiation is followed by a comparable increase in the num-
ber suffering from its complications. Radiation-induced injury to
the small and large bowel, known clinically as “radiation enteri-
tis”, is a well-recognized complication following radiotherapy for
abdominopelvic malignancies.2,3 The literature on the medical
and surgical management of patients with radiation enteritis is
extremely limited and consists predominantly of case series and
small cohorts.2,3 In fact, the only Level 1 study is a double-blinded
randomized-controlled trial showing that loperamide is superior
to placebo in the management of diarrhea in patients with chronic
radiation enteritis.4
The diagnosis of chronic radiation-induced injury to the bowel
is established in patients with prior abdominopelvic irradiation
whose clinical symptoms are compatible with suggestive radio-
logic findings, such as bowel thickening or distension2,5,6 without
an alternative etiology (ischemia or infection). For those patients
who go on to require an operation, most commonly for obstruc-
tion or perforation, it is important to note that irradiated intes-
tines are vulnerable due to poor wound-healing, and dissection
and manipulation of the bowel in this region may be technically
challenging.3,6,7 The optimal surgical management is supported by
limited data and, as such, remains under much debate.
1. How does radiation affect the bowel?
Radiation therapy causes damage to cellular DNA which sub-
sequently leads to cell death.8 This effect is more pronounced in
mitotically active cells such as tumor cells; however, other divid-
ing cells in normal tissue may be affected as well. The small and
large bowel may be particularly sensitive to radiation due to its
rapid cellular turnover rate,9 particularly at the mucosal level.
The toxicity of radiation to intestines is often distinguished into
an acute phase and a chronic (sometimes progressive) phase.2,10
228
PMPH_CH26.indd 228
Acute radiation injury usually occurs 2 to 3 weeks after medical
radiation exposure and is histologically characterized by epi-
thelial denudation and mucosal ulceration.2 Symptoms of acute
radiation enteritis include abdominal pain, diarrhea, and fre-
quent bloody stools. These symptoms often subside within 2 to 6
weeks after completion of radiotherapy and rarely require surgical
intervention.10
Chronic radiation enteritis typically develops 6 months to 6
years after radiotherapy, even though toxicity after several decades
has been reported.3,11 The pathology of chronic radiation enteri-
tis is believed to result from an obliterative endarteritis result-
ing in chronic microvascular ischemia of the intestines.2 Clinical
features include malabsorption and chronic diarrhea, as well
as obstructions, perforations, and fistula formation; it has been
reported that one-third of these patients will require surgery.7
Answer: Radiation enteritis is distinguished into an acute
and a chronic phase. The acute phase is often transient and rarely
requires surgical intervention. Some patients develop chronic
radiation enteritis due to ischemia caused by obliterative endar-
teritis, and about one-third of these patients may present with
symptoms that require an operation. (Grade C recommendation)
2. Is there a critical radiation dose in which serious bowel
injury occurs?
There are several risk factors associated with the development
of chronic radiation enteritis including radiation dose, volume
of irradiated small bowel, and concomitant use of chemothera-
py.2 In a literature review by Emami et al., the total dose at which
5% of patients are expected to experience serious bowel toxicity
(defined as requiring an intervention) at 5 years (TD5/5) is 50 Gy
if a third of the volume of the small bowel was irradiated.12 For
the same small bowel volume, the dose at which 50% of patients
would experience serious toxicity at 5 years (TD50/5) is 60 Gy. The
TD5/5 and TD50/5 for a third of the volume of the colon is slightly
higher at 55 and 65 Gy, respectively.12 These results are corrob-
orated by subsequent studies of patients with chronic radiation
enteritis who needed surgical therapy, showing a total radiation
dose in the range of 47 to 62 Gy.7,11
5/21/2012 9:09:21 PM

Answer: TD5/5 for the small and large bowel is 50 and 55 Gy,
respectively. (Grade C recommendation)
3. Is IMRT less harmful to the bowel than conventional
radiotherapy?
Traditionally, external-beam radiation was delivered using a two-
beam or four-beam approach in which a constant dose rate is
administered to a defined field. Newer techniques, such as three-
dimensional–conformal radiation therapy (3D-CRT) and intensity-
modulated radiation therapy (IMRT) use advanced imaging to
improved precision of irradiation to target tissues.13 In particular,
IMRT permits variable control of the intensity of the beam within
the same field, which limits normal tissue exposure.13 Portelance
et al. showed a significant reduction in mean percentage volume
of small bowel receiving >45 Gy by use of IMRT (11%) compared
with conventional four-beam radiation (34%), in patients with cer-
vical cancer.13 Other authors have corroborated these results,14,15
but whether IMRT actually reduces the incidence of chronic radi-
ation enteritis remains unclear. In a case–control study by Mundt
et al., a significant 40% reduction in chronic gastrointestinal tox-
icity was noted in patients with gynecologic malignancy treated
with IMRT compared with historical controls treated with con-
ventional radiotherapy.16 The median follow-up time in this study
was 19 months, suggesting that long-term data are warranted to
support its conclusions.
Answer: IMRT reduces the volume of healthy small bowel
irradiated and lowers the rate of gastrointestinal toxicity at
19 months. (Grade B recommendation)
4. Surgical management: bowel resection or bypass?
Symptoms of acute radiation enteritis are normally transient and
usually resolve within 2 weeks of completion of radiotherapy.11
For chronic radiation enteritis, most studies suggest that surgi-
cal therapy should be avoided as long as possible because of dif-
ficulties operating irradiated bowel.5-7,11 Fibrosis and adhesions
may make resection technically challenging (risking iatrogenic
enterotomy), and anastomotic leak rates are higher due to poor
tissue healing.3 Also, short bowel syndrome (SBS) can develop if
there is extensive resection of bowel (or even subextensive resec-
tion if absorptive capacity has been affected).7 Despite attempts
at conservative management, approximately one-third of patients
with chronic radiation enteritis will undergo surgery.2,7 The most
common indications for surgery are persistent obstruction due
to strictures or adhesions, perforation, and fistulization.3,5-7 The
data on surgical management of patients with radiation enteritis
is limited and consists primarily of case series (Level 4 evidence).
The choice between resection with anastomosis or bypass as the
most appropriate surgical approach has been the topic of most
studies.
In an influential review of historical series published in 1976,
Swan et al. noted that patients who had intestinal bypass rather
than resection had a lower operative mortality (21% vs. 10%) and
a lower rate of anastomotic dehiscence (36% vs. 6%), suggesting
bypass is the procedure of choice.5 A decade later, Galland et al.
showed that extensive resection allowing anastomosis of healthy
bowel ends in 12 patients resulted in only one anastomotic leak.6
In a more recent literature analysis, Meissner evaluated data of all
patients reported in 41 publications (search criteria not defi ned)
on the surgical management of chronic radiation enteritis.3 The
PMPH_CH26.indd 229
Radiation Injury to the Small and Large Bowel ■ 229
author noted that of 801 patients, 71% of patients presented with
obstruction and the most common sites of radiation injury were
the lower ileum, caecum, and sigmoid colon, while low rates of
injury were noted in the ascending and transverse colon. Bowel
resection with ileotransversecolonic anastomosis was associated
with a decreased rate of anastomotic insufficiency and postop-
erative mortality compared with ileoileal anastomosis (4% vs.
25.5% anastomotic insufficiency; 3% vs. 24.7% mortality), sug-
gesting that frequently compromised areas of the bowel are
prone to anastomotic dehiscence. Ileotransversecolonic bypass
was also associated with low rates of anastomotic leak (1.6%),
but the author noted a higher rate of progressive radiation injury
for bypass procedures (38%) when compared with resection with
ileotransversecolonic anastomosis (7.2%), possibly reflecting the
fact that irradiated bowel is left behind. Meissner concludes that,
when feasible, extensive resection with anastomosis of healthy
bowel segments is safe for complications of chronic radiation
enteritis.3
In addition, there is concern about leaving irradiated bowel
in the abdomen following bypass procedures due to the risk of
malignant transformation,7 even though there is no study to date
that examines if rates of malignant bowel disease are lower after
surgical resection for radiation enteritis. Subsequent authors have
continued to favor bowel resection as the procedure of choice,
noting an anastomotic dehiscence rate in the range of 0% to
9%.7,17 In a study of 109 patients with chronic radiation enteritis
who underwent intestinal resection or conservative management,
Regimbeau et al. note that 5% of patients died postoperatively,
while 5-year survival for patients without recurrence of primary
malignancy was 71% after resection compared with 51% after con-
servative management.7
Answer: There is no convincing evidence suggesting the
optimal surgical procedure for complications of chronic radia-
tion enteritis. The available data suggest that extensive resection
with anastomosis of healthy bowel segments is associated with a
lower rate of morbidity and mortality than bowel bypass surgery.
(Grade C recommendation)
5. What is the risk of SBS after surgery?
Complications following surgery for chronic radiation enteritis
are intimately related to the condition of the irradiated bowel.3
Onodera et al. and Regimbeau et al. present similar operative mor-
bidity rates of 22% and 29%, respectively, including anastomotic
leak, wound infection, and small bowel obstruction.7,17 Regimbeau
et al. also noted that reoperation with further intestinal resection
was performed in 34% of patients, raising the concern for SBS. In
fact, 20% of all cases of SBS are caused by radiation enteritis,18,19
but the risk of developing SBS after surgery for radiogenic bowel
injury remains unreported.20
The prognosis for these patients is poor, as shown in a study
of 48 adults with postresection SBS secondary to radiotherapy,
in which 1- and 5-year survival were 83% and 68%, respectively.20
Vantini et al. reported similar 1- and 5-year survival (85% and
65%, respectively), noting that this patient group had more com-
plications and lower survival than patients with other causes
of SBS.19
Answer: The incidence of SBS after surgery for radiogenic
bowel injury remains unknown. Notably, patients with SBS sec-
ondary to radiotherapy seem to have a worse prognosis than
patients with other causes of SBS. (Grade C recommendation)
5/21/2012 9:09:21 PM
 230 ■ Surgery: Evidence-Based Practice

Clinical Question Summary

Question
1 How does radiation affect
the bowel?
2 Is there a critical radiation
dose in which serious
bowel injury occurs?
3 Is IMRT less harmful to the
bowel than conventional
radiotherapy?
4 Surgical management: bowel
resection or bypass?
5 What is the risk of SBS
after surgery?
Answer Level of Grade of References
Evidence Recommendation
Chronic radiation enteritis is caused by 4 C 2, 7-11
radiation-induced obliterative endarteritis,
and about one-third of these patients will
require surgery for their symptoms.
Five percent of patients experience serious 4 C 12
bowel toxicity at 5 years (requiring
intervention) if the bowel is irradiated with
a total dose of 50 Gy.
IMRT reduces the rate of chronic bowel 3b B 16
toxicity at 19 months, compared with
conventional radiotherapy.
Extensive resection with anastomosis of 4 C 3, 5-7
healthy bowel segments is associated with
lower morbidity and mortality than bowel
bypass surgery.
Incidence of SBS after surgery for radiogenic 4 C 20
bowel injury remains unknown.

REFERENCES 12. Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to

1. Walsh D. Deep tissue traumatism from roentgen ray exposure.
Br Med J. 1897;2(1909):272-273.
2. Theis VS, Sripadam R, Ramani V, et al. Chronic radiation enteri-
tis. Clin Oncol (R Coll Radiol). 2010;22(1):70-83.
3. Meissner K. Late radiogenic small bowel damage: Guidelines for
the general surgeon. Dig Surg. 1999;16(3):169-174.
4. Yeoh EK, Horowitz M, Russo A, et al. Gastrointestinal function
in chronic radiation enteritis—effects of loperamide-N-oxide.
Gut. 1993;34(4):476-482.
5. Swan RW, Fowler WC, Jr., Boronow RC. Surgical management
of radiation injury to the small intestine. Surg Gynecol Obstet.
1976;142(3):325-327.
6. Galland RB, Spencer J. Natural history and surgical manage-
ment of radiation enteritis. Br J Surg. 1987;74(8):742-747.
7. Regimbeau JM, Panis Y, Gouzi JL, et al. Operative and long term
results after surgery for chronic radiation enteritis. Am J Surg.
2001;182(3):237-242.
8. Bismar MM, Sinicrope FA. Radiation enteritis. Curr Gastroen-
terol Rep. 2002;4(5):361-365.
9. MacNaughton WK. Review article: New insights into the patho-
genesis of radiation-induced intestinal dysfunction. Aliment
Pharmacol Ther. 2000;14(5):523-528.
10. Hauer-Jensen M. Late radiation injury of the small intestine.
Clinical, pathophysiologic and radiobiologic aspects. A review.
Acta Oncol. 1990;29(4):401-415.
11. Turina M, Mulhall AM, Mahid SS, et al. Frequency and surgical
management of chronic complications related to pelvic radia-
tion. Arch Surg. 2008;143(1):46-52; discussion 52.
therapeutic irradiation. Int J Radiat Oncol Biol Phys. 1991;21(1):
109-122.
13. Portelance L, Chao KS, Grigsby PW, et al. Intensity-modulated
radiation therapy (IMRT) reduces small bowel, rectum, and
bladder doses in patients with cervical cancer receiving pel-
vic and para-aortic irradiation. Int J Radiat Oncol Biol Phys.
2001;51(1):261-266.
14. Nutting CM, Convery DJ, Cosgrove VP, et al. Reduction of small
and large bowel irradiation using an optimized intensity-modulated
pelvic radiotherapy technique in patients with prostate cancer. Int J
Radiat Oncol Biol Phys. 2000;48(3):649-656.
15. Guerrero Urbano MT, Henrys AJ, et al. Intensity-modulated
radiotherapy in patients with locally advanced rectal cancer
reduces volume of bowel treated to high dose levels. Int J Radiat
Oncol Biol Phys. 2006;65(3):907-916.
16. Mundt AJ, Lujan AE, Rotmensch J, et al. Intensity-modulated
whole pelvic radiotherapy in women with gynecologic malig-
nancies. Int J Radiat Oncol Biol Phys. 2002;52(5):1330-1337.
17. Onodera H, Nagayama S, Mori A, et al. Reappraisal of surgi-
cal treatment for radiation enteritis. World J Surg. 2005;29(4):
459-463.
18. Thompson JS. Inflammatory disease and outcome of short bowel
syndrome. Am J Surg. 2000;180(6):551-554; discussion 554-555.
19. Vantini I, Benini L, Bonfante F, et al. Survival rate and prog-
nostic factors in patients with intestinal failure. Dig Liver Dis.
2004;36(1):46-55.
20. Boland E, Thompson J, Rochling F, et al. A 25-year experience
with postresection short-bowel syndrome secondary to radia-
tion therapy. Am J Surg. 2010;200(6):690-693; discussion 693.

PMPH_CH26.indd 230 5/21/2012 9:09:21 PM

 Commentary to Radiation Injury to
the Small and Large Bowel
Daniel L. Dent
Mejaddam and King are to be commended for their review and
analysis of the literature on the topic of radiation enteritis. This is
an extremely timely topic given the recent devastating events in
Japan. This is also a very challenging topic due to the lack of high-
grade literature and as a result it is a particularly difficult topic for
young surgeons to grasp. However, I can honestly state that this
summary of the literature represents the single most clear sum-
mary on radiation enteritis that I have ever read. This is due to a
combination of the clarity of writing by the authors and the for-
mat of the chapter that gets at key clinical questions that trouble
the clinician when managing the patient with the disease.
The only caveat in the authors’ recommended approach is
that the reader must be careful to recognize that while “sur-
gical therapy should be avoided as long as possible,” radiation
enteritis is a progressive disease and many patients do ultimately
231
PMPH_CH26.indd 231
require surgical intervention. It is imperative not to delay sur-
gery when it is indicated as this can negatively impact the
patient’s outcome.
These operations are as challenging as any in the realm of
general surgery. As the authors indicated, efforts should be made
to resect so as to remove the diseased bowel. At times, this may
require removing the most damaged portion of the GI tract in
a piecemeal fashion, and this is unsettling to the inexperienced
surgeon. However, the guiding principle during this dissection
relates to damage to the surrounding structures. If the surround-
ing structures can be preserved, the irradiated bowel is resectable
regardless of the damage that will be created to the diseased intes-
tine that is being removed.
Again, the authors are to be commended for their concise and
extremely clear summary of a very difficult disease.
5/21/2012 9:09:21 PM
 CHAPTER 27
Ischemic Colitis
Thomas D. Conlee, Daniel J. Bonville, and Jonathan J. Canete
INTRODUCTION
Ischemic colitis (IC), first described as such by Marston et al. in
1966,1 is considered to be an illness of the elderly. It is most often a
reversible condition where the colonic mucosa is starved of adequate
blood supply. Additionally, ischemia of the colon is the most com-
mon form of intestinal ischemia. While it still affects elderly patients
with multiple medical comorbidities most often, it can be seen in
younger patients with hypercoagulopathies and woman using oral
contraceptives.
The incidence of IC is thought to be grossly underestimated
due to its often subclinical nature, but has been responsible for
1 in every 2000 hospital admissions with the average patient age
of 70 years.2 IC manifests as varying degrees of disease depend-
ing on its cause and is most often transient without the need for
surgical intervention. Marston also described three forms of the
disease: transient, stricture, and gangrenous. Early diagnosis with
CT scan and colonoscopy, the gold standard in evaluating colonic
ischemia, and intervention are important to control it as a source
of septic shock or even death.
Although its etiology is most often due to low-flow states and/
or small-vessel occlusion, a thoughtful history would elucidate
recent aortic intervention that would explain an acute change in
the blood supply to the colon. Watershed areas of the colon, rep-
resented by the splenic flexure and distal sigmoid colon, are often
affected when the natural blood supply has been altered.
IC ranges from mild episodes manifested as transient abdomi-
nal pain and diarrhea to septic shock as seen in the most severe
disease progression following colonic perforation. Additional signs
and symptoms observed depending on the degree of disease are
abdominal tenderness, bloody diarrhea, nausea, vomiting, fever,
leukocytosis, and bandemia. Approximately 15% of patients with
IC progressing to gangrene.3 Even with timely surgical interven-
tion, this group of patients has a mortality range of 40% to 75%.4,5
The degree of disease is the determining factor for intervention.
Mild disease is often treated with intravenous antibiotics and bowel
rest, while severe disease is managed with segmental or complete
colonic resection, most often as a surgical emergent procedure.
232
PMPH_CH27.indd 232
RISK FACTORS
1. What are the risk factors for IC?
The evidence elucidating risk factors for IC is inconsistent, and
there are no prospective studies to evaluate. However, there are
numerous retrospective studies that depict a number of risk fac-
tors that are frequently identified.
Many medical conditions have been cited that put patients at
risk of IC. Fernández et al.6 studied risk factors of IC in 161 patients
admitted to a single institution and applied control patients in a
1:2 ratio to develop their conclusions. Of these subjects, diabetes
mellitus, dyslipidemia, heart failure, peripheral arteriopathy, the
use of aspirin and digoxin were found to be significant, indepen-
dent risk factors. Similarly, Chung et al.,7 retrospectively analyzed
153 patients and determined hypertension, cardiovascular dis-
ease, diabetes mellitus, and malignancy to be significant risk fac-
tors in the prognosis of IC.
Other retrospective studies analyzed risk factors other than
those directly affecting the underlying disease of the cardio-
vascular system. Chang et al., 8 in a large-scale, pharmaceutical
funded retrospective study sought to confirm irritable bowel
syndrome (IBS) and constipation as significant risk factors for
IC. In addition to confirming this, other risk factors with odds
ratios >2 were identified as shock, dysentery, bloating, colon
carcinoma, cardiovascular disease, dyspepsia, abdominal, aor-
tic or cardiovascular surgery, 12-month laxative, H2 receptor
blocker, and oral contraceptive use.
In a single institution study, Preventza et al.9 retrospec-
tively evaluated young women (<50 years) diagnosed with IC via
colonoscopy and found 52% of the 25 patients were taking oral
contraception. This finding only strengthens the previously sited
study regarding oral contraceptive pill (OCP).
Answer: Risk factors for IC appear to be shock, cardiovascular
disease, diabetes mellitus, peripheral arterial disease, hypertension,
hyperlipidemia, IBS, constipation, malignancy, aortic and cardio-
vascular surgery, dyspepsia, prolonged laxative use, and OCP in
young women. (Level 2 evidence, Grade B recommendation)
5/21/2012 9:10:44 PM

2. Is there an association of IC with thrombotic or thromboem-
bolic conditions?
A number of small studies evaluate the prevalence of coagulation
abnormalities in patients with IC. The references below describe
the larger, more robust studies. Arterial thromboembolic disease
affecting the mesenteric vasculature often spares the blood sup-
ply to the colon. The embolus, which traditionally stems from a
cardiac source, often travels embolizing to a point distal to the
middle colic artery take-off ,and therefore more often occludes
small bowel blood supply.
Midian-Singh et al.,10 in an attempt to elucidate the potential
cause of otherwise idiopathic IC, evaluated 18 patients and found
five to have coagulation abnormalities including factor V Leiden
and activated protein C resistance, protein S deficiency, prothrom-
bin 20210G/A mutation, and anticardiolipin antibody.
Another study by Koutroubakis et al.,11 in a prospective,
case–control design looked for the prevalence of hypercoaguable
states in ambulatory patients diagnosed with mild to moderate
IC. The study showed one or several prothrombotic disorders in
26 of the 36 patients (72%) with IC. An elevated antiphospholipid
antibody was found most common among acquired thrombotic
diseases while factor V Leiden disease was most common among
congenital diseases. Although this study is limited by its size, the
prevalence of these disorders in ambulatory patients may justify a
thrombotic workup when other risk factors are not apparent.
Hourmand-Ollivier et al.12 found patients with nongangre-
nous, IC were more likely to have a potential cardiac source of a
thromboembolism when compared with an appropriate control
group. Therefore, they recommended that these patients undergo
a cardiac work-up to rule out the source of an embolism. In
another study, by Collet et al.,13 33% of ambulatory patients with
nongangrenous IC were found to have a potential cardiac source
of thromboembolism. The work-up included taking a focused his-
tory, obtaining an electrocardiogram, analysis of a Holter moni-
tor, and a transthoracic echocardiogram.
Answer: Limited literature shows that there is an associa-
tion between coagulation abnormalities and IC. The degree of
this association is difficult to define further, hence when IC is
diagnosed without a clear explanation of its cause, a coagulation
work-up appears to be worthwhile. Thromboembolic disease may
affect the colon and a search for a cardiac source may be war-
ranted in at least ambulatory patients with IC. (Level 3 evidence,
Grade C recommendation)
DIAGNOSIS
3. Do colonoscopic findings predict disease progression?
Although IC is a clinical diagnosis most frequently aided by visu-
alizing the colonic mucosa via colonoscopy or sigmoidoscopy, it is
important to understand the clinical significance of its findings.
Grades 1–3 of IC during endoscopic evaluation have been
defined to guide treatment. Mild to moderate disease has been
described as Grades 1 and 2, respectively. Severe disease—
described as Grade 3, which shows evidence of full-thickness bowel
wall ischemia—is managed with resection of at least that segment
of bowel to control the gangrenous source of illness. Forde et al.14
has documented a reliable relationship between endoscopic and
the histological findings of IC.
PMPH_CH27.indd 233
Ischemic Colitis ■ 233
In a series by Champagne et al. out of Albany, New York,15
patients who survived emergency surgery for a ruptured abdomi-
nal aortic aneurysm (AAA) were offered a colonoscopy to evaluate
the integrity of the bowel wall. Overall, 62 of 72 patients under-
went endoscopic evaluation and 39% were found to have some
degree of colonic ischemia. Eighteen patients (Grades 1 and 2)
were initially managed nonoperatively, while those with Grade 3
ischemia underwent an exploratory laparotomy for bowel resec-
tion. One patient initially found to have a negative colonoscopy
was later found to have transmural ischemia during cholecystec-
tomy. Also, two patients progressed from Grade 2 to 3 ischemia
during repeat colonoscopy.
Chung et al.7 described ulcerations found endoscopically
to be an independent risk factor of severe IC with an odds ratio
of 9.9 and a 95% CI of 2.0 to 48.8. Houe et al.16 published a review
of prior literature regarding the usefulness of endoscopy follow-
ing aortic repair. Without objective data, it was concluded based
on seven prospective studies that only an exploratory lapartomy
can conclusively document transmural bowel ischemia, while
endoscopy can merely raise the suspicion.
Answer: Reliable data has shown that colonoscopy can gen-
erally be used to determine the likelihood of being full-thickness
disease warranting surgical resection. The limitation is its abil-
ity to only visualize the mucosa. (Level 2 evidence, Grade B
recommendation)
PREVENTION
4. Are there any appropriate screening tests?
There is very little literature that describes screening tests to
evaluate IC due to its nature of disease. One may view the use of
colonoscopy in patients at risk (i.e., patients after AAA repair) as
a screening tool. See Question 3 in this chapter for further details
on the utility of colonoscopy in patients with IC.
One study describes a serum marker as a screening tool fol-
lowing aortic repair. Nagata et al.17 studied serum procalcitonin
(PCT) level to assess its value as a screening marker for colonic
ischemia following elective aortic repair in Japan. This prospec-
tive study analyzed data from 93 patients where the PCT levels
were determined on post-operative day #2. With a cut-off level of
2.0 ng/ml, its sensitivity and specificity to diagnose IC was 100%
and 83.9% respectively, with a false-negative rate of 0%, and false-
positive rate of 16.1%.
Answer: There is a little evidence in the literature showing
any reliable screening tests are helpful to predict which patients
will develop IC. (Level 3 evidence, Grade C recommendation)
TREATMENT
5. Do antibiotics make a difference in the management of IC?
Antibiotic use is routinely recommended for the management
of moderate and severe colonic ischemia.18 However, the basis of
such recommendations stems from experimental studies from the
early 20th century and its shared use in other forms of colonic
inflammation.
In 1945, Sarnoff et al.19 demonstrated a decreased incidence
of ischemic necrosis and a 40% improved survival with the use
5/21/2012 9:10:44 PM
 234 ■ Surgery: Evidence-Based Practice

of antibiotics in a canine model of mesenteric venous ischemia.19
Poth and McClure20 saw a four-fold improved survival with
antibiotic-treated dogs, using their canine model of mesenteric
arterial ischemia. Animal models have also demonstrated the
utility of antibiotics in minimizing ischemia-associated bacterial
translocation.21 A systematic review by Diaz-Nieto22 reported on
several retrospective case series which included antibiotics in the
conservative management of patients with IC.
The initial management of IC can parallel other forms of coli-
tis. The symptoms and signs of IC (bloody diarrhea, fever, tachy-
cardia and leukocytosis) are also seen in colitis from other causes
(inflammatory bowel disease and infectious). In these settings,
antibiotics are empirically added as the diagnostic work-up is
initiated. In the case of inflammatory bowel disease, progression
to fulminant colitis and toxic megacolon are routine indications
for treatment. A 3- to 5-day course is routinely recommended, at
which time surgery may be necessary if no improvement is seen.
Answer: There are a limited number of retrospective case
series that include antibiotics as part of the treatment of IC. There
is no comparative human data that antibiotic use confers an
advantage. Experimental animal studies suggest decreased bowel
damage, decreased bacterial translocation, and prolonged sur-
vival. Because antibiotics are useful in the management of other
severe forms of colitis of which ischemia is part of the differen-
tial diagnosis, the recommendation for their routine use remains
sound. (Level 4 evidence, Grade C recommendation)
6. Can primary anastomosis be safely performed during surgi-
cal management of IC?
Historically, an emergent colectomy was managed over two or even
three separate procedures. As literature has dictated that a primary
anastomosis can safely be performed following a colonic injury
under certain circumstances, the above question must be asked.
However, due to the vascular nature of IC and the uncertainty of
the colon’s future blood supply, there is significant risk great risk in
not treating this disease most conservatively.
Biondo et al.23 out of Spain studied the outcomes of 211 patients
who underwent emergent left colon resection and all had primary
anastomoses. Three of these patients were diagnosed with colonic
ischemia as the source of the problem. Of these three patients who
underwent a resection and primary anastomosis, one patient died,
but none were documented as having a dehiscence of the anasto-
mosis. Paterno et al.24 reported performing primary anastomosis
in 17 of 48 patients who had surgery for IC with “good results”; 13
of these patients had a right hemicolectomy. However, they did
not report whether any of these patients had developed an anasto-
motic leak or whether any had protective loop ileostomy.
Antolovic et al.25 reviewed 85 prospectively collected cases
in which 20% had resection and primary anastomosis only, 36%
had resection, anastomosis, and diverting ostomy, and 42% had
resection and ostomy. The patients with no stoma formation had a
lower mortality, but this likely is due to a selection bias in treating
the most critical patients with an ostomy.
Answer: There are reports of primary anastomosis dur-
ing resection for IC both with and without a diverting ostomy.
Patients who are hemodynamically stable with isolated right
colon ischemia may be better candidates when considering this
strategy. However, careful consideration in each case is warranted
when considering primary anastomosis following resection for
IC. (Level 4 evidence, Grade C recommendation)
7. Does reimplantation of the Inferior Mesenteric Artery (IMA)
improve colonic viability following aortic reconstruction?
Senekowitsch et al.26 in a randomized trial out of Austria com-
pares IMA reimplantation with controls after both symptom-
atic and asymptomatic infrarenal AAA repair. No significant
difference was found when comparing situations where IC was
found.
Of the 128 comparable patients by means of IMA patency
who were randomized to ligation or reimplant, 16 patients had a
histologically proven IC. The IMA was replanted in 6 and ligated
in 10 patients. Ligation of the IMA did not lead to a significantly
elevated risk for developing IC (p = .203).
However, even in endovascular aneurysm repair (EVAR),
where the IMA is universally sacrificed by exclusion, the inci-
dence of clinically symptomatic IC is 1.3% to 2.9%.27 In another
report, Perry et al.28 performed a large outcomes study showed the
incidence of IC after EVAR to be 0.5% compared with 1.9% IC for
open elective repair, and 8.9% for repair of a ruptured AAA.
Answer: Reimplantation of the IMA does not improve colonic
viability following aortic reconstruction. (Level 2 evidence, Grade
B recommendation)

Clinical Question Summary

Question
1 What are the risk factors for
IC?
2 Is there an association of
IC with thrombotic or
thromboembolic conditions?
Answer Level of Grade of References
Evidence Recommendation
Cardiovascular disease, diabetes mellitus, 2 B 5-9
shock, peripheral arterial disease,
hypertension, hyperlipidemia, IBS,
constipation, malignancy, aortic and
cardiovascular surgery, dyspepsia,
prolonged laxative use, OCP in young
women.
Thromboembolic disease may affect the colon 3 C 10-13
and a search for a cardiac source may be
warranted in at least ambulatory patients
with IC which do not present with an
obvious cause (i.e., low-flow state).

(Continued)

PMPH_CH27.indd 234 5/21/2012 9:10:44 PM

 Ischemic Colitis ■ 235

(Continued)
Question
3 Do colonoscopic findings
predict disease progression?
4 Are there any appropriate
screening tests?
5 Do Antibiotics make a
difference in the management
of IC?
6 Can primary anastomosis
be safely performed during
surgical management of IC?
7 Does Reimplantation of
the IMA improve colonic
viability following aortic
reconstruction??
Answer Level of Grade of References
Evidence Recommendation
In most cases, yes. Colonoscopy should 2 B 7, 14-16
continue to be performed for diagnosis
of IC. While it can predict the degree
of disease, it cannot confirm full-
thickness colonic injury requiring surgical
intervention.
No. In a rare diseases like IC, tests such 3 C 17
as colonoscopy or blood tests in
asymptomatic patients at risk are not cost
worthy.
There are a limited number of retrospective 4 C 18-22
case series that include antibiotics as part
of the treatment of IC. However, there is
no comparative human data that antibiotic
use confers an advantage. There are animal
data that support antibiotic use in IC.
There are reports of primary anastomosis 4 C 23-25
during resection for IC both with and
without a diverting ostomy. However,
careful consideration in each case is
warranted when considering primary
anastomosis following resection for IC.
No. No significant difference was found in 2 B 26-28
a randomized study. EVAR is now being
performed in greater volume without an
increase in ischemic bowel.

REFERENCES 11. Koutroubakis IE, Sfiridaki A, Theodoropoulou A, Kouroumalis EA.

1. Marston A, Pheils MT, Thomas ML, Morson BC. Ischemic coli-
tis. Gut. 1966;7:1-15.
2. Brandt L, Boley S, Goldberg L, Mitsudo S, Berman A. Colitis in
the elderly. A reappraisal. A J Gastroenterol. 1981;76:239-245.
3. Greenwald DA, Brandt LJ. Colonic ischemia. J Clin Gastroen-
terol. 1998;27:122.
4. Guivarc’h M, Roullet-Audy JC, Mosnier H, Boche O. Ischemic
colitis. [A surgical case series of 88 patients]. J Chir (Paris).
1997;134:103.
5. Longo WE, Ward D, Vernava AM, Kaminski DL. Outcome of patients
with total colonic ischemia. Dis Colon Rectum. 1997;40:1448.
6. Fernandez JC, Calvo LN, Vazquez EG, et al. Risk factors associ-
ated with the development of ischemic colits. W J Gastroenterol.
2010;16(36):4564-4569.
7. Chung JW, Cheon JH, Park JJ, Jung ES, Choi EH, Kim H. Devel-
opment and validation of a novel prognostic scoring model for
ischemic colitis. Dis Colon Rect. 2010;53:1287-1294.
8. Chang L, Kahler KH, Sarawate C, Quimbo R, Kralstein J. Assess-
ment of potential risk factors associated with ischemic colitis.
Neurogastroenterol Motil. 2008;20:36-42.
9. Preventza OA, Lazarides K, Sawyer MA. Ischemic colitis in
young adults: A single-institution experience. J Gastroenterol
Surg. 2001;5:388-392.
10. Midian-Singh R, Polen A, Durishin C, et al. Ischemic colitis
revisited: A prospective study identifying hypercoagulability as
a risk factor. South Med J. 2004;97(2):120-123.
Role of acquired and hereditary thrombotic risk factors in colonic
ischemia of ambulatory patients. Gastroenterol. 2001;121:56-65.
12. Hourmand-Ollivier I, Bouin M, Saloux E, et al. Cardiac sources
of embolism should be routinely screened in ischemic colitis. Am
J Gastroenterol. 2003;98:1573-1577.
13. Collet T, Even C, Bouin M, et al. Prevalence of electrocardio-
graphic and echocardiographic abnormalities in ambulatory
ischemic colitis digestive diseases and sciences. Dig Dis Sci. 2000:
45(1):23-25.
14. Ford KA. The endoscopy corner: Reversible ischemic colitis—
correlation of colonoscopic and pathologic changes. Am J
Gastroenterol. 1979;72(2):182-185.
15. Champagne BJ, Darling RC, Daneshmand M, et al. Outcomes
of aggressive surveillance colonoscopy in ruptured abdominal
aortic aneurysms. J Vasc Surg. 2004;39:792-796.
16. Houe T, Thorboll JE, Sigild U, Liisberg-Larsen O, Schroeder TV.
Can colonoscopy diagnose transmural ischaemic colitis after
abdominal aortic surgery? An evidence-based approach. Eur J
Vasc Endovasc Surg. 2000;19:304-307.
17. Nagata J, Kobayashi M, Nishikimi N, Komori K. Serum procal-
citonin (PCT) as a negative screening test for colonic ischemia
after open abdominal aortic surgery. Eur J Vasc Endovasc Surg.
2008;35:694-697.
18. Brandt LJ, Boley SJ. AGA technical review on intestinal ischemia.
Gastroenterology. 2000;118:954-968.
19. Sarnoff SJ, Fine J. Effect of chemotherapy on ileum subjected to
vascular injury. Ann Surg. 1945;121:74-82.

PMPH_CH27.indd 235 5/21/2012 9:10:44 PM

 236 ■ Surgery: Evidence-Based Practice
20. Poth EJ, McClure JN. Intestinal obstruction: The protective
action of sulfasuxidine and sulfathalidine to ileum following
vascular damage. Ann Surg. 1950;131:159-170.
21. Redan JA, Rush BF, Lysz TW, Smith S, Machiedo GW. Organ
distribution of gut-derived bacteria caused by bowel manipula-
tion or ischemia. Am J Surg. 1990;159:85-90.
22. Diaz-Nieto R, Varcada M, Ogunbiyi O, et al. Systematic review
on the treatment of ischaemic colitis. Colorectal Dis. March 30,
2010;(Epub).
23. Biondo S, Pares D, Kreisler E, et al. Anastomotic dehiscence after
resection and primary anastomosis in left-sided colonic emer-
gencies. Dis Colon Rectum. 2005;48:2272-2280.
24. Paterno F, McGollicuddy EA, Schuster KM, Longo WE. Ischemic
Colitis: Risk factors for eventual surgery. Am J Surg. 2010;200:
646-650.
PMPH_CH27.indd 236
25. Antolovic D, Koch M, Hinz U, et al. Ischemic colitis – analy-
sis of risk factors for postoperative mortality. Langen Arch Surg.
2008;393:507-512.
26. Senekowitsch C, Assadian A, Assadian O, Hartleb H, Ptakovsky H,
Hagmuller GW. Replanting the inferior mesentery artery during
infrarenal aortic aneurysm repair: Influence on postoperative
colon ischemia. J Vasc Surg. 2006;43:689-694.
27. Mehta M, Roddy S, Darling C, III, et al. Infrarenal
abdominal aortic aneurysm repair via endovascular versus
open retroperitoneal approach. Ann Vasc Surg. 2005;19(3):
374-378.
28. Perry RJ, Martin MJ, Eckert MJ, et al. Colonic Ischemia compli-
cating open vs endovascular abdominal aortic aneurysm repair.
J Vasc Surg. 2008;48:272-277.
5/21/2012 9:10:44 PM
 Commentary on Ischemic Colitis
Fred A. Luchette
Ischemic colitis (IC), first described by Boley in 1963, remains a diag-
nostic dilemma despite the advances in radiographic imaging and
laboratory testing.1 This is largely due to nonspecific nature of the
signs and symptoms at the time a patient seeks medical attention. This
evidence-based review classifies the existing literature using seven
practical clinically based questions. Most of the literature investigat-
ing these areas consists of Class 2 and 3 studies. However, the authors
have done a good job summarizing the studies of IC from the past
10 years and make appropriate recommendations. My comments will
be focused on the authors’ approach to those seven questions.
1. What are the risk factors for IC?
The authors succinctly identify the various comorbidities, physi-
ologic states, and some medications associated with IC. Additional
classes of medications that predispose to colon ischemia are also
worthy of mentioning, including antibiotics, appetite suppressants
(phentermine), chemotherapeutic agents (vinca alkaloids and tax-
anes), constipation-inducing agents, decongestants (pseudoephed-
rine), cardiac glucosides, diuretics, ergot alkaloids, statins, illicit
drugs, immunosuppressive agents, nonsteroidal anti-inflammatory
drugs, psychotropic medications, serotonin agonists/antagonists,
and vasopressors. Other iatrogenic causes for IC, particularly
right-sided ischemia, are in the domain of diagnostic and inter-
ventional angiography due to plaque embolization.
2. Is there an association of IC with thrombotic or thromboem-
bolic conditions?
Another etiology for the hypercoagulable state is deficiency of
protein Z, an important regulator of coagulation. Plasma concen-
trations were demonstrated to be significantly lower in patients
who also had factor V Leiden deficiency or antiphospholipid anti-
bodies and a definitive diagnosis of IC.2 Cardiac surgery requiring
cardiopulmonary bypass may be a source of atheromatous plaque
emboli leading to IC.
3. Do colonoscopic findings predict disease progression?
The recommendation is that colonoscopy can generally be used to
determine the degree of ischemia on the basis of standard grad-
ing criteria and thus identify patients requiring surgical resection
for full-thickness gangrene. However, this recommendation does
not answer the posed question. Rather, colonoscopy allows direct
assessment of the colonic mucosa, the most sensitive area of the
237
PMPH_CH27.indd 237
colon affected by ischemia, and should be the first test utilized for
assessing the extent of the disease. It is the mainstay of diagnosis.
4. Are there any appropriate screening tests?
Numerous other studies are worth mentioning. Various laboratory
markers of ischemia are known to lack sensitivity and specificity
to reliably make the diagnosis of IC, including L-lactate, D-lactate,
lactate dehydrogenase, d-dimer, creatine phosphokinase, amy-
lase, leukocytes, alkaline phosphatase, inorganic phosphate,
acid-binding protein, and α-glutathione S-transferase. However,
a recent study used intestinal fatty acid binding protein (i-FABP)
as an early marker of intestinal ischemia. This enzyme is present
in mature enterocytes of the small intestine, with the highest con-
centration in the villi.3
Additional screening tests that may be useful in evaluating
the vasculature include duplex ultrasound of the splanchnic ves-
sels, contrast-enhanced magnetic resonance angiography, com-
puted tomography (CT) angiography, and digital subtraction
angiography, the gold standard for assessing the vasculature of the
intestine. Recent studies have demonstrated that state-of-the-art
multislice scanners, which offer slice thicknesses of no more than
2 mm, have several advantages over conventional angiography.4,5
5. Do antibiotics make a difference in the management of IC?
Despite the lack of Class 1 studies, our intuition tells us that broad-
spectrum antibiotics make common physiologic sense as the stan-
dard of care for IC to cover both aerobic and anaerobic bacteria. In
the presence of a compromised colonic mucosal barrier, the endog-
enous microflora of the colon will quickly translocate into the portal
venous circulation, resulting in bacteremia and an increased risk for
hepatic abscess. Antibiotics should be considered adjunctive ther-
apy for ischemic colitis to reduce morbidity and mortality rates. It
is inconceivable to think that any institutional review board would
approve any type of prospective study to address this question.
6. Can primary anastomosis be safely performed during surgi-
cal management of IC?
About 20% of patients with acute IC will require an emergent opera-
tion with an associated mortality rate of up to 60%, depending on the
overall septic state of the patient.6 Only rarely would a patient who
requires emergent colectomy not also have a perforation with associated
fecal peritonitis, or at least bacterial peritonitis. This clinical situation is
5/21/2012 9:10:44 PM
 238 ■ Surgery: Evidence-Based Practice
completely different from a stab wound to the left colon, which is diag-
nosed only a few hours after the injury was created and is associated
with minimal contamination in the absence of established peritonitis.
Thus, with IC limited to the right colon without perforation and viable
margins, primary anastomosis is appropriate. However, in the setting of
an emergent operation and a patient with disease that involves the left
colon, the procedure must be directed at correcting the life-threatening
disease with minimal anesthesia time. When the IC is related to aortic
reconstructive surgery, anastomosis is contraindicated because of the
risk of anastomotic leak and subsequent contamination of the aortic
prosthesis. Thus, until there is an appropriate prospective randomized
trial to evaluate the outcome of primary anastomosis versus ostomy for
left colon IC, resection and ostomy remain the appropriate procedures.
7. Does reimplantation of the IMA improve colonic viability
following aortic reconstruction?
One approach to reducing the risk of IC during aortic reconstruc-
tion is assessment of the stump pressure index when considering
reimplantation of patent inferior mesenteric arteries.7 This practice
has not been widely embraced. As noted by the authors, routine
reimplantation does not prevent postoperative colonic ischemia
but may be advantageous in patients in whom colonic perfusion
is borderline. Most reports on this topic include small numbers of
patients, which limits the power of the study.
PMPH_CH27.indd 238
REFERENCES
1. Boley SJ, Schwartz S, Lash J, Sternhill V. Reversible vascular occlu-
sion of the colon. Surg Gynecol Obstet. 1963;116:53-60.
2. Koutroubakis IE, Theodoropoulus A, Sfiridaki A, Kouroumalis
EA. Low plasma Z levels in patients with ischemic colitis. Dig Dis
Sci. 2003;48:1673-1676.
3. Lieberman JM, Sacchettini J, Marks C, Marks WH. Human intes-
tinal fatty acid binding protein: Report of an assay with studies
in normal volunteers and intestinal ischemia. Surgery. 1997;121:
335-342.
4. Savastano S, Teso S, Corra S, Fantozzi O, Miotto D. Multislice
CT angiography of the celiac and superior mesenteric arteries:
Comparison with arteriographic fi ndings. Radiol Med. 2002;103:
456-463.
5. Stuercke CA, Haegele KF, Jendreck M, et al. Multislice com-
puted tomography angiography of the abdominal arteries:
comparison between computed tomography angiography and
digital subtraction angiography fi ndings in 52 cases. Australas
Radiol. 2004;48:142-147.
6. Theodoropoulou A, Koutroubakis IE. Ischemic colitis: Clini-
cal practice in diagnosis and treatment. World J Gastroenterol.
2008;14(48):7302-7308.
7. Van Damme H, Creemers E, Limet R. Ischaemic colitis following
aortoiliac surgery. Acta Chir Belg. 2000;100:21-27.
5/21/2012 9:10:44 PM

Pseudomembranous Colitis
INTRODUCTION
Pseudomembranous colitis, also known as antibiotic-associated
colitis is an inflammatory process of the colon that is almost
always associated with an overgrowth of the bacterium Clostrid-
ium difficile. C. difficile is an anaerobic, gram-positive bacterium
that is highly transmissible. It was first described in 1935 as a col-
onizing organism in children.1 Later, it became recognized as a
widespread environmental organism located in soil and mud. It
was also found in dung of many large mammals.2 Pseudomem-
branous colitis was initially described by Finney in 18933 but was
not linked to any bacterial involvement until 1978.4 This discovery
followed a flurry of study in the late 1970s.
Pseudomembranous colitis is characterized by several symp-
toms including diarrhea with mucous, crampy abdominal pain,
nausea, fever, and dehydration. There is often an associated ileus.
Colonoscopy shows characteristic pseudomembranes on the
colonic mucosa. The disease can progress, even with treatment,
and complications such as toxic megacolon and sepsis with muli-
torgan failure can be lethal. It is the leading cause of health-care–
associated diarrhea and was estimated to total USD1.3 billion
in U.S. health-care costs in 2002. This amounted to USD12,825
per hospital admission.5 Further study in 2009 included hospi-
talizations for recurrent disease and totaled USD3.4 billion.6 The
incidence and associated costs are increasing. C. difficile colitis
is responsible for nearly 350,000 admissions annually.7 This is a
focus of American hospital systems, as Medicare reimbursement
is now limited for many hospital-acquired complications.
1. What is the pathogenesis of pseudomembranous colitis?
C. difficile produces toxins that lead to its pathogenic effects; the
two most important are toxin A and toxin B.8,9 These have been
linked to genes that are absent on nonpathogenic strains. Toxin A
and toxin B are cytotoxins causing glycosylation of proteins
in the cytoskeleton. This loosens the tight junctions between
colonic cells causing profound secretory diarrhea.7 The majority
of pathogenic strains produce both toxin A and toxin B. Recent
239
PMPH_CH28.indd 239
CHAPTER 28
Burke Thompson
data have shown organisms producing toxin B alone can cause
pseudomembranous colitis, but these strains only account for 7%
to 10% of cases.10 A binary toxin called C. difficile transferase is
found in more virulent strains.
2. How do you diagnose C. difficile colitis?
In the clinical setting of diarrhea associated with current hospital-
ization or recent antibiotic therapy, diagnosis of C. difficile colitis
is critical to guide treatment. Patients have watery diarrhea often
with mucous of blood. They may have as many as 10 stools a day or
more. C. difficile colitis diarrhea has a characteristic odor, familiar
to nurses caring for these patients. On examination, the abdomen
may be distended and tender. Leukocytosis can be significant.
Colonoscopy or sigmoidoscopy can show pseudomembranes on
the colonic mucosa. Biopsies can be taken to confirm the diag-
nosis. Histologic findings include a “volcano” lesion representing
an eruption of fibrinopurulent exudates and debris in an area of
denuded mucosa.11 The current mainstay of diagnosis starts with
the demonstration of C. difficile toxins in a diarrhea sample.12 This
alone is not always definitive. Full diagnosis includes stool culture,
detection of toxin in stool, and detection of C. difficile antigen.
Culture detection of C. difficile in the stool may not con-
fi rm active disease. Toxin detection in the stool is required to be
certain. C. difficile toxin A and toxin B are now detected using
enzyme immunoassays (ELISA). The sensitivity of this test for
the diagnosis of C. difficile colitis ranges from 63% to 94% with a
specificity between 75% and 100%.7 The positive predictive value
varies according to the incidence of infection in the population
so many hospital systems require repeated testing (two or three
consecutive samples) to confi rm diagnosis. Antigen testing by
ELISA has a higher sensitivity but a lower specificity than toxin
ELISA. Some facilities use the antigen test as a screen. If it is
positive, however, a confi rmatory toxin ELISA must be done.
Recently, a toxin B polymerase chain reaction (PCR) test has
been tested;7 it is still in development and is not yet commer-
cially available. Th is test has shown promise with high sensitiv-
ity and specificity.
5/21/2012 9:11:18 PM
 240 ■ Surgery: Evidence-Based Practice

3. What patients are at risk for developing pseudomembranous MILD TO MODERATE DISEASE
colitis?
These patients are clinically stable. The antibiotic of concern should
Intrinsic risk factors for pseudomembranous colitis include
be stopped and the patients should be fluid resuscitated. Support-
advanced age and number of comorbidities. The rate of pseudomem-
ive care with attention to electrolytes and nutrition is important.
branous colitis in people over 65 years is 20 times higher than in
Strong consideration should be given to starting metronidazole
younger people.13 Increased number of comorbidities increases a
500 mg orally three times a day for 10 to 14 days. Antiperistaltic
patient’s exposure to health-care facilities and therefore exposure
agents should be avoided as these may lead to toxic megacolon.24,25
to C. difficile.
Extrinsic risk factors are more familiar. The exposure to
broad-spectrum antibiotics is the most well-recognized risk
SEVERE DISEASE
factor.14-16 One study, a retrospective review of 1384 patients
with pseudomembranous colitis, showed that two-thirds had
There is a lack of Level 1 data and consensus on defining severe
received antibiotics within the 2-month period prior to diag-
disease in pseudomembranous colitis. An attempt to define severe
nosis.7 Another study showed that 94% of hospitalized patients
pseudomembranous colitis was made by the UK Department of
with pseudomembranous colitis had exposure to antibiotics
Health Steering Group on Healthcare Associated Infection.26 Signs
before or during hospitalization.17 The first antibiotic linked to
of severe disease include white blood cell count over 15,000, rising
pseudomembranous colitis is clindamycin. Even though other
creatinine, fever, and signs on physical examination and radiog-
antibiotics, including metronidazole, have also been associated
raphy of colitis. Metronidazole has been shown to have a signifi-
with pseudomembranous colitis, clindamycin is one of the main
cant treatment failure rate. Oral vancomycin 125 mg orally four
agents used in treatment. The usual antibiotic responsible for
times a day for 10 to 14 days should be used in these patients.27,28
C. difficile colitis parallels the common, in vogue, antibiotics used.
Zar et al.29 showed that the rate of cure for pseudomembranous
Initially these were clindamycin, cephalosporins, and amoxicillin.
colitis treated with vancomycin was 97% compared to that of met-
More recently, fluoroquinolones have been linked. Pepin et al.18
ronidazole which was 76%. The reason for this is thought to be
demonstrated the current hazard risk associated with using fluo-
that oral vancomycin is not as readily absorbed by the gut so it
roquinolones was significantly higher than for clindamycin, mac-
acts intraluminally in the colon.
rolides, or cephalosporins.
Severe cases that do not respond to oral vancomycin can be
Residence at acute care hospitals and long-term care facilities
given higher doses, up to 500 mg four times a day via nasogastric
is also a strong risk factor for C. difficile colitis. The colonization in
tube. Vancomycin enemas may also be given. Intravenous met-
such populations is 20% to 40%, which is much higher than in the
ronidazole 500 mg four times a day is also recommended.30,31 Oral
community.7 Patient-to-patient transfer is suspected. Many facili-
rifampicin 300 mg twice daily and intravenous immunoglobulin
ties use isolation procedures to try to prevent spread. Length of
400 mg/kg may also be given. The data to support these thera-
stay in such facilities has also been associated with increased risk.
pies are far from robust, but the poor prognosis may justify try-
Debast et al.19 showed a 4% increased risk of C. difficile colitis with
ing these modalities. Patients not responding to medical therapy
each day of hospitalization. Dial et al. showed that hospitalization
should be seen by a surgeon.
longer than a week increases the risk by fivefold.
Alternate therapies have been investigated with limited suc-
Immunosuppression also increases the risk of developing
cess. Agents include fusidic acid, teicoplanin, nitazoxanide, and
pseudomembranous colitis.16,20 Disruption of the normal colonic
rifaximin.32 Probiotics have failed to demonstrate efficacy.31
barrier and malnutrition in these patients may exacerbate this
Anion-binding resins including oral cholestyramine do not work
added risk. Similarly, patients with Crohn’s disease or ulcerative
as primary agents but may have some benefit as an adjunct, espe-
colitis have some increased risk of C. difficile colitis and may have
cially in recurrent cases.33 These agents bind the C. difficile toxin
higher associated morbidity and mortality.21
in the gut and have the benefit of not altering gut flora. A new
Gastric acid suppression has also been implicated in increas-
toxin-binding resin tolevamer has been developed to specifically
ing the risk of C. difficile colitis. While there is no Level 1 data, a
treat C. difficile colitis.33,34 Trials are ongoing, and this agent is not
case–control study by Dial et al.22 reviewed 1672 cases in the U.K.
yet commercially available. Fecal bacteriotherapy has been shown
matching each case to 10 healthy controls. Multivariate analysis
in a limited study by Bakken35 to have a success rate of nearly 90%
showed that current use of proton pump inhibitors lead to a three-
in patients with recurrent disease. In this procedure, donor stool is
fold increased risk of C. difficile colitis. Given the other benefits of
given as an enema with varying volumes investigated. Adminis-
proton pump inhibitor therapy, it was not recommended to stop
tration via a nasoduodenal tube is also described in this study.
the therapy based on this finding. Other comorbidities may be a
It is hoped that commercial “artificial stool” products might be
source of confounding in the studied population.
developed in the future. Vaccines have been successful in animal
4. How do you treat pseudomembranous colitis? studies, and early human data are encouraging.36

Once diagnosed, it is helpful to stratify patients to guide

therapy.23 EMERGENCE OF A VIRULENT STRAIN

A hypervirulent strain has been identified in several outbreaks

ASYMPTOMATIC PATIENTS of C. difficile-associated diarrhea.37,38 This strain was identified as
ribotype 27, or B1/NAP1/027, by pulse-field electrophoresis and
No therapy is required. These patients must be closely followed for restriction endonuclease analysis. A study from Quebec identified
changes in clinical status that may warrant therapy. this new strain in 80% of patients in a severe outbreak. It had been

PMPH_CH28.indd 240 5/21/2012 9:11:19 PM

 Pseudomembranous Colitis ■ 241

previously isolated in 1.8% of cases at that facility.39 The virulent
strain leads to twice the normal mortality compared with the
other strain. This virulent strain has been reported in the United
States and also in other parts of the world.40 Some studies refute
the reported increased morbidity and mortality attributed to this
strain.41,42 This virulent strain is responsible for some nosocomial
epidemics and will play an important ongoing role.
5. When do you operate on pseudomembranous colitis?
There is a lack of Level 1 data to direct the timing of surgical inter-
vention for pseudomembranous colitis. Large-scale randomized-
controlled studies have not been done. That being said, there are
some published opinions, guidelines, and recommendations. The
procedure of choice is subtotal colectomy with end ileostomy. At
operation, parts of the colon may appear normally externally, but
it is important to remove all of the colon down to the distal rectum
because the disease begins on the mucosa first and progresses to a
full thickness process. A small retrospective study by Koss et al.43
found indications for surgery to include peritonitis, systemic
toxicity, toxic megacolon, and perforation. Synnott et al.44 did a
similar study determining the indications for surgery to include
systemic toxicity with pyrexia, marked leukocytosis, and progres-
sive organ failure despite appropriate medical management.
The patients with fulminant pseudomembranous colitis that
require operation have a mortality of 33% to 57%.45 Mortality
is reduced if surgery is done before a long period of pressor ther-
apy is required. A multidisciplinary panel of experts convened
to clarify the surgeon’s role in C. difficile colitis. These guide-
lines were published in Infection Control and Hospital Epidemi-
ology.46 They state colectomy should be considered for severely ill
patients. Serum lactate levels and white blood cell count were
found to be useful guides. Lactate level of 5 mmol/L and white
blood cell count of 50,000 cells/ml were found to be associated
with increased perioperative mortality. Subtotal colectomy with
ileostomy, as described above, is the recommended operation.
The timing of surgery remains unclear. Certainly, once sepsis
and organ failure set in, it is indicated. Optimal surgical timing
would be just prior to this, which is obviously often difficult to
predict.

Clinical Question Summary

Question
1 How do you diagnose Clostridium
dificile colitis?
2 How do you treat asymptomatic
pseudomembranous colitis?
3 How do you treat mild to moderate
pseudomembranous colitis?
4 How do you treat severe
pseudomembranous colitis?
5 When do you operate on
pseudomembranous colitis?
Answer Grade of References
Recommendation
Use ELISA to detect toxin A and toxin B B 7, 12
Consider PCR once available. C 7
No treatment C 24, 25
Stop antibiotic of concern. C 24, 25
Resuscitate with fluids and correct electrolytes. C 24, 25
Metronidazole 500mg orally three times a day. C 24, 25
Oral vancomycin 125mg four times a day for 10 to A 29
14 days.
Give IV metronidazole 500mg four times a day. B 26, 30
In refractory cases, give vancomycin enemas four C 26, 30
times a day.
In recurrent cases, consider fecal bacteriotherapy. C 35
Perform subtotal colectomy and ileostomy once C 43, 44, 45, 46
there is evidence of perforation, severe sepsis,
or organ failure.

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a description of a new pathogenic anaerobe, Bacillus difficilis.
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2. Hafiz S. Clostridium difficile and its toxins [PhD Thesis]. Leeds:
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3. Larson HE, Parry JV, Price AB, Davies DR, Dolby J, Tyrrell DA.
Undescribed toxin in pseudomembranous colitis. Br Med J. 1977;
1:1246-1248.
4. Finney JMT. Gastroenterostomy for cicatrizing ulcer of the pylo-
rus. Johns Hopkins Med J. 1893;4:53-55.
5. Kyne L, Hamel MB, Polavaram R, Kelly CP. Healthcare costs asso-
ciated with nosocomial diarrhea due to Clostridium difficile. Clin
Infect Dis. 2002;34:346-353.
6. Dubberke ER, Wertheimer AI. Review of current literature on the
economic burden of Clostridium difficile infection. Infect Control
Hosp Epid. 2009;30:57-66.
7. Ananthakrishnan AN. Clostridium difficile infection: Epidemiol-
ogy, risk factors and management. Nat Rev Gastroenterol Hepatol.
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8. Rupnik M, Wilcox, MH, Gerding DN. Clostridium difficile infec-
tion: New developments in epidemiology and pathogenesis. Nat
Rev Micro. 2009;7:526-536.

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 242 ■ Surgery: Evidence-Based Practice
9. Voth DE, Ballard JD. Clostridium difficile toxins: Mechanism of
action and role in disease. Clin Micro Rev. 2005;18:247-263.
10. Drudy D, Harnedy N, Fanning S, et al. Isolation and character-
ization of toxin A-negative, toxin B-positive Clostridium difficile
in Dublin, Ireland. Clin Micro Infect. 2007;13:298-304.
11. Fekety RN, Shah AB. Diagnosis and treatment of Clostridium
difficile colitis. JAMA. 1993;269:71-75.
12. Wren, M. Clostridium difficile isolation and culture techniques.
Clostridium difficile, Methods in Molecular Biology, Mullany P
and Roberts AP, eds. Springer Science+Business Media; 2010.
13. Bartlett JG, Gerding DN. Clinical recognition and diagnosis of
Clostridium difficile infection. Clin Infect Dis. 2008;46(Suppl 1):
S12-S18.
14. Gerding DN. Clostridium difficile 30 years on: What has or has not
changed and why? Int J Antimicrob Agents. 2009;33(Suppl 1):S2-S8.
15. Gerding DN, Johnson S, Mulligan ME, Silva J, Jr. Clostridium
difficile associated diarrhea and colitis. Infect Contr Hosp Epide-
miol. 1995;16:459-477.
16. Diggs NG, Surawicz CM. Evolving concepts in Clostridium dif-
ficile colitis. Curr Gastroent Rep. 2009;11:400-405.
17. Owens RC, et al. Antimicrobial associated risk factors for Clostrid-
ium difficile colitis. Clin Infect Dis. 2008;46(Suppl 1):S19-S31.
18. Pepin J, et al. Emergence of fluoroquinolones as the predomi-
nant risk factor for Clostridium difficile-associated diarrhea:
a cohort study during an epidemic in Quebec. Clin Infect Dis.
2005;41:1254-1260.
19. Debast SB, et al. Successful combat of an outbreak due to
Clostridium difficile ribotype 027 and recognition of specific risk
factors. Clin Micro Infect. 2009;15:427-434.
20. Cohen SH, et al. Clinical practice guidelines for Clostridium dif-
ficile infection in adults. 2010 update by the Society of Healthcare
Epidemiology of America and the Infectious Diseases Society of
America. Infect Contr Hosp Epidemiol. 2010;31:431-455.
21. Issa M, et al. Impact of Clostridium difficile on inflammatory
bowel disease. Clin Gastroenterol Hepatol 2007;5:345-351.
22. Dial S, Alrasadi K, Manoukian C, et al. Risk of Clostridium dif-
ficile diarrhea among hospital inpatients prescribed proton pump
inhibitors: Cohort and case control studies. Can Med Assoc J.
2004;171:33-38.
23. Faris B, Blackmore A, Haboubi N. Review of medical and surgi-
cal management of Clostridium difficile infection. Tech Coloproc-
tol. 2010;14:97-105.
24. Novak E, Lee JG, Seckman CE, et al. Unfavorable effect of atro-
pinediphenoxylate (Lomotil) therapy in lincomycin caused
diarrhea. JAMA. 1976;235:1451-1454.
25. Poutanen SM, Simor AE. Clostridium difficile associated diar-
rhea in adults. Can Med Assoc J. 2004;171:51-58.
26. Department of Health. Clostridium difficile infection: How to
deal with the problem, a board to ward approach. Department of
Health Steering Group on Healthcare Associated Infection. 2008
Department of Health; Gateway reference 9833.
27. Louie T, Gerson M, Grimard D, et al. Results of a phase three
trial comparing tolevamer, vancomycin, and metronidazole
in patients with Clostridium difficile associated diarrhea. 47th
Interscience Conference on Antimicrobial Agents and Chemo-
therapy, Chicago; 2007.
28. Wilcox MH, Howe R. Diarrhoea caused by Clostridium difficile:
response time for treatment with metronidazole and vancomy-
cin. J Antimicrob Chemother. 1995;36:673-679.
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29. Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A compari-
son of vancomycin and metronidazole for the treatment on
Clostridium difficile-associated diarrhea, stratified by disease
severity. Clin Infect Dis. 2007;45:302-307.
30. Bartlett JG. Clinical practice: Antibiotic-associated diarrhea.
N Eng J Med. 2002;346:334-339.
31. Pillai A, Nelson R. Probiotics for treatment of Clostridium dif-
ficile associated colitis in adults. Cochrane Database Systematic
Review. 2008;CD004611.
32. Nelson R. Antibiotic treatment for Clostridium difficile associ-
ated diarrhea in adults. Cochrane Database Systematic Review.
2007;CD004610.
33. Tedesco FJ. Treatment of recurrent antibiotic associated
pseudomembranous colitis. Am J Gastroenterol. 1982;77:
220-221.
34. Louie TJ, Peppe J, Watt CK, et al. Tolevamer, a novel non-antibiotic
polymer, compared with vancomycin in the treatment of mild
to moderately severe Clostridium difficile associated diarrhea.
Clin Infect Dis. 2006;43(4):411-420.
35. Bakken JS. Fecal bacteriotherapy for recurrent Clostridium dif-
ficile infection. Clin Micro. 2009;15:285-289.
36. McMaster-Baxter NL, Musher DM. Clostridium difficile: Recent
epidemiologic findings and advances in therapy. Pharmacother-
apy. 2007;27:1029-1039.
37. Loo VG, Poirier L, Miller MA, et al. A predominately clonal
multi-institutional outbreak of Clostridium difficile associated
diarrhea with high morbidity and mortality. N Engl J Med.
2005;353(23):2442-2449.
38. McDonald LC, Killgore GE, Thompson A, et al. An epidemic,
toxin-gene variant strain of Clostridium difficile. N Engl J Med.
2005;353(23):2433-2441.
39. Labbe AC, Poirier L, Maccannell D, et al. Clostridium difficile
infections in a Canadian tertiary care hospital before and dur-
ing a regional epidemic associated with the B1/NAP1/027 strain.
Antimicrob Agents Chemother. 2008;52(9):3180-3187.
40. Khanna S, Pardi DS. The growing incidence and severity of
Clostridium difficile infection in inpatient and outpatient set-
tings. Expert Rev Gastroenterol Hepatol. 2010;4(4):409-416.
41. Cloud J, Noddin L, Pressman A, Hu M, Kelly C. Clostridium
difficile strain NAP1 is not associated with severe disease in a
non-epidemic setting. Clin Gastroenterol Hepatol. 2009;7(8):
868-873.
42. Morgan OW, Rodrigues B, Elston T, et al. Clinical severity of
Clostridium difficile PCR ribotype 027: A case-case study. PloS
One. 2008;3(3):1812.
43. Koss K, Clark MA, Sanders DSA, Morton D, Keighley MRB, Goh
J. The outcome of surgery in fulminant Clostridium difficile coli-
tis. Col Dis. 2005;8:149-154.
44. Synnott K, Mealy K, Merry C, Kyne L, Keane C, Quill R. Timing
of surgery for fulminating pseudomembranous colitis. Br J Surg.
1998;85:229-231.
45. Dallal RM, Harbrecht BG, Boujoukas AJ, et al. Fulminant
Clostridium difficile: An underappreciated and increasing cause
of death and complications. Ann Surg. 2002;235(3):363-372.
46. McDonald LC, Coignard B, Dubberke E, Song X, Horan T, Kutty
PK; Ad Hoc Clostridium difficile Surveillance Working Group.
Recommendations for surveillance of Clostridium difficile-
associated disease. Infect Control Hosp Epidemiol. 2007;28(2):
140-145.
5/21/2012 9:11:19 PM
 Commentary on
Pseudomembranous Colitis
Pamela A. Lipsett
This chapter addresses five important questions regarding the rec-
ognition, identification, diagnosis of patients with pseudomem-
branous colitis, and the medical and surgical therapy. Clostridium
difficile-associated diarrhea (CDAD) is a major cause of nosoco-
mial and antibiotic-associated diarrhea (AAD) (10–30%), and it
is the commonest recognized cause of pseudomembranous colitis
(96–100%). The overall attack rate of AAD in hospitals is 3.2% to
29%, with an incidence among hospitalized and long-term care
patients of 25 to 60 cases per 100,000 bed-days. The identification
of patients with CDAD is important whether or not the patients
are symptomatic, as C. difficile is easily transmissible, with spores
long-lasting in the environment. Further, hand hygiene with com-
monly used gels is not effective at killing these spores.
Rapid identification of those patients with CDAD as opposed
to another cause of systemic illness is essential. Identification of
CDAD as a definitive cause of infectious signs and symptoms is
especially important in critically ill patients and postoperative
patients who have many alternative potential causes of systemic
signs of inflammation, and even potentially organ failure. Has
this chapter been fully clear in educating us about the most cur-
rent thoughts about diagnostic strategies in this rapidly evolving
field? Perhaps some additional information is needed.
Methods currently in use for the detection of C. difficile toxin
include toxigenic culture, cytotoxicity assay, initial screening
with glutamate dehydrogenase (GDH) antigen tests with positive
screens followed by subsequent assays to detect toxins A and B, and
most recently molecular assays to detect the tcdB gene.1-4 Because
the sensitivity and specificity of these diagnostic tests vary greatly,
it is essential for the clinician to know which test their labora-
tory uses and to what extent the test will reject the possibility of
Diagnostic test* Sensitivity
GeneOhm Cdiff assay (PCR) 92–96
Xpert C. difficile test (PCR) 94–96
ProGastro Cd assay (PCR) 77–92
Quick Chek Complete 62–84
GDH/EIA 42–90
*Compilation of Refs [1-4].
243
PMPH_CH28.indd 243
C. difficile infection, or confirm the presence of the pathogen and
toxin.1-4 This chapter does not describe the previously commonly
used nonmolecular two-step diagnostic method, and only briefly
mentions the possible use of PCR for diagnosis. A two-step pro-
tocol has been recommended: testing for an abundant C. difficile
antigen, glutamate dehydrogenase (GDH), by a rapid and sensitive
enzyme-linked immunosorbent serologic assay (ELISA), followed
by cytotoxin testing of GDH-positive samples to confirm toxin
production in vivo. This method achieves relatively high sensitiv-
ity and specificity and can rapidly report results for most samples
that are negative for C. difficile but can still take up to 48 h to report
low-level cytotoxin positivity. The first commercially available real-
time PCR assay (the BD GeneOhm Cdiff assay; BD Diagnostics,
San Diego, CA) was approved in 2008 to directly detect the toxin
B (tcdB) gene in stool to aid in the diagnosis of CDAD. There are
now at several commercially available molecular methods to diag-
nose C. difficile toxin.3 The estimated sensitivity and specificity
of these tests are shown in the table below. Generally speaking,
when compared with nonmolecular methods, molecular meth-
ods detect 30% to 35% more positive specimens. Further the
methods compare very favorably with the “gold standard” of the
toxigenic culture and they are available much more quickly for
clinical decision making.4
Some patients with C. difficile will not have diarrhea and
will simply have a distended abdomen, leuckocytosis, and signs
of systemic illness. As part of the search for an etiology, patients
may undergo computerized tomographic (CT) scans, which may
demonstrate unexpected colonic disease. The scan may show, in
the case of fulminant colitis, edematous and thick-walled colon
with thumbprinting. Other findings could include the presence
Specificity Predictive Value
Positive Negative
94–100 100 97–98
96–97 92–93 96–99
95–98 69–94 95–99
96–100 52–100 85–99
90–100 99–100 79–94
5/21/2012 9:11:19 PM
 244 ■ Surgery: Evidence-Based Practice
of pericolic stranding, ascites, pancolitis, and megacolon. These
findings should prompt consideration of C. difficile as a potential
etiology.
The most recent Cochrane analysis addressing antibiotic treat-
ment for CDAD suggests there is uncertainty about whether mild
CDAD requires treatment.5 Further most studies exclude patients
with severe disease and have a high risk of bias. This evidence-
based review suggests that vancomycin may not be better than the
other proposed treatments. However, current expert opinion does
clearly prefer vancomycin for severe disease. We should further
emphasize the importance of not treating asymptomatic patients.
There is growing concern about resistance to metronidazole and
expert opinion suggests this should not be used for first line treat-
ment in severely ill patients.
Several novel therapies have been studied in randomized-
controlled trials, mostly for prevention of recurrence of CDAD.
For example, the use of fidaxomicin versus vancomycin for the
treatment of recurrent C. difficile has shown that the rates of clini-
cal cure were not inferior to those with vancomycin (88.2% with
fidaxomicin and 85.8% with vancomycin).6 However, there were
fewer patients with recurrence in patients who received fidaxomi-
cin (15.4%) versus vancomycin (25.3%). The role of fidaxomicin in
primary CDAD is currently uncertain. Further, two monoclonal
antibodies against toxin A and toxin B were tested against placebo
in a randomized control trial with an endpoint of recurrence at
84 days.7 Patients who were treated with antibodies had a recur-
rence rate of 7% versus 25% (p < .0001).
Perhaps the most difficult decision for a surgeon to make is
the one to proceed to surgical intervention in the setting of severe
CDAD disease. While the indication for operation is obvious in
the presence of perforation or peritonitis (which are rare), the
decision to operate and the timing of such have not emanated
from clinical trials, but rather from reports of clinical experi-
ence. Using lactate and white blood cell elevations as prompters
for invasive action comes from reports that have used statistical
methods in case series where favorable and unfavorable outcomes
were used to determine important predictive measures. Expert
opinions considered these recommendations to aide providers as
to when an operation may be indicated. However, these few clin-
ical features simplify a complex and integrated decision process.
In a severely ill patient in whom CDAD is considered likely or is
confirmed, medical therapy (vancomycin and intravenous met-
ronidazole) and resuscitation should be initiated immediately. If
the trajectory of illness is not abated or is worsening within 24 h,
operative intervention should be considered. As correctly noted
by Thompson, the colon is often normal appearing externally
and one may be tempted to reconsider the operative plan. While
the operative procedure of choice has not been studied prospec-
tively, the series with the best outcomes over the past 10 years
have performed a subtotal colectomy. Often the right colon is
quite severely diseased and a more selective left-sided colectomy
has been associated with a high mortality in some series. Hav-
ing said this, a novel approach has been recently reported. Th is
approach utilized laparoscopic ileostomy and on-table irrigation
PMPH_CH28.indd 244
with 8 L of PEG3350/electrolyte colonic irrigation, followed by
postoperative antegrade infusion of colonic vancomycin. 8 Using
a historical controls who underwent open surgery and colon
resection, mortality was substantially lower (19% vs. 50%), and
patients were successfully managed without resection (93%)
with this less-invasive approach. Th is new procedure was per-
formed in patients who were quite ill and appeared to have many
of the risk factors present and in whom resection was previously
advised. Thus, while no high-level-evidence–based recommen-
dations can be made, this new approach seems to be reasonable
in skilled hands.
Finally, the prudent use of antibiotics for defi ned infec-
tions with shorter duration and using antibiotics for accepted
prophylaxis may well help prevent a significant number of
C. difficile infections. Further, attention to appropriate infec-
tion control measures to limit the spread of disease may well
address the rising rates of C. difficile.
REFERENCES
1. Chapin KC, Dickenson RA, Wu F, Andrea SB. Comparison of
five assays for detection of Clostridium difficile toxin. J Mol Diag.
2011;13(4):395-400. Epub April 29, 2011.
2. Naaber P, Stsepetova J, Smidt I, Rätsep M, Kõljalg S, Lõivukene K,
Jaanimäe L, Löhr IH, Natås OB, Truusalu K, Sepp E. Quanti-
fication of Clostridium difficile in antibiotic-associated diar-
rhea patients. J Clin Microbiol. August 24, 2011. [Epub ahead
of print.]
3. Tenover FC, Baron EJ, Peterson LR, Persing DH. Laboratory diag-
nosis of clostridium difficile infection can molecular amplification
methods move us out of uncertainty? J Mol Diag. August 17, 2011.
[Epub ahead of print.]
4. Kvach EJ, Ferguson D, Riska PF, Landry ML. Comparison of BD
GeneOhm Cdiff real-time PCR assay with a two-step algorithm
and a toxin A/B enzyme-linked immunosorbent assay for diag-
nosis of toxigenic Clostridium difficile infection. J Clin Microbiol.
2010;48(1):109-114. Epub October 28, 2009.
5. Nelson RL, Kelsey P, Leeman H, Meardon N, Patel H, Paul K, Rees R,
Taylor B, Wood E, Malakun R. Antibiotic treatment for Clostrid-
ium difficile-associated diarrhea in adults. Cochrane Database Sys-
tematic Review. September 7, 2011;9:CD004610.
6. Louie TJ, Miller MA, Mullane KM, Weiss K, Lentnek A, Golan Y,
Gorbach S, Sears P, Shue YK; OPT-80-003 Clinical Study Group.
Fidaxomicin versus vancomycin for Clostridium difficile infection.
N Engl J Med. 2011;364(5):422-431.
7. Lowy I, Molrine DC, Leav BA, Blair BM, Baxter R, Gerding DN,
Nichol G, Thomas WD, Jr., Leney M, Sloan S, Hay CA, Ambrosino
DM. Treatment with monoclonal antibodies against Clostridium
difficile toxins. N Engl J Med. 2010;362(3):197-205.
8. Neal MD, Alverdy JC, Hall DE, Simmons RL, Zuckerbraun
BS. Diverting loop ileostomy and colonic lavage: An alterna-
tive to total abdominal colectomy for the treatment of severe,
complicated Clostridium difficile associated disease. Ann Surg.
2011;254(3):423-429.
5/21/2012 9:11:19 PM

Colon and Rectal Cancer
Including Adjuvant
Robert P. Sticca, Erik G. Fetner, and Jay M. MacGregor
INTRODUCTION
Colorectal cancer is both a national and worldwide health prob-
lem. In 2008, it was estimated to affect 1,235,208 people world-
wide1 and in 2010 it was estimated to affect 142,570 people in
the United States.2 Although in recent years, US statistics have
demonstrated improvements in survival after initial diagnosis
of colorectal cancer, it still remains the second leading cause of
cancer-related death, accounting for an estimated 51,370 deaths
in 2010.1 Worldwide there was an estimated 609,051 deaths2 from
colorectal cancer in 2008. Risk factors that have been cited for
colorectal cancer include age >50 years, cigarette smoking, exces-
sive red meat consumption, lack of dietary fiber, obesity, seden-
tary lifestyle, excessive alcohol consumption, inflammatory bowel
disease, radiation exposure, and genetic predisposition. The exact
etiology of sporadic colorectal cancer is unknown and is probably
multifactorial. Approximately 20% of cancers of the colon and rec-
tum are felt to be attributable to hereditary syndromes including
familial adenomatous polyposis (FAP), attenuated FAP (AFAP),
hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syn-
drome), and familial colorectal cancer. Intensive research over the
past two decades coupled with the discovery of specific mutations
in the hereditary colorectal cancer syndromes have elucidated the
steps in carcinogenesis of colorectal cancer.
Once established, colorectal cancer can spread through four
different pathways including direct extension to other organs, lym-
phatic metastasis to regional lymph nodes, intraperitoneal metas-
tasis, and hematogenous metastasis to distant organs. The principle
mode of therapy for colorectal cancer is surgical excision, which
is designed to remove the primary tumor and regional lymph
nodes. The anatomy of the blood supply and lymphatic drainage
of the colon and rectum dictate the type and extent of resection for
colorectal cancers. Adenocarcinomas of the rectum have a worse
prognosis than their colonic counterparts when comparing similar
stages, due to the lack of a serosal covering of the rectum and the
enclosed spaces of the pelvis. Several questions in the management
of colorectal carcinoma have engendered controversy, some due to
new technology and others due to conflicting or inadequate data.
245
PMPH_CH29.indd 245
CHAPTER 29
INITIAL EVALUATION AND DIAGNOSIS
1. What is the best preoperative staging method for locore-
gional disease in rectal cancer?
Advances in imaging have greatly improved the preoperative
evaluation of patients diagnosed with colorectal cancer. The accu-
racy, applicability and cost-effectiveness of these technologies to
the management of rectal cancer have been studied extensively.
Accurate staging of rectal cancer is necessary for prognosis, man-
agement, and the evaluation of therapeutic response. Endorectal
ultrasound (ERUS) is the most accurate method for assessment of
invasion of rectal carcinoma into the rectal wall (T-stage), which
remains the most important factor in treating patients with rectal
cancer.3 The accuracy of ERUS for T-staging is 80% to 95% versus
65% to 75% for computed tomography (CT) and 75% to 85% for
magnetic resonance imaging (MRI).4 Advantages of ERUS include
cost-effectiveness, well tolerated by patients, able to perform with-
out anesthesia, ability to accurately measure size, circumference,
and distance of tumor from anatomic landmarks, and the ability
to examine anal sphincters.5
The sensitivity and specificity of ERUS vary by T-stage. Recent
meta-analysis reports an ERUS sensitivity and specificity of 88%
and 98% for T1, 81% and 96% for T2, 96% and 91% for T3, and 95%
and 98% for T4.6 T2 lesions are subject to overstaging by ERUS,
which may be related to classification of peritumoral fibrosis as
tumor, hematomas from associated preoperative biopsies, and
fear of understaging.
The accuracy of ERUS is directly correlated to the skill of the
operator. Garcia-Aguilar report a 10% to 15% difference in T-staging
between three board-certified colorectal surgeons.7 With train-
ing, ERUS accuracy has been shown to increase from 50% to over
90%.8 Interestingly, more recent data and larger sample sizes gen-
erally show a decrease in the accuracy of ERUS. A 2002 study of
more than 400 patients found ERUS to be less than 70% when less
experienced practitioners were performing the ultrasonography.8
A 2005 meta-analysis of ERUS showed accuracy of 85% with a
trend toward decreased accuracy in more recent studies.9 These
data suggest accuracy of ERUS may be highly correlated with
5/21/2012 9:11:55 PM
 246 ■ Surgery: Evidence-Based Practice
operator experience. There appears to be a learning curve of 50
cases for interpretation of tumor depth and greater than 75 cases
for node assessment when using ERUS.8
A meta-analysis by Puli et al.10 found the nodal sensitivity and
specificity of ERUS to be 73.2% and 75.8%, respectively. There is a
wide variance in the accuracy of metastatic nodal disease by imag-
ing modality: 62% to 87% for ERUS, 22% to 73% for CT, and 39% to
95% for MRI.11 Part of the difficulty in accurately evaluating meta-
static nodal disease relates to the fact that size is a poor predictor
of lymphatic metastasis in rectal cancer. Half of metastatic lymph
nodes are smaller than 5 mm and 8% are smaller than 2 mm.12
Although more than half of metastatic nodes are located
within 3 cm of the primary tumor, an inherent limitation of ERUS
is its inability to evaluate nodes outside the focal range of the
transducer. MRI is able to evaluate the entire mesorectum and
iliac anatomy. The best reports of MRI evaluation of nodal disease
in rectal cancer were obtained when value was placed on irregular
contour of nodes and heterogenous signal, rather than node size,
resulting in a sensitivity of 85% and a specificity of 97%.13 MRI
is preferable over CT for evaluation of infi ltration of neighbor-
ing organs due to its greater contrast resolution.14 CT scan and
positron emission tomography (PET) scan are both useful in the
staging of distant metastasis.
Answer: ERUS is the most accurate method for staging of
depth of invasion, while MRI is the most accurate method for
staging lymph node metastasis.
MANAGEMENT
2. Is local excision an appropriate method of treatment for
rectal cancer?
Having traditionally been a modality used in poor-risk surgical
patients unable to withstand a major resection, local surgery for
rectal cancer began to be investigated and reported in the past
three decades as a possible curative alternative to radical surgery
in early stage rectal cancers. Early reports in the 1980s by Grigg
et al.15 and Hager et al.16 showed encouraging results and helped
foster an interest in transanal excision (TAE). Follow-up studies
in the early-1990s by Gall and Hermanek17 and Willet et al.18 had
low recurrence rates for T1 and T2 tumors with favorable histol-
ogy. Beginning in 1998–2000 and throughout the next decade
evidence was mounting that the early promise of TAE as an
equivalent oncologic option was not holding up. Multiple studies
showed that TAE was associated with a three- to five-fold higher
risk of tumor recurrence and a low rate of salvage once recurrence
was detected.19-21 Taylor et al.22 reported the Vancouver experience
of a 30% local recurrence rate for T1 and T2 tumors treated by
local excision alone. The University of Minnesota reported a com-
parison of 108 patients with T1 and T2 treated by TAE versus 153
with T1N0 and T2N0 rectal adenocarcinomas treated by radical
resection. The overall recurrence for T1 treated locally was 21%
compared with 9% in radical resections. Differences in survival
rate between local and radical resection were significantly worse
in T2 tumors.23 Madbouly et al.24 reported the Cleveland Clinic
experience on locally resected T1 tumors showing an estimated
5-year recurrence rate of 29%. Fourteen of 15 patients with a recur-
rence underwent salvage treatment with 56.2% 5-year survival.
Memorial Sloan-Kettering published their experience revealing
both a higher risk of local recurrence and significantly poorer
PMPH_CH29.indd 246
long-term survival among patients treated with TAE as compared
with radical resection. There will be circumstances in which
patients have significant comorbidities prohibiting major surgi-
cal resection or who have made the informed decision to choose
the functional benefits of TAE over rectal resection, but, as Nash25
concludes, they must be informed that TAE offers significantly
inferior oncologic results, including a greater risk of cancer-
related death.
Answer: Local excision has been shown to have higher local
recurrence and poorer long-term survival in retrospective studies;
therefore, it is not recommended unless significant comorbidities
prohibit radical surgical resection.
3. Is minimally invasive surgery equivalent to open surgery for
rectal cancer?
The accepted standard for rectal cancer surgery is by open tech-
nique with total mesorectal excision (TME) championed by Heald
et al.26 of the Basingstoke Group, United Kingdom. TME is of sin-
gular importance in improving local recurrence rates and sur-
vival after rectal cancer surgery. The ability to answer the above
question is ultimately dependent on oncologic outcome provided
by laparoscopic surgery, but perioperative issues and complica-
tion rates are also a component to be considered. Extended long-
term oncologic results from randomized-controlled trials (RCTs)
are still pending, but there are indicators that suggest that laparo-
scopic surgery for rectal cancer will prove to provide equivalent
long-term results and the short-term benefits that are associated
with minimally invasive surgery for patients with rectal cancer.
There are reports showing that local recurrence, lymph node
harvest, and oncologic clearance are not compromised and may
be equivalent to open surgery.27 The short-term outcomes of open
versus laparoscopic-assisted low anterior resection (LAR) in
patients with mid to low rectal cancers who had been treated with
preoperative chemoradiation were examined in a randomized
trial of 340 patients reported by Kang et al.28 They reported that
the laparoscopic group had significantly better time to return of
bowel function (38 vs. 60 h), time to normal oral diet (85 vs. 93 h),
and time to defecation (96 vs. 123 h). There were no significant
differences in respect to circumferential resection margin, macro-
scopic quality of TME specimen, number of nodes harvested, or
perioperative morbidity.
Prospective randomized trials with long-term results by
Lujan et al.,29 Braga et al.,30 and Ng et al.31 have shown similar
local recurrence rates and disease-free survival of laparoscopi-
cally treated patients compared with their open surgery coun-
terparts. The CLASICC trial for colon cancer also included rectal
cancer and showed a higher rate of positive margins in the 3-year
follow-up.32 These negative findings have been suggested to be due
to the learning curve in the use of laparoscopic technique. Other
studies have shown equivalent outcomes in laparoscopic versus
open surgery.33
As with any tool, its efficacy is related to the skill of the user
(learning curve) and the situation in which its use is required
(patient selection). Laparoscopic surgery certainly has a learning
curve and appropriate patient selection is necessary in any sur-
gery.34 In the hands of an experienced surgeon who employs TME,
laparoscopic surgery for rectal cancer seems to provide compa-
rable benefit and improved short-term advantage to the carefully
selected patient.35 Future results on long-term outcomes will con-
tinue to define this option for surgeons and patients.
5/21/2012 9:11:55 PM
 Colon and Rectal Cancer Including Adjuvant ■ 247

Answer: RCTs have shown that laparoscopic surgery is equiv- the patients who did not have a diverting ostomy with LAR while
alent to open surgery for oncologic outcomes, with the benefits of combined results of all RCTs demonstrated clinical leak rates of
shorter recovery and quicker return of bowel function. 19.6% in the no ostomy group, and 6.3% in the diverting ostomy
group (risk ratio 0.33, 95% confidence interval 0.21–0.53).
4. Should diverting ostomy be performed with LAR in rectal In these RCTs, the need for urgent reoperation was four times
cancer? greater in the patients who did not have a diverting ostomy with
4% of the diverting ostomy group requiring reoperation and 16%
Resection of low-lying rectal cancers as low as 4 cm superior to
of the no ostomy patients requiring reoperation (risk ratio 0.28,
the anal verge has been made possible by improvements in surgical
95% confidence interval 0.17–0.48). There was no significant
techniques and equipment as well as improved neoadjuvant thera-
difference in mortality between the patients who had diverting
pies over the past three decades. Circular staplers and better under-
ostomy or no ostomy in the RCTs, as there were very few deaths
standing of pelvic anatomy has allowed for LAR of rectal tumors,
in either arm of these studies. The ostomy group mortality was
defined by many as located below the peritoneal reflection. These
0.6% while the no ostomy group was 1.2%, with two deaths in the
methods have allowed for lower anastamosis, preservation of anal
ostomy group and four deaths in the no ostomy group (risk ratio
sphincters, and avoidance of permanent colostomy. Leaks from
0.58, 95% confidence interval 0.14–2.33). Recognition and timely
these anastamosis can be disastrous, resulting in pelvic abscess,
treatment of anastomotic leaks and better critical care capabili-
sepsis, reoperation, prolonged hospital stay, subsequent poor func-
ties may be responsible for the low mortality rates. Quality of life
tion, and increased mortality. Mortality rates as high as 26%36 have
evaluations were not performed in these studies, with the quality
been reported while the risk of local recurrence is increased after
of life factors of urgent reoperation or drainage of pelvic abscess
anastomotic leak from LAR. The role of a diverting ostomy proxi-
in the no ostomy patients competing with the quality of life issues
mal to the anastamosis has been controversial. Recent meta-analy-
of an ostomy and subsequent reoperation for ostomy takedown
sis and RCTs have provided better insight into this question.
in the ostomy group. In addition, there is recognized morbidity
There have been six RCTs37-42 comparing the use of a defunc-
and mortality (albeit low) from the ostomy takedown procedure
tioning ostomy with no ostomy in patients who have undergone
should be recognized when considering this question.
LAR for rectal cancer. In addition, there have been three recent
There have been over 21 nonrandomized studies, including
meta-analyses43,44 including both the RCTs and many retrospec-
11,429 patients between 1984 and 2008, that have analyzed this
tive reports. The RCTs ranged in sample size from 34 to 256
question. A meta-analysis of these studies demonstrated similar
patients, with a total of 648 patients included in all six trials. In
results to the RCTs with a lower clinical anastomotic leak rate
these trials patients were excluded if there was evidence of leak
(relative risk 0.74, 95% confidence interval 0.67–0.83, p < .001) and
intraoperatively or if the surgeon made the decision to perform a
lower reoperation rate (relative risk 0.28, 95% confidence interval
defunctioning stoma. A definition of anastomotic leak has been
0.23–0.35, p < .001) in the patients who had a diverting ostomy
proposed by Peel45 in 1991 as the leak of luminal contents from
performed at the time of LAR. In the nonrandomized studies
a surgical joining between two hollow viscera. This definition
the mortality between the cohorts was significantly lower with
can include both clinical and nonclinical (radiographic) leaks.
a mortality of 0.7% (relative risk 0.42, 95% confidence interval
In these RCTs, nonclinical leaks were excluded from the study as
0.28–0.61, p < .001) in the ostomy group versus 2% in the no
the evaluation for them was variable between studies, and they
ostomy group.36
were not of clinical significance. Recently the International Study
Answer: The use of a diverting ostomy after LAR decreases
Group of Rectal Cancer has proposed a classification of anasta-
the clinical leak rate and need for urgent reoperation; therefore, it
motic leaks after LAR (Table 29.1) and a more encompassing def-
is a recommended component of this procedure for rectal cancer.
inition of an anastomotic leak as “A defect of the intestinal wall
integrity at the colorectal or colo-anal anastomotic site (including
5. Does total mesorectal excision (TME) decrease local recur-
suture and staple lines of neorectal reservoirs) leading to a com-
rence and improve long-term survival in rectal cancer?
munication between the intra- and extraluminal compartments. A
pelvic abscess close to the anastomosis is also considered as anasto- Local recurrence remains a significant problem in the treatment of
motic leakage”.46 The six RCTs were conducted prior to this defini- rectal cancer. Heald et al.47 first described the complete excision of
tion of anastamotic leak. Therefore in these RCTS the definition of visceral mesorectal tissue, now known as TME, in 1982 showing
clinical leaks varied, but all included clinical findings of localized a decrease in local recurrence from nearly 40% to less than 10%.
or generalized peritonitis, feculent drainage from drains, or need More recent data have shown overall local recurrence rates of 3%
for urgent reoperation. The distance of the anastamosis from the to 13% after TME.48-50 The addition of preoperative radiation to
anal verge varied in the studies, ranging from a maximum of 4 TME further decreases local recurrence rates without an increase
cm to anywhere below the peritoneal reflection. All RCTs indi- in overall survival.51 Local recurrence rates after 5 and 10 years are
vidually found the clinical leak rate to be significantly higher in reported to be less than 5% in curative cases.52 TME involves sharp

Table 29.1 Classification of anastomotic leaks (proposed by the International Study Group of Rectal Cancer)46
Grade Type of Leak
A Anastomotic leakage requiring no active therapeutic intervention.
B Anastomotic leakage requiring active therapeutic intervention but manageable without re-laparotomy.
C Anastomotic leakage requiring re-laparotomy.

PMPH_CH29.indd 247 5/21/2012 9:11:55 PM

 248 ■ Surgery: Evidence-Based Practice

dissection to keep the visceral layer intact while recognizing the
importance of the circumferential margin’s predictive value in local
recurrence.53 Meticulous dissection is required to avoid breach of
the mesorectum which, when perforated, is associated with local
recurrence.54 TME is associated with increased sphincter preserva-
tion and decreased frequency of abdominoperineal resection.55,56
The 5-year tumor-free survival rate after TME is approxi-
mately 80%.52 Heald and Ryall55 report 5-year disease-free survival
by stage at 94%, 87%, and 58% for stages 1, 2, and 3, respectively.
TME is associated with an absolute overall and cancer-specific
survival benefit of 30%.47,55,56 Thanks in part to TME, some coun-
tries report rectal cancer survival having overtaken that of colon
cancer.57,58 Cases involving TME are associated with a mortality
of 3% to 7%, and a morbidity of 53%.59 Anastomotic leakage is a
major complication of TME; the incidence of leakage following
TME in low rectal tumors is 7% to 9%.60 Heald et al.61 reported
a leak rate of 12% when performing TME while Carlsen et al.62
reported a leak rate of 16%. Anastomotic leakage is the most sig-
nificant cause of postoperative death in patients undergoing TME
and LAR. Preoperative radiotherapy is known to further increase
the risk for leakage.63 Additional drawbacks to TME include an
increased operative time and a higher rate of gastrointestinal, uri-
nary, and sexual dysfunction although nerve sparing techniques
appear to mitigate the risk of genitourinary complications.64
Answer: TME decreases local recurrence and improves long-
term survival in rectal cancer.

Clinical Question Summary

Question Answer Level of Grade of References
Evidence Recommendation
1 What is the best preoperative ERUS for depth of invasion. MRI for 2b B 3-14
staging method for locoregional lymph nodes.
disease in rectal cancer?
2 Is local excision an appropriate No, unless unfit for radical surgery. 2b B 15-25
method of treatment for rectal
cancer?
3 Is minimally invasive surgery Initial RCTs show equivalent oncologic 2 B 26-35
equivalent to open surgery for outcomes with shorter recovery.
rectal cancer? Long-term oncologic results are
pending.
4 Should diverting ostomy be Yes, it decreases the clinical leak rate 1a A 36-46
performed with LAR in rectal and need for reoperation.
cancer?
5 Does TME decrease local TME decreases local recurrence and 2b B 47-64
recurrence and improve long-term improves long-term survival in
survival in rectal cancer? rectal cancer.

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5/21/2012 9:11:55 PM
 Commentary on Colon and Rectal
Cancer Including Adjuvant
Nicholas J. Petrelli
The chapter entitled “Colon and Rectal Cancer including Adju-
vant” goes into detail with an excellent review of the literature of
five provocative questions in the diagnosis and management of
colon and rectal cancer. The questions that are reviewed are the
following:
1. What is the best preoperative staging method for locoregional
disease in rectal cancer?
2. Is local excision an appropriate method of treatment for rectal
cancer?
3. Is minimally invasive surgery equivalent to open surgery for
rectal cancer?
4. Should diverting ostomy be performed with LAR [low anterior
resection] in rectal cancer?
5. Does TME [total mesorectal excision] decrease local recurrence
and improve long-term survival in rectal cancer?
I will take each of these questions and comment on the answers
by Sticca et al.
The first question deals with the best preoperative staging
technology for local regional disease in rectal cancer. The authors
state that endorectal ultrasound is the most accurate method for
staging the depth of invasion of a cancer while magnetic resonance
imaging (MRI) is the most accurate method for staging lymph
node metastases. I agree with this conclusion. However, in the era
of modern technology, we sometimes forget the importance of a
physical examination. Hence, a rectal examination by an educated
finger can establish fi xation of the tumor. As the authors state, the
accuracy of endorectal ultrasound is directly related to the skill of
the operator. However, this is also true of the radiologist reading
the MRI. Interestingly, the literature has documented that a 10%
to 15% difference in T-staging for endorectal ultrasound occurred
between three board-certified colorectal surgeons.1 The staging of
lymph node metastases in rectal cancer by MRI is still not opti-
mal. However, at present, it is the best technology that is available
to surgeons. Within the decade, there is no question that genomic
profi ling will be a tremendous advantage in the staging of lymph
node metastases.
Regarding the second question as to whether local excision is
an appropriate method of treatment for rectal cancer, the authors
conclude that local excision has been shown to have higher local
recurrence and poorer long-term survival in retrospective studies
and, therefore, is not recommended unless significant comorbidi-
ties prohibit radical surgical resection. I believe that the majority of
surgeons would agree with the authors’ conclusion. The real issue
251
PMPH_CH29.indd 251
here is that there are more than likely patients that will benefit
from local excision of rectal cancer, but we do not have the means
to identify those individuals today. The morphology and pathol-
ogy of the tumor does not necessarily help in separating out those
patients who will benefit from local excision versus those who will
fail. Again, as in the first question, this is where genomic profiling
may eventually help. The first prospective clinical trial on local
excision for rectal cancer was done by Steele et al.2 of the Cancer
and Leukemia Group B (CALGB) NCI Cooperative Group (Proto-
col #8984). In this trial of 110 eligible patients for local excision at a
median follow-up of 48 months, there were 4 of 59 T1 (7%) failures
and 10 of 51 T2 (20%) failures with a 6-year failure-free survival
of 78%. Just as importantly, this trial also demonstrated that the
technical aspects of local excision are not as easy as some surgical
atlases seem to make. For example, 51 post-surgery patients were
ineligible either because of staging, positive margins, or size crite-
ria of the trial. I agree with the authors that unless there are signif-
icant comorbidities which prohibit radical surgical resection, or if
the patient refuses radical surgical resection, then local excision
is an option. It is important to remember that local recurrence in
rectal cancer can have severe consequences on the patient’s qual-
ity of life. Hence, performing the correct surgical procedure the
first time is critical to avoid a local recurrence and its subsequent
consequences.3,4
The third question deals with minimally invasive surgery ver-
sus open surgery for rectal cancer. For this question the authors
document the randomized control trials that have shown that lap-
aroscopic colon surgery is equivalent to open surgery for onco-
logic outcomes with benefits of shorter recovery and quicker
return of bowel function. This question demonstrates the impor-
tance of prospective randomized Phase III trials in the oncology
arena. The Phase III prospective randomized trial is the gold
standard in oncology. The first prospective Phase III randomized
trial comparing laparoscopically assisted colectomy versus open
colectomy for colon cancer in the United States was performed
by the Clinical Outcomes of Surgical Therapy Study Group. This
multi-institutional study demonstrated that the rates of recurrent
cancer were similar after laparoscopically assisted colectomy and
open colectomy suggesting that the laparoscopic approach is an
acceptable alternative to open surgery for colon cancer.5
Question four involved a diverting ostomy performed with low
anterior resection in rectal cancer. The authors’ answer is that the
use of a diverting colostomy after low anterior resection decreases
the anastomotic leak rate and need for urgent reoperation; therefore,
5/21/2012 9:11:56 PM
 252 ■ Surgery: Evidence-Based Practice
it is a recommended component of this procedure for rectal cancer.
There is no question that an anastomotic leak can lead to severe
morbidity and potential mortality. Mortality rates as high as 26%
have been reported.6 It is important to note that several of the stud-
ies referenced by the authors were prior to the era of preoperative
radiation for rectal cancer. In general, preoperative radiation is
considered in patients with T3 and/or N positive lymph nodes on
endoscopic rectal ultrasound and MRI as described in question
one. I agree with the authors that the use of a diverting ostomy
after low anterior resection decreases the clinical leak rate and the
need for reoperation and is a recommended component for this
procedure. In essence, it is the safest approach for the patient.
The last question approached by Sticca et al. concerns total
mesorectal excision; whether it decreases local recurrence and
improves long-term survival in patients with rectal cancer. The
authors answer this question in the affirmative. My only com-
ment to this question, which I would have liked the authors to
have added to their answer, is the following: “surgeons who are
not trained to performed total mesorectal excision should not be
allowed to treat patients with rectal cancer.”
PMPH_CH29.indd 252
REFERENCES
1. Garcia-Aguilar J, Pollack J, Lee SH, et al. Accuracy of endorec-
tal ultrasonography in preoperative staging of rectal tumors. Dis
Colon Rectum. 2002;45:10-15.
2. Steele GD, Herndon JE, Bleday R, Russell A, Benson AB, Hussain
M, Burgess AM, Tepper JE, Mayer RJ. Sphincter sparing treat-
ment for distal rectal adenocarcinoma. Ann Surg Oncol. 1999;6(5):
443-441.
3. Sticca R, Rodriguez-Bigas M, Penetrante R, Petrelli N. Curative
resection of Stage I rectal cancer: Natural history, prognostic fac-
tors and recurrence patterns. Cancer Invest. 1996;14(5):491-497.
4. Chorost M, Petrelli N, McKenna M, Kraybill W, Rodriguez-Bigas
M. Local excision of rectal cancer. Am Surg. 2011;67(8):774-779.
5. Nelson H, Sargent D, Wieand S, Fleshman J, Anvari M, Stryker S,
Beart R, Hellinger M, Flanagan R, Peters W, Ota D. A comparison
of laparoscopically assisted and open colectomy for colon cancer.
N Engl J Med. 2004;350(20):2050-2059.
6. Tan WS, Tang CL, Shi L, Eu KW. Meta-analysis of defunction-
ing stomas in low anterior resection for rectal cancer. Br J Surg.
2009;96(5):462-472.
5/21/2012 9:11:56 PM

Tumors of the Anal Region
Marjun P. Duldulao and Julio Garcia-Aguilar
BACKGROUND
Anal cancer is a rare malignancy accounting for approximately 2%
of all gastrointestinal cancers.1 In the United States, approximately
5200 new cases are diagnosed annually, resulting in an estimated 700
deaths, and the incidence of anal carcinoma continues to increase.2
ANAL REGION: ANATOMY AND
HISTOLOGY
The anal region is divided into two main areas: the anal canal and
the anal margin. The division that demarcates these two regions
coincides with the intersphincteric groove or anal verge. The prox-
imal portion of the anal canal begins at the palpable superior edge
of the anorectal ring, which corresponds with the point where the
distal rectum enters the puborectalis sling, and extends to the anal
verge at the palpable outer edge of the internal sphincter muscle or
intersphincteric groove. The anal margin corresponds to the peri-
anal skin extending 5 cm from the anal verge. The dentate line is
an important anatomic landmark of the anal canal that represents
the fusion of the hindgut and the proctodeum during embryologic
life. Below the dentate line the anal canal is covered by squamous
epithelium. Immediately above the dentate line there is a 1- to
2-cm region of transitional or cloacogenic epithelium that con-
tains squamous, transitional, and cuboidal cells. Proximally, the
cloacogenic epithelium progressively transforms into the normal
columnar epithelium of the lower rectum. The anal glands open to
the anal crypts located al the level of the dentate line. The crypts
are separated from one another by the columns of Morgani. The
proximal anal canal above the dentate line typically drains to the
internal iliac and pelvic lymph nodes, and the distal anal canal
and anal margin drain to the inguinal nodal basin.
CANCERS OF THE ANAL REGION
Tumors of the anal region are defined based on their location in
the anal canal or anal margin. Tumors of the anal canal are further
253
PMPH_CH30.indd 253
CHAPTER 30
subclassified according to their histologic features. In this chapter,
we present an overview of the different cancers that affect each
anatomic region and their histologic features, detailing risk fac-
tors, prognosis, treatment modalities, and outcomes for each.
TUMORS OF THE ANAL CANAL
Squamous Cell Carcinoma
Squamous cell carcinoma (SCC) is the most common cancer of
the anal canal, representing 80% of all anal cancers. Numerous
risk factors for SCC have been described, including human papil-
loma virus (HPV),3 smoking, receptive anal intercourse, human
immunodeficiency virus (HIV),4 immunosuppression, sexually
transmitted diseases, and cervical, vulvar, or vaginal cancer.5
Diagnosis and Evaluation
The most common presenting symptoms in patients with anal
canal SCC are bleeding, anal pain, or the sensation of a mass.
However, up to 20% of patients may be asymptomatic.6 Diag-
nosis includes digital rectal examination (DRE) combined with
anoscopy or proctoscopy, and lesions are biopsied to confirm
diagnosis. Careful palpation of the inguinal nodal basin with fine-
needle aspiration or core-needle biopsy of enlarged lymph nodes
is important to determine the extent of disease. Imaging modali-
ties such as computed tomography (CT) are also routinely used
to identify distant metastatic disease (in the lungs or liver) and
enlarged lymph nodes in regions not amenable to direct physical
examination (such as the paraaortic and iliac nodes). The over-
all sensitivity of CT in detecting regional lymph node disease in
pelvic malignancies is approximately 50%.7 Positron emission
tomography (PET) is another imaging option that may facilitate
the detection of regional lymph node disease (Level 3b evidence),
and the combination of PET and CT has been shown to improve
the sensitivity for detection of nodal regional disease compared
with conventional CT (89% vs. 62%).8 Other studies substantiate
the usefulness of PET imaging for detecting regional disease;9,10
5/21/2012 9:12:30 PM
 254 ■ Surgery: Evidence-Based Practice
but as many of these patients never undergo surgery; the true sen-
sitivity of this imaging modality cannot be confirmed without
histologic confirmation of the nodal staging. Furthermore, cur-
rent imaging modalities are not able to detect microscopic disease
and are only useful to identify patients with relatively large nodal
disease. Endoanal ultrasound (EAUS) is also used in the evalua-
tion and staging of anal cancer because it can determine the depth
of invasion into the sphincter complex and in assessing regional
lymph nodes; however, its role in staging is not yet clear.
The extent of the disease is determined by the size of the pri-
mary tumor (T), the location of the regional nodal metastasis (N),
and the presence of distant metastasis (M), according to the Amer-
ican Joint Committee on Cancer (AJCC) staging guidelines.11
Prognosis and Treatment, and Follow-up
Prognosis for SCC in the anal canal is directly related to staging.
This has been highlighted in recent studies that have examined
tumor staging and oncologic outcomes.12-14 Bilimoria et al.13 used
the National Cancer Database (1985–2000) to evaluate 19,199
patients with SCC in the anal canal and determined survival rates
based on tumor stage. They found that the highest survival was
observed in patients with lower T-stage and lower overall dis-
ease stage (Stages I–II), and that the 5-year overall survival rates
decreased with increasing disease stage from 70% (Stage I) to 19%
(Stage IV). Lymph node metastasis also influenced prognosis, with
5-year overall survival rates decreasing from 63% to 38% in lymph
node negative and positive patients, respectively.14 Ajani et al.12
prospectively studied 644 patients and determined that patients
with tumors >5 cm in diameter and positive lymph nodes had sig-
nificantly worse disease-free and overall survival compared with
patients with smaller tumors and negative lymph nodes. Other
factors associated with prognosis include gender, age, socioeco-
nomic status, and ethnicity; however, studies have yet to substan-
tiate the reasons underlying these disparities.
SCC of the anal canal has historically been treated by abdom-
inoperineal resection (APR) and permanent colostomy. Patients
undergoing APR as primary treatment have a 27% to 47% local
failure rate and a 5-year survival rate of 40% to 70%.6,15 However,
over three decades ago Nigro et al.16 demonstrated that a complete
clinical response (cCR) could be achieved in patients using a com-
bination of chemotherapy and radiation (CRT). This observation
led to numerous large studies designed to investigate the efficacy
of chemotherapy and/or radiation as a treatment for anal-canal
SCC.17-19 The United Kingdom Coordinating Committee on Can-
cer Research (UKCCCR) Anal Cancer Working Group launched
one of the first randomized Phase III trials comparing the effica-
cies of radiation (RT) alone with CRT for treating anal-canal SCC
cancer.17 Five hundred and eighty-five patients were randomized
into two groups; each group received 45 Gy of RT with or without
concurrent 5-fluorouracil (5-FU) and mitomycin C (MMC). The
3-year local failure rate, defined as persistent disease 6 weeks after
initial therapy, colostomy for recurrent disease or colostomy after
treatment morbidity was significantly lower in patients treated
with CRT compared with those treated with RT alone (39% vs. 61%;
p < .0001). A similar trial conducted by the European Organization
for Research and Treatment of Cancer (EORTC 22861) random-
ized 110 patients to receive RT alone or concurrently with 5-FU
and MMC.18 The 5-year local failure rate was lower in the CRT
group compared with RT alone (32% vs. 50%; p = .02). Patients
in the CRT group also showed an increase in cCR compared
PMPH_CH30.indd 254
with RT (80% vs. 54%), a lower incidence of local recurrence, and
lower colostomy rate at 5-year follow-up. The RTOG 87-04 trial
conducted in the United States evaluated the efficacy of MMC in
the treatment regimen for anal-canal SCC.19 Their trial random-
ized 291 patients to receive either 5-FU and RT or 5-FU/MMC
and RT. Local failure was found to be lower in the 5-FU/MMC-RT
group compared with the 5-FU-RT treatment arm (16% vs. 34%;
p = .0008). These patients also experienced a lower incidence of
colostomy at 4-year follow-up (9% vs. 22%; p = .002). No differ-
ence was observed in overall survival between the two treatment
arms; however, disease-free survival at 4 years was higher in the
5-FU/MMC-RT group (73% vs. 51%; p = .0003). These studies
established the combined modality treatment of 5-FU, MMC, and
RT as the primary treatment for SCC of the anal canal.
Cisplatin has been utilized for the treatment of SCC of the
head and neck, cervix, and the esophagus with beneficial effects.
The RTOG 98-11 trial compared the efficacy of a cisplatin-based
regimen with 5-FU/MMC chemotherapy for the treatment of
SCC of anal canal.20 Six hundred and forty-four patients were
randomized to receive either standard 5-FU/MMC and RT or
cisplatin/5-FU and RT. The 5-year disease-free and overall sur-
vival was comparable between the groups. The most signifi-
cant difference was observed in the colostomy rate, which was
higher in patients who received cisplatin compared with MMC
(19% vs. 10%; p = .02).
Newer chemotherapeutic regimens are also being evaluated
to improve treatment outcomes. In the EORTC 22011-40014
Phase II trial, Matzinger et al.21 demonstrated improved complete
response rates using a combination of MMC and cisplatin com-
pared with MMC and continuous infusion 5-FU. However, the
cisplatin-containing regimen was associated with higher toxicity.
Other biologic agents such as cetuximab, a monoclonal antibody
against epidermal growth factor receptor (EGFR), have also been
identified as a feasible treatment option for the treatment of anal
canal SCC.22-24 The efficacy of these newer regimens has yet to be
confirmed in Phase III clinical trials.
Patients are usually evaluated 8 to 12 weeks after initial CRT
by physical examination with DRE. Biopsies are only performed
if there is persistence of disease or suspicion of progression. Indi-
cations for biopsy include persistence or development of a new
ulceration, enlarging mass, or increasing anal pain.25 Patients
with complete eradication of disease should have continued
follow-up every 3 to 6 months for 5 years with physical examina-
tion and anoscopy and possible radiologic evaluation of involved
nodal basins at least annually for the first 3 years. If no contin-
ued regression of disease is observed after serial examination or if
there is disease progression, more aggressive therapy may be war-
ranted. Evidence of progression on physical examination should
be confirmed with biopsy and patients should be restaged with
radiologic imaging.
Despite the efficacy of CRT for anal-canal SCC, approximately
30% of patients experience treatment failure. For these patients,
APR may be the only option. However, APR in this patient popula-
tion requires complex reconstructive myocutaneous flap procedures
and is associated with high morbidity due to surgical complica-
tions related to the perianal wound.26-29 As such, the option of less
invasive surgical therapies, such as local excision (LE), or further
CRT have been studied as possible treatment options for selected
patients with who fail primary treatment with CRT. However, use
of LE for the management of recurrent or persistent disease after
CRT is very limited.30 No studies have reported the effectiveness
5/21/2012 9:12:30 PM

of LE after failed CRT. Thus, APR remains the treatment option
of choice for salvage therapy in patients with loco-regional failure
after CRT and several studies report a 5-year survival rate ranging
from 39% to 64% after salvage surgery.30-32 Following salvage sur-
gery, patients should be followed every 3–6 months for 5 years.
LE has also been considered as a treatment option for early and
small (<1-cm diameter) anal cancers. In a retrospective study per-
formed across 17 institutions in France, Ortholan et al.33 reviewed
69 patients with early stage tumors (T1 or Tis; <1 cm diameter).
Of the 69 patients, 26 underwent LE and 43 were treated with RT
alone. Twenty-three of the 26 patients who underwent LE were
treated with concurrent RT; the remaining three patients had LE
alone. Recurrence was low in patients who received RT either alone
(9%) or in conjunction with LE (12%) compared with patients
treated with LE alone (33%).33 No prospective clinical trials have
examined the efficacy of CRT and LE for small anal-canal SCC,
but the studies which have investigated LE alone for anal-canal
SCC report inconsistent results,34,35 though most report a high
rate of local recurrence.36,37 These studies suggest that LE alone
may not be sufficient in controlling the disease.
Anal Intraepithelial Neoplasia
Anal intraepithelial neoplasia (AIN) is highly associated with HPV
infection and the precise overall incidence is currently unknown.
AIN can be classified into three grades: AIN I is classified as low-
grade dysplasia, while AIN II and III are equivalent to high-grade
dysplasia and has the highest malignant potential. Recently, the
term squamous intraepithelial lesion (SIL) has replaced AIN. Now,
SIL is subdivided into high-grade (HSIL), which is equivalent to
AIN II and III, and low-grade (LSIL) which is equivalent to AIN I.38
Diagnosis and Evaluation
Anal cytology similar to Pap smear has been utilized to screen
high-risk patients for the presence of SIL. High-resolution anos-
copy with the application of 3% acetic acid and appropriate mag-
nification is the best way to diagnose these lesions in patients with
a positive anal cytology. The malignant potential of LSIL and HSIL
is not entirely known but, similar to cervical cancer, these lesions
are thought to progress to invasive anal cancer. In patients with
HIV, the disease appears to be more aggressive and this popula-
tion may be at highest risk for developing invasive cancer.39
Prognosis and Treatment, and Follow-up
Very few studies have examined the management of SIL, espe-
cially in high-risk patients. LSIL is thought to have low malignant
potential and is mainly managed with close follow-up at 6-month
intervals. Topical applications of trichloroacetic acid, imiquimod,
podophyllotoxin, and cryotherapy have been utilized to treat
LSIL.39 However, the management of HSIL remains highly debat-
able. Devaraj et al.40 followed 40 HSIL patients with HIV with
close observation and found that patients who progressed to inva-
sive carcinoma could be managed successfully with CRT. HIV
status did not influence treatment outcomes in these patients.40-42
Surgical options including wide LE or ablation with electrocau-
tery, photodynamic therapy, and infrared coagulation of all vis-
ible lesions have been described for the treatment of HSIL, but
studies are limited.43,44 Currently, frequent surveillance of patients
with HSIL at 6-month intervals is recommended.42
PMPH_CH30.indd 255
Tumors of the Anal Region ■ 255
Adenocarcinoma
Adenocarcinoma of the anal canal represents less than 20% of
anal cancers.45 These tumors arise from the anal glands within the
cloacogenic zone of the anal canal or from the columnar elements
within the transitional epithelium of the upper anal canal. The
diagnosis of these tumors is controversial because they are his-
tologically indistinguishable from rectal adenocarcinoma and in
most patients it is impossible to differentiate between a low rectal
adenocarcinoma extending to the anal canal and an anal adeno-
carcinoma extending to the distal rectum.
Diagnosis and Evaluation
Common presenting symptoms of adenocarcinoma include a
lump, pruritus, or bleeding. There is often a delay in diagnosis
and patients may present with metastatic disease upon initial
diagnosis.46
Prognosis and Treatment, and Follow-up
The long-term survival is poor with a 5-year survival of 4% to 5%.
In a survey of colorectal surgeons the most appropriate procedure
for the surgical management of anal adenocarcinoma was shown
to be APR.47 Combined modality treatments including CRT and
surgery is also an option for adenocarcinoma of the anal canal.
Patients undergo a resection after CRT, similar to patients with
rectal adenocarcinoma. Chang et al.46 has recently reviewed the
outcomes of 34 patients diagnosed with adenocarcinoma of the
anal canal in a single institution over a 20-year span and found
that patients treated with combined modality treatment and
radical resection had improved survival compared with patients
treated with combined modality treatment and LE.46 Other retro-
spective reviews also support the use of multi-modality treatment
approaches, although the optimal CRT regimen for adenocarci-
noma has yet to be determined.48 Nonetheless, these studies sug-
gest that neoadjuvant CRT followed by radical surgical resection
may provide the best local control and survival,48,49 and thus treat-
ment of anal adenocarcinoma mirrors the recommendations for
treatment of rectal cancer.50
Anorectal Melanoma
Anorectal melanoma accounts for less than 3% of all malignan-
cies of the anorectum and accounts for approximately 1% of all
melanomas.51
Diagnosis and Evaluation
Symptoms are indistinguishable from other benign conditions,
and most lesions are diagnosed at a late stage. The presence of
a pigmented lesion in the anus may be indicative of melanoma;
however 10% to 29% of lesions may be amelanotic, and thus
histologic diagnosis by immunohistochemical staining with
melanoma antigen HMB-45 and S-100 protein or Fontana stain-
ing for melanin are utilized.52
Prognosis and Treatment, and Follow-up
The prognosis of patients with anorectal melanoma is poor and
up to 40% of patients have distant metastasis at the time of diag-
nosis. The role of CRT remains unclear, and optimal surgical
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 256 ■ Surgery: Evidence-Based Practice
management continues to be debated.52-55 A recent study by Kiran
et al.53 evaluated survival in 109 patients from the SEER database
undergoing either LE or APR for anal melanoma. They found that
patients who underwent LE had similar 3- and 5-year survival
rates compared with patients who were treated with APR. Addi-
tional studies also support these findings.52-55
In nonmetastatic disease, APR may be associated with impro-
ved local control;56 however, studies suggest that despite this
aggressive treatment there is no survival benefit compared with
LE.57 Given the overall poor prognosis of anorectal melanoma, LE
is advised for localized tumors, reserving APR for palliation.
TUMORS OF THE ANAL MARGIN
Squamous Cell Carcinoma
SCC of the anal margin is approximately five to tenfold less com-
mon than SCC of the anal canal.58
Diagnosis and Evaluation
These tumors resemble SCC occurring elsewhere in the skin
and typically have rolled everted edges with central ulcerations.
Patients present with complaints of a painful mass, pruritus,
bleeding, tenesmus, or incontinence, and small lesions are often
misdiagnosed. Staging SCC of the anal margin is similar to SCC
of the skin and is based on overall size and lymph node involve-
ment. Physical examination with DRE and palpation of inguinal
nodal basins is imperative. Although slow growing, chest radio-
graph and CT may be warranted to determine distant metastasis.
The incidence of lymph node metastasis increases with increasing
tumor size; 0% in tumors <2 cm, 23% in tumors 2 to 5 cm, and
67% in tumors >5 cm.58
Prognosis and Treatment, and Follow-up
Management of small localized lesions (<2 cm) may be adequately
treated by wide LE with 1 cm margins with a favorable 5-year sur-
vival rate of approximately 88%.59 For larger, deeper tumors (T2–4
or N1), recurrent tumors after repeated LE or tumors that involve
the anal sphincter, APR may be required.60 In patients with syn-
chronous inguinal lymph node metastasis, a groin dissection is
recommended.61 Radiation with or without chemotherapy may be
utilized as primary treatment or for salvage treatment after failure
of LE. Mendenhall et al.61 reported on a small cohort of 16 patients
treated with RT alone or CRT for T2 and T3 anal-margin SCC,
and all were disease-free on 2-year follow-up. However, Papillon
et al.58 described a series of 57 patients treated with brachytherapy
and external beam irradiation (EBRT) who had a local recurrence
rate of 12% and a 16% inguinal metastasis rate. In patients treated
with EBRT alone, 22% died from primary disease. Thus, the uti-
lization of RT alone for the treatment of SCC of the anal margin
should be used with caution.
Basal Cell Carcinoma
The incidence of basal cell carcinoma (BCC) of the anal margin is
exceedingly low, comprising 0.2% of all anorectal cancers.62 Similar
to BCC of the skin, BCC of the anal margin rarely metastasizes.
PMPH_CH30.indd 256
Diagnosis and Evaluation
BCC of the anal margin presents with similar symptoms to
benign disease and is often misdiagnosed as hemorrhoids or anal
fissures.
Prognosis and Treatment, and Follow-up
Wide LE is the treatment of choice for primary surgical manage-
ment. In one study, the recurrence rate following this approach
was shown to be 24%.62 However, the local recurrences were ade-
quately treated with repeated wide LE and subsequently associ-
ated with favorable outcomes.62,63 APR is recommended only in
patients with advanced disease that extends deep into the anal
canal and invades surrounding tissues.60
Bowen’s Disease
Bowen’s disease is another rare lesion of the anal margin and is
often described as a slow-growing intraepidermal SCC. Similar to
HSIL of the anal canal, Bowen’s disease may serve as a precursor
to SCC of the anal margin. These lesions most often occur in the
fift h or sixth decades of life.
Diagnosis and Evaluation
Bowen’s disease is characterized by discrete erythematous and
scaly or crusting plaques. Intralesional foci of ulcerations may
indicate invasive SCC which occurs in approximately 6% of these
patients.64 Patients often present with burning or itching sensa-
tion in the anal region, or bleeding.
Prognosis and Treatment, and Follow-up
Surgical management of Bowen’s disease consists of wide LE with
biopsies taken 1 cm from the edge of lesion and microscopically
clear margins; this is the current treatment of choice.64 Recurrence
is often treated with a wider LE and reported 5-year survival rate
in patients with recurrent disease is approximately 75%.65
Paget’s Disease
Paget’s disease of the perianal skin is rare. These lesions may occur
within the sixth or seventh decades of life.
Diagnosis and Evaluation
These lesions represent a very slow-progressing intraepithelial
adenocarcinoma characterized histologically by the presence of
Paget cells which stain positive with Periodic acid–Schiff base.66
Paget’s disease is often associated with synchronous visceral
malignancies. These occur with a reported occurrence ranging
from 32% to 86%.67,68 A complete colonoscopy is therefore war-
ranted to determine the presence of other cancers.
Prognosis and Treatment, and Follow-up
Surgical management of Paget’s disease consists of wide LE with
microscopically clear margins. Paget’s disease often extends
beyond gross margins and has a high recurrence rate. Large
lesions often necessitate a skin-graft or local flap for closure of
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 Tumors of the Anal Region ■ 257

the remaining defect. APR is only recommended for perianal invade into the sphincter muscles may need APR.69 Only a few
Paget’s disease with invasive adenocarcinoma or other associated case series describe the surgical management of these patients and
malignancies.60 thus the optimal treatment remains under debate.60

Verrucous Carcinoma CONCLUSION

Verrucous carcinoma is often referred to as “giant condyloma
acuminatum” or “Buschke-Lowenstein tumor”.
Diagnosis and Evaluation
Tumors often present as a large, exophytic, warty, cauliflower-
like mass. These lesions range in size from 1 to 30 cm. Larger
lesions may harbor invasive SCC and invade into the surrounding
tissue and pelvic cavity. The extent of disease is best assessed by
CT scan.
Prognosis and Treatment, and Follow-up
CT scan is necessary to determine the extent of resection.60 Super-
ficial lesions may be managed by wide LE, however lesions that
Tumors of the anal region are rare. SCC of the anal canal is often
associated with HPV, and prognosis of patients depends on ini-
tial T and N stage. Combined CRT is the primary treatment of
SCC of the anal canal with surgery reserved for salvage therapy.
Follow-up is recommended with frequent physical examina-
tion, routine imaging, and selective biopsy of suspicious lesions.
In general, lesions of the anal margin can be managed surgically
with either wide LE or APR depending on tumor invasiveness.
ACKNOWLEDGMENTS
The authors thank Nicola Solomon, PhD, for assistance in writing
and editing the manuscript.

Clinical Question Summary

Question
Risks for anal-canal SCC
Best imaging modality for
initial evaluation anal-canal
adenocarcinoma
Factors associated with OS in
anal-canal adenocarcinoma
Most appropriate treatment
for anal-canal SCC
Using LE for the management
of anal-canal SCC
Management for AIN II/III
or HSIL
Answer Levels of Grade of References
Evidence Recommendation
HPV infection, history of cervical cancer 2 A 3-5
in women, immunosuppression, HIV
infection.
Diagnostic CT. The efficacy of PET 3 B 6-10
imaging as an adjunct or replacement of
diagnostic CT is still debatable, however,
recent reports have found clinical useful
in evaluating lymph nodes not enlarged
on CT scans.
Disease stage as established by AJCC 2 A 12-14
staging criteria.
5-FU/MMC plus RT. 1 A 16-24
Local excision is not recommended for 3 B 30-37
anal-canal SCC due to increased
likelihood of local recurrence. APR
provides optimal control in the event of
failed CRT and necessary salvage therapy
after failed CRT.
Frequent surveillance every 6 months, 3 B 38-42
especially in high-risk populations such
as HIV infected patients.

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5/21/2012 9:12:30 PM
 CHAPTER 31
Inherited Colorectal
Cancer Syndromes
Vitaliy Y. Poylin, Kristin B. Niendorf, and Robert D. Madoff
INTRODUCTION
As early as 1913, a pathologist Aldred Warthin used a simple tool,
family history collection, to describe the first hereditary cancer
syndrome, now considered to be the Lynch syndrome (hereditary
colorectal cancer syndrome or HNPCC). Between 5% and 10% of
all colorectal cancers arise in the setting of hereditary cancer syn-
dromes. With the advent of the molecular age, the genetic basis of
these diseases has been clarified, and effective cancer screening
and prevention strategies exist. A century later, it has become even
clearer that family history collection is the first step in identifying
those families at risk. A precise understanding of inherited col-
orectal cancer genetics is important for identifying at-risk indi-
viduals, improving cancer surveillance and prevention, as well as
developing better diagnostic and therapeutic approaches.
1. How prevalent are inherited colorectal cancer syndromes?
Identifying the true prevalence of inherited colorectal cancer has
proven complex. Approximately 25% to 40% of cases have been
estimated to have a familial component (at least one first-degree
relative affected by colorectal cancer).1-5 Between 5% and 10% of
patients with new diagnosis of colon cancer thought to have rec-
ognized inherited cancer syndromes.1-3,5 Most of the available data
come from a combination of population studies and cancer regis-
tries. These sources can help explain the variability in the preva-
lence of reported hereditary colon cancers. Epidemiologic studies
of North American and Western European populations suggest
that the rate is between 5% and 7%.3-5 A Colorectal Registry from
Spain places the rate at 5% or below.6 The California Cancer Sur-
vey suggests that the number is even lower.7 However, a recent twin
study of the Swedish and Finnish populations suggested that the
rates were higher, possibly up to 15%. The significant variability of
prevalence may be explained by differences in populations studied,
selection bias of colorectal registries as well as variable methodology
and difficulties defining hereditary cancer. In addition, the major-
ity of studies listed above concentrate mostly on patients of western
European descent and thus it may not be possible to generalize the
observations to the rest of the world population.
260
PMPH_CH31.indd 260
Answer: There is significant variability in the estimated prev-
alence of inherited colorectal cancers. Based on existing studies,
approximately 5% to 7% of colon cancers have an identifiable
inherited syndrome; however, this number may only be true for
patients of European descent. (Grade B recommendation)
2. What are the major inherited colorectal cancer syndromes?
The classic hereditary cancer syndromes include familial adenom-
atous polyposis (FAP) syndrome and Lynch syndrome (HNPCC).
More recently, several other familial associations with colorectal
cancer and/or polyposis have been described including MYH-
associated polyposis (MAP), hyperplastic polyposis (HPP)/
serrated pathway syndrome, familial colorectal cancer X, Peutz–
Jeghers syndrome (PJS), PTEN hamartoma tumor syndrome
(PHTS), and juvenile polyposis syndrome (JPS).
ADENOMATOSIS POLYPOSIS SYNDROMES
FAP syndrome and related syndromes account for about 1% of
all colorectal cancers. Classic FAP is characterized by hundreds
of adenomas developing, typically, by the second decade of life.
Nearly all patients with classic FAP will develop colorectal carci-
noma (average age at diagnosis of 39 years) if untreated via colec-
tomy.3 Extracolonic manifestations include polyps of the gastric
fundus and duodenum; osteomas; dental anomalies; congenital
hypertrophy of the retinal pigment epithelium (CHRPE); soft
tissue tumors; desmoid tumors; and other cancers (small bowel,
pancreas, thyroid [papillary], CNS [medulloblastoma], liver
[hepatoblastoma in children], and bile duct). Three subtypes of
FAP exist: attenuated FAP (AFAP), Gardner syndrome, and Tur-
cot syndrome. AFAP is characterized by later onset disease with
fewer than 100 polyps; usually localized to the right side of the
colon.2,8,9 Turcot syndrome involves colonic polyposis and CNS
tumors, most notably medulloblastomas. Turcot syndrome can be
due to mutations in the same gene, APC, as classic FAP but has
also been described in individuals with mismatch repair genes
typically associated with Lynch syndrome. Gardner syndrome
5/22/2012 5:23:14 PM

carries adenomatous colonic polyposis with additional features
that include benign osteomas and soft tissue tumors.
MAP syndrome frequently presents similarly to FAP/AFAP
with multiple adenomas or polyposis coli and early-onset colorec-
tal cancers. However, MAP is inherited in an autosomal-recessive
pattern without clear dominant transmission, as is typically seen
in classic FAP. MAP can also present with few or no polyps and, in
some cases, duodenal polyposis and/or duodenal adenocarci-
noma. Reported extraintestinal features are similar to FAP and can
be variably expressed: cystic fundic gland polyps/gastric cancer,
CHRPEs, osteomas, dental anomalies, skin lesions, and sebaceous
gland hyperplasia and carcinoma.8,10
Familial colorectal cancer type X (FCCTX) was coined in
2005 to describe the accumulated evidence of families with col-
orectal cancer, but without clearly demonstrated FAP or HNPCC.4
The average age of colon cancer diagnosis is almost 10 years older,
higher adenoma to carcinoma ratio, with more adenomas. At
this time, it was proposed that the term Lynch syndrome be used
for families with known hereditary mismatch-repair defects and
FCCTX for those without identifiable defects.11
HYPERPLASTIC/MIXED POLYPOSIS
SYNDROMES
HPP syndrome has been proposed for those families with a pre-
dilection for hyperplastic or serrated polyposis. Distinction of
syndromes has proven difficult and various other terminologies
include serrated pathway syndrome (SPS), dependent on the his-
tologic features of the polyps.11 Increased risk for colorectal can-
cers has been reported in several families with HPP.12 The similar
hereditary mixed polyposis syndrome (HMPS) presents with
a mixture of juvenile, adenomatous, hyperplastic, and mixed
polyps.
HAMARTOMATOUS POLYPOSIS
SYNDROMES
Juvenile polyposis (JPS) is characterized by large numbers of hama-
rtomatous polyps of the gastrointestinal tract. When five or more
of these polyps (or within the context of a family history JPS) are
recognizable as “juvenile” ( i.e., similarity to inflammatory solitary
colorectal hamartomas that occur in children, but JPS can occur in
adults) this meets the criteria for diagnosis of JPS.7 There is an
increased risk for malignancies with colon cancer being the most
frequent (~40% lifetime risk).7 JPS can also concurrently occur
with hereditary hemorrhagic telangiectasia (HHT), a syndrome
associated with arteriovenous malformations and telangiectasias
of the skin and mucosa.
PJS typically presents with multiple gastrointestinal hamar-
tomatous polyps and mucocutaneous pigmentation. Cancer risks
include colorectal malignancies as well as cancers of the ovary, testis
and other organs. PTEN hamartoma tumor syndrome (including
Cowden syndrome and Bannayan–Riley–Ruvalcaba syndromes)
has polyposis, typically hamartomatous, but also includes tumors
of the breast and uterus. Noncancerous features include thyroid
anomalies, macrocephaly, and several other features. Hamartoma-
tous polyp syndromes, PJS, JPS, and Cowden disease when com-
bined, cause less than 1% of colorectal cancers.2,6
PMPH_CH31.indd 261
Inherited Colorectal Cancer Syndromes ■ 261
NONPOLYPOSIS SYNDROMES
Nonpolyposis syndromes, most significantly including Lynch
syndrome (HNPCC), accounts for 4% to 6% of all colon
cancers.2,13,14 Individuals with Lynch syndrome have risks for the
following cancers (life time rate): colorectal (80%), endometrium
(20–60%), stomach (11–19%), ovary (9–12%), hepatobiliary tract
(2–7%), urinary tract (4–5%), small bowel (1–4%), and central
nervous system (1–3%).15 Two-thirds of colon cancers occur in the
proximal colon and, pathologically, the tumors frequently show
a poorly differentiated mucinous appearance, lymphocytic infi l-
trates, histologic heterogeneity, and signet-cell features. Muir–
Torre syndrome is a subtype of Lynch syndrome that includes
sebaceous gland adenomas and keratoacanthomas in addition to
visceral cancers.
Answer: FAP, MAP, and Lynch syndrome (HNPCC) account
for more than 90% of currently identified inherited colon cancer
syndromes. (Grade B recommendation)
3. What are the molecular mechanisms of the most common
inherited colorectal cancer syndromes?
FAP is caused by a germ-line mutation in APC, a tumor suppressor
gene. The inheritance pattern is autosomal-dominant. Individuals
with FAP are born with one mutated copy of APC in all of their cells;
the somatic inactivation of the second copy leads to polyp develop-
ment. Approximately 80% of patients with FAP have a familial his-
tory of the disease. In the other 20%, mutations are presumed to
develop in somatic cells de novo. The APC gene is located on chro-
mosome 5 and mutations in various parts of the APC gene tend to
lead to different phenotypes. For example, AFAP most commonly
occurs when mutations are at extreme 5′ and 3′ ends of the APC
gene; the presence of desmoids tumors is associated with mutations
between codons 1403 and 1578.9 MAP is inherited in an autosomal-
recessive fashion via biallelic mutations in the MYH (MUTYH)
gene. Lynch syndrome (HNPCC) is caused by a germ-line mutation
in any of several genes that participate in the DNA mismatch repair
(MMR) system. These germ-line defects in the MMR system result
in microsatellite instability in the tumor. Genes responsible for
this condition include MLH1, MSH2, MSH6, and PMS2, with the
first two listed genes responsible for most Lynch syndrome cases.
Lynch syndrome is inherited in an autosomal-dominant pattern.
Biallelic mutations in MMR genes have been reported and appear
to result in a syndrome, which includes neurofibromatosis-like
features (e.g., café-au-lait macules) as well as childhood hemato-
logic malignancies, brain tumors, and colorectal cancers. Of note,
recent reports suggest that deletions in the EPCAM (TACSTD1)
gene impact the MMR pathway and lead to Lynch syndrome with
similarly increased colorectal cancer and other risks.10,16 All of the
hamartomatous polyposis syndromes are inherited in an autosom-
al-dominant fashion. Specific mutations include the STK11 (LKB1)
gene for PJS; MADH4 (SMAD4), BMPR1A, or ENG for JPS; PTEN
for Cowden syndrome. Causative genes for HPP/serrated pathway
syndrome are unknown at this point. A locus for hereditary mixed
polyposis syndrome has been mapped to 15q although there is sug-
gested linkage to a JPS-related gene as well.
Answer: Major inherited cancer syndromes identified at this
point are caused by mutations in a distinct gene or genes, most
often inherited in an autosomal-dominant fashion. FAP is caused
by a mutation in the APC gene, MAP is caused by mutations in
the MYH gene, and Lynch syndrome (HNPCC) is caused by a
5/22/2012 5:23:14 PM
 262 ■ Surgery: Evidence-Based Practice

mutation in one of the following: MLH1, MSH2, MSH6, PMS2,
and EPCAM (TACSTD1) (Grade A recommendation).
4. How should an individual with a suspected inherited col-
orectal cancer syndrome be evaluated?
Hereditary colorectal cancer syndromes are identified via careful
medical and family history evaluation. Families with hereditary
cancer syndromes tend to carry the following hallmark features:
multiple individuals with the same or related cancers (e.g., col-
orectal cancers or endometrial plus colorectal cancers); early age of
onset for given cancer; multiple generations affected by the cancer
(except in the case of MAP, which is recessive); and unusual features
(e.g., sebaceous neoplasms in Muir–Torre syndrome). FAP and
MAP are typically identified via the presentation of adenomatous
polyposis, frequently in the context of a family history of early-on-
set colorectal cancer. Given the less obvious clinical presentation
of Lynch syndrome (HNPCC), several criteria sets based on family
history have been proposed: Amsterdam (classic), Amsterdam II,
Modified Amsterdam, Bethesda Guidelines, and Revised Bethesda
Guidelines (outlined in Table 31.1). The sensitivity for some of
these criteria range, in at least one study, from approximately 61%
to 94% when applied to families carrying germ-line mutations in
MLH1 and MSH2.14 The National Comprehensive Cancer Net-
work (NCCN) publishes guidelines for detection, prevention, and
risk reduction with a subsection on colorectal cancer and high-
risk syndromes. These comprehensive guidelines outline the com-
plex identification process for patients likely to have hereditary
cancer syndromes and propose testing, treatment, and manage-
ment protocols (www.nccn.org). The NCCN recommends referral
for genetic counseling for any of the following:
1. Individuals meeting Revised Bethesda or Amsterdam Criteria
(Table 31.1).
2. Individuals with >10 adenomas.
3. Individuals with multiple gastrointestinal hamartomatous or
HPP.
4. Individuals with a known family history of a hereditary cancer
syndrome.
In addition to family and medical history cues, colorectal
tumors in young patients (under the age of 60) exhibiting patho-
logic evidence of microsatellite instability including tumor-
infi ltrating lymphocytes, Crohn’s-like lymphocytic reaction,
mucinous/signet ring differentiation, medullary growth pattern
should be further evaluated for possible Lynch syndrome. Tumor
studies begin with immunohistochemistry for the genes’ prod-
ucts implicated in Lynch syndrome (MLH1, MSH2, MSH6, and
PMS2). With IHC, absence of staining for a given gene product
suggests a germ-line mutation in that gene but approximately 10%
of individuals with Lynch syndrome will have normal staining
for MMR proteins.17 Microsatellite instability testing (MSI) may
be performed at certain centers. MSI-High (MSI-H) tumors are
suggestive, but not diagnostic for Lynch syndrome. Clarification
of MSI-H can be done by testing for hypermethylation of the MLH1
promoter or due to somatic mutation of the BRAF gene, both of

Table 31.1 Lynch Syndrome Criteria (as Described in National Comprehensive Cancer Network Colorectal
Cancer Guidelines)
Amsterdam Criteria24
At least three relatives with colorectal cancer; all of the following should be present:
1. One should be a first-degree relatives of the other two
2. At least two successive generations must be affected
3. At least one of the relatives with colorectal cancer must have received a diagnosis before the age of 50 years
4. Familial adenomatous polyposis (FAP) should be excluded
5. Tumors should verified by pathological examination
Amsterdam II
At least three relatives must have a cancer associated with hereditary nonpolyposis colorectal cancer (colorectal, endometrial, small
bowel, ureter, or renal-pelvis); all of the following should be present:
1. One must be a first-degree relative of the other two
2. At least two successive generations must be affected
3. At least one of the relatives with cancer associated with hereditary nonpolyposis colorectal cancer should be diagnosed before the
age of 50 years
4. Familial adenomatous polyposis (FAP) should be excluded
5. Tumors should be verified whenever possible
Revised Bethesda Criteria36
Tumors from individuals should be tested for MSI in the following situations:
1. Colorectal cancer diagnosed in a patient who is less than 50 years of age
2. Presence of synchronous or metachronous Lynch-syndrome-associated tumors, regardless of age (CRC, endometrial, gastric,
ovarian, pancreas, ureter and renal pevis, biliary tract, brain [usually glioblastoma], small intestinal cancers as well as sebaceous
gland adenomas and keratoacanthomas [Muir-Torre syndrome])
3. Colorectal cancer with the MSI-H histology (tumor-infiltrating lymphocytes, Crohn’s-like lymphocytic reaction, mucinous/signet
ring differentiation, medullary growth pattern) diagnosed in a patient who is less than 60 years of age
4. Colorectal cancer diagnosed in a patient with one or more first-degree relatives with a Lynch syndrome related cancer, with one of
the cancers being diagnosed under the age of 50 years
5. Colorectal cancer diagnosed in a patient with two or more first- or second-degree relatives with Lynch syndrome–related cancers
(see above), regardless of age

PMPH_CH31.indd 262 5/22/2012 5:23:14 PM


which cause a MSI-H effect in tumors and make Lynch unlikely
if present. The NCCN Guidelines provides suggestions for genetic
testing protocols; however, genetic counseling is recommended
prior to germ-line genetic testing to ensure appropriate evaluation.
Answer: Patients with significant family history or significant
clinical features should be suspected of having hereditary colorectal
cancer syndrome and evaluated with molecular genetic testing and
should receive genetic counseling. (Grade B recommendation)
5. What is the appropriate surgery for a patient with an inher-
ited colorectal cancer syndrome?
Surgery is indicated for almost all patients with classic FAP. Colon
cancer under the age of 10 has not been reported and cancer
between ages 11 and 15 years is relatively uncommon. Although
the chance of developing cancer increases as patients get older, age
itself should not be the sole determinate in the timing of surgery.
The severity of the disease (based on family history and the number
and distribution of colonic polyps) should dictate the timing and
type of surgery. The two main types of surgery available for patients
with FAP are total abdominal colectomy with an ileorectal anasto-
mosis (IRA) and a total proctocolectomy (TPC) with either an end
ileostomy or an ileal pouch anal anastomosis (IPAA). Patients with
<20 rectal polyps and no rectal malignancy qualify for an IRA.
IRA is a simple, straightforward operation that has lower compli-
cation rates, allows for better function, and is much less likely to
affect fertility rates than IPAA; important considerations in this
are generally younger population of patients. IRA is particularly
well suited to patients with AFAP. However, if this option is chosen,
a strict surveillance schedule must be followed and many patients
will require an interval completion proctectomy. For patients with
severe rectal polyposis or rectal cancer, proctocolectomy should be
performed with either end ileostomy or IPAA.
Another factor that can affect the timing and type of surgery
is the relative success of chemoprevention. The use of nonsteroi-
dal anti-inflammatory drugs such as sulindac has been shown to
reduce the number and size of colonic adenomas. This effect can
be maintained for a number of years, but does not completely pro-
tect the individual from developing colon cancer. For individuals
with mild disease, chemoprevention in combination with surveil-
lance can be used to delay surgery, and similarly, for patients with
minimal rectal disease, chemoprevention can be used after IRA to
delay timing of a proctectomy.18
Duodenectomy or pancreatoduodenectomy is sometimes
required if patients have large duodenal adenomas that are not
amendable to endoscopic resection or if dysplasia is identified.
These are very complex procedures, but the chance of recurrent
polyp formation and cancer is significantly lower when compared
with the much less invasive local polyp resection.19
Desmoid tumors are an increasing cause of morbidity and
mortality in FAP. They tend to be slow growing, but often involve
areas, such as the root of the mesentery, that can make resection
very difficult, hazardous, and sometimes impossible. Their growth
is sometimes triggered by surgery itself. Surgical treatment for
desmoid tumors remains controversial. In general, minimal sur-
gery with attempts at a clear margin should be performed and
only for symptomatic patients.20,16
Patients with Lynch syndrome have a high chance of develop-
ing multiple colorectal cancers (synchronous and metachronous)
as well as extracolonic malignancies (especially endometrial and
ovarian). Emphasis should be placed on colorectal surveillance
PMPH_CH31.indd 263
Inherited Colorectal Cancer Syndromes ■ 263
and removal of any polyps. Partial colectomy followed by contin-
ued surveillance are the mainstay of surgical treatment for patients
with Lynch syndrome once cancer develops. The rate of metachro-
nous large-bowel malignancy is at least 45%, high enough that
prophylactic TAC with IRA should at least be discussed.21 Rectal
cancer is not as common in HNPCC, so proctectomy should not
be suggested during an initial consultation for colon cancer.
The chance of gynecologic malignancies is significantly inc-
reased in patients with HNPCC and prophylactic hysterectomy
should be discussed as an alternative to surveillance, particularly
if the patient is undergoing a colon resection.22 The risk of gyneco-
logic malignancy increases with age. Prophylactic oophorectomy
and hysterectomy should be discussed when the patient completes
childbearing (even without the presence of colonic malignancy),
since these procedures are risk reducing and there is no evidence
that surveillance lowers the risk of endometrial or ovarian cancer
in patients with HNPCC.
Patients with hamartomatous polyposis syndromes have a
higher chance of developing colonic and extracolonic malignan-
cies when compared with the general population, but the risk is
lower when compared with adenomatous polyposis syndromes.
While strict surveillance is required, a segmental resection can be
considered if a cancer is diagnosed. If a metachronous cancer or
more polyps develop, a prophylactic colectomy can be considered,
but currently there is no firm evidence to support this approach.
For patients with HPP, prophylactic surgery should be discussed,
but no conclusive recommendations can be made at this time.
Answer: For most patients with FAP, total proctocolectomy
with or without an ileoanal pouch should be performed. Total
abdominal colectomy with an ileorectal anastomosis can be con-
sidered for patients with AFAP. Prophylactic surgery is not
indicated for patients with HNPCC, but close colonoscopic sur-
veillance is required. Should a colon cancer be diagnosed in a
HNPCC patient, total abdominal colectomy with an ileorectal
anastomosis is generally recommended, but segmental colectomy
can be considered. In addition, a discussion about prophylactic
surgery for gynecologic malignancy should be had, especially in
postmenopausal women. (Grade B recommendation)
6. What is appropriate surveillance for patients with an inher-
ited colorectal cancer syndrome?
For patients with known FAP, a surveillance schedule depends on
the severity of the disease at the time of presentation as well as
the family history. If no adenomas are identified during the initial
colonoscopy, then a sigmoidoscopy or colonoscopy every 1 to 2
years is recommended or until adenomas start to develop. When
adenomas appear, a colonoscopy and polypectomy should be per-
formed every 6 to 12 months (depending on polyp burden) until
a colectomy is planned. If an IRA is chosen as a surgical option,
then a sigmoidoscopy should be performed every 6 to 12 months
(depending on polyp burden) after surgery. There have been some
reports of polyps developing in the pouch after an IPAA, and there
is the possibility of retained rectal mucosa, which predisposes
these patients to the subsequent development of malignancy; the
optimal schedule of surveillance after an IPAA is not clear at this
point.23 For family members of affected individuals with classic FAP
(APC mutation positive), surveillance schedule will depend on the
APC status. Individuals with detected APC mutations should be
treated as classic FAP patients: flexible sigmoidoscopy or colonos-
copy every 6 to 12 months starting between 10 and 15 years of age.
5/22/2012 5:23:14 PM
 264 ■ Surgery: Evidence-Based Practice
If no APC mutation is detected, these individuals are considered
to be at average risk and are screened accordingly. If the individ-
ual is not tested, more frequent surveillance schedule should be
suggested—flexible sigmoidoscopy or colonoscopy annually start-
ing at 10 to 15 years until the age of 24, then every 2 years until
the age of 34 if no polyps were detected or genetic testing done. If
no polyps were detected, endoscopy should be performed every
3 years until the age of 44 and 3 to 5 years thereafter.9,24,25
If APC mutation is not detected, MYH testing should be
considered, and family members are entered into the surveil-
lance program similar to FAP patients who were not tested for
APC (see above).
For patients with AFAP, surveillance should start before the
age of 21 with colonoscopy every 1 to 2 years as long as polyp
burden is small. Between the ages of 21 and 40, if polyp burden
remains small, colonoscopy should be performed after every 1 to 2
years. After the age of 40, or if polyp burden increases, colectomy
with ileorectal anastomosis should be strongly considered with
continuous surveillance of the rectum every 6 to 12 months after
surgery.24 Duodenal adenomas and carcinomas tend to develop
later in life. Surveillance frequency will depend on polyp burden
detected at upper endoscopy. For patients without polyps, endos-
copy can be repeated every 4 to 5 years. If 1 to 4 small adenomas are
detected, the surveillance interval is decreased to 2 to 3 years. For
5 to 19 and larger polyps, upper endoscopy is recommended every
1 to 2 years. For moderate polyposis of >20 polyps, EGD should be
repeated every 6 to 12 months. For severe polyposis of with signs
of dysplasia, surgical resection should be recommended.23,24
When genetic testing does not reveal biallelic MYH mutation
in patients with suspected MAP, they should be surveyed as FAP
individuals. For patients who are biallelic-MYH-mutation posi-
tive, colonoscopy is recommended every 2 to 3 years as long as
polyp burden is small, and EGD for every 3 to 5 years starting at
the age of 35. If polyp burden is large or is increasing overtime, the
surveillance period is decreased to every 6 to 12 months and
surgery should be recommended. For family members of MYH-
mutation positive patients, if the MYH status is unknown or if
they are biallelic MYH positive, colonoscopy starting between the
age of 25 and 30 for every 3 to 5 years, and EGD for every 3 to 5
years starting at the age of 30 to 35 are recommended.
For HNPCC, periodic and frequent surveillance has been
shown to decrease the chance of colorectal cancer and allows
for the detection of cancer at an earlier stage. There are no stud-
ies that directly compare the various surveillance periods. How-
ever, new cancer has been detected as early as 2 to 3 years after a
colonoscopy in these patients.13 Colonoscopy screening should be
started at 20 to 25 years of age and continued every 1 to 2 years
until polyps are detected. At that point colonoscopy should done
every 6 to 12 months and surgical options discussed. There is
no clear evidence for routine screening for endometrial cancer,
but yearly gynecologic examination is recommended and pro-
phylactic hysterectomy and bilateral salpingo-oopherectomy after
childbearing is done.14,22,24 After a partial colectomy is performed,
surveillance should continue on a similar schedule since the chance
of metachronous cancer remains high. Although rectal cancer is less
common in HNPCC than colon cancer, it is still significantly higher
than in the general population. If an IRA is performed, surveillance
of the rectum should be continued, but the optimal surveillance
schedule has not been established. Sigmoidoscopy should be per-
formed at least every 2 to 3 years,26 and as the procedure is simple,
many authorities recommend annual examinations. To screen for
PMPH_CH31.indd 264
gastric and small bowel cancers, EGD should be considered starting
between 30 and 35 years of age, repeated every 2 to 3 years. Capsule
endoscopy every 2 to 3 years has been suggested, but there are no
compelling evidence supporting this strategy at this point.24
Evidence for surveillance in hamartomatous polyposis syn-
dromes is very limited due to the rarity of these conditions. Periodic
surveillance of the colon and small bowel should be performed, but
the interval between these studies is not clear and should probably
be referred to centers with significant experience with these condi-
tions. For PJS, colonoscopy and EGD should be started in late teens
and continued every 2 to 3 years. Other extracolonic malignancies
will require radiologic surveillance with computed tomography
(CT) scans (small bowel and pancreas) as well as magnetic reso-
nance imaging (MRI) for screening of breast cancer.
Answer: For FAP, a sigmoidoscopy or colonoscopy should be
performed every 6 to 12 months starting at the age of 12 or until
polyps start to develop; once polyps develop, a full colonoscopy
should be performed until surgery is planned. Even after surgery,
especially after an IRA, surveillance should be continued regularly
because the chance of cancer is not totally eradicated. For patients
with AFAP, colonoscopy surveillance should start before the age of
21 and continued every 1 to 2 years. Colonoscopy frequency should
be decreased after the age of 40 or if polyp burden is increasing. A
periodic upper endoscopy should be performed in both conditions
to screen for duodenal adenomas. For HNPCC, a colonoscopy
every 1 to 2 years should be performed starting between the ages
of 20 and 25 and continued even after a partial colectomy or an
IRA is performed. Regular screening for gynecologic malignancies
should be performed. (Grade B recommendation)
7. What is the role of genetic counseling and testing in inher-
ited colorectal cancer?
To date, over 100 hereditary cancer syndromes have been reported
and each syndrome carries a degree of complexity. Currently in
Lynch syndrome alone at least five clinical criteria exist, more
than five models are available for calculating mutation probabili-
ties, and three (or more) steps are available for tumor analysis, and
germ-line testing for the multiple associated genes may include
sequencing, Southern blotting, multiplex ligation-dependent
probe amplification, and cDNA sequencing/RT-PCR expression
analyses—all of which contribute to calculation of risk assess-
ment for the disease, but may not ultimately prove or disprove
the existence of a syndrome. Genetic counselors—healthcare
professionals with graduate degrees in medical genetics/genetic
counseling—use medical histories and pedigree analyses to deter-
mine the probability of a hereditary cancer syndrome and to offer
the appropriate options of genetic tests. Patients are informed of
the risks and benefits of genetic testing including the potential
impact on the patient’s health and family members’ health. Discus-
sions also address patient concerns regarding genetic discrimina-
tion and sharing of information with family members. The NCCN
recommends genetic counseling referral for any patient likely to
carry a hereditary cancer syndrome. Genetic counseling services
are available in person or via telephone or Internet (www.nsgc.
org) and are frequently covered benefits in many health plans.3
Answer: Individuals with suspected inherited colorectal can-
cer syndrome should be referred to an experience genetic coun-
selor. Counseling will help with identification, risk stratification,
and long-term management of patients and families with these
conditions. (Grade B recommendation)
5/22/2012 5:23:14 PM
 Inherited Colorectal Cancer Syndromes ■ 265

Clinical Question Summary

Question Answer Grade of References
Recommendation
1 How prevalent are There is significant variability in the estimated prevalence of B 1, 3, 4, 6, 8
inherited colorectal inherited colorectal cancers. Based on existing studies,
cancer syndromes? approximately 5% to 7% of colon cancers have an identifiable
inherited syndrome; however, this number may only be true
for patients of European descent
2 What are the major Familial adenomatous polyposis (FAP), MYH associated B 2-5, 7-10,
inherited colorectal polyposis (MAP), and Lynch syndrome (HNPCC) account for 12-14, 36
cancer syndromes? more than 90 percent of currently identified inherited colon
cancer syndromes
3 What are the molecular Major inherited cancer syndromes identified at this point are A 2, 9, 27
mechanisms of caused by mutations in a distinct gene or genes, most often
the most common inherited in an autosomal dominant fashion. FAP is caused
inherited colorectal by a mutation in APC gene, MAP is caused by mutations in
cancer syndromes? the MYH gene, and Lynch syndrome is caused by a mutation
in one of the following: MLH1, MSH2, MSH6, PMS2 and
EPCAM (TACSTD1)
4 How should an Patients with significant family history or significant clinical B 3-4, 10, 12, 33
individual with a features should be suspected of having hereditary colorectal
suspected inherited cancer syndrome and evaluated with molecular genetic
colorectal cancer testing and should receive genetic counseling
syndrome be
evaluated?
5 What is the appropriate For most patients with FAP, total proctocolectomy with or B 19, 22-29
surgery for patient without an ileoanal pouch should be performed. Total
with inherited abdominal colectomy with an ileorectal anastomosis can be
colorectal cancer considered for patients with attenuated FAP. Prophylactic
syndrome? surgery is not indicated for patients with Lynch syndrome,
but close colonoscopic surveillance is required. Should a
colon cancer be diagnosed in a Lynch syndrome patient,
total abdominal colectomy with an ileorectal anastomosis
is generally recommended, but segmental colectomy can
be considered. In addition, a discussion about prophylactic
surgery for gynecological malignancy should be had,
especially in postmenopausal women
6 What is appropriate For FAP, a sigmoidoscopy or colonoscopy should be performed B 9, 10, 29-31,
surveillance for patient every 6 to 12 months starting at age 12 years or until polyps 34, 35, 37
with an inherited start to develop; once polyps develop, a full colonoscopy
colorectal cancer should be performed until surgery is planned. Even after
syndrome? surgery, especially an IRA, surveillance should be continued
regularly since the chance of cancer is not totally eradicated.
For patients with attenuated FAP, colonoscopy surveillance
should start before age of 21 years and continued every 1
or 2 years. Colonoscopy frequency should be decreased
after age of 40 years if polyp burden is increasing. A periodic
upper endoscopy should be performed in both conditions
to screen for duodenal adenomas. For Lynch syndrome,
a colonoscopy every 1 or 2 years should be performed
starting between the ages of 20 and 25 years and continued
even after a partial colectomy or an IRA is performed.
Regular screening for gynecological malignancies should be
performed
7 What is the role of Individuals with suspected inherited colorectal cancer B 4, 13, 15, 32,
genetic counseling and syndrome should be referred to an experienced genetic 33
testing in inherited counselor. Counseling will help with identification, risk
colorectal cancer? stratification, and long term management of patients and
families with these conditions

PMPH_CH31.indd 265 5/22/2012 5:23:14 PM

 266 ■ Surgery: Evidence-Based Practice
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5/22/2012 5:23:14 PM

Preoperative Bowel Preparation
INTRODUCTION
In many areas in medicine and surgery, decisions are often based
on tradition, dogma, and the teachings of those who have come
before us based on their experience. Not that there is anything
inherently wrong with practicing experience-based medicine
when that experience is the best available evidence upon which to
base our clinical decisions. The problem lies in the all too present
case when higher-quality evidence emerges and we find ourselves
as clinicians and surgeons tied to the ingrained dogma of our past
practice. Like many areas in this text, the topic of bowel prepa-
ration is one where significant clinical equipoise, at least from a
practice standpoint, exists. This chapter attempts to address the
issue of whether or not the best current evidence supports the
routine use of mechanical bowel preparation (MBP) for colon sur-
gery. It will also touch upon the emerging questions of periopera-
tive tissue oxygenation and fluid management when it comes to
outcomes during colon surgery.
MECHANICAL BOWEL PREPARATION
1. Does MBP prior to colon surgery affect the incidence of sur-
gical site infection (SSI) or anastomotic complications when
compared with no bowel preparation?
MBP before elective colon surgery has been the standard surgi-
cal practice for over a century.1 Many of us have grown up and
matured as surgeons in an era where MBP was the standard of
practice. Historically, for the most part, the controversy with this
topic was regarding the particular protocol used to prepare the
bowel for surgery. The theory behind MBP with or without an oral
antibiotic regimen was based on the theory that by reducing the
intraluminal contents and bacterial load, postoperative complica-
tions of anastomotic failure and infections would be reduced.1-3
The utility of bowel preparation was questioned by Hughes in
a prospective randomized trial presented in 1972. Albeit a small,
single center trial with 46 patients in the bowel preparation group
267
PMPH_CH32.indd 267
CHAPTER 32
John K. Bini
and 51 in the nonprepped group, Hughes looked at three outcome
measures: wound infection, peritonitis, and death. He found that
vigorous MBP conveyed no advantage in any of his outcome mea-
sures.4 Since Hughes’ study in 1972, multiple other studies have
been conducted refuting the efficacy of MBP.5-15 There have also
been several meta-analysis that have failed to show any positive
advantage regarding anastomotic or infectious complications
with the routine application of preoperative MBP.16-24 Of the pro-
spective trials refuting the routine use of MBP, all looked at anas-
tomotic and infectious complications.5-15
Four studies in particular standout. Bucher published a study
in the British Journal of Surgery in 2005.11 In this study, which
compared patients prepared with 3 L of polyethylene glycol as
an MBP and no preparation, postoperative complications were
recorded prospectively. They considered abdominal infectious
complications to be anastomotic leak, intra-abdominal abscess,
peritonitis, and wound infection. They found that the group who
underwent bowel preparation had an overall abdominal infec-
tious complication rate of 22%, compared with 8% of those who
did not receive a mechanical preparation. Anastomotic leak rate
in the treated group was 6% compared with 1% in the nontreated
group although this difference did not reach statistical signifi-
cance.11 Th is study also found that patients undergoing bowel
preparation had statistically significant longer lengths of hospi-
tal stay as well as a significantly higher rate of extra-abdominal
morbidity.11
A randomized clinical trial published by Pena-Soria et al.
in 2008 looked at patients undergoing elective colon or proxi-
mal rectal resection with primary anastomosis performed by a
single surgeon who was blinded to study arm.15 They analyzed
129 patients, 65 who received polyethylene glycol preparation
(Group A) and 64 who did not (Group B).15 Thirty patients (23.2%)
developed wound infection (Group A = 24.6% and Group B = 17.2%;
NS). There were three cases of intra-abdominal sepsis (Group A =
4.6%).15 The anastomotic failure rate was 5.4% (n = 7), four patients
in Group A (6.2%) versus three patients in Group B (4.7%) (NS).15
When SSI and anastomotic failure were combined, the compli-
cation rate in Group A was 35.4% versus 21.9% for Group B.15
5/22/2012 5:23:54 PM
 268 ■ Surgery: Evidence-Based Practice
Pena-Soria concluded that a single surgeon will not have a higher
rate of either SSI or anastomotic failure if he/she routinely omits
preoperative MBP.15
Contant et al. completed a multicenter noninferiority trial
that was published in The Lancet in 2007, which compared bowel
preparation with polyethylene glycol or sodium phosphate to no
bowel preparation.13 The study was performed at 13 hospitals and
they randomly assigned 1431 patients who were going to have
elective colorectal surgery to either receive MBP or not.13 Patients
who did not have MBP had a normal meal on the day before the
operation.13 Those who did were given a fluid diet, and MBP with
either polyethylene glycol or sodium phosphate.13 The primary
endpoint was anastomotic leakage, and the study was designed
to test the hypothesis that patients who are given MBP before col-
orectal surgery do not have a lower risk of anastomotic leakage
than those who are not.13 Seventy-seven patients were excluded:
46 who did not have a bowel resection; 21 because of missing
outcome data; and 10 who withdrew, cancelled, or were excluded
for other reasons.13 The rate of anastomotic leakage did not differ
between groups: 32/670 (4.8%) patients who had MBP and 37/684
(5.4%) in those who did not (difference 0.6%; 95% confidence
interval (CI), −1.7% to 2.9%; p = .69).13 Patients who had MBP had
fewer abscesses after anastomotic leakage than those who did not
(2/670 [0.3%] vs. 17/684 [2.5%], p = .001).13 Other septic compli-
cations, fascia dehiscence, and mortality did not differ between
groups and based on their findings, they advised that MBP before
elective colorectal surgery can safely be abandoned.13
Jung et al. published the results of their multicenter ran-
domized clinical trial comparing MBP with no MBP in patients
undergoing elective colon surgery.14 Their primary endpoints
were cardiovascular, general infectious, and surgical-site com-
plications within 30 days, and secondary endpoints were death
and reoperations within 30 days.14 A total of 1343 patients were
evaluated, 686 randomized to MBP and 657 to no MBP.14 There
were no significant differences in overall complications between
the two groups: cardiovascular complications occurred in 5.1% and
4.6%, respectively, general infectious complications in 7.9% and
6.8%, and surgical-site complications in 15.1% and 16.1%.14 At
least one complication was recorded in 24.5% of patients who
had MBP and 23.7% who did not.14 The authors of this study con-
cluded that MBP does not lower the complication rate and can be
omitted before elective colonic resection.14
Multiple meta-analyses and reviews exist in the current
literature that address the subject MBP.1,16-24 Four of the meta-
analyses reported statistical differences in leak rate.19-21,24 Three
meta-analyses found no significant difference between the MBP
and the no MBP groups.18,22,23
A meta-analysis published by Guenaga et al. in 2005 as a
Cochrane systematic review was an update of a previously pub-
lished review from 2003.19,21 This review included nine trials with
a total of 1592 patients.19 The primary outcome measure was anas-
tomotic leakage. Other outcomes looked at included mortality,
peritonitis, the need for reoperation, and superficial surgical site
infection. The authors of this review found a statistically higher
anastomotic leak rate in the group that received a preoperative
MBP (odds ratio [OR], 2.03; 95% CI, 1.276–3.26; p = .003).19 They
concluded that routine MBP should be eliminated as it has no
proven benefit and it may also increase anastomotic failure.19
Slim et al. published a recent meta-analysis that included 4859
patients (2452 in the MBP group and 2407 in the no MBP group)
PMPH_CH32.indd 268
and 14 clinical trials.23 Their primary outcome was anastomotic
leakage; secondary outcomes were other septic complications.
The authors of this review found no statistical difference between
the groups for anastomotic leakage (OR, 1.12; 95% CI, 0.82–1.53;
p = .46), pelvic or abdominal abscess (p = .75), and wound sepsis
(p = .11). When all SSIs were considered, the meta-analysis favored
no MBP (OR, 1.40; 95% CI, 1.05–1.87; p = .02). Slim et al. also
found that the particular regimen of MBP used did not impact
the outcome measures reviewed.23 They concluded that although
it did not confirm the harmful effect of MBP as suggested by pre-
vious meta-analyses. Their meta-analysis including almost 5000
patients demonstrated with a high level of evidence that any kind
of MBP should be omitted before colonic surgery.23
The current literature shows no clear evidence that MBP sig-
nificantly affects the incidence of SSI either positively or negatively.
However, it is clear that MBP does not increase the risk of SSI after
elective colon surgery. Concerning anastomotic complications,
again, no clear evidence exists that MBP significantly affects the
incidence of anastomotic complications. Based on available trials
and reviews, these are Grade A recommendations.
2. Are there major risks associated with preoperative MBP?
Although it is accepted that the practice of MBP is generally safe
in and of itself, there are many potential complications associated
with it especially in patients with preexisting cardiac and renal
disease. The majority of these complications, which exist in mul-
tiple case reports, although rare, are primarily due to the sequel
of severe electrolyte derangements. The electrolyte derangements
include renal failure requiring dialysis, ischemic colitis, dehydra-
tion, seizures, cardiac arrythmias, cardiac arrest, and death.25-37
There are significant and potentially lethal outcomes associ-
ated with bowel preparation in and of itself. Although the practice
of clearing the colon of contents is necessary for accurate endo-
scopic visualization, in light of no clear benefit regarding its use
prior to elective surgery, the rare but significant complications
associated with the process must be considered. The current avail-
able data support a Grade B recommendation that YES, there are
significant risks associated with preoperative MBP.
3. Should MBP be performed prior to colorectal surgery?
Despite the strong evidence that mechanical bowel preparation
does not reduce complications in elective colon surgery, many
surgeons continue to routinely prepare their patients. It is because
of this that Eskicioglu et al. embarked upon a comprehensive
review which was published in the Canadian Journal of Surgery
as a clinical practice guideline endorsed by the Canadian Society
of Colon and Rectal Surgeons in December 2010.1 These authors
reviewed 14 randomized clinical trials and 8 meta-analyses.1
Based on their findings, these authors made six clinical recom-
mendation regarding various aspects of perioperative manage-
ment of elective colorectal surgery patients.1 Importantly, they
concluded that there was good evidence to support the routine
omission of MBP for patients undergoing routine elective right-
and left-sided colon resections.1 Regarding low-anterior resection
and rectal resections with and without protective ileostomy, they
found insufficient evidence to support or refute the routine use of
bowel preparation.1
Regarding the routine use of MBP prior to elective colon sur-
gery, the majority of the evidence supports omitting the practice.
5/22/2012 5:23:55 PM

The major body of the evidence is presented in the setting of
open surgical procedures involving the colon. Specific evidence
addressing laparoscopic surgery and rectal surgery does not sup-
port recommendations either for or against MBP in these set-
tings. There are some randomized trials and meta-analyses that
report higher infectious and anastomotic complication rates in
patients undergoing MBP prior to elective surgery. However, most
evidence merely support the assertion that no advantage to MBP
exists. The procedure is uncomfortable for patients and may be
associated with rare but serious medical complications in patients
with preexisting renal and cardiac disease.1,25-37
Based on the availability of high-quality medical evidence,
the answer to the question of whether MBP should be routinely
performed prior to colorectal surgery is NO. It should also be
noted that data are mixed regarding low-rectal surgery requiring
anastomosis as one study did show an increase in pelvic abscess
with bowel preparation when a protective ostomy was not used.13
It is therefore recommended that in cases of elective colon surgery
that the practice of MBP be eliminated. In low-rectal surgery, if
diversion is not planned, MBP is probably appropriate. The litera-
ture supports this as a Grade A recommendation.
PERIOPERATIVE FLUID MANAGEMENT
4. Does intraoperative fluid volume affect the incidences of
postoperative complications and anastomotic complications in
colorectal surgery?
The effect of perioperative fluid management on outcomes in
elective colon surgery is another area that warrants critical inspec-
tion. There are a limited number of clinical studies in the last
decade that compared the effect of restrictive with liberal periop-
erative fluid volume regimens on postoperative recovery time and
complications.38-41 Patients treated with restrictive fluid manage-
ment show significantly lower increase in body weight and pass
flatus and feces earlier.38 However, data of the impact of volume
restriction on postoperative hospital stay are inconsistent.38,41
A recent animal study by Marjanovic et al. sought to deter-
mine the effect of perioperative volume management on the integ-
rity of intestinal anastomosis.38 The authors randomized 21 rats
to three experimental groups (n = 7 rats/group): control group
CO (9 mL/kg/h crystalloid infusion), volume restriction group
(3 mL/kg/h), and animals with volume overload (36 mL/kg/h). An
end-to-end small bowel anastomosis was performed with eight
nonabsorbable interrupted inverting sutures.38 At reoperation on
the 4th postoperative day, the anastomotic segment was dissected
and the bursting pressure was measured. As a second parame-
ter for the quality of anastomotic healing, hydroxyproline con-
centration was examined with a spectrophotometric method.38
Histologically, structural changes of the anastomotic segments
were assessed by two pathologists. The group found that burst-
ing pressure was lowest in volume overload and significantly
lower in volume restricted group. 38 Additionally, hydroxypro-
line concentration in volume overload group was significantly
lower compared with volume restricted group, and in all animals
with volume overload a marked submucosal edema was found.38
Marjanovic et al. concluded that the quantity of crystalloid infu-
sion, applied intraoperatively, has a significant impact on func-
tional (bursting pressure) and structural (hydroxyproline) stability
PMPH_CH32.indd 269
Preoperative Bowel Preparation ■ 269
of intestinal anastomoses in the early postoperative period and
that volume overload may have deleterious effects on anastomotic
healing and postoperative complications in digestive surgery, pos-
sibly because of a marked bowel wall edema.38
Brandstrup et al. conducted a randomized clinical trial that
investigated the effect of a restrictive fluid management strategy
versus a standard regimen on complications after colorectal sur-
gery.40 They randomized 172 patients to either a restricted or a stan-
dard intraoperative and postoperative intravenous fluid regimen.
The restricted regimen aimed at maintaining preoperative body
weight and the standard regimen resembled everyday practice.
The primary outcome measures were complications and the sec-
ondary measures were death and adverse effects.40 The restrictive
fluid regimen significantly reduced postoperative complications
both by intention-to-treat (33% vs. 51%, p = .013) and per-protocol
(30% vs. 56%, p = .003) analyses.40 The numbers of both cardiopul-
monary (7% vs. 24%, p = .007) and tissue-healing complications
(16% vs. 31%, p = .04) were significantly reduced.40 There were no
deaths in the restricted group and four deaths in the standard
group. They showed that restricted fluid management in elective
abdominal surgery significantly reduces postoperative mortal-
ity and morbidity.40 This was expressed in lower cardiopulmo-
nary (i.e., myocardial infarction, pneumonia) and tissue healing
(i.e., anastomotic failure) complications.40
Khoo et al. conducted a prospective randomized controlled
trial (RCT) of multimodal perioperative management protocol in
patients undergoing elective colorectal resection for cancer.39 Par-
ticipants were stratified by sex and requirement for a total mesorec-
tal excision and were centrally randomized.39 Protocol patients
received intravenous fluid restriction, unrestricted oral intake with
prokinetic agents, early ambulation, and fixed regimen epidural
analgesia.39 Control patients received intravenous fluids to prevent
oliguria, restricted oral intake until return of bowel motility, and
weaning regimen epidural analgesia criteria.39 The primary end-
point was postoperative stay. Secondary endpoints were postop-
erative complications, readmission rates, and mortality.39 Of the 70
patients recruited, the median stay was significantly reduced in the
protocol group (5 vs. 7 days; p = .001).39 Patients in the control arm
were 2.5 times as likely to require a postoperative stay of more than
5 days.39 Patients in the group that was fluid restricted had fewer
cardiorespiratory and anastomotic complications and two deaths,
both occurred in controls.39 These authors concluded that a mul-
timodal management protocol can significantly reduce postopera-
tive stay following colorectal cancer surgery and that morbidity and
mortality are not increased.39 Although limited in numbers of par-
ticipants, these studies indicate a higher risk for anastomotic insuf-
ficiency for patients with liberal fluid management.38-40
The available evidence in pertaining to fluid volume dur-
ing colon surgery support a Grade A recommendation that YES,
fluid volume affects the incidence of operative and anastomotic
complications in colorectal surgery. Regarding a restrictive fluid
management strategy during colorectal surgery, there are clini-
cal and laboratory data to support the practice. Although clinical
trials are few and relatively small when considering the numbers
of patients, they do favor a restrictive vice liberal perioperative
fluid management strategy.38-41 It is further recommended that
attempts should be made in hemodynamically stable patients
undergoing elective colon surgery requiring an anastomosis to
follow a restrictive fluid management strategy to minimize the
risk of anastomotic complications.
5/22/2012 5:23:55 PM
 270 ■ Surgery: Evidence-Based Practice

PERIOPERATIVE OXYGEN included atelectasis, pneumonia, respiratory failure, and mor-

ADMINISTRATION
5. Does perioperative fraction of inspired oxygen (FiO2) affect
the incidences of SSI and anastomotic complications in colorec-
tal surgery?
The perioperative administration of supplemental oxygen has
been variably reported with respect to SSIs.42-44 In 2007, Brasel and
the members of the Evidence Based Reviews in Surgery Group
determined that the risk of SSI was reduced with administration
of perioperative oxygen.42 They based their assertion largely on
the findings of a 2005 RCT by Belda et al.42,43
Belda conducted a double-blind, RCT of 300 patients aged
between 18 and 80 years who underwent elective colorectal sur-
gery in 14 Spanish hospitals.43 Patients were randomly assigned
to either 30% or 80% FIO2 intraoperatively and for 6 h after sur-
gery. Anesthetic treatment and antibiotic administration were
standardized.43 The primary outcome measure was any SSI. Sec-
ondary outcomes included the return of bowel function and the
ability to tolerate solid food, ambulation, suture removal, and
duration of hospitalization.43 SSI occurred in 35 patients (24.4%)
administered 30% FIO2 and in 22 patients (14.9%) administered
80% FIO2 (p = .04).43 The risk of SSI was 39% lower in the 80%
FIO2 group (relative risk [RR], 0.61; 95% CI, 0.38–0.98) than in
the 30% FIO2 group.43 None of the secondary outcomes varied
significantly between the two treatment groups.43 These findings
led the authors to conclude that patients receiving supplemental
inspired oxygen had a significant reduction in the risk of wound
infection, which appears to be an effective intervention to reduce
SSI in patients undergoing colon or rectal surgery.43
Most recently, Meyhoff and the PROXI Trial group conducted
a trial in 14 hospitals with 1386 patients that looked at SSI infec-
tion in patients undergoing acute or elective laparotomy.44 This
group set out to assess whether the use of 80% oxygen reduces
the frequency of SSI without increasing the frequency of pulmo-
nary complications in patients undergoing abdominal surgery.44
The PROXI trial was a patient- and observer-blinded random-
ized clinical trial.44 Patients were randomly assigned to receive
either 80% or 30% oxygen during and 2 h after surgery.44 The
primary outcome was SSI within 14 days. Secondary outcomes
tality.44 The authors found that SSI occurred in 131 of 685 patients
(19.1%) assigned to receive 80% oxygen versus 141 of 701 (20.1%)
assigned to receive 30% oxygen (OR, 0.94; 95% CI, 0.72–1.22;
p = .64).44 Atelectasis occurred in 54 of 685 patients (7.9%) assigned
to receive 80% oxygen versus 50 of 701 (7.1%) assigned to receive
30% oxygen (OR, 1.11; 95% CI, 0.75–1.66; p = .60), pneumonia in
41 (6.0%) versus 44 (6.3%) (OR, 0.95; 95% CI, 0.61–1.48; p = .82),
respiratory failure in 38 (5.5%) versus 31 (4.4%) (OR, 1.27; 95%
CI, 0.78–2.07; p = .34), and mortality within 30 days in 30 (4.4%)
versus 20 (2.9%) (OR, 1.56; 95% CI, 0.88–2.77; p = .13).44 This large
study concluded that the administration of 80% oxygen compared
with 30% oxygen did not result in a difference in risk of SSI after
abdominal surgery.44
Results of various studies and reviews provide conflict-
ing findings regarding the use of supranormal levels of oxy-
gen to reduce SSI. However, it does not appear that elevated
supplemental oxygen levels are deleterious. Certain types of
gastrointestinal surgery may benefit from higher oxygen levels.
However, no clear data exist to support the general practice of
using higher levels of oxygen than what are needed to support
systemic oxygenation.
On the subject of increased perioperative oxygen levels to
reduce SSI, results of various studies and reviews are conflict
ing. Although certain types of gastrointestinal surgery may ben-
efit from higher oxygen levels, no clear data exist to support the
general practice of using higher levels of oxygen than what are
needed to support systemic oxygenation.42-44 However, it should
be noted that there is little cost or risk associated with the use
of high oxygen levels. Also, there appears to be a mechanism for
its benefit via higher measured oxygen tension in the tissues,
improved leukocyte activity and lower bacterial counts.45 There-
fore, one may consider a higher FiO2, particularly when operating
on obese patients as they have higher SSI rate and more poorly
perfused subcutaneous tissues. Because of the conflicting data, we
can only make a Grade D recommendation regarding the rela-
tionship between perioperative FiO2 and complications following
colorectal surgery, and can only conclude that significant clinical
equipoise still exists regarding the appropriate level of oxygen to
be administered during colorectal surgery.

Clinical Question Summary

Question Answer Grade of References
Reccomendation
1 Does mechanical bowel No clear evidence exists that mechanical bowel preparation A 1, 3, 4, 5, 6,
preparation prior to significantly affects the incidence of SSI. There is some 7, 8, 9, 10,
colon surgery affect the data that suggest that SSI may be increased in patients who 11, 12, 13,
incidence of surgical site undergo mechanical bowel preparation prior to elective 14, 15, 16,
infection or anastomotic colon surgery. It is clear however that mechanical bowel 17, 18, 19,
complications when preparation does not increase the risk of SSI after elective 20, 21, 22,
compared to no bowel colon surgery. 23, 24
preparation?

(Continued)

PMPH_CH32.indd 270 5/22/2012 5:23:55 PM

 Preoperative Bowel Preparation ■ 271

(Continued)
Question
2 Are there majors risks
associated with pre-
operative mechanical
bowel preparation?
3 Should mechanical bowel
preparation be performed
prior to colorectal
surgery?
4 Does intra-operative
fluid volume affect the
incidences of post-
operative complications
and anastomotic
complications in colorectal
surgery?
5 Does peri-operative FiO2
affect the incidences of
surgical site infection and
anastomotic complications
in colorectal surgery?
Answer Grade of References
Reccomendation
No clear evidence exists that mechanical bowel preparation
significantly affects the incidence of anastomotic
complications. There is some data that suggest that
anastomotic complications may be increased in patients
who undergo mechanical bowel preparation prior to
elective colon surgery. It is clear however that mechanical
bowel preparation does not increase the risk of
anastomotic complications after elective colon surgery.
Yes. While it is accepted that the practice of mechanical bowel B 25, 26, 27,
preparation is generally safe in and of itself, there are many 28, 29,
potential risks associated with it especially in patients with 30, 31,
pre-existing cardiac and renal disease. They include renal 32, 33,
failure requiring dialysis, ischemic colitis, dehydration, 34, 35,
seizures, cardiac arrythmias, cardiac arrest and death. 36, 37
No. Routine mechanical bowel preparation should not be A 1, 3, 4, 5, 6,
performed in patients undergoing elective colon surgery 7, 8, 9,
where there is no plan to perform intra-operative 10, 11, 12,
endoscopy. 13, 14, 15,
16, 17, 18,
19, 20, 21,
22, 23, 24
Yes. Although limited in numbers of participants, clinical A 38, 39, 40,
studies indicate a higher risk for anastomotic insufficiency 41
and medical complications for patients with liberal
perioperative fluid management compared to those who
have a restrictive fluid management regimen.
Results of various studies and reviews provide conflicting D 42, 43, 44,
findings regarding the use of supranormal levels of oxygen 45
in order to reduce SSI. It does not however appear that
elevated supplemental oxygen levels are deleterious. Certain
types of gastrointestinal surgery may benefit from higher
oxygen levels, however, no clear data exist to support the
general practice of using higher levels of oxygen than what is
needed to support systemic oxygenation.

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30. Tan HL, Liew QY, Loo S, et al. Severe hyperphosphatemia and
associated electrolyte and metabolic derangement following
the administration of sodium phosphate for bowel preparation.
Anaesthesia. 2002;57:478-483.
31. Ullah N, Yeh R, Ehrinpreis M. Fatal hyperphosphatemia from a
phosphasoda bowel preparation. J Clin Gastroenterol. 2002;34:
457-458.
32. Adverse Drug Reactions Advisory Committee. Electrolyte dis-
turbances with sodium picosulfate bowel cleansing products.
Aust Advers Drug React Bull. 2002;21:1.
33. Franga DL, Harris JA. Polyethylene glycol-induced pancreatitis.
Gastrointest Endosc. 2000;52:789-791.
34. Boivin MA, Kahn SR. Symptomatic hypocalcemia from oral
sodium phosphate: A report of two cases. Am J Gastroenterol.
1998;93:2577-2579.
35. Oh JK, Meiselman M, Lataif LE, Jr. Ischemic colitis caused by
oral hyperosmotic saline laxatives. Gastrointest Endosc. 1997;45:
319-322.
36. Vukasin P, Weston LA, Beart RW. Oral fleet phospho-soda
laxative-induced hyperphosphatemia and hypocalcemic tetany
in an adult: Report of a case. Dis Colon Rectum. 1997;40:497-499.
37. Adverse Drug Reactions Advisory Committee. Electrolyte dis-
turbances with oral phosphate bowel preparations. Aust Advers
Drug React Bull. 1997;16:2.
38. Marjanovic G, Villain C, Juettner E, zur Hausen A, Hoeppner J,
Hopt UT, Drognitz O, Obermaier R. Impact of different crys-
talloid volume regimes on intestinal anastomotic stability. Ann
Surg. 2009;249:181-185.
39. Khoo CK, Vickery CJ, Forsyth N, et al. A prospective random-
ized controlled trial of multimodal perioperative management
protocol in patients undergoing elective colorectal resection for
cancer. Ann Surg. 2007;245:867-872.
40. Brandstrup B, Tonnesen H, Beier-Holgersen R, et al. Effects of
intravenous fluid restriction on postoperative complications:
Comparison of two perioperative fluid regimens: A randomized
assessor-blinded multicenter trial. Ann Surg. 2003;238:641-648.
41. MacKay G, Fearon K, McConnachie A, et al. Randomized clini-
cal trial of the effect of postoperative intravenous fluid restriction
on recovery after elective colorectal surgery. Br J Surg. 2006;93:
1469-1474.
42. Brasel K, McRitchie D, Dellinger P. Canadian Association of Gen-
eral Surgeons and American College of Surgeons Evidence Based
Reviews in Surgery. 21. The risk of surgical site infection is reduced
with perioperative oxygen. Can J Surg. 2007;50(3):214-216.
43. Meyhoff CS, Wetterslev J, Jorgensen LN, Henneberg SW, Høgdall
C, Lundvall L, et al. Effect of high perioperative oxygen fraction
on surgical site infection and pulmonary complications after
abdominal surgery: The proxi randomized clinical trial. JAMA.
2009;302(14):1543-1550.
44. Belda FJ, Aguilera L, García de la Asunción J, Alberti J, Vicente R,
Ferrándiz L, et al. Supplemental perioperative oxygen and the
risk of surgical wound infection: A randomized controlled trial.
JAMA. 2005;294(16):2035-2042.
45. Greif R, Akca O, Horn EP, Kurz A, Sessler DI. Supplemental
perioperative oxygen to reduce the incidence of surgical-wound
infection. N Engl J Med. 2000;342(3):161-167.
5/22/2012 5:23:55 PM
 Commentary on Preoperative
Bowel Preparation
To Prep or Not to Prep: What is the Question?
Donald E. Fry
The chapter by Bini entitled “Preoperative Bowel Preparation”
correctly summarizes the clinical trials over the past decade that
have demonstrated no benefit in the prevention of surgical site
infection (SSI) by using mechanical bowel preparation (MBP)
alone in elective colon surgery. This chapter and other referenced
articles have concluded that old dogma has been overturned and
that the new evidence favors the omission of MBP in the future.
To reach this conclusion requires that the history and evolution of
colon surgery be ignored. MBP remains a critical part of the con-
stellation of several interventions that are necessary for all elec-
tive colon resections. To ignore its appropriate context is to put
patients at-risk.
HISTORY OF COLON PREPARATION
In the late-1930s, sulfa compounds were developed with activity
against pathogenic bacteria. One of the earliest efforts to use sulfa
derivatives was for oral colonic antimicrobial bowel preparation.
Systemic antibiotics for the prevention of SSI had not been devel-
oped. Elective colon surgery in the 1930s was noted to have a mor-
tality rate of 10% to 12% and SSI rates greater than 80%. The reason
for the staggering rate of infection in elective colon surgery,1 and
the reason for the vigorous pursuit of oral intestinal antisepsis was
because MBP alone was ineffective in the prevention of SSI.
MBP alone has been recognized since the 1930s not to reduce
microbial concentration on the mucosal surface. Garlock and
Seley2 knew that. Firor and Poth knew it.3 The distal human col-
orectum has 1012 bacteria per gram on the mucosal surface.4 The
oral antibiotic bowel preparation was pursued through the 1950s
and 1960s, because MBP alone did not reduce SSI rates.
Finally, in the 1970s the oral antibiotic bowel preparation in
conjunction with MBP was shown to reduce SSIs when compared
to placebo controls. Washington et al.5 successfully used oral
neomycin and tetracycline, while Clarke et al.6 demonstrated the
effectiveness of oral neomycin and erythromycin base that had
been popularized by Nichols and Condon.7 MBP was necessary
to evacuate the massive microbe-laden stool bulk. MBP permitted
oral antibiotics to access and reduce the microbial concentration
at the mucosal surface.
273
PMPH_CH32.indd 273
In parallel developments of the late-1960s and 1970s, systemic
antibiotics prevented SSIs in elective colon surgery. This was first
demonstrated by Polk and Lopez-Mayor.8 In 1983, Baum et al.9
showed that additional trials of systemic antibiotics in elective
colon surgery were not necessary. Song and Glenny10 presented
evidence that perioperative systemic antibiotics need not be con-
tinued postoperatively. Through this development of systemic
antibiotics, MBP alone persisted as a practice.
Thus, in the 1970s and 1980s systemic preventive antibiotics
and the oral antibiotic bowel preparation evolved. By the 1990s,
surgeons in the United States used both methods together.11,12 The
logic was that oral antibiotics reduced luminal bacterial concen-
trations, and systemic antibiotic provided a safety net to cover
contamination of the soft tissues. Lewis provided a convincing
clinical trial and a meta-analysis of an additional 12 clinical tri-
als which demonstrated reduction (p < .0001) in SSI rates using
the oral antibiotic bowel preparation and systemic antibiotics
together, as opposed to systemic antibiotics alone.13
However, in the United States the 1990s also brought the era
of managed care. The preoperative admission day for MBP and
the oral antibiotic preparation were eliminated. MBP was to be
performed by the patient and their family at home prior to same-
day admission and operation. Compliance with MBP was poor
and negated potential benefits of orally administered antibiotics.
Patients complained about the discomfort of MBP and the oral
antibiotics (e.g., erythromycin) at home. Surgeons correctly chal-
lenged whether suboptimal MBP actually served any purpose,
and disillusionment emerged about any preparation for elective
colon surgery. This led to clinical trials which have been consis-
tent and correct in their conclusions. As was known 70 years ago,
the answer remained that MBP alone did not reduce SSIs.
WHAT IS THE QUESTION?
The real question should be “How can we improve MBP, oral anti-
biotic administration, and preoperative systemic antibiotics into
a refined strategy that gives the best outcomes?” Preoperative sys-
temic antibiotics alone have left us with an SSI rate that exceeds
20% in most studies of colon resection with 30 days of postoperative
5/22/2012 5:23:55 PM
 274 ■ Surgery: Evidence-Based Practice
follow-up.14-16 The study by Lewis13 and my own meta-analysis17
indicate that SSIs can be further reduced with MBP and oral anti-
biotic bowel preparation. The real questions are as follows:
How can we improve mechanical preparation? It must be thorough
and complete. Patients and surgeons must understand its
importance. MBP may need to extend over 2 to 3 days to be
tolerated and complete. Elderly patients may need supervised
MBP in ambulatory facilities or even an additional preoperative
day to insure completeness. Intravenous volume support may
be necessary in the elderly. Ineffective preparation is a patient
liability. Bucher et al.18 used a polyethylene glycol preparation
only 12 to 16 h before the operation. Residual polyethylene
glycol solution laden with billions of microbes will increase
SSIs if MBP is ineffective. We need better tolerated and more
effective MBP methods.
What is the best timing of oral antibiotic administration? The
oral antibiotics cannot be given simultaneously with MBP as
antibiotics will pass undissolved from the colon. MBP must be
complete before the administration of the oral antibiotics. The
best timing appears to be 18 to 24 h before the skin incision, but
that has not been tested with controlled trials.
What is the best oral antibiotic choice? Neomycin-erythromycin
has been effective as has neomycin-metronidazole. Lewis19 has
challenged whether neomycin is needed at all. There are many
drugs that are poorly absorbed that could have utility in this
clinical role. Better choices require alternative evaluation.
Is Clostridium difficile infection a risk of oral antibiotics with
MBP? A report identifies a retrospective association.20 This risk
may underscore the need for a probiotic strategy to recolonize
the patient after operation. More studies are necessary.
CONCLUSIONS
MBP alone does not reduce SSI. No further studies are needed.
The real question is whether evidence-based efforts can be gen-
erated to refine and improve oral antibiotic bowel preparation,
which must be performed in conjunction with effective MBP.
REFERENCES
1. Poth EJ. Historical development of intestinal antisepsis. World
J Surg. 1982;6:153-159.
2. Garlock JH, Seley GP. The use of sulfanilamide in surgery of the
colon and rectum. Preliminary report. Surgery. 1939;5:787.
3. Firor WM, Poth EJ. Intestinal antisepsis with special reference to
sulfanilylguanidine. Ann Surg. 1941;114:663-671.
4. Ahmed S, Macfarlane GT, Fite A, et al. Mucosa-associated bac-
terial density in relation to human terminal ileum and colonic
biopsy samples. Appl Environ Microbiol. 2007;73:7435-442.
PMPH_CH32.indd 274
5. Washington JA, II, Dearing WH, Judd ES, Elveback LR. Effect
of preoperative antibiotic regimen on development of infection
after intestinal surgery: Prospective, randomized, double-blind
study. Ann Surg. 1974;180:567-571.
6. Clarke JS, Condon RE, Bartlett JG, et al. Preoperative oral antibi-
otics reduce septic complications of colon operations: Results of
prospective, randomized, double-blind clinical study. Ann Surg.
1977;186:251-259.
7. Nichols RL, Briodo P, Condon RE, et al. Effect of preoperative
neomycin-erythromycin intestinal preparation on the incidence
of infectious complications following colon surgery. Ann Surg.
1973;178:453-459.
8. Polk HC, Jr., Lopez-Mayor JF. Postoperative wound infection: A
prospective study of determinant factors and prevention. Sur-
gery. 1969;66:97-103.
9. Baum ML, Anish DS, Chalmers TC, et al. A survey of clinical tri-
als of antibiotic prophylaxis in colon surgery: Evidence against
further use of no-treatment controls. N Engl J Med. 1981;305:
795-799.
10. Song F, Glenny AM: Antimicrobial prophylaxis in colorectal
surgery: a systematic review of randomized controlled trials.
Br J Surg. 1998;85:1232-1244.
11. Solla JA, Rothenberger DA. Preoperative bowel preparation.
A survey of colon and rectal surgeons. Dis Colon Rectum.
1990;33:154-159.
12. Nichols RL, Smith JW, Garcia RY, et al. Current practices of pre-
operative bowel preparation among North American colorectal
surgeons. Clin Infect Dis. 1997;24:609-619.
13. Lewis RT. Oral versus systemic antibiotic prophylaxis in elective
colon surgery: A randomized study and meta-analysis send a
message from the 1990s. Can J Surg. 2002;45:173-180.
14. Milsom JW, Smith DL, Corman ML, et al. Double-blind com-
parison of single-dose alatrofloxacin and cefotetan as prophy-
laxis of infection following elective colorectal surgery. Am
J Surg. 1998;176(Suppl 6A):46S-52S.
15. Itani KMF, Wilson SE, Awad SS, et al. Ertapenem versus cefo-
tetan prophylaxis in elective colorectal surgery. N Engl J Med.
2006;355:2640-2651.
16. Smith RL, Bohl JK, McElearney ST, et al. Wound infection after
elective colorectal resection. Ann Surg. 2004;239:599-607.
17. Fry DE. Colon preparation and surgical site infection. Am J Surg.
2011 (in press).
18. Bucher P, Gervaz P, Soravia C, et al. Randomized clinical
trial of mechanical bowel preparation versus no preparation
before elective left-sided colorectal surgery. Br J Surg. 2005;92:
409-414.
19. Lewis RT, Goodall RG, Marien M, et al. Is neomycin necessary
for bowel preparation in surgery of the colon? Oral neomycin
plus erythromycin versus erythromycin-metronidazole. Can
J Surg. 1989;32:265-278.
20. Wren SM, Ahmed N, Jamal A, Safadi BY. Preoperative oral anti-
biotics in colorectal surgery increase the rate of Clostridium dif-
ficile colitis. Arch Surg. 2005;140:752-756.
5/22/2012 5:23:55 PM

INTRODUCTION
Acute appendicitis remains the most common intra-abdominal
surgical emergency requiring operation. The lifetime risk of devel-
oping appendicitis is around 7% to 12%; however, the lifetime rate
of an appendectomy is 12% for men and 25% for women. Appen-
dicitis can occur at any age but is most frequently seen in patients
in their second and fourth decade of life, with a mean age of 31.3
and a median age of 22 years.1
Early reports describe a potentially lethal inflammatory dis-
ease process of the right lower quadrant (RLQ), then known as
“perityphlitis.” In 1886, Reginald Fitz2 first described this inflam-
matory disease process of the RLQ as appendicitis, including
the clinical sequelae of abscess formation and perforation. Even
today, the diagnosis of acute appendicitis remains a challenging
clinical entity. This condition is more difficult to diagnose at the
extremes of age: in the very young and elderly because of a lack of
history, late presentation and often less than impressive physical
examination. The diagnoses can also be challenging in women of
childbearing age who have a wider list of differential diagnoses.
The timely and accurate recognition of patients requiring
urgent surgical and nonsurgical management continues to be the
overriding principle in the workup and treatment of patients with
suspected appendicitis. Delays in the diagnosis and treatment of
appendicitis can result in an increased morbidity and mortality.
In addition, untimely presentation and a lack of access to emer-
gency healthcare present surgeons with complicated patients
and associated morbidities. Krajewski et al. recently published
a retrospective review that shows a significant, inverse relation-
ship between economic status and perforated appendicitis. This
study compared Canadian data of health systems with the U.S.
data, revealing that rates of perforated appendicitis in American
patients increased as income level decreases.3 As patients continue
to present, the body of evidence grows; as budgets are scrutinized
and resources strained, it seems desirable that evidence-based
guidelines ought to be developed.
In this chapter, we try to answer a few common issues that
clinicians face when dealing with the diagnosis and management
275
PMPH_CH33.indd 275
CHAPTER 33
Appendicitis
Damon Kalcich and Peter P. Lopez
of acute appendicitis. Important questions to consider in the care
of a patient with appendicitis include how to make an accurate
diagnosis, whether to treat it medically or surgically, and whether
to proceed surgically with an open or laparoscopic approach. The
answers to these questions are based on an evidence-based review
of the literature.
1. What clinical signs and symptoms are most reliable to rule
in or out appendicitis?
The history and physical examination remains the most reliable
predictor for the diagnosis of appendicitis.4 By performing a thor-
ough history and physical examination, an experienced clini-
cian can accurately diagnose acute appendicitis in the majority
of cases.5 The presentation of acute appendicitis can vary widely.
A typical patient will present with vague abdominal pain (usu-
ally epigastric region) followed by anorexia, nausea, with or
without vomiting. The pain then shifts to the RLQ as the inflam-
mation of the appendix progresses to involve the overlying perito-
neum. Common symptoms of appendicitis include periumbilical
abdominal pain and anorexia in nearly 100%, of cases, nausea in
90%, and migration of pain from the periumbilical area to the
RLQ around 50% of the time.6 Lee et al.7 reported that the most
reliable symptom in making the diagnosis of appendicitis is the
classic pattern of migratory abdominal pain from periumbilical to
the RLQ. Occasionally, patients will complain of dysuria, hematu-
ria, urgency and frequent urination, and diarrhea or constipation
from inflammation adjacent to the ureter, bladder, colon, and rec-
tum. As all clinicians have found, these clinical features are not
entirely reliable. However, the history and physical examination
continues to remain the most reliable indicator for appendicitis.
Most patients with appendicitis except the very young, very old,
and those who are neurologically impaired will have some degree
of tenderness on palpation of the abdomen. In more than 95% of
patients with acute appendicitis, the sequence of symptoms was
anorexia, followed by abdominal pain, and then vomiting.8 In
1996, a meta-analysis performed by Wagner et al.9 reported the
sensitivity, specificity, and positive likelihood ratio with a 95%
confidence interval (CI) for fi ndings on the clinical examination
5/22/2012 5:24:34 PM
 276 ■ Surgery: Evidence-Based Practice
characteristic of appendicitis. They reported the sensitivity, speci-
ficity, and positive likelihood ratio for RLQ pain (0.81, 0.53, 7.31–
8.46); fever (0.67, 0.79, 1.94); and anorexia (0.68, 0.36, 1.27).
Physical examination findings are determined by the ana-
tomic position of the inflamed appendix and whether it has
ruptured. A retrocecal appendix can give rise to tenderness in
the right flank or in the right upper quadrant, whereas a pelvic
appendix can give rise to little abdominal tenderness but pain on
rectal examination. A patient who presents with uncomplicated
appendicitis may present with a slight elevation in temperature
(by 1°C or 1.8°F) and a slight elevation in heart rate, otherwise
vital signs are normal. Patients with peritonitis will prefer to lie
still, as any motion will tend to worsen their pain. If the appendix
lies in the classic anterior position, abdominal pain will be maxi-
mal at McBurney’s point, with rebound tenderness elucidated in
the RLQ.10 Palpation of the left lower quadrant (LLQ) may cause
RLQ pain, also known as Rovsing’s sign.
Deviations from these commonly associated physical findings
usually are related to the anatomic position of the inflamed appen-
dix. The common anatomic locations of the appendix include
paracolic (the appendix lies in the right paracolic gutter lateral to
the cecum), retrocecal (the appendix lies posterior to the cecum
and may be partially or totally extraperitoneal), preileal (the
appendix is anterior to the terminal ileum), postileal (the appen-
dix is posterior to the ileum), promontoric ( the tip of the appendix
lies in the vicinity of the sacral promontory), pelvic (the tip of the
appendix lies in or toward the pelvis), and subcecal (the appendix
lies inferior to the cecum).11 Wakeley12 performed a postmortem
analysis of 10,000 cases and described the frequency of the loca-
tion of the appendix as follows: retrocecal, 65.3%; pelvic, 31%; sub-
cecal, 2.3%; preileal, 1%; and right paracolic and postileal, 0.4%.
When the appendix occupies an unusual location, the diagnosis
of appendicitis can be more difficult and may contribute to delays
in presentation, diagnosis, and treatment.
Answer: Abdominal pain often localized to the epigastrium
or periumbilical associated with anorexia and nausea is the most
reliable diagnostic finding on history and physical examination.
(Grade B recommendations)
2. What is the best laboratory test to help make the diagnosis
of appendicitis?
The use of laboratory values in diagnosing appendicitis has been
disappointing as no one test has been found to be highly sensi-
tive and specific. The white blood cell count (WBC) was found
to be of limited value for making the diagnoses of appendicitis
in one study.13 On the other hand, Anderson et al. concluded
that a leukocytosis was actually more diagnostic of advanced
or complicated appendicitis than noncomplicated acute cases.14
The sensitivity of an elevated WBC above 10,000 cells/μL for acute
appendicitis is 70–90%, but the specificity is very low.15 A value
greater than 18,000 cells/μL suggests complicated appendici-
tis with either gangrene or perforation. The diagnostic value of
C-reactive protein (CRP) and erythrocyte sedimentation rate in
diagnosing appendicitis has been both controversial and disap-
pointing.16 A recent paper by Yang et al.17 found that the use of
WBC and CRP individually or together had a high sensitivity to
differentiate patients with appendicitis but a very low specificity.
In another study in adults, the finding of a normal WBC count
and a normal CRP level was highly predictive of no appendici-
tis.18 Other studies have shown that inflammatory cytokines and
PMPH_CH33.indd 276
acute-phase reaction proteins such as interleukin-6 (IL-6), tumor
necrosis factor (TNF-alpha), lipopolysaccharide-binding protein,
alpha1-glycoprotein (alpha1GP), and endotoxin are also elevated
in this patient population. The result of many of these studies
is that these inflammatory markers are elevated in appendicitis
(high sensitivity) but that many are not specific enough to reliably
diagnose the disease.19-21 In a study, Lycopoulou et al.22 reported
the sensitivity and specificity of the use of WBC >10, (75% and
76%), CRP >10 mg/L, (62% and 94%), and serum amyloid protein
(SSA) >45 mg/L, (86% and 83%), in diagnosing acute appendicitis
in children. Procalcitonin was found to be increased in rare cases
of severe inflammation after appendiceal perforation and gangre-
nous appendicitis but because of its low sensitivity, it cannot be
recommended for the diagnosis of acute appendicitis.23
Answer: Overall, laboratory markers of acute inflamma-
tion in acute appendicitis remain highly sensitive but relatively
nonspecific when it comes to making the diagnosis of acute
appendicitis. No one test has been found to be both highly sensi-
tive and specific for reliable diagnosis of appendicitis. (Grade B
recommendations)
3. Does giving a patient with suspected appendicitis pain medi-
cine decrease the ability to make the diagnosis of appendicitis?
It has been taught that patients with abdominal pain should not
receive narcotics for fear of masking a surgical condition, such as
appendicitis in patients who present with acute abdominal pain.
In a retrospective study by Aydelotte et al., 24 charts were reviewed
for 75 patients diagnosed with acute appendicitis and were con-
firmed intra-operatively. A total of 10 men and 14 women received
narcotics prior to surgical evaluation, and 28 men and 14 women
were not given narcotics prior to surgical evaluation. In this study,
there was no statistically significant difference between the two
groups of patients in regard to the length of hospital stay, the
time to operation, complication rate, perforation rate, or negative
appendectomy rate. The authors concluded that the administra-
tion of narcotics before evaluation of the patient by a surgeon
for acute appendicitis had no effect on patient outcomes. Attard
et al. assessed the safety of early pain relief in patients with acute
abdominal pain and found that the use of analgesia did not affect
the diagnostic workup of these patients.25 A matched case–control
study performed in an emergency room (ER) with patients pre-
senting with suspected appendicitis did the early use of analgesia
delay treatment of these patient’s acute appendicitis.26 The authors
found that there was no delay in treatment with opiates but there
appears to be a delay in treatment with the use of nonsteroidal
anti-inflammatory analgesia. A prospective randomized double-
blind study of parenteral tramadol analgesic use versus placebo in
68 emergency department (ED) patients with RLQ pain resulted
in significant levels of pain control without concurrent normal-
ization of abdominal pain.27 In another prospective, double-
blind study in ED patients with undifferentiated abdominal pain,
patients were randomized to receive placebo or morphine sulfate
(MS).28 Diagnostic accuracy, however, did not differ between MS
and control groups (64.2% vs. 66.7%). These results support the
practice of early provision of analgesia to patients with undiffer-
entiated abdominal pain. A prospective double-blind crossover
study by Wolfe et al.29 also evaluated administration of morphine
to the suspected appendicitis patient and its impact on their physi-
cal examination. The authors concluded that patients with signs of
appendicitis who received morphine had significant improvement
5/22/2012 5:24:34 PM

in their pain but were without changes in their physical examina-
tion. In the pediatric population, the findings were consistent as
well. In another prospective randomized study performed in chil-
dren with a presumptive diagnosis of appendicitis, the children
were given either parenteral MS or placebo.30 The authors found
no difference in the time to surgical decision and no decrease in
pain after 30 min between morphine at a dose of 0.1 mg/kg and
placebo. A separate randomized study in children with acute
abdominal pain concluded that morphine was found to effectively
reduce the intensity of pain and did not seem to impede the diag-
nosis of appendicitis.31
Answer: Giving pain medicine to adults and children sus-
pected of acute appendicitis does not adversely affect the ability to
diagnosis appendicitis. Analgesia should not be withheld pending
clinical investigation in patients with suspected acute appendicitis.
(Grade B recommendation)
4. What is the best diagnostic imaging modality to diagnose
acute appendicitis?
Many different radiologic modalities have been used to diag-
nose acute appendicitis. The optimal radiologic technique used
to diagnose acute appendicitis should be accurate, quick, safe,
readily available, cost efficient, and should provide little risk or
discomfort to the patient. The use of abdominal ultrasound (US)
and computed tomography (CT) has proven extremely useful in
diagnosing this disease. However, routine use of these modalities
in all patients with suspected appendicitis is not well established.32
Despite the recent increase in their use, these tests have not consis-
tently increased the diagnostic accuracy of making the diagnosis
of acute appendicitis in all patient populations.
The use of plain radiography for diagnosing acute gastrointes-
tinal diseases has been around since the early 1900s. The appear-
ance of an opaque fecalith in the RLQ is often quoted as being the
hallmark radiographic finding in acute appendicitis, but less than
5% to 8% of patients present with this finding.33 Other common
but nonspecific findings on plain fi lms include localized paralytic
ileus, loss of the cecal shadow, blurring of the right psoas muscle,
and rightward scoliosis of the lumbar spine.34 In a recent study
of 821 consecutive patients hospitalized for suspected appen-
dicitis, no individual radiographic finding was highly sensitive
or specific in ultimately making the diagnosis of appendicitis.35
Plain abdominal radiographs may be indicated when other acute
abdominal conditions such as gastric or duodenal perforation,
intestinal obstruction, or ureteral calculus are part of the differ-
ential as the cause of the RLQ abdominal pain.36 Overall, plain
abdominal radiographs are not cost effective and lack both sensi-
tivity and specificity in the diagnosis of appendicitis.
Deutsch and Leopold37 first visualized the inflamed appendix
using US in 1981. US has become a more frequently used radio-
logic test to rule out appendicitis in children and pregnant women
because of concerns toward exposure to ionizing radiation from
CT scans. Its accuracy in diagnosing appendicitis has been ham-
pered by the interference of the US image by overlying bowel gas, the
slow development of a transducer with enough spatial resolution
to pick up small structures such as the appendix as well as the
highly variable operator-dependent interpretation and techni-
cal expertise at individual hospitals.38 With the advancement in
US technology and the use of the graded compression technique
when scanning the RLQ, the ability to visualize the appendix has
improved. The graded compression technique involves applying
PMPH_CH33.indd 277
Appendicitis ■ 277
steady, gradual pressure to the RLQ in an effort to collapse the
normal bowel and eliminate bowel gas in the area in order to visu-
alize the appendix. The inflamed appendix when seen by US com-
monly includes the following findings: an appendix of 7 mm or
more in an anteroposterior diameter, an immobile, thick-walled,
noncompressible luminal structure seen in cross-section referred
to as a target lesion, or the presence of an appendicolith, a blind-
ending structure consisting of anechoic lumen surrounded by
mucosa, and a hypoechoic thickened wall adjacent to the cecum.39
Despite these well-described US findings, there is no evidence-
based standard of findings by which an individual radiologist can
use to make the diagnosis of appendicitis. In a prospective study
by Rettenbacher et al.40 using US to diagnose appendicitis, the
authors used six different US findings. Unfortunately, they did not
state the number of these findings necessary to make their diagno-
sis of appendicitis. In a recent systemic review of the use of US to
diagnose acute appendicitis in adults and adolescent patients, the
accuracy of using graded compression US was reported to have an
overall sensitivity of 0.86 (CI, 0.83–0.88) and a specificity of 0.81
(CI, 0.78–0.84) with a positive likelihood ratio 5.8 (CI, 3.5–9.5).41
US is most reliable in centers with considerable experience
using this modality to diagnose acute appendicitis. In a meta-
analysis looking at the sensitivity and specificity of US in diag-
nosing appendicitis in adults and children, the results are as
follows: for U/S in children 88% sensitivity and 94% specificity,
and for U/S in adults 83% sensitivity and 93% for specificity.42 In
another study reporting on the sensitivity and specificity of U/S
in making the diagnosis of appendicitis in adults and children,
it was reported an overall 83% sensitivity and 98% sensitivity.43
The sensitivity (range 66–100%) and specificity (range 95–96%)
of US in diagnosing acute appendicitis in pregnant patients are
reported.44 However, it is recommended that if an U/S is negative
or inconclusive in a pregnant patient with a suspected diagnosis
of appendicitis, another imaging study such as CT or magnetic
resonance imaging (MRI) should be performed.45
CT has been used as a diagnostic modality for acute abdomi-
nal pain since it became available in the late 1970s. Helical CT
scans have excellent resolution, are widely available, are opera-
tor independent, and are easy to interpret making them often
the preferred diagnostic test to rule out appendicitis. Find-
ings strongly suggestive of acute appendicitis on a standard
abdominal CT scan include (1) a thick wall (>2 mm), often with
“targeting” (concentric thickening of the inflamed appendix wall);
(2) increased diameter of the appendix (>7 mm); (3) an appendi-
colith; (4) a phlegmon or abscess; or (5) free fluid.46 Stranding
of the adjacent fatty tissues in the RLQ is also commonly asso-
ciated. The top four CT findings suggestive of appendicitis are
an enlarged appendix, appendiceal wall thickening, appendiceal
wall enhancement, and periappendiceal fat stranding.47,48 If air
is seen in the appendix or if the appendiceal lumen is fi lled with
contrast and there are no other abnormalities seen on a CT,
these fi ndings virtually eliminate appendicitis as the diagnosis.
It has been thought that appendicitis could not be excluded if
the appendix was not visualized on a CT scan. A more recent
report, however, concluded that nonvisualization of the appen-
dix on a CT scan was negative for appendicitis in 98% of cases.49
CT is also useful in diagnosing an appendiceal abscess and can
be used to guide percutaneous drainage. CT can also be helpful
in diagnosing other causes of acute abdominal pain in patients
suspected of acute appendicitis.
5/22/2012 5:24:34 PM
 278 ■ Surgery: Evidence-Based Practice
The performance of CT scans to evaluate the RLQ pain has
increased considerably since Rao et al.50 reported an accuracy rate
of 98% with administration of rectal contrast in diagnosing acute
appendicitis. Rao also reported that the use of CT at his institu-
tion decreased the rate of removal of a normal appendix from
20% before the introduction of CT scanning to 7% after.51 Other
authors have not found CT to be as accurate. Perez et al.52 found
the accuracy of CT in diagnosing appendicitis to be 80%. Morris
et al.53 reported a diagnostic accuracy of 90% at their institution.
In a study performed by Holloway et al.,54 using a well-defined CT
imaging protocol as an adjunct to the clinical diagnosis of acute
appendicitis, they found the accuracy of CT to be 97.8% with a neg-
ative appendectomy rate of 3%. These same authors also reported
on 104 patients who underwent appendectomy without their CT
protocol who had a negative appendectomy rate of 12.5%. In a ret-
rospective review of CT use in the pediatric population suspected
of appendicitis, a normal appendix was removed in 7% of chil-
dren who underwent CT prior to appendectomy, 11% with the use
of US prior to appendectomy, and an 8% negative appendectomy
rate when no preoperative radiologic study was performed.55 In a
recent retrospective study, the use of preoperative CT scans only
decreased the negative appendectomy rate for women of child-
bearing age (women 45 years and younger).56 Livingston et al.57
found that the rate of nonperforated appendicitis increased since
1995 with the liberal use of CT scans but the rate of perforated
appendicitis also increased during the same period. Krajewski
et al.58 showed that the incidence of perforated appendicitis was
higher for lower socioeconomic patients than that of the patients
in the higher socioeconomic group in the United States from 2001
to 2005 but those same authors found no difference in perforated
appendicitis rates between the lower and higher socioeconomic
patients in Canada.
Although many studies have found CT to be accurate in
diagnosing acute appendicitis, there is still controversy regarding
the optimal technique. Three common techniques used include a
focused appendiceal CT using rectally administered contrast, the
unenhanced or the use of oral and/or intravenous contrasted CT
of the abdomen and pelvis. Every institution has their own prefer-
ence to which version they prefer to use to diagnose appendicitis,
all of which seem to have the same reported accuracy.59,60
In a systemic review performed by van Redan et al.61 compar-
ing graded compression US with CT in the diagnosis of appendi-
citis, the authors found that the respective mean sensitivities for
CT and graded compression US were 91% (95% CI, 84%, 95%) and
78% (95% CI, 67%, 86%) (p < 0.017) and the respective mean speci-
ficities for CT and graded compression US were 90% (95% CI, 85%,
94%) and 83% (95% CI, 76%, –88%) (p < 0.037). Calculated posi-
tive OR or Odds Ratio for CT and graded compression US were
9.29 (95% CI, 6.86, 12.58) and 4.5 (95% CI, 3.03, 6.68), respectively
(p = 0.011) The authors from their meta-analysis of head-to-head
comparison studies in patient populations with a high prevalence
of appendicitis concluded that CT was found to have a better test
performance than the graded compression US in making the
diagnosis. The authors recommend the use of CT in patients sus-
pected of acute appendicitis.
Should CT be used routinely in the diagnostic evaluation
of patients suspected of appendicitis? Because of the increasing
reports of excellent accuracy rates of CT diagnosing appendicitis,
some have called for the routine use of CT for all patients with
possible appendicitis.52,62-64 Others have questioned the need for
PMPH_CH33.indd 278
the routine use of CT for all patients especially those with clas-
sic clinical presentations. McCay and Shepherd65 recommended
only ordering CT on patients presenting to the ER suspected of
having appendicitis if their Alvarado score66 is between 4 and 6.
For a score of less than 3, no CT or U/S was recommended as
appendicitis was doubtful. The authors do, however, recommend
a surgical consult for an Alvarado score of 7 or more. In a pro-
spective randomized study of patients presenting to the ER for
possible appendicitis comparing clinical assessment versus CT,
the reported diagnostic accuracy was 90% for clinical assessment
and 92% for CT.67 The authors concluded that clinical assessment
unaided by CT reliably identifies patients with acute appendici-
tis who need an operation. They do not advocate the routine use
of CT for diagnosis of suspected appendicitis. In our prospective
randomized study performed in women of childbearing age who
presented to the ER with the suspected diagnosis of appendicitis,
patients were randomized to the clinical assessment only arm or
the CT arm.68 In this study, the reported accuracy for the diagno-
sis of appendicitis was 93% for both clinical assessment and CT.
The authors concluded that a CT scan is as good as clinical assess-
ment alone and reliably identifies women of childbearing age
who need an appendectomy. In a recent retrospective study, the
negative appendectomy rate for patients who had a CT scan prior
to appendectomy was 6%. The negative appendectomy rate was
unchanged for patients who underwent an appendectomy based
on clinical examination alone.69 The study also found that preop-
erative CT scans increased the appendectomy rate only in patients
with a low clinical suspicion of appendicitis. In a retrospective
study in children reported by Martin et al.,70 the liberal use of CT
scans did not decrease the negative appendectomy rate. In con-
clusion, the selective use of CT scans seems more appropriate in
diagnosing suspected appendicitis. This study should be reserved
as an adjunct in clinical settings in which other sources of pathol-
ogy other than appendicitis may cause pain or the clinical history
alone is not helpful in making the diagnosis.
MRI for the evaluation of acute appendicitis has been per-
formed more frequently recently in order to avoid the risks asso-
ciated with ionizing radiation. MRI has become a frequently
performed test in pregnant women and children with symptoms
of appendicitis and a nondiagnostic US.71 MRI has good reso-
lution and has been shown to be accurate in diagnosing acute
appendicitis.72 MRI is considered positive for acute appendicitis
when the appendix is enlarged (>7 mm); the appendiceal wall
is thicker than 2 mm, or there are signs of inflammatory changes
surrounding the appendix, such as fat stranding, phlegmon, or
abscess formation.73 MRI has been shown to be safe and reliable
in diagnosing acute appendicitis in pregnant patients.74,75 No IV
contrast should be given to pregnant patients because gadolinium
is a category C drug and potentially teratogenic.
In a recent multicenter diagnostic study of MRI in patients
with suspected appendicitis, the authors suggest that if MRI
is found to be sufficiently accurate in the general population of
patients with suspected appendicitis, MRI could replace CT in
some or all patients. This could limit or obviate the ionizing radia-
tion exposure and decrease the risk of contrast medium-induced
nephropathy with CT.76 Limitations to the use of MRI are that it is
a more expensive test, MRI is not always widely available, images
can be degraded by motion, and a specialist needs to interpret the
MRI images. Until these limitations can be overcome, MRI should
not be a first-line test to rule out appendicitis.
5/22/2012 5:24:34 PM

Answer: The most accurate imaging modality for making the
diagnosis of appendicitis is CT. The routine use of performing CT
on all patients suspected of appendicitis cannot be recommended
at this time. (Grade B recommendation)
5. Does giving antibiotics to patients with appendicitis who
undergo appendectomy decrease postoperative infectious
complications?
Appendicitis once diagnosed is usually followed by an appen-
dectomy. Antibiotics should be given as soon as the diagnosis is
suspected. The bacteria that populate the appendix are similar to
the bacterial flora of the colon. The antibiotics chosen for patients
with appendicitis should provide coverage for gram-negative and
gram-positive aerobic and anaerobic bacteria, along with anaer-
obes. Bacteriodes fragilis and Escherichia coli are the two most
common organisms grown from peritoneal cultures after acute
appendicitis.
Acute appendicitis is a polymicrobial infection. In 1938,
William Altemeier isolated at least four different organisms per
specimen in patients with perforated appendicitis.77 More recent
reports demonstrate on average up to 12 organisms per specimen
from patients with gangrenous or perforated appendicitis.78 Few
bacteria are cultured from the peritoneal fluid of patient’s with
acute appendicitis only; however, bacteria are recovered from
peritoneal fluid in over 80% patients with a gangrenous or per-
forated appendix. Two common postoperative complications fol-
lowing appendectomy are wound infections and intra-abdominal
abscesses. Prior to the use of antibiotics, there was a 10% to 40%
rate of wound infections and intra-abdominal abscesses after
appendectomy.79,80
All patients undergoing appendectomy for acute appendicitis
should receive antibiotics preoperatively.81 The use of antibiotics to
reduce postoperative morbidity following appendectomy has been
studied. Gorbach in his review of antimicrobial prophylaxis for
appendectomy reported a reduction in the rate of postoperative
infectious complication in all operations for acute appendicitis and
especially in patients with perforated and/or gangrenous appendi-
citis.82 In another analysis of clinical studies by Pottecher et al.,83
they reported that a single preoperative dose of systemic antibiotic
reduced the postoperative sepsis rates after appendectomy. They
also reported that if the appendix was perforated, then antibiotic
therapy should last longer than one dose and should not be con-
sidered prophylaxis but treatment. In a study by Mui et al., a single
dose of preoperative antibiotics was found to be adequate for the
prevention of postoperative infective complications in patients
with nonperforated appendicitis.84 Another study also supported
the fact that only one preoperative dose of antibiotic is needed to
prevent postoperative infectious complications in patients with
nonperforated appendicitis and the use of any further postopera-
tive antibiotics does not decrease the rate of surgical site infections
(SSI).85 Patients with perforated and complicated appendicitis can
be treated with antibiotics for 5–7 days.86
Anderson et al. performed a meta-analysis of randomized or
controlled clinical trails investigating the use of antibiotics ver-
sus placebo for patients with suspected appendicitis who under-
went an appendectomy.87 The authors evaluated 45 studies with
9576 patients. Their outcome measures were wound infection,
intra-abdominal abscess, hospital length of stay, and mortality.
They concluded that the use of antibiotics is superior to placebo
PMPH_CH33.indd 279
Appendicitis ■ 279
in preventing wound infection and intra-abdominal abscesses
in patients with acute, gangrenous, and perforated appendicitis.
They were unable to determine the optimal duration of antibiotic
treatment for complicated cases from their analysis. The authors
found that a single dose of antibiotics may have the same impact
as multiple doses, although it is best to administer the first dose of
antibiotics preoperatively. The choice of antibiotic selection should
be based on the bacteriology of appendix and provide a coverage
for gram-negative, gram-positive, and anaerobic organisms.
A recent prospective study by Fraser et al. of pediatric patients
with perforated appendicitis examined early transition to oral
antibiotics in comparison with a traditional 5-day intravenous
antibiotic course. Patients were transitioned to oral antibiot-
ics as soon as they tolerated a diet and discharged, to complete
a total 7-day regimen of IV/PO antibiotics. This group had no
increased morbidity compared with the group receiving 5 days of
IV antibiotics.88
Answer: Antibiotic prophylaxis is effective in preventing
postoperative wound infections and intra-abdominal abscesses.
For nonperforated appendicitis, the one-time preoperative dose of
antibiotic seems to be sufficient to decrease infectious complica-
tions. The optimal duration of administration of antibiotic needs
to be further evaluated in patients with complicated appendicitis.
(Grade B recommendation)
6. What operation is better for treating acute appendicitis:
laparoscopic (LA) or open appendectomy (OA)?
The treatment for acute appendicitis has been to perform an
appendectomy through a RLQ incision since its introduction by
McBurney89 in 1894. The first LA was performed by Semm90 in
1983. This new surgical technique was slow to be accepted because
the standard open technique provided excellent therapeutic effi-
cacy combined with its low morbidity and mortality rates. The
use of LA varies considerably. It seems that the most important
determinate of whether a patient will have an open or an LA is
the preference or the experience of the treating surgeon, which
may vary significantly even within an institution.91 During the
traditional OA technique performed through a muscle split-
ting incision in the RLQ, the appendix is usually ligated with an
absorbable suture. Inversion of the appendiceal stump has been
advocated to prevent leakage and fistulization, but studies have
shown no difference in complication rates between inversion and
simple ligation of the appendiceal stump.92 The peritoneal cavity
is typically irrigated after an appendectomy. The skin incision is
normally closed without complications, although if the wound is
grossly contaminated, one may consider delayed primary closure
or simply allow the wound to heal by secondary intention.93 Leav-
ing an intraperitoneal drain has not been shown to be useful even
in cases of a perforated appendix.94
Is LA better than OA? The answer to this question depends
on the outcomes being measured. Over the last 20 years, various
studies have looked at the duration of operation, the cost of opera-
tion, the cost of hospitalization, the length of hospital stay, the
time to return to work, and postoperative pain often with conflict-
ing results.95-98 Although many of the randomized control trails
(RCTs) comparing LA and OA are plagued by several biases, they
represent the best evidence available.
Two early meta-analyses of LA versus OA for acute appen-
dicitis have confirmed the benefit of the laparoscopic approach
5/22/2012 5:24:34 PM
 280 ■ Surgery: Evidence-Based Practice
in relation to less pain, a faster recovery, and a lower incidence
of wound infections compared with OA.99,100 As surgeons become
more skilled in minimally invasive surgical techniques, the inci-
dence of LA has become more common.101 Reported complications
after LA include injury to bowel, bladder, and ureter, bleeding
from epigastric vessels, iliac vessels, and mesentery, appendiceal
stump leak, wound infection, and intra-abdominal abscess. One
of the reported complications of LA is leaving a long stump and
risking recurrent symptoms.102
The Cochrane Library published a systemic review of ran-
domized clinical trails comparing open with LA in 2010.103 This
review included randomized clinical trials comparing LA versus
OA in adults and children. The authors included 67 studies, of
which the majority of (56) studies compared laparoscopic (with
or without diagnostic laparoscopy) versus OA in adults. The
authors reported that wound infections were less likely after LA
than after OA (OR 0.43; CI, 0.34–0.54), but the incidence of intra-
abdominal abscess was increased after LA (OR 1.87; CI, 1.19–2.93).
The duration of LA was 10 min (CI, 6–15) longer to perform than
of OA. Pain on post-op day 1 was reduced by 8 mm (CI, 5–11 mm)
on a 100-mm visual analog scale after LA compared with OA. Hos-
pital stay was shortened by 1.1 day (CI, 0.7–1.5) after LA. Return to
normal activity, work, and sports occurred earlier after LA than
after OA. Although the operation costs of LA were significantly
higher, the costs outside the hospital were reduced. Diagnostic
laparoscopy reduced the risk of a negative appendectomy, but
this effect was stronger in fertile women (RR 0.2; CI, 0.11–0.34)
as compared with unselected adults (RR 0.37; CI, 0.13–1.01). The
authors concluded that in clinical settings where surgical exper-
tise and equipment are available and affordable, LA seems to hold
various advantages over OA. They recommend that LA be done for
patients with suspected appendicitis especially in young patients,
female patients, obese patients, and employed patients.
Answer: The data supports the use of performing LA for
patients with acute appendicitis if the surgical expertise and
equipment are available. (Grade B recommendation)
7. Is interval appendectomy necessary?
Patients presenting with a periappendiceal mass or abscess diag-
nosed preoperatively by physical examination or imaging studies
can be treated with antibiotics with the potential of having their
periappendiceal abscess drained by image-guided percutaneous
catheter.104 With the increased use of CT in the workup of acute
appendicitis, the ability to identify complicated appendicitis pre-
operatively has allowed for the utilization of initial nonoperative
therapy.105 Generally, antibiotics for 7 to 14 days with or without
catheter drainage have been necessary to treat those patients. An
interval appendectomy has been advocated after the abscess and
surrounding inflammation have resolved, usually 6 to 8 weeks
after initial nonoperative treatment to prevent recurrent appendi-
citis and to treat other tumor pathology of the cecum and appen-
dix.106 Alternative treatment options of complicated appendicitis
have included early aggressive resection,107 or initial conservative
treatment with interval appendectomy only if symptoms recur.108,109
Immediate appendectomy may be technically demanding because
of the distorted anatomy and the challenges faced when closing an
inflamed/necrotic appendiceal stump. Many times, the immedi-
ate exploration ends up with an ileocecal resection or a right-sided
hemicolectomy due to inflammation distorting the tissue planes or
PMPH_CH33.indd 280
a suspicion of malignancy. Following successful nonsurgical treat-
ment of a periappendiceal mass, the need for interval appentectomy
(IA) has recently been questioned as the risk of recurrence is rela-
tively small (0.2–7%).8,110,111
In two other recent retrospective studies, it was found that chil-
dren presenting with complicated appendicitis could be successfully
treated with conservative treatment followed by appendectomy.112,113
Roach et al.114 concluded from their data that children who presented
with prolonged symptoms and a discrete appendiceal abscess or
phlegmon, drainage, and performance of a delayed appendectomy
should be the treatment of choice. In another study, children with
complicated appendicitis were initially treated nonoperatively and
then had a laparoscopic interval appendectomy; the conclusion
was that the surgery could be safely performed, and was associated
with a shorter hospital stay, with minimal morbidity, analgesia, and
scarring. These authors recommended that interval LA be routinely
performed because it eliminates the risk of recurrent appendicitis
and serves to excise undiagnosed carcinoid tumors.115 Another
group compared initial LA with initial nonoperative management
and interval appendectomy for complicated appendicitis in chil-
dren in a randomized prospective study.116 These authors found that
the initial laparoscopic surgery took longer but that the overall days
in the hospital, infection rates, and total costs did not differ between
the two treatment strategies.
In a large retrospective study performed by Kaminski et al.,117
32,938 patients were hospitalized with acute appendicitis. Emer-
gency appendectomy was performed in 31,926 (97%) patients.
Nonoperative treatment was used initially in 1012 patients (3%). Of
these, 148 (15%) had an IA and the remaining 864 (85%) did not. In
their study, only 39 patients (5%) had a recurrence of appendicitis
after a median follow-up of 4 years. Males were more likely to have
a recurrence of their symptoms than females. Median length of
hospital stay was 4 days for the admission for recurrent appendicitis
compared with 6 days for the IA admission. The authors concluded
that they cannot justify the practice of routine interval append
ectomy after initial successful nonoperative treatment of appendi-
citis based on the observation that most patients undergo appen-
dectomy initially, and those who are treated nonoperatively have
a low recurrence rate of appendicitis. In a similar retrospective
study in children reported by Paupong et al.,118 there were 6439
patients, of which 6367 (99%) underwent initial appendectomy for
acute appendicitis. Seventy-two (1%) patients were initially man-
aged nonoperatively and 11 patients had IA. Of the remaining 61
patients without IA, 5 (8%) developed recurrent appendicitis. The
authors concluded that because recurrent appendicitis is rare in
children after successful nonoperative treatment of perforated
appendicitis, performance of routine interval appendectomy is
not necessarily indicated.
Adult patients who present with an appendiceal mass in the
RLQ are commonly managed nonoperatively and then scheduled
for an interval appendectomy following resolution of the inflam-
matory appendiceal mass. This mass could represent a perforated
appendix, complicated Crohn’s disease, or a perforated colon can-
cer. Tekin et al.119 reported their experience with not performing
routine interval appendectomy after successful treatment of an
appendiceal mass. Four patients (4%) in their series had another
diagnosis found for their appendiceal mass (two cecal cancers, one
cecal diverticulitis, and one Crohn’s disease). The recurrence rate
of appendicitis in their series was 14.6% with most recurrences
happening in the first 6 months after initial presentation. Patients
5/22/2012 5:24:34 PM

who present with recurrent symptoms should undergo interval
appendectomy. They concluded that routine interval appendec-
tomy after initial successful conservative treatment is not justi-
fied but they recommend that a protocol should be developed for
the management of patients presenting with an appendiceal mass.
Similar recommendations were reported by Lai et al.120 In their
study, five patients were found to have colon cancer, and the rate
of recurrent appendicitis was 25.5% with 83% of patients present
with recurrent symptoms within 6 months of their initial pre-
sentation. They recommend that adult patients who recover from
conservative treatment of an appendiceal mass should undergo
colonoscopy to detect any underlying disease and interval appen-
dectomy should only be offered to patients who present with
recurrent symptoms.
Stevens and de Vries121 reported on their experience of per-
forming an interval appendectomy only after symptoms developed
rather than routinely offering it to their patients with complicated
appendicitis. They concluded that the rate of appendectomies
performed dropped by 63% and the total length of hospital stay
also decreased by 4 days. A group from China reported that by
performing an interval appendectomy only after symptoms devel-
oped was more cost effective than performing routine interval
appendectomy.122 In their study, the authors showed that perfor-
mance of routine interval appendectomy would increase the cost
per patient by 38% compared with follow-up and appendectomy
after recurrence of symptoms.
In a systemic review of the nonsurgical treatment of appen-
diceal abscess or phlegmon, the need for an interval appendectomy
was evaluated.123 Findings from the meta-analysis: nonsurgical
treatment fails in 7.2% of cases (CI, 4.0–10.5), the risk of recurrent
symptoms is 7.4% (CI, 3.7–11.1), the risk of finding malignant disease
is 1.2% (CI, 0.6–1.7), and the risk of finding an important benign
disease is 0.7% (CI, 0.2–11.9) during follow-up. From their meta-
analysis (mainly from retrospective studies), the authors support
the practice of nonsurgical treatment without interval appendec-
tomy in patients with appendiceal abscess or phlegmon. Another
recent systemic review has confirmed that nonoperative manage-
ment of complicated appendicitis will be successful in the majority
of cases with a low incidence of recurrent symptoms. As a result, the
routine use of interval appendectomy is no longer justified.124
Answer: The routine performance of interval appendectomy
after nonoperative treatment of complicated acute appendicitis
is not supported. Interval appendectomy should be performed
when patients present with recurrent symptoms. Patients present-
ing with an appendiceal mass managed conservatively should
undergo further workup to rule out other pathologies for their
mass. (Grade B recommendation)
8. Should antibiotic treatment replace appendectomy for acute
appendicitis?
Nonoperative treatment of acute appendicitis with antibiotics
alone has been reported to be successful.125,126 Andersson writes that
an increasing amount of circumstantial evidence suggests that
not all patients with appendicitis will progress to perforation and
that resolution may be a common event.127,128 Other evidences
of resolving appendicitis are reports of a history of recurrence,
obviously a consequence of spontaneous resolution, which can be
found in up to 6.5% of patients not operated on for appendici-
tis.129 In the past, appendectomy has been associated with higher
PMPH_CH33.indd 281
Appendicitis ■ 281
morbidity and mortality especially in older patients, those with
perforation and sepsis, and those who have a normal appendix
at the time of appendectomy. To date, unfavorably high rates of
recurrent symptoms of appendicitis (up to 70% at 1 year) have
been reported in patients who have received antibiotic treatment
alone for their acute appendicitis.130,131
In 1995, Eriksson and Granstrom132 reported an RCT of
appendectomy versus antibiotics alone in 40 patients suspected
to have appendicitis, who presented with abdominal pain for less
than 72 h. Twenty patients underwent surgery and 20 patients
received intravenous antibiotics for 2 days, followed by an 8-day
course of oral antibiotics. The authors concluded that antibiotic
treatment in patients with acute appendicitis was as effective as
surgery. However, they reported a 15% negative appendectomy
rate for the surgery group and a 40% recurrence rate of appen-
dicitis that led to appendectomy within 1 year of treatment in
the nonoperative group. A recent multicenter trial randomly
allocated 252 male patients (age 18–50) to either antibiotic treat-
ment (intravenous cefotaxime and tinidazole for 2 days followed
by oral ofloxacin and tinidazole for 10 days) or appendectomy
for acute, uncomplicated appendicitis. The trial concluded that
antibiotic treatment could serve as an alternative to appendecto-
my.133 The complication rate among the surgery group was 14%
(17/124), mainly wound infections. Of the 128 patients enrolled
in the antibiotic group, 15 patients (12%) were operated on within
the first 24 h due to the lack of improvement in symptoms and
apparent local peritonitis. The operation showed that seven of
these patients (5%) had a perforation of their appendix. The rate
of recurrence of appendicitis in the antibiotic group was 14%. In
another meta-analysis of antibiotic therapy versus appendectomy
for acute appendicitis, the authors concluded that even though
antibiotics may be used as primary treatment for selected patients
with uncomplicated appendicitis, they do not feel that this treat-
ment should supersede appendectomy at the present time.134 They
found that selection bias and crossover to surgery in the RCTs
suggest that appendectomy is still the gold standard therapy for
acute appendicitis.
A total of 113 patients were successfully treated with antibiotics
and were sent home for oral antibiotic therapy for 10 days. The recur-
rence rate within 1 year was 15% (16 patients) in the group treated
with antibiotics. Overall, the success rate of conservative manage-
ment of acute appendicitis with antibiotics is ~70% at best for male
patients with unequivocal clinical and laboratory signs of uncom-
plicated appendicitis. In another recent randomized clinical trail
of antibiotic therapy versus appendectomy for acute appendicitis in
unselected patients, the authors concluded that antibiotic treatment
appears to be a safe first-line therapy in unselected patients with
appendicitis.135 In this study, only 52% of patients randomized to
antibiotics were followed up through. In both of these studies, the
conclusions have, however, been made on the basis of only 1 month
to 1 year of follow-up data. The continued lifetime risk for, and the
associated morbidity and mortality of, nonoperative treatment with
antibiotics only for acute appendicitis remains unknown and needs
to be investigated. The recommendation of antibiotic treatment as
an alternative to the surgical treatment of acute appendicitis cannot
be recommended at this time.136
Answer: Although antibiotics may be used as the primary
treatment for selected patients with uncomplicated appendicitis,
surgery continues to remain the primary treatment option for the
treatment of acute appendicitis. (Grade B recommendation)
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 282 ■ Surgery: Evidence-Based Practice

Clinical Question Summary

Question Answer Level of Grade of References
evidence Recommendation
1 What clinical signs Abdominal pain often localized to the 4 C 4-12
and symptoms epigastrium or periumbilical region and
are most reliable associated with anorexia and nausea is
to rule in or out the most reliable diagnostic findings on
appendicitis? history and physical examination.
2 What is the best Overall laboratory markers of acute 2b B 13-23
laboratory test inflammation in acute appendicitis remain
to help make highly sensitive but relatively nonspecific
the diagnosis of when it comes to making the diagnosis
appendicitis? of acute appendicitis. No one test has
been found to be both highly sensitive and
specific for acute appendicitis.
3 Does giving a patient Giving pain medicine to adults and children 3b B 24-31
with suspected suspected of acute appendicitis does not
appendicitis pain adversely affect the ability to diagnose
medicine decrease appendicitis. Analgesia should not be
the ability to make withheld pending clinical investigation
the diagnosis of with suspected acute appendicitis.
appendicitis?
4 What is the best The most accurate imaging modality for 2b B 32-74
diagnostic imaging making the diagnosis of appendicitis is CT.
modality to diagnose The routine use of performing CT on all
acute appendicitis? patients suspected of appendicitis cannot
be supported at this time.
5 Does giving antibiotics Antibiotic prophylaxis is effective in 2b B 75-86
to patients with preventing postoperative wound
appendicitis infections and intra-abdominal abscesses.
who undergo For nonperforated appendicitis, the
appendectomy one-time preoperative dose seems
decrease to be sufficient to decrease infection
postoperative complications. The optimal duration of
complication rates? administration of antibiotics needs to
be further evaluated in patients with
complicated appendicitis.
6 What operation is The data support the use of performing LA 2b B 87-101
better for treating for patients with acute appendicitis if the
acute appendicitis: surgical expertise and equipment are
LA or OA? available.
7 Is interval The routine performance of interval 3b B 102-122
appendectomy appendectomy after nonoperative
necessary? treatment of complicated acute
appendicitis is not supported. Interval
appendectomy should be performed
when patients present with recurrent
symptoms. Patients presenting with an
appendiceal mass managed conservatively
should undergo further workup to rule
out other pathologies for their mass.
8 Should antibiotic Although antibiotics may be used as the 3b B 123-134
treatment replace primary treatment for selected patients
appendectomy for with uncomplicated appendicitis,
acute appendicitis? surgery continues to remain the primary
treatment option for the treatment of
acute appendicitis.

PMPH_CH33.indd 282 5/22/2012 5:24:34 PM


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INTRODUCTION
There are one million new cases of hemorrhoids per year in
the United States.1 Sixteen million people in total are affected
annually2,3 and 168,000 people are hospitalized for complications
related to this disease.4 Nearly two million ambulatory care visits
per year are reported for hemorrhoids in the United States5 mak-
ing this disease a significant healthcare issue.
Hemorrhoids are classified as internal, external, or mixed.
Internal hemorrhoids (IHs) are vascular cushions found above the
dentate line and external hemorrhoids (EHs) are found below
the dentate line.1 IHs are further classified based on their symp-
toms: first degree hemorrhoids are those that cause bleeding but
do not prolapse; second degree hemorrhoids prolapse out of the
anal canal during defecation and spontaneously return to their
anatomical position; third degree hemorrhoids prolapse and
require digital replacement; and fourth-degree hemorrhoids are
permanently prolapsed and cannot be reduced.
Evaluation starts with history and physical examination pay-
ing close attention to complaints of anal bleeding, itching, dis-
charge, discomfort, pain, or prolapse. One should also document
the type of bowel function the patient is having including consis-
tency of stool, the presence of straining, and any incontinence if
present. Endoscopic evaluation of the rectum should be utilized to
exclude the presence of any additional pathology prior to consid-
ering a management strategy.
Nonoperative Management
1. Does fiber reduce the symptoms of hemorrhoids?
After one’s workup confirms the presence of symptomatic hemor-
rhoids, the management starts with diet modification. In a meta-
analysis of seven randomized control trials (RCTs), the fiber had a
beneficial effect in the treatment of symptomatic hemorrhoids.6 The
risk of persistent symptoms was reduced by 47% in patients treated
with the fiber (risk reduction [RR], 0.47; 95% CI, 0.32–0.68). The effect
on arm bleeding showed a significant difference in favor of the fiber
(RR, 0.50; 95% CI, 0.28–0.89). No significant difference was seen in
287
PMPH_CH34.indd 287
CHAPTER 34
Hemorrhoids
Clarence E. Clark III
patients with prolapse, pain, or itching. The majority of the patients
in these studies had Grade I–II hemorrhoids. No study addressed the
effects of fiber on Grade III–IV hemorrhoids alone in an RCT.
Answer: Dietary fiber improves symptoms including bleed-
ing in patients with Grade I–II hemorrhoids with a potential ben-
efit in higher grade hemorrhoids. (Grade A recommendation)
2. Is observation with no procedural intervention a viable option?
The potential impact of doing nothing for symptomatic hemorrhoids
should be discussed with the patient along with described minor
procedures and operative treatment options. An examination of the
natural history of a first episode symptomatic Grade II hemorrhoids
showed that treatment with rubber band ligation (RBL) had a better
prognosis over observation alone over a 48-month follow-up, includ-
ing the need to treat (hemorrhoidectomy for recurrent symptoms
performed in 29.6% vs. 40.2%) and relief of symptoms after treatment
(48% vs. 19.8%).7 However, the authors note that 25% of the observa-
tion group did remit within their 48-month follow-up period.
Answer: Early intervention with RBL is superior to the observa-
tion of IHs. This study shows that the observation significantly increa-
ses the risk of developing symptomatic hemorrhoids requiring surgery.
Intervention should be considered early in these patients in light of
the clear benefit of symptom relief. (Grade A recommendation)
MANAGEMENT IHS
Anal dilation, injection sclerotherapy (IS), cryotherapy, infrared
coagulation (IRC), laser therapy, diathermy coagulation, and RBL
have been described as outpatient options for treating hemor-
rhoids. Here we will discuss the evidence-based data of these
treatment modalities.
3. Is there a clear advantage of one minor procedure strategy
over another?
A randomized prospective study in Europe with a 17-year follow-up
compared anal dilatation with surgical hemorrhoidectomy for
Grade II–III hemorrhoids.8 Three groups were examined: Group A
5/22/2012 5:25:10 PM
 288 ■ Surgery: Evidence-Based Practice
underwent Milligan9 hemorrhoidectomy (41 patients) with no
retractor, Group B had the original Lord’s six finger dilation with
a dilator (46 patients), and Group C underwent anal dilation as
described previously without the dilator (51 patients). More patients
were symptom-free in Group A (52%) versus Group B (23%) and
Group C (27%) after treatment. Recurrence of hemorrhoids was
lower for the hemorrhoidectomy group. Fecal incontinence was
the major complication found during follow-up for Groups B and
C (52% of the total patients).
A meta-analysis by MacRae et al.10 compared several of the
minor procedures and surgical hemorrhoidectomy with no treat-
ment. Overall, patients undergoing hemorrhoidectomy had a signif-
icantly better response to treatment than did patients treated with
RBL (p = .001), although this was at a cost of a significantly greater
risk of complications (p = .02) and pain (p < .0001). For Grade III
hemorrhoids alone, no difference was shown. RBL was shown to be
significantly better than IS in resolution of symptoms (p = .005).
This difference was shown for both Grades I and II hemorrhoids
(p = .007) and Grade III hemorrhoids (p = .042), with no signifi-
cant difference in the complication rate. Patients treated with RBL
were less likely to require further therapy than those treated with
either sclerotherapy (p = .031) or IRC (p = .0014), although the pain
was significantly more likely to occur following RBL (IS, p = .03;
IRC, p < .0001). No difference was found between sclerotherapy
and infrared photocoagulation for any of the outcome measures.
Recommendations from this article reveal that RBL should
be the first-line treatment for Grade III prolapsing hemorrhoids,
reserving hemorrhoidectomy for patients whose symptoms are
not relieved after treatment, and RBL appears to be the therapy of
choice for Grades I–II hemorrhoids.
A more recent meta-analysis of RCT of RBL versus excisional
hemorrhoidectomy (closed [CH] or open [OH])11 found RBL to be
as effective for Grade II hemorrhoids. For Grade III hemorrhoids,
the recurrence rate was improved with hemorrhoidectomy. Symp-
toms (incontinence, anal stenosis, sepsis, and significant bleeding),
the time from intervention to return to work, and complications
were higher for excisional hemorrhoidectomy.
Answer: RBL is preferred over anal dilation, sclerotherapy, and
infrared photocoagulation. RBL is the therapy of choice for Grades I
and II IHs. RBL should be the first-line treatment for Grade III pro-
lapsing hemorrhoids, reserving hemorrhoidectomy for patients whose
symptoms are not relieved after treatment. Anal dilation should be
abandoned due to significant morbidity. (Grade A recommendation)
4. Has one operative strategy proven to be superior to others?
If nonoperative management fails, surgery may be required. Vari-
ous operative approaches to hemorrhoids have been prospectively
analyzed, including OH versus CH, stapled hemorrhoidectomy or
hemorrhoidopexy (SH), and hemorrhoidectomy with bipolar scis-
sors hemeroidectomy (BSH) and harmonic scalpel (HSH).
OH versus CH
Many RCTs have compared OH versus CH with no clear advantage
of one technique over another. Recent RCTs have shown that CH
offers faster healing time. Arbman et al. found that at 3 weeks,
86% of patients in the Ferguson group (CH, n = 38) had com-
pletely healed wounds compared with 18% in the MMH (OH,
n = 39) group (p < .001).12 Arroyo et al. also found that healing
during the first postoperative month was faster in the CH group
PMPH_CH34.indd 288
(n = 100) compared with OH group (n = 100) (90% vs. 40%;
p < .05).13 Another RCT of 80 patients (40 OH, 40 CH) showed that
the mean operating time in the OH group (35 ± 7 min) was signifi-
cantly shorter than in the CH group (45 ± 8 min; p < .001).14 No sig-
nificant differences were observed in the duration of hospital stay or
in the mean duration of the inability to work. They also found that
the mean healing time was significantly shorter in the CH group
(2.8 ± 0.5 weeks) than in the OH group (3.5 ± 0.6 weeks; p < .001).
The data for CH versus OH do not favor one procedure over
another. No clear difference is seen with regard to postoperative
pain. CH appears to offer faster wound healing but OH offers shorter
operative time and possibly improved morbidity.13 It is important to
note that most of these studies did include internal and EHs.
Harmonic Scalpel, Bipolar Diathermy
The original description of Milligan–Morgan hemorrhoidectomy
(MMH) used scissors for excision.9 HSH and BSH are alternative
modalities for hemorrhoid excision. Recently, a prospective double-
blind randomized trial of 86 patients with prolapsing hemor-
rhoids looked at MMH versus BSH versus HSH.15 There was no
significant difference in the complication rates among the three
groups. There was no case of failure of hemostasis in the BSH
and HSH groups. HSH and BSH were found to be associated with
less operative blood loss when compared with MMH (p = .036
and .028, respectively), though this has little clinical relevance.
Cheung et al. noted that HSH is as safe and effective, with simi-
lar complication and recurrence rates, as diathermy or scissor
excision–ligation hemorrhoidectomy. They also noted that HSH
has less postoperative pain.
Stapled Hemorrhoidopexy
A more recent, novel approach to hemorrhoidectomy is SH also
known as Procedure for Prolapse and Hemorrhoids (PPH) and
stapled hemorrhoidectomy. Longo’s hemorrhoidopexy, as des-
cribed in 1998, does not involve removing mucosa or hemor-
rhoidal tissue.16,17 The purpose of the procedure is to remove the
feeding vessels to the hemorrhoids to treat symptomatic hemor-
rhoids. Jayaraman et al.18 looked at the outcomes of this technique
by performing a meta-analysis of 12 RCTs of stapled circular hem-
orrhoidopexy versus conventional OH or CH for the treatment of
Grade III and IV hemorrhoids. Follow-up periods ranged from 6
to 39 months with a median follow-up period of 7–14 months.
A trend to more complaints of hemorrhoidal bleeding in
patients with SH was seen (9 trials, 699 patients, OR 1.33, CI, 0.84–
2.08) as well as a significantly higher proportion of patients with
complaints of prolapse after SH (8 studies, 798 patients, OR 2.96, CI,
1.33–6.58, p = .008). Patients with SH were less likely to complain
of pruritus ani at the final follow-up than those with CH (4 studies,
273 patients, OR 0.66, CI, 0.29–1.50).
A nonsignificant trend showed that patients with SH were more
likely to complain of difficulties with soiling, hygiene, or inconti-
nence. Trends showing a higher proportion of patients with peria-
nal skin tags were seen in the SH group as compared with CH at
all time points. A nonsignificant trend demonstrated that patients
with SH were more likely to require repeat operations of any nature
in the long-term follow-up for their hemorrhoids. Patients with SH
were significantly more likely to have recurrent hemorrhoids in the
long-term follow-up at all time points than those with CH (7 trials,
537 patients, OR 3.85, CI, 1.47–10.07, p = .006).
5/22/2012 5:25:11 PM

Chung et al. analyzed 88 patients with Grade III hemorrhoids
(HSH = 45, PPH = 43) and a median follow-up period of 15 months
(range, 6–30).19 Comparing the two groups, the authors found no
significant observable difference in operation time, blood loss, or
time to first bowel movement. They state that PPH derives greater
short-term benefits, with reduced pain, shorter length of hospital
stay, and earlier return to work. Recommendations cannot be drawn
from this data due to the short follow-up and small sample size.
Computer-guided BSH (LigaSureTM) has also been compared with
PPH20 showing that postoperative pain scores, patient satisfaction,
and self-assessment of activity were almost identical in both treat-
ment groups. They also note that 9 of 25 PPH patients had skin tags
and prolapsed hemorrhoids removed with conventional diathermy.
The authors revealed that the inability of PPH to address these addi-
tional findings is a disadvantage of this treatment modality. Kraemer
et al. used LigaSureTM whenever there is a need for more extensive
excision or anodermal reconstruction, such as in fourth-degree
piles. The design of the RCT prevents one to draw definitive recom-
mendations regarding the use of PPH. The data do confirm findings
that PPH is not a good choice for Grade IV hemorrhoids.
Answer: Conventional excisional hemorrhoidectomy is pre-
ferred over PPH. Conventional excisional surgery is the “gold
standard” in the surgical treatment of Grade III and IV IHs. The
data for CH versus OH do not favor one procedure over the other.
PPH is not a good choice for Grade IV IHs. No clear recommen-
dations can be made based on the current data favoring PPH over
BSH or HSH for the treatment of symptomatic hemorrhoids.
Recommendations could not be made favoring BSH or HSH over
traditional MMH. Trends of intraoperative bleeding, however,
do favor the use of newer technologies over scissors for excision.
(Grade B recommendations)
PERIOPERATIVE CONSIDERATIONS
5. What is the best strategy for controlling postoperative pain?
Various perioperative analgesia strategies have been studied
including the use of viscous lidocaine, epidural anesthesia, locally
injected bupivacaine/ropivacaine, botulinum toxin injection,
posterior perineal block, ischiorectal fossa block, transcutaneous
electrical nerve stimulation, transdermal fentanyl patch, ketorolac
tromethamine injection, and spinal block.9,15,21-38
In one RCT, local injection of bupivacaine after hemorrhoid-
ectomy provided initial pain relief, but patients did not obtain an
overall analgesic benefit.22 Botulinum injection (20 U) into the inter-
nal sphincter showed pain relief at days 6 and 7 with no significant
difference in pain control in the early postoperative period.9
RCT that did show significant pain relief in the early postop-
erative period and reduced opioid consumption utilized posterior
perineal block, perianal ropivacaine injection, ischiorectal fossa
block, lidocaine injection with topical anesthetic prior to injec-
tion, and pudendal nerve block.23,24,26,34,35 One study compared
local with spinal anesthesia and found that the local perianal
nerve block for hemorrhoidectomy is superior to the spinal block
due to a lower incidence of post-op urinary retention and less
requirement of parenteral analgesics after surgery.32
Answer: Injection of local anesthetic reduces postoperative
pain after hemorrhoidectomy. Perianal, posterior perineal, and
pudendal nerve injections are all effective in pain control. Botox
injection improves pain control in the late recovery period. (Grade
A recommendation)
PMPH_CH34.indd 289
Hemorrhoids ■ 289
6. Does low volume resuscitation reduce postoperative urinary
retention?
Toyonaga et al. reviewed series of over 2000 anorectal surgeries
and found that hemorrhoidectomy, female sex, the presence of pre-
operative urinary symptoms, diabetes mellitus, the need for post-
operative analgesics, and more than three hemorrhoids resected
were independent risk factors for urinary retention.39 They also
showed that perioperative fluid restriction, including limiting the
administration of intravenous fluids, significantly decreased the
incidence of urinary retention (7.9 vs. 16.7%, p < .0001). Other
studies support that this finding40-42 including the administration
of at least 1000 mL of intravenous fluid perioperatively produced
a significant increase in postoperative urinary retention.42 Zaheer
et al. in contrary reported that perioperative fluids were not asso-
ciated with urinary retention in hemorrhoid surgery.28
Answer: Data support the use of perioperative fluid restric-
tion in anorectal surgery. Hemorrhoidectomy has been associated
with urinary retention and limiting fluid administration may pre-
vent this morbidity. (Grade B recommendation)
MANAGEMENT OF THROMBOSED EHS
7. What is the best management strategy for symptomatic EHs?
The most common findings with EHs are pain and/or ulceration
of a thrombus through the skin.1 Conservative measures are often
utilized which include a combination of localize hygiene, tub
baths, dietary changes, stool softeners, and oral and topical anal-
gesics. There are very few quality studies looking at the manage-
ment of EHs exclusively.
Greenspon et al.43 retrospectively reviewed that outcomes of
231 patients with thrombosed EHs. 119 (51.5%) were initially
treated conservatively and 112 (48.5%) were treated surgically with
a mean follow-up of 7.6 months (up to 7 years); 97.3% of the sur-
gical patients had excision of their EHs and 2.7% incision. Time
to symptom resolution was 24 days for conservatively managed
patients versus 3.9 days for surgical patients (p < .0001). The fre-
quency of recurrence was significantly higher for the conservative
group (25.4%) than for the surgical group (6.3%; p < .0001). These
data favor excision of thrombosed EHs over conservative therapy.
Jongen et al. focused on the clinical outcomes of the 340
patients who underwent outpatient office excision of symptomatic
EHs.44 All wounds were left open and follow-up was achieved in
70% of the patients. Postoperative complications are rare (1.3–7.7%).
Anal stenosis, urinary retention, and fecal retention were not seen
in this series. Recurrence rate was 9.2%. Based on their analysis,
the authors recommend excision under local anesthesia in the
office for thrombosed EHs.
A prospective randomized trial examined conservative ther-
apy versus surgery for the treatment of thrombosed EHs.45 Three
arms each had 50 patients: the first group was treated conserva-
tively with 0.2% glyceryl trinitrate (GTN) ointment; the second
group by incision and the third by excision of the thrombosed EH.
At 4 days, there was a significantly less pain in patients treated
by excision as compared with those treated with GTN or incision
(p < .001). At 1 year, all clinical outcomes significantly favored
excision of thrombosed hemorrhoids. Based on their data, the
authors recommend excision of perianal thrombosis under local
anesthesia as the method of choice because it prevents recurrence
of perianal thrombosis and development of anal skin tags.
5/22/2012 5:25:11 PM
 290 ■ Surgery: Evidence-Based Practice

Answer: Excision of symptomatic EHs is preferred over symptomatic EHs due to improved symptom relief. Practitioners
observation with topical agents or incision of hemorrhoid. Exci- can safely perform this procedure in the outpatient office setting.
sion of EHs under local anesthesia is the method of choice for (Grade B recommendation)

Clinical Question Summary

Question
1 Does fiber reduce the symptoms of
hemorrhoids?
2 Is observation with no procedural
intervention a viable option?
3 Is there a clear advantage of one
minor procedure over the others?
4 Has one operative strategy proven
to be superior to the others?
Answer Grade of References
Recommendation
Yes. Fiber has a clear benefit for Grade I–II A 6
hemorrhoids with a likely benefit for
Grade III–IV as well.
No. Clear benefit with intervention for Grade II A 5
and greater haemorrhoids.
Yes. RBL is superior to anal dilation, A 8, 10, 11
sclerotherapy and infrared photocoagulation.
Yes. Conventional hemorrhoidectomy is superior B 12-14, 18-20, 22
to PPH but no significant difference between
MMH and FH.

Clinical Question Summary

Question
1 Does low volume resuscitation
reduce postoperative urinary
retention?
2 What is the best strategy for
controlling postoperative pain?
3 What is the best management
strategy for symptomatic EHs?
Answer Grade of References
Recommendation
Yes. Keeping fluid administration less than 1 L B 28, 39-42
perioperatively will reduce the occurrence of
urinary retention.
Injection of local anesthetic perianal, posterior A 22-25, 34, 35
perineal, or pudendal nerve improves pain
control and reduces opioid use.
Excision over topical agents and incision. B 9, 20, 21

Levels of Evidence
Subject Year References Level of Strength of Findings
Evidence Recommendation
Fiber diet 2006 6 1a A Fiber improves and reduces
symptoms from hemorrhoids.
First-line treatment of 2005 10 1b A RBL is the first-line therapy
IHs followed by hemorrhoidectomy if
symptoms persist or Grade IV.
Open or closed 2002 14 2b B Both are acceptable operative
technique strategies with no significant
difference in outcomes.
Conventional 2006 18 1a A Conventional hemorrhoidectomy is
hemorrhoidectomy superior to PPH.
or PPH
Fluid restriction 2006 39 2b B Fluid restriction perioperatively
reduces postoperative urinary
retention.
Management of 2004 43 2b B Excision is superior to topical agents
symptomatic EHs and incision of EHs.

PMPH_CH34.indd 290 5/22/2012 5:25:11 PM


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 Commentary on Hemorrhoids
Stanley M. Goldberg
Clarence E. Clark deserves a lot of credit for a first-class review of
the literature on the management of hemorrhoids.
I was pleased to see the recommendation of the use of
rubber band ligation, but unfortunately some of the literature
is based on using poor equipment in performing this simple
clinic procedure. It is critical to band the tissue high in the anal
canal and the Hinkel-James® retractor is a great asset in this
operation.
Regarding anal dilatation, I was pleased to see that this tech-
nique has no p lace in the armamentarium of the modern colon
and rectal surgeon.
Clark has utilized the best studies to date regarding rub-
ber band ligation for Grade II and some Grade III hemorrhoids.
Excisional hemorrhoidectomy is indicated if the symptoms do
not respond to rubber band ligation or the major symptoms are
related to the external component.
I was so pleased to see that Clark found that several large
studies suggested that the strategy of excision not incision is the
proper management of a thrombosed external hemorrhoid with
multiple blood clots as an outpatient procedure. It is rare for us
to take the patient with a thrombosed external hemorrhoid to the
operating room. Local anesthesia in the prone jack-knife position
works beautifully.
Regarding open versus closed hemorrhoidectomy, the only
benefit of the closed technique is that the surgeon is always think-
ing about closing the wound and therefore he/she does not remove
too much tissue and create a stricture.
The Harmonic Scalpel is an expensive tool to use while
performing hemorrhoid surgery. Regarding the Procedure for
Prolapse and Hemorrhoids (PPH), I wish the authors would
have elaborated more about the serious complications asso-
ciated with the PPH procedure. Conventional excisional sur-
gery is the “gold standard” in the surgical treatment of Grade
III (not responding to rubber band ligation) and Grade IV
hemorrhoids.
293
PMPH_CH34.indd 293
SOURCES IN THE LITERATURE
1. Brusciano L, Ayabaca SM, Pescatori M, et al. Reinterventions
after complicated and failed stapled haemorrhoidopexy. Dis
Colon Rectum. 2004;47:1846-1851.
2. Angelone G, Giardiello C, Prota C. Stapled hemorrhoidopexy.
Complications and 2-year postoperative follow-up. Ann Surg.
2006;242:29-35.
3. Cheetham MJ, Mortensen NJ, Nystrom PO, Kamm MA, Phillips
RK. Persistent pain and fecal urgency after stapled haemorrhoid-
ectomy. Lancet. 2000;356:730-733.
4. McDonald PJ, Bona R, Cohen CR. Rectovaginal fistula after sta-
pled haemorrhoidopexy. Colorectal Dis. 2004;6:64-65 (letter).
5. Cipriani S, Pescatori M. Acute rectal obstruction after PPH sta-
pled haemorrhoidectomy. Colorectal Dis. 2002;4:367-370.
6. Giordano P, Bradley B, Peiris L. Stapled closure of the rectal
lumen following stapled haemorrhoidopexy: Case report. Dis
Colon Rectum. 2008;(in press).
7. Brown S, Baraza W, Shorthouse A. Total rectal lumen oblitera-
tion after stapled haemorrhoidopexy: A cautionary tale. Tech
Coloproctol. 2008;11:357-358.
8. McCloud JM, Jameson JS, Scott AN. Life-threatening sepsis fol-
lowing treatment for haemorrhoids: A systematic review. Col-
orectal Dis. 2006;8:748-755.
9. Cirocco WC. Life threatening sepsis and mortality following
stapled hemorrhoidopexy. Surgery. 2008;143:824-829.
10. Herold A, Kirsch JJ. Pain after stapled haemorrhoidectomy.
Lancet. 2000;356:2187-2190 (letter).
11. Pessaux P, Lermite E, Tuech JJ, et al. Pelvic sepsis after stapled
hemorrhoidectomy. J Am Coll Surg. 2004;199:824-825.
12. Maw A, Eu KW, Seow-Choen F. Retroperitoneal sepsis compli-
cating stapled hemorrhoidectomy: Report of a case and review of
the literature. Dis Colon Rectum. 2002;45:826-828.
13. Jayaraman S, Colquhoun PH, Malthaner R. Staples versus con-
ventional surgery for hemorrhoids (Review). The Cochrane
Collaboration 2008, Issue 4.
5/22/2012 5:25:11 PM
 CHAPTER 35
Anorectal Fissure, Stricture,
Abscess, and Fistula
W. Brian Perry and Joshua A. Tyler
INTRODUCTION
Complaints involving the anorectal region are common in clinical
practice, but are frequently poorly understood and misdiagnosed.
Often, patients are referred for “hemorrhoids,” which may actually
be a number of other conditions. Correct treatment depends on
timely and accurate diagnosis. Once this occurs, evidence-based
interventions may be applied for anal fissure, stricture, abscess,
and fistula. Hemorrhoids and pilonidal disease are covered in
other chapters.
1. What nonoperative therapies are effective in the treatment
of anal fissures?
Many patients with acute anal fissures experience complete heal-
ing with little direct intervention. Another sizable portion will
improve with simple means such as increasing dietary fiber, sitz
baths, and nonsteroidal anti-inflammatory drugs. Should these
methods fail, medical therapies directed at lowering anal sphinc-
ter pressures have been shown to be effective.1
Topically applied nitric oxide donors such as glyceryl trinitrate
(GTN) reliably relax the internal anal sphincter. Multiple controlled
randomized trials and a recent Cochrane Review2 have shown that
GTN is statistically better than placebo at healing anal fissure
(about 50–35%). Headache is the most commonly reported adverse
event associated with GTN use and results in therapy interrup-
tion in as much as a quarter of patients. Recurrence of anal fissures
approaches 50% in patients who report initial healing with GTN.
Topical calcium channel blockers have been shown to facili-
tate healing in 65% to 95% of patients with anal fissures, also
statistically better than placebo. Headache is again the primary,
therapy limiting side effect, but is less frequent than is seen with
GTN. Oral calcium channel blockers are more effective than pla-
cebo, but less effective than topical preparations.1
Botulinum toxin injection directly into the internal anal
sphincter causes a temporary “chemical sphincterotomy” which
allows for healing of 60% to 80% of anal fissures. Minor inconti-
nence to flatus (up to 18%) and stool (<5%) is the most common
side effect and typically improves as the toxin wears off. Little
294
PMPH_CH35.indd 294
consensus exists regarding dosing or optimal injection site(s), but
all studies show an advantage over placebo. Recurrence rates of
40% to 50% at 1 year have been reported.2
Summary: Nonoperative therapies that relax the internal anal
sphincter are safe and are superior to placebo in healing anal fis-
sures. Recurrence rates after cessation of therapy are significant.
(Level 1a evidence, Grade A recommendation)
2. What are the results of lateral internal sphincterotomy (LIS)
for fissures?
Multiple studies and a recent Cochrane review have clearly estab-
lished LIS as the surgical treatment of choice for chronic anal
fissures. Healing rates of >90% and minor incontinence rates of
<10% are the norm. No difference has been shown between open
or closed techniques.1,3 A tailored or calibrated sphincterotomy,
which aims to limit the amount of sphincter divided, has been
shown to have equivalent or slightly worse healing rates, but less
incontinence.4 Posterior sphincterotomy with fissurectomy is
inferior to LIS in both healing and incontinence rates.5 Small
studies on surgical options such as advancement flaps that do not
divide muscle show promising results, but more work is needed
before these techniques can be universally recommended.6,7 Mul-
tiple studies and both Cochrane Reviews confirm the superiority
of LIS to any medical therapy in terms of durable fissure healing
with low rates of troubling incontinence.
Summary: LIS is the surgical treatment of choice for anal fis-
sures and is far superior to any medical therapy. (Level 1a evidence,
Grade A recommendation)
3. How are anal strictures best treated?
Stricture or stenosis of the anal canal is typically caused by hem-
orrhoidectomy or other anorectal procedures. This rare condition
causes difficulty with evacuation of the rectum, pain, and bleed-
ing. Patients with mild to moderate degrees of narrowing are
often helped by the addition of fiber and fluids to their diet, digital
dilation, or LIS, although those with chronic tight strictures
require surgical management.
5/22/2012 5:25:46 PM

Several local skin advancement flap techniques have been
described; each aims to bring healthy tissue into the anal canal to
increase its diameter while minimizing donor site morbidity. The
house advancement flap brings a broad-based flap into the anal
canal and allows primary closure of the donor site and can be done
bilaterally if necessary.8 Results have generally been good, with sig-
nificant improvement seen in up to 90%.9 A Y–V sliding flap may
be technically less challenging, but necrosis of the tip limits its use
to strictures in the distal anal canal. Rhomboid rotational flaps
are more difficult to perform and have success rates between the
other two. Because of the heterogeneity of these patients and the
relative rarity of this condition, randomized trials are diffi-
cult; most reports are case series of less than 50 patients using a
single technique. Farid et al. randomized 60 patients with anal
stenosis to receive a house flap, rhomboid flap, or Y–V anoplasty.
The house flap performed the best, with durable quality of life
improvement at 1 year.10
Summary: Flap procedures are effective in treating anal stric-
tures. Choice of technique depends on the patient and surgeon
factors. (Level 2b–3 evidence, Grade C recommendation)
4. What is the role of antibiotics in the treatment of perirectal
abscesses?
Incision and drainage is the definitive treatment of perirectal
abscess. Antibiotics have not been shown to have any effect on
the time to complete healing nor recurrence rates in patients with
uncomplicated perirectal abscesses. Of the available studies, immu-
nocompromised patients were excluded, including those with dia-
betes, immunosuppression, or cellulitis of the wound. Although no
studies have been done comparing antibiotics in addition to drain-
age versus drainage alone in the above populations, the decision to
use antibiotics must be made on a case-by-case basis.11 In addition,
according to the American Heart Association’s 2007 revision of the
guidelines for the prevention of infective endocarditis, antibiotic
prophylaxis for patients with gastrointestinal-associated infection,
or infection of the skin or soft tissue is indicated only for patients
with a prosthetic valve, heart transplant, history of infectious endo-
carditis, and congenital heart defects.12
Summary: Antibiotics are generally not indicated for peri-
rectal abscess following adequate incision and drainage. Excep-
tions may include immunocompromised patients and those at
high risk for infectious endocarditis. (Level 2c evidence, Grade B
recommendation)
5. What are the best operative strategies for drainage of peri-
rectal abscess?
No randomized controlled trials comparing drainage techniques
for perirectal abscess exist in the current literature. Uncompli-
cated perirectal abscesses are drained through the perianal skin
at the point of maximal induration, with care taken to avoid the
sphincter complex.11 The cavity should be thoroughly examined
to assess for extensions such as a horseshoe abscess which may
require a counter-incision.13 If a fistula tract is found, a draining
seton may be placed to promote abscess drainage, allowing defi ni-
tive treatment to be delayed until a later date if necessary.
Summary: Incision and drainage is the mainstay of treatment
for perirectal abscesses. If a fistula-in-ano or unexpected abscess
extensions are found, additional techniques such as seton place-
ment or counter incisions may be necessary. (Level 2c evidence,
Grade B recommendation)
PMPH_CH35.indd 295
Anorectal Fissure, Stricture, Abscess, and Fistula ■ 295
6. Following drainage of a perirectal abscess, can the develop-
ment of a fistula-in-ano be predicted or prevented?
Little literature exists on the risk of subsequent fistula develop-
ment following initial perirectal abscess drainage. In a retrospec-
tive observational study, Hamadani et al. observed 148 patients
after perirectal abscess drainage without evidence of fistula at the
time of initial operation. Mean follow-up was 38 months. Predic-
tors of subsequent fistula-in-ano development or recurrence of
abscess included individuals younger than age 40 at the time
of presentation (p < .01), as well as patients that were nondiabetic.
Nondiabetics were greater than twice as likely to develop fistula or
recurrence than diabetics (HR 2.69, p = .04). Gender, smoking sta-
tus, perioperative antibiotics, and human immunodeficiency virus
(HIV) status were not found to be significant. (Level 2s evidence,
Grade B recommendation)
7. What are the best operative approaches to simple fistula-
in-ano?
A simple fistula-in-ano is generally accepted to primarily involve
the internal sphincter muscle (intersphincteric fistulae). More
complex fistulas tend to branch, and are more likely to involve
the external sphincter muscle. Simple fistulae may be treated by
fistulotomy with or without marsupialization of wound edges,
and fistulectomy. Numerous studies of simple fistulae show fistu-
lotomy to be superior to fistulectomy, with shorter healing times,11
and lower risks of recurrence and incontinence (less than 10% for
each), provided that the internal opening has been properly iden-
tified and the fistula tract did not involve the external sphincter.14
These results were replicated in a recent study of a prospectively
collected regional outcomes registry for fistula treatment, which
showed a high success rate in the treatment of simple fistula with
fistulotomy compared with other treatment modalities.15 Fistulo-
tomy and fistulectomy are generally contraindicated in complex
fistulae as well as in patients with Crohn’s disease due to longer
healing times and an increased risk of incontinence.
Fistulotomy is appropriate for simple fistula-in-ano with high
rates of healing and low rates of incontinence. (Level 2b evidence,
Grade B recommendation)
8. How are setons used in the treatment of anal fistulas?
Setons are used in the treatment of anal fistula to control peria-
nal or perirectal sepsis. Setons are used either in a draining or in
a cutting capacity. Draining setons are used most commonly in
complex fistula tracts as well as in patients with Crohn’s disease.
These hold the fistula tract open and allow purulence to drain,
thus controlling the abscess. These allow a decrease in perirectal
inflammation, both controlling acute abscesses and allowing time
for perioperative planning when sphincter-sparing techniques
may be employed. Cutting setons have utility in complex fistulae
that involve the external sphincter. Made of either silk suture or
vessel loops, they are serially tightened, allowing a slow division
of the external sphincter muscle with subsequent fibrosis and scar
formation to limit the anatomic defect. The use of cutting setons
results in a low recurrence rate; however, this leads to an inconti-
nence rates of 10% to 60%, particularly in patients with high fis-
tula openings.16,17
Summary: Setons have long been used in the treatment of
complex fistula-in-ano. Draining setons may be used to control
perianal sepsis although awaiting optimal timing for definitive
5/22/2012 5:25:46 PM
 296 ■ Surgery: Evidence-Based Practice
surgical management, as well as in Crohn’s disease. Cutting set-
ons may be used in complex fistula management with low recur-
rence rates, but may lead to higher rates of incontinence. (Level
2c–3b evidence, Grade C recommendation)
9. What are the results of various sphincter-sparing techniques
in the treatment of fistula-in-ano?
Sphincter-sparing options for the treatment of complex fistula-in-
ano include fibrin glue, fistula plug, seton placement, endorectal
advancement flap (ERAF), and ligation of transsphincteric fis-
tula tract. Fistulotomy is contraindicated in fistulae which would
require the division of a significant portion of the external sphinc-
ter muscle due to high rates of incontinence. No single study has
prospectively compared all of these modalities, but several small
series have evaluated each individually, or in comparison with
one another.
The use of fibrin glue, an attractive option because no sphinc-
ter is divided, showed promise in early studies, with initial clo-
sure rates of 60% to 70%.11 Subsequent studies, however, have
been unable to achieve similar results with many showing
closure rates of closer to 40%. Singer randomized patients to
fibrin sealant plus closure of internal opening, fibrin sealant
plus antibiotics, or fibrin sealant plus both, with failures being
offered retreatment. Closure rates at 1-year follow-up were only
44%, 25%, and 35%, respectively, with no significant difference
between groups.18
Bioabsorbable xenograft fistula plugs, one made by Cook Sur-
gical (Surgisis, Cook Surgical, Bloomington, IN) and the other
made by Gore (Bio-A Fistula Plug, W.L. Gore and Associates,
Newark, Delaware), represent another method of tract oblitera-
tion. Similar to the results with fibrin glue, initial studies were
promising; Champagne et al. showed an 83% success rate at
1-year average follow-up.10 Later studies have been unable to repli-
cate this, with success rates ranging from 40% to 60% depending
on both the complexity of the fistula and the length of the tract.
Simple fistulas tend to fare better, as do those with tracts longer
than 4 cm; one study has noted that smokers and diabetics tend
to not heal with plug placement.19,20 Both fibrin glue and fistula
plugs have been shown to enable the closure of the fistula tract in
Summary Table
Question Year References
What nonoperative therapies are 2005 1, 2
effective in the treatment of anal
fissures?
What are the results of LIS for 2005 1, 3
fissures?
How are anal strictures best treated? 2010 10
What is the role of antibiotics in the 2008 1, 2
treatment of perirectal abscesses?
What are the best operative 2006 1, 3
strategies for drainage of
perirectal abscess?
PMPH_CH35.indd 296
some patients with a minimal side-effect profi le and virtually no
reports of effects on continence.
ERAF also remains a viable option in the closure of complex
anal fistulae. This procedure entails the mobilization of either a
partial or a full-thickness flap of the rectum that covers the inter-
nal opening of an anal fistula. It is generally used in complex
fistulae and those with high openings, as well as those that have
failed prior plug treatment. Several trials have compared ERAF
with fistula plug. One small prospective randomized study was
halted early due to high recurrence rates with the fistula plug
compared with ERAF (relative risk 6.40 (95% confidence inter-
val, 1.70–23.97); p < .001).21 This study was small, however, with
only 16 patients per treatment group. Another retrospective case–
control study also compared ERAF with plug, and found similar
results, with 63% success rate in the ERAF group compared with
32% in the plug group (p = .008).22
Another relatively new procedure that has gained recent
attention is the ligation of intersphincteric fistula tract (LIFT)
procedure. This procedure involves exposing the intersphinc-
teric groove, identifying the fistula tract, and ligating of the tract.
Success rates using the LIFT procedure ranged from 57% to 82%
in two recent prospective observational studies, and most of the
patients undergoing the procedure had complex fistulae that had
failed prior attempts at repair.23,24 Another study incorporated a
reinforcing bioprosthetic material in conjunction with the LIFT
procedure and reported 94% success rates with minimal to no
effects on continence.25
Many options exist in the treatment of complex fistula-in-
ano, and there are limited well-done randomized, prospective
trials comparing the options discussed above. No definitive algo-
rithm exists, and there is great variability in complex fistula types
(cryptoglandular origin vs. Crohn’s disease) and anatomic loca-
tions (transsphincteric vs. suprasphincteric). More studies are
needed to better delineate optimal treatment regimens in this
patient population.
Complex fistula-in-ano may be successfully treated with fibrin
glue, fistula plug, ERAF, or LIFT procedure. Success rates vary
widely, but incontinence rates are infrequent with all of the above
procedures. (Level 2a–3b evidence, Grade C recommendation)
Level of Grade of Findings
Evidence Recommendation
1a A Better than placebo;
recurrence common.
1a A LIS is treatment of choice.
2c C House flap seems to work
best.
2c B Not indicated for majority
of patients.
2c B Incision and drainage
mainstay of treatment.
(Continued)
5/22/2012 5:25:46 PM

(Continued)
Question Year References
Following drainage of a perirectal 2009 4 2a
abscess, can the development of
a fistula-in-ano be predicted or
prevented?
What are the best operative 2010 1, 5
approaches to simple fistula-in-ano?
How are setons used in the treatment 2009 7, 8
of anal fistulas?
What are the results of various 2010 1, 9–16, 26
sphincter-sparing techniques in the
treatment of fistula-in-ano?
REFERENCES
1. Perry WB, Dykes SL, Buie WD, et al. Practice parameters for the
management of anal fissures (3rd revision). Dis Colon Rectum.
2010;53(8):1110-1115.
2. Nelson R. Non surgical therapy for anal fissure. Cochrane Data-
base Syst Rev. 2006;(4):CD003431. Review.
3. Nelson R. Operative procedures for fissure in ano. Cochrane
Database Syst Rev 2005;(2):CD002199.
4. Elsebae MM. A study of fecal incontinence in patients with
chronic anal fissure: Prospective, randomized, controlled trial
of the extent of internal anal sphincter division during lateral
sphincterotomy. World J Surg. 2007;31:2052-2057.
5. Abcarian H. Surgical correction of chronic anal fissure: Results
of lateral internal sphincterotomy vs. fissurectomy-midline
sphincterotomy. Dis Colon Rectum. 1980;23:31-36.
6. Leong AF, Seow-Choen F. Lateral sphincterotomy compared
with anal advancement flap for chronic anal fissure. Dis Colon
Rectum. 1995;38:69-71.
7. Singh M, Sharma A, Gardiner A, et al. Early results of a rota-
tional flap to treat chronic anal fissures. Int J Colorectal Dis.
2005;20:339-342.
8. Christensen MA, Pitsch RM, Jr., Cali RL, et al. “House” advance-
ment pedicle flap for anal stenosis. Dis Colon Rectum. 1992;35:
201-203.
9. Sentovich SM, Falk PM, Christensen MA, et al. Operative results
of House advancement anoplasty. Br J Surg. 1996;83:1242-1244.
10. Farid M, Youssef M, El Nakeeb A, et al. Comparative study of
the house advancement flap, rhomboid flap, and Y-V anoplasty
in treatment of anal stenosis: A prospective randomized study.
Dis Colon Rectum. 2010;53:790-797.
11. Whiteford MH, Kilkenny J, 3rd, Hyman N, et al. Practice param-
eters for the treatment of perianal abscess and fistula-in-ano
(revised). Dis Colon Rectum. 2005;48(7):1337-1342.
12. Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective
endocarditis: Guidelines from the American Heart Association: A
guideline from the American Heart Association Rheumatic Fever,
Endocarditis and Kawasaki Disease Committee, Council on Car-
diovascular Disease in the Young, and the Council on Clinical
Cardiology, Council on Cardiovascular Surgery and Anesthesia,
and the Quality of Care and Outcomes Research Interdisciplinary
Working Group. J Am Dent Assoc. 2008;139 Suppl:3S-24S. Review.
13. Rosen SA, Colquhoun P, Efron J, et al. Horseshoe abscesses and
fistulas: How are we doing? Surg Innov. 2006;13(1):17-21.
PMPH_CH35.indd 297
Anorectal Fissure, Stricture, Abscess, and Fistula ■ 297
Level of Grade of Findings
Evidence Recommendation
B Nondiabetics and patients
<40 higher risk.
2b B Fistulotomy appropriate
for simple fissures.
2c–3b C Setons are appropriate
for some patients.
2a–3b C Success rates vary,
incontinence rare.
14. Stremitzer S, Strobl S, Kure V, et al. Treatment of perianal sepsis
and long-term outcome of recurrence and continence. Colorectal
Dis. 2010. [Epub ahead of print]
15. Hyman N, O’Brien S, Osler T. Outcomes after fistulotomy:
Results of a prospective, multicenter regional study. Dis Colon
Rectum. 2009;52(12):2022-2027.
16. Ritchie RD, Sackier JM, Hodde JP. Incontinence rates after cut-
ting seton treatment for anal fistula. Colorectal Dis. 2009;11(6):
564-571.
17. Malik AI, Nelson RL. Surgical management of anal fistulae: A
systematic review. Colorectal Dis. 2008;10(5):420-430.
18. Singer M, Cintron J, Nelson R, et al. Treatment of fistulas-in-ano
with fibrin sealant in combination with intra-adhesive antibiot-
ics and/or surgical closure of the internal fistula opening. Dis
Colon Rectum. 2005;48(4):799-808.
19. McGee MF, Champagne BJ, Stulberg JJ, et al. Tract length pre-
dicts successful closure with anal fistula plug in cryptoglandular
fistulas. Dis Colon Rectum. 2010;53(8):1116-1120.
20. Schwandner T, Roblick MH, Kierer W, et al. Surgical treatment
of complex anal fistulas with the anal fistula plug: A prospective,
multicenter study. Dis Colon Rectum. 2009;52(9):1578-1583.
21. Ortiz H, Marzo J, Ciga MA, et al. Randomized clinical trial of anal
fistula plug versus endorectal advancement flap for the treatment of
high cryptoglandular fistula in ano. Br J Surg. 2009;96(6):608-612.
22. Christoforidis D, Pieh MC, Madoff RD, et al. Treatment of trans-
sphincteric anal fistulas by endorectal advancement flap or
collagen fistula plug: A comparative study. Dis Colon Rectum.
2009;52(1):18-22.
23. Bleier JI, Moloo H, Goldberg SM. Ligation of the intersphincteric
fistula tract: An effective new technique for complex fistulas. Dis
Colon Rectum. 2010;53(1):43-46.
24. Shanwani A, Nor AM, Amri N. Ligation of the intersphincteric
fistula tract (LIFT): A sphincter-saving technique for fistula-in-
ano. Dis Colon Rectum. 2010;53(1):39-42.
25. Ellis CN. Outcomes with the use of bioprosthetic grafts to rein-
force the ligation of the intersphincteric fistula tract (BioLIFT
procedure) for the management of complex anal fistulas. Dis
Colon Rectum. 2010;53(10):1361-1364.
26. Hamadani A, Haigh PI, Liu IL, et al. Who is at risk for devel-
oping chronic anal fistula or recurrent anal sepsis after initial
perianal abscess? Dis Colon Rectum. 2009;52(2):217-221.
27. Champagne BJ, O’Connor LM, Ferguson M, et al. Efficacy of
anal fistula plug in closure of cryptoglandular fistulas: Long-
term follow-up. Dis Colon Rectum. 2006;49(12):1817-1821.
5/22/2012 5:25:46 PM
 Commentary on Anorectal Fissure,
Stricture, Abscess, and Fistula
W. Brian Perry and Joshua A. Tyler had a large topic to summarize
and they have reached some excellent conclusions. Their advice
on the management of anal fissure is spot-on. I have read all this
literature and have tried all the new therapies, but a properly per-
formed lateral internal sphincterotomy with minimal division of
the sphincter muscle is the treatment of choice for a chronic anal
fissure. The surgeons should never incise muscle cephalad to the
proximal portion of the fissure.
Fortunately, anal strictures are rare in the United States
because most colon and rectal surgeons perform a closed hemor-
rhoidectomy and are very cautious regarding the removal of ano-
derm. Because of the paucity of this problem, good randomized
studies are not available.
I was especially pleased to see their discussions regarding the
use of antibiotic in the management of perirectal abscesses. I only
wish all the family practitioners and emergency physicians could
read this chapter.
298
PMPH_CH35.indd 298
Stanley M. Goldberg
The discussion of setons was excellent and this technique
should be utilized whenever a surgeon is in doubt as to how much
muscle is involved with the fistula or if there is any indication that
a patient may have Crohn’s disease.
The authors were correct in their assessment of the current
method to management complex fistulas. More prospective trials
are indicated, but I think LIFT (Lateral Intersphincteric Fistula
Transection) will win out in the end because no foreign material
is needed and no sphincter muscle is divided.1
REFERENCE
1. Bleier J, Moloo H, Goldberg SM. Ligation of the intersphincteric
fistulas tract: An effective new technique for complex fistulas. Dis
Colon Rectum. 2010;53(1):43-46.
5/22/2012 5:25:46 PM

Fecal Incontinence and Surgical
Management of Constipation
INTRODUCTION
Constipation is a symptom-based disorder of unsatisfactory def-
ecation. It involves infrequent stools, difficult stool passage, or
a combination of the two. More than 2 million clinic visits per
year can be attributed to constipation. Prevalence has been esti-
mated between 1.9% and 27.2% in North America with an average
of 14.2%.1 Constipation can be a symptom of other disease pro-
cesses, a side effect of medications, or inadequate dietary habits,
or have no identifiable cause. It can be classified as normal transit,
obstructed defecation, or slow transit.2
Fecal incontinence is the loss of voluntary control of feces,
either liquid or solid, from the bowel. It is a condition that is
socially embarrassing and isolating and those affected often need
to plan their lives around the disorder. The true prevalence of
the disorder is unknown and estimates vary greatly because of
the influence of social stigma, varying the defi nition of incon-
tinence, and varying frequencies of occurrence. In a survey of
the general population, 12.1% of women had an episode of fecal
incontinence in the past year with 2.5% of women having one or
more episodes per week.3 In general, fecal incontinence is more
common in women and institutionalized patients and its preva-
lence increases with age.4
FECAL INCONTINENCE
1. What is the initial evaluation and management of patients
with fecal incontinence?
The evaluation of fecal incontinence begins with a careful his-
tory and physical examination. The type of incontinence, whether
it is to gas, liquid stool, or solid stool, should be ascertained as
well as the frequency at which it occurs. In addition, the use of
coping mechanisms, such as wearing a pad or a diaper, and life-
style changes should be assessed. Physical examination includes
anal inspection and digital rectal examination. Both are poor for
detecting sphincter defects.5
299
PMPH_CH36.indd 299
CHAPTER 36
Sarah Pesek and Neil Hyman
Factors that contribute to fecal incontinence can be noted
while taking a past medical history. Obstetrical trauma is the
most common contributing factor in adult females, though incon-
tinence may not manifest until years afterward. There is increased
risk with instrumental delivery, large birth weight, and prolonged
second stage of labor. Up to 35% of primiparas have sphincter
injury though some remain asymptomatic.6 Trauma also may
lead to incontinence in the form of pelvic fracture leading to nerve
damage or by direct sphincter injury. Furthermore, spinal injuries
may also contribute. Neurologic damage from diabetes and stroke,
and neurologic disorders such as multiple sclerosis and dementia
and mental disorders may also lead to incontinence.7
Several scoring systems have been developed to assess the
severity of fecal incontinence. Grading systems can be used to
objectify and measure improvement or worsening of fecal inconti-
nence after treatment or intervention.5 Two primary domains are
considered: the frequency and type of stool loss and the impact of
fecal incontinence on daily life.8 The most commonly used scale is
the Cleveland Clinic Florida (Wexner) fecal incontinence score.9
Initial treatment begins with medical management. Dietary
and lifestyle modifications are effective for patients with mild symp-
toms. Foods that cause urgency or diarrhea should be avoided.7
Fecal incontinence commonly is made worse by liquid stools or
diarrhea. Fiber supplementation has been shown to decrease the
proportion of incontinent stools in patients with loose or liquid
stools by more than 50%.10
Loperamide (Imodium299®) reduces stool weight, small bowel
motility, urgency, stool volume, and frequency of bowel move-
ments.11 In two studies in patients with chronic diarrhea, lop-
eramide use results in improved incontinence symptoms when
compared with placebo. More patients on diphenoxylate for chronic
diarrhea achieved full continence when compared with placebo.
However, loperamide may be superior to diphenoxylate.12
Biofeedback is another method used to improve bowel control.
Three main modalities have been described: rectal sensitivity train-
ing, strength training, and co-ordination training. One small trial
showed significant improvement in incontinent episodes per week
and overall incontinence status in patients receiving biofeedback
5/22/2012 5:26:21 PM
 300 ■ Surgery: Evidence-Based Practice
compared with controls.13 However, a 2006 Cochrane Review
found no evidence that biofeedback offers any advantage over
other conservative managements.14
Answer: The initial evaluation of fecal incontinence begins
with a history and physical examination. Initial management is
medical, including fiber and loperamide. Biofeedback may
improve symptoms. (Grade B recommendation)
2. What is the workup for patients being considered for sur-
gery to treat fecal incontinence?
Endoanal ultrasound can be used to diagnose sphincter defects in
patient with suspected injury. In identifying internal and exter-
nal sphincter defects, it has sensitivity and specificity approach-
ing 100% when performed by an experienced clinician.5 However,
the presence of a sphincter defect does not always correlate with
symptoms of incontinence. In a study of 335 incontinent patients,
115 continents and 18 asymptomatic volunteers, defects were
found in 65%, 43%, and 22%, respectively.15
Anal manometry can be used to define the functional weak-
ness of the internal or external anal sphincters and the length of
the high pressure zone of the anal canal. Patients with inconti-
nence have been shown to have low resting and low squeeze
pressures, but there are significant variations even within asymp-
tomatic subjects dependent on age, gender, and parity.5,7 Studies
have shown that preoperative manometric readings do not corre-
late with outcomes following anal sphincter repair and peripheral
nerve evaluation, but can predict the likelihood of restoration of
continence following repair of rectal prolapse.16-19
The pudendal nerve terminal motor latency (PNTML) mea-
sures neuromuscular integrity between the terminal portion of
the pudendal nerve and the anal sphincter. Bilateral, not unilat-
eral, prolonged PNTML is associated with poorer function in the
incontinent patient with the intact sphincter, but the majority
of incontinent patients have normal PNTML.20 The presence of
pudendal neuropathy has been proposed to be a factor predicting
the success following anal sphincter repair.21 Laurberg et al. ana-
lyzed a group of 19 patients and saw an 80% success rate in those
without neuropathy, compared with only 11% with neuropathy
(p < .05).22 This finding has been confirmed by other studies. How-
ever, pudendal neuropathy is not universally accepted as a predic-
tor of failure following repair.21
Answer: Endoanal ultrasound is useful for diagnosing anal
sphincter defects. Anal manometry readings may be used to define
functional weakness. PNTML studies may predict the outcome of
anal sphincter repair. (Grade B recommendation)
3. What are the indications and outcomes for anal sphincter
repair?
Anal sphincter repair can be done for any type of injury of the
external anal sphincter. Anterior reconstruction is most com-
monly reported, because obstetrical injury is the most frequent
indication and most outcome data pertain to this type of patient.
Good-to-excellent results have been suggested in 31% to 83% of
patients.5 However, good results tend to deteriorate over time. In
one study, less than 10% were completely continent to liquid and
solid stools for 5 years.23 In another, only 14% were fully conti-
nent at a median of 69 months.24 In a third study, no patients were
found to be fully continent after 10 years.25 For patients under-
going repeat anal sphincter repair, the short-term and long-term
results are similar to those without a previous repair.26
PMPH_CH36.indd 300
When overlapping sphincter repair was compared with direct
end-to-end repair in a randomized clinical trial, there was no benefit
noted with an overlapping sphincteroplasty.27 Similarly, in another
nonrandomized study, outcomes were similar between end-to-
end, overlapping, and plication techniques.28 Levatorplasty can be
performed at the same time as anal sphincter repair. In one study
when performed simultaneously, 63% of patients reported good-to-
excellent results.29 In another, 77% report subjective improvement.30
These results are comparable with anal sphincter repair alone, but
no studies exist directly comparing the two methods.
Answer: Anal sphincter repair is indicated for properly
selected patients with external anal sphincter defects. Short-term
results are reasonable but deteriorate over time. The role of leva-
torplasty is unclear. (Grade A recommendation)
4. Is there a role for an artificial sphincter or a sacral nerve
stimulator (SNS)?
Artificial sphincters were initially developed to treat urinary
incontinence and were modified and adapted for treatment of fecal
incontinence.31 The devise is placed around the existing sphinc-
ter complex after perineal dissection. For patients that retain the
device, artificial bowel sphincter provides good continence of
solid and liquid stools. Complete continence has been achieved
in up to 63% with 79% of patients continent to both solid and liq-
uid stools.32 However, the complication rate is high and adverse
events are seen in virtually all patients.33 Revisional surgery was
required in 46% of patients and the explantation rate is 20% to
30%.5,32 Absolute contraindications to this procedure include
active perineal sepsis, Crohn’s disease, radiation proctitis, severe
scarring in the perineum, or anoreceptive intercourse.5
Candidates for SNS typically have an intact external sphincter
(with or without previous repair), symptoms of fecal incontinence
(1+ episodes per week), failed conservative therapy, and be able to
follow up reliably.34 SNS is a two-stage procedure with a diagnostic
peripheral nerve evaluation stage followed by a permanent thera-
peutic implantation stage. Patients receive the permanent implant
only if the diagnostic stage produces clinical improvement, defined
as a reduction in the frequency of fecal incontinence by at least
50% over a 2-week period.35
For patients that achieve chronic implantation, 83% achieve
≥50% reduction in episodes of incontinence at 1 year. At 3 years,
87% meet this goal. Approximately 40% of patients have perfect
continence at 1 year.36 Interventions to optimize function are com-
mon and include reprogramming of the device and repositioning of
leads.37 The incidence of complications range from 5% to 26% in var-
ious studies.5 The most common adverse effect is pain at the implan-
tation site.36,37 The screening test has a low complication rate.36
Answer: Artificial bowel sphincters are effective in treating
fecal incontinence in patients who retain the device; however,
there is a high complication rate. SNS is a promising intervention
for fecal incontinence. Both modalities remain largely experimen-
tal at the present time. (Grade B recommendation)
CONSTIPATION
5. What treatments are effective in the medical management
of constipation?
Management of symptomatic constipation typically begins with
dietary modification, which includes a high-fiber diet and fluid
5/22/2012 5:26:21 PM

supplementation. Physical activity may also be helpful.38 A graded
increase of up to 25 g per day of fiber has been suggested.39 This
dose has been shown to increase stool frequency. Increasing fluid
intake to 1.5 to 2 L per day has also been shown to increase stool
frequency and decreases the need for laxatives in those already
consuming a high-fiber diet.40 However, for patients with slow-
transit constipation or pelvic floor dysfunction (PFD), fewer than
30% improve.41
When dietary management fails, laxatives and other drugs
may be used.38 Polyethylene glycol (PEG) can be used to promote
bowel function. A meta-analysis reviewing studies comparing
PEG with placebo showed a significant increase in stools per
week and a good tolerability to the drug in general.42 A Cochrane
review comparing PEG and lactulose found PEG to be better in
terms of stools per week, improvement in abdominal pain and
the need for additional products.43 Tegaserod has been shown to
increase spontaneous bowel movements, but has been withdrawn
from general use due to its increasing cardiovascular risk.39
Lubiprostone has been shown to have an effect in both acute and
chronic treatments. When used in a 4-week study, it was found
to increase the number of spontaneous bowel movement when
compared with placebo at each weekly time point.44 Similarly,
a meta-analysis looking at studies lubiprostone showed benefit
when compared with placebo for treatment of constipation.45
However, adverse effects are frequent with nausea occurring in
up to 31% of patients.44
Other common agents, such as milk of magnesia, senna,
bisacodyl, and stool softeners, may be used for chronic constipa-
tion. However, inconsistent results are reported in the literature.46
Additionally, long-term laxative use can result in the patient devel-
oping a cathartic colon.
Answer: Initial management of constipation begins with
dietary management. If this fails, PEG and lubiprostone have been
shown to increase stool frequency. (Grade A recommendation)
6. What role do anorectal physiology and colonic transit time
studies have in assessment of constipation?
A colonic transit study documents gastrointestinal motility
objectively. The pattern of radio-opaque markers can distinguish
between colonic inertia and PFD. The test is simple, inexpensive,
and repeatable in assessing slow-transit constipation.38 When slow
colonic transit has been adequately documented before colectomy
for refractory constipation, an improved rate of good outcomes
has been reported (90% vs. 67%).47
Defecography provides a dynamic evaluation of the entire
defecation process. It can identify abnormalities such as rec-
tocele, sigmoidocele, abnormal perineal descent, nonrelax-
ation of the puborectalis, intussusception, occult prolapse, and
incomplete emptying of the rectum.48 However, the relevance
of defocography findings is controversial as many normal indi-
viduals show abnormal findings.49 Anorectal manometry may
show paradoxical sphincter contraction in patients with anis-
mus or with obstructed defecation, but this may also be seen
in normal patients. 50 Hirschsprung’s disease may be suggested
by an absent rectoanal inhibitory reflex. 38 Electromyography
may be used to evaluate puborectalis relaxation and is used to
identify patients with paradoxical puborectalis contraction or
nonrelaxation.48
A balloon expulsion test quickly estimates the overall pel-
vic floor function and can be used to exclude PFD. A prospective
PMPH_CH36.indd 301
Fecal Incontinence and Surgical Management of Constipation ■ 301
study showed it to have a specificity and negative predic-
tive value for excluding PFD of 89% and 97%, respectively.
A nonpathologic test may avoid the use of other pelvic f loor
investigations. 51
Answer: Anorectal physiology and colonic transit time
studies may serve to differentiate between slow transit and out-
let obstruction and identify the underlying pathophysiology in
patients who fail to improve with dietary management. (Grade B
recommendation)
7. What are the selection criteria and outcomes for colectomy
in slow-transit constipation?
Colectomy is only considered for patients after diet and medi-
cal interventions have failed and following a thorough workup.
Candidates for total abdominal colectomy have slow-transit con-
stipation without concomitant PFD. Patients with documented
slow colonic transit before colectomy reported an improved
rate of good outcomes. In general, patients who undergo com-
plete physiologic evaluation with manometry, defecography,
and colonic transit studies showed improved median satis-
faction rate when compared with incomplete evaluation, 89%
vs. 80%.47
Total abdominal colectomy with ileorectal anastomosis yields
a clinical improvement in 50% to 100% of patients with slow-transit
constipation.52 Segmental colonic resection has disappointing
results with up to a 100% failure rate.47 Factors that predict failure
include psychiatric factors, PFD, and abnormal small bowel transit.
Patients with generalized intestinal dysmotility have a diminished
long-term success rate of 13%.53
Complications occur in approximately one-third of patients.2
They include small bowel obstruction, persisting abdominal pain,
frequent bowel movements, fecal incontinence, and persistent or
recurring constipation. Fecal incontinence was found in 6% of
patients following total abdominal colectomy.52
Answer: Total abdominal colectomy with ileorectal anas-
tomosis should be cautiously considered for patients with slow-
transit constipation who have failed nonsurgical management. A
careful physiologic evaluation should be performed prior to sur-
gery. (Grade B recommendation)
8. What is the management of PFD?
Patients with nonrelaxing or paradoxical puborectalis are unable
to relax the pelvic floor appropriately at straining or Valsalva. Pel-
vic floor exercises and biofeedback can be used for these patients.
Success rates of biofeedback have been reported that range
between 30% and 90% with no technique having a superior suc-
cess rate.54,55 A randomized clinical trial of patients with severe
PFD who failed initial medical management compared the out-
come of five weekly biofeedback sessions with that of PEG)and
five weekly sessions of constipation prevention. Eighty percent in
the biofeedback group reported major improvement which was
significantly greater than the PEG group. Results were sustained
at 12 and 24 months.56 A retrospective study showed that the out-
come of biofeedback was not influenced by age, gender, duration
of symptoms, or rectal pain. Outcomes improved if the patient
completed five sessions and were related to the patient’s willing-
ness to complete treatment.57
Answer: Biofeedback is an appropriate treatment for PFD.
(Grade B recommendation)
5/22/2012 5:26:21 PM
 302 ■ Surgery: Evidence-Based Practice

9. What is the role of surgery for rectocele with an associated transvaginal approach to have lower subjective and objective fail-
defecation disorder? ure rates and lower rate of postoperative enterocele.60 No differ-
ence in rates of incontinence or dyspareunia was observed.
A rectocele results from the breakdown of endopelvic fascial sup-
The transperineal approach can be performed in combina-
port in the rectovaginal septum. Repair is generally indicated in
tion with anal sphincter repair and/or levatorplasty for symptom-
patients where a symptomatic rectocele is large, some say >4 cm, if
atic rectocele and sphincter defect. An improvement in evacuation
it fails to empty on defocography and if manual support of the vag-
and continence has been seen in 75% of patients.61 Mesh can be
inal wall or rectum is necessary for satisfactory defecation.38,58
inserted via a transvaginal or a transperineal approval to reduce
Approaches for rectocele repair include transvaginal, trans-
the risk of recurrence and dyspareunia. However, this has not
perineal, and transanal repair. The transvaginal repair is tradi-
been shown to be more effective than traditional repair.60
tionally performed by gynecologists. It has been shown to correct
The stapled transanal rectal resection (STARR) procedure has
the anatomic defect in 76% to 96% of patients.59 Improvement in
been advocated for patients with obstructive defecation syndrome
defecation symptoms has been reported in up to 90% of patients.2
(ODS) with internal rectal prolapsed with or without rectocele.62
However, there is a failure to relieve evacuatory difficulty or lower
In an analysis of two large STARR registries in Europe, a signifi-
rectal symptoms in 33%. Fecal incontinence is found in 36%, and
cant improvement in ODS symptoms at 6 months that was main-
25% suffer dyspareunia postoperatively. Some authors recom-
tained at 12 months was found. Complications occurred in 21%
mend the use of defect-specific repair to reduce the risk of dys-
to 36% of patients and included staple line complications, major
pareunia, which has been shown to reduce constipation in more
bleeding, and postsurgical stenosis. Defecatory urgency and new-
than 80% of patients.38
onset incontinence were also observed.63,64
The transanal repair is traditionally used by colorectal sur-
Answer: Surgical repair of rectocele can be performed via
geons. Outcomes of this method include decreased constipation
a transvaginal, transanal, or transperineal repair. Encouraging
in 48% to 71% and correction of need for digital assistance of def-
results have been seen in patients who underwent a STARR pro-
ecation in 54% to 100%.38 A Cochrane review of two small trials
cedure for ODS. (Grade B recommendation)
comparing the transanal and transvaginal approaches showed the

Clinical Question Summary

Question
1 What is the initial evaluation and
management of patients with fecal
incontinence?
2 What is the workup for patients being
considered for surgery to treat fecal
incontinence?
3 What are the indications and outcomes
for anal sphincter repair?
4 Is there a role for an artificial sphincter
or a sacral nerve stimulator (SNS)?
5 What treatments are effective in the
medical management of constipation?
6 What role do anorectal physiology and
colonic transit time studies have in
assessment of constipation?
7 What are the selection criteria and
outcomes for colectomy in slow-transit
constipation?
8 What is the management of PFD?
9 What is the role of surgery for rectocele
with an associated defecation disorder?
Answer Grade of References
Recommendation
Evaluation consists of a focused history and B 5-14
physical examination. Initial management is
medical in most cases.
Endoanal ultrasound can diagnose anal B 5, 7, 15-22
sphincter defects. Anal manometry and
PNTML may predict the outcome of repair.
Repair is indicated for highly selected patients A 5, 23-30
with sphincter defects. Short-term results
are reasonable.
Both appear effective in treating fecal B 31-37
incontinence, but remain largely
experimental.
Management begins with dietary changes. PEG A 38-46
and lubiprostone may be used if this fails.
In patients who fail dietary management, they B 47-51
may help differentiate between slow-transit
and outlet obstruction.
Colectomy should be considered for B 2, 47, 51-53
refractory slow-transit constipation in
highly selected patients.
Biofeedback is appropriate treatment for B 54-57
highly symptomatic patients.
Symptomatic rectoceles can be repaired via B 38, 58-64
transanal, transvaginal or transperineal
approaches.

PMPH_CH36.indd 302 5/22/2012 5:26:21 PM


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patients undergoing colectomy for colonic inertia. Dis Colon
Rectum. 2001;44(2):179-183.
53. Redmond JM, Smith GW, Barofsky I, et al. Physiological tests
to predict long-term outcome of total abdominal colectomy
for intractable constipation. Am J Gastroenterol. 1995;90(5):
748-753.
54. Jorge JM, Habr-Gama A, Wexner DS. Biofeedback therapy in
the colon and rectal practice. Appl Psychophysiol Biofeedback.
2003;28(1):47-61.
PMPH_CH36.indd 304
55. Khaikin M, Wexner SD. Treatment strategies in obstructed defe-
cation and fecal incontinence. World J Gastroenterol. 2006;12(20):
3168-3173.
56. Chiarioni G, Whitehead WE, Pezza V, et al. Biofeedback is supe-
rior to laxatives for normal transit constipation due to pelvic
floor dyssynergia. Gastroenterology. 2006;130(3):657-664.
57. Gilliland R, Heymen S, Altomare DF, et al. Outcome and predic-
tors of success of biofeedback for constipation. Br J Surg. 1997;84(8):
1123-1126.
58. Zbar AP, Lienemann A, Fritsch H, et al. Rectocele: Pathogenesis
and surgical management. Int J Colorectal Dis. 2003;18(5):369-384.
59. Kudish BI, Iglesia CB. Posterior wall prolapse and repair. Clin
Obstet Gynecol. 2010;53(1):59-71.
60. Maher C, Feiner B, Baessler K, et al. Surgical management of
pelvic organ prolapse in women. Cochrane Database Systematic
Review. 2010(4):CD004014.
61. Ayabaca SM, Zbar AP, Pescatori M. Anal continence after recto-
cele repair. Dis Colon Rectum. 2002;45(1):63-69.
62. Schwandner O, Stuto A, Jaybe D, et al. Decision-making algo-
rithm for the STARR procedure in obstructed defecation syn-
drome: Position statement of the group of STARR Pioneers. Surg
Innov. 2008;15(2):105-109.
63. Schwandner O, Furst A. Assessing the safety, effectiveness, and
quality of life after the STARR procedure for obstructed defeca-
tion: Results of the German STARR registry. Langenbecks Arch
Surg. 2010;395(5):505-513.
64. Jayne DG, Schwandner O, Stuto A. Stapled transanal rectal resec-
tion for obstructed defecation syndrome: One-year results of the
European STARR Registry. Dis Colon Rectum. 2009;52(7):1205-
1212; discussion 1212-1214.
5/22/2012 5:26:21 PM

Rectovaginal Fistula
Joshua D. Schulte, Kelly Ming, Michelle M. Olsen, and Philip F. Caushaj
INTRODUCTION
Rectovaginal fistula is a condition of protean manifestations for
the suffering patient. Unlike patients with anorectal fistula sec-
ondary to cryptoglandular etiology, these patients usually develop
this complication following an obstetrical delivery. This condition
not only affects the patient’s self-esteem and social relationships,
but also the patient’s quality of life significantly.
Most patients with rectovaginal fistula present clinically with
passage vaginally of stool, flatus, purulent discharge, or frequent
urinary tract infections. Patients may also note pain or pressure
referred to the perineum. This may be associated with dyspaure-
nia. Although not classically presenting symptoms, these patients
may experience tenesmus and frank fecal incontinence.
Rectovaginal fistulas are anatomically divided into low, mid,
and high; this may refer to either vagina or rectum. Nevertheless,
functionally and in regards to treatment, they should be consid-
ered either low or high based on anorectal sphincter complex.1
This classification is essentially determined by the relationship of
the fistula to the anorectal sphincter anatomy. Distal or lower fis-
tulas are easily evident on physical examination which includes
digital rectal examination, anoscopy, and bi-manual examination
of the vagina and rectum. The surgical management is guided by
the anatomic basis of the rectovaginal fistula.
1. Who is at risk to develop a rectovaginal fistula?
Rectovaginal fistula commonly occurs following vaginal deliver-
ies. Venkatesh et al.2 reviewed the incidence of rectovaginal fistulas
following vaginal deliveries in 20,500 women. Their study revealed
that 5% of all normal deliveries suffered an episiotomy associated
with either a third or fourth degree lacerations of the perineum. Of
the patients with fourth degree lacerations that were recognized
and repaired primarily, 10% of these cases disrupted following
primary repair usually secondary to sepsis. Eighty-eight percent
of rectovaginal fistulas occur following these injuries.3 Worldwide
the incidence to develop rectovaginal fistula following vaginal
delivery is 1%. The higher incidence of rectovaginal fistula in sub-
Saharan Africa and South Asia is thought to be primarily due to
the limitation of access to quality obstetrical care and prolonged
305
PMPH_CH37.indd 305
CHAPTER 37
obstructed delivery.4,5 Primiparity, midline episiotomies, increased
birth weight, and use of vaginal forceps are the confounding fac-
tors that along with the perineal laceration etiologically seem to be
causative in the formation of rectovaginal fistulas.6
Other causes for rectovaginal fistula are rare but must be
considered. Inflammatory bowel diseases, specifically Crohn’s
disease, is the next most frequent etiology.1 Other diseases that
may lead to this situation are given in Table 37.1. These conditions
include carcinoma, radiation therapy, diverticulitis, foreign body
including pessary, penetrating trauma, infectious processes, and
congenital anomalies; pelvic, perineal, and anorectal surgeries
that include vaginal hysterectomy, low anterior resection, stapled
hemorroidectomy, and recurrent rectocele repair, anorectal eroti-
cism, chemotherapy, and neoadjuvant chemoradiation.7
Answer: The most common risk factor to develop rectovagi-
nal fistula is obstetrical injuries occurring after vaginal deliveries.3
Inflammatory bowel disease is the next most common risk factor
occurring in up to 9% of patients with a history of Crohn’s dis-
ease.8 Other less common conditions include carcinoma, radiation
therapy, diverticulitis, penetrating trauma, infection, and pelvic
surgery.7 (Grade B recommendation)
2. How do patients with rectovaginal fistulas present clinically?
Most patients will complain of flatus, feces, purulent discharge,
frequent urinary tract infections, or malordous vaginitis.
Table 37.1 Etiology of Rectovaginal Fistula
Obstetrical Penetrating trauma
Crohn’s disease Infectious diseases
Colorectal carcinoma Congenital anomalies
Anal carcinoma Pelvic, perineal, and anorectal surgery
Radiation therapy Low anterior resection
Diverticulitis Stapled hemorrhoidectomy
Foreign body (pessary) Anorectal eroticism
Recurrent rectocele repair Neoadjuvant chemoradiation
Chemotherapy
5/22/2012 5:26:54 PM
 306 ■ Surgery: Evidence-Based Practice
A significant percentage of rectovaginal fistula patients may also
experience tenesmus and/or fecal incontinence. This may be dif-
ficult to elucidate historically as some patients may not recognize
the source of the incontinence primarily due to debility, etc. The
differential diagnosis for patients that present with these com-
plaints is all inclusive of the conditions previously reviewed.
Rectovaginal fistulas are most often found at the dentate line.
The usual communication occurs between the posterior fornix of
the vagina and the anus.9 Most colorectal surgeons define the fistula
based on the anorectal opening. Gynecologists will define this fistu-
lous opening based on the vaginal opening. This specialty-specific
consideration not withstanding, the anatomic basis for the fistula
must be clearly defined to determine what types of treatment strat-
egies are needed. Consequently, depending on the specialty of the
examiner, there will be low, mid, and high fistulas and multiple
combinations thereof. There can be a high vaginal fistula with mid
rectal opening as well as a high rectal fistula with vaginal open-
ing. Fistulas that are low and in close proximity to the vaginal
fourchette and involve the anus are primarily anovaginal fistu-
las. High rectovaginal fistulas include an internal orifice that is
proximal to the dentate line in regards to the anorectal sphincter
mechanism (i.e., puborectalis muscle) or in relation to the orifice
opening and proximity to the cervix.
Answer: Most patients will complain of flatus, feces, puru-
lent discharge, frequent urinary tract infections, or malordous
vaginitis. A significant percentage of rectovaginal fistula patients
may also experience tenesmus and/or fecal incontinence. (Grade
B recommendation)
3. How do we establish the diagnosis of rectovaginal fistulas?
A thorough and focused history should be obtained, which will
allow the clinician to pinpoint the diagnostic modalities to search
for the cause of a patient’s rectovaginal fistulas. The patient’s medi-
cal history and medical records, to include previous diagnostic stud-
ies, should be carefully reviewed. This focused approach will allow
the further elucidation of whether carcinoma, radiation therapy, or
inflammatory bowel disease may be the precipitating disorder.
The physical examination of the rectovaginal fistula patient
should include a thorough assessment of the vagina, perineum,
and anorectal sphincter mechanism. A bivalved speculum exami-
nation of the posterior vaginal wall must be carried out with care-
ful attention for any anatomical deficits that may be present. The
examiner should look carefully for evidence of vaginitis, malodor-
ous discharge, nonspecific inflammation, mucopurulent drainage,
and of course feces.1-7 An inspection of the perineum to include
anal and vaginal orifices as well as the perineal body needs to be
performed. Obvious external evidence of fistulization, fissures, or
other processes can be visualized. The presence or absence of the
perineal body can be ascertained. The presence of cloacae dem-
onstrates severe previous injury to the area. This external inspec-
tion will also allow for recognition of other diseases that may be
associated with rectovaginal fistula such as cystoceles, uterine
prolapse, and pelvic inflammatory disease. Tender, inflamed, and
otherwise uncomfortable processes may require an examination
under anesthesia to allow proper classification and diagnosis. The
examiner should be able to perform a digital rectal examination as
well as an examination that places a digit into both the vagina and
the rectum. This bi-digital examination will allow for evalua-
tion of the compliance of the rectovaginal septum, the integrity,
and mass of the perineal body, and whether or not the anorectal
sphincter mechanism has been violated by the usual antecedent
PMPH_CH37.indd 306
obstetrical injury. The perineal body is often thin on nonexistent
in rectovaginal fistula patients that have a concomitant sphincter
injury. These patients may present with a functional cloacae com-
bining the genitourinary and gastrointestinal points of egress.
Careful documentation of these injuries needs to occur to plan
appropriate treatment. Rectovaginal fistula may on bi-manual
examination demonstrate an irregularity of the posterior vaginal
wall that is usually a small area of irregular mucosa and the site of
the vaginal orifice. This area can usually be gently probed.
All patients should undergo an anoscopy (preferably with
a slotted side viewing scope), rigid proctosigmoidoscopy, and
fiberoptic colonoscopy to eliminate possible proximal causes for
the rectovaginal fistula. Most low fistulas can be easily diagnosed
whereas most high fistulas are problematic diagnostically. Some
investigators utilize a probing method to establish the diagnosis
whereas others would not attempt to blindly probe these areas.
When the fistula cannot be established by these simple meth-
ods, other diagnostic modalities need to be considered. The sim-
plest method to establish the presence of a rectovaginal fistula is
the methylene blue retention enema test. This requires the place-
ment of a vaginal tampon into the vagina and the administration
of a methylene blue retention enema via the anus. The patient is
allowed to rest in the left lateral position. After 1 h of observa-
tion, the presence of methylene blue on the tampon is the sine qua
non for the presence of an abnormal communication between the
vagina and the anorectum. A less commonly performed technique
required placing the patient into the lithotomy position with a
slight trendelenburg position and instilling the vagina with warm
saline. Thereupon, a rigid proctoscope is inserted into the rectum
and gentle insufflation is carried out. The presence of air bubbles
in the vagina usually establishes the presence of the rectovaginal
fistula, but may not confirm the anatomic classification.
When the previously discussed diagnostic evaluations have
not identified the site or the presence of a rectovaginal fistula, the
need to consider other adjunctive tests to establish the diagnosis
must be utilized. Diagnostic imaging has been useful in this regard.
Studies have reported a role for computerized axial tomography
that has a sensitivity of 60% in defining the location of the fistula.11
The introduction of coiled endoanal MRI has changed the evalu-
ation of these disorders by demonstrating an excellent visualiza-
tion of the pelvis, vagina, and anorectum. Some studies have a
remarkable specificity approaching 100%.12 Anal ultrasound is
also a useful adjunct in the diagnosis and the assessment of the
anorectal sphincter status. Unfortunately, the literature demon-
strates a variable success rate for this modality ranging from 7% to
78%.13,14 This modality is operator-specific and consequently less
accurate than endoanal MRI. Some authors have recommended
the addition of hydrogen peroxide prior to the performance
of an endoanal ultrasound to improve the accuracy of the anal
ultrasound.14,15 Most colorectal surgeons still employ an ultra-
sound not as a diagnostic tool, but for preoperative assessment of
the anorectal sphincter which is often compromised.
Other contrast studies may be indicated and are easily
obtained. These studies include proctography, vaginography, and
cinedefecography.10 Although these adjunctive procedures have
been used more significantly in the past, there remains a role for
them currently.
Answer: The diagnosis of a rectovaginal fistula begins with a
through history and physical examination. The physical examina-
tion should include a rectal examination, bi-manual rectovaginal
examination, and anoscopy. All patients should undergo a
5/22/2012 5:26:55 PM

fiberoptic colonoscopy to eliminate proximal causes. Other help-
ful maneuvers include the vaginal methylene blue tampon test
and water bubble test as previously described. Radiologic studies
include CT scan which has a sensitivity of 60% and MRI which
has a sensitivity of 100% in some studies.11,12 Anal ultrasound is
helpful for preoperative assessment of the anorectal sphincter
complex and has a sensitivity of 7% to 78% in diagnosing fistulas if
used with hydrogen peroxide.13,14 Other contrast studies are avail-
able which include proctography, vaginography, and cinedefecog-
raphy. (Grade C recommendation)
4. What are the indications for abdominal repair of rectovagi-
nal fistula?
The traditional approach for rectovaginal fistula treatment is sur-
gical. Medical therapy for the treatment of non-Crohn’s–related
fistulas is nonexistent. Following the evaluation of the patient and
diagnosis of a rectovaginal fistula, a careful preoperative assess-
ment of the patient and related comorbid conditions is necessary.
The anatomic classification of the fistula as well as the etiology
will significantly determine the operative approach and ultimate
outcome. High fistulas are generally approached transabdomi-
nally and may require bowel resection especially if the fistula was
caused by a colonic or rectal disorder. Small bowel fistulas to the
vagina are exceedingly rare but may possibly require small bowel
resection. If the rectovaginal fistula is secondary to a previous
hysterectomy, then a resection of bowel may not be indicated pro-
vided the fistula is taken down and the openings closed and then
protected with an interposition of omentum, muscular flaps, or
fascial flaps to maintain isolation of the repair.15
Many approaches have been used to treat the variety of fistu-
las that can develop. Transanal, transperineal, transcoccygeal, and
transabdominal surgeries including pouch anal anastomosis with
or without interposition of tissue and with or without fecal diversion
and/or urinary diversion are all valid surgical options dependent on
the cause and the anatomic location of the fistula.7,15-17 Hampton and
Bacon favored abdominal anal pull-through with perineal repair.18
Turner-Warwick preferred an abdominal operation with interposi-
tion of omentum.19 Others have interposed gracilis muscle.20 Mason
exposed the area by dividing the rectum and the sphincters, closing
the fistula in layers and reconstructing the rectum.21
High rectovaginal fistulas are approached through the abdo-
men. The preoperative strategy requires understanding of the
anatomic location, etiology, and the confounding issues relating
to the surrounding tissues such as radiation to the area, sepsis,
and arborization of the fistula. The issue surgically is to develop
and conduct the operation in minimally involved tissue planes.
Rectal resection with coloanal anastomosis procedure was
initially developed by Sir Allen Parks et al.22 This procedure
includes dissection and mobilization of the rectum below the fis-
tula site and furthermore requires mobilization of the proximal
colon from its lateral attachments including takedown and mobi-
lization of the splenic flexure. Thus, by definition, this includes
proctectomy and coloanal anastomosis. The anastomosis has been
performed with either a mucosectomy or a double-staple tech-
nique. Nowacki reported functionally good results in 18 out of
23 patients undergoing this procedure for radiation-induced rec-
tovaginal fistula.23 Additional studies have reported similar suc-
cess for radiation-induced rectovaginal fistula.24,25 Other studies
have advocated interposition and/or on-lay grafts utilizing omen-
tum to treat the fistula with varied success. Steichen pioneered the
PMPH_CH37.indd 307
Rectovaginal Fistula ■ 307
use of staplers as an adjunct in the treatment for these disorders.26
Recent literature has advocated laparoscopic, hand-assisted, and
robotic treatments for the management of these complicated
fistulas.27-29 However, further evidence is lacking regarding the
superiority of these newer technical advances.
Answer: High fistulas are traditionally repaired through an
abdominal approach. These may include primary repair with
an interposition flap or repair with bowel resection.15 Many
techniques have been described including abdominal anal pull-
through with perineal repair, abdominal operation with inter-
position of omentum or interposition of gracilis muscle, and
reconstruction of the rectum after dividing the rectum and the
sphincters. If bowel resection is performed, the coloanal anasto-
mosis can be constructed with either a mucosectomy or a double-
staple technique.23 (Grade B recommendation)
5. What are the indications for perineal and transanal repair
of rectovaginal fistula?
Any attempt to repair a rectovaginal fistula must primarily address
the anorectal openings, even though the fistula may have primar-
ily originated from a vaginal source (i.e., obstetrical trauma).
Many surgeons, both general and gynecological, prefer to repair
the fistula using the transvaginal approach.30 The transvaginal
repair is not recommended based on the literature because the
high-pressure zone is in the rectum and the consequent direction
of flow is from rectum to vagina. If the repair of the rectal open-
ing is accomplished surgically, it is often unnecessary to deal with
the vagina and allow the vagina to close secondarily. Conversely,
no matter how meticulously the technique is performed via the
vagina, if the rectal closure fails so does the repair.
The initial report regarding the use of anterior rectal advance-
ment flap in a posttraumatic rectovaginal fistula was described by
Noble in 1902 with subsequent modification of that technique by
Laird in 1948.31,32 This technique is for low-lying rectovaginal fistula
without associated sphincter injury, and this variant is not common.
The theoretical advantages of this repair and the various techniques
and principles of this procedure have remained relatively constant,
which is to address the high-pressure defect in the anorectum.
The basic technique for the transanal flap repair is to create a
flap of substantive depth including mucosa, submucosa, and even
partial thickness of the internal sphincter. This flap is raised in
the cephalad direction for at least a length of 5 cm. The dissection
is usually completed at the point when the rectal opening is easily
reached and the defect can be covered without any tension. After
the flap has been created, the internal opening is cored out and
any defect in the sphincter complex or in the rectovaginal sep-
tum is sutured primarily. Then the flap is sutured in a tension-free
place. The vaginal opening is left open to drain.
Previous studies that have evaluated outcomes for this repair
have had inconsistent results.33-42 These studies have had hetero-
geneous populations, different surgical techniques, and inconsis-
tent follow-up. Consequently, a wide range of success is seen in
larger studies. However, as there is no contrary Level 1 evidence to
refute, this is the standard treatment for traumatic low rectovagi-
nal fistula without coexisting incontinence.
The other commonly used approach for simple or low rec-
tovaginal fistulas is to perform a mucosal advancement flap with
an overlapping sphincteroplasty. Generally, these patients have
partial incontinence to flatus or feces or frank fecal incontinence.
Secondarily, these patients have suffered from an obstetrical
5/22/2012 5:26:55 PM
 308 ■ Surgery: Evidence-Based Practice
injury that has violated the anorectal sphincter mechanism. The
sphincteroplasty is carried out in a manner that allows repair of
the primary defect, corrects the underlying sphincter injury, and
interposes musculature by repairing the muscles of the perineal
body thereby buttressing the repair.
Kodner et al. from Washington University in St. Louis reported
on 107 endorectal advancement flaps for repair of rectovaginal fis-
tula secondary to all causes (obstetrics, septic, traumatic, postop-
erative, and Crohn’s).33 Sixteen percent had persistent rectovaginal
fistula following repair. Eight percent required a second procedure.
Continence was unchanged in 80% and improved in 18%. The
authors concluded that endorectal flap improved or cured 93% of
the rectovaginal fistulas avoiding fecal diversion and stoma.
A Cleveland Clinic trial reviewed the endorectal advancement
flap performed during a 5-year period for rectovaginal fistula in 52
patients.34 Immediate fistula occurred in 6%. Statistically signifi-
cant higher recurrence rates occurred following previous history
of surgical repair. A subsequent study from the same institution
reviewed 34 patients with rectovaginal fistula and reported a suc-
cess rate of 63.6%.35 The only factor that seemed to alter the out-
come negatively was an association with Crohn’s disease.
The University of Minnesota reviewed their data with
endorectal advancement flaps in 81 patients.33 The etiology in
this series was obstetrical in 74%, perineal infection in 10%,
operative trauma in 7%, and unknown in 8%. Overall success
rate was 83%. The main predictors for success were correlated to
the number of pervious repairs. If no previous repairs had been
carried out, then the success rate was 88%. If two or more previ-
ous repairs were attempted, then the success rate was 55%. Th is
study demonstrates that one should be hesitant to offer endorec-
tal advancement flap repair to those who had undergone two or
more previous repairs.
A follow-up study by Tsang from the same group at University
of Minnesota analyzed the outcomes of RVF repairs based on pre-
operative sphincter status.37 Fift y-two women underwent 62 repairs
for simple obstetrical rectovaginal fistulas. Forty-eight percent
had varying degrees of fecal incontinence before surgery. There
were 27 endorectal advancement flaps and 35 sphincteroplasties
(28 with and 8 without levatorplasty). Success rates were 41% with
endorectal advancement flap and 80% with sphincteroplasties
(96% with and 33% without levatorplasty). An endorectal advance-
ment flap was successful in 50% of patients with normal anorec-
tal sphincter function, but in only 33% of patients with abnormal
sphincter function. Results were better in patients with sphincter
defects. Poor outcomes in this study were associated with increased
number of previous endorectal advancement flap repairs, but not
with previous sphincteroplasties.
Khanduja reported on the effectiveness of combining an
endorectal advancement flap with sphincteroplasty for symp-
tomatic patients with rectovaginal fistula and anorectal sphincter
injury.38 In addition to the mucosal advancement flap, 65% of patients
underwent a two-layer repair of anorectal sphincter with reapprox-
imation of the puborectalis muscle in eight patients. Thirty percent
of patients underwent a one-layer repair of the anorectal sphincter
and 5% underwent reapproximation of the anorectal sphinc-
ter alone. Continence was restored in 70% and incontinence was
improved in 30% with the only manifestation of incontinence
being to liquid stool or flatus.
In summary, the use of mucosal advancement flap repair is
appropriate for most simple rectovaginal fistulas. Obviously, the
success is determined based upon the etiology of fistula, anatomical
PMPH_CH37.indd 308
considerations, the number of previous attempted repairs, and the
presence of an associated anorectal sphincter injury.
Answer: Low vaginal fistulas are repaired via a transanal
or a perineal approach. The common procedures used include an
anterior rectal advancement flap and mucosal advancement flap
with or without an overlying sphincteroplasty.33-42 Anterior rectal
flaps have a varied success rates reported in the literature and do
not have any Level 1 evidence to support its use. However, mucosal
advancement flaps have been studied much further.33-38 The success
rate ranges from 33% to 83% depending on the number of previ-
ous repairs and if an associated sphincter injury is present.38 This
procedure is most successful in patients who have never had a previ-
ous repair and present with a simple rectovaginal without sphincter
injury. (Grade B recommendation)
6. What is the management for rectovaginal fistulas secondary
to Crohn’s disease?
Following obstetrical injury, Crohn’s disease is the second most
common etiology of rectovaginal fistula with a risk rate of 35%
in a population-based cohort study regarding 9% of all fistulous
etiologically.8 Rectovaginal fistula is related to the frequency
and severity of large bowel involvement.43-49 Rectovaginal fistula
occurs in 3.5% and 23% of patients with Crohn’s disease involv-
ing the small and large bowel, respectively.50,51 The presence of
a rectovaginal fistula increases the risk of proctectomy during a
patient’s course with the disease.46,52
Patients with no or mild symptoms may not require any
treatment.8,43,45,53 Symptomatic patients should be treated with
a multidisciplinary approach, in which medical treatment and
drainage of local sepsis are the initial steps before any definitive
treatment attempts are considered.1,43,54 Although immunosup-
pressants including biological agents are effective in intestinal
Crohn’s disease, their role in fistulous perianal Crohn’s disease
is controversial.55-62 Attempts at surgical closure have had vary-
ing degrees of success.63 A previously failed repair does not mean
that a subsequent repair will be unsuccessful. Although a primary
repair will fail 29% to 54%, the chance of a secondary repair being
successful does not change for Crohn’s disease patients.64 This
contrasts with non-Crohn’s disease patients.37,65
A minority of patients suffering from Crohn’s disease with rec-
tovaginal fistula and associated anal ulcers/fistula may be candi-
dates for surgical therapy. The majority undergo proctocolectomy.
The University of Minnesota retrospectively evaluated 51 patients
with Crohn’s disease that underwent 65 procedures.66 These pro-
cedures included seton drainage (n = 35), endorectal advancement
flap (n = 8), fibrin glue injection (n = 8), transperineal repair (n = 6),
collagen plug placement (n = 4), and bulbocavernosus flap (n = 4).
All patients were being treated for Crohn’s disease at the time of
surgery and 26/51 (51%) had received preoperative infliximab treat-
ment—minimum of three infusions, 5 mg/kg. Ten patients under-
went preoperative diversion. At a mean follow-up of 38.6 months,
27/51 (53%) fistulas healed and in 24/51 (47%) it reoccurred. Sixty
percent of diverted patients healed, whereas 51% of nondiverted
repairs were successful. Neither active proctitis nor infliximab ther-
apy significantly altered tissue healing. Twenty-seven percent of the
patients eventually required proctectomy. The presence of a stoma
was not found statistically to improve healing after repair.
In patients with complex rectovaginal fistulas and anal ulcer-
ations secondary to Crohn’s that are refractory to traditional therapy,
the Cleveland Clinic has proposed the transanal sleeve advance-
ment flap. Transanal sleeve advancement flap is a circumferential
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 Rectovaginal Fistula ■ 309

dissection of the anal mucosa/submucosa beginning at the dentate
line and proceeding cephalad until the rectum is mobilized. The
anal ulcerations and the opening of the low-lying rectovaginal fis-
tula are excised. The rectal lining is then anastomosed to the den-
tate line.67 The Cleveland Clinic reported their initial experience
with 12 points68; 1-year following surgery, two-thirds of the patients
had healed their fistula, although 38% of the prior group required
additional surgery to prompt healing. Their recommendation based
on this initial small volume trial was to offer this alternative only to
selected patients when their other alternative would be total procto-
colectomy and permanent stoma.
Answer: Treatment for rectovaginal fistulas secondary to
Crohn’s disease depends on the severity of symptoms. Patients
with minimal symptoms may not require any treatment although
patients with severe disease may be treated with medical therapy or
surgery, or a combination of both modalities. Surgical treatment is
usually reserved for patients that have complex fistulas with associ-
ated ulcerations. The procedures described include seton drainage,
endorectal advancement flap, transperineal repair, collagen plugs,
bulbocavernosus flap, and transanal sleeve advancement, all of
which have varying success rates.66 If all of the above measures fail,
then most patients will need to undergo a total proctocolectomy.
(Grade B recommendation)
7. Are there miscellaneous procedures used in the surgical
armamentarium to treat rectovaginal fistulas?
There are a variety of situations that require alternative surgical
approaches in the management of rectovaginal fistula. Not all of
these alternative situations are successful. When a substantive
destruction of the perineal body and sphincter/rectovaginal sep-
tum exists, as in a cloaca, occasionally a more complex repair is
required. A perineoproctectomy may be indicated in such a situa-
tion. This is usually only performed for a low rectovaginal fistulas.
The rectovaginal fistula tract is excised or divided; the anorectal
sphincter, vagina, and rectal mucosa are all identified, mobilized,
and repaired primarily. The Ferguson Clinic reported on a series of
95 patients operated on for rectovaginal fistula via a septal repair
after conversion to a fourth degree perineal laceration.69 Excellent
to good functional results occurred in 97% of patients.
Fistulotomy has been advocated in the literature to treat
rectovaginal fistulas. This procedure is mentioned to definitively
proscribe its use and is only mentioned as an abhorrent historical
procedure.9
Fibrin glue and a variety of plugs, primarily Surgis, have
anecdotally been used to treat rectovaginal fistulas.64,70,71 There is a
dearth of literature to support their use.72 This literature is limited
to small series reporting results. When these agents are applied
to long fistulas secondary to cryptoglandular sepsis/abscess, there
may be data to support their use. With regard to rectovaginal fis-
tula, there is a paucity of data to recommend the use of these prod-
ucts except for exceptional causes.
The transvaginal repair of rectovaginal fistula is well described
in the literature.73 This procedure has not gained in popularity
because of the superiority of transanal repair. By occluding and
repairing the rectal orifice (the high-pressure zone is ablated),
there is no requirement to repair the vagina in these repairs.
The purpose of tissue transfer procedures for patients with
rectovaginal fistulas is to provide healthy tension-free, well-
vascularized tissue in the area of the repair. A number of tissue
transfers such as gracilis, rectus, gluteus, and bulbocavernosus are
available and have been used extensively for rectovaginal fistulas
secondary to radiation injury.73
Rectovaginal fistula secondary to gynecologic and rectal
malignancy or radiation therapy for these tumors typically are
typically high or at least anatomically above the sphincter mecha-
nism. The first issue is whether definitive surgical therapy can be
performed for cure. If only palliative options are to be considered,
the options are diverting stoma, endoscopic stent placement, and
other alternative treatments.
Answer: There are a variety of situations and techniques that
require alternative approaches. A perineoproctectomy can be uti-
lized when there is substantive destruction of the perineal body
and sphincter complex.69 Fibrin glue and a variety of plugs have
been described in the literature, but are mostly successful in long
fistulas secondary to cryptoglandular sepsis/abscess.64,70-72 Tis-
sue transfer techniques provide a tension-free, well-vascularized
repair, which are most successful in patients that have under-
gone radiation therapy. Transvaginal repair and fistulotomy have
been described, but are not recommended due to the high fail-
ure rate. Palliative options include stents and diverting stomas
which can be utilized in patients with rectal malignancy. (Grade
C recommendation)

Clinical Question Summary

Question
1 Who is at risk to develop a
rectovaginal fistula?
2 How do patients with
rectovaginal fistulas present
clinically?
3 How do we establish the
diagnosis of rectovaginal
fistulas?
4 What are the indications
for abdominal repair of
rectovaginal fistula?
Answer Grade of References
Recommendation
The most common risk factors include obstetric trauma, B 1-7
inflammatory bowel disease, cancer, diverticulitis,
penetrating trauma, and pelvic surgery.
Most patients will complain of flatus, feces, purulent B 9
discharge, frequent urinary tract infections, or
malordous vaginitis.
History and physical examination, colonoscopy, endoanal C 10-14
MRI, CT scan, anal ultrasound, and contrast studies
(proctography, vaginography, and cinedefecography).
High fistulas above the sphincter complex. Repairs B 7, 15-29
include bowel resection with coloanal anastomosis and
primary repairs with interposition flaps.

(Continued)

PMPH_CH37.indd 309 5/22/2012 5:26:55 PM

 310 ■ Surgery: Evidence-Based Practice

(Continued)
Question
5 What are the indications for
perineal and transanal repair
of rectovaginal fistula?
6 What is the management
for rectovaginal fistulas
secondary to Crohn’s disease?
7 Are there miscellaneous
procedures used in the
surgical armamentarium to
treat rectovaginal fistulas?
Answer Grade of References
Recommendation
Low fistulas below the sphincter complex. Repair B 30-42
options include an anterior rectal advancement flap
and mucosal advancement flap with or without an
overlying sphincteroplasty.
Multimodal including medical and surgical treatments. B 8, 37, 43-68,
Surgery ranges from seton drainage to 74, 75
proctocolectomy depending on severity of symptoms.
Multiple procedures can be used with varying success C 9, 15, 71
including perineoproctectomy, fibrin glue, plugs, and
tissue transfer procedures.

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5/22/2012 5:26:55 PM
 Commentary on
Rectovaginal Fistula
The chapter entitled “Rectovaginal Fistula” by Schulte, Ming,
Olsen and Caushaj provides an excellent review of a difficult clin-
ical problem. Overall, the literature on treatment of rectovaginal
fistulas is characterized by small single-institution series with-
out Level 1 evidence. The authors address several important
questions including (1) Who is at risk to develop a rectovaginal
fistula? (2) How do patients with rectovaginal fistulas present
clinically? (3) How do we establish the diagnosis of rectovagi-
nal fistulas? (4) What are the indications for abdominal repair
of rectovaginal fistula? (5) What are the indications for perineal
and transanal repair of rectovaginal fistulas? (6) What is the
management for rectovaginal fistulas secondary to Crohn’s dis-
ease? and (7) Are there miscellaneous procedures used in the
surgical armamentarium to treat rectovaginal fistulas?
Although the most common cause of rectovaginal fistula is
obstetric trauma, it is important to recognize the global differences
in the presentation and subsequent treatment of rectovaginal fis-
tulas in developed and underdeveloped nations. Obstetric fistulas
are relatively common in underdeveloped countries.1 In Africa
and Asia, an estimated 3.5 million women are affected by obstet-
ric fistula and an estimated 130,000 new cases occur each year.2
Although hospitals have been built solely to treat women with
obstetric fistula in these regions, the backlog of cases in Northern
Niger alone is believed to be at least one million women.1,3 The pri-
mary cause of these fistulas is obstructed labor in women or girls
who have no access to obstetric care and have obstructed labor for
3 or 4 days. The birth is often associated with a stillborn and the
necrotic tissue and rectovaginal septum slough resulting in a large
fistula. For every maternal death from obstructed labor it is esti-
mated that there are 1.8 obstetric fistulas.4 Such fistulas are often
quite large and may also involve adjacent organs such as the blad-
der with associated bowel and urinary incontinence. The social
consequences of such fistulas are significant and there are high
rates of divorce, separation, abandonment, and social isolation.
Rectovaginal fistulas may also occur as a complication of a
variety of other pelvic and anorectal procedures including hyster-
ectomy, low anterior resection, ileal pouch anal anastomosis, the
procedure for prolapse and hemorrhoids (PPH), and the stapled
transanal rectal resection (STARR) procedure. Anastomotic vagi-
nal fistulas may occur in up to 13% of women after low anterior
resection for rectal cancer; risk factors include low anastomosis
and preoperative radiation.5 Ileoanal pouch vaginal fistulas may
occur in 4% to 14% of women and typically have an early or late
presentation.6 Early fistulas are commonly a manifestation of
312
PMPH_CH37.indd 312
Patricia L. Roberts
anastomotic leakage or pelvic sepsis while late fistulas are more
likely to be caused by unsuspected Crohn’s disease. Meticulous
surgical technique and ensuring that the perivaginal tissues are
separated from the rectum when performing a stapled anastomosis
help avoid such fistulas.
As the authors point out, the signs and symptoms of rec-
tovaginal fistula are generally straightforward; passage of stool
or air per vagina. Despite straightforward signs and symptoms,
most patients delay in seeking medical attention. The commonly
offered reasons are social embarrassment, the desire to have more
children prior to embarking upon a repair, or the belief (propa-
gated by some gynecologists) that their “symptoms are to be
expected after childbirth.” Women with a colovaginal fistula from
diverticular disease often have few abdominal symptoms and may
initially present to a gynecologist with complaints of malodorous
vaginal discharge.
The authors have provided a stepwise approach to establish-
ing the diagnosis of a rectovaginal fistula. Low rectovaginal fistu-
las are fairly easy to diagnose in the clinic/hospital if one knows
what they are looking for and other adjuncts such as vaginal tam-
pons and methylene blue and sigmoidoscopy with insufflations or
air with water in the vagina are rarely needed. If a fistula is diag-
nosed with the methylene blue method, the location of the fistula
still needs to be determined by the surgeon in vivo. On digital rec-
tal examination, an anterior dimple or roughening is commonly
palpated. Anoscopy confirms this finding and a probe can usu-
ally be passed into the vagina quite easily in the office. Obstetric
fistulas are generally quite distal and easy to demonstrate in this
way. Pouch vaginal or anastomotic vaginal fistulas may require
contrast examinations to demonstrate and are difficult to visual-
ize endoscopically. The key points to evaluate in the office are the
integrity of the anal sphincter with determination of continence,
the status of the tissue around the fistula, and the location of the
fistula (in relation to the anal verge). Assessment of these factors
is mandatory to establish the optimal treatment for a rectovaginal
fistula; for instance, rectovaginal fistulas with total sphincter dis-
ruption require sphincter repair in addition to repair of the fistula
itself. Recurrent fistulas with tissue loss in patients who have had
multiple repairs may require tissue transfer techniques such as a
gracilis muscle transposition or a bulbocavernosus flap.
The authors have thoroughly outlined the indications for
abdominal repair of rectovaginal fistulas—generally high fistulas,
more appropriately termed colovaginal fistulas, will require an
abdominal repair and resection of the affected segment of bowel.
5/22/2012 5:26:55 PM

The optimal initial procedure for an obstetric fistula is the
source of an ongoing debate. The most commonly performed pro-
cedures include endorectal advancement flaps with or without con-
comitant sphincter repair and transperineal procedures including
episioproctotomy and layered repair. A substantial number of
women with obstetric fistulas have an underlying sphincter defect
and some degree of fecal incontinence. Such patients require repair
of the underlying sphincter defect in addition to fistula repair.
Performing an endorectal advancement flaps without addressing
the underlying sphincter defect is associated with a failure rate of
up to 60%.7 Episioproctotomy (or essentially conversion of the fis-
tula to a fourth degree perineal laceration with layered repair) is
another option.8 It is difficult to compare the results of the various
procedures; there have been no randomized trials and the avail-
able literature contain relatively small single-institution series with
heterogeneous groups of patients. There has been renewed interest
in collagen fistula plugs or a modification of the plug with a special
button; the results have generally been disappointing. These proce-
dures have the advantage of having minimal morbidity.
Patients with Crohn’s disease are particularly challenging to
treat. Up to 10% of women with Crohn’s disease develop a rec-
tovaginal fistula during the course of their disease. The optimal
repair should be put into context with the symptoms (some women
with rectovaginal fistulas and Crohn’s are remarkably minimally
symptomatic), and any associated anal or rectal disease. Local
repairs are not advisable in the setting of active Crohn’s procti-
tis. The ultimate rate of success with Crohn’s fistulas is about 50%
and a cohort of women ultimately requires fecal diversion and/or
proctectomy.9 It is helpful to discuss this with the patient to frame
the initial discussion.
The failure rate after repair of rectovaginal fistula is significant.10,11
Failed repairs are often associated, at least initially, with a larger and
more symptomatic fistula. Failure of a repair is often emotionally
devastating to the patient. Multiply recurrent or persistent fistulas,
particularly those associated with tissue loss may then require tis-
sue transfer techniques such as a gracilis muscle transposition or a
bulbocavernosus flap. With the extent of the dissection and mobili-
zation with these repairs, temporary fecal diversion, with a laparo-
scopic loop colostomy may be performed. Although fistula healing
is eventually achieved in the majority of patients, concerns about
self-image (from the cosmetic appearance of the site) in addition to
alterations in sexual function, including dyspareunia, may impact
overall satisfaction with the procedure and quality of life.
PMPH_CH37.indd 313
Rectovaginal Fistula ■ 313
Treatment for rectovaginal fistulas is challenging. The opera-
tive approach depends on a variety of factors including the size,
location, condition of the surrounding tissues, and association
with concomitant disease, such as Crohn’s disease. Although
a successful repair is ultimately achieved in the majority of
patients, ultimate healing may require a number of different
repairs.
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10. Pinto RA, Peterson RV, Shawki S, et al. Are there predictors of
outcome following rectovaginal fistula repair? Dis Colon Rec-
tum. 2010:53:1240-1247.
11. Roberts PL. Rectovaginal and rectourethral fistulas. In: J Pem-
berton, ed. Shackleford’s Surgery of the Alimentary Tract. 6th ed.
Philadelphia, PA: WB Saunders/Elsevier; 2007:1945-1957.
5/22/2012 5:26:55 PM
 CHAPTER 38
Lower Gastrointestinal Bleeding
Kerry G. Bennett and Steven Schwaitzberg
INTRODUCTION
Lower gastrointestinal bleeding (LGIB) represents 20% to 33%
of gastrointestinal (GI) bleeding but is likely underreported.1
Advances in diagnosis and treatment have led to a shift from sur-
gery as the mainstay of treatment to less invasive modalities. An
important principle in approaching LGIB in patients is to differen-
tiate the site of bleeding; that is, determine if the bleeding source
is proximal or distal to the ileocecal valve. The major causes of
LGIB are diverticulosis, inflammatory bowel disease (IBD), colitis,
carcinoma, angiodysplasia, and anorectal disease with diverticu-
losis, and IBD as the most common etiologies.2
Evidence in LGIB contains few prospective studies.3 The
majority of evidence is historical, based on small case series,
cohorts, and expert opinion. The time-tested tool of colonoscopy
for diagnosis and treatment is used widely at present with vary-
ing results. When taking into account the rating scheme for the
strength of recommendations, much of the current clinical prac-
tice is based on Level 4 evidence. That is, the evidence level is
based on case reports or case series or expert opinion and not on
high-quality meta-analyses, randomized controlled trials (RCT)
or RCT with a very low risk of bias. This is likely due to chal-
lenges secondary to the nature of LGIB, which does not easily lend
itself to RCT or large analyses. Further, there are many challenges
to diagnosis and therapy secondary to differences in individual
patients, services, and treating facilities. Availability of coordinat-
ing services such as nuclear medicine and interventional radiology
often determines what options are available for an individual at a
specific institution.
In this chapter, we review the available literature regarding
LGIB. We focus on the diagnostic and therapeutic options and
the supporting data and end with a summary of current recom-
mendations in the management of LGIB.
1. What is the ideal order of diagnostic testing in the setting
of LGIB?
First, evaluation to differentiate an upper from a lower source of
GI bleeding must be done. Data reveal that approximately 10%
314
PMPH_CH38.indd 314
of patients thought to have LGIB are found to actually be bleeding
from proximal to the ileocecal valve.4,5 In brief, for brisk active
bleeding, the available modality that best provides rapid diagno-
sis and treatment of the bleeding is the first choice. Colonoscopy
may be the most accurate single-stage evaluation as suggested
by the only RCT done on LGIB.5,6 Unfortunately, it is not always
readily available. Angiography is emerging as a possible first-line
diagnostic test in facilities with a strong interventional radiology
department but can be associated with a relatively low diagnostic
yield unless the bleeding is brisk enough.7,8 In slow active bleed-
ing, current recommendations include beginning with a colonos-
copy or a tagged red blood cell scan (TRBC). If the scintigraphy is
positive, proceed with an angiogram. If the scintigraphy is nega-
tive, proceed with either angiography, colonoscopy, or repeat TRBC
scan.9,10 As LGIB patients are often volume–depleted, complica-
tions from dye injection must also be considered. These problems
can be minimized by using scintigraphy or computer tomography
(CT) before angiogram.9-12 Surgery is the best approach for severe
bleeding.13
Answer: Colonoscopy is the most accurate modality and
allows for diagnosis and treatment of LGIB. (Grade C recom-
mendation) The ideal order of tests in the setting of LGIB is
best determined by available resources in each treatment setting
although traditionally colonoscopy is used first and angiogra-
phy has been used if colonoscopy fails or cannot be performed.
(Grade C and D recommendations). Scintigraphy and CT prior
to angiography can help further differentiate proximal sources
and decrease complications secondary to angiography. (Grade C
recommendation)
2. What is the diagnostic accuracy of colonoscopy, radionu-
clide scanning, and angiography in the setting of LGIB?
Scintigraphy and angiography alone are often not sufficient
to guide surgical resection, and recommendations are based
on Level 4 evidence. Hunter and Pezim14 found that up to 42%
of patients can have an undesirable result if limited surgi-
cal resection is planned on the basis of Tc-99–labeled RBCs
alone. Although angiogram alone is of limited sensitivity and
5/22/2012 5:27:32 PM
 Lower Gastrointestinal Bleeding ■ 315

specificity, the yield of positive arteriography can be improved 4. What is the diagnostic accuracy of Tc-99 sulfur colloid
with the use of scintigraphy prior to angiogram.7,15 In a study (Tc-99m) injection versus Tc-99 TRBCs?
done in 1998, the complication rate of angiogram has been
In 1982, Alavi27 reported on the intravenous administration of
found to be 11%, whereas the diagnostic yield of site localiza-
Tc-99m (Level 4 evidence) and the ability to detect bleeding rates
tion for colon resection was 12%.16 More recent data in a small
as low as 0.05 mL/min even in patients with negative arteriog-
(34 patients) retrospective study at one institution reveal that
raphy. In the next year, Winn et al.28 presented a retrospective
angiogram results in bleeding localization in 33% of patients
review in 63 patients that suggested that if the Tc-99m study
tested with 10/11 patients controlled successfully with embo-
were negative, then 15% of arteriograms were positive. At the
lization. One embolization-related complication occurred
same time, other authors suggested 85% sensitivity, 100% speci-
(perforation of ischemic bowel) and no hemorrhagic complica-
ficity, and 91% accuracy with the Tc-TRBC, but sensitivity for
tions occurred.17
scintigraphy reported in the literature ranges from 20 to 95.29-31
Helical CT and CT angiogram (CTA) have emerged as a
Markisz et al.30 found no occurrences of positive arteriogram
good diagnostic tool for identification of LGIB. CTA has been
when scintigraphy was negative. There is very little comparative
found to be 70% to 80% sensitive and 100% specific for evalu-
literature except in 1985 when Siddiqui et al.32 compared Tc-99m
ation of LGIB.18-22 Multidetector row helical CT (MDCT) has
and TRBC in 27 patients prospectively (Level 1b evidence) and
been found to be 92% accurate in detection and localization of
found a greater sensitivity in the TRBC group. Both Tc-99m and
hemorrhage. 23 Twenty-six patients with massive GI hemorrhage
TRBC produced positive results in 70% of patients studied.32
were studied with MDCT and the result showed that MDCT
Other retrospective studies show a high sensitivity and less spec-
was 90% sensitive and 99% specific with an accuracy of 88%
ificity with TRBC suggesting that its greatest utility may be as a
and a negative predictive value of 98%.11 Th is suggests that arte-
screen for patients in whom angiography will be helpful. Local-
riogram may not be indicated in negative MDCT studies. In
ization for surgical resection using either form of Tc-99 study
2005, it became accepted that MDCT is readily available and
without a different localization study is often not possible.33-43
sufficiently sensitive as an initial screen for LGIB.12 As early
Further, arteriogram may be most helpful in those patients with
as 1976, studies comparing arteriogram and pan endoscopy
early positivity on scintigraphy.31
in LGIB were done. Chaudry5 found that 63% of 55 patients
Answer: TRBC appears superior to Tc-99m injection. (Grade B
studied with active bleeding were endoscopically controlled
recommendation) In both tests, only about half of the patients
even when the colon was unprepped. Haykir et al. 24 evaluated
will have positive results. If scintigraphy is positive, further
magnetic resonance (MR) and CT colonography with con-
localization studies are needed to improve anatomic accuracy
ventional colonoscopy and found that MR was slightly more
in surgical resection. (Grade C recommendation) Arteriography
accurate than CT and similar to conventional colonoscopy in
has its greatest utility when scintigraphy is negative. (Grade C
sensitivity with discovery of the lesion 96% of the time. (Level 3b
recommendation) Overall, both these nuclear medicine scans
evidence).
lack accuracy and should not be used in brisk bleeding. (Grade C
Answer: Colonoscopy has traditionally been the most accu-
recommendation)
rate method of diagnosing LGIB and considered to be the gold
standard for diagnosis and treatment of LGIB. (Grade C rec-
ommendation) Angiography is emerging as a possible first- 5. What is the clinical effectiveness of intra-arterial vasopres-
line for diagnosis and treatment. (Grade D recommendation) sin infusion versus transcatheter embolization?
Scintigraphy may help determine candidates for angiographic
Vasopressin has been found to be highly (92%) effective in
screening, but it is not sufficient for operative planning alone.
stopping LGIB. (Level 4 evidence ) Athanasoulis et al.44 stud-
(Grade D recommendation) MDCT appears very promising as
ied 24 patients hemorrhaging from colonic diverticulosis and
a readily available, noninvasive modality for operative planning;
found that in 22 of the patients studied bleeding ceased with
however, further studies are needed to confi rm this. (Grade D
the selective infusion of intra-arterial vasopressin. Fourteen
recommendation)
(58%) of the patients in this study underwent surgical resection
for persistent hemorrhage, rebleeding, or planned resection.
This is consistent with prior reporting.44,45 (Level 4 evidence)
3. Does urgent colonoscopy need to be performed for LGIB?
Intra-arterial vasopressin has also been found to control colonic
Historically, colonoscopy has been believed to be the most accu- hemorrhage in 63% of the patients studied with a rebleed rate of
rate method of diagnosing LGIB. At least two studies25 have 16%.46 As practitioners have become more effective and adept with
questioned this claim. Both studies suggest that urgent colonos- intra-arterial infusion, rates of bleeding control have increased
copy may confer little benefit for patients hospitalized for LGIB. up to at least 90%, but the rebleed rate can approach 50%.47
Unfortunately, small sample size (up to 85 patients studied) limits Since 1965 when Baum et al.48 described mesenteric angio-
interpretative power. Further, the majority of patients who bleed graphy for the diagnosis of GI bleeding, this modality has
less than four units of packed red blood cells (PRBC) cease bleed- become well utilized in the diagnosis and treatment of LGIB.48
ing without intervention.26 Colonoscopy is the diagnostic and Although angiography was first employed as a diagnostic tool
therapeutic treatment of choice for acute LGIB and the timing where bleeding was identified by the identification of extra-
must be determined by the clinical setting.13 vasation of contrast material, it is now used therapeutically by
Answer: Recently, a question has emerged regarding con- selective and super-selective embolization. Numerous reports
sidering colonoscopy to be the traditional gold standard for the show that intra-arterial embolization has similar-to-improved suc-
diagnosis and treatment of LGIB. (Grade D recommendation) The cess rates than that of vasopressin, and concomitant increased
exact timing of colonoscopy needs further study. complications.45,49-52 (Level 4 evidence) Hemorrhage control

PMPH_CH38.indd 315 5/22/2012 5:27:33 PM

 316 ■ Surgery: Evidence-Based Practice
appears to be similar, but the rebleed rate is less with embo-
lization than with vasopressin infusion.53 More recently, super-
selective embolization has been utilized with great success
and less necrotic complications.54-60 There appears to be no
difference between specific etiologies of LGIB and the rate of
embolization success.61
Answer: Intra-arterial vasopressin infusion is excellent (app-
roximately 90% success rate) for cessation of bleeding, but has sig-
nificant drawbacks such as systemic vasoconstriction, coronary
ischemia, and a variable but significant rate of rebleeding after
therapy cessation. (Grade D recommendation) Embolization is
as effective as vasopressin infusion, improves selective control,
avoids systemic side effects, and has less early rebleeding but an
increased rate of colon ischemia. (Grades C and D recommenda-
tions) Super-selective therapy does not eliminate ischemia risk
to the colon, has decreased the amount of surgery performed for
acute LGIB, and appears to decrease complication rates. (Grade D
recommendation) Late rebleeding rate is the same with vasopres-
sin and embolic therapy.
6. What is the role of capsule and push endoscopy in LGIB?
The established diagnostic tools of endoscopic gastroduodenos-
copy (EGD) and colonoscopy for GI bleeding have often been
used prior to angiography and scintigraphy. Capsule endoscopy
offers a novel approach to hemodynamically stable patients
and can lead to changes in clinical management and improved
outcomes.62-67 A meta-analysis showed that diagnostic yield is
greater for capsule than for push endoscopy and small bowel
radiography.68 Recent innovations and an increase in use of
capsule endoscopy have found its greatest utility in obscure GI
bleeding.69 Obscure GI bleeding occurs in up to 10% to 20% of
patients with LGIB and is most commonly defined as bleeding
that is persistent or recurrent without a source identified on stan-
dard investigational diagnostic tools such as upper endoscopy
and colonoscopy.70 Push enteroscopy has not been well studied
secondary to lack of widespread availability and patient stability
at the time of presentation.70
Answer: Patients with obscure (persistent, recurrent bleed-
ing without an identified source) GI bleeding are candidates for
capsule or push endoscopy after negative upper endoscopy and
colonoscopy. (Grade D recommendation)
7. What are the criteria for surgical intervention in LGIB and
what operation should be done?
Patients who require more than two units of blood should receive
an evaluation to localize the source of bleeding expeditiously.71,72
Surgery is best for those patients that continue to bleed, those that
rebleed, and is ideally done after localization to minimize bowel
resection. Testing can delay therapy, but this must be balanced
with ensuring the source of bleeding, especially if it is proximal
or distal to the ileocecal valve.71 (Level 4 evidence) Localization
of massive LGIB lowers perioperative mortality when compared
with blind resection, but remains high at about 8% to 18%.8,11,23
(Level 4 evidence) The literature reveals great variability in rates
PMPH_CH38.indd 316
of morbidity of emergent subtotal colon resection. Many do
report that it is well tolerated and associated with a low rebleeding
rate although conflicting reports of high morbidity and mortal-
ity exist.16,73-76 Many patients with LGIB do not require colonic
resection. McGuire26 showed that bleeding stopped in 99% of
cases where four or less units of PRBC were transfused. (Level 4
evidence) Many authors have noted that up to 97% of patients
with LGIB are managed nonoperatively.77-79 Transfusion require-
ments have been offered as a reason to resect.80 Various recom-
mendations have been made. Those who present to the emergency
department in a hypotensive state can benefit from earlier resec-
tion and has been found to be associated with lower perioperative
mortality.75,81
Answer: Grade C recommendations currently are that patients
who present with LGIB and receive more than two units of blood
should undergo expeditious localization of the bleeding source.
Persistent bleeding with anatomic localization can facilitate seg-
mental resection. Patients who are not candidates for segmental
resection (i.e., unable to localize preoperatively) and continued
bleeding or rebleed are well treated with a subtotal colectomy and
ileo-rectostomy. (Grade C recommendations)
CONCLUSIONS
Due to the nature of LGIB, it is important to remember that
almost all recommendations are considered to be Grade C or D
defi ned by the U.S. Preventive Services Task Force as “Grade C:
At least fair scientific evidence suggests that there are benefits
provided by the clinical service, but the balance between benefits
and risks are too close for making general recommendations.
Clinicians need not offer it unless there are individual consid-
erations” and “Grade D: At least fair scientific evidence suggests
that the risks of the clinical service outweigh potential benefits.
Clinicians should not routinely offer the service to asymptom-
atic patients.” Obviously, patients with LGIB are symptomatic
and the risk:benefit ratio is in favor of localization and bleeding
cessation.
Current recommendations in the management of LGIB:
Localization:
1. Localization of the bleeding with the cause and site should be
determined by the early use of colonoscopy, and use of CT,
CTA, or digital subtraction angiography.
2. Nuclear scintigraphy assists in the localization of bleeding and
the use of angiography.
Interventions:
1. Colonoscopic bleeding to control hemorrhage is best used in
acute diverticular and postpolypectomy bleeding.
2. Angiographic embolization.
3. Surgery-localized resection or subtotal colectomy. The extent
of surgical resection is often largely based on preoperative
localization studies and their accuracy.
5/22/2012 5:27:33 PM
 Lower Gastrointestinal Bleeding ■ 317

Clinical Question Summary

Question Answer Grade of Level of References
Recommendation evidence
1 What is the ideal Differentiate upper gastrointestinal (UGI) CC, DC 444 4, 12, 54-88
order of diagnostic from lower gastrointestinal (LGI) sources.
testing in the setting Colonoscopy may be the single best test at
of LGIB? most institutions and angiography at others. In
slow active bleeding starting with colonoscopy,
scintigraphy or CT followed by angiogram is
scintigraphy is positive.
2 What is the Colonoscopy is the gold standard for diagnosis and CD, DD 4444 2, 5-7, 11-24,
diagnostic accuracy treatment of LGIB. Angiography is emerging as 46
of colonoscopy, a possible first-line for diagnosis and treatment.
radionuclide Scintigraphy may help determine candidates
scanning, and for angiographic screening and is not adequate
angiography in the for preoperative planning alone. CT appears
setting of LGIB? promising as a highly available, noninvasive
modality for operative planning.
3 Does urgent Urgent colonoscopy may not be needed as the D 4 25
colonoscopy need natural history for most bleeding is to stop.
to be performed for The exact timing of colonoscopy needs
LGIB? further study.
4 What is the Tc-99 labeled RBCs appear superior to Tc-99 sulfur BC 1b4 27-43
diagnostic accuracy colloid injection. For all comers, about half of
of Tc-99sulfur the scans will be positive. Angiography is not
colloid injection vs. indicated when scintigraphy is negative. Positive
Tc-99 TRBCs? scans should be followed up with further
localization studies to improve
anatomic accuracy.
5 What is the clinical Intra-arterial vasopressin ceases bleeding in the D, C, D 444 44-46,
effectiveness of majority of patients. Embolization is as effective 48-61, 53
intra-arterial as vasopressin infusion, improves selective
vasopressin infusion control, avoids systemic effects, has less early
vs. transcatheter rebleeding but an increased rate of colon
embolization? ischemia. The late rebleeding risk is 10% to
15% with either technique.
6 What is the role of Patients with obscure (persistent, recurrent D 4 62-67, 70
capsule and push bleeding without an identified source) LGIB
endoscopy in LGIB? are candidates for capsule or push endoscopy
after negative upper endoscopy and
colonoscopy, if available.
7 What are the Patients who bleed two or more units of blood CCC 444 8, 11, 16, 23,
criteria for surgical should receive an evaluation to localize the 26, 71-81
intervention in LGIB source of bleeding expeditiously. Clinical
and what operation stability and available testing options will
should be done? determine to what extent localization studies
can be performed so that excessive transfusion
is avoided (>10 units). Persistent bleeding
with true anatomic localization may allow
for segmental resection otherwise subtotal
colectomy with ileo-rectostomy should be
performed.

PMPH_CH38.indd 317 5/22/2012 5:27:33 PM

 318 ■ Surgery: Evidence-Based Practice
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nal bleeding?(2)(2). Curr Surg. 2001;58:323-327.
52. DeBarros J, Rosas L, Cohen J, Vignati P, Sardella W, Hallisey M.
The changing paradigm for the treatment of colonic hemorrhage:
Super selective angiographic embolization. Dis Colon Rectum.
2002;45:802-808.
53. Gomes AS, Lois JF, McCoy RD. Angiographic treatment of gas-
trointestinal hemorrhage: Comparison of vasopressin infusion
and embolization. AJR Am J Roentgenol. 1986;146:1031-1037.
54. Nawawi O, Young N, So S. Superselective coil embolization
in gastrointestinal haemorrhage: Early experience. Australas
Radiol. 2006;50:21-26.
55. Kickuth R, Rattunde H, Gschossmann J, Inderbitzin D, Ludwig
K, Triller J. Acute lower gastrointestinal hemorrhage: Minimally
invasive management with microcatheter embolization. J Vasc
Interv Radiol. 2008;19:1289-1296, e2.
56. Chin AC, Singer MA, Mihalov M, et al. Super selective mesen-
teric embolization with microcoils in a porcine model. Dis Colon
Rectum. 2002;45:212-218.
57. Burgess AN, Evans PM. Lower gastrointestinal haemorrhage and
super selective angiographic embolization. ANZ J Surg. 2004;74:
635-638.
58. Ledermann HP, Schoch E, Jost R, et al. Superselective coil embo-
lization in acute gastrointestinal hemorrhage: Personal experience
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Lower Gastrointestinal Bleeding ■ 319
in 10 patients and review of the literature. J Vasc Interv Radiol.
1998;9(5):753-760.
59. Frodsham A, Berkmen T, Ananian C, Fung A. Initial expe-
rience using N-butyl cyanoacrylate for embolization of lower
gastrointestinal hemorrhage. J Vasc Interv Radiol. 2009;20(10):
1312-1319.
60. Kuo Wt, Lee De, Saad WE, et al. Superselective microcoil embo-
lization for the treatment of lower gastrointestinal hemorrhage.
J Vasc Interv Radiol. 2003;14(2):1503-1509.
61. Khanna A, Ognibene SJ, Koniaris LG. Embolization as fi rst-line
therapy for diverticulosis-related massive lower gastrointestinal
bleeding: Evidence from a meta-analysis. J Gastrointest Surg.
2005;9(3):343-352.
62. Carey EJ, Leighton JA, Heigh RI, et al. A single-center experi-
ence of 260 consecutive patients undergoing capsule endos-
copy for obscure gastrointestinal bleeding. Am J Gastroenterol.
2007;102(1):89-95.
63. Laine L, Sahota A, Shah A. Does capsule endoscopy improve
outcomes in obscure gastrointestinal bleeding? Gastroenterol-
ogy. 2010;138(5):1673-1680.
64. Albert JG, Schulbe R, Hahn L, et al. Impact of capsule endoscopy
on outcome in mid-intestinal bleeding: A multicentre cohort
study of 285 patients. Eur J Gastroenterol Hepatol. 2008;20:
971-977.
65. Pennazio M, Santucci R, Rondonotti E, et al. Outcome of patients
with obscure gastrointestinal bleeding after capsule endoscopy:
Report of 100 consecutive cases. Gastroenterology. 2004;126:
643-653.
66. Neu B, Ell C, May A, et al. Capsule endoscopy versus standard
tests in influencing management of obscure digestive bleeding:
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205;100:1736-1742.
67. Estevez E, Gonzalez-Conde B, Vazquez-Iglesias JL, et al. Diag-
nostic yield and clinical outcomes after capsule endoscopy in 100
consecutive patients with obscure gastrointestinal bleeding. Eur
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68. Triester SL, Leighton JA, Leontiadis GI, et al. A meta-analysis
of the yield of capsule endoscopy compared to other diagnostic
modalities in patients with obscure gastrointestinal bleeding.
Am J Gastroenterol. 2005;100:2407-2418.
69. Raju GS, Gerson L, Das A, et al. American Gastroenterological
Association (AGA) technical review on obscure gastrointesti-
nal bleeding. Gastroenterology. 2007;133:1697-1717.
70. de Leusse A, Vahedi K, Edery J, et al. Capsule endoscopy or push
enteroscopy for first-line exploration of obscure gastrointestinal
bleeding? Gastroenterology. 2007;132:855-862.
71. Rozycki GS, Tremblay L, Feliciano DV, et al. Three hundred con-
secutive emergent celiotomies in general surgery patients: Influ-
ence of advanced diagnostic imaging techniques and procedures
on the diagnosis. Ann Surg. 2002;235:681-688; discussion 8-9.
72. Strate LL, Saltzman JR, Ookubo R, et al. Validation of a clinical
prediction rule for severe acute lower intestinal bleeding. Am J
Gastroenterol. 2005;100:1821-1827.
73. Baker R, Senagore A. Abdominal colectomy offers safe man-
agement for massive lower GI bleed. Am Surg. 1994;60:578-581;
discussion 82.
74. Farner R, Lichliter W, Kuhn J, et al. Total colectomy versus lim-
ited colonic resection for acute lower gastrointestinal bleeding.
Am J Surg. 1999;187:587-591.
75. Field RJ, Sr., Field RJ, Jr., Shackleford S. Total abdominal colec-
tomy for control of massive lower gastrointestinal bleeding.
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76. Setya V, Singer JA, Minken SL. Subtotal colectomy as a last resort
for unrelenting, unlocalized, lower gastrointestinal hemorrhage:
Experience with 12 cases. Am Surg. 1992;58:295-299.
77. Bokhari M, Vernava AM, Ure T, Longo WE. Diverticular hem-
orrhage in the elderly—is it well tolerated? Dis Colon Rectum.
1996;39:191-195.
78. Al Qahtani AR, Satin R, Stern J, Gordon PH. Investigative
modalities for massive lower gastrointestinal bleeding. World J
Surg. 2002;26:620-625.
PMPH_CH38.indd 320
79. Buttenschoen K, Buttenschoen DC, Odermath R, Beger HG.
Diverticular disease-associated hemorrhage in the elderly. Lan-
genbecks Arch Surg. 2001;386:8-16.
80. Rios A, Montoya MJ, Rodriguez JM, et al. Severe acute lower gas-
trointestinal bleeding: Risk factors for morbidity and mortality.
Langenbecks Arch Surg. 2007;392:165-171.
81. Clarke CS, Afifi AY. Impact of blood transfusion on outcome in
patients admitted for gastrointestinal hemorrhage. Curr Surg.
2000;57:493-496.
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 PART V

THE LIVER

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PMPH_CH39.indd 322 5/22/2012 5:28:06 PM

Newer Techniques in Liver Surgery
Anil S. Paramesh, Robert Cannon, Joseph F. Bue11
1. What is new in liver imaging studies?
Imaging of the liver is integral to a liver surgeon’s perspective,
allowing for proper planning of liver resections. Imaging stud-
ies have continued to improve over the past few years and have
increased the scope of liver surgery preparation.
Although ultrasound is the current standard for surveillance
of chronic hepatitis patients for hepatocellular carcinoma (HCC),1
it is with the knowledge that it has decreased sensitivity for smaller
lesions and it may be difficult to find smaller masses in a cirrhotic liver.
Newer techniques such as contrast-enhanced ultrasound use car-
bon dioxide microbubbles to help detect and differentiate liver
masses and evaluate flow differences in the liver parenchyma.2
Contrast ultrasound detects liver masses better than routine
ultrasound. One study determined that the sensitivity and speci-
ficity of contrast-enhanced ultrasonography for discrimination of
benign versus malignant lesions was 100% and 63%, respectively.3
This modality is useful for detecting smaller lesions (<1 cm), very
superficial lesions, or lesions close to the ligamentum teres.
One of the advances in ultrasonic evaluation of the liver is
transient elastography measurement. With this technique, we can
measure the stiffness of the liver noninvasively, which would cor-
relate with the level of fibrosis, without the need for a liver biopsy.4
Such assessment would be an adjunct in preoperative assessment
for a liver resection.
Intraoperative ultrasound remains a valuable tool during a
liver resection. Smaller lesions (between 2 and 5 mm) can be picked
up with this technique, all of these smaller lesions may have been
missed by other imaging studies.5 With the advent of laparoscopic
liver resections, laparoscopic probes are available to be used in
such cases as well.
The most commonly performed test for liver masses remains
a triple-phase (unenhanced, arterial, and portal phases) con-
trast CT scan. With newer 64 row scanners, we are now able to
see much better anatomy. Arterial enhancing masses with rapid
portal washout are diagnostic for primary liver cancers and have
almost done away with the need for biopsies. Metastatic lesions are
also well visualized, with some (renal cell/breast primary) show-
ing arterial enhancement, while others (colon/stomach primary)
323
PMPH_CH39.indd 323
CHAPTER 39
showing lower attenuation. Three-dimensional (3D) reconstruc-
tions are also possible, allowing assessment of spatial relation-
ships with vascular structures to plan resection.
Magnetic resonance imaging (MRI) has recently gathered pop-
ularity as a valuable imaging tool for liver masses/resection. Triple-
phase MRI scans using gadolinium-based contrast are possible,
with a much lower volume of contrast. Two newer MRI contrast
agents gadobenate dimeglumine (MultiHANCE™) and gadoxetate
disodium (Eovist®) have a dual route of excretion, both by renal and
hepatobiliary means. Five percent of the injected dose is taken up
by hepatocytes and excreted through the biliary system. Thus, liver
lesions which contain hepatocytes will take up contrast and can be
differentiated from ones that do not on delayed films.
2. Is ablation equivalent to resection for liver tumors?
Ablation of liver tumors, especially radiofrequency ablation (RFA),
has rapidly gained popularity in the last decade. By this technique,
high-frequency alternating current is applied via probes into
tumor tissue. Ions in the tissue that attempt to follow the change
in direction of current become heated. As the temperature of the
local tissue elevates beyond 60°C, necrosis occurs.6 Most RFA
probes are placed by ultrasound guidance. A zone of necrosis usu-
ally 0.5 to 1 cm around the mass is typically sought-after to ensure
complete tumor necrosis. RFA was initially tested for HCC, but it
is now being used for colorectal cancer (CRC) metastases as well
with good outcomes reported.7
However, RFA has its limitations. Recurrence has been quoted
to be one of the biggest drawbacks of this technique when com-
pared with resection.8 RFA is harder to accomplish with lesions
>4 cm.9 Although larger probes are being developed, in most
instances multiple overlapping ablations may be necessary to get
the entire tumor with margins. This leads to the risk of small nests
of tumor cells being left behind. Another risk is the presence of
large vessels adjoining the tumor. This may offer thermal protec-
tion from the heat of the probes, and adjacent tumor may not heat
enough to necrose. RFA is also difficult to perform on lesions near
the dome or adjacent stomach or colon, for risk of injury. Finally,
recurrence may be dependent on operator technical expertise.
5/22/2012 5:28:06 PM
 324 ■ Surgery: Evidence-Based Practice
Despite this, RFA has been reported to have up to 46% 3-year
survival rates post treatment of CRC metastases,7 which was simi-
lar to surgical resection results. Five-year survival rates of 54%
have been reported post primary RFA treatment for HCC.10
So, is RFA a better option than surgical resection? RFA is cer-
tainly a minimally invasive option and can be done percutaneously
or laparoscopically these days. The overall complication rate would
be lower with RFA versus resection. RFA can spare uninvolved
liver, which may need to be removed as part of a resection. RFA
is certainly cheaper than a liver resection. RFA can be performed
again for local recurrence with good local control.10
However, the comparison may not be that easy. To our knowl-
edge, there are no good prospective randomized clinical trials
comparing RFA with resection for CRC metastases. Many com-
parisons are retrospective, and in most cases, the RFA patients
tend to have lesser disease than their resection controls. In the
setting of HCC, there have few studies doing actual comparisons.
One study from China11 randomized 180 patients to ablation ver-
sus resection. When analyzed for intention-to-treat, there was
no difference in overall and disease-free survival rates at 4 years
between the groups. Another study from Italy12 showed sustained
(median follow-up 31 months) complete response rate of 97.2%
and 5-year survival rates of 68.5% when small (≤2 cm) HCC were
treated with RFA as primary therapy in 218 patients. These results
are comparable to resection candidates.
Thus, there is some evidence that RFA can effectively treat
and control small malignancies of the liver when done appropri-
ately. It may be considered as possible therapy for a small, centrally
located lesion, with no significant adjacent vessels, and meticulous
follow-up to watch for local recurrence. However, given the lack
of long-term studies comparing RFA with resection, the gold stan-
dard probably remains a partial resection.
3. Is percutaneous ablation equivalent to operative ablation?
RFA via a less invasive route such as a percutaneous ablation in a
radiology suite may be attractive compared with a surgical proce-
dure requiring general anesthesia in the operating room. Indeed,
previous studies had shown a higher morbidity rate with open
surgical RFAs compared with radiological percutaneous RFAs.13
However, when looking at the most important variables, includ-
ing local recurrence and survival rates, most of the literature would
support a surgical approach, whether it is open or laparoscopic.
There is little doubt that an intraoperative ultrasound would
be able to pick up additional smaller lesions that may be missed by
transcutaneous ultrasound or even a CT/MRI scan (CT, computed
tomography).5 This may even change the planned procedure.
In a large meta-analysis of 5224 patients that had RFA for pri-
mary and secondary lesions in the liver, a surgical approach (open
or laparoscopic) was shown in a multivariate analysis to be an
independent factor associated with reduced recurrence rates com-
pared with a percutaneous approach.14 Another study looked at
228 HCC tumors undergoing percutaneous versus surgical RFA.
The surgical group had better 1- and 3-year survival compared
with the percutaneous group for tumors >3 cm in size.15
Also, with minimally invasive laparoscopy, the perceived benefit
of a percutaneous approach may be less. The reported complication
rates after a laparoscopic RFA are no different from a percutaneous
approach.13 Aside from laparoscopic ultrasonography, retractors
may be placed to push the liver away from adjacent viscera, reduc-
ing the chance of injury and ensuring a better ablation.
PMPH_CH39.indd 324
There is some evidence that temporary occlusion of hepatic
flow (Pringle maneuver) during the RFA, either via open or laparo-
scopic approach, may increase the success rates of RFA.14 As dis-
cussed previously, large blood vessels adjacent to tumor may act as
a heat sink, not allowing the tumor to reach necrosis temperatures.
However, with temporary occlusion of blood flow, this risk factor
is negated. This concept is even being attempted for percutaneous
RFAs, via balloon catheter occlusion.16
Thus, while the success rates of RFA via any approach is very
operator-dependant, based on current literature, it seems that a
surgical approach may be able to visualize tumors better, protect
against visceral injury and treat lesions better. With a laparoscopic
approach, surgical morbidities may be further reduced.
4. Is there a benefit to resecting noncolorectal liver metastases?
There is little doubt that surgical resection, when possible, offers
good chance of long-term tumor-free survival. It has also been
demonstrated that surgical resection of metastatic neuroendo-
crine tumors, including the possibility of liver transplantation,
also offers a proven survival benefit.17 However, it is the possibility
of survival benefit for resection of noncolorectal, nonneuroendo-
crine (NCRNNE) liver metastases that appears controversial and
undecided as yet.
Most published studies had few patients and are not compa-
rable with each other as they may include some NCRNNE meta-
stases, different primary malignancies, different chemotherapy
regimens, and different time-to-onset of tumor (synchronous vs.
metachronous).18
Despite this, it remains clear that certain patients with
NCRNNE liver metastases may actually benefit from resection.19 In
general, there should be no extrahepatic spread; a single metastatic
lesion would fare better than multiple lesions; synchronous metas-
tases fare worse than metachronous ones. In the case of metachro-
nous tumors, a longer disease-free interval (DFI) from the primary
tumor (usually at least 12–24 months) indicates a better prognosis.
As would be expected, a proper surgical resection with adequate
margins would lend to better results, and debulking procedures
without the benefit of adjuvant therapies may be wasted.
With regard to individual primary cancers, foregut primaries
tend to have worse prognoses than non-foregut ones.20 Resecting
hepatic metastases from pancreas, stomach, and cutaneous mela-
nomas generally have bad prognoses; metastases from kidney,
adrenal, ovarian, and testicular tumors tend to have better prog-
noses; and metastases from sarcomas, breast, and uveal melano-
mas tend to have an intermediate prognosis.18,19
Pancreatic cancer: Among pancreatic primary tumors, a pan-
creatic cystadenocarcinoma may have better prognosis than a
pancreatic ductal adenocarcinoma.21 A DFI >24 months would be
preferable. In a series reported by Yamada et al.,22 six patients under-
went curative hepatectomy for metastatic pancreatic cancer. Five of
these patients died of recurrence between 4 and 52 months, the non-
recurrence occurring in a patient who had cystadenocarcinoma; and
the 1-, 3- and 5-year survival rates were 66.7%, 33.3%, and 16.7%.
Stomach cancer: Synchronous en-bloc resection of a stomach
cancer in contact with the left lobe of the liver may result in long-
term survival.23 In a metaanalysis by Shirabe et al,24 there were 12
studies and a total of 229 patients who underwent hepatic resec-
tion for metastatic gastric cancer. More than 50% of patients died
of recurrence within 2 years, and only 11% (25 patients) made it
beyond 5 years. Interestingly, 11 of these 25 survivors underwent
5/22/2012 5:28:06 PM

synchronous resections. Some of the possible prognostic fac-
tors implicated were the presence of lymphovascular invasion in
the primary tumor and surgical margins <10 mm (both poor
prognosis).
Breast cancer: Liver resection has been associated with increa-
sed survival for metastatic breast carcinoma in selected patients.25
In a review of nine published studies of metastatic breast cancer to
the liver (all over 10 patients), Elias et al.26 noted that the median
overall survival of the 296 patients was 57 months with curative
resection. Aside from undergoing a curative resection, a hormone-
negative breast tumor was a significant (poor) prognostic factor in
older women.
Ovarian cancer: Cytoreductive surgery, in combination with
chemotherapy, is the standard treatment for advanced ovarian
carcinoma. The inclusion of hepatic resection as part of a cytore-
ductive surgical plan has been shown to improve survival.27 In a
review of 35 patients with liver resections for metastatic ovarian
cancer, the Mayo Clinic showed that overall median disease-free
survival was 27.4 months. Among patients with no macroscopic
residual disease, the median survival has increased to 41.3 months.
Residual tumor <1 cm was associated with significantly improved
survival, as was a DFI of >1 year. Number, distribution, or tumor
grade of liver metastases did not appear to affect survival.
Renal cancer: Over the course of their disease, up to 50% of
renal cancer patients will develop metastases, and 20% of these
will develop hepatic metastases (although may not be confined to
liver). Most of these cancers are adenocarcinomas which tend to be
aggressive. In a report of their experience with review of the litera-
ture, Aloia et al.28 described 19 patients who underwent liver resec-
tion for metastatic renal cell carcinoma. Five-year disease-free and
overall survival rates were 25% and 26%, respectively. Significant
positive prognostic factors were a DFI of >24 months, metasta-
ses size <5 cm, R0 resection, and male sex. With the introduction
of newer chemotherapeutic agents for renal cancer,29 it is possible
that survival rates will continue to improve.
Other cancers: There have been reports of liver metastatic resec-
tions from other primary tumors, including lung,30 sarcomas,31 and
adrenocortical32 cancers, but most of these series are very small. A
longer DFI between primary cancer and metastases development,
as well as trying to complete an R0 resection remain the best prog-
nostic factors.
5. Is HCC better treated with resection or transplant?
HCC accounts for 80% to 90% of primary liver cancers. Worldwide,
the incidence of new cases ranges between 500,000 and 1 million
annually.33 The treatment regimen for HCC is controversial in
different parts of the world for several reasons; the etiology of
HCC, extent of liver disease and availability of donor organs
for transplant.
The etiology of the liver cancer is important; in the Far East
nations, where Hepatitis B is rampant, HCC tends to occur in a
younger demographic, usually in the fourth to fift h decade. In the
western countries, however, other etiologies tend to cause HCC
more commonly, especially Hepatitis C and more recently, non-
alcoholic steatohepatitis. These diseases tend to cause HCC in an
older demographic, usually the sixth or seventh decade and are
also associated with more comorbidities. Hence, a liver resection
may be harder among this group.
Improved surgical care has demonstrated improved outcomes
after liver resections for HCC. For patients with well-preserved
PMPH_CH39.indd 325
Newer Techniques in Liver Surgery ■ 325
liver function, minimal portal hypertension, tumor confined
within the liver and with no major vascular involvement, liver
resection can provide good results. Currently, overall 5-year
survival after liver resection ranges between 30% and 60% with
only a 3% operative mortality rate.33 In very early cases of HCC,
5-year survival rates >90% has even been reported after resec-
tion.34 Unfortunately, <30% of patients with diagnosed HCCs can
undergo an operative resection. This is usually because of preex-
isting advanced liver disease (cirrhosis) precluding this. In a study
looking at 295 patients undergoing resection for HCC, 4-year
survival rates were twofold higher among noncirrhotic patients
than among cirrhotic patients.35 Another problem with resection
for HCC is recurrence of tumor. HCC will likely recur in up to
50% to 80% of patients after resection within 2 years, based on the
size and characteristics of the tumor.36 But re-resection is always
an option in a healthy patient.
A normal liver can tolerate up to 80% resection and will likely
regenerate within 4 to 6 weeks. However, HCC tends to occur in
the background of cirrhosis. Resection ability may depend on the
Child-Pugh class of the patient; in general, class A patients may
tolerate a 50% resection of their liver and a class B may tolerate
up to 25%. A Child’s class C patient usually cannot tolerate a liver
resection.
There are no large randomized trials that have directly com-
pared resection with transplant in cirrhotic patients. There have
been several single-center studies that have shown overall and
recurrence-free survival benefits for transplantation compared
with resection in Childs A and B patients with early HCC.37,38
Liver transplantation for HCC came to the forefront after a
landmark study by Mazzaferro et al.39 in 1996. The study demon-
strated that patients transplanted with small hepatic tumors (single
tumor <5 cm or up to three tumors, each <3 cm) could have excel-
lent outcomes with 4-year survival rates of 75%. These rates are
equivalent to transplantation for cirrhosis without tumor. In addi-
tion, recurrence rates post transplant are low.40 These criteria are
now known as the Milan criteria and are widely used across the
world as criteria for transplantation.
In the United States today, HCC candidates are given prior-
ity for transplant as long as they fall within the Milan criteria.
Liver transplant candidates are currently ranked by a scoring sys-
tem called the MELD (Model for Endstage Liver Disease) score
(in pediatrics, called the PELD score).41 The score is calculated
by a logarithmic formula using the patient’s creatinine, INR,
and bilirubin levels. The calculated score ranges between 6 and
40 (capped at 40 maximum). Patients with HCC are automati-
cally given a priority score of 22 (unless their calculated score is
already higher), with a 10% increase in score every 3 months that
they are not transplanted. This is because in most cases, these
patients may not have enough hepatic dysfunction to derive a
higher score by themselves, and the value of transplanting these
patients while they are still in the window period of being within
the Milan criteria is recognized.
The last point to discuss is the availability of donor liv-
ers. Many countries do not have a nationwide allocation system
that would allow transplantation to happen in a consistent fash-
ion. Even in the United States, although these patients are given
priority points on their MELD score, this may not be enough to
get them transplanted in a timely fashion. Based on geographic
region, there is a huge variability in average MELD scores in the
United States.42 In regions with large cities (and consequent large
waiting lists), the average MELD score of patients transplanted is
5/22/2012 5:28:06 PM
 326 ■ Surgery: Evidence-Based Practice
higher than the 22 priority points assigned to HCC candidates.
This may be in contrast to regions with smaller lists, where HCC
patients may be transplanted faster. Although there appears to be
some discrepancy in nationwide allocation, this system currently
exists to allow local organs to stay locally, so as to reduce ischemic
time. Unfortunately, the current dropout rate for HCC candidates
on the waitlist is about 20%,43 usually because of progression of
their cancer.
Because of this scarcity of available organs, transplant centers
frequently will consider bridging therapy to allow more wait time
on the list. This may include initial resection, chemoembolization,
or ablation therapies.1 The benefit of such therapies is debatable,
although there is some evidence that this will reduce tumor bur-
den and reduce dropout rates on the waiting list, although it may
not increase overall survival.
There are other factors to consider as well; studies looking at
newer immunosuppression therapies and chemotherapy agents
that may reduce the recurrence rates of HCC either after resection
or transplant are currently underway and may impact the deci-
sion of transplant versus resection in the future.
In summary, there is probably little argument that resection
for HCC is probably beneficial for a healthier individual, with
early tumor and no cirrhosis. Likewise, transplantation is prob-
ably the logical choice in a frankly cirrhotic patient with early
tumor. The controversy still lies within the best treatment option
for early HCC in a mildly cirrhotic patient. There is some evidence
that transplant may offer better overall and recurrence-free sur-
vival. However, this decision must be weighed with consideration
of local availability of livers and waiting time. The benefit of bridg-
ing therapies and newer agents to prevent recurrence is yet to be
determined.
6. Is laparoscopic liver surgery going to become the standard
of care?
With the advent of laparoscopic surgery in various surgical are-
nas, it seems logical that liver surgery may be approached through
laparoscopic means as well. Laparoscopic liver resection was
first reported in 1992.44 Most of the initial reports on this pro-
cedure usually involved minor wedge resections. However, since
that time, several centers have reported large laparoscopic series
containing major liver resections for cancer, posterior liver resec-
tions, and even living donor hepatectomies. With the introduc-
tion of devices such as the Harmonic Scalpel ®, LigaSureTM, and
staplers which can be used to divide the liver laparoscopically, this
procedure is becoming commonplace.
The benefits of a laparoscopic liver resection are similar to
the benefits of any other laparoscopic procedure; studies have
shown less pain, less chance of intra-abdominal adhesions,
better cosmesis, shorter hospital length of stay with equiva-
lent complication rates compared with open resections, and
maintenance of oncologic goals when necessary.45,46 In a review
of 2804 laparoscopic liver resections performed worldwide,46
overall mortality was 0.3% and morbidity was 10.5%. The most
common procedure was a wedge resection (45%); hemihepate-
ctomies accounted for about 20% of all the operations. Con-
version to an open procedure occurred in 4.1% of procedures.
PMPH_CH39.indd 326
In a single-center review of 300 laparoscopic liver resections
compared with 100 contemporaneous open resections that were
matched for age, type of resection, cirrhosis, and malignancy,
Koff ron et al.47 showed that the laparoscopic group had shorter
operative times, less blood loss and transfusions, less complica-
tions, and shorter hospital length of stay. There is also evidence
that a laparoscopic resection in a cirrhotic patient may lead to
less post operative ascites.48
Some of the early concerns of laparoscopic liver resection
relate to a significant learning curve, for example, increased
risk of bleeding which may be difficult to control and gas embo-
lism. Although laparoscopic liver resection remains a compli-
cated procedure, there is gaining acceptance of this procedure
throughout the world. Concerns of possible carbon dioxide
embolism have largely been put to rest, as no significant com-
plications from this have been noted. There have been no sig-
nificant reports of port site metastases. There have been isolated
reports of argon gas embolization when it used for coagulation
on large vessels,49 and caution is advised on such cases. Because
most reports have shown decreased operative and recovery
times, in most cases, a laparoscopic approach may be cheaper
as well.
There have been no randomized trials comparing laparo-
scopic with open resections for cancer resections of the liver. A
meta-analysis of eight retrospective studies comparing laparo-
scopic versus open liver resections for malignancy between 1998
and 200550 showed similar overall and disease-free survival at
5 years post surgery; operative blood loss and hospital length of
stay were significantly shorter in the laparoscopic group. In the
reported literature, surgical margins free of cancer were attained
in 81% to 100% of cases.46
Laparoscopic surgery is now being performed routinely in
some centers for living donation as well. Th is pushes the envelope
even further, for now the liver resection needs to be performed
with meticulous preservation of the vessel length and the bile
ducts. The parenchymal dissection is typically performed with-
out division of the blood supply, thus lending to increased risk of
bleeding. However, centers have started reporting good outcomes
with left lateral segmentectomies51 and even right hepatectomies
in donors,52 compared with open surgeries. The ethical question
of whether this is safe for a donor arises. But similar to the accep-
tance of laparoscopic donor nephrectomies, laparoscopic donor
hepatectomies can offer the same advantages of better cosmesis,
recovery, and acceptance.
So, will laparoscopy replace open procedures in the setting
of liver resections? There is no doubt that there is a steep learning
curve and the mindset of established surgeons may need revision.
However, there is no evidence that this approach is any riskier,
and in many instances, may even be better than open procedures.
Similar to other major laparoscopic surgeries today, there may
be a time of “growing pains” when this transition occurs. Future
training of surgeons may start with laparoscopic resections, with
open procedures limited to complicated patients, similar to the
cholecystectomies performed today. At the Northwestern Univer-
sity in Chicago, laparoscopic liver resections have increased from
10% to 80% of all liver resection procedures performed between
2002 to 2007.47
5/22/2012 5:28:06 PM
 Newer Techniques in Liver Surgery ■ 327

Clinical Question Summary

Question
1 What is appropriate radiologic screening for
HCC among high risk patients
2 What is the appropriate radiologic study for
suspicious HCC lesions
3 Is RFA equivalent to resection for liver tumors?
4 Is percutaneous RFA equivalent to operative
RFA?
5 Is there a benefit to resection for non
colorectal, non neuroendocrine metastases to
the liver?
6 Is early HCC with mild cirrhosis better treated
with resection or transplant?
7 Is laparoscopic resection for liver cancer
equivalent to open resections?
8 Is laparoscopic living donor hepatectomy
equivalent to open procedures?
Answer Grade of References
Recommendation
Ultrasound q 6 to 12 months B 1
Contrast CT/MRI/US. At least one B 1
study for lesions >2 cm. At least two
concordant studies for lesions between
1 and 2 cm.
Although there are good retrospective C 7-12
results from selected RFA candidates,
resection, when possible, remains
standard of care.
While there may be some operator B 14, 15
dependency, several large series have
shown better survival and decreased
recurrence rates with operative RFA.
May be of benefit in selected patients. C 18-32
Only limited case series are reported.
While there is some evidence that C 37, 38
recurrence rates may be lower with
transplant, availability of livers locally
needs to be figured. Benefit of adjuvant
therapy needs to be determined.
No RCTs. However, several series have C 46, 50
shown equivalent oncologic results
with less surgical morbidity. Data
suggests it may be equivalent in
selected patients.
No RCTs. Limited case series show good C 51, 52
results.

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5/22/2012 5:28:06 PM

Hepatic Infections: Pyogenic
Abscess, Amebic Abscess,
and Hydatid Cyst
INTRODUCTION
Among the various infectious diseases that affect the liver, pyo-
genic abscess, amebic abscess, and hydatid cyst have historically
been the concern of the surgeon. The fundamentals of our under-
standing of pyogenic and amebic abscesses can be traced to two
seminal publications by Ochsner et al.1,2 in the 1930s. For hydatid
liver disease, which was rare in the United States, a publication
in English of equivalent importance had to wait until Moreno
Gonzalez et al.’s 1991 report describing their 25-year experience
in Spain.3 Though separated by more than half a century, each
publication made a major impact on the surgical management of
liver abscess and hydatid cyst.
From the critical perspective of evidence-based practice,
these papers present Class III–IV data with Grade C recommen-
dations. Liver abscess and hydatid disease are relatively uncom-
mon and occur in a heterogeneous patient population, making
rigorous, high-level clinical studies difficult to perform. The high
morbidity and mortality associated with these hepatic infections
is proof that clinically relevant questions regarding their manage-
ment remain inadequately answered. Recently, trials that address
specific aspects of the diagnosis and treatment of liver abscess
and hydatid cyst have emerged, which meet the high standards of
evidence-based practice and will be noted in this chapter.
1. What are the incidence and epidemiologic characteristics of
liver abscesses and hydatid cysts?
Pyogenic liver abscesses are relatively uncommon, but their inci-
dence varies by geographic region and patient population. In 1938,
Ochsner et al.2 reported an incidence of 8 per 100,000 admis-
sions to New Orleans’ Charity Hospital.2 A large series from the
Johns Hopkins Hospital in Baltimore reported that from 1973 to
1993 the incidence increased from 13 to 20 per 100,000 hospital
admissions and that the increase was attributed to the increase in
patients seen during that time interval with malignant disease,
329
PMPH_CH40.indd 329
CHAPTER 40
David M. Levi and Andreas G. Tzakis
especially hepatobiliary and pancreatic cancer.4 Does this change
reflect a true increase in incidence or simply the experience of
the authors? The inherent bias of case series limits a high-level
evidence-based answer. A group from Alberta, Canada reported
an incidence of 2.3 per 100,000 hospital admissions, the majority
of patients being male and older.5 In most large case series, the
average patient age is between 50 and 70 years, with a slight pre-
dominance of men.4-6 Pyogenic liver abscesses are more common
in Asia; a retrospective series from Taiwan reported an incidence
of 446 cases per 100,000 hospital admissions.7 The authors specu-
late that different bacteriology and patient factors accounts for
this variation.
Amebiasis results from infection with the protozoan parasite
Entamoeba histolytica. The liver is the most common extraintesti-
nal site of ameba infection. The organism is found throughout the
world and the infection is common in places with inadequate sani-
tation. In the United States, the amebic liver disease is seen pre-
dominantly in individuals that have traveled to or have emigrated
from endemic areas.8 In adults, men are more commonly affected
than women; while children, boys and girls are equally affected.
Possibly, the higher rate of alcohol use by men contributes to this
difference.8 Conditions that affect cell-mediated immunity, such
as extremes of age, pregnancy, corticosteroid therapy, malignancy,
and malnutrition, may also increase the chances that E. histolytica
infection results in invasive disease with liver involvement.
Hydatid cystic disease of the liver results from infection
with the larval form of the tapeworm Echinococcus granulosus.
Although found worldwide, it is endemic in South America, Med-
iterranean countries, the Middle East, Australia, and Asia.9 The
liver is the most common site for echinococcal infection followed
by the lung. In children, pulmonary involvement is more common
than liver disease.10
Answer: Pyogenic abscess, amebic abscess, and hydatid cyst
of the liver are distinct disease entities, with varying epidemio-
logic characteristics. Not surprisingly, their pathophysiology and
clinical characteristics vary as well. (Grade C recommendation).
5/22/2012 5:28:39 PM
 330 ■ Surgery: Evidence-Based Practice
2. What is the pathophysiology of liver abscesses and hydatid
cysts? For pyogenic abscesses, what are the most common caus-
ative organisms? What are the clinical features of the three
entities?
Most pyogenic liver abscesses arise secondary to an infection that
originates elsewhere in the body. They can be categorized by the
mode of spread to the liver. Knowledge of these routes and mecha-
nisms aids in diagnosis and often dictates treatment. The liver can
become the site of abscess formation via (1) the biliary tree, from
ascending cholangitis; (2) the portal vein, as in pylephlebitis result-
ing from appendicitis or diverticulitis; (3) the hepatic artery, as in
bacteremia from endocarditis or an oral cavity abscess; (4) direct
extension, from a contiguous disease process; and (5) post trau-
matic, from penetrating injuries or iatrogenic events. Rarely no
source is found.
In the past, the most common underlying etiology was acute
appendicitis.2 However, biliary tract pathology is now the most com-
mon cause of pyogenic liver abscess, accounting for 40% to 60% of
cases.11,12 Malignant biliary obstruction has been noted to be a more
frequent cause than in the past.4,13 Pyogenic abscess formation as
a procedure-related complication is being reported anecdotally in
recent years. These iatrogenic events include abscess formation after
biliary intervention, hepatic tumor ablation or embolization, hepatic
artery thrombosis after liver transplantation, and hepatic artery or
biliary injury during laparoscopic cholecystectomy.12,14-17
The microbiology of pyogenic liver abscesses varies and
often reflects the underlying etiology and route of liver involve-
ment. Many liver abscesses are polymicrobial, including anaer-
obes. Klebsiella pneumoniae, Escherichia coli, and Enterococcus
species predominate in series where biliary tract pathology is
the common etiology.11 In case series from New York and San
Diego, K. pneumoniae was the most common cause of pyogenic
liver abscess and was noted to be particularly virulent.11,18 Staphy-
lococcus aureus, Streptococcus species, Pseudomonas aeruginosa,
and Candida species are among the important but less common
causative organisms.19,20 Because the causative organism is unpre-
dictable and may be due to resistant organisms, cultures from the
abscess (including those for anaerobic bacteria) are important for
determining the optimal antimicrobial therapy.
Liver abscesses due to E. histolytica infection occur most com-
monly in patients that have spent time in an endemic area. Infection
occurs when individuals ingest food or water contaminated with
feces containing E. histolytica; sexual transmission is uncommon.
Although E. histolytica infection occurs in men and women equally,
invasive amebic diseases, such as abscess formation, predominate
in men at a ratio of about 3:1.21 Once ingested, the organism pen-
etrates the intestinal mucosa eventually reaching the portal venous
system. In the liver, E. histolytica has membrane-based molecules
that shield it from complement mediated lysis and releases proteases
that destroy host IgA and IgG allowing abscess formation.8
Hydatid cyst of the liver is caused by the parasitic tapeworm,
E. granulosus. Infected canines (definitive host) harbor the adult
tapeworm in their small intestine and shed eggs in their feces. Live-
stock (intermediate host), including sheep, goats, pigs, and cows, are
exposed to the parasite when they ingest eggs in fecally contami-
nated food or water. Humans are considered accidental intermediate
hosts.22 Ingested eggs release oncospheres which penetrate the small
intestine, access the circulation, and are carried to various organs,
usually the liver or lungs. In the target organ, a cystic structure
develops and gradually enlarges stimulating a host inflammatory
PMPH_CH40.indd 330
response. A fibrous, sometimes calcified pericyst forms and within
the cyst protoscolices and daughter cysts proliferate.
Answer: Pyogenic abscess, amebic abscess, and hydatid cyst
are distinct infectious diseases with different pathophysiological
aspects. This accounts for their differences in clinical presenta-
tion, diagnosis, and treatment. (Grade C recommendation).
3. What are the clinical features of the three entities and how
can these be distinguished?
Many of the clinical characteristics of the three entities are simi-
lar, nonspecific, and inconsistently present making their respective
diagnosis dependent on adjunct testing and imaging. Pain, local-
ized to the right-upper quadrant and epigastrium, is common.
Pain radiating to the right scapular region suggests right hemidia-
phragm irritation. Fever is common to all three entities; nausea and
vomiting, weight loss, malaise, anorexia, chills are less common,
but equally nonspecific.22-25 Patients with amebiasis can have diar-
rhea from colitis and symptoms from a simultaneous liver abscess.8
Elderly patients may present with only fever of unknown origin.
The physical examination findings of fever, upper abdomi-
nal tenderness, and hepatomegaly may suggest the diagnosis of
a hepatic infection. These coupled with relevant historical clues
may suggest the diagnosis. Travel to an endemic area may suggest
amebic abscess or hydatid cyst, whereas a recent biliary procedure
or history of diverticulitis suggests pyogenic abscess. In a large
series of adults in Pakistan, distinguishing between patients with
pyogenic and amebic abscess was studied. The authors found that
patients with pyogenic abscess were usually older with a history
of diabetes, more likely to present with jaundice, and pulmonary
findings. Patients with amebic abscess were younger with epigas-
tric pain, lower serum albumin levels, and positive amebic titres.26
It is unlikely that their conclusions hold true for patients in non-
endemic areas.
Complications resulting from hepatic infections can be dra-
matic and life-threatening. Patients with pyogenic abscess can
present with systemic sepsis and hemodynamic instability. Hydatid
cysts can rupture into the peritoneal cavity causing anaphylaxis, the
biliary tree causing cholangitis, the pleural space, or pericardial sac.
To complicate diagnostic efforts further, hydatid cysts can become
secondarily bacterially infected yielding a mixed pyogenic abscess.
Answer: Because the signs and symptoms of hepatic infection
are nonspecific, we depend heavily on adjunct testing and imag-
ing for making a diagnosis and distinguishing between the three
entities. (Grade C recommendation).
4. What diagnostic tests and imaging studies are useful for
obtaining an accurate diagnosis?
Diagnosis of and differentiation between pyogenic abscess, ame-
bic abscess, and hydatid cyst on clinical grounds may be impos-
sible. Other diagnoses in the differential, including cystic liver
neoplasms, can further complicate diagnostic efforts. Serologic
tests are available to assist in the diagnosis of E. histolytica or
E. granulosus infection. In the setting of a mass lesion of the liver,
both are highly sensitive and specific.8,22 Microscopic examina-
tion of stool samples or a rectal mucosal biopsy may yield ame-
bic trophozoites, supporting but not proving the diagnosis of
an amebic abscess. Once a cystic liver lesion is identified to be a
pyogenic abscess, computerized tomography (CT) or ultrasound
(US) guided aspiration of the cyst fluid is important to isolate the
causative organism(s) and tailor antimicrobial therapy.
5/22/2012 5:28:39 PM
 Hepatic Infections: Pyogenic Abscess, Amebic Abscess, and Hydatid Cyst
Modern imaging studies that exploit the nuanced radiographic
characteristics of liver abscesses and hydatid cysts have become
imperative for an accurate diagnosis. CT is slightly superior to US
for detecting small liver abscesses; both have made radionucleotide
scans second-line studies.4 Magnetic resonance imaging (MRI)
can occasionally be useful but does not add greatly to CT imaging.
Also, CT offers the potential for guided, diagnostic aspiration and
therapeutic drainage; a distinct advantage over MRI.
Pyogenic liver abscesses are solitary or multifocal discrete
masses, usually round or lobulated. Contrast-enhanced CT demon-
strates peripheral rim enhancement with central low attenuation.
They can be complex with loculations and may have an air-fluid
level. In a recent study of 58 patients with pyogenic abscess, CT
was the imaging study used for making the diagnosis in 56 cases,
or 97% of the time.13
CT and US are the imaging modalities of choice for diagnosing
amebic liver abscess. Both are very sensitive but lack needed specific-
ity. Imaging may reveal solitary or multiple lesions, usually less com-
plex than pyogenic abscesses. Ultrasonographic features include a
smooth wall, hypoechoic center with internal echoes. Because many
amebic abscesses are treated nonoperatively, serial US examinations
are ideal for tracking the progress of medical therapy.
The distinct morphologic features of hydatid cysts are usu-
ally detected on imaging studies and can help discriminate them
from liver abscesses. Hydatid cysts may be single or large with
multiple satellites. The wall can appear thickened, surrounded by
pericyst of compressed liver parenchyma. Calcification of the wall,
when present, is seen on CT and produces vivid acoustic shadows
on US. Septations and lobulations are readily detected by both
modalities. US is especially good for detecting the sediment-like
cyst contents made of scolices. The sediment moves, remaining in
the dependent portion of the cyst as the patient’s position is varied
for the exam.
Answer: The use of serologic testing for amebic abscess and
hydatid cyst, and bacterial and fungal cultures of aspirates from a
suspected pyogenic abscess are important tools aided in accurate
diagnosis. CT and US have become very important for detecting
and characterizing liver abscesses and cysts and guiding treat-
ment. (Grade C recommendation).
5. What is the treatment for liver abscess and hydatid cyst?
In recent years, evidenced-based studies have emerged and address
controversies regarding the treatment of pyogenic abscess, ame-
bic abscess, and hydatid cyst. The fundamental precepts guiding
the treatment of pyogenic liver abscess are the administration of
appropriate antibiotics and/or antifungal agents, drainage of the
abscess, and treatment of the root cause. When the abscess is sec-
ondary to biliary obstruction, biliary drainage via the transhe-
patic or endoscopic retrograde route may be required.
Historically, open surgery with either abscess drainage or
hepatic resection was regarded as the treatment of choice.4 Percu-
taneous drainage has developed with the emergence of interven-
tional radiology, and has almost replaced open surgical drainage.13
Correspondingly, there has been a significant decrease in mor-
tality related to pyogenic abscess.11 There are still proponents of
open surgical drainage as more effective for patients with large,
multifocal, and multiloculated abscesses, but the trend toward
percutaneous drainage is clear. 27 In a nonrandomized series
comparing open drainage with percutaneous drainage, Ferraioli
et al. 28 reported no percutaneous drainage failures while open
PMPH_CH40.indd 331
■ 331
surgical drainage was associates with longer hospitalization and
greater morbidity.28
Small abscesses, defined as >3 cm may be treated with anti-
biotics alone in selected patients.29 In a randomized trial of 64
patients, Yu et al.30 demonstrated that percutaneous aspiration
without catheter placement was as effective as percutaneous drain-
age, with no difference in length of hospitalization or mortality.30
The mainstay of treatment for amebic liver abscess is met-
ronidazole. The majority of patients will respond needing no
drainage. There is controversy regarding the role of percutane-
ous drainage in the management of amebic liver abscess. It has
been suggested that aspiration or drainage of large abscesses may
shorten the time to resolution. In one detailed review, the author
suggests that intervention beyond medical management should be
reserved for patients for whom the diagnosis is uncertain, seri-
ously ill patients that may benefit from more rapid treatment, and
patients that have not responded as expected with resolution of
fever and decreased abdominal pain within 4 days.8
The treatment of echinococcal cyst depends on the patient’s
condition and on the presence or absence of complicating factors.
In two reports, Dziri et al.31,32 carefully conducted a comprehen-
sive review of the evidence-based treatment strategies for hydatid
cyst. For uncomplicated cysts, randomized trials have shown
that management alone with albendazole and/or mebendazole is
superior to placebo, but is not dependable for achieving complete
resolution of all cysts.
Surgery remains the standard treatment for hydatid cysts
in the liver, although the optimal procedure remains a question.
The main surgical options include hepatic resection and pericys-
tectomy (radical procedures) and cyst fenestration and evacu-
ation of the cyst contents (conservative procedures). Although
there is no randomized comparison, most series suggest that radi-
cal resection is associated with lower mortality. In general, radical
procedures probably pose greater perioperative risks and conser-
vative procedures have a higher associated cyst recurrence rate.31
Placement of the omentum in the surgical bed after resection or
pericystectomy or in the residual cyst after fenestration results in
fewer complications such as abscess formation.33 Laparoscopic
fenestration has been demonstrated to be safe, but high level data
are lacking with regard to its effectiveness compared with an open
procedure. Percutaneous drainage plus albendazole or mebenda-
zole is a strategy for treating uncomplicated hydatid cysts that has
gained the support of some researchers.31 Complicated hydatid
liver cysts includes those that rupture or fistulize into adjacent
organs or cavities. In general, more radical procedures have been
advocated for complicated cysts. Because of the complexity and
variability of complicated hydatid cysts, it is difficult to general-
ize from existing series as to the best approach.32 A combination
of medical treatment and an individualized, aggressive surgical
approach is usually warranted.
Answer: The treatment of pyogenic liver abscess has become
less invasive over the years, with percutaneous drainage and anti-
biotics supplanting surgery in most cases. Amebic liver abscess
respond to medical treatment with metronidazole, although there
is occasionally a role for percutaneous drainage or aspiration. Sur-
gery is the standard therapy for hydatid liver cysts. Radical proce-
dures are effective, but carry higher perioperative risk than more
conservative procedures. More study is needed before laparo-
scopic and percutaneous procedures can be advocated. (Grade B
recommendation).
5/22/2012 5:28:39 PM
 332 ■ Surgery: Evidence-Based Practice

Clinical Question Summary

Question
1 What are the incidence
and epoidemiologic
characteristics of liver
abscesses and hydatid cysts?
2 What is the pathophysiology
of liver abscesses and hydatid
cysts? For pyogenic abscesses,
what are the most common
causative organisms? What
are the clinical features?
3 What are the clinical features
of the three entities and how
can these be distinguished?
4 What diagnostic tests and
imaging studies are useful
for obtaining an accurate
diagnosis?
5 What is the treatment for liver
abscess and hydatid cyst?
Answer Grade of References
Recommendation
Pyogenic abscess, amebic abscess, and hydatid cyst C 2, 4-10
of the liver are distinct diseases. Epidemiologic,
pathophysiologic, and clinical characteristics vary
as well.
Pyogenic abscess, amebic abscess, and hydatid cyst C 2, 4, 11-22
are distinct infectious diseases with different
pathophysiological aspects. This accounts for their
differences in clinical presentation, diagnosis, and
treatment.
Because the signs and symptoms of hepatic infection are C 8, 22-26
nonspecific, we depend heavily on adjunct testing and
imaging for diagnosis and distinguishing between the
3 entities.
Serologic testing for amebic abscess and hydatid cyst, C 4, 8, 13, 22
and bacterial and fungal cultures of aspirates from
a suspected pyogenic abscess are aids to accurate
diagnosis. CT and US are important for detecting and
characterizing liver abscesses and cysts, and guiding
treatment.
Percutaneous drainage and antibiotics have supplanted B 4, 8, 11, 13,
surgery in most cases. Amebic liver abscess are treated 27-33
with metronidazole and occasionally with percutaneous
drainage or aspiration. Surgery is the standard therapy
for hydatid liver cysts, More study is needed before
laparoscopic and percutaneous procedures can be
advocated.

REFERENCES
1. Ochsner A, DeBakey M. Liver abscess part I: Amebic abscess
analysis of 73 cases. Am J Surg. 1935;29:173-194.
2. Ochsner A, DeBakey M, Murray S. Pyogenic abscess of the liver:
II. An analysis of 47 cases with review of the literature. Am J
Surg. 1938;40:292-319.
3. Moreno Gonzalez E, Rico Selas P, Marinez B, et al. Results of
surgical treatment of hepatic hydatidosis: Current therapeutic
modifications. World J Surg. 1991;15:254-263.
4. Huang CJ, Pitt HA, Lipsett PA, et al. Pyogenic hepatic abscess.
Ann Surg. 1996;223:600-607.
5. Kaplan GG, Gregson DB, Laupland KB. Population-based study
of the epidemiology of and risk factors for pyogenic liver abscess.
Clin Gastroenterol Hepatol. 2004;2:1032-1038.
6. Alvarez Perez JA, Gonzalez JJ, Baldonedo RF, et al. Clinical
course, treatment, and multivariate analysis of risk factors for
pyogenic liver abscess. Am J Surg. 2001;181:177-186.
7. Chan KS, Chen CM, Cheng KC, et al. Pyogenic liver abscess: A
retrospective analysis of 107 patients during a 3-year period. Jpn
J Infect Dis. 2005;58:366.
8. Stanley SL. Amoebiasis. Lancet. 2003;361:1025-1034.
9. Sayek I, Bulent Tirnaksiz M, Dogan R. Cystic hydatid disease:
Current trends in diagnosis and management. Surg Today.
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10. Balci AE, Eren N, Eren S, Ulku R. Ruptured hydatid cysts of the
lung in children: Clinical review and results of surgery. Ann Tho-
rac Surg. 2002;74:889-892.
11. Rahimian J, Wilson T, Oram V, et al. Pyogenic liver abscess: Recent
trends in etiology and mortality. Clin Infect Dis. 2004;39:1654-1659.
12. Lam YH, Wong SK, Lee DW, et al. ERCP and pyogenic liver
abscess. Gastrointest Endosc. 1999;50:340-344.
13. Mezhir JJ, Fong Y, Jacks LM, et al. Current management of pyo-
genic liver abscess: Surgery is now second-line treatment. J Am
Coll Surg. 2010;210:975-983.
14. Mezhir JJ, Fong Y, Fleischer D, et al. Pyogenic abscess after hepatic
artery embolization: A rare but potentially lethal complication.
J Vasc Interv Radiol. 2011;22:177-182.
15. Kong WT, Zhang WW, Qiu YD, et al. Major complications
after radiofrequency ablation for liver tumors: Analysis of 255
patients. World J Gastroenterol. 2009;15:2651-2656.
16. Nikeghbalian S, Salahi R, Salahi H, et al. Hepatic abscesses after
liver transplant: 1997–2008. Exp Clin Transplant. 2009;7:256-260.
17. Stewart L, Robinson TN, Lee CM, et al. Right hepatic artery injury
associated with laparoscopic bile duct injury: Incidence, mecha-
nism, and consequences. J Gastrointest Surg. 2004;8:523-530.
18. Lederman ER, Crum NF. Pyogenic liver abscess with a focus
on Klebsiella pneumoniae as a primary pathogen: An emerging
disease with unique clinical characteristics. Am J Gastroenterol.
2005;100:322-331.

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 Hepatic Infections: Pyogenic Abscess, Amebic Abscess, and Hydatid Cyst
19. Smith BM, Zyromski NJ, Allison DC. Community-acquired
methicillin-resistant Staphylococcus aureus liver abscess requir-
ing resection. Surgery. 2007;141:110-111.
20. Ulug M, Gedik E, Girgin S, et al. Pyogenic liver abscess caused by
community acquired multidrug resistance Pseudomonas aerugi-
nosa. Braz J Infect Dis. 2010;14:218.
21. Acuna-Soto R, Maguire JH, Wirth DF. Gender distribution in
asymptomatic and invasive amebiasis. Am J Gastroenterol. 2000;95:
1277-1283.
22. Eckert J, Deplazes P. Biological, epidemiological, and clinical
aspects of echinococcosis, a zoonosis of increasing concern. Clin
Microbiol Rev. 2004;17:107-135.
23. Conter RL, Pitt HA, Tompkins RK, et al. Differentiation of pyogenic
from hepatic abscess. Surg Gynecol Obstet. 1986;162:114-120.
24. Akgun Y, Tacyildiz IH, Celik Y. Amebic liver abscess: Changing
trends over 20 years. World J Surg. 1999;23:102-106.
25. Hoffner JR, Kilaghbian T, Esekogwu VI, et al. Common presenta-
tions of amebic liver abscess. Ann Emerg Med. 1999;34:351-355.
26. Lodhi S, Sarwari AR, Muzammil M, et al. Features distinguish-
ing amebic from pyogenic liver abscess: A review of 577 adult
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■ 333
27. Tan YM, Chung AY, Chow PK, et al. An appraisal of surgical and
percutaneous drainage for pyogenic liver abscesses greater than
5 cm. Ann Surg. 2005;241:485-490.
28. Ferraioli G, Garlaschelli A, Zanaboni D, et al. Percutaneous
and surgical treatment of pyogenic liver abscesses: Observation
over a 21-year period in 148 patients. Dig Liver Dis. 2008;40:
690-696.
29. Hope WW, Vrochides DV, Newcomb WL, et al. Optimal treat-
ment of hepatic abscess. Am Surg. 2008;74:178-182.
30. Yu SC, Ho SS, Lau WY, et al. Treatment of pyogenic liver abscess:
Prospective randomized comparison of catheter drainage and
needle aspiration. Hepatology. 2004;39:932-938.
31. Dziri C, Haouet K, Fingerhut A. Treatment of hydatid cyst
of the liver: Where is the evidence? World J Surg. 2004;28:
731-736.
32. Dziri C, Haouet K, Fingerhut A, Zaouche A. Management of
cystic echinococcosis complications and dissemination: Where
is the evidence? World J Surg. 2009;33:1266-1273.
33. Balik AA, Basoglu M, Celebri F, et al. Surgical treatment of
hydatid disease of the liver: Review of 304 cases. Arch Surg. 1999;
134:166-169.
5/22/2012 5:28:40 PM
 CHAPTER 41
Malignant Liver Tumors
Susanne Carpenter and Yuman Fong
INTRODUCTION
Primary and metastatic hepatic malignancies present aggressive
disease processes that require aggressive management strategies.
Although chemotherapy has an important role, particularly in
patients presenting with unresectable disease, surgical and ablative
therapies are mainstays of both palliative and curative treatments.1-6
Since the advent of true anatomic hepatic resections in the 1950s,
surgical indications for hepatectomy have gradually expanded with
increasing safety and decreasing mortality rates.7,8 Recent decades
have seen the advent of segmental hepatic resections, which have
ushered in a new era of expanded definitions of respectability.8 His-
torically, bilobar disease was considered unresectable.9 However,
some authors are now advocating aggressive resection strategies
for bilobar disease with neoadjuvant chemotherapy and portal vein
embolization with subsequent attempts at curative and palliative
surgical interventions with the intent of prolonging survival.9,10
Although the evidence for partial hepatectomy is not based on any
randomized controlled trial (RCT), the conclusions of many single
and multi-institutional experiences have shaped current trends in
hepatobiliary surgery, and have produced outcomes that obviate
continued pursuit of currently accepted surgical management.11,12
One example of this is the Milan criteria, which originated from
a single-institutional series and has been built upon by many dif-
ferent institutions.13,14 Unfortunately, practice patterns in the treat-
ment of malignant liver tumors can vary widely by institution, and
there is a glut of institutional protocols in today’s literature in the
absence of RCTs.
This chapter will review the evaluation, diagnosis, and man-
agement of primary and secondary hepatic malignancies with
specific attention to optimal use of imaging modalities, staging
criteria, treatment algorithms, as well as minimally invasive, abla-
tive, and palliative therapies.
INITIAL EVALUATION AND DIAGNOSIS
1. What is the standard staging of patients prior to hepatic
resection?
334
PMPH_CH41.indd 334
Although there is widespread acceptance of the use of American
Joint Committee on Cancer (AJCC) staging criteria for colorec-
tal hepatic metastases,15 there exists a fair amount of controversy
regarding the staging of hepatocellular carcinoma (HCC). The
most obvious weakness is that AJCC staging focuses on anatomic
extent of disease without considering treatment or liver function
status, and is based on survival of patients undergoing resec-
tion, which makes it of limited use to the majority of patients
with HCC who present with late stage disease or with medical
contraindications to resection.16,17 Several different centers have
developed their own tumor staging and classification systems,
but these have yielded disparate survival rates at supposedly
early stages, likely secondary to the construction of these stag-
ing systems with patients at advanced tumor stage or disparate
liver functions.18-21 To circumvent some of these deficiencies, a
consensus conference originating from the American Hepato
Pancreato Biliary Association (AHPBA) concluded that a one
or both of the AJCC and Cancer of the Liver Italian Program
(CLIP) stages should be reported.17 Nonetheless, the most fre-
quently used and most accurate algorithm to predict outcomes
following resection or transplantation in the United States is
currently the AJCC.22-24
2. What imaging techniques are best used for delineating
malignant from benign liver lesions?
Preoperative work-up of patients with hepatic malignancies typi-
cally includes some combination of ultrasound (US), computed
tomography (CT), magnetic resonance imaging (MRI), and [18F]
fluorodeoxyglucose (FDG)-positron emission tomography (PET).
For metastatic disease, a combination of PET and MRI or PET/CT
is frequently used.25 The superiority of PET scanning in detecting
extrahepatic disease over CT scanning has been demonstrated
by an RCT wherein patients were scanned with either CT alone
or with CT with a separate PET scan, which demonstrated that
futile laparotomy could be avoided for one in every six patients
with enhanced detection of extrahepatic disease.26 Similarly, the
superiority of MRI over CT has been demonstrated by multiple
5/22/2012 5:29:14 PM

strenuous comparisons and meta-analyses thereof.27,28 However,
much debate surrounds the optimal combination of preoperative
and surveillance imaging techniques, with many concluding that
while on a per-patient basis, PET has consistent sensitivity greater
than 90% and superior to MRI sensitivity around 75%, the two
modalities perform similarly on a per-patient basis.27-30 Regardless
of the level of support for PET scanning, in preoperative imaging,
a “surgical map” detailing proximity of lesions to major vascu-
lar structures, and in relationship to segmental liver anatomy is
required, such that PET cannot be employed as a sole means of
imaging. It must be used in concert with either CT or MRI.
The primary weakness of PET is its inability to detect lesions
<1 cm in diameter.31,32 Chemotherapy further complicates imag-
ing choices by producing changes in liver parenchyma that can
obscure otherwise obvious differences in tissue echogenicity
or enhancement.33-37 For instance, hepatic lesions exhibit impa-
ired FDG uptake following chemotherapy when compared with
chemotherapy-naïve patients, likely as a result of diminished
hexokinase activity.38 CT accuracy also suffers following chemo-
therapy in that chemotherapy-induced steatohepatitis results in a
darker-appearing liver, which results in obscured views of resid-
ual hypovascular (thus hypoattenuated) residual tumors.29,33,39 US
can be useful intraoperatively for guidance as to lesion location,
and to ensure that lesions have been completely resected; however,
fatty livers can also impair US accuracy, particularly in lesions
<1 cm in diameter.40 In the delineation of HCC, PET is less useful,
and US, CT, and MRI are more commonly employed.41
Radiologists assert that contrast-enhanced imaging is essen-
tial in the differentiation of malignant from benign hepatic
lesions, and point out that uniform features can be used to accu-
rately establish malignant diagnoses via imaging.42 These features
relate to tumor appearance (heterogeneity vs. homogeneity with
contrast) and the interface of a tumor with its surroundings, and
were established by comparing the findings of multiple experts
over multiple images and modalities with pathologic confirma-
tion.42 Many imagers also value liver-specific MRI contrast agents
like mangafodipir trisodium, ferucarbotran, and superparamag-
netic iron oxide (SPIO) as superior tools in lesion delineation, with
some authors asserting the superiority of SPIO in the detection of
small HCC tumors in single-institutional series.43-45 It is generally
accepted that MRI provides the most accurate lesion characteriza-
tion in the differentiation of benign from malignant lesions.46
MANAGEMENT
3. What are the treatment algorithms for various liver
malignancies?
Over the past decade, many conferences have been convened, and
consensus statements and expert opinions have been offered to
support consistency in treatment protocols and indications for
resection of malignant liver lesions. These statements are based
primarily on compilations of data from several large series com-
bined with expert opinion. One such statement defines colorectal
lesions as absolutely unresectable in patients who have untreat-
able or extensive extrahepatic disease, those who are unfit for sur-
gery, or those with involvement of >70% of the liver (or more than
six segments).47 Others take a more simple approach, describing
resectable tumors as those that would leave behind an adequate
liver remnant if completely resected.48 For otherwise healthy
PMPH_CH41.indd 335
Malignant Liver Tumors ■ 335
noncirrhotic patients, the minimum published safe volume for a
future liver remnant (FLR) is 20% of preoperative liver volume,
whereas cirrhotics must have at least 40% FLRs.49
Several authors have proposed that liver resection should be
considered the treatment of choice for single lesions arising in
noncirrhotic livers or those with Child Pugh A cirrhosis with well-
preserved liver function, whereas transplantation should be con-
sidered the standard for curative therapy in patients with Childs B
and C cirrhosis who meet the Milan criteria.4,50 In terms of surgi-
cal technique, small tumors (<5 cm) located at the periphery of the
hepatic parenchyma, or well-away from major vascular structures,
are considered amenable to segmentectomy. Major hepatectomy,
typically defined as resection of three or more hepatic segments based
on Couinaud classifications, is recommended for tumors >5 cm,
or those invading hilar structures.51
HCC
Several major debates have emerged regarding the treatment
schemes for HCC. They primarily concern transplantation versus
resection as curative therapy.9,52 Among the most argued princi-
ples are the parameters for resection versus transplantation ver-
sus combinations of resection and ablation for curative therapy,
particularly in both early and bilobar HCC.4,5,9,52 The biggest step
in the development of treatment algorithms for HCC came with
the evolution of the Milan criteria. This originated with a study
by Mazzaferro et al.13 published in the New England Journal of
Medicine in 1996, detailing the treatment of 48 cirrhotic patients
with small HCC that was deemed unresectable by virtue of tumor
location, by multifocality, or by advanced hepatic insufficiency
related to cirrhosis.13 The study noted superior disease-free and
overall survival in those patients in patients who had one tumor
<5 cm in diameter or no more than three tumors with none
>3 cm in diameter.13 Although there has yet to be an RCT directly
comparing resection and transplantation, there are many strong
advocates in both camps and many retrospective comparative
reviews, and it is clear that patients with smaller less extensive
tumors fair much better than their counterparts with large multi-
nodular or diff use tumors following transplantation.53 One of the
drawbacks of transplantation is the significant loss of patients
from the transplant waiting list secondary to death or disease
progression, and some argue that this should preclude transplant
as the first consideration of therapy.54 Yet, some centers advocate
expansion of the Milan criteria to include more patients, but again
this is based on single-institutional reviews.55 In addition to the
absence of an RCT, other obstacles in the currently available liter-
ature include a dearth of retrospective case control studies which
compare patients based on liver function, as well as a selection
bias in studies comparing transplant and resection wherein trans-
plant patients typically have more severe cirrhosis and smaller
tumors.56 Thus, more robust evidence and uniform treatment cri-
teria are needed to elucidate the optimal surgical management of
this disease.
COLORECTAL HEPATIC METS
Colorectal carcinoma has a poor prognosis when metastatic to the
liver, obviating the need for aggressive surgical therapy for the 20%
5/22/2012 5:29:14 PM
 336 ■ Surgery: Evidence-Based Practice
to 30% of patients who are potentially resectable.57,58 Treatment
algorithms for colorectal hepatic metastases fi nd themselves in
more agreed-upon territory, with most surgeons and practitioners
acknowledging that surgical treatment is the keystone of curative
therapy and that resection should be attempted so long as patients
exhibit adequate functional status, are free of extrahepatic disease,
and will maintain an adequate liver remnant.2,59-61 Transplanta-
tion for hepatic metastasis was investigated in the 1990s, but it
is generally not offered secondary to poor outcomes seen then.62
While it is clear that small metastases confined to small liver area
should be resected, resection criteria for more extensive disease
are constantly changing.57 In patients with bilobar hepatic metas-
tases, several specialized centers have reported 5-year survival as
high as 60% in properly selected patients undergoing a two-stage
resection strategy combined with chemotherapy and portal vein
embolization, with completeness of resection and response to che-
motherapy being essential to favorable outcome.60,63,64 It should be
mentioned that even in the previous study with highly selected
patients at a high-volume center, 28% of patients who entered the
multi-stage treatment were not able to complete the second stage
of complete resection, either secondary to disease progression or
medical decompensation.60 This aggressive treatment style war-
rants further investigation and optimization.
Management of synchronous colorectal primary and metastatic
hepatic disease is controversial with strategies that vary regarding
timing of chemotherapy, liver, and colonic resections.61 Most of the
data consist of single institution reports or retrospective reviews
which has prompted many senior investigators to demand further
evidence.65 The order and extent of resection can vary widely between
institutions and patients, especially in patients with more extensive
disease. While the more traditional approach of stepwise resection of
the primary lesion followed by a second operation to remove a hepatic
metastasis has yielded relatively favorable outcomes, several centers
have reported relatively favorable outcomes with synchronous resec-
tion of synchronous metastases.59,66-68 However, Capussotti et al.67
have reported that patients with more than three metastases exhibit
more favorable overall survival with delayed resection of hepatic
lesions with the appropriate adjuvant therapy. Other investigators
advocate a “reverse” approach with the first operation being resec-
tion of hepatic disease followed by a second colon resection, with
most reporting survival results similar to those of synchronous and
traditional two-stage procedures, but again this data is generated
only by small single-institutional series.40,61,69 Further investigations
are needed to optimize the current treatment strategies for extensive
colorectal hepatic metastases.
NEUROENDOCRINE
The treatment of neuroendocrine liver metastases (NLM) is also
confounded by a wide array of institutional treatment strategies
combined with indolent disease processes and a lack of RCTs
to mandate uniform treatment strategies.70 Most data is gener-
ated from single- or multi-institutional reviews, and the lack of
RCTs seems insurmountable in this relatively rare, histologically
inconsistent disease process.70 Moreover, as Gurusamy et al.71,72
point out, there are many obstacles to RCT investigations of
NLM treatment, including that to show a statistically significant
10% difference in survival between surgical debulking and other
PMPH_CH41.indd 336
palliative treatment, 776 patients would be required. Because of
the indolent nature of the disease, even incomplete resection of
NLM can confer survival and symptom benefits.73,74 In patients
with unresectable disease, hormonal suppression, ablative thera-
pies, or loco-regional chemotherapies can be of some benefit, but
in the absence of data to compare the relative efficacy of these var-
ious techniques, it seems that choices of nonsurgical intervention
is largely based on institutional preference.70,75 Transplantation
for NLM is almost never indicated secondary to the high risk of
rapid disease recurrence and diminished actuarial survival com-
pared with patients receiving transplants for all indications.75-79
Nonetheless, there is some evidence to suggest that transplanta-
tion may be beneficial to patients with hepatic metastases from
gastroenteropancreatic carcinoid disease.80 Thus, it is apparent
that patients with NLM amenable to removal of 80% to 90% of the
tumor volume should undergo surgical resection, whereas algo-
rithms for other treatment strategies are less clear.70
TECHNIQUES OF RESECTION
Surgical techniques as well as amount of tissue manipulation have
been indirectly associated with patient survival.81 Moreover, posi-
tive margins of resection have been associated with recurrence,
which can be correlated with surgical technique.82 It is important
that hepatic resections be undertaken by experienced surgeons
at high-volume centers. The same principles apply to minimally
invasive resection in which advanced laparoscopic experience, in
addition to HPB experience, is essential to favorable outcomes.
4. How are ablative therapies used in the treatment of liver
malignancies?
Currently, ablative therapies are performed via laparoscopic, open,
and percutaneous approaches.6 Many different ablative technolo-
gies have been suggested and investigated. Many involve some sort
of thermal injury to the diseased tissue. Among the most frequently
employed in clinical practice are radiofrequency ablation (RFA)
and microwave coagulation therapy (MCT), which are discussed in
detail below. Several other ablative technologies are under investiga-
tion. For example, laser ablation, which has demonstrated favorable
results in 432 HCC patients with unresectable disease or with medi-
cal contraindications to resections.83 Irreversible electroporation
(IRE) increases cell membrane permeability via alteration of trans-
membrane potential and resultant disruption of lipid bilayer integ-
rity and induce cell death.84 IRE has shown promise in preclinical
studies, but remains unestablished in clinical practice.85 Thus, with-
out the support of RCT evidence and significant clinical experience,
that is afforded RFA and MCT, many new techniques have roles in
the therapy of hepatic malignancy that are still to be decided.
MCT has been studied primarily with hepatic colorectal
cancer metastases. One RCT evaluated 30 patients with multiple
(2-9) hepatic colorectal metastases.86 The patients were randomly
assigned to either MCT (14) or hepatectomy (16), but investigators
found differences in 1-, 2-, and 3-year survival percentages to be
statistically insignificant with 71%, 57%, and 14% in the micro-
wave group versus 69%, 56%, and 23% in the hepatectomy group
(p = .83).86 Although these results suggest that MCT should be
considered in patients with multiple lesions, the power of this study
is very small and survival of 14% at 3 years is low when compared
5/22/2012 5:29:14 PM

with more recent studies.87 The remainder of currently available
literature consists of primarily retrospective series.88-90 One use-
ful study evaluated the use of MCT in combination with resec-
tion in patients with bilobar colorectal metastases to the liver.90
Tanaka et al.90 reviewed 53 patients undergoing hepatectomy with
microwave ablation employed only in cases where complete resec-
tion was not possible (16), and found similar survival percentages
between patients treated with resection alone and resection with
MCT.90 Although some heterogeneity among adjuvant therapies
between the patient groups may confound the data, the suggestion
remains that with aggressive treatment, ablation of unresectable
lesions in conjunction with partial resection can confer survival
benefits similar to those seen in complete resection.
RFA is perhaps the most established ablative therapy. The
most recent ASCO consensus statement regarding RFA for the
treatment of hepatic metastases from colorectal cancer called
for more evidence and survival data, and presented an evidence
review rather than a practice guideline.6 There are no published
RCTs for the use of RFA for colorectal hepatic metastases. Many
recognize its use as adjunctive to surgical therapy, or as palliative
in cases of patients who are medically unfit for surgery or those
with extrahepatic disease for whom the risks and morbidity of
surgery outweigh any potential survival benefit.6,59
However, much more debate is held in the arena of HCC
treatment. Many investigators disagree with the pursuit of studies
paralleling RFA and surgery, contending that resection should be
employed over RFA whenever possible to provide definitive treat-
ment rather than risk local recurrence with RFA as indicated by
multiple retrospective reviews.91-93 For instance, one prospective
database analysis out of MD Anderson revealed that local recur-
rence rates can increase as much as 32% when RFA is employed
when compared with resection, even in lesions that are <3 cm in
diameter.94 One RCT that was performed in China studied 230
patients with HCC meeting the Milan criteria and receiving RFA
or lesion resection, and confirmed the suspicions of many retro-
spective reviews that overall and recurrence-free survival are sig-
nificantly better when resection is employed.95 In this particular
trial, 5-year recurrence rates were 63% in the RFA group and 42%
in the resection group (p = .017), and overall survival was 76% in
the resection group versus 55% in the RFA group. Unfortunately,
although RFA is attractive in unresectable patients, some of the
same features that make lesions unresectable, like proximity to
large vessels, as well as large lesion size, are the same features that
are thought to affect higher recurrence rates.91 Mazzaferro et al.
do advocate the use of RFA in cirrhotics with small HCC lesions
who are awaiting transplant; however, they caution that this strat-
egy is not as useful when lesions are >3 cm or when >1 year elapses
from ablation to transplant secondary to the risk of recurrence.96
Thus, while ablative approaches are helpful in cases when resec-
tion is not possible, or is medically contraindicated, resection is
widely accepted as the gold standard of treatment for resection of
colorectal liver metastases.91,96
5. What are the palliative procedures performed by surgeons
in relation to liver malignancies?
Unfortunately, despite increased clinical awareness and surveil-
lance programs in the United States, the majority of HCC patients
present with late stage disease that is beyond the abilities of
currently available curative therapies.97 Moreover, even patients
who present in early stages can recur following radical therapies
PMPH_CH41.indd 337
Malignant Liver Tumors ■ 337
at rates as high as 50%.98,99 The case is similar for patients with col-
orectal carcinoma, with 15% of patients presenting with stage IV
disease, and up to 50% developing metastases to the liver at some
point during their course of treatment.100,101 Finally, some patients
with neuroendocrine hepatic metastases require mere debulking
measures to achieve a long-term sustainable quality of life.70 Thus,
a surgeon’s armamentarium must contain knowledge of techniques
for palliative management of unresectable hepatic metastases.
Putting aside the afore-discussed debate regarding the effi-
cacy of RFA versus resection for resectable disease, RFA alone
or in combination with hepatic resection has shown benefit in
patients with unresectable hepatic tumors.87,102 One large study
examined 234 patients with colorectal hepatic metastases which
had progressed despite chemotherapy or were associated with
extrahepatic disease.103 Laparoscopic RFA was employed and
showed a median survival of 24 months with increased efficacy
in patients with tumors <3 cm in diameter or with <3 hepatic
lesions.103 Although the available literature on MCT is less exten-
sive, it has also shown benefit in patients with unresectable hepatic
metastases of various histologies.104 However, direct comparison of
percutaneous RFA and MCT in a retrospective setting has shown
that RFA yields decreased local recurrence with increased ablative
efficacy after fewer treatments.105
Other interventions that were considered in past litera-
ture include percutaneous ethanol injection for local ablation of
HCC. However, five RCTs have demonstrated the superiority of
local control conferred by RFA versus ethanol injection for the
treatment of early stage HCC.106-108 Newer techniques like laser
ablation, and use of ablative technologies in combination with
loco-regional chemotherapeutic and gene therapy interventions
warrant further investigation.109
Cytoreductive surgery also has a place in the palliation of
various liver tumors. Perhaps the most effective arena for cytore-
duction of hepatic metastases is that of neuroendocrine tumors.
Several authors have shown improved symptom control and
survival even with incomplete resections of hepatic neuroendo-
crine metastases.70,73,74 Until recently, cytoreductive intervention
in peritoneal carcinomatosis of colorectal origin was thought
to be contraindicated in the presence of lymph node or hepatic
metastases. However, some investigators are now showing favor-
able results with a combination of liver resection, peritoneal deb-
ulking, and intraperitoneal chemotherapy.110-112 Furthermore,
while it has been studied in small numbers, several centers report
favorable results following cytoreductive surgery for advanced or
unresectable HCC, with one study of 72 patients demonstrating a
5-year survival of 62% with the use of cytoreduction and sequen-
tial resection for initially unresectable HCC.113-115
6. How are minimally invasive therapies used in the treatment
of liver malignancies?
Proponents of laparoscopic resection point to benefits shown in
several series like shorter hospital lengths of stay, lower rates of
blood transfusion, lower overall operative complications, cost
effectiveness, and equivocal efficacy.91,116-119 Since the first stud-
ies in the 1990s demonstrating feasibility of laparoscopic resec-
tions were reported, more than 2800 laparoscopic liver resections
have been reported in 127 articles.120 Of those, at least half
were performed to remove malignant lesions and 35% of those
malignancies were colorectal hepatic metastases. Of the 2800
cases, 75% were performed with pure laparoscopy, 17% were
5/22/2012 5:29:14 PM
 338 ■ Surgery: Evidence-Based Practice

hand-assisted, and 2% were laparoscopic-assisted or hybrid.120
Procedures described included wedge resection or segmentectomy
(45%), anatomic left lateral sectionectomy (20%), right hepatec-
tomy (9%), and left hepatectomy (7%).120 In malignant resections,
negative margins were achieved in 82% to 100% of cases.120
Given the novelty of many currently employed techniques of
laparoscopic resections as well as the inevitable absence of long-
term follow-up data, perhaps the best data available are consen-
sus opinion from the International Position on Laparoscopic
Liver Surgery, which reflects the recommendations of 45 invited
experts in both laparoscopic and open liver surgery.121 According
to the consensus conference, laparoscopic liver resections can be
divided into three subtypes: (1) biopsies and small wedge resec-
tions, (2) resections of the left lateral or anterior hepatic segments
(4b, 5, and 6), and (3) hemihepatectomies, trisectionectomies, and
resections of the “difficult posterior segments (4a, 7, 8).” 121
Major centers are experimenting with many novel surgical
approaches like single-incision hepatic resections.122 Techniques and
devices utilized for parenchymal transection and ligation of major
vascular structures, and hemostasis are also rapidly evolving, and
there does not seem to be a uniform opinion as to which is best; how-
ever, a recent meta-analysis of RCTs indicates that all new methods
should be compared against the clamp-crush technique as a gold
standard.123 The data for these techniques is still in early phases of
feasibility and efficacy reports.121 Indications for laparoscopic resec-
tion established by consensus were lesions ≤5 cm, located in periph-
eral segments 2 through 6.121 The coming years will likely bring with
them longer-term data on larger scales which are likely to establish
laparoscopic resections as the standard of care.121
DISCUSSION
Data for the treatment of malignant liver tumors are based on
a culmination of the experiences and opinions of many great
surgeons at excellent medical centers. However, treatment algo-
rithms and guidelines remain driven largely by Level 2 and 3
evidence, and are unconfirmed by RCTs. Many new technologies
are emerging that will likely provide excellent adjuncts or alter-
natives to surgical resection. Minimally invasive liver surgery
represents the future of liver resection and warrants vigorous
investigative focus.

Clinical Question Summary

Question Answer Levels of Grade of References
Evidence Recommendations
1 What is the standard Several systems available Consensus A 18-24
staging of patients Conference
prior to hepatic AJCC is US standard based on
resection? 1-3
2 What imaging MRI best overall at analyzing liver and 1-3 A 27-30, 46
techniques are best lesion characteristics
used for delineating PET most sensitive (90%) for 1-2 A
malignant from metastases pre-chemo
benign liver lesions? Clinically, MRI or CT used in
conjunction with PET
3 What are the HCC – Milan criteria for transplantation 2-3 B HCC: 4, 5, 9, 13,
treatment algorithms though some propose changes. 14, 52
for various liver Otherwise, resection where possible
malignancies? Colorectal – completely resect 2 B Colorectal: 2, 57,
synchronous and metachronous 59-61
lesions whenever possible
Neuroendocrine – cytoreduction 2 B NLM: 70, 72-74
can be of benefit
4 How are ablative RFA – variable strategies: 1 A RFA: 6, 91-93
therapies used in the I. As combo with resection for
treatment of liver extensive bilateral disease
malignancies? II. Percutaneously or laparoscopically
in cirrhotics with poor resection
tolerance
5 What are the RFA 1c A RFA: 87, 102, 104
palliative procedures
performed by Cytoreduction 1c A Cytoreduction:
surgeons in relation 110, 111, 113,
to liver malignancies? 114
6 How are minimally Laparoscopic liver resection should be 1c A Laparoscopy:
invasive therapies considered whenever possible 91, 116-120
used in treatment of
liver malignancies?

PMPH_CH41.indd 338 5/22/2012 5:29:14 PM


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113. Shimada M, Takenaka K, Kawahara N, et al. Surgical treatment
strategy for patients with stage IV hepatocellular carcinoma.
Surgery. 1996;119:517-522.
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114. Tang ZY, Yu YQ, Zhou XD, et al. Three decades’ experience in
surgery of hepatocellular carcinoma. Gan To Kagaku Ryoho.
1997;24 Suppl 1:126-133.
115. Usatoff V, Isla AM, Habib NA. Liver resection in advanced hepa-
tocellular carcinoma. Hepatogastroenterology. 2001;48:46-50.
116. Belli G, Fantini C, D’Agostino A, et al. Laparoscopic versus
open liver resection for hepatocellular carcinoma in patients
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results. Surg Endosc. 2007;21:2004-2011.
117. Koffron A, Geller D, Gamblin TC, Abecassis M. Laparoscopic
liver surgery: Shift ing the management of liver tumors.
Hepatology. 2006;44:1694-1700.
118. Koff ron AJ, Auffenberg G, Kung R, Abecassis M. Evaluation of
300 minimally invasive liver resections at a single institution:
Less is more. Ann Surg. 2007;246:385-392; discussion 392-394.
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119. Lesurtel M, Cherqui D, Laurent A, Tayar C, Fagniez PL. Laparos-
copic versus open left lateral hepatic lobectomy: A case-control
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120. Nguyen KT, Gamblin TC, Geller DA. World review of lapa-
roscopic liver resection-2,804 patients. Ann Surg. 2009;250:
831-841.
121. Buell JF, Cherqui D, Geller DA, et al. The international position
on laparoscopic liver surgery: The Louisville Statement, 2008.
Ann Surg. 2009;250:825-830.
122. Gaujoux S, Kingham TP, Jarnagin WR, D’Angelica MI, Allen
PJ, Fong Y. Single-incision laparoscopic liver resection. Surg
Endosc. 2010;25(5):1489-1494.
123. Pamecha V, Gurusamy KS, Sharma D, Davidson BR. Techniques
for liver parenchymal transection: A meta-analysis of randomized
controlled trials. HPB (Oxford). 2009;11:275-281.
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 PART VI

PORTAL HYPERTENSION

PMPH_CH42.indd 343 5/22/2012 5:29:47 PM

PMPH_CH42.indd 344 5/22/2012 5:29:47 PM

Management of Portal
Hypertension: A Surgical
Perspective
Sukru Emre and Manuel I. Rodriguez-Davalos
1. What is the incidence and risk of mortality in patients with
portal hypertension (PHTN) and bleeding gastroesophageal
varices (GEV)?
PHTN can be one of the most severe complications of cirrhosis.
This hemodynamic abnormality is related to bleeding from GEV,
ascites, and hepatic encephalopathy (HE). Despite advances in its
treatment and control, the 6-week mortality of variceal hemor-
rhage is still 10% to 20%.1,2
GEV are present in 30% of well-compensated cirrhotics, and
60% of patients with decompensated cirrhosis, the increase in varix
size is 10% to 20% from small to large in 1 year and the index of
variceal bleeding is >20% in patients with large varices.3,4 PHTN can
also occur as a result of occlusion of the extrahepatic portion of the
portal vein (EHPVO). This entity is also called noncirrhotic PHTN.
This entity has particular importance in this chapter because this
vascular disorder of the liver is the second leading cause of PHTN
in developing countries following cirrhosis in developed countries,
and the most common etiology in children. In the case of EHPVO,
surgical intervention may be the first-line treatment.5-7
Despite advances in medical, endoscopic, and interventional
techniques as well as the improvements made in the field of liver
and multivisceral transplantation, surgical shunts are still impor-
tant in the armamentarium of transplant and hepatobiliary sur-
geons who are often confronted with a select group of patients that
are not candidates for other modalities.
2. How do you describe the anatomy of the portomesenteric
system?
The portal venous system collects venous flow from the superior
mesenteric vein (SMV), inferior mesenteric vein (IMV), and splenic
vein (SV). The trunk formed by their union is the portal vein (PV),
which enters into the liver and divides into branches through its
substance and ends in capillaries. The branches are single and des-
titute of valves.
345
PMPH_CH42.indd 345
CHAPTER 42
The PV is formed behind the upper border of the head of the
pancreas by the junction of the SV and the SMV, in front of the
vena cava. The IMV drains into the SV in most of the population
but may also join the SV and the SMV to form trifurcation, or drain
into the SMV.8,9 The PV enters into the liver, divides into branches
through its substance, and ends in capillaries. The PV branches are
single and destitute of valves. In most cases, the PV divides just
prior to entering the liver into left (LPV) and right PV branches
and then follows Couinaud’s segmental anatomy.
The anatomy of the LPV is the particular interest in this chap-
ter because the meso-Rex bypass (previously called REX shunt)
became possible due to the anatomy at the recessus of Rex, where
the umbilical vein (UV) enters into the LPV. During fetal devel-
opment, the UV carries oxygenated blood form mothers placenta
to the LPV. Recessus of Rex is located between the lateral and the
medial segments of the left lobe.9,10
3. What is the definition and pathophysiology of PHTN?
PHTN is defined as a pathological increase of PV pressure above
the normal range of 5 to 8 mmHg. Hepatic vein pressure gradient
(HVPG) is one of the standard measurements utilized in assessing
the degree of PHTN. HVPG is the difference between the wedged
and the free hepatic venous pressures, normally between 3 and
6 mmHg. HVPG > 10 mmHg is considered as PHTN. Although
it is a general belief that esophageal variceal bleeding occurs on
patients with gradients >12 mmHg,4,11,12 there are reports indicat-
ing that the degree of PHTN does not always predict bleeding.13
Patients with presinusoidal PHTN HPVG measurement is not
increased because sinusoidal pressure is within normal limits.
Portal pressure is proportionally related to blood flow in the
portal system and resistance to the portal flow. The most impor-
tant and common initial abnormality is the compromised vascu-
lar lumen secondary to fibrosis formation as seen in cirrhosis. The
obstruction can also be mechanical in nature, caused by a thrombus
or an outflow obstruction at the level of the sinusoids or hepatic
5/22/2012 5:29:47 PM
 346 ■ Surgery: Evidence-Based Practice
venous obstruction. This leads to the formation of collateral ves-
sels that divert the portal blood to systemic circulation in addition
to a splanchnic vasodilation secondary increase in PV flow. Nitric
oxide, glucagon, and prostacyclin, along with other compounds,
are involved in this phenomenon, which aggravates this hyperdy-
namic state. The pathophysiology of PHTN is important in this
surgical chapter because of the reduced arterial pressure, increase
in cardiac output preceded by expanded plasma volume in rela-
tion to renal sodium retention and changes in peripheral resis-
tance that may be directly correlated with the candidacy of this
patient for the different procedures to be discussed.8,14
4. What is the classification and treatment algorithm for bleed-
ing PHTN?
PHTN can be classified as
a. prehepatic
b. hepatic
i. presinusoidal
ii. sinusoidal
iii. postsinusoidal
c. posthepatic
Based on this standard classification, therapeutic modalities
can be addressed depending on the level where the obstruction
to the portal flow occurs. Among the most common prehepatic
causes are EHPVO, which many time is idiopathic; portal vein
thrombosis (PVT) that can be related to cirrhosis; cancer; inher-
ited or acquired prothrombotic conditions; focal inflammation; or
postoperative complications. The most common causes of hepatic
PHTN are cirrhosis, schistosomiasis (presinusoidal), congenital
hepatic fibrosis, and sarcoidosis. Postsinusoidal reasons are hepatic
vein thrombosis (Budd-Chiari syndrome) and veno-occlusive dis-
ease (VOD); and posthepatic usually related to cardiac etiologies or
inferior vena caval web.5,7,12,15
In May 2010, a workshop on the methodology of diagnosis
and therapy in PHTN met for the Baveno V consensus meeting.
This group of experts, who were responsible for most of the major
achievements in the field and authors of Level 1 and 2 studies on
the topic, reviewed therapeutic modalities in patients with PHTN
and issued evidenced-based recommendations for the conduct of
trials and guidelines for patient management.2 This position paper
divides their therapeutic options into five categories: pre-primary
prophylaxis, prevention of first bleeding episode, treatment of
acute bleeding, management of treatment failures, and prevention
of rebleeding.
The last two categories are of special interest in this review
since the patients that fail endoscopic and pharmacological ther-
apy are the groups in which surgical treatment may be of use.
In adult patients with cirrhosis, the recommendations for
fi rst-line treatment to prevent rebleeding is a combination of
β-blockers and endoscopic variceal band ligation (EBL), and a
follow-up of hemodynamic response. Isosorbide mononitrate
can be added to patients that do not have an adequate hemody-
namic response or are unable to be treated with EBL. According
to the Baveno V therapeutic options, patients who fail to respond
to endoscopic and pharmacological treatment should then be
assessed for transjugular intrahepatic portosystemic shunt (TIPS)
or surgical shunting (SS) in appropriate candidates. Transplanta-
tion provides good long-term outcomes when available, in which
case TIPS are often used as a bridge.2
PMPH_CH42.indd 346
5. TIPS versus SS: When is surgery the treatment of choice and
when is a surgical procedure is considered for the treatment of
bleeding PHTN?
Patients with PHTN and/or liver cirrhosis would benefit from
surgical interventions when medical treatment fails, as TIPS pro-
cedure cannot be performed secondary to patients’ anatomical
problems, small children with long-term life expectancy without
transplantation especially biliary atresia patients with successful
Kasai procedure or children with EHPVO.1,16
The concept of selectivity was described by Warren and Zeppa16
in their landmark paper, in which they utilized a distal splenorenal
shunt (DSRS) and emphasized maintaining portal pressure and
flow to the liver (hepatopedal) via the SMV while alleviating the
portal pressure in the gastroesophageal and splenic areas. DSRS
was the first selective shunt described that addresses the left-sided
PHTN including esophageal and gastric varices. DSRS is largely
used when medical treatments failed in patients with cirrhosis and
PHTN. Preventing recurrent episodes of bleeding and diminishing
HE and liver failure should be a priority in SS.16,17
Another important concept to be discussed in the particular
case of extra hepatic vein obstruction is the physiologic redirec-
tion of blood from the spleno-mesenteric system into the LPV.
Due to the physiologic advantages it offers, the meso-Rex bypass
has become the standard procedure in such cases wherein this is
a concern.6,18 TIPS is a minimally invasive percutaneous way to
decompress the portal system. This procedure is performed by
placing a stent within the liver that connects the PV to the hepatic
vein therefore decompressing the portal system and preventing
bleeding. Compared with other medical therapies, TIPS is an
effective tool in decreasing portal pressures and it significantly
decreases recurrent variceal hemorrhage, but increases the like-
lihood of HE and has no effect on survival.19 In a 2009 update
of the American Association for the Study of Liver Diseases
practice guidelines, Boyer and Haskal 20 reviewed the role of TIPS
in the management of PHTN-related variceal bleeding. They sug-
gested that TIPS should only be utilized when pharmacologic and
endoscopic therapies fail. Their recommendation also included the
use of expanded polytetrafluoroethylene (ePTFE)-covered stents
to decrease the incidence of shunt thrombosis. The authors also
showed that TIPS are slightly more cost-effective than DSRS at 5
years, but the two approaches are equal in efficacy.20 On the other
hand, multicenter trial conducted by Henderson et al.21 showed that
thrombosis, stenosis, and reintervention rates were significantly
higher in the TIPS group with the p < .001.21 There are also absolute
contraindications for TIPS procedure including congestive heart
failure, multiple hepatic cyst, sepsis, unrelieved biliary obstruction,
severe pulmonary hypertension and hepatoma. The obstruction of
PV or all hepatic veins used to be considered relative contraindica-
tions in the past. In patients with portal hypertension, anticoagula-
tion therapy is the first line treatment. TIPS procedure should be
preferred over liver transplantation when patients fail to improve
with anticoagulation since the current data indicates that 1- and 10
years transplant free survival rates after TIPS is favorable.20
Porto-caval shunt (PCS) surgery is a very effective tool in pre-
venting rebleeding from GEV in patients with PHTN, but it is
controversial as there is an increased risk of HE and no survival
advantage.22 A large multicenter trial of TIPS versus DSRS was
conducted in well-selected patients who failed to medical and
endoscopic treatments.21 In this study, the rebleeding incidence
was 5.5% in DSRS group versus 10.5% in TIPS; not significant
5/22/2012 5:29:47 PM

with no difference in survival. On the other hand, this study also
showed that TIPS group had very high reintervention rates (DSRS,
11%; TIPS, 82%; p < .001). This study also revealed that ascites for-
mation, need for transplant, quality of life, and costs were not sig-
nificantly different between two groups.21
One of the undesired side effects of TIPS procedure is the devel-
opment of worsening encephalopathy. In some published series the
incidence of worsening encephalopathy reached 20% to 31%.23 In
contrast, the incidence of encephalopathy occurred 10% to 15% of the
cases after selective shunt surgery in many different series.16,17,21,23,24
As it was mentioned at the beginning of this chapter, there are
patients who will not be candidates for TIPS or medical therapy
and therefore it is important to understand the value of SS and the
meso-Rex bypass and their specific indications.
Surgical shunts can be classified into totally diverting shunts,
partially diverting shunts, and selective shunts.
6. What would be the proper evaluation for shunt surgery?
Perhaps the most important factor in the decision-making of the
surgical treatment of PHTN is the status of the patient. Evaluating
the hepatic reserve, by utilizing either Child-Turcotte-Pugh score
(CPT) or the Model for End-Stage Liver Disease (MELD) facili-
tates the surgical decision making.25 A complete medical evalua-
tion of comorbidities such as obesity, age, preexisting cardiac or
pulmonary conditions, and active infection are essential. Patients
with PHTN may develop porto-pulmonary hypertension. When
shunt surgery is considered in patients with PHTN, measuring the
pulmonary artery pressure is paramount important since shunt
surgery is contraindicated in patients with pulmonary hyperten-
sion. We also suggest that evaluation of socioeconomic issues such
as medical access, treatment cost and distance to the center should
be taken into account before any type of therapy is chosen.18,21,24-27
Evaluation should also include liver biopsy, liver function
tests, complete blood count, tests for hypercoaguable states, and
adequate imaging to define the anatomy of the portomesenteric
system as well as confirming the patency of the intrahepatic PV
branches, in the case of the meso-Rex bypass for EHPVO in chil-
dren. Superina et al.31 have contended that not identifying the pat-
ency of the intrahepatic PV branches on preoperative imaging is
not a contraindication for the procedure since in most cases the
patency of the intrahepatic PV branches will be identified intra-
operatively after dissection of the recessus of Rex. On the other
hand, in one of our cases, an intraoperative portagraphy revealed
the totally collapsed intrahepatic PVs, which led us to abandon
the operation. Since then, it has been our policy to perform a pre-
operative transhepatic portography to confirm the patency of the
intrahepatic PV branches. The operative technique includes per-
forming an intraoperative portal venography after LPV is accessed
via the UV. The neck of the patient should be prepared in case the
internal jugular (IJ) vein is needed for the bypass. Often there is
a septum of liver encountered between segments III and IV, and
needs to be divided to get adequate exposure to the LPV.28-31
Different conduits have been described for the creation of
the bypass, IJ, the UV in which case if recanalized with adequate
length only one anastomosis may be needed, if the length of the
UV is not enough this can be used as a bridge with the IMV.10
Others have used the SV, saphenous vein, coronary vein, synthetic
vascular, or cryopreserved vein grafts.18,32 After patency has been
confirmed, the LPV to IJ anastomosis is performed with running
6-0 monofilament sutures. After the conduit is brought to the
PMPH_CH42.indd 347
Management of Portal Hypertension: A Surgical Perspective ■ 347
vicinity of the SMV via transmesocolic fashion, the end-to-side
anastomosis is performed between the conduit and the SMV using
6-0 polypropylene sutures. Patients are usually anticoagulated
postoperatively with low molecular weight heparin (LMWH) and
depending on their coagulation work-up preoperatively they will
either continue on LMWH or transitioned to aspirin. In special
cases a heparin drip will be started intraoperatively.
7. What procedure is indicated based on the etiology, classifica-
tion, and anatomy of PHTN as well as spleno-mesenteric system?
In 1945, Whipple and Blakemore introduced the clinical use of
the portosystemic shunting concept that Eck had experimentally
performed and published in 1877.33-35 It was in the following years
that the concept of preservation of portal flow was recognized as
key to the survival of these patients. Although PCS were dem-
onstrated to be an excellent way to decompress the GEV, most
patients developed hepatic decompensation and the long-term
survival rates were poor.18,25,36
These procedures were usually done by anastomosing the PV,
SV, or SMV to the vena cava, the left renal vein or another major
tributary of the vena cava. All are considered total shunts.37,38
PCS AND LOW DIAMETER H-GRAFTS
The original PCSs were performed in an end-to-side fashion, and were
effective in decreasing the portal pressures, but deprived the liver
from the portal blood flow. Julian and Metcalf39 described the side-
to-side PCS as preserving hepatopedal flow. These shunts have high
patency rates. Severe encephalopathy is the major complication
of this type of shunt procedure with variable long-term survival.38
The outcomes of elective shunts such as Warren’s DSRS to total
shunts such as the PCSs were compared in clinical trials. These
studies revealed that postshunt encephalopathy was seen in 18% to
30% of patients with excellent long-term shunt patency.33,40,41 PCS
are still utilized by many groups and the concept of low diameter
has been utilized in the mesocaval position.36,40
MESOCAVAL SHUNT
The concept of shunting SMV flow to vena cava began in the 1950s.
It was further developed by Lord et al.42 in the 1960s and then cham-
pioned by Drapanas41 in 1972. His original series, presented at the
American Surgical Association, consisted of 25 patients with 8%
mortality using the procedure on Child’s class B and C patients.40
His technique utilized knitted Dacron 19- to 22-mm graft. His
description and results have been cited by many groups. There were
discussions and disagreements in terms of selectivity and higher
incidence of HE due to the size of the graft. These discussions
played an important role for the development of the small diam-
eter (8–10 mm) synthetic vascular interposition graft utilization
for mesocaval shunt (MCS). Before analyzing other evidence-based
studies, it is important to mention that prior to the Drapanas paper,
others had described the use of interposition grafts between vessels,
mainly homografts like jugular vein from the patient and Teflon
grafts.43 Scudamore et al.35 published their experience of using a
medium size (10 mm) PTFE graft in Vancouver. They reported 0%
rebleeding rate, 0% mortality, and 20% postshunt encephalopathy
in their patients with a mean follow-up time of 14 months.35
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 348 ■ Surgery: Evidence-Based Practice
A prospective German study conducted by Paquet et al.44
analyzed 100 patients with mesocaval interposition shunts with
12.2% incidence of encephalopathy, 10% incidence of early mor-
tality, and 65% long-term survival. Interestingly, it was shown in
sequential portal perfusion studies that 75% of the patients main-
tained their hepatopedal flow immediately after the MCS shunt
procedure. When this study was repeated 2 years later, only 38%
of the patients maintained hepatopedal flow, indicating that the
MCS becomes nonselective shunt by time. A prospective con-
trolled study comparing the outcomes of DSRS with MCS per-
formed using 10-mm interposition synthetic grafts was published
by Mercado et al.45 This study showed that DSRS group had sig-
nificantly less shunt thrombosis rates than MCS (4.3% vs. 27%).
There was also a higher incidence of HE in the MCS group com-
pared with DSRS group (36% vs. 4.3%).
From a technical point of view, all the authors agreed that the
vena cava to interposition graft anastomosis should be performed
as a first step to eliminate exposure problems at the level of the
vena cava and to avoid the prolonged occlusion of the SMV. The
length of the PTFE graft is crucial; it must be long enough to pass
inferiorly around the lower border of the third portion of the duo-
denum; it should also not be redundant since redundancy could
cause kinking of the graft.
SPLENORENAL AND
SPLENOCAVAL SHUNTS
The original concept of utilizing the SV as a conduit for shunt-
ing the portal blood flow in patients with PHTN goes back to the
beginning of PHTN surgery.35 In early reports, the proximal SV
was anastomosed to the renal vein due to their proximity, divert-
ing blood flow from the high-pressure portal system into the low-
pressure systemic venous circulation.39 This operation is called a
proximal or central splenorenal shunt.
Warren et al.16 at the University of Miami developed a new
shunt procedure in which the distal end of the SV was anasto-
mosed to the side of the left renal vein. They were able to show
a decrease in incidence of HE while maintaining hepatic func-
tion by preserving the SMV flow to the liver. Although some of
the results were not reproducible by all groups and the utility
in patients with advance liver disease especially Child’s class C
cirrhotics has been challenged by many, until the development
of liver transplantation (LT), many of these patients had lim-
ited options for treatment once medical therapy had failed.17,21
A variant of these selective shunts is the splenocaval, which,
as described by Orozco, has the same principal as the Warren.
However, when the renal vein is not feasible for anastomosis
secondary to large spleen pushing the left kidney distally, this
variation of DSRS may be a reasonable option by anastomosing
the distal SV to the vena cava directly.46 Other efforts were done
to insure the preservation of hepatopedal flow and prevent Eck’s
syndrome, such as the left gastric venous caval shunt described
by Inokuchi et al.47,48
Generally, all portosystemic shunts have more than 90% con-
trol preventing variceal bleedings. In terms of their outcomes,
selective shunts are superior to the nonselective shunts with fewer
incidences of postshunt encephalopathy and other morbidities.23
One of the major complications of the DSRS is the develop-
ment of the PVT. Total and partial PVT were seen on 13 (10.5%)
and 22 (17.7%) patients.49
PMPH_CH42.indd 348
MESENTERIC TO LEFT PV BYPASS
(MESO-REX BYPASS)
The concept of the mesenteric to LPV bypass (MLPVB) was origi-
nally reported by de Ville de Goyet for the treatment of PVT after
LT by accessing the PV in the fissure between the medial and
lateral segment of the left lobe of the liver (recessus of Rex). The
original technique uses the patients left IJ vein anastomosed end-
to-side to the LPV and implanted in the SMV.28,29 The term Rex
shunt is no longer used because this bypass redirects portal flow
from the spleno-mesenteric system into the liver restoring physi-
ologic hepatopedal flow. Therefore, this procedure is not only ana-
tomically a bypass, but also functionally a bypass.
The meso-Rex bypass has shown to improve growth and
neuro-cognition in children with EHPVO especially if it is per-
formed earlier.18,30
The meso-Rex bypass has also been described in adult patients
that have developed PVT as a complication of other procedures and as
described originally for PVT posttransplant with good success.15,50-52
DEVASCULARIZATION PROCEDURES
Nonshunting procedures were developed as a life-saving tempo-
rary measure to control/prevent esophageal and gastric variceal
bleeding in patients with total thrombosis of portomesenteric sys-
tem. Between 1967 and 1973, Hassab53 in Egypt and Sugiura and
Futagawa54 in Japan described devascularization procedures of the
esophagus in one or two stages depending on the patient’s over-
all medical condition. Multiple modifications have been made to
the original procedures in both pediatric and adult patients with
good results especially in patients with Child’s class A and B. These
changes include modifications to the esophageal transection, avoid-
ing splenectomy and performing single stage operation. We prefer
to perform this procedure after variceal bleeding is controlled and
patient becomes hemodynamically stable. Performing the surgery
with transabdominal approach, ligating and dividing of the splenic
artery rather than splenectomy, ligating varices entering the distal
5 cm of the esophagus via abdominal approach,, minimizing the gas-
tric devascularization to proximal 1/3 of the stomach, exploring the
posterior aspects of the stomach wall for large variceal veins enter-
ing to the stomach and ligating them, using appropriate size circular
intraluminal stapler device for esophageal transection are impor-
tant steps for successful outcomes. In most cases now we reserve
devascularization in patients in whom there are no shunt or bypass
options with life-threatening variceal bleeding. In selected groups,
the mortality rate in these cases is between 6% and 7% with approx-
imately10% rebleeding rate and no HE.54-56
8. What is the role of emergency shunt surgery and transplan-
tation in patients with bleeding esophageal varices?
In a randomized clinical trial, Orloff et al. 57 showed excellent
results with PCS in emergency situations over the years with only
6% of their patients were referred to LT secondary to progression
of liver disease. Other groups have not been able to reproduce the
similar results; they have reported 13% to 40% mortality in emer-
gency cases. The report from the Baveno V consensus conference
on PHTN suggests utilizing medical, endoscopic, and radiologic
alternatives as a first-line treatment for patients with variceal
bleedings. Emergent surgery is used as a last resource in case of
failure of other treatment modalities.2
5/22/2012 5:29:47 PM
 Management of Portal Hypertension: A Surgical Perspective ■ 349

The definitive procedure for the treatment of PHTN in dec-
ompensated cirrhotic patients is LT. The current survival data
reported on patients receiving LT are higher than the observed on
nonresponders to the medical treatment for recurrent esophageal
variceal bleeding. As a result, the success of LT has revolution-
ized the field.10,22 We believe that LT is a life-saving procedure for
decompensated cirrhotic patient with gastroesophageal variceal
bleeding. On the other hand, availability of cadaveric organs is
unpredictable and current organ allocation system in the United
States does not prioritize patients with bleeding esophageal varices.
This will create a dilemma to perform timely transplantation in
this patient population.
9. When balloon tamponade is indicated using Sengstaken–
Blakemore tube and how is this performed?
Balloon tamponade of the bleeding esophageal varices using
Sengstaken–Blakemore tube is indicated when overwhelming
bleeding cannot be controlled with medical treatment and/or TIPS
procedure. Development of new technologies such as TIPS, more
aggressive secondary prophylaxis with variceal band ligation pro-
cedures resulted in less and less use of balloon tamponade. On the
other hand, we do believe that knowing how to use Sengstaken–
Blakemore tube appropriately is still important especially large
hepatology/liver transplant units. Sengstaken–Blakemore tube
is more complex form of nasogastric tube with several internal
channels and two inflatable balloons, one for the stomach and
more elongated one for the esophagus. It is important to make
sure that the stomach balloon is in the stomach. Stomach balloon
is inflated and approximately 1 kg traction is applied. This is very
important to compress the gastroesophageal junctional varices. If
bleeding cannot be controlled, inflating the esophageal balloon
is indicated to control bleeding. Known complications of this
procedure are development of pressure ulcers and rupture of the
esophagus and stomach.58-60

Clinical Question Summary

Question Answer Levels of Grade of References
Evidence Recommendation
1 What is the incidence The 6-week mortality of variceal haemorrhage is 1A, 1C A 1-4
and risk of mortality still 10% to 20%. GEVs are present in 30% of
in patients with well-compensated cirrhotics, and 60% of patients
portal hypertension with decompensated cirrhosis. The increase in
(PHTN) and bleeding varix size is 10% to 20% from small to large in
gastro-esophageal 1 year and the index of variceal bleeding is >20%
varices (GEV) in patients with large varices.
2 How do you describe The portal venous system collects venous flow from 1A A 8-10
the anatomy of the the SMV, IMV, and SV. The trunk formed by their
portomesenteric union is the PV, which enters into the liver and
system? divides into branches through its substance and
ends in capillaries. The branches are single and
destitute of valves. The PV is formed behind the
upper border of the head of the pancreas by the
junction of the SV and SMV, in front of the vena
cava. The IMV drains into the SV in most of the
population but may also enter the junction of
the SV and the SMV or drain into the SMV.
3 What is the definition PHTN is defined as a pathological increase of PV 1A, 1B A 4, 11-13
and pathophysiology pressure (PVP) above the normal range of 5 to
of PHTN? 8 mmHg. PVP is proportionally related to blood
flow in the portal system and resistance to the
portal flow. The most important and common
initial abnormality is the compromised vascular
lumen secondary to fibrosis formation as seen in
cirrhosis. The obstruction can also be mechanical
in nature, caused by a thrombus or an outflow
obstruction at the level of the sinusoids or hepatic
veins. This leads to the formation of collateral
vessels that divert the portal blood to systemic
circulation, in addition to a splanchnic vasodilation
secondary increase in PV flow. Nitric oxide,
glucagon, and prostacyclin, along with other
compounds, are involved in this phenomenon that
aggravates this hyperdynamic state.

(Continued)

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 350 ■ Surgery: Evidence-Based Practice

(Continued)
Question Answer Levels of Grade of References
Evidence Recommendation
4 What is the PHTN can be classified as (1) prehepatic; (2) hepatic 1A, 1B A 2, 5, 7, 12,
classification and (i. presinusoidal, ii. sinusoidal, and iii. postsi- 16
treatment algorithm nusoidal); (3) post hepatic. Treatment algorithm
for bleeding PHTN? includes medical treatment (β-blocker,
octreotide) and endoscopic band ligation. When
medical treatment fails, TIPS or shunt surgery is
indicated. Patient with decompensated cirrhosis
LT will be the ideal operation. In patients with
EHPVO, the meso-Rex bypass is the treatment
of choice.
5 TIPS versus shunt: Patients with PHTN and/or liver cirrhosis 2B B 1, 6, 17-25
When is surgery would benefit from surgical interventions when
the treatment of medical treatment fails. If TIPS procedure
choice and when is cannot be performed secondary to patients’
a surgical procedure anatomical problems, patients with Child’s
is considered for class A cirrhosis and small children with
the treatment of long-term life expectancy without trans-
bleeding PHTN? plantation or children with EHPVO surgical
treatment is indicated.
6 What would be the Evaluation should include complete blood count, 3B B 19, 22,
proper evaluation liver function tests, tests for hypercoaguable 25-33
for shunt surgery? states, and liver biopsy. A complete medical
evaluation of comorbidities such as obesity, age,
preexisting cardiac or pulmonary conditions,
and active infection are essential. Evaluation of
socioeconomic issues such as medical access,
treatment cost, and distance to the center
should also be taken into account. Obtaining
adequate imaging of the porto-mesenteric
system including the patency of the intrahepatic
PV branches in case of EHPVO is crucial.
Evaluating the hepatic reserve, by utilizing either
CPT or MELD facilitates the surgical decision
making.
7 What procedure A patient with cirrhosis, selective shunt such as 1B, 3B, 4 B 19, 24, 26,
is indicated based DSRS is preferred to minimize the postshunt 37-50
on the etiology, encephalopathy. A variety of the PCS are also
classification, used successfully. For a patient with EHPVO,
and anatomy of the meso-Rex shunt is the treatment of
PHTN as well as choice. Patients with porto-mesenteric
spleno-mesenteric thrombosis, nonshunt surgical procedure
system? such as Sugiura operation will be life-saving.
8 What is the role Only one group has shown excellent results with 1A, 2B A 2, 10, 23,
of emergency PCS in emergency situations with only 6% of the 58
shunt surgery patients were referred to LT. Other groups have
and transplantation not been able to reproduce the similar results;
in patients with they have reported 13% to 40% mortality in
bleeding esophageal emergency cases. The report from the Baveno V
varices? suggests that emergent surgery is used as a
last resource. LT is the ultimate treatment
with decompensated cirrhotic patients with
bleeding GEV.

(Continued)

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 Management of Portal Hypertension: A Surgical Perspective ■ 351

(Continued)
Question Answer Levels of Grade of References
Evidence Recommendation
9 When balloon Balloon tamponade of the esophageal varices using 4 B 59-61
tamponade is Sengstaken–Blakemore tube is indicated when
indicated using bleeding cannot be controlled with medical
Sengstaken– treatment and/or TIPS procedure. Many times it
Blakemore tube is necessary to stabilize a patient for endoscopic
and how is this or surgical procedure. Appropriate application
performed? of Sengstaken–Blakemore tube is important.
It is a more complex form of nasogastric tube
with several internal channels and two inflatable
balloons, one for the stomach and more elongated
one for the esophagus. It is important to make
sure that the stomach balloon is in the stomach.
Stomach balloon is inflated and approximately
1 kg traction is applied. This is very important
to compress the gastroesophageal junctional
varices. If bleeding cannot be controlled,
inflating the esophageal balloon is indicated to
control bleeding.

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5/22/2012 5:29:48 PM

Management of Intractable
Ascites: The Evidence
Mark I. E. Cockburn and Adora Fou-Cockburn
INTRODUCTION
Ascites can be the result of liver cirrhosis (75% of patients present-
ing with ascites), malignancy (10%), cardiac failure (3%), pancrea-
titis (1%), tuberculosis (2%), or other rarer causes.1 When ascites
develops as a complication of liver disease, it is associated with a
poor prognosis.2 Almost 10% of patients with cirrhosis and ascites
develop intractable/refractory ascites3 and medically intractable/
refractory ascites is generally thought to presage death due to liver
failure with relatively small 1- and 2-year survival rates.4,5 Accord-
ing to the International Ascites Club, refractory ascites is defined
as ascites that cannot be mobilized or whose early recurrence
after paracentesis cannot be satisfactorily prevented by medical
therapy.6
1. What is the medical management of ascites?
The aim of treatment of ascites is to improve sodium balance or
circulatory function until liver transplantation or until the disease
runs its natural course. Upright posture activates sodium-retaining
systems and impairs renal perfusion and sodium excretion. In one
study bed rest improved the response to diuretics7 but no clinical
trials have shown that bed rest actually improves the efficacy of
medical treatment.
Although the use of low-salt diets is almost universally rec-
ommended, this approach is not backed by the results of con-
trolled clinical trials. In one controlled study, a slightly reduced
salt diet (120 mmol/d) was equally effective in patients with
ascites when compared with low-salt diet (50 mmol/d).8 There are
no significant differences in survival between patients receiving
salt-restricted or -unrestricted diets, although the survival of
patients with previous gastrointestinal bleeding was better in the
low-salt group.9
There are both controlled and uncontrolled clinical trials
showing that spironolactone is the drug of choice for the ini-
tial treatment of secondary hyperaldosteronism. 8-11 The recom-
mended dose of spironolactone is 100 to 200 mg once daily. When
severe hyperaldosteronism is present, the dosage may be increased
353
PMPH_CH43.indd 353
CHAPTER 43
to 400 mg/d.11 Loop diuretics, such as furosemide, are frequently
used as an adjunct to spironolactone therapy. The initial oral dose
of furosemide is usually 20 to 40 mg/d, and is generally adjusted
upward every few days up to a maximum of 160 mg/d.
Answer: There is Level 1b evidence that spironolactone is the
diuretic of choice in the management of patients with liver cirrho-
sis and ascites. (Grade A recommendation).
2. What is the role of paracentesis in the management of intrac-
table ascites?
There are many randomized controlled trials comparing therapeu-
tic paracentesis with diuretics in cirrhotic patients with ascites12-16
and these have shown that paracentesis was more effective than diu-
resis in eliminating ascites and shortened the duration of hospi-
talization. Tito et al.17 showed that total paracentesis was as effective
and as safe as repeated partial paracentesis. Paracentesis-induced
circulatory dysfunction (PICD) is the most common complication
of large-volume paracentesis and refers to the effective hypov-
olemia and renal impairment seen after large-volume paracentesis.
When the ascites is tapped, the intraabdominal pressure rapidly
falls, thereby improving the venous blood return to the right heart
and a transient increase in cardiac output may occur.18 There is
also resultant hyponatremia, which suggests that the paracentesis-
induced decrease in effective volume may also stimulate vasopressin
secretion with subsequent retention.19 Logically the use of plasma
expanders has been suggested to prevent PICD. Gines et al.16 con-
ducted a large multicenter RCT that demonstrated the superiority
of albumin compared with synthetic plasma expanders in pre-
venting PICD.
There are no absolute contraindications to perform paracen-
tesis, but the procedure should be avoided in patients with dissem-
inated intravascular coagulopathy and extreme caution should
be taken in patients with intraabdominal adhesions or with a
distended urinary bladder.
Answer: There is Level 1b evidence that shows paracentesis
superior to diuretics in eliminating ascites and shortening hospi-
tal stay in patients with ascites. (Grade A recommendation).
5/22/2012 5:30:22 PM
 354 ■ Surgery: Evidence-Based Practice
3. What is the role of transjugular intrahepatic portosystemic
shunt (TIPS) in the management of intractable ascites?
There are five RCTs that have compared the effects of TIPS versus
large-volume paracentesis as a treatment for intractable ascites.20-24
One hundred and sixty-two patients out of a total of 330 enrolled
underwent TIPS, while 168 underwent large-volume paracen-
tesis. TIPS eliminated ascites in two-thirds (67%) of the patients
undergoing this procedure (TIPS), while large-volume paracen-
tesis controlled ascites in 23% of the patients undergoing large-
volume paracentesis.25 This meta-analysis also showed that TIPS
is associated with a trend toward improved survival. In another
meta-analysis on the data from four of the RTCs,21-24 it was shown
that patients receiving TIPS showed a significantly better survival
than patients receiving paracentesis.26 Of note is that not all the
patients in those four RTCs had refractory ascites, but recidivant
ascites. The RTC20 that was not included in this meta-analysis was
that with the worst outcomes. In this study,20 none of the Child-
Pugh class C patients eliminated their ascites and their overall
survival was significantly worse in the TIPS group. Hence, TIPS
is generally considered to be contraindicated in Child-Pugh class
C patients.
The superiority of TIPS in the treatment of refractory ascites
is still controversial and paracentesis remains the first option in
treating refractory ascites.27 When the frequency of paracentesis is
greater than three times per month TIPS insertion should be con-
sidered, but this decision depends on practical and patient issues
and the informed discussion about the risks of encephalopathy
and consent with the patient.28
The major complications of TIPS include (1) stenosis which
can occur in up to 70% of patients with bare stents within the
fi rst year.29 The advent of polytetrafluoroethylene (PTFE) cov-
ered stents has significantly reduced the incidence of TIPS
stenosis. 30-32 (2) Dislocation of the stent or its migration to the
right heart or lungs. (3) Onset of or worsening hepatic enceph-
alopathy which can occur 20% to 30% of the time after TIPS
insertion. In a meta-analysis of RCTs comparing TIPS with
large-volume paracentesis as a treatment for refractory ascites,
the patients who received TIPS had an odds ratio of 2.26 for the
development of hepatic encephalopathy after TIPS. 25 In those
patients whose encephalopathy is refractory to medical man-
agement, occlusion or reduction in shunt size is mandatory. 33
(4) TIPS can induce intravascular hemolysis, occurring in 10%
of patients (especially those with bare stents). (5) Development of
cardiac failure (2.5%), renal failure (4.3%), and liver failure (1.9%).
(6) Bacterial infection of the stent itself or endotipsitis which
often cannot be treated successfully. 34
Clinical Question Summary
Question Answer
1 What is the medical management Spironolactone is the diuretic of
of ascites? choice in the management of
patients with liver cirrhosis
and ascites.
2 What is the role of paracentesis Paracentesis superior to diuretics
in the management of intractable in eliminating ascites and
ascites? shortening hospital stay in patients
with ascites.
PMPH_CH43.indd 354
Answer: There are Level 1a and 1b evidence that supports TIPS
in the control of intractable ascites in carefully selected patients.
Potential complications of TIPS need to be considered when being
used in patients. (Grade A recommendation).
4. How does TIPS compare with peritoneovenous shunts in the
treatment of medically intractable ascites?
Rosemurgy et al.35 conducted a prospective randomized trial com-
paring TIPS to peritoneovenous shunts in the treatment of medically
intractable ascites. In this study 32 patients were prospectively ran-
domized to undergo TIPS or peritoneovenous (Denver) shunts and
all had failed medical therapy. After TIPS versus peritoneovenous
shunts, median (mean ± SD) duration of shunt patency was similar:
4.4 months (6 ± 6.6 months) versus 4 months (5 ± 4.6 months).
Assisted shunt patency was longer after TIPS: 31.1 months (41 ± 25.9
months) versus 13.1 months (19 ± 17.3 months) (p < .01, Wilcoxon
test). After TIPS 19% of patients had irreversible shunt occlusion
versus 38% of patients after peritoneovenous shunts. Survival after
TIPS was 28.7 months (41 ± 28.7 months) versus 16.1 months
(28 ± 29.7 months) after peritoneovenous shunts. Control of ascites
was achieved sooner after peritoneovenous shunts than after
TIPS (73% vs. 46% after 1 month), but longer-term efficacy favored
TIPS (85% vs. 40% at 3 years). They concluded that peritoneovenous
shunts control ascites sooner, but TIPS provides better long-term
efficacy and this study promoted the use of TIPS for medically
intractable ascites if patients undergoing TIPS have prospects
beyond short-term survival.
Answer: There is Level 1b evidence that proves that TIPS pro-
vides better long-term efficacy in the management of medically
intractable ascites compared with peritoneovenous shunts. (Grade A
recommendation).
5. When should liver transplantation be considered in patients
with intractable ascites?
Ascites is usually an indicator of advanced cirrhosis and we know
that patients with ascites refractory to medical management have
a particularly poor prognosis. Liver transplantation is not a treat-
ment for refractory ascites per se, but rather needs to be considered
for all patients who present with end-stage hepatic failure whether
or not it is accompanied by refractory ascites. Liver transplanta-
tion in patients who have developed refractory ascites secondary
to cirrhosis is the only therapy that addresses the underlying liver
disease in addition to improving the ascites.27
Answer: There is no data that supports liver transplantation
solely for the management of intractable ascites. No recommenda-
tions can be made based on the evidence.
Levels of Grade of References
Evidence Recommendation
1b A 11
1b A 12-17
(Continued)
5/22/2012 5:30:22 PM

(Continued)
Question Answer
3 What is the role of transjugular TIPS can control intractable ascites in
intrahepatic portosystemic carefully selected patients.
shunt (TIPS) in the management
of intractable ascites?
4 How does TIPS compare with TIPS provides better long-term
peritoneovenous shunts in efficacy in the management
the treatment of medically of medically intractable ascites
intractable ascites? compared to peritoneovenous
shunts.
5 When should liver transplantation There is no data that supports liver
be considered in patients with transplantation solely for the
intractable ascites? management of intractable ascites.
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5. Guardiola J, Xiol X, Escribia JM, et al. Prognosis assessment of
cirrhotic patients with refractory ascites treated with a peritone-
ovenous shunt. Am J Gastroenterol. 1995;90:2097-2102.
6. Arroyo V, Gines P, Gerbes AL, et al. Definition and diagnostic cri-
teria of refractory ascites and hepatorenal syndrome in cirrhosis.
International ascites club. Hepatology. 1996;23:164-176.
7. Ring-Larsen H, Henrikcen JH, Wilken C, Clausen J, Pals H,
Christensen NJ. Diuretic treatment in decompensated cirrhosis
and congestive heart failure: Effect of posture. Br Med J. 1986;292:
1351-1353.
8. Bernardi M, Laffi G, Salvagnini M, et al. Efficacy and treatment
of the stepped care medical treatment of ascites in liver cirrho-
sis: A randomized control clinical trial comparing two diets with
different sodium content. Liver. 1993;13:156-162.
9. Gauthier A, Levy VG, Quinton A, et al. Salt or no salt in the treat-
ment of cirrhotic ascites: A randomized study. Gut. 1986;27:705-709.
10. Fogel MR, Saughney VK, Neal EA, Miller RG, Knauer CM, Greg-
ory PB. Diuresis in the ascites patient: A randomized control trial
of three regimens. J Clin Gastroenterol. 1981;3(Suppl 1):73-80.
11. Perez-Ayuso RM, Arroyo V, Planas R, et al. Randomized compara-
tive study of efficacy of furosemide versus spironolactone in
patients with liver cirrhosis and ascites. Gastroenterology. 1983;84:
961-968.
12. Gines P, Arroyo V, Quintero E, et al. Comparison of paracente-
sis and diuretics in the treatment of cirrhotics with tense ascites.
Results of a randomized study. Gastroenterology. 1987;93:234-341.
13. Sola R, Vila MC, Anreu M, et al. Total paracentesis with Dextran
40 vs diuretics in the treatment of ascites in cirrhosis: A random-
ized control study. J Hepatol. 1994;20:282-288.
14. Cotrim HP, Garrido V, Parana R, et al. Paracentesis associated
to dextran-70 in the treatment of ascites in patients with chronic
liver disease: A randomized therapeutic study. Arq Gastroenterol.
1994;31:125-129.
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Management of Intractable Ascites: The Evidence ■ 355
Levels of Grade of References
Evidence Recommendation
1b A 20-24
1b A 35
– – –
15. Hagengue H, Ink O, Ducreux M, Pelletier G, Buffet C, Etienne
JP. Treatment of ascites in patients with liver cirrhosis without
neither hyponatremia nor renal insufficiency. Results of a ran-
domized study comparing diuretics and punctures compensated
by albumin. Gastroenterol Clin Biol. 1992;16:751-755.
16. Gines A, Fernandez-Esperrach G, Monescillo A, et al. Random-
ized trial comparing albumin, dextran 70, polygeline in cirrhotic
patients with ascites treated by paracentesis. Gastroenterology.
1996;111:1002-1010.
17. Tito L, Gines P, Arroyo V, et al. Total paracentesis associated
with intravenous albumin management of patients with cirrho-
sis and ascites. Gastroenterology. 1999;98:146-151.
18. Pozzi M, Osculati G, Boari G, et al. Time course of circulatory
and humoral effects of rapid total paracentesis in cirrhotic pati-
ents with tense, refractory ascites. Gastroenterology. 1994;106:
709-719.
19. Gines P, Tito L, Arroyo V, et al. Randomized comparative study
of therapeutic paracentesis with and without intravenous albu-
min in cirrhosis. Gastroenterology. 1998;94:1493-1502.
20. Lebrec D, Givily N, Hadengue A, et al. Transjugular intrahepatic
portosystemic shunts: Comparison with paracentesis in patients
with cirrhosis and refractory ascites: Randomized trial. J Hepatol.
1996;25:135-144.
21. Rossle M, Ochs A, Gulberg V, et al. A comparison of paracentesis
and transjugular intrahepatic portosystemic shunting in patients
with ascites. N Eng J Med. 2000;342:1701-1707.
22. Gines P, Uriz J, Calahorra B, et al. Transjugular intrahepatic
portosystemic shunting versus paracentesis plus albumin for
refractory ascites in cirrhosis. Gastroenterology. 2002;123:
1839-1847.
23. Sanyal AJ, Gening C, Redy KR, et al. The North American study
for the treatment of ascites. Gastroenterology. 2003;124:634-641.
24. Salerno F, Merli M, Roggio O, et al. Randomized control study
of TIPS versus paracentesis plus albumin in cirrhosis with severe
ascites. Hepatology. 2004;40:629-635.
25. D’Amico G, Luca A, Morabito A, et al. Uncovered transjugular
intrahepatic portosystemic shunt for refractory ascites: a meta-
analysis. Gastroenterology. 2005;129:1282-1293.
26. Salerno F, Camma C, Enea M, et al. Transjugular intrahepatic
portosystemic shunt for refractory ascites: A meta-analysis of indi-
vidual patient data. Gastroenterology. 2007;133:825-834.
27. Salerno F, Guevara M, Bernardi M, et al. Refractory ascites:
pathogenesis, definition, and therapy of a severe complication in
patients with cirrhosis. Liv Int. 2010;30(7):937-947.
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28. Moore KP, Wong F, Gines P, et al. The management of ascites in
cirrhosis: Report on the Consensus Conference of the Interna-
tional Ascites Club. Hepatology. 2003;38:258-266.
29. Sanyal AJ, Freedman AM, Luketic VA, et al. The natural history
of portal hypertension after transjugular intrahepatic portosys-
temic shunts. Gastroenterology. 1997;112:889-898.
30. Barris J, Ripoll C, Banares R, et al. Comparison of transjugular
intrahepatic portosystemic shunt dysfunction in PTFE-covered
stent grafts versus bare stents. Eur J Radiol. 2005;55:120-124.
31. Angermayer B, Cejna M, Koenig F, et al. Survival in patients
undergoing transjugular intrahepatic portosystemic shunt:
ePTFE-covered stent grafts versus bare stents. Hepatology.
2003;38:1043-1050.
PMPH_CH43.indd 356
32. Rossi P, Salvatori F, Fanelli F, et al. Polytetrafluoroethylene cov-
ered nitinol stent graft for transjugular intrahepatic portosystemic
shunt creation: 3 year experience. Radiology. 2004;231:820-823.
33. Kerlan RK, Jr., LaBerge JM, Baker EL, et al. Successful reversal of
hepatic encephalopathy with intentional occlusion of transjugu-
lar intrahepatic portosystemic shunts. J Vasc Interv Radiol. 1995;
6:917-921.
34. Mizrahi M, Adar T, Shouval D, et al. Endoptipsitis-persistent infec-
tion of transjugular intrahepatic portosystemic shunt: Pathogen-
esis, clinical features and management. Liv Int. 2010;30:175-183.
35. Rosemurgy AS, Zervos EE, Clark WC, et al. TIPS versus perito-
neovenous shunt in the treatment of medically intractable ascites.
A prospective randomized trial. Ann Surg. 2004;239(6):883-891.
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Hepatic Encephalopathy
INTRODUCTION
Hepatic encephalopathy continues to be a difficult problem for
many patients with liver disease, but rigorous scientific evidence
for a clear therapeutic approach is sorely lacking. Even the clas-
sification and grading of this condition are exceptionally difficult
to define, with no single test or examination having been shown to
be sufficiently precise or accurate in the diagnosis and/or assess-
ment of the severity of encephalopathy. The purpose of this chap-
ter is to present what evidence exists in the context of a number of
relevant clinical questions.
1. Who is at risk of developing hepatic encephalopathy?
Generally the more advanced the degree of liver disease the more
likely that hepatic encephalopathy will develop. However, precipi-
tating factors are critically important in not only the diagnosis, but
also the management of hepatic encephalopathy. It would be fair
to say that most episodes of encephalopathy are associated with a
precipitant. There are a multitude of possible precipitants, which
include the following:1
• Drugs: sedatives, analgesics, tranquilizers
• Infectious: spontaneous bacterial peritonitis, UTI, pneumonia
• Nutritional: constipation, excessive dietary protein
• Electrolyte abnormalities: hypokalemia, hyponatremia
• Acid-base disorders: acidosis, alkalosis
• Renal: dehydration, renal failure
• Hematological: gastrointestinal bleeding
• Metabolic: hypoglycemia
• Surgery
• Transjugular intrahepatic portosystemic shunt (TIPS)
• Superimposed liver injury: hepatitis, toxin-induced liver injury
• Hepatocellular carcinoma
Patients with portal vein thrombosis and extensive portosys-
temic shunting without significant parenchymal liver disease can
also occasionally develop encephalopathy.
357
PMPH_CH44.indd 357
CHAPTER 44
Terence O’Keeffe and Tun Jie
Hyponatremia is of particular concern as it is both an inde-
pendent risk factor for the development of encephalopathy, and is
also predictive of poor prognosis in patients whose levels are below
135 mmol/L.2,3 Additionally, it has been suggested that patients with
cirrhosis who are malnourished or have diabetes mellitus appear to
have a higher frequency of developing hepatic encephalopathy.4 A
larger study did not provide evidence that nutritional status was an
independent risk factors for the presence of encephalopathy, thus
this risk factor remains unclear.5
In a study from 2007, 257 patients were assessed for risk fac-
tors for the onset of severe encephalopathy. Elevated ammonia
levels, serum bilirubin, lactate level, a prolonged International
Normalized Ratio (INR), and the Model for End-Stage Liver Dis-
ease (MELD) score were all shown to be predictive factors on uni-
variate analysis, and on multivariate logistic regression analysis
elevated ammonia levels, and the MELD score remained indepen-
dent predictors of the development of encephalopathy.6
Also, in a report from 2010, it was suggested that there might
be genetic variations in the clinical expression of encephalopa-
thy, which appears to be related to variations in the promoter
region of the glutaminase gene.7 This may be a promising area of
future study.
Summary: There are specific precipitating factors that are
associated with the development of hepatic encephalopathy, and
these need to be taken into account and treated as part of the
management of this disease.
Answer: Identification of precipitating factors can help identify
those patients at risk to develop encephalopathy. (Level 2b evidence;
Grade B recommendation).
2. Are there different types of hepatic encephalopathy?
Hepatic encephalopathy has been classified clinically into three
major categories according to the underlying hepatic condition.8
Type A occurs in patients with acute liver failure. Type B occurs in
patients with encephalopathy caused by portosystemic shunting,
but without intrinsic liver disease. Type C is encephalopathy of
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 358 ■ Surgery: Evidence-Based Practice
cirrhosis associated with portosystemic shunting, and this is also
the most common form. It may be episodic or persistent. Episodic
encephalopathy is often caused by precipitating factors (such as
those addressed above), which should be treated by addressing
these underlying causative factors. However, it may also occur
without a recognizing precipitating factor, when is known as
spontaneous episodic hepatic encephalopathy. When the enceph-
alopathy lasts beyond 4 weeks or is recurrent it is considered per-
sistent. Both episodic and persistent forms of encephalopathy may
be adequately suppressed by therapy, but will often reappear after
discontinuation of medications.
Minimal or “subclinical” hepatic encephalopathy represents
a particular problem as it has been used in the past to describe
patients who have no recognizable clinical symptoms of brain
dysfunction. Diagnosis was made on the basis of abnormal psy-
chometric tests in the face of normal neuropsychiatric examina-
tion. It is difficult, therefore, to ascertain whether this is a separate
clinical entity or whether it is merely an early manifestation of the
disease process.
Unfortunately, there have been no attempts to assess the sci-
entific validity of the above classification, but it is impossible to
discuss this aspect of hepatic encephalopathy in isolation, with-
out considering how to grade the severity of the encephalopathy,
which we deal with in the following section.
Summary: No clear scientific data exists to assess the validity
of the current classification of hepatic encephalopathy.
Answer: The classification above, which is based on expert
opinion alone, is recommended as it is endorsed by the major-
ity of the national and international hepatology societies. (Level 5
Evidence; Grade D recommendation).
3. Can you grade the severity of hepatic encephalopathy?
One of the major barriers to timely diagnosis and treatment of
hepatic encephalopathy is the lack of well-validated and standard-
ized assessment tools. The first grading system to assess the sever-
ity of hepatic encephalopathy was developed in the 1970s and has
become known as the West Haven system of classification. This
uses a five-point grading scale starting at grade 0 and ending at
grade 4.9,10 This grading system is based purely on the physician’s
clinical judgment by assessment of the patient’s mental status, and
takes approximately 15 min to complete. One of the drawbacks
of this system is the lack of objective measures regarding level of
consciousness, as it is based on changes of intellectual functioning
and behavior. The Glasgow Coma Scale (GCS), for example, does
not form part of this scoring system. Neither has this grading tool
being subjected to a large well-validated trial.
Other authors have proposed different scoring systems such
as the hepatic encephalopathy scoring algorithm (HESA). In their
paper from 2008, Hassanein et al.11 noted a moderately strong
association between the two grading systems (r = 0.60), and they
felt that their results suggested that HESA could be more sensi-
tive to mental status impairment in the middle grades of hepatic
encephalopathy than the West Haven criteria.
This algorithm was prospectively tested in 70 adult patients
with cirrhosis, suffering from hepatic encephalopathy grades III
and IV, who were randomized to standard medical therapy or stan-
dard therapy with albumin dialysis. A total of 597 evaluations were
performed in these patients over 5 days, and the investigators noted
that there was significant separation between the grades using the
parameters that they had adopted. They also noted that the GCS was
PMPH_CH44.indd 358
less precise in defining minimal hepatic encephalopathy (i.e., grades
to I–II).12 They concluded that the HESA was a useful extension of
the West Haven criteria, which merited further validation.
Other tools that have been used to assess hepatic encephal-
opathy include the portal-systemic encephalopathy (PSE) index,
which was originally described in 1977 and combines the patient’s
mental state with the arterial ammonia levels, degree of asterixis,
electroencephalogram (EEG) findings, and the results of the
number connection test.10 However, in acute encephalopathy, the
PSE index has not been determined to be superior to other clini-
cal grading systems and is associated with high rates of error.13
Psychometric tests can also be performed, but require adjustment
for demographic and cultural confounding variables. EEG and/or
evoked responses are nonspecific and are incapable of providing a
specific diagnosis of hepatic encephalopathy.14 Neuropsychologi-
cal testing, likewise, does not provide significant specificity for the
diagnosis.15 Current recommendations for episodic or persistent
hepatic encephalopathy are that a clinical grading system should
be used for quantification. GCS may also provide additional use-
ful information in stages III and IV.8
There are also well-known associations between encephalop-
athy and abnormalities seen via neuroimaging techniques such as
magnetic resonance imaging (MRI), computed tomography (CT),
or positron emission tomography. For example, cirrhotic patients
often demonstrate high signal intensity on T1-weighted MRI
images in the basal ganglia.16 This is thought to be related to depo-
sition of manganese as the causative factor.17 Although these MRI
abnormalities correlate with EEG findings, they may not correlate
with clinical signs or symptoms and so may not be as useful to
assist in grading of severity of encephalopathy.
The bispectral index (BIS) has also been used to help differen-
tiate severity. Dahaba et al.18 reported in a study in 2008 that they
were able to achieve an 87% agreement across grades 1 to 4 of hepatic
encephalopathy (West Haven criteria) using specific BIS value cutoffs
for the various grades. Not surprisingly, the discriminative power of
the BIS index was higher for high-grade (grades 3 and 4) than for
low-grade (grades 1 and 2) hepatic encephalopathy. Mean BIS values
correlated well with West Haven grades (r 2 = 0.90).
Another study looked at critical flicker frequency in diag-
nosing hepatic low-grade encephalopathy. The involved subjects
trying to discriminate the threshold frequencies at which life was
perceived as fused or flickering light. They found using a CFF cut-
off value of 39 Hz, a 100% separation of patients with manifest
hepatic encephalopathy from noncirrhotic controls was achieved.
Statistically significant correlations were found between CFF and
psychometric testing. They concluded that CFF was a sensitive,
simple and reliable parameter for quantification of low-grade
headache encephalopathy severity in cirrhotic patients, and it may
be useful in the detection and monitoring of subclinical hepatic
encephalopathy.19 One of the advantages of this study was the rela-
tively large patient population with cirrhosis—92 patients, which
is larger than most of the other reports mentioned in this section.
However, like BIS testing, it does not lend itself to simple bedside
examination, as it requires sophisticated machinery, a dedicated
examiner, and 90 min to complete the entire test.
Summary: The West Haven criteria is the most common
grading system used to classify hepatic encephalopathy, although
the discriminatory power is not especially high, and the criteria
were developed over 30 years ago. Newer scoring systems and/or
objective tests hold promise, but await validation in large, well-
designed clinical trials.
5/22/2012 5:30:57 PM

Answer: Grades III and IV of hepatic encephalopathy can
probably be accurately classified, by a number of the methods
listed above, whereas grades I and II are less accurately defined.
(Level 2b evidence; Grade B recommendation).
4. How can you differentiate hepatic encephalopathy from other
causes of confusion?
The confusion that is seen with hepatic encephalopathy may
clinically be similar to many other disease states and a thor-
ough history and physical, together with a comprehensive evalu-
ation is required to make sure that other diagnoses can be reliably
excluded.1
The differential diagnosis may include the following:
1. Intracranial pathology: hemorrhage, stroke, mass-occupying
lesion
2. Central nervous system infection: meningitis, encephalitis,
abscess
3. Metabolic endocrinopathies: ketoacidosis, uremia, thyroid
dysfunction
4. Alcohol withdrawal, delirium tremens or Wernicke’s
encephalopathy
5. Postictal following a seizure
Unfortunately, it is all too common for patients with liver
disease to have multiple causes of confusion, such as uremia asso-
ciated with hepatorenal syndrome in addition to hepatic encephal-
opathy. It is also usually necessary to perform neuroimaging such
as a head CT or an MRI scan to exclude the presence of struc-
tural lesions as a cause of the abnormal mental state. However, as
detailed in the section above, these scans may not be specific for
the diagnosis, but may reveal important findings such as cerebral
edema or even uncial herniation.
The role of ammonia in diagnosing hepatic encephalopathy
remains controversial, with previously reported discrepancies
between blood levels and hepatic encephalopathy severity due in
part to problems with the chemical assays used for ammonia. If
properly processed (i.e., drawn in a nonheparinized container,
immediately placed on ice, and assayed within 30 min) there is
good correlation between blood ammonia levels and severity of
encephalopathy.20,21 In a study from 2003, Ong et al.22 found sig-
nificant correlations between the arterial total ammonia level,
venous total ammonia level and venous partial pressures of
ammonia to the severity of hepatic encephalopathy. The West
Haven criteria were used to classify encephalopathy, and fast-
ing blood samples were drawn immediately after testing, sent to
the lab on ice, and analyzed within 30 min. Although all four
measures of ammonia increased with the severity of hepatic
encephalopathy, the correlation coefficients were relatively weak
(r 2 = 0.52–0.61), and there was substantial overlap in the total
ammonia levels by grade of hepatic encephalopathy.22 In a study
from 2005, the correlation between plasma ammonia levels and
hepatic encephalopathy was only sufficiently discriminatory in
patients with acute liver failure and not in those with chronic liver
disease (r 2 = 0.91 vs. 0.30).23
Therefore it is felt that a normal blood ammonia level in a
patient with severe mental status changes is not supportive of the
diagnosis of hepatic encephalopathy. However, ammonia levels
may be moderately elevated in patients with cirrhosis without
encephalopathy, and an elevated serum ammonia level in a coma-
tose patient is not sufficient alone to exclude coexistent conditions
that may contribute to a decreased level of consciousness.
PMPH_CH44.indd 359
Hepatic Encephalopathy ■ 359
A recent study looked at the discriminatory power of serum
nitric oxide in diagnosing hepatic encephalopathy, and Papa-
dopoulos et al.24 showed that compared with serum ammonia,
nitric oxide was more sensitive than ammonia (96.8% vs. 87.9%),
using a cutoff of 75 μg/dL for ammonia levels.24 However, it was
less specific overall than ammonia, and it performed better as an
exclusionary test. The combination of nitric oxide and ammonia
levels holds some promise to help in the diagnosis as well as in the
assessment of severity of encephalopathy.
Summary: An elevated blood ammonia level in the absence
of structural lesions on neuroimaging studies supports the diag-
nosis of hepatic encephalopathy.
Answer: Thorough diagnostic evaluation is required to exc-
lude alternative diagnoses, including brain imaging. Ammonia
levels can help to discriminate hepatic encephalopathy, (Level 2b
evidence; Grade B recommendation).
5. What is the underlying cause of hepatic encephalopathy?
Hepatic encephalopathy represents the clinical manifestation of
functional disturbances in cells involved in neurotransmission,
and there are a number of competing hypotheses regarding these
pathways and the cells involved.
One theory proposes that encephalopathy is due to a dis-
order of astrocyte function, secondary to edema within these
cells interfering with cerebral neurotransmission. Th is theory is
attractive due to the associated cerebral edema and raised intrac-
ranial pressure that are often seen in these patients. However,
it is unclear if the astrocyte edema is related to the neurotox-
icity of other substances, which may precipitate encephalopathy
(such as hyponatremia, inflammatory cytokines, and benzodiaz-
epines) or whether it is the astrocyte itself that is the cause of the
problem.25
Not surprisingly, ammonia has also been suggested as the
principal neurotoxin causing encephalopathy. It has multiple neu-
rotoxic effects, such as impairing amino acid metabolism, inhib-
iting the generation of postsynaptic potentials, and altering the
transit of amino acids, water and electrolytes in astrocytes and
neurons. Elevated ammonia levels may be directly neurotoxic,
and/or sensitize the astrocytes and neurons to injury by other
pathways and mediators.1 The clinical improvement that is often
seen with treatment that decreases serum ammonia levels also
lends credence to this theory. Unfortunately for this hypothesis
up to 10% of patients with significant encephalopathy have nor-
mal serum ammonia levels, as well as patients with chronic liver
disease having hyperammonemia without encephalopathy.
Seminal work in the 1980s suggested that γ-aminobutyric
acid (GABA), which is a neuroinhibitory substance produced in
the gastrointestinal tract, was responsible for encephalopathy due
to increased GABAergic tone in the brain.26 Proposed mechanisms
have included increased brain GABA content, altered integrity
of the receptor complex or the presence of increased amounts of
substances with modulatory activity at the receptor site.27 Experi-
mental models have shown that neurotoxins can increase the
production of receptors, which can then stimulate the conversion
of cholesterol to neurosteroids.28 Neurosteroids are subsequently
released from the astrocyte that are capable of binding to their
receptor within the neuronal GABA receptor complex and can
increase inhibitory neurotransmission. This possible role for neu-
rosteroids with GABA receptor modulatory properties might offer
a plausible alternative explanation of the increased GABAergic
tone in HE.29
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 360 ■ Surgery: Evidence-Based Practice
It is however clear that at this time, that there is no single uni-
fying theory to explain the development of encephalopathy from
the current available theories. Due to space constraints we can-
not deal exhaustively with all the theories in this text, but a more
extensive review is available in Zakim and Boyer’s Hepatology.30
More research will be required to fully elucidate the underlying
mechanisms causing encephalopathy.
Summary: No single theory exists that completely explains
the pathogenesis of hepatic encephalopathy.
Answer: Neurotoxins likely play a role, but it is likely the cause
is multifactorial. (Level 4 evidence; Grade C recommendation).
6. Which therapies are effective for hepatic encephalopathy?
Despite decades of research, there is still lack of a clear under-
standing of the pathogenesis of hepatic encephalopathy. Cur-
rent treatments for hepatic encephalopathy are largely based on
clinical experience, and some are extrapolated from experimen-
tal animal models. Only recently have data started to accumu-
late from evidence-based clinical trials in the treatment of hepatic
encephalopathy.
The management of patients with hepatic encephalopathy
depends on the precipitating factors, the severity, and the etiology
of the liver failure. In patients with chronic hepatic dysfunction,
encephalopathy often occurs episodically, caused by precipitating
factors previously discussed.31 In patients with acute liver failure,
hepatic encephalopathy is often a late finding, and is associated
with cerebral edema and extensive hepatocellular damage. Drug-
related hepatotoxicity, such as acetaminophen toxicity and other
idiosyncratic drug reactions, accounts for more than 50% of the
acute liver failure cases in the United States. Therefore, the first step
in management of patients with hepatic encephalopathy is to iden-
tify the cause in a timely fashion. Treatment of the precipitating
factors and administration of pharmacologic agents can often
improve the symptoms of encephalopathy.
LACTULOSE
Lactulose is a synthetic disaccharide (galacto-fructose), which
passes through small bowel unmodified because of the lack of spe-
cific disaccharidase in human enterocytes. It is metabolized by the
colonic bacteria enzymes into gas and acids. Ammonia is trapped
in the acidic colonic environment by forming nonabsorbable NH4+.
The osmotic diarrhea induced by lactulose further increases the
fecal nitrogen clearance32 and reduces colonic bacterial load. Elk-
ington et al.33 first demonstrated the therapeutic value of the lactu-
lose in patients with chronic hepatic encephalopathy in a small
double-blind clinical trial in early the 1970s. Since then, lactulose
has become a mainstay treatment for patient with hepatic enceph-
alopathy. However, there is limited data to show the efficacy of
lactulose from well-designed, randomized, controlled clinical tri-
als. A Cochrane review of the beneficial effects of nonabsorbable
disaccharides did not show statistical significant in improvement
of encephalopathy or mortality.34 The study was based on data of
10 trials with high methodological quality; however, most of the
early trials were underpowered because of the relative small sample
size. More recently it was shown that lactulose help improve
cognitive functions and quality of life in patients with minimal
hepatic encephalopathy,35,36 and to prevent encephalopathy after
acute variceal bleed.37
PMPH_CH44.indd 360
The optimal dose of lactulose has yet to be verified in clinic
trials. Patients are often instructed to titrate the dose of lactulose
to achieve 2 to 4 loose stools daily. Lactulose can be administrated
as a retention enema in comatose patients. The utility of lactulose
in patients with encephalopathy associated with acute fulminant
liver failure is uncertain.
ANTIBIOTICS
The rationale of using antibiotics in patients with hepatic enceph-
alopathy is to eliminate the colonic bacteria, in particular, the
urease-producing bacteria, to reduce the production of ammo-
nia. Neomycin was first proposed as the long-term treatment for
hepatic encephalopathy based on a small clinical trial with 20
patients.38 A double-blinded, randomized, placebo-controlled trial
compared neomycin and placebo in the treatment of patients with
hepatic encephalopathy (n = 39) and failed to demonstrate any
improvement.39 Blanc et al.40 also failed to show the efficacy of the
combination of lactulose-neomycin versus placebo in a larger trial
(n = 80). Recently, neomycin has fallen out of favor because of the
ototoxicity and nephrotoxicity risks associated with long-term
aminoglycoside use.
Rifaximin, a nonabsorbable derivative of rifampin, received
an orphan drug status as a treatment for hepatic encephalopathy
in 2005. In a Phase 3, multicenter, randomized, double-blind,
placebo-controlled trial with 299 patients in remission for recur-
rent hepatic encephalopathy, Bass et al.41 showed treatment of a
dose of 550 mg rifaximin twice daily was more effective than pla-
cebo to maintain remission. In this study, patients in both treat-
ment and control groups also received lactulose. The episodes of
recurrent encephalopathy causing hospitalization were 22% in
the treatment group and 46% in the placebo group (p < .01). In
another recent randomized trial of patients with minimal hepatic
encephalopathy, Bajaj et al.42 reported improvements seen in driv-
ing simulator performance and cognitive performance, but not in
ammonia levels or MELD scores.
DIETARY MODIFICATION
To reduce the intestinal ammonia production, low-protein diets
have been routinely advocated as part of the management of hepatic
encephalopathy in the past. This practice was not supported by
strong evidence. Moreover, protein intake restriction may lead to
worsening nutritional status, which has been recognized as a seri-
ous problem as encephalopathy. A randomized study conducted
in cirrhotic patients admitted for an episode of encephalopathy
showed no benefit from receiving a low-protein diet. Those patients
on the low-protein diet had evidence for exacerbating protein
breakdown compared with those who received normal diet.43
Summary: The principle of management of hepatic enceph-
alopathy is to correct the precipitating factors and to reduce the
ammonia level. Lactulose and rifaximin should be considered
as the first-line treatment for hepatic encephalopathy. Lactulose
can be administrated orally or as retention enema. The dose of
lactulose should be titrated to two to four loose stools daily, while
rifaximin can be taken orally 550 mg twice daily.
Answer: Lactulose and rifaximin are effective treatments for
hepatic encephalopathy. Low-protein diets have no beneficial
5/22/2012 5:30:57 PM

effects. (Lactulose: Level 2b evidence, rifaximin: Level 1b evidence;
Grade B recommendation).
7. What predicts the development of hepatic encephalopathy
following TIPS?
TIPS is an effective treatment modality in controlling variceal
bleeding, improving refractory ascites, and lately, treatment of
patients with Budd-Chiari syndrome.44-46 However, from 20%
to 77% of the patients undergoing TIPS can develop hepatic
encephalopathy, with the rate of development of encephalopathy
dependent on the patient’s residual liver function.47-49 The sever-
ity of encephalopathy following TIPS is variable and ranges from
encephalopathy that is easily controllable with antibiotics or
disaccharides to chronic encephalopathy, which can be refractory
to conventional treatment.
In a retrospective review of 136 patients who underwent TIPS
placement, followed up at 3 to 6 months postplacement, 47 patients
(34.5%) developed new or worsening encephalopathy. Of these, 69%
developed new encephalopathy and 31% had worsening of preex-
isting encephalopathy. Analysis showed that preexisting encephal-
opathy was the only significantly predictive variable in determining
the subsequent development of encephalopathy following TIPS
insertion.50
A recent meta-analysis showed that patients who underwent
TIPS despite much better in control of ascites, these patients, had
significantly more episodes of encephalopathy and more severe
episodes.51 Older age and lower mean arterial pressure (MAP)
were found to be independent risk factors for the development of
encephalopathy following TIPS. Other studies have shown that in
addition to age, patients who had an episode of hepatic enceph-
alopathy prior to a TIPS procedure were more likely to develop
encephalopathy following placement of the shunt.52,53 The Child-
Turcotte-Pugh (CTP) score has also been shown to be associated
with risk of encephalopathy post-TIPS placement.
The new generation of polytetrafluoroethylene-covered (PTFE)
stents has been shown to significantly reduce the risks of stent
dysfunction, but it has not shown to significantly alter the risk of
developing encephalopathy post-TIPS placement. In an observa-
tional study of 78 patients who received PTFE-covered stent, 44.8%
developed a episodic hepatic encephalopathy during the postpro-
cedure follow-up. Only 8% of the patients developed encephalopa-
thy refractory to conventional treatments and required reduction
of the stent diameter. The risk factors that were found associated
with post-TIPS encephalopathy included advanced age, high creati-
nine levels, and low serum sodium and albumin levels.54
Summary: There incidence of episodic hepatic encephalopa-
thy after TIPS, is high but only a small percentage of the enceph-
alopathy is refractory to medical management. The complete list
of risk factors associated with post-TIPS hepatic encephalopathy
remain to be elucidated.
Answer: Certain predictive factors exist that can predict
hepatic encephalopathy post-TIPS placement. (Level 3a evidence;
Grade B recommendation).
8. Does hepatic encephalopathy increase mortality?
When considering hepatic encephalopathy and its effects on mor-
tality, it is important to remember that encephalopathy is not
included in the calculation of the MELD score.55 The MELD score
is calculated using the following formula:
PMPH_CH44.indd 361
Hepatic Encephalopathy ■ 361
MELD = 3.78 [Ln serum bilirubin [mg/dL]) + 11.2 (Ln INR) +
9.57 (Ln serum creatinine [mg/dL]) + 6.43
Because listing for transplantation now almost exclusively uses
the MELD score, no priority is given to patients with severe recur-
rent or resistant hepatic encephalopathy. However, the CTP has
also been shown to correlate with survival, and this scoring sys-
tem does include encephalopathy.56 This score is calculated by
assigning points to different levels of total serum bilirubin, serum
albumin, INR, ascites, and the presence of hepatic encephalopa-
thy giving a severity of liver disease. It has largely been superseded
by the MELD score at this time.
Failure to demonstrate that encephalopathy independently
predicts survival could be related to the close association that it
has with liver function status. Additionally, difficulties with accu-
rately staging hepatic encephalopathy may have influenced older
data regarding the failure of encephalopathy to predict survival in
advanced liver disease.
More recent work, such as a study performed by Stewart
et al.57 in 2007 suggests that the presence of hepatic encephalopa-
thy is an independent risk factor for mortality in the two patient
populations that they studied; post-TIPS procedure and those hos-
pitalized for hepatic decompensation. This study also confirmed
that the MELD score and the CTP score were markedly associated
with survival. Also, a systematic review of factors associated with
survival from 2006 showed that encephalopathy was predictive
of mortality in 7 out of 31 studies that were assessed to have good
methodology.58 It may be that further refinements to the grading
system for encephalopathy will enable us to make accurate predic-
tions regarding survival in these patients.
It is interesting to note that there is a subpopulation of patients
who have severe hepatic encephalopathy and poor survival but
have a moderately low MELD score.59 A more detailed analysis of
the effect of the subtypes of hepatic encephalopathy (severe, dis-
abling, chronic, or recurrent versus precipitated, self-limited, and
episodic) is probably necessary to add more predictive power to
the MELD score for this subgroup of patients.1
Summary: There is evidence that hepatic encephalopathy
increases mortality and can improve the accuracy of the MELD
score. More work remains to be done to establish whether there
are specific subtypes of encephalopathy that affect mortality more
than others.
Answer: Mortality is likely increased by the presence of hepatic
encephalopathy. (Level 3 evidence; Grade C recommendation).
9. Will hepatic encephalopathy resolve following transplantation?
Transplantation is probably the single most effective treatment for
hepatic encephalopathy. Most studies have demonstrated that the
encephalopathy is reversed by the transplantation, even in very
severe cases such as acquired hepatocerebral degeneration.60-63
It is nonetheless unfortunate that the presence of hepatic
encephalopathy pretransplant may well affect the cognitive
function in the same patient posttransplant. In a study from
2011, 52 consecutive patients with cirrhosis completed neurop-
sychological testing prior to transplantation, and then 6 and 12
months following the transplant. Following transplantation,
both global cognitive function and brain volume as assessed by
MRI scanning were poorer in those patients who had hepatic
encephalopathy prior to receiving their transplant. Th is is con-
sistent with at least two other studies and shows that cognitive
5/22/2012 5:30:57 PM
 362 ■ Surgery: Evidence-Based Practice

defects can linger following transplantation.60,64 Th is may be
due to neurotoxic affects contributing to the encephalopathy, or
may be related to the underlying cause of the liver disease, for
example alcoholism. Long-term studies have shown significant
differences in MRI imaging lesions in liver transplant patients
compared with healthy controls, which may account for these
long-term differences.65
There have also been two case reports describing hepatic
encephalopathy in patients who had undergone liver transplan-
tation. In the first report, two patients who had distal splenore-
nal shunts placed following transplantation to treat portal vein
thrombosis, and two other patients had spontaneous splenorenal
shunts, all developed hepatic encephalopathy despite their liver
transplant.66 The other report dealt with a single patient, whose
retroperitoneal varices were the cause of the portosystemic shunt-
ing.67 This demonstrates that portosystemic shunting in liver
transplant recipients, even with stable graft function, can be asso-
ciated with hepatic encephalopathy. The authors all recommended
restoration of portal blood flow by either surgical or angiographic
means to treat the encephalopathy.
Summary: Hepatic encephalopathy is reversed by liver trans-
plantation, usually completely in most patients, although increas-
ing evidence suggests that continuing subtle cognitive defects may
remain. These may be related to the underlying cause of the dis-
ease, or poorly understood mechanisms of neurological damage.
Answer: Encephalopathy usually reverses following trans-
plantation, although subtle cognitive deficits may remain. (Level 4
evidence; Grade C recommendation).
Level of evidence: 4
Strength of Recommendation: C

Clinical Question Summary

Question
1 Who is at risk of developing
hepatic encephalopathy?
2 Are there different types of
hepatic encephalopathy?
3 Can you grade the severity of
hepatic encephalopathy?
4 How can you differentiate
hepatic encephalopathy from
other causes of confusion?
5 What is the underlying cause of
hepatic encephalopathy?
6 Which therapies are effective
for hepatic encephalopathy?
7 What predicts the development
of hepatic encephalopathy
following TIPS?
8 Does hepatic encephalopathy
increase mortality?
9 Will hepatic encephalopathy
resolve following
transplantation?
Answer Level of Grade of References
Evidence Recommendation
Identification of precipitating factors can 2b B 1, 2, 3, 4, 5, 6
help identify those patients at risk to
develop encephalopathy.
Hepatic Encephalopathy is usually 5 D 8
classified into one of three forms.
Grades III and IV of hepatic 2b B 8, 9, 10, 11,
encephalopathy can probably be 12, 13, 18,
accurately classified, but grades I and II 19
are less accurately defined.
Thorough diagnostic evaluation is 2b B 20, 21, 22, 23,
required to exclude alternative 24
diagnoses. Ammonia levels help to
discriminate hepatic encephalopathy.
Neurotoxins likely play a role in the 4 C 25, 26, 27, 28,
pathogenesis, but it is likely the cause 29, 30
is multifactorial.
Lactulose and rifaximin are effective 2b, 1b B 33, 34, 35, 36,
treatments for hepatic encephalopathy. 37, 39, 40,
41, 42, 43
Specific predictive factors exist that can 3a B 47, 48, 49, 50,
predict hepatic encephalopathy post- 51, 52, 53,
TIPS placement. 54
Mortality is likely increased by the 3 C 57, 58, 59
presence of hepatic encephalopathy.
Encephalopathy usually reverses following 4 C 60, 61, 62, 63,
transplantation, although subtle 64
cognitive deficits may remain.

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5/22/2012 5:30:57 PM
 Commentary on Hepatic
Encephalopathy
Jamal J. Hoballah
In this chapter, Drs. O’Keeffe and Jie from the University of Ari-
zona have done a remarkable job examining the etiology, diagnosis,
and treatment of hepatic encephalopathy. The task is particularly
difficult as the etiology, diagnosis, and treatment of this condi-
tion are so poorly understood. The evidence that they present is
compelling and may lead one to a feeling of utter hopelessness as
there remains so much that needs to be understood. It seems that
we are left utilizing the West Haven criteria to grade severity of
disease and acute management, as adjuncts to the system remain
to be adequately validated.
For Grade I and II hepatic encephalopathy, most patients
require computed tomography to exclude other causes of altered
mental status. This may demonstrate signs of cerebral edema;
however, signs of intracranial hypertension (midline shift, ven-
tricular compression, etc.) are generally not present. Treatment
of the condition remains largely supportive. Lactulose has been
utilized to decrease intestinal absorption of ammonia, but its util-
ity in improving outcome and decreasing encephalopathy has yet
to be demonstrated. Similarly, evidence to advocate antibiotics
and dietary modification in this patient population does not exist.
Furthermore, sedatives dependent upon hepatic clearance, such
as benzodiazepines, should routinely be avoided. If sedation is
necessary, then haloperidol is generally the agent of choice.
For Grade III and IV hepatic encephalopathy, patients should
be intubated for airway protection and monitored closely in the
intensive care unit. Like other aspects in the management of this
disease, type of sedation and anesthesia utilized for intubation
has not been clearly delineated. Propofol, which clears rapidly
from the body by multiple mechanisms, is usually the sedative of
choice as it does not increase intracranial pressure (ICP). Utiliz-
ing ICP monitors in these patients remains an area of controversy.
365
PMPH_CH44.indd 365
Proponents advocate that ICP monitors will help to guide therapy,
whereas detractors argue that the risks of invasive procedures far
outweigh their benefit. Furthermore, little evidence exists that
demonstrates survival benefit with ICP monitors in patients with
hepatic encephalopathy. As with traumatic brain injury, target
goals of ICP of less than 20 and cerebral perfusion pressure (CPP)
of greater than 60 should be met.
Simple techniques to meet ICP and CPP goals include head of bed
elevation to greater than 30 degrees, minimizing agitation, optimiz-
ing oxygenation, and maintaining a partial pressure of carbon dioxide
between 35 and 40. Prolonged periods of hyperventilation may lead
to cerebral vasoconstriction and associated hypoxia. Analgesic sup-
port should be minimized. If necessary, dilaudid or fentanyl should
be utilized instead of morphine or meperidine as the latter have active
metabolites that can worsen hepatic and renal failure. Mannitol has
been shown to reduce ICP and mortality in this population, whereas
hypertonic saline and dexamethasone have not. Hypertonic saline
has been shown to decrease ICP, but no survival benefit could be
demonstrated. Fevers should be treated with cooling blankets and
other environmental techniques. Non-steroidal antiinflammatory
drugs and acetaminophen should be avoided as these have been
shown to worsen renal and hepatic failure, respectively. Refractory
ICP elevations may require barbiturate coma to manage.
Prophylaxis for seizures should be aggressively pursued as
seizure occurrence markedly increases cerebral oxygen consump-
tion and ICP, and reduces CPP. Phenytoin should be used prefer-
entially over benzodiazepines.
Overall, hepatic encephalopathy remains a difficult entity to
manage. As the disease is poorly understood, new modalities for
treatment have been slow to develop. The authors of the article
should be commended for their excellent overview of the topic.
5/22/2012 5:30:57 PM
 CHAPTER 45
Elective Non-hepatic
CHAPTERSurgery
2 in
Cirrhotic Patients
Jared C. Brandenberger and Vafa Ghaemmaghami
INTRODUCTION
Though first noted as hardening of the liver associated with jaun-
dice in ancient times by Hippocrates and Galen, the term cir-
rhosis was first coined by René Leannec in the 18th century. In
Greek “kirrhos” means orange-yellow; cirrhosis is the end result
of repeated hepatocellular injury, which leads to replacement of
hepatic parenchyma with scar and regenerative nodules. Its hall-
marks are hepatocellular failure and portal hypertension, both of
which remain after the causative agent has been removed.
Liver transplantation has become the mainstay of defini-
tive treatment, and remains the only option for cure in certain
patients. As medical therapy for complications of cirrhosis has
improved, the available number of organs for transplantation has
failed to keep pace. This has resulted in an ever growing popula-
tion of patients living with cirrhosis. It has been estimated that
10% of cirrhotics undergo at least one operative procedure during
the last 2 years of their lives. This reality mandates that general
surgeons become informed regarding proper preoperative opti-
mization, therapeutic approaches, and perioperative consider-
ations in this high-risk population.
1. Is laparoscopic cholecystectomy (LC) safe in cirrhotics with
symptomatic gallstone disease?
Multiple retrospective studies (Table 45.1) have been published
describing various authors’ experience with LC in the setting of
compensated cirrhosis (Child-Turcotte-Pugh [CTP] A/B, Model
for end-stage liver disease [MELD] < 8). Although not controlled,
the conclusion from these small series was that LC is a safe option
with lower morbidity than open cholecystectomy (OC). Postop-
erative morbidity ranged from 15% to 36%.1-6 The most common
complications associated with LC in cirrhosis include bleeding,
bile leak, wound infection, worsening of ascites, port site infec-
tion, and pulmonary infection.2,7,8
El-Awadi et al.9 performed a prospective randomized study
comparing the risks of OC with LC in cirrhotic patients. This
study confirmed significant benefits to patients undergoing LC
366
PMPH_CH45.indd 366
over OC with respect to operative time, morbidity, resumption of
diet, need for blood transfusion, and hospital stay.9
When comparing patients with cirrhosis to those without,
there is a greater need for conversion to an open procedure, longer
operative time, increased need for transfusion, increased overall
morbidity, and increased incidence of acute cholecystitis.7,10
Answer: In compensated cirrhotics with symptomatic gall-
stone disease, LC is safe, resulting in less overall morbidity than an
open approach. Operative risks in these patients are significantly
higher than in the general population without cirrhosis. Conclu-
sions cannot be made about LC in patients with CTP C cirrhosis,
since most authors deem their operative risks to be unacceptably
high. (Grade B recommendation)
2. When and how should abdominal wall defects be repaired
in cirrhotics?
Umbilical hernia (UH) is very common in cirrhotics. Although
cirrhotics may also have inguinal (IH) and ventral hernias (VH),
UH is by far the most common and significant abdominal wall
defect in this population. Increased intraabdominal pressure,
relative malnutrition, and recanalization of the umbilical vein
are all thought to play a role in the prevalence of this condition
in the cirrhotic population. Historically, indications for opera-
tion included incarceration, ulceration, and leak; however, con-
servative management leads to increased emergent intervention,
with an expected increase in morbidity and mortality.11 There is
significant data in the recent literature to support elective UH
repair (UHR) in the well-compensated cirrhotic population with
minimal increase in morbidity over the noncirrhotic population
(Table 45.2).11-17 One study from the Netherlands showed that in
patients with UH and ascites (median MELD = 23, range 18–27),
elective repair in 17 patients carried a 0% risk of mortality or
hepatic decompensation, an 18% wound complication rate, and a
24% rate of recurrence. Contrastingly, a similar group managed
expectantly had a 77% complication rate—9 incarcerations, and
one spontaneous rupture and evisceration. Almost half (46%)
underwent emergent repair, with a 40% complication rate. Th is
5/22/2012 5:32:15 PM
 Elective Non-hepatic Surgery in Cirrhotic Patients ■ 367

Table 45.1 Retrospective Studies on Safety of Laparoscopic Cholecystectomy in Cirrhotics with Symptomatic
Gallstone Disease
Authors Procedure CTP Number of Patients Morbidity (%) Mortality (%) Level of Evidence
Cucinotta et al.1 LC A/B 22 36 0 4
2
Shaikh et al. LC A/B 20 15 0 4
3
Urban et al. LC A/B/C 25 52 4 2b
Tuech et al.4 LC A/B 26 27 0 4
5
Leandros et al. LC A/B 34 17.6 3 2b
6
Leone et al. LC A/B 24 20.8 0 2b
Puggioni et al.7 LC A/B/C 351 20.86 0.59 2a
8
Delis et al. LC A/B 220 19 0 2b
El-Awadi et al.9 LC/OC A/B 110 (55/55) 23.6 (12.7/34.5) 0 (0/0) 1b
10
Clark et al. LC A 15 0 0 4

Table 45.2 Repair of Abdominal Wall Defects in Cirrhotics

Authors Procedure Number of Complications Recurrence Mortality Level of
Patients (%) (%) (%) Evidence
Gray et al.11 UHR 127 9.5 NR 0.8 2b
Marsman et al.12 UHR 17 18 24 0 4
13
Carbonell et al. AWH 32022 16.5 NR 2.5 2b
14
Ammar et al. UHR (trad/mesh) 80 (40/40) 39 (40/37.5) 15 (14.2/2.7) 0 (0/0) 1b
Youssef et al.15 UHR (mesh/trad) 40 (20/20) 30 (40/20) 25.7 (10/35) 87.5 (10/15) 1b
16
Elsebae et al. UHR (drain/none) 24 (12/11) 69.6 (25/100) 16.6 (8.3/27.3) 0 (0/0) 1b
17
Belli et al. Lap UHR/IHR 14 78.5 0 0 4
Park et al.18 UHR/IHR/VHR 53 NR 1.9 1.9 4
20
Patti et al. Mesh IHR 32 6.3 0 0 4
Schlenker et al.19 Preoperative TIPS 7 29 NA 14% 4
NR = not reported; AWH = abdominal wall hernia repair (excluding IHR); Trad = traditional.

group had an overall mortality of 15%.12 One small retrospective
study by Park et al.18 shows no increase in operative risk for CTP
C patients undergoing hernia repair. Th is group, however, has
been sparsely studied.
Perioperative control of ascites is mandatory in the cirrhotic
undergoing UHR. The most common measure is aggressive medi-
cal management with diuretics and intermittent paracentesis. The
use of drains in selected patients has been advocated, and with
appropriate antibiotic prophylaxis, does not appear to increase
the rate of infection.15,16 However, the most effective treatment for
refractory ascites in patients with UH is the transjugular intrahe-
patic portosystemic shunt (TIPS).18,19 This should be considered
and aggressively pursued prior to elective repair in patients with
ascites refractory to conservative management.
The traditional method for UHR a primary repair, overlap-
ping in a “vest over pants” fashion if feasible,14-16 However, there
has been recent data showing safety and increased durability of
repair with prosthetic mesh.14,15 Both studies cited show a signifi-
cant decrease in recurrence of UH. There was a small but signifi-
cant increase in superficial infection with the mesh groups. In
neither study did this mandate mesh removal or precipitate recur-
rence. With regard to IH, a study by Patti et al.20 demonstrated
that Lichtenstein repair in cirrhotics is not only safe and effective,
but also significantly improves quality of life.
Laparoscopy for abdominal wall defects in the cirrhotic patient
has been addressed in reports and small case series; it is a versatile
and widely applied modality and may become more prevalent as
more studies are published. A review by Belli et al.17 followed up
14 patients over 8 months after laparoscopic incisional repair and
URH. No recurrences or deaths were reported in their small series.
Answer: Elective UHR and IH repair (IHR) is safe early in the
course of cirrhosis, with morbidity comparable to the noncirrhotic
population. The use of mesh is associated with a slight increase in
wound complications, but significantly less recurrence. Ascites
should be aggressively controlled in the perioperative period, with
consideration given to TIPS. The use of laparoscopy is promising
for abdominal wall defects. (Grade B recommendation)
3. How can cirrhotic patients be optimized preoperatively to
improve outcomes?
Complications of portal hypertension, especially ascites and
hemorrhage, have the most profound impact on outcomes after
operation. Perioperative control of coagulopathy is of the utmost
importance in these patients, as bleeding and transfusion have
been shown to have a direct effect in mortality.21 Vitamin K
administration, although usually ineffective due to synthetic
dysfunction, can help correct deficiency due to malabsorption in

PMPH_CH45.indd 367 5/22/2012 5:32:16 PM

 368 ■ Surgery: Evidence-Based Practice
Table 45.3 Mortality Risk in Cirrhotic Patients With or Without Portal Hypertension
Procedure No Portal Hypertension (HR [CI])
Cholecystectomy 3.4 (2.3–5.0)
Colectomy 3.7 (2.6–5.2)
CABG 8.0 (5.0–13.0)
AAA Repair 5.0 (2.6–8.0)
HR = hazard ratio; CI = confidence interval; CABG = coronary artery bypass grafting; AAA = abdominal aortic aneurysm.
cholestatic patients. In a study of invasive procedures in cirrhot-
ics being evaluated for liver transplant, Gianni et al.22 showed an
increase in postprocedure bleeding with severe thrombocytopenia
(platelets < 75 K/mm3). Coagulopathy as assessed by international
normalized ratio (INR) was not associated with postprocedure
bleeding.22 However, in a study of trauma patients with blunt
splenic injury, coagulopathy was associated with increased
mortality, and aggressive correction was recommended.23 Fran-
zetta et al.24 found coagulopathy, as well as tense ascites and
hypoalbunemia, to be a significant predictor of mortality in their
retrospective review.24 Although studied in the transplant litera-
ture, agents such as tranexamic acid, aprotenin, desmopression,
and recombinant factor VIIa have not been studied in this patient
population. Thromboelastography has been shown to be a useful
adjunct in transplantation for cirrhotics, and can help precisely
direct component therapy.25 This advantage has yet to be demon-
strated in those patients undergoing nonhepatic surgery.
Early and aggressive diuresis is the fi rst step in achieving
control of ascites. A strict low-sodium diet combined with potas-
sium sparing and loop diuretics are the most common initial
therapeutic measures.18 Paracentesis can also be used acutely to
control large volume ascites in the perioperative period; however,
it is important to replace albumin to maintain intravascular
volume.15,16,18,19,26 Performance of a TIPS procedure addresses both
portal decompression and ascites, and strong consideration
for elective placement should be given prior to any significant
intraabdominal undertaking, as it is preferred to peritone-
ovenous shunting.19,26
Prophylaxis and treatment of hepatic encephalopathy had
also been investigated extensively for liver resection and TIPS.27,28
Lactulose titrated to three bowel movements daily remains the
mainstay of treatment, and may be supplemented with rifaximin,
metronidazole, and neomycin as indicated.28 A recent double-
blind placebo controlled trial confirmed the benefits of rifaxi-
min not just in treatment, but remission from encephalopathy
over a 6-month study period. In this study by Bass and et al.,29
299 patients were randomized to rifaximin treatment versus pla-
cebo. The group treated with rifaximin had significantly less hos-
pitalizations and less incidents of breakthrough encephalopathy.
Adverse events did not differ between the groups.29
Answer: Early and aggressive therapy directed at control of
ascites and coagulopathy should be instituted to improve peri-
operative outcomes in cirrhotics. More study is needed to assess
whether strategies effective in the transplant population are effec-
tive in this population as well. (Grade C recommendation)
4. What factors are most predictive of morbidity/mortality
risk in the cirrhotic population?
One of the most important perioperative factors predictive of
morbidity and mortality in the cirrhotic population is the need for
emergency surgery. Farnsworth et al.30 described in their study a
PMPH_CH45.indd 368
Portal Hypertension (HR [CI])
12.3 (7.6–19.9)
14.3 (9.7–21.2)
22.7 (10.0–53.8)
7.8 (2.3–26.5)
significant increase in both 1- and 3-month mortality in an emer-
gent surgical group versus an elective cohort. In the elective and
emergent groups, 1- and 3-month mortality increased from 17%
and 21% to 19% and 44%, respectively. Both differences were sta-
tistically significant.30 Neeff et al.31 reported a fivefold difference in
mortality for those patients undergoing emergent versus elective
surgery (47% vs. 9%). This highlights the need for an aggressive,
appropriate, elective intervention in certain clinical situations,
some of which are highlighted above.
The presence of portal hypertension also has a large impact
on patient survival and complication rates. A study by Csikesz
et al.32 highlighted this risk factor, showing that within a sample
of 22,569 patients with cirrhosis, those with signs of portal hyper-
tension were at significantly increased risk for increased mortal-
ity from four index operations (Table 45.3). This mortality risk
was confirmed in a study of 4000 patients undergoing colorectal
procedures. Wound, urinary, and pulmonary complications were
also noted in this study.33
Answer: The presence of portal hypertension and need for
emergency surgery are strong predictors of increased periopera-
tive morbidity and mortality in the cirrhotic patient population.
(Grade C recommendation)
5. Which scoring system most accurately predicts periopera-
tive morbidity and mortality in patients with cirrhosis?
The CTP score was developed in 1964 to stratify risk for patients
undergoing portosystemic shunting. It awards 1 to 3 points in five
categories: encephalopathy, ascites serum bilirubin, albumin, and
coagulopathy. Patients are then divided into classes based on their
scores: A (5–6 points), B (7–9), and C (10–15).
The main drawback to the CTP scoring system cited repeatedly
in the literature is its inherent use of subjective measures (ascites
and encephalopathy). When applied consistently in a homog-
enous patient population, this can predict morbidity/mortality
risk quite well; however, interpretations hamper its use between
investigators.30,32,34,35 The MELD score was initially developed to
stratify short-term risk in cirrhotic patients undergoing TIPS, but
was quickly adapted for use in organ allocation by UNOS and
Eurotransplant. It uses three parameters: serum bilirubin, INR,
and creatinine; and has the advantage of objectivity.
Northrup et al.36 performed a retrospective study of 140 post-
operative cirrhotic patients (50% were intraabdominal). Though not
compared with CTP score, MELD was the only significant inde-
pendent predictor of 30-day mortality. Befeler et al.37 concluded
that a MELD score >14 more accurately predicted outcomes than
CTP class C, while a second group identified the threshold as 8 for
major morbidity.37,38 Few studies exist that compare prognostica-
tion of morbidity using MELD versus CTP scoring systems. Results
from these single-institution experiences were mixed—one showed
that the MELD score was more accurate in the setting of gallbladder
disease,8 while two showed correlation between the two.30,35
5/22/2012 5:32:16 PM
 Elective Non-hepatic Surgery in Cirrhotic Patients ■ 369

The largest retrospective study to examine this issue involved 772
postoperative cirrhotic patients. Two control groups were included
in the analysis. The authors concluded that the most important pre-
dictors of both short- and long-term mortality were age, ASA score,
and hepatic dysfunction as measured by MELD score.39
Answer: The MELD scoring system appears to be superior to
the CTP system in a population of cirrhotic patients undergoing
major surgery. Contributions of comorbidities, such as from ASA
scoring, may help refine this system to better stratify surgical risk.
(Grade D recommendation)

Clinical Question Summary

Question
1 Is laparoscopic cholecystectomy
(LC) safe in cirrhotics with
symptomatic gallstone disease?
2 When and how should
abdominal wall defects be
repaired in cirrhotics?
3 How can cirrhotic patients be
optimized preoperatively to
improve outcomes?
4 What factors are most
predictive of morbidity/
mortality risk in the cirrhotic
population?
Answer Grade of References
Recommendation
In compensated cirrhotics, LC is safe, with less B 1-10
morbidity than OC. More study is needed to
define the role of LC in patients with CTP C
cirrhosis.
Elective UHR and IHR is safe in compensated B 11-20
cirrhosis. Mesh repair is associated with
an increase in wound complications, but
significantly less recurrence. Ascites should
be aggressively controlled, with TIPS if
refractory. Laparoscopic repair may become
more prevalent.
Early and aggressive control of ascites and C 15, 16, 18, 19,
coagulopathy improves perioperative 21-29
outcomes in cirrhotics.
Portal hypertension and emergent intervention C 30-33
are predictors of increased morbidity and
mortality in cirrhotics.

5 Which scoring system The MELD scoring system appears to be superior D 30-39
most accurately predicts to the CTP.
perioperative morbidity and
mortality in patients with
cirrhosis?

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2. Shaikh AR, Muneer A. Laparoscopic cholecystectomy in cir-
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5. Leandros E, Albanopoulos K, Tsigris C, et al. Laparoscopic
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tomy in cirrhotic patients. Dig Surg. 2001;18(6):449-452.
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8. Delis S, Bakoyiannis A, Madariaga J, et al. Laparoscopic chole-
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open cholecystectomy in cirrhotic patients: A prospective ran-
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11. Gray SH, Vick CC, Graham LA, et al. Umbilical herniorrhaphy
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14. Ammar SA. Management of complicated umbilical hernias in
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15. Youssef YF, El Ghannam M. Mesh repair of non complicated
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operation in Child-Turcotte-Pugh class C cirrhosis and refrac-
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19. Schlenker C, Johnson S, Trotter JF. Preoperative transjugular intra-
hepatic portosystemic shunt (TIPS) for cirrhotic patients undergoing
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20. Patti R, Almasio PL, Buscemi S, et al. Inguinal hernioplasty
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21. Telem DA, Schiano T, Goldstone R, et al. Factors that predict
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30. Farnsworth N, Fagan SP, Berger DH, et al. Child-Turcotte-Pugh
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32. Csikesz NG, Nguyen LN, Tseng JF, et al. Nationwide volume and
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33. Nguyen, GC, Correia AJ, Thuluvath PJ. The impact of cirrhosis
and portal hypertension on mortality following colorectal sur-
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34. Kim SY, Yim HJ, Park SM, et al. Validation of a post-operative
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35. Hoteit M, Ghazale AH, Bain AJ, et al. Model for end-stage liver
disease score versus Child score in predicting the outcome of
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36. Northup PG, Wanamaker RC, Lee VD, Adams RB, Berg CL.
Model for end-stage liver disease (MELD) predicts nontrans-
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2005;242(2):244-251.
37. Befeler AS, Palmer DE, Hoff man W, et al. The safety of intra-
abdominal surgery in patients with cirrhosis: Model for end stage
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predicting outcome. Arch Surg. 2005;140(7):650-654.
38. Perkins L, Jeff ries M, Patel T. Utility of perioperative scores for
predicting morbidity after cholecystectomy in patients with cir-
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5/22/2012 5:32:16 PM
 Commentary on Elective
Non-hepatic Surgery in
Cirrhotic Patients
Bruce Gelb and H. Leon Pachter
Dr. Brandenberger and Ghaemmaghami’s chapter on “Elective
non-hepatic surgery in cirrhotic patients” addresses important
issues in the high risk and complicated subset of surgical patients
with end stage liver disease. While liver transplantation is the ulti-
mate surgical therapy in cirrhotic patients, the paucity of donor
organs and factors that preclude the feasibility of transplantation
in certain patients leaves surgeons with a non-ideal population that
requires surgical intervention. As the authors appropriately note,
improved medical management and understanding of patients
with cirrhosis has led to an increased prevalence of patients living
with cirrhosis in need of surgical intervention.
Sufficient literature exists addressing the level of safety and
expected morbidities in Child’s A, and to a lesser extent Child’s B cir-
rhosis. Unfortunately, studies are insufficient and underpowered in
Child’s C cirrhosis to provide the high level evidence needed for firm
recommendations on how to best manage these patients surgically.
Operative risk is not absolute with cirrhosis, but rather corre-
lates with the degree of physiologic derangement associated with
hepatic synthetic function, hepatic reserve, and portal hypertension.
Indeed, patients with Child’s A cirrhosis have relatively preserved
hepatic function, and therefore carry a lower risk of morbidity and
mortality compared to less compensated cirrhotic patients.
As the authors show, multiple studies suggest that Laparo-
scopic Cholecystectomy in Child’s A and select Child’s B patients
is a relatively safe procedure when performed electively. Morbid-
ity increases in Child’s B and C. Performing LC on Child’s B is
technically more difficult than in Child’s A patients and is asso-
ciated with significantly longer operative times, increased intra-
operative blood loss, and requires more frequent conversion to
an open procedure1. Portal hypertension increases the risk of
bleeding from the liver bed. Judicious preoperative correction of
coagulopathy and platelets is essential. In cirrhotic patients, we
recommend liver transplantation evaluation and listing prior to
cholecystectomy.
It is imperative to avoid certain technical pitfalls when per-
forming LC in the cirrhotic patient. 1) Avoid abdominal wall
varices during laparoscopic port placement. We advocate the use
of placing an umbilical or infra-umbilical Hassan port first via
direct cutdown and peritoneal entry under direct visualization.
Supraumbilical port placement is particularly hazardous due to
frequent umbilical vein recanalization secondary to portal hyper-
tension. Transillumination of the abdominal wall will assist in
371
PMPH_CH45.indd 371
helping avoid subcutaneous abdominal wall varices during the
placement of additional laparoscopic ports. 2) Utilization of har-
monic scalpel as an adjunct to diathermy during the gallbladder
dissection helps decrease intraoperative bleeding, gall bladder
perforation, and operative times using this technique in Child’s
A and B patients.2 3) Exercise a lower threshold for performing
subtotal cholecystectomy. Bleeding from the liver bed can be
particularly troublesome during dissection and retraction of the
gallbladder. Chronic inflammation, portal venous collaterals, and
robust lymphatics can make dissection of the cystic duct espe-
cially hazardous as one nears the porta hepatis. It may be neces-
sary to use a stapling device to ligate and divide the cystic duct
and artery. 4) Argon Beam Coagulation and judicious utilization
of topical hemostatic agents (avateen, cyano-acrylate, or oxidized
cellulose agents) are particularly useful in aiding hemostasis. 5)
Drain placement in the gallbladder fossa is advocated.
Regarding repair of abdominal wall defects in cirrhotics, the
reviewed literature supports the elective repair of umbilical her-
nias, as they are quite common in this population for the reasons
noted by the authors. Deferring surgery until urgent or emergent
presentation (incarceration, ulceration or rupture) is a misstep
and leads to unacceptable outcomes compared to earlier opera-
tive management. The authors are correct in advocating for the
control of ascites. Medical management with diuretics is the first
step in management with intermittent paracentesis as warranted.
For patients who fail to improve significantly with medical man-
agement, TIPS should be considered prior to elective repair. All
patients with ascites must be evaluated for spontaneous bacte-
rial peritonitis (SBP) prior to surgery by diagnostic paracentesis
and cell count, and elective surgery must be deferred until SBP
is adequately treated. As the authors note, adequate nutrition is
essential for healing in these patients.
The decision to use mesh in UHR must be balanced with the
risk of infection. We recommend avoiding the use of nonabsorb-
able mesh in patients who have had multiple bouts or a recent
history of SBP. Ascites reaccumulation in the repair bed can be
particularly problematic and difficult to manage and is associated
with a high rate of recurrence. Our experience in using mesh as
an overlay or underlay of a primary tissue repair has been helpful
in reducing subcutaneous fluid accumulation. Drain placement
in the subcutaneous tissues in patients with moderate to large
umbilical hernia defects or redundant skin is also helpful.
5/22/2012 5:32:16 PM
 372 ■ Surgery: Evidence-Based Practice
The third question addresses the preoperative optimization
of cirrhotic patients, and is arguably the most important factor in
limiting perioperative morbidity and mortality.
Preoperative optimization of ascites has been addressed ear-
lier, but it is important to emphasize (though only briefly men-
tioned by the authors) that aggressive diuretic therapy or large
volume paracentesis can precipitate circulatory collapse and acute
renal failure. This is best temporized by the administration of con-
centrated salt-poor albumin for plasma expansion3 +/‒ splanchnic
vasoconstrictors (i.e. octreotide and midodrine).
Intraoperative hemorrhage as a consequence of portal hyper-
tension and coagulopathy is a major obstacle in cirrhotic patients.
Directed correction of coagulopathy can be better guided with
the use of thromboelastography. Thrombopoietin (TPO) recep-
tor agonists are currently under investigation as a potential future
therapy for thrombocytopenia.4
The use of protease inhibitors in liver transplantation is mainly
due to increased fibrinolysis associated with resection of diseased
liver and to ischemia/reperfusion injury of a transplanted liver5,6
and therefore, has minimal application outside of hepatic resec-
tion in cirrhotic patients or liver transplantation.
The factors most predictive of morbidity/mortality in cir-
rhotic patients clearly parallel the extent of portal hypertension
and the need for emergency surgery. The key to offsetting these
factors is early recognition of patients likely to require surgery.
Obviously little can be done in unexpected situations such as
trauma, but keen forethought can prevent an elective umbilical
hernia repair or bowel surgery from becoming a perioperative
disaster. Cooling off a bout of acute cholecystitis or appendicitis
with antibiotic therapy and percutaneous drainage is more likely
to allow the surgeon the opportunity of coming back another day
and winning the fight rather than dooming the patient.
The final topic of which scoring system is best to predict poor
outcomes in cirrhotic patients is a tricky one. Yes, the Child-
Turcotte-Pugh scoring system is partly based on subjective mea-
sures and neglects the contribution of renal function to risk of
morbidity/mortality, but it is the most recognized system across
the medical specialties. The MELD scoring system is clearly a
more objective measuring tool in patients with end stage liver dis-
ease (the same can be said of the APACHE-II), but is less under-
stood outside the realm of transplant surgery and hepatology.
PMPH_CH45.indd 372
On a final note, it is important to consider the following ques-
tions prior to performing an operation in a cirrhotic patient: Is
the procedure technically feasible and relatively safe? Does the
risk of performing surgery outweigh the risk of nonsurgical or
less invasive management? Is the patient sufficiently optimized
with regard to ascites, renal function, cardiac status, pulmonary
function, and infection control? Is there adequate expertise and
specialty assistance (Hepatology, Nephrology, Critical Care,
Anesthesia, Transplant and Hepatobiliary Surgery) available to
assist in the perioperative management of a patient with highly
complex problems and diminished reserve and limited abil-
ity to handle complications? Cirrhotic patients are clearly an
exceptionally difficult group of patients to treat, especially when
undergoing the physiological insult of operative intervention.
Their management requires a highly specialized and multidisci-
plinary approach, often best suited in a tertiary care setting.
REFERENCES
1. Nguyen KT, Kitisin K, Steel J et al. Cirrhosis is not a contraindica-
tion to laparoscopic cholecystectomy: results and practical recom-
mendations. HPB. 2011;13:192-197.
2. Bessa SS, Abdel-Razek AH, Aharaan MA et al. Laparoscopic
cholecystectomy in cirrhotic: A prospective randomized study
comparing the conventional diathermy and the harmonic scalpel
for gallbladder dissection. J Lap Adv Surg Tech. 2011;21(1):1-5.
3. Sola-Vera J, Minana J, Ricart E et al. Randomized trial compar-
ing albumine and saline in the prevention of paracentesis-induced
circulatory dysfunction in cirrhotic patients with ascites. Hepatol-
ogy. 2003;37:1147-1153.
4. A Phase 2, Randomized, Multicenter, Placebo-Controlled, Double-
Blind, Parallel-Group Study to Evaluate the Efficacy, Safety, and
Population Pharmacokinetics of Once-Daily Oral E5501 Tablets
Used Up to 7 Days in Subjects With Chronic Liver Diseases and
Thrombocytopenia Prior to Elective Surgical or Diagnostic Proce-
dures. www.clinicaltrials.gov, identifier: NCT00914927.
5. Ryu HG, Jung CW, Lee CS, Lee J. Nafamostat Mesilate Attenu-
ates Postreperfusion Syndrome during Liver Transplantation. Am
J Transplant. 2011;(11):977-983.
6. Makwana J, Paranjape S, Goswami J. Antifibrinolytics in liver sur-
gery. Indian J Anaesth. 2010 Nov-Dec;54(6):489-495.
5/22/2012 5:32:16 PM
 PART VII

THE GALLBLADDER AND

BILE DUCTS

PMPH_CH46.indd 373 5/22/2012 5:32:52 PM

PMPH_CH46.indd 374 5/22/2012 5:32:53 PM

INTRODUCTION
Cholelithiasis constitutes one of the most common causes of gas-
trointestinal symptoms requiring hospital admission and emer-
gency department visits and thus also represents a major source
of healthcare system expenditure. The defi nitive treatment of
symptomatic or complicated cholelithiasis is cholecystectomy. For
many years, open-cholecystectomy was reserved for symptomatic
cases or case involving significant complications. The introduc-
tion of laparoscopic surgery and the availability of laparoscopic
cholecystectomy as a less-invasive alternative to the open proce-
dure have fueled a new discussion about the current indications
for cholecystectomy.
The aim of this review is to present the available data and to
provide recommendations that could be used as guidelines in the
treatment of asymptomatic cholelithiasis.
1. How frequent is this problem in the general population?
Gallstones are not a new disease entity. Autopsy reports from
Egyptian and Chinese mummies have demonstrated the presence
of gallstones more than 3500 years ago. In the 20th century, gall-
stone disease represents a major health problem with about 10% to
15% of the adults of the Western population having gallstones, more
than 20 million in the United States alone. One million patients
are newly diagnosed every year (about 1 in 200). In the United
States, gallstone disease represents approximately USD 6.2 billion
in direct and indirect healthcare costs, with a 20% increase since
1980, and it accounts for 1.8 million ambulatory visits.1
The majority of patients with gallstones will remain asymp-
tomatic (the so-called “silent gallstones”) with only 1% to 4% of
patients presenting symptoms per year. Approximately 10% will
present symptoms 5 years after the diagnosis, and 20% in the next
20 years.2 In Western Europe the prevalence of gallstones is simi-
lar to that in the United States, ranging from 5.9% to 21.9%.3 Inter-
estingly, despite the similar incidence, there are six times as many
cholecystectomies in the United States compared with Europe, a
difference primarily due to variation in the indications for surgi-
cal treatment among different nations.
375
PMPH_CH46.indd 375
CHAPTER 46
Silent Gallstones
Abdul Saied and James C. Doherty
Laparoscopic surgery and its well-documented advantages
in terms of length of hospital stay, decreased postoperative pain,
faster recovery, and shorter time to full preoperative activity, have
facilitated the transition from open-cholecystectomy as the gold
standard treatment of symptomatic gallstones to laparoscopic
cholecystectomy. In the United States, laparoscopic cholecystec-
tomy is the most common abdominal operation with 750,000 sur-
geries performed annually.4
2. What is the natural history of asymptomatic (silent) gallstones?
To better understand this pathology we should first define
the entity. Asymptomatic cholelithiasis exists when gallstones
are detected in the absence of gallstone-related symptoms. These
symptoms are grouped as biliary colic or gallstone-related com-
plications such as acute cholecystitis, acute cholangitis, or biliary
pancreatitis.
The understanding of the natural history of gallstones has
changed significantly in the past 100 years. In 1904, William J. Mayo
offered the famous dictum “There is no innocent gallstone.” On
the other hand, several studies from the 1980s established the
innocuous nature of asymptomatic gallstones when subjected to
long-term follow-up.5-7 Much controversy still exists about the
role of silent gallstones in gallbladder cancer, cholangitis, and
choledocolithiasis.
Most of the Western population with silent gallstones will
remain asymptomatic throughout their lives and do not require
any treatment.8 The rates of conversion of asymptomatic chole-
lithiasis varies within a range of 10% to 18% in 10- to 15-year
follow-up, and with an annual risk of developing biliary pain of
1% to 4%.7,9 On the other hand, symptomatic gallstones have a
1.2% risk of developing complications and a 50% risk of develop-
ing biliary pain.10 The cumulative probability of developing com-
plications after 10 years is 3% in asymptomatic patients and 7% in
symptomatic patients.11
Ransohoff and Gracie12 published conversion rates of 10%,
15%, and 18% for 5, 10, and 15 years, respectively. These findings
correlate with the observations by Hermann,13 who concluded that
the longer the patient lives with gallstones the more likely they are
5/22/2012 5:32:53 PM
 376 ■ Surgery: Evidence-Based Practice
to experience pain or complications. Other authors have found
similar rates of conversion with increasing numbers of symptom-
atic patients with age and longer follow-up.13-16 Conversely, other
investigators have observed that the longer patients were asymp-
tomatic, the less likely they were to develop symptoms.8,17-19
It is important to note that the risk of having a life-threatening
complication (cholangitis with sepsis or severe pancreatitis) from
asymptomatic gallstones is extremely low with almost no reported
cases without first experiencing biliary symptoms.
3. Is prophylactic cholecystectomy justifiable from a risk–
benefit standpoint?
As presented in the previous section, the risk of having biliary
symptoms or complications from asymptomatic gallstones ranges
from 1% to 4% annually with higher rates in the elderly popula-
tion. Prophylactic cholecystectomy to prevent biliary symptoms
and associated complications, such as pancreatitis, cholangitis,
choledocolithiasis, or cholcystitis, requires consideration of the
operative risks of laparoscopic cholecystectomy as well as those of
general anesthesia.
The establishment of the minimally invasive technique of lap-
aroscopic cholecystectomy as the standard treatment of gallstone
disease has certainly broadened the indications for cholecystec-
tomy and decreased the surgical threshold. However, laparoscopic
cholecystectomy still carries a 1% risk of common bile duct injury,
a 3% risk of bile leaks, and a 1% or 2% risk of wound infection,
bleeding, retained stones, and sludge or bile spillage with/without
abscess formation. Moreover, one must also consider the compli-
cations associated with general anesthesia such as venous throm-
boembolism, pneumonia, myocardial infarction, and atelectasis.20
One argument in support of prophylactic cholecystectomy
centers around the increased technical challenges associated
with surgery for symptomatic and/or complicated disease. Such
surgery has been shown to require increased operative time
(106 vs. 92 min), and to increase the laparoscopic-to-open con-
version rate (8.8% vs. 4.72%, p < .005). Moreover, while overall
operative mortality is only around 0.6%, it increases with age
(0.14–0.4% in patients <50 years and 4.5% in those >65 years).21
This observation argues for early aggressive treatment of the
asymptomatic young patient rather than waiting until the patient
becomes symptomatic at an advanced age. To this day, no ran-
domized controlled trial exists that compares cholesystectomy
with expectant management for silent gallstones. Furthermore,
additional observational studies would be necessary to determine
whether a randomized trial would even be justified. Thus, at pres-
ent, the evidence-based recommendation for the general popula-
tion of patients with gallstones is that cholecystectomy should only
be offered to patients with symptomatic gallstones. No compelling
high-level clinical data exists that would support the practice of
prophylactic cholecystectomy. (Grade B recommendation).
4. Is prophylactic cholecystectomy cost-effective?
In the absence of strong clinical data, some might argue that early
operative management versus expectant management of asymp-
tomatic gallstones might be justified based on economic consid-
erations. Certainly, early operative management would reduce
the healthcare costs associated with some of the highly morbid
complications of gallstones such as acute cholecystitis, acute cho-
langitis, and biliary pancreatitis. Also, cholecystectomy could be
PMPH_CH46.indd 376
offered to younger low-risk patients rather than older high-risk
patients with associated decreased healthcare costs.
Nevertheless, such healthcare savings are likely to be dwarfed
by the costs associated with the performance of an expensive and
not totally benign intervention (laparoscopic cholecystectomy) on
a large population of patients for a highly prevalent disease. While
it remains an intriguing question, no detailed economic analysis
has been published that examines the cost-effectiveness of pro-
phylactic cholecystectomy versus expectant management. In the
absence of such data, there is no compelling economic argument
that would support the practice of prophylactic cholecystectomy
in the general population. (Grade C recommendations)
5. Should prophylactic cholecystectomy be performed in certain
at-risk populations?
The concept of selective prophylactic cholecystectomy (cholecystec-
tomy for specific groups of presumably high-risk patients) has been
evaluated by different authors with no clear consensus. Among
the specific high-risk groups that have been studied are diabetics,
solid-organ transplant recipients, patients with sickle cell disease
(SCD), and patients at increased risk for gallbladder cancer.
DIABETES MELLITUS
Diabetic patients are considered a high-risk group because the
complications of gallstone disease are more severe those of the
general population in part due to the masking of the symptoms
of acute cholecystitis by autonomic neuropathy.22 Neverthe-
less, the value of prophylactic cholecystectomy in this group of
patients remains controversial. Some authors have shown major
complications rates similar to those of nondiabetic patients with
low 14.5% rates of biliary symptoms.23 Chapman et al.24 found
an increase in the prevalence of gallstones in diabetics compared
with controls, but only noninsulin-dependent diabetes was
found to be an independent factor in multivariate analysis. In
a Swedish study, Persson and Thulin25 found similar prevalence
rates in diabetics compared with nondiabetic controls (14.4% vs.
12.5%).
Friedman et al. compared expectant management versus pro-
phylactic cholecystectomy in diabetic patients using a model of
probability and outcomes estimates. Th is analysis showed no
benefit derived from prophylactic cholecystectomy and improved
life expectancy with conservative management.26 Thus, there is no
evidence to support selective cholecystectomy in diabetic patients,
and expectant management is recommended.
TRANSPLANT PATIENTS
Prophylactic cholecystectomy for patients with silent gallstones
waiting for solid-organ transplantation has been strongly rec-
ommended.27 The authors argue that such patients are at-risk to
develop more severe complications secondary to their immu-
nosuppression making surgery more difficult and raising their
morbidity and mortality. Conversely, several other authors have
presented data supporting expectant management of silent gall-
stones in transplanted patients.28-31 Thus, no clear consensus exists
as to the role of prophylactic cholecystectomy in transplantation
patients.
5/22/2012 5:32:53 PM
 Silent Gallstones ■ 377

SICKLE CELL DISEASE
The accelerated hemolysis in SCD patients produce an increase in the
formation of pigmented gallstones. The prevalence of gallstones is
approximately 52% in homozygous patients and 20% in heterozygous
patients with a 50% incidence of complications, a significantly higher
rate than that of non-SCD patients.32 Symptomatic gallstone disease
can present a significant diagnostic dilemma in the SCD patient
because biliary symptoms can be confused with vaso-occlusive crisis
producing a delay in diagnosis and treatment in this population.
Most authors agree that this group of patients benefit from
prophylactic cholecystectomy.20,33,34 The recommended approach
is laparoscopic with perioperative partial exchange transfusion to
lower the Hb-S to <50%. This specific approach has been associ-
ated with a lower risk of veno-occlusive crises.35
GALLBLADDER CANCER AND
GALLSTONES
There have been several attempts to associate gallstones with
gallbladder cancer. However, no causative relationship has been
proven. Specific populations have an increase risk of gallbladder
cancer including North American Native American women,
and the people of certain South America countries (Colombia,
Chile, Bolivia). 20 This cancer risk has been estimated to be
increased as much as fourfold in the presence of gallstones,
and about 80% to 90% of the patients with gallbladder cancer
have gallstones. 36 On the other hand, only 0.01% of the patients
with symptomatic gallstones will develop cancer.18 Large stones
>3 cm have showed stronger association with gallbladder can-
cer. 36 For general populations, prophylactic cholecystectomy is
not indicated to prevent gallbladder cancer. Nevertheless, indi-
viduals from the aforementioned high-risk populations with
>3 cm gallstones might benefit from a more aggressive approach,
especially given the fact that gallbladder cancer usually presents
at an advanced stage with poor survival. Such patients should
be treated on a case-by-case basis with acknowledgement of the
absence of strong supporting evidence. Other recommendations
for cholecystectomy to prevent cancer are porcelain gallbladder
and gallbladder polyps >10 mm. 37 These recommendations are C
(exception being recommendation for prophylactic cholecystec-
tomy in the setting of sickle cell disease where this is a Grade B
recommendation).

Clinical Question Summary

Question Answer Levels of Grade of Reference
Evidence Recommendation
1 How frequent is this problem in 10% to 15% of Western population 1-4
the general population?
2 What is the natural history of 1–4% of patients will develop 1-4
asymptomatic (silent) gallstones? symptoms yearly
3 Is prophylactic cholecystectomy Not justifiable, risk of complications is 2b B 5, 18, 19
justifiable from risk–benefit lower than morbidity and mortality
standpoint? from the procedure
4 Is prophylactic cholecystectomy Not for general population 4 C 22
cost-effective?
5 Should prophylactic Only recommended for sickle cell 2b B 24, 25, 27,
cholecystectomy be performed patients, not recommend for 29-32, 33
in certain at-risk populations? diabetic, transplant patients or to
prevent gallbladder cancer

REFERENCES
1. Everhart JE, Ruhl CE. Burden of digestive diseases in the United
States part II: Lower gastrointestinal diseases. Gastroenterology.
2009;136:741-754.
2. Gallstones and laparoscopic cholecystectomy. NIH Consens
Statement. 1992;10:1-28.
3. Aerts R, Penninckx F. The burden of gallstone disease in Europe.
Aliment Pharmacol Ther. 2003;18(Suppl 3):49-53.
4. Stinton LM, Myers RP, Shaffer EA. Epidemiology of gallstones.
Gastroenterol Clin North Am. 2010;39:157-169, vii.
5. Ransohoff DF, Gracie WA, Wolfenson LB, Neuhauser D. Prophylac-
tic cholecystectomy or expectant management for silent gallstones. A
decision analysis to assess survival. Ann Intern Med. 1983;99:199-204.
6. McSherry CK, Glenn F. The incidence and causes of death follow-
ing surgery for nonmalignant biliary tract disease. Ann Surg. 1980;
191:271-275.
7. Gracie WA, Ransohoff DF. The natural history of silent gall-
stones: The innocent gallstone is not a myth. N Engl J Med. 1982;
307:798-800.
8. Friedman GD. Natural history of asymptomatic and symptom-
atic gallstones. Am J Surg. 1993;165:399-404.
9. Zubler J, Markowski G, Yale S, Graham R, Rosenthal TC. Natu-
ral history of asymptomatic gallstones in family practice office
practices. Arch Fam Med. 1998;7:230-233.
10. Beckingham IJ, Krige JE. ABC of diseases of liver, pancreas, and
biliary system: Liver and pancreatic trauma. Br Med J. 2001;322:
783-785.

PMPH_CH46.indd 377 5/22/2012 5:32:53 PM

 378 ■ Surgery: Evidence-Based Practice
11. Prevalence of gallstone disease in an Italian adult female popu-
lation. Rome Group for the Epidemiology and Prevention of
Cholelithiasis (GREPCO). Am J Epidemiol. 1984;119:796-805.
12. Ransohoff DF, Gracie WA. Treatment of gallstones. Ann Intern
Med. 1993;119:606-619.
13. Hermann RE. The spectrum of biliary stone disease. Am J Surg.
1989;158:171-173.
14. Glenn F. Silent gallstones. Ann Surg. 1981;193:251-252.
15. Glenn F. Surgical management of acute cholecystitis in patients
65 years of age and older. Ann Surg. 1981;193:56-59.
16. McSherry CK, Ferstenberg H, Calhoun WF, Lahman E, Virshup M.
The natural history of diagnosed gallstone disease in symptomatic
and asymptomatic patients. Ann Surg. 1985;202:59-63.
17. Lowenfels AB, Domellof L, Lindstrom CG, Bergman F, Monk
MA, Sternby NH. Cholelithiasis, cholecystectomy, and cancer: A
case-control study in Sweden. Gastroenterology. 1982;83:672-676.
18. Attili AF, De Santis A, Capri R, Repice AM, Maselli S. The natu-
ral history of gallstones: The GREPCO experience. The GREPCO
Group. Hepatology. 1995;21:655-660.
19. NIH Consensus conference. Gallstones and laparoscopic chole-
cystectomy. JAMA. 1993;269:1018-1024.
20. Sakorafas GH, Milingos D, Peros G. Asymptomatic cholelithiasis:
Is cholecystectomy really needed? A critical reappraisal 15 years
after the introduction of laparoscopic cholecystectomy. Dig Dis
Sci. 2007;52:1313-1325.
21. McSherry CK. Cholecystectomy: The gold standard. Am J Surg.
1989;158:174-178.
22. Schwesinger WH, Diehl AK. Changing indications for laparo-
scopic cholecystectomy. Stones without symptoms and symptoms
without stones. Surg Clin North Am. 1996;76:493-504.
23. Del Favero G, Caroli A, Meggiato T, et al. Natural history of gall-
stones in non-insulin-dependent diabetes mellitus. A prospective
5-year follow-up. Dig Dis Sci. 1994;39:1704-1707.
24. Chapman BA, Wilson IR, Frampton CM, et al. Prevalence of gall-
bladder disease in diabetes mellitus. Dig Dis Sci. 1996;41:2222-2228.
PMPH_CH46.indd 378
25. Persson GE, Thulin AJ. Prevalence of gallstone disease in patients with
diabetes mellitus. A case-control study. Eur J Surg. 1991;157:579-582.
26. Friedman LS, Roberts MS, Brett AS, Marton KI. Management of
asymptomatic gallstones in the diabetic patient. A decision anal-
ysis. Ann Intern Med. 1988;109:913-919.
27. Kao LS, Kuhr CS, Flum DR. Should cholecystectomy be per-
formed for asymptomatic cholelithiasis in transplant patients?
J Am Coll Surg. 2003;197:302-312.
28. Jackson T, Treleaven D, Arlen D, D’Sa A, Lambert K, Birch DW.
Management of asymptomatic cholelithiasis for patients await-
ing renal transplantation. Surg Endosc. 2005;19:510-513.
29. Greenstein SM, Katz S, Sun S, et al. Prevalence of asymptomatic
cholelithiasis and risk of acute cholecystitis after kidney trans-
plantation. Transplantation. 1997;63:1030-1032.
30. Lord RV, Ho S, Coleman MJ, Spratt PM. Cholecystectomy in car-
diothoracic organ transplant recipients. Arch Surg. 1998;133:73-79.
31. Melvin WS, Meier DJ, Elkhammas EA, et al. Prophylactic chole-
cystectomy is not indicated following renal transplantation. Am
J Surg. 1998;175:317-319.
32. Walker TM, Hambleton IR, Serjeant GR. Gallstones in sickle cell
disease: Observations from The Jamaican Cohort study. J Pediatr.
2000;136:80-85.
33. Fall B, Sagna A, Diop PS, Faye EA, Diagne I, Dia A. Laparoscopic
cholecystectomy in sickle cell disease. Ann Chir. 2003;128:702-705.
34. Vecchio R, Cacciola E, Di Martino M, Gambelunghe AT, Mura-
bito P, Cacciola RR. Laparoscopic surgery in sickle cell disease.
Surg Endosc. 2002;16:1807-1808.
35. Al-Mulhim AS, Al-Mulhim FM, Al-Suwaiygh AA. The role of lap-
aroscopic cholecystectomy in the management of acute cholecystitis
in patients with sickle cell disease. Am J Surg. 2002;183:668-672.
36. Godrey PJ, Bates T, Harrison M, King MB, Padley NR. Gall stones
and mortality: A study of all gall stone related deaths in a single
health district. Gut. 1984;25:1029-1033.
37. Tewari M. Contribution of silent gallstones in gallbladder cancer.
J Surg Oncol. 2006;93:629-632.
5/22/2012 5:32:53 PM
 Commentary on
Silent Gallstones
David H. Livingston
The management of patients with asymptotic cholelithiasis has
been a classic surgical question for decades. Prior to the introduc-
tion of ultrasonography only patients with symptoms underwent
oral cholecystography and the presence of silent gallstones could
only be determined by autopsy series. Asymptomatic cholelithia-
sis is increasingly being diagnosed today, mainly as a result of the
widespread use of abdominal ultrasonography and other forms
of imaging for the evaluation of patients for unrelated or vague
abdominal complaints. The widespread use of computed tomog-
raphy for the evaluation of abdominal pain has also added to
our knowledge about the prevalence in the population. Though
the true prevalence is unknown and difficult to determine, large
ultrasound-based studies from Europe suggest a prevalence of 19%
in female and 10% in males.1 Those studies also found that the
incidence was about 5% for new stones when the population was
studied at 5- and 10-year intervals. Overall, a reasonable estimate
cholelithiasis in most Western countries is 10% to 20% depending
upon gender with two-thirds being asymptomatic at the time of
diagnosis. Given the prevalence of stones it is no wonder why chole-
cystectomy is one of the most common operation in the United
States. During the open-cholecystectomy era, the risk–benefit ratio
for “prophylactic” cholecystectomy came down strongly on the side
of leaving asymptotic stones alone.2 As laparoscopic cholecystec-
tomy is now entering its third decade following its introduction the
authors rightly ask whether this has changed the equation. As well
described, the authors have examined the issue from risk–benefit
and cost-effectives standpoints and found that there continues to
be no compelling evidence for performing routine cholecystectomy
for asymptomatic cholelithiasis.
A more aggressive approach leaning toward elective cholecys-
tectomy has been suggested in certain high-risk groups. The role of
diabetes should play no role in the management of asymptomatic
gallstones. Similarly, although there is a marked increased inci-
dence of stones in patients with sickle cell disease, the low incidence
of conversion to symptomatic stones in this group does not justify
379
PMPH_CH46.indd 379
cholecystectomy unless there is clear documentation of benefit.
Although others have suggested that patients with hematologic
diseases who had emergency cholecystectomies had increased
complication, the actual need for emergent cholecystectomy is not
increased and should not change the recommendation that asymp-
tomatic stones should be left alone.3
Lastly, while most patients with gall bladder cancer have stones,
no causative link has ever been determined. This is not surprising
since the incidence of gall bladder cancer is exceedingly small, espe-
cially compared with the population of patients with gallstones.
Again, there is no justification for using prophylactic cholecystec-
tomy in the general population as a cancer deterrent.
In summary, the authors have found no compelling evidence
to change the standard practice of observation for asymptom-
atic cholelithiasis. As with most issues general surgery, choosing
appropriate patients for surgical intervention are usually met with
superior outcomes. Despite its safety and efficacy, laparoscopic
cholecystectomy still carries a 1% risk of bile duct injury and an
overall perioperative morbidity of 5%. Laparoscopic cholecystec-
tomy is also one of the top 10 reasons for litigation. Thus although
a “diligent” questioner could probably elicit gastrointestinal symp-
toms in anyone with “asymptomatic” cholelithiasis, the data tell us
that these are the type of stones that should neither be overturned
nor removed.
REFERENCES
1. Attili AF, De Santis A, Capri R, Repice AM, Maselli S. The natu-
ral history of gallstones: The GREPCO experience. The GREPCO
Group. Hepatology. 1995;21:655-660.
2. Glenn F. Silent gallstones. Ann Surg. 1981;193:251-252.
3. Walker TM, Hambleton IR, Serjeant GR. Gallstones in sickle cell
disease: Observations from The Jamaican Cohort study. J Pediatr.
2000;136:80-85.
5/22/2012 5:32:53 PM
 CHAPTER 47
Acute Cholecystitis
John S. Oh
EPIDEMIOLOGY AND HISTORY
Acute cholecystitis is a common disease that affects up to 10% of
patients worldwide. Cholelithiasis accounts for 90% to 95% of all
causes of acute cholecystitis, while acalculous cholecystitis accounts
for the remaining 5% to 10%.1 While the majority of patients with
gallstones are asymptomatic, 1% to 4% will develop acute chole-
cystitis annually. With a prevalence of 20 million patients in the
United States with gallstones, this results in 1 million hospitaliza-
tions with 700,000 operative procedures, and an annual cost of
USD 5 billion.2,3
Over the past few decades, there have been major advance-
ments in the use of radionuclide technology, ultrasound (US), and
laparoscopic surgery. The purpose of this chapter is to provide
evidence-based recommendations for the diagnosis and treatment
of this common disease.
PATHOPHYSIOLOGY
In the majority of cases, the pathogenesis of acute cholecystitis
results from an obstruction of the cystic duct by a gallstone. The
subsequent increase in intraluminal pressure within the gallblad-
der causes an acute inflammatory response. Secondary bacterial
infections may also occur with enteric organisms (most com-
monly Escherichia coli, Klebsiella, and Streptococcus faecalis).
Acute acalculous cholecystitis usually occurs in the setting of
prolonged critical illness. The main causes for acalculous chole-
cystitis are thought to be gallbladder ischemia (during periods of
shock or trauma) and biliary stasis (during prolonged fasting or
parenteral nutrition).
1. What are the clinical criteria required for the diagnosis of
acute cholecystitis?
Over 100 years ago, John Benjamin Murphy fi rst described the
eponymous “Murphy’s sign.” This sign, often used as a confir-
matory physical fi nding in acute cholecystitis, is elicited upon
380
PMPH_CH47.indd 380
palpation of the right-upper quadrant. During deep inspiration,
palpation of a tender, inflamed gallbladder will cause the patient
to cease inspiration. This sign, along with a consistent history, is
used to diagnose cholecystitis to this day.
In 2002, Trowbridge4 conducted a comprehensive review on
the literature to find which components of the history, physical
exam, or basic laboratory measures identified patients requir-
ing diagnostic imaging for acute cholecystitis. The authors only
included studies with a control group that did not have cholecysti-
tis. Finally, the studies had to base the diagnosis of cholecystitis on
an adequate gold standard. Of the 195 studies identified, 17 were
included in the final study.
There was no single clinical or laboratory finding with a sig-
nificantly high positive or significantly low negative likelihood
ratio to rule in or rule out the diagnosis of acute cholecystitis. In
the study by Trowbridge, Murphy’s sign had the highest positive
likelihood ratio at 2.8, and right-upper quadrant tenderness had
a negative likelihood ratio of 0.4. However, both 95% confidence
intervals (CI) included 1.0. Furthermore, verification bias in the
studies reviewed could have artificially elevated the rule out power
of right-upper quadrant tenderness. Murphy’s sign, on the other
hand, may have had a higher than estimated rule in power due to
verification bias.
The authors then concluded that it would be logical to assume
a combination of fi ndings, or “clinical gestalt,” would have a
higher likelihood ratio for diagnosing acute cholecystitis. To iden-
tify the impact of the “clinical gestalt,” the authors estimated the
likelihood ratio of diagnosing acute cholecystitis based on two
randomized trials of early versus delayed cholecystectomy. Using
estimations of the impact of “clinical gestalt” on findings at lapa-
rotomy, the likelihood ratio increased to 25 to 30. Unfortunately,
the available literature could not identify the specific combination
of findings that could account for this likelihood ratio.4
In 2005, Mills et al.5 examined predictive capability of vari-
ous laboratory and physical examination measures to distinguish
acute cholecystitis from normal gallbladders using ultrasonic
diagnosis of acute cholecystitis. This retrospective study included
177 patients, and identified four significant predictors including
5/22/2012 5:33:29 PM

elevated levels of alkaline phosphatase, total bilirubin, and white
blood cell count, and a clinical or ultrasonic Murphy’s sign. Based
on this relatively small retrospective study, the authors suggested
using these clinical predictors to determine which patients will
require emergent imaging for acute cholecystitis.
Answer: There is no single or set of clinical criteria that can
reliably predict or rule out cholecystitis. The best clinical predictor
is the clinical “gestalt,” using a combination of history and exam
findings. (Grade C recommendation).
2. What is the optimal imaging study for the diagnosis of acute
cholecystitis?
Imaging studies for gallbladder diseases have undergone many
changes since the oral cholecystography was introduced in 1924.
This modality remained the standard for diagnosis of acute chole-
cystitis for decades until US technology was introduced. Today,
US is the most commonly used imaging modality for suspected
cholecystitis. In 1994, a meta-analysis of the diagnostic perfor-
mance of dynamic, real-time US showed an unadjusted sensitivity
of 94% and specificity of 78% in the diagnosis of acute cholecysti-
tis.6 These investigators also included adjustments for verification
bias in their estimates, resulting in a decrease of sensitivity to 88%
and increase in specificity to 80%.
For acute cholecystitis, radionuclide imaging has improved
test characteristics with a sensitivity of 97%, and a specificity of
90% in the same meta-analysis.6 Finally, oral cholecystography
had a sensitivity of 63% with a specificity of 100% for acute chole-
cystitis. However, these studies lack portability, and include expo-
sure to radiation.
Computed tomography (CT) scan is often used to evaluate
other abdominal pathology, and in a retrospective review of 117
patients with right-upper quadrant abdominal pain, the use of CT
was compared with US as the initial imaging modality.7 The CT
scan had inferior test characteristics compared with US, with a
sensitivity of 39% and a specificity of 93%. However, depending on
the CT findings used to diagnose acute cholecystitis, the sensitivity
can be improved to 92%, with a specificity of 97% according to a
more recent retrospective review of 75 patients.8 Anecdotally, CT
scan has been used to diagnose complications of cholecystitis such
as perforation of the gallbladder, or other pathologic conditions
that may mimic acute cholecystitis.
Answer: Radionuclide imaging is the preferred study to
diagnose acute cholecystitis based on sensitivity and specificity;
however, dynamic US is the preferred initial imaging study based
on availability and portability. (Grade B recommendation) CT
scan may be useful for diagnosing alternate conditions. (Grade D
recommendation).
MANAGEMENT
3. Should laparoscopic or open cholecystectomy be performed
in acute and complicated acute cholecystitis?
Carl August Langenbuch, a German surgeon, performed the
first series of successful open cholecystectomies in 1886, and this
remained the standard of care for 100 years. After the first laparo-
scopic cholecytectomy was performed in 1986, it rapidly became
the new standard of care over the next two decades with little sup-
porting evidence.9 The Cochrane group performed a systematic
PMPH_CH47.indd 381
Acute Cholecystitis ■ 381
review of randomized trials comparing laparoscopic to open-
cholecystectomy in patients with symptomatic cholelithiasis.10
This review excluded trials of patients exclusively diagnosed with
acute cholecystitis, and only included trials where the majority of
patients (more than half) had symptomatic cholelithiasis. A total
of 38 trials were included in the analysis with over 2300 patients
in this analysis. There were no significant differences in mortal-
ity or complications to include intraoperative, minor, and bile
duct injuries. There was also no significant difference in operating
time. However, hospital stay (‒3.15 days, 95% CI ‒3.94 to ‒2.35)
and convalescent days (‒22.51 days, 95% CI ‒36.89 to ‒8.13) were
significantly shorter in the laparoscopic surgery group. It is worth
mentioning that only three studies in this review reported on con-
valescent days, and that none of the trials could be classified as low
risk of bias.
In the early 1970s, small incision cholecystectomy was intro-
duced as a method to reduce the morbidity and cost of cholecystec-
tomy.11 Another Cochrane group systematic review was performed
to compare the small incision to open-cholecystectomy.12 For
purposes of the review, a small incision cholecystectomy was arbi-
trarily defined as <8 cm, and could be performed through a sub-
costal or midline incision. This review included seven randomized
trials with a total of 571 patients. Again, none of the trials could
be classified as low bias risk. There was no overall difference in
complications or operative time. There were no common bile duct
injuries in either group. There was, however, a significantly shorter
hospital stay for the small incision group (‒1.97 days, 95% CI ‒2.56
to ‒1.39). None of the trials reported on mortality.
Another Cochrane review compared laparoscopic with small
incision cholecystectomy.13 This review included 13 randomized
trials with 2337 patients. As in the previous reviews, trials of
patients exclusively with acute cholecystitis were not included. The
overall methodological quality of these trials was high. There were
no differences between groups in terms of complications, conva-
lescence, or mortality. However, the small incision cholecystec-
tomy group had a significantly shorter operative time (16.4 min,
95% CI 8.9–23.8). They concluded that both minimally invasive
techniques (small incision or laparoscopic) were equivalent, and
the choice is up to individual surgeon preference.
A meta-analysis of results of laparoscopic cholecystectomy
for severe versus nonsevere acute cholecystitis was performed by
Borzellino et al.14 Severe acute cholecystitis was defined as gangre-
nous, empyematous, or perforated cholecystitis. All other causes
of gallbladder inflammation, to include mucoceles or hydrops,
were considered nonsevere. This study evaluated seven case series
with a total of 1408 patients, of which 469 had severe acute chole-
cystitis and 939 had nonsevere acute cholecystitis. There were
no randomized trials included in this review. Of the seven stud-
ies, six were retrospective and one was prospective. The relative
risk for conversion to an open cholecystectomy was found to be
3.22 (95% CI 2.48–4.18) in favor of nonsevere cholecystitis. The
relative risk for overall complications was 1.61 (95% CI 1.17–2.21),
again in favor of nonsevere cholecystitis. There was only one study
that reported on bile duct injury, with no significant differences
between the two groups, and only two studies reported on mor-
tality, again with no significant differences. Three of the included
studies reported on local complications, with no significant dif-
ferences between the groups with a relative risk of 1.16 (95%
CI 0.59–2.26). This particular finding was surprising, considering
the increased complexity of performing laparoscopy in the setting
5/22/2012 5:33:29 PM
 382 ■ Surgery: Evidence-Based Practice
of severe cholecystitis. This was explained by surgeons having a
lower threshold for conversion to an open procedure in severe
cases, thereby mitigating the negative consequences of laparos-
copy in complex cases.
In 1998, a single-center, prospective randomized trial of lap-
aroscopic versus open cholecystectomy for cholecystitis was pub-
lished. This study enrolled and randomized 63 patients.15 The two
groups were similar in preoperative characteristics, with similar
proportions of patients with gangrene or empyema of the gallblad-
der. Perioperative antibiotics and management of suspected com-
mon bile duct stones were standardized in both groups. This trial
had similar operative times for both procedures, with no deaths in
either group. The laparoscopic group, however, had a significantly
shorter hospital stay (median 4 [IQR 2–5] vs. 6 [5–8] days, p = .0063).
The open group had a significantly higher rate of major complica-
tions (0 vs. 7 [23%] p = .0048) to include severe wound infections,
sepsis, and incisional hernias. In addition, the mean duration
of sick leave for those patients that were employed at the time
was significantly shorter for patients in the laparoscopic group
(13.9 vs. 30, p < .0001).
In 2005, Johansson et al.16 published a prospective, rando-
mized trial of open versus laparoscopic cholecystectomy for
acute cholecystitis. To minimize treatment bias, the patients
and staff involved in the post operative care were blinded to the
type of operation. In addition to peri-operative antibiotics and
operative management, postoperative pain management and
sick leave were standardized between the two groups. Seventy
patients were randomized in this study, with post operative hos-
pital stay as the primary endpoint. There were no common bile
duct injuries or mortality in either group. There was no differ-
ence in postoperative complications, pain score at discharge, or
sick leave. Operative times were shorter in the open group, and
direct costs were equivalent. The postoperative hospital stay was
significantly shorter in the laparoscopic group (median 2 days
for both groups), with more patients discharged on the day after
surgery in the laparoscopic group. Th is study showed how pre-
conceptions regarding postoperative pain and convalescence
can influence outcomes.
Answer: Minimally invasive techniques, whether small inci-
sion or laparoscopic, are favored over open-cholecystectomy based
on shorter hospital stay, although the meta-analysis is based mainly
on studies of patients without cholecystitis. There appear to be no
differences in terms of bile duct injury or mortality, and most stud-
ies also show no differences in terms of major postoperative com-
plications. (Grade B recommendation).
4. What should the timing of surgical intervention be?
The risks and benefits of early versus delayed cholecystectomy
for acute cholecystitis have been controversial. Complications
related to early cholecystecomy result from acute inflammation
obscuring the anatomy, whereas complications from late chole-
cystectomy result from fibrous adhesions. To resolve this contro-
versy, the Cochrane group performed a review in 2006 analyzing
early versus late laparoscopic cholecystectomy for acute calculous
cholecystitis.17 The early intervention group was defined as having
surgery within 7 days of symptom onset, versus the late group,
defined as the intention to perform cholecystectomy 6 weeks after
symptom onset. After screening the literature, five studies were
included with a total of 451 patients. Although none of the studies
PMPH_CH47.indd 382
could be conducted in a double-blinded fashion, four out of five
studies were of high methodological quality.
When comparing early with late cholecystectomy, there
were no deaths in any of the trials. There were no differences
with respect to common bile duct injury, wound infection, and
bile leak. There were also no differences in terms of conversion
to open-cholecystectomy. A repeat analysis using only the high-
quality trials again revealed no difference in these outcomes. In
addition, the incidence of nonresolving or recurrent cholecytitis
was 17.5% in the delayed group. These patients had to undergo
emergent cholecystectomy, and the conversion to open rate was
45% in this group. Hospital stay was 4.5 days shorter on average
for the early group, and two patients in the delayed group devel-
oped cholangitis.
In many of the studies reviewed, common bile duct stones,
gallbladder perforation, or severe concommittent cardiopulmo-
nary disease were exclusionary criteria. This should be bore in
mind whenever the risk–benefit analysis of early laparoscopic
intervention is considered.18 In addition, many of the outcomes
such as common bile duct injury had low event rates making detec-
tion of patterns difficult.
In 2004, a meta-analysis by Papi et al.19 also reviewed early
versus late cholecystectomy in acute cholecystitis. This analysis
reviewed open and laparoscopic techniques, with early surgery
performed within 7 days of symptom onset versus 6 to 12 weeks
in the delayed group. This meta-analysis found no differences in
perioperative morbidity, with the only difference being shorter
hospital stays. The difference in hospital stay was even more pro-
nounced when only open-cholecsytectomy was considered (10.6 ±
1.8 days in the early group versus 20.4 ± 4.2 days in the delayed
group; p = .006).
Answer: Early intervention is preferred in acute cholecysti-
tis based on shortened hospital stays and avoidance of readmis-
sions for recurrent cholecystitis. However, the risks and benefits
of urgent versus delayed surgery must be weighed carefully in
patients who are at high-operative risk. The choice of procedures
in patients with common bile duct stones is important, and should
based on the experience of the surgeon performing the procedure.
(Grade A recommendation).
5. What is the role of nonoperative management?
Only one randomized controlled trial compared cholecystectomy
(open or laparoscopic) with nonoperative management.20 A total
of 64 patients were randomized to delayed surgery versus obser-
vation. The delayed surgery group was operated on at a median of
3.6 months after randomization, and 4/31 patients (13%) refused
operation based on freedom from symptoms. Of the patients
randomized to the observation group, 10/33 patients underwent
surgery (30% failure rate). A significantly greater proportion of
patients randomized to the operative group underwent cholecys-
tectomy compared with the observation group after 8 years of
follow-up (87% vs. 30%, p < .0001).
There were no significant differences between the groups in
either gallstone-related complications or admissions for pain (6/31
[19%] with cholecystectomy vs. 12/33 [36%] with observation, p = .16).
Gallstone-related complications included acute cholecystitis, pan-
creatitis, and common bile duct stones. There were no deaths in
either group related to gallstone disease. Three out of 27 patients
that underwent operation had a major operative complication, to
5/22/2012 5:33:29 PM

include one common bile duct injury that required a biliary-
enteric anastamosis, and one patient who was initially random-
ized to the nonoperative group that had two major complications
(11% vs. 10%, p = 1.00).
Based on this single trial, it appears that a large proportion of
patients with acute cholecystitis can be managed without surgery.
It bears mentioning that this trial excluded patients with severe
comorbid diseases, as well as patients with evidence of gallblad-
der perforation or gangrene. The median age of patients in the
observation group was also relatively young compared with the
surgery group (47 and 58 years, respectively). While most recent
randomized controlled trials on acute cholecystitis focused on the
timing of surgery, this trial offered some insight into the tradeoffs
between operative versus nonoperative intervention.21
Answer: Nonoperative management of patients with acute
cholecystitis has significant tradeoffs in terms of morbidity,
with a large proportion of patients eventually requiring surgery
despite best practices of nonoperative management. (Grade D
recommendation).
6. Do percutaneous cholecystostomy tubes improve outcomes
in high-risk surgical patients?
A systematic review of percutaneous cholecystostomy procedures
for acute cholecystitis was performed by Winbladh et al.22 in 2009.
The vast majority of the studies evaluated were retrospective case
series, and inclusion criteria varied widely. Most of the case series
defined a successful cholecystostomy procedure as a decrease
in fever, symptom resolution, and reduction in white blood cell
count. In these terms, percutaneous cholecystostomy was success-
ful in 85% of patients.
Morbidity related to the procedure itself was not well-defined
in most case series, and there was wide variability in the qual-
ity of reporting. Catheter slippage was reported in 9% of patients;
however, this may be under-reported as follow-up was mainly
restricted to in hospital stays. Procedure-related mortality was
0.36%, and all-cause mortality in the high-risk patient population
was 15.4%.
Over 40% of patients eventually underwent cholecystectomy
with an overall operative mortality rate of 2.08%. None of the pro-
spective studies in this review directly compared cholecystostomy
with cholecystectomy, and it was difficult to make comparisons
among many of the case series. As a result, no definitive conclu-
sions can be drawn. It does appear that the overall mortality rate
for high-risk patients with cholecystitis is high. However, this may
be a reflection of the overall poor prognosis.
One prospective, randomized trial evaluated percutaneous
cholecystostomy followed by early laparoscopic cholecystectomy
versus medical management followed by late cholecystectomy.23
Seventy high-surgical-risk patients were randomized. Patients in
the first group were treated with a percutaneous cholecystostomy
within 8 h of admission followed by laparoscopic cholecystec-
tomy within 96 h if they achieved symptom resolution and an
APACHE II score <12. In the second group, delayed cholecystec-
tomy was performed 8 weeks after recovery.
PMPH_CH47.indd 383
Acute Cholecystitis ■ 383
The group undergoing percutaneous cholecystostomy and
early laparoscopic cholecystectomy had reduced total hospital stays
(mean 5.3 days vs. 15.2 days, p = .001), and earlier resolution of
symptoms (mean 15 vs. 55 h, p = .001). The adverse events related to
the percutaneous catheter were minor. There were no procedure-
related deaths in either group. Based on this single study, percu-
taneous cholecystostomy may be beneficial in terms of symptom
resolution and decreased length of hospital stay. The conclusions
drawn from this study, however, are biased due to nonblinding,
lack of an intent-to-treat analysis, and small sample size.
Answer: Percutaneous cholecystostomy tubes may offer
symptomatic resolution in high-risk patients with relatively low
procedural-related complications. (Grade D recommendation).
7. What is the role of antibiotics in acute cholecystitis?
There are no randomized controlled trials comparing antibiotics
with no antibiotics in patients with acute cholecystitis. Although
acute cholecystitis is primarily an inflammatory process, systemic
antibiotics are routinely prescribed with very little evidence to
support their efficacy.
A study of control subjects versus patients with gallstones was
published in 1996 describing the yield of positive bile cultures for a
variety of biliary tract conditions.24 None of the control subjects had
positive cultures, whereas 46% of patients with acute cholecystitis
had positive cultures. That percentage increased to 58% with the
presence of common bile duct stones, and 98% with cholangitis.
The most frequent isolates identified were E. coli, Streptococcus,
Klebsiella, and Enterobacter. Current prophylactic regimens are
tailored against these pathogens. However, with obstruction of
the cystic duct, bacterial infection is thought to be a secondary,
and not primary, process in acute cholecystitis. Furthermore,
there is no evidence that antibiotics penetrate into the bile in
cholecystitis.
One retrospective study of 302 patients in 1975 found no
benefit from antibiotics in terms of local complications such as
empyema or pericholecystic abcess formation. However, there did
appear to be a lower incidence of wound infection and sepsis with
periopertive use of broad spectrum antibiotics.25 The patients that
were most susceptible to infectious complications were >60 years
of age with a history of diabetes.
Various randomized controlled trials have evaluated dif-
fering antibiotic regimens in acute cholecystitis and cholangitis,
although no conclusions can be drawn regarding duration of anti-
biotics, or the role of routine biliary tract cultures.26-28 A recent
consensus statement recommended guiding antibiotic therapy
based on severity of disease and changing empirically adminis-
tered antimicrobials according to identified causative organisms
and susceptibility testing.29
Answer: Perioperative antibiotics may decrease the incidence
of wound infection in cholecystectomy. Empiric antibiotics should
cover the most common organisms based on local pathogen pro-
fi les, and tailored based on causative organisms and susceptibil-
ity testing. Antibiotic use should be based on severity of disease.
(Grade C recommendation).
5/22/2012 5:33:29 PM
 384 ■ Surgery: Evidence-Based Practice

Clinical Question Summary

Question
1 What are the clinical
criteria required
for the diagnosis of
acute cholecystitis?
2 What is the optimal
imaging study for the
diagnosis of acute
cholecystitis?
3 Should laparoscopic
or open
cholecystectomy be
performed in acute
and complicated
acute cholecystitis?
4 What should the
timing of surgical
intervention be?
5 What is the role
of nonoperative
management?
6 Do percutaneous
cholecystostomy
tubes improve
outcomes in high-
risk surgical patients?
7 What is the role of
antibiotics in acute
cholecystitis?
Answer Level of Grade of References
Evidence Recommendation
There is no single or set of clinical criteria that 3, 2b C 4, 5
can reliably predict or rule out cholecystitis.
The best clinical predictor is the clinical
“gestalt.”
Radionuclide imaging is the preferred study based 2a, 3b B 6-8
on sensitivity and specificity; however, dynamic
US is the preferred initial imaging study based
on availability and portability.
Minimally invasive techniques are favored over 1a, 3a, 2b B 10, 12-16
open cholecystectomy based on shorter
hospital stay. The systematic reviews are
mainly based on mixed population studies of
symptomatic cholelithiasis and cholecystitis.
Early intervention is preferred in acute 1a A 17, 19
cholecystitis. However, the risks and benefits
of urgent versus delayed surgery must be
weighed carefully in patients who are high
operative risk.
Nonoperative management of patients with acute 1b D 20
cholecystitis has significant tradeoffs in terms
of morbidity.
Percutaneous cholecystostomy tubes may 3a, 1b C 22, 23
offer symptomatic resolution in high-risk
patients with relatively low procedure-related
complications.
Perioperative antibiotics can help decrease 3a, 2b C 25-28
the incidence of wound infection in
cholecystectomy. Empiric antibiotics should be
tailored based on the causative organism and
susceptibility testing. Antibiotic use should be
based on severity of disease.

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5/22/2012 5:33:29 PM
 CHAPTER 48
Common Bile Duct Stones
Adrian W. Ong and Charles F. Cobb
INTRODUCTION
Common bile duct stones (CBDS) are a common problem faced by
general surgeons. The diagnosis and surgical treatment of CBDS
has evolved in the past three decades, with the advent of mini-
mally invasive methods for the treatment of biliary tract prob-
lems. We reviewed the literature in order to answer commonly
encountered questions.
QUESTIONS TO BE ADDRESSED
1. Are less invasive methods such as magnetic resonance cho-
langiopancreatography (MRCP) and endoscopic ultrasound
(EUS) as accurate as endoscopic retrograde cholangiopancre-
atography (ERCP), intraoperative cholangiography or surgery
in the detection of CBDS?
2. What is the best approach to evaluate and treat patients with
suspected CBDS?
3. If choledochotomy is done during common bile duct exploration
(CBDE), is T-tube drainage (TT) necessary?
4. What is the optimal method of biliary decompression and
timing of decompression in patients with acute cholangitis due
to CBDS?
5. Is cholecystectomy necessary after endoscopic treatment of
CBDS in patients both with and without gallstones (GS)?
METHODS
An online search of PubMed and the Cochrane library was
performed for all English language articles on human subjects
from 1998 up to December 2010, using the terms “common bile
duct stones,” “endoscopic retrograde cholangiopancreatography,”
“magnetic retrograde cholangiopancreatography,” “endoscopic
ultrasound,” “T-tube,” and “common bile duct exploration.” Abst-
racts were reviewed and selected for suitability with regard to the
questions being examined, and the relevant articles obtained for
386
PMPH_CH48.indd 386
further review. Nonsystematic review articles, expert opinion
without explicit critical appraisal, noncontrolled case series were
excluded from forming evidence-based recommendations.
Suitable articles were graded according to the levels of
evidence developed by the Oxford Centre for Evidence-Based
Medicine, and grades of recommendations formulated based on
the same system. The two authors reviewed the suitable articles
independently initially and a consensus was reached as to build-
ing evidence-based recommendations.
1. Are less invasive methods such as magnetic resonance cho-
langiopancreatography (MRCP) and endoscopic ultrasound
(EUS) as accurate as endoscopic retrograde cholangiopancre-
atography (ERCP), intraoperative cholangiography or surgery
in the detection of CBDS?
With the widespread use of laparoscopic cholecystectomy (LC),
there has been more attention paid to diagnosing CBDS preop-
eratively. Detection of CBDS preoperatively has several perceived
advantages: it may allow for better preoperative planning with
management of patient expectations, possibly shorten opera-
tive time by eliminating intraoperative common bile duct (CBD)
evaluation, and may facilitate treatment planning in the event of
laparoscopic and endoscopic failure to extract CBDS. ERCP, the
established modality for detection of CBDs preoperatively, has
been associated with significant risks and complications. In a
large registry of more than 11,000 ERCPs, the postoperative com-
plication rate was 9.8%, with low-volume centers having a higher
complication rate compared with high-volume centers. In this
large database, pancreatitis occurred in 2.7%, bleeding in 0.9%,
and perforation in 0.3%.1 Less invasive modalities for preoperative
CBDS detection might avert some of these complications. MRCP
and EUS have emerged as the two most popular modalities for the
detection of CBDS and will be the focus of this review. We exam-
ined studies comparing the performance of MRCP and EUS using
ERCP, IOC, surgery as the reference standard. Papers where clini-
cal follow-up and/or where transabdominal ultrasound served as
a reference standard were excluded.
5/22/2012 5:34:10 PM

MRCP
MRCP is highly sensitive and specific in general when compared
with the other invasive imaging modalities.2-7 However, its per-
formance in the detection of small stones may be inferior to
these other imaging modalities. Zidi et al.8 found that MRCP was
not sensitive enough for the detection of small CBDS (<7 mm).
Others9,10 have similarly found decreased sensitivity for small
stones (<5 mm) with MRCP compared with EUS. In a systematic
review with meta-analysis, Romagnuolo et al.11 compared the per-
formance of MRCP with the “gold standard,” which included sur-
gery, IOC, percutaneous transhepatic cholangiography (PTHC),
computed tomography, ERCP, and EUS. They found that MRCP
was “less sensitive” in the detection of CBDS (sensitivity 92%) or
differentiating between malignant from benign disease (sensitiv-
ity 88%), but had excellent sensitivity (97–98%) in detecting the
presence of obstruction or the level of obstruction. It was recom-
mended that the role of MRCP should be further assessed through
large outcome studies in selected patient samples.
EUS
EUS demonstrates excellent sensitivity and specificity in the detec-
tion of CBDS as compared with ERCP.12-14 Its performance may
even better than ERCP as suggested by Karakan et al.13 and Ney
et al.14 mainly due to its ability to detect small stones (<5 mm). A
consensus panel composed of sonographers has deemed EUS to be
as sensitive and more specific than ERCP in detection of CBDS.15
A systematic review by Tse et al.16 concluded that EUS was safe
and accurate in the detection of CBDS with Level 2a evidence.
MRCP VERSUS EUS
In a systematic review, with seven randomized controlled trials,
EUS was found to be more sensitive than MRCP in the detection
of CBDS (151/163 vs. 133/163, 93% vs. 82%; odds ratio 0.34, 95%
confidence interval [CI] 0.17–0.70), but similar in specificity and
overall accuracy. The authors concluded that both tests were reli-
able low-risk substitutes for diagnostic ERCP.17 Of the seven trials,
only one showed a difference in sensitivity.18 In this trial, EUS was
more sensitive than MRCP in the detection of choledocholithiasis
(80% vs. 40%). The overall accuracy of MRCP for any abnormality
was 61% (95% CI 0.41–0.78) compared with 89% (CI 0.72–0.98) for
EUS. Kondo et al.9 found that for small stones, EUS was more sen-
sitive than MRCP. Another systematic review has found MRCP to
be less sensitive than EUS for CBDS detection.19
Recommendations
In the detection of CBDS, MRCP is reliable, but is less sensi-
tive than ERCP particularly for small calculi (≤5 mm). (Grade B
recommendation)
EUS is as sensitive and specific compared with ERCP. (Grade A
recommendation)
EUS is a more invasive procedure than MRCP, but it is more
sensitive than MRCP particularly for small calculi. (Grade B
recommendation)
PMPH_CH48.indd 387
Common Bile Duct Stones ■ 387
2. What is the best approach to evaluate and treat patients with
suspected CBDS?
As preoperative ERCP is an invasive procedure with risks and
complications outlined above, and as laparoscopic methods of
CBD clearance are gaining acceptance among surgeons, there is
continued debate as to the optimal approach to patients with sus-
pected CBDS. The general aims of any approach are to minimize
complications, reduce redundant procedures, shorten in-hospital
length of stay and avoiding long-term procedural complications.
Several issues are debated in the current literature: in patients
with suspected CBDS, should the endoscopic or surgical approach
be utilized first? If surgery is to be utilized first, should ERCP be
done intraoperatively or postoperatively for retained stones, or
should it be considered only for laparoscopic stone extraction fail-
ures. Should MRCP or EUS be employed first prior to any invasive
procedure?
Clayton et al.20 performed a meta-analysis of 12 randomized
trials with both open and laparoscopic methods, and found that
there were no differences in morbidity, mortality, duct clearance
success rate or need for additional procedures between the endos-
copy (ERCP) and surgery versus the surgery alone group. Mar-
tin et al.21 similarly in a meta-analysis separately analyzed open
surgery and laparoscopic surgery. Open surgery was superior to
ERCP for CBD clearance, but there were no differences in morbid-
ity or mortality rates between open surgery and ERCP. When the
laparoscopic first approach was compared with both preoperative
and postoperative ERCP, there were no differences in morbidity
or mortality, although single-stage treatment with LC followed
by intraoperative ERCP was a safer approach with less morbidity
compared with preoperative ERCP in one randomized controlled
trial.22 In mild-to-moderate gallstone pancreatitis, a randomized
trial demonstrated that if a surgery-first approach was utilized,
postoperative ERCP would be necessary in only 24% of patients.23
However, it should also be noted that in another randomized trial,
when laparoscopic CBDE (LCBDE) was done instead of postoper-
ative ERCP, although long-term complication rates were low, there
was a higher incidence of postoperative bile leak (6/41 vs. 0/45).24 In
general, LCBDE is safe: Riciardi et al.25 found that of 346 patients
who had LCBDE in whom 78% had transcystic exploration (TC)
and 22% had laparoscopic choledochotomy (LCD), 95.6% had no
long-term biliary complications after a mean follow-up period of
43 months. Possible obstacles to a wider adoption of LCBDE by
surgeons include the need to acquire advanced laparoscopic skills
and the timely availability of the appropriate instruments in the
emergency setting.
The role of MRCP and EUS in the approach to patients with
suspected CBDS has been evaluated in several studies: For MRCP,
a policy of selective imaging based on risk stratification for CBDS
appears to have reduced redundant procedures and preserved a
low rate of missed CBDS (<1.5%).26 In another study, the selective
use of MRCP based on risk stratification of CBDS reduced the
potential negative ERCP rate from 48% to 16%.27 That ERCP
should be selectively done based on clinical assessment is high-
lighted by Sharma et al.28: Of 200 consecutive ERCPs, 102 (51%)
had positive pathology. If there were more than one indication to
do ERCP based on clinical, ultrasound findings, and liver serum
profi le, the yield was >85%, while if there was one indication, the
yield was 25%.
The use of EUS preoperatively has also reduced the need for
ERCP. A systematic review with meta-analysis of four randomized
5/22/2012 5:34:10 PM
 388 ■ Surgery: Evidence-Based Practice
trials of EUS-guided ERCP versus ERCP alone concluded that the
use of EUS-guided ERCP reduced the need for ERCP in 67% of
patients, and also reduced the overall complication rate, and also of
post-ERCP pancreatitis (relative risk = 0.21 [95% CI 0.06–0.85]).29
In a randomized trial comparing the EUS-guided approach with
an ERCP-first approach, the use of EUS potentially would have
spared 75% of patients from ERCP at the expense of 25% unneces-
sary EUS examinations.30 Other randomized trials have supported
using EUS before ERCP with reduction in complication rates and
higher rates of successful initial biliary imaging.31,32
Because both MRCP and EUS have the potential to limit
unnecessary ERCPs, the choice between the two tests may be
determined by several practical factors: EUS is invasive, usually
requires patient sedation, relies on the availability of specialized
practitioners, is user-dependent, but logically can be combined
with ERCP at the same endoscopy session if indicated, thereby
improving efficiency. MRCP on the other hand is not very user-
dependent, is noninvasive, but requires a separate endoscopy ses-
sion if preoperative CBD clearance is contemplated.
Based on the above data, a strategy using routine preopera-
tive ERCP would result in many unnecessary invasive procedures.
Some studies therefore support the selective use of ERCP based on
the pretest probability of having CBDS,27,33 with the patients with
the highest pretest probability proceeding directly to ERCP preop-
eratively. However, some randomized trials where the prevalence
of CBDS was high (>70%) found that a surgery-first approach was
just as efficient as an endoscopy-first approach with similar com-
plication rates.34-37 Williams et al.38 has recommended (Grade B
recommendation) that in patients with low or uncertain suspicion
of CBDS, EUS, or MRCP be used as the initial diagnostic modality
instead of ERCP. They also recommended against using ERCP as a
purely diagnostic modality if the clinician was not confident that
CBDS was present.
Recommendations
Routine preoperative ERCP for suspected CBDS is not
recommended.
If preoperative imaging is contemplated, EUS or MRCP
should be used in place of ERCP if there is not a high likelihood of
CBDS. (Grade B recommendation)
In patients with suspected CBDS, a surgery-fi rst strategy
(LC + LCBDE or open CBDE if indicated) is equivalent to an
endoscopy-first strategy in terms of safety and efficacy. The surgery-
first strategy may shorten the hospital length of stay and reduce
redundant procedures. (Grade A recommendation)
3. If choledochotomy is done during common bile duct explo-
ration (CBDE), is T-tube drainage (TT) necessary?
The insertion of a T-tube after choledochotomy and stone extrac-
tion is widely practiced. The objectives of TT are purportedly to
prevent uncontrolled bile leakage from the choledochotomy, and to
facilitate subsequent removal of retained stones. However, compli-
cations involving T-tubes have been described. In a retrospective
study, Wills et al.39 found that of 274 patients with T-tubes, 42 (15%)
had a total of 60 complications. The median duration of TT was
16 days in complicated T-tube insertions and 14 days in uncom-
plicated T-tube insertions. Complications included acute cholangi-
tis, fluid and electrolyte problems and leak when the T-tube was in
situ; prolonged fistula, localized pain, and biliary peritonitis when
PMPH_CH48.indd 388
T-tubes were removed. Complications were similar between open
and laparoscopic cases, and resulted in two deaths.
Primary closure of the CBD (PC) has therefore been proposed
as a safe and efficient alternative to TT. A retrospective series of
100 LCD with PC found that PC after CBDE had a low rate of bil-
iary complications: documented bile leak requiring laparoscopic
re-intervention occurred in only two patients, one from the PC
suture line and the other from the cystic bed.40
In a meta-analysis of randomized trials of PC versus TT after
open CBDE, Gurusamy and Samraj41 found no differences in bile
peritonitis, bile fistula, bile leak requiring reoperation, residual
stones and perioperative mortality. When PC versus TT were
compared after LCD, several randomized controlled trials found
no differences in biliary complications, with shorter hospital stays
and operative time seen in the primary closure groups. The size of
the CBD was not a factor in these trials, being equivalent in the
PC and TT groups.42-44
Some authors have advocated using TT in certain situations
when evidence of cholangitis with pus in the CBD is seen, or when
more than four or five stones are cleared.45,46 Alternatively, in these
situations, primary closure after placement of a biliary stent could
be a simpler option than TT.47
The abovementioned trials suggest that after verification of
duct clearance intraoperatively, primary duct closure with or
without biliary stenting is safe compared with TT. Long-term
follow-up of patients after primary closure or TT are needed to
address the incidence of biliary strictures.
Recommendation
In open or laparoscopic surgery, after verification of duct clear-
ance intraoperatively, primary closure of the choledochotomy
with or without biliary stenting is a safe alternative to TT with no
differences in complication rates. Routine T-tube placement after
choledochotomy is not necessary. (Grade A recommendation)
4. What is the optimal method of biliary decompression and
timing of decompression in patients with acute cholangitis due
to CBDS?
The mortality rate of acute cholangitis due to CBDS is approxi-
mately 1% to 5%.48-50 Bile and serum endotoxin levels correlate
with the presence of the components of Charcot’s triad, and bil-
iary decompression is effective as it has been shown to promptly
decrease bile and serum endotoxin levels.50
Whether surgery or endoscopic drainage should be performed
was addressed by Lai et al.51 in a randomized trial: 82 patients were
randomized at the time of ERCP to surgery or endoscopic sphinc-
terotomy (ES). In this study, however, surgery was undertaken after
a mean of 2 h after randomization whereas in the endoscopic group,
ES was done at the same setting as ERCP. The findings were that
endoscopic drainage with ES was associated with lower mortal-
ity and shorter duration of ventilatory support. Mode of drainage
was an independent predictor of mortality in their analysis, along
with serum albumin, creatinine, leukocyte count, platelet count,
age, serum urea nitrogen, and concomitant medical problems. The
authors concluded that urgent endoscopic drainage should be con-
sidered for patients with adverse prognostic factors. Another study
involving only 22 patients with cholangitis randomized patients
after emergency ERCP. This study failed to show any advantage
of endoscopic decompression in terms of immediate mortality or
5/22/2012 5:34:11 PM

morbidity.52 That endoscopic drainage is the preferred method
over surgery is also noted by a systematic reviews and a consensus
conference38,53 as well as nonrandomized studies.48,49,54,55
There is no high-level evidence in the literature comparing the
effectiveness and safety of percutaneous transhepatic biliary drain-
age (PTBD) to endoscopic and surgical drainage. Pessa et al.56 stud-
ied 42 patients who underwent percutaneous transhepatic drainage
for acute cholangitis. Only 12 patients with cholangitis were due to
bile duct stones. All were successful despite a 17% incidence of non-
dilated ducts. Sepsis began to resolve in 22 of 24 after 24 h. There
was a 7% complication rate. PTBD is considered an alternative
option if endoscopic drainage is not possible. A consensus confer-
ence has considered both these modes of drainage (endoscopic and
PTBD) as preferred therapies over open surgery.53
The timing of biliary decompression has not been clearly
established in the literature. Rather, the literature has focused on
identifying risk factors for clinical deterioration. Yeung et al.57
in a study of 171 patients with cholangitis, found 31 that did not
respond to conservative measures after 6 h and underwent emer-
gent biliary drainage. Logistic regression demonstrated five fac-
tors: age > 75 years, history of smoking, prothrombin time, size
of the CBD, and blood glucose as predictors for need for emergent
ERCP. The authors concluded that age > 75 years and smoking his-
tory were important factors that predicted failure of conservative
management, and that this subset of patients could benefit from
emergent intervention before deterioration. Another prospective
study of 142 consecutive patients with acute cholangitis found that
31 (21.8%) patients required emergency ERCP, with four factors—
heart rate > 100/min, albumn < 30 g/dL, bilirubin > 50 mcmol/L,
and prothrombin time > 14 s—that were associated with failure
of medical treatment. However, the timing of emergency ERCP
was not explicitly stated in their paper.58 Another retrospective
study found that 13 patients who did not respond to antibiotics
after 24 h did not have complications if they were drained <72 h.
On the other hand, 12 patients where antibiotics had failed and
who were not drained until >3 days later developed a 33% rate
of septic complications. The authors conclude that urgent biliary
decompression was indicated in patients who do not respond early
(<24 h) to antibiotics.59 At the Tokyo consensus conference, no
evidence-based recommendations were produced with regard to
timing of drainage.53
Recommendations
In patients with acute cholangitis, urgent endoscopic biliary decom-
pression is preferred over surgery. (Grade B recommendation)
There is insufficient evidence to recommend a specific time
period where urgent biliary decompression should occur.
5. Is cholecystectomy necessary after endoscopic treatment of
CBDS in patients both with and without gallstones (GS)?
There are differences of opinion among authors regarding the need
to remove the gallbladder (GB) after ERCP/endoscopic sphinctero-
tomy (ES) in retrospective studies: In a large series of 371 patients
with both GS and CBDS who underwent endoscopic extraction,
Saito et al.60 found that acute cholecystitis occurred in 5.9%, and
recurrent CBDs in 9.7%, with a mean duration of follow-up of 7.7
years. They advocated that cholecystectomy may not always be
necessary. Kwon et al.61 found that in 146 patients followed-up for
PMPH_CH48.indd 389
Common Bile Duct Stones ■ 389
a mean of 24 months after endoscopic removal of CBDS, the over-
all rate of cholecystectomy was 4.8%: it was 6.8% (4/59) in patients
with GS and 3.4% (3/87) in patients without GS. The authors rec-
ommended that cholecystectomy be reserved for patients with
symptoms. Other nonrandomized studies similarly concluded
that in elderly patients, postponement of surgery after ERCP and
stone clearance in asymptomatic patients was justified.62,63
On the other hand, in a systematic review, McAlister et al.64
examined the role of cholecystectomy after ES. The authors recom-
mended proceeding with cholecystectomy due to the higher rate
of biliary complications in patients managed expectantly. Method
of cholecystectomy or patient ASA class did not seem to influence
outcome. Boerma et al.65 randomized patients with proven GS to
expectant management versus laparoscopic cholecystectomy after
ES. The wait-and-see group had a 47% incidence of recurrent bil-
iary complications versus 2% in the cholecystectomy group, with
a median follow-up time of 30 months (range 15–67 months). In
terms of higher-risk patients, Lau et al.66 similarly randomized
older patients (>60 years) with proven GS and found that at 5
years, 5.8% of patients in the cholecystectomy group versus 25.4%
in the group with GB in situ had recurrent biliary events. Taragona
et al.67 randomized 100 “high-risk” patients to open surgery with
CBDE if needed versus ERCP with ES only, and found that survival
at 1 year was similar, with the surgery group developing signifi-
cantly less biliary complications (6% vs. 12%). In a retrospective
study, octogenarians who underwent ERCP/ES without LC had
a significantly higher rate of recurrent biliary events compared
with those with underwent ERCP/ES and LC (48% vs. 10%) with a
mean follow-up of 126 months.68 The authors recommended that
age not be the sole factor in selecting patients for elective LC after
ERCP/ES. Williams38 reached a similar conclusion in another sys-
tematic review, recommending cholecystectomy for “all patients
with CBDS and symptomatic gallbladder stones unless there are
specific reasons for considering surgery inappropriate.” (Grade B
recommendation)
On the other hand, in patients with no GS in the GB in situ,
the evidence for elective cholecystectomy is less convincing. Ando
et al.69 followed up 1042 patients prospectively with a median
follow-up of 7.5 years, and found that patients with acalculous
gallbladders had a lower risk of recurrent stones when cholecys-
tectomy was not performed than patients with calculous gall-
bladders (11.3% vs. 23.9% in 15 years, relative risk = 2.16, 95% CI
1.21–3.87). In a retrospective study of 100 patients who underwent
ERCP with GB in situ, 28% developed biliary complications. In
patients with GS, 13 of 52 (25%) had acute cholecystitis versus
4 of 48 (8.3%) of those without GS (p = .02). However, the pres-
ence of GS was not an independent risk factor for predicting acute
cholecystitis in multivariate analysis in this study.70 Other stud-
ies involving long-term follow-up after ES have also shown that
the presence or absence of the GB did not affect the likelihood
of recurrent CBDS, and that acute cholecystitis was uncommon
when there were no GS in the GB in situ.71-74 In a consensus con-
ference, Nagino et al.53 concluded that patients with acalculous
gallbladders need not have cholecystectomy after sphincterotomy
as the incidence of cholecystitis was low, about 1%. Of note, the
recurrent stones observed by some of these studies71,73 were mostly
of the brown pigment type rather than cholesterol stones, raising
the possibility that these were primary bile duct stones related to
bile stasis and bacterial infection of the bile duct.75 Thus, prophy-
lactic cholecystectomy would not necessarily be of benefit.
5/22/2012 5:34:11 PM
 390 ■ Surgery: Evidence-Based Practice
Recommendation
In patients with proven gallstones, prophylactic cholecystectomy
should be offered to patients after ES unless there are specific
unfavorable patient-related factors. (Grade A recommendation)
Clinical Question Summary
Question
1 Are less invasive methods
such as magnetic resonance
cholangiopancreatography
(MRCP) and endoscopic
ultrasound (EUS) as accurate
as endoscopic retrograde
cholangiopancreatography
(ERCP), intraoperative
cholangiography or surgery in
the detection of CBDS?
2 What is the best approach to
evaluate and treat patients
with suspected CBDS?
3 If choledochotomy is done
during common bile duct
exploration (CBDE), is T-tube
drainage necessary?
4 What is the optimal method
of biliary decompression and
timing of decompression in
patients with acute cholangitis
due to CBDS?
5 Is cholecystectomy necessary
after endoscopic treatment of
CBDS in patients both with
and without gallstones (GS)?
PMPH_CH48.indd 390
In patients with no gallstones after ES, acute cholecystitis is
uncommon, and recurrent biliary complications may be a result
of primary bile duct stones. Routine cholecystectomy therefore
may not be necessary. (Grade C recommendation)
Answer Level of Grade of References
Evidence Recommendation
In the detection of CBDS, MRCP is 2b B 2-11, 76, 77
reliable, but is less sensitive than ERCP
particularly for small calculi (≤5 mm)
EUS is as sensitive and specific compared 1b A 12-19, 29
to ERCP
EUS is a more invasive procedure than 2b B 9, 17-19, 78
MRCP, but it is more sensitive than
MRCP particularly for small calculi
Routine preoperative ERCP is not 2b B 26-33, 85,
recommended. If preoperative imaging 88
is contemplated, EUS or MRCP should
be used in place of ERCP if there is not
a high likelihood of CBDS
In patients with suspected CBDS, a 1b A 20-24,
surgery-first strategy (LC + LCBDE or 34-38, 79,
open CBDE if indicated) is equivalent 80, 81,
to an endoscopy-first strategy in terms 82, 83,
of safety and efficacy. The surgery-first 84, 86,
strategy may shorten hospital length of 87, 89,
stay and reduce redundant procedures 90, 96
In open or laparoscopic surgery, 1b A 40-47, 91,
after verification of duct clearance 97-98
intraoperatively, primary closure of
the choledochotomy with or without
biliary stenting is a safe alternative to
T-tube drainage with no differences
in complication rates. Routine T-tube
placement after choledochotomy is not
necessary
In patients with acute cholangitis, urgent 2b B 48-55, 92,
endoscopic biliary decompression is 93
preferred over surgery
There is insufficient evidence to – – –
recommend a specific time period
where urgent biliary decompression
should occur
Prophylactic cholecystectomy should be 1b A 64-68, 94,
offered to patients after ES unless there 99
are unfavorable by patient-related factors,
in patients with proven gallstones
After ES, in patients with no gallstones, 2b C 53, 69-74,
acute cholecystitis is uncommon, and 95
recurrent biliary complications may be
a result of primary bile duct stones.
Routine cholecystectomy therefore may
not be necessary
5/22/2012 5:34:11 PM

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74. Lai K-H, Lin L-F, Lo G-H, et al. Does cholecystectomy after endo-
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75. Vitetta L, Sali A, Little P, et al. Primary “brown pigment” bile
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76. Hintze RE, Adler A, Veltzke W, et al. Clinical significance of
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78. Ainsworth AP, Rafaelson SR, Wamberg PA, et al. Is there a dif-
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 CHAPTER 49
Benign Biliary Strictures
Demetrius Pertsemlidis and David S. Pertsemlidis
INTRODUCTION
Benign bile duct strictures are the consequence of severe iatro-
genic injuries occurring mostly during biliary surgery. Since the
introduction of laparoscopic cholecystectomy in the United States
in 1988, the incidence of biliary strictures doubled and the long-
term mortality tripled, in comparison with patients undergoing
uncomplicated cholecystectomy.1-6
In a cohort of 42,474 open cholecystectomies, the incidence of
biliary strictures was 0.2%. Rapid rise of iatrogenic biliary stric-
tures in the early laparoscopic era was followed by gradual decline
reflecting experience with the new approach and improvement of
technology in optics and instruments; however, a national Aus-
tralian audit in 1995 revealed a high rate of 0.7%. The majority of
the biliary strictures caused by iatrogenic injuries are discovered
late in the postoperative period.7 In four large series, the mean
interval between open or laparoscopic cholecystectomy and diag-
nosis of the biliary stricture was 18.7 months. Biliary strictures
resulting from anastomotic failure occur in about 10% of patients
after pancreatico-duodenectomy.8-10
The value of selective or routine intraoperative cholangio-
graphy (IOC) is still debated. The surgical literature indicates
that use of C-arm fluoroscopy and improvement in the quality of
imaging have virtually eliminated the concern of misinterpreta-
tion of cholangiograms. The threshold of indications for IOC has
been lowered substantially, when problems of biliary anatomy or
suspected injury arise during surgery. Clinical studies strongly
suggest superiority of IOC in the prevention of iatrogenic biliary
injuries.11,12 Differentiation between benign and malignant bil-
iary strictures has markedly improved. The clinical, biochemical,
molecular, and pathologic parameters augmented by imaging
and genetic analysis have advanced the differential diagnostic
accuracy.
In the remote past (1930–1960), the dominant approach for
bilio-enteric reconstructions was duct-to-duct and duodeno-
biliary anastomoses, whereas Roux-Y hepatico-jejunostomy was
seldom utilized. In the past three to four decades, the Roux-Y
394
PMPH_CH49.indd 394
hepatico-jejunostomy has become the principal bilio-enteric
reconstruction leading to a success rate of 90%.1
1. What predisposes to benign biliary strictures?
The vast majority of benign bile duct strictures are iatrogenic,
either from injury during biliary surgery or anastomotic failures
during pancreatico-duodenectomy. Rarely, direct injury to the bile
duct can also occur during subtotal pancreatectomy for neoplasm
or nesidioblastosis, coring out of the pancreatic head for chronic
pancreatitis, or pancreatic necrosectomy. The intrapancreatic
portion of the bile duct can be occluded in chronic alcoholic or
autoimmune pancreatitis and ampullary strictures may be caused
by endoscopic sphincterotomy, chronic use of one or more biliary
stents, or surgical ampullectomy.
Intraoperative distinction between a normal bile duct and
the cystic duct can be difficult in the open and especially in lap-
aroscopic cholecystectomy because of similar size, color, and loss
of three-dimensional perception. The gallbladder infundibulum
and the cystic duct are in very close proximity to the main bile
duct, right hepatic duct and artery. The millimeter distance
separating these structures can be obscured from bleeding or
obliterated by acute or chronic inflammation, especially in a
contracted gallbladder. Aberrant right hepatic artery arising
from the superior mesenteric can distort the normal anatomy.
The common site of ligation, transection, burn, or resection
is the mid-portion of the 7-cm-long extrahepatic bile duct. Exces-
sive vertical traction of the fundus, rather than lateral traction
of Hartmann’s pouch, may produce tenting and accidental resec-
tion of the entire cystic-bile duct junction. Failure to identify the
junction and isolate the cystic duct may result in loss of a major
segment of the bile duct corresponding to Bismuth Type 2 or
Strasberg Type E2 injury.13,14
Thermal injuries to the bile duct and other organs in the sub-
hepatic region can be treacherous because of difficult intraop-
erative recognition and common underestimation of the extent
of damage.
5/22/2012 5:34:45 PM

Aside from direct instrumental or thermal injuries, caused by
surgical, endoscopic or percutaneous transhepatic interventions,
anastomotic failures from ischemia, tension or infection are com-
mon causes of biliary strictures. These strictures are almost always
short, allowing distinction from the longer cholangiocarcinomas.
Extrinsic compression by cysts, large impacted gallstones
(Mirizzi syndrome), tumors, and chronic alcoholic or autoim-
mune pancreatitis can cause stenosis or occlusion of the bile duct,
leading to cholestasis-induced stones, cholangitis, jaundice, and
severe pruritus. Inherited choledochal cysts are treated with radi-
cal resection because of malignant predisposition and the recon-
structions are similar and as complex as in the severe biliary
iatrogenic strictures.
Primary sclerosing cholangitis (PSC) has a strong association
with ulcerative colitis and affects two-thirds of young men with
this disease. This association correlates with the extent of colitis,
being tenfold higher (5.5%) with pancolitis, compared with 0.5%
with disease confined to the left side. Overall, 3.7% of patients with
ulcerative colitis will have PSC, and conversely colitis coexists in
70% to 100% of patients with PSC. The biology and clinical course
of the two diseases are independent, both in the time of clinical
expression and response to treatment. Cholangiocarcinoma devel-
ops in 10% to 20%, chronic pancreatitis in 20% to 40% in PSC
patients and the risk of pancreatic cancer is 15-fold higher than
in the unaffected population. The risk of colon cancer is fivefold
higher when the two diseases coexist over a follow-up period of
25 years. Long periods of indolent quiescence are not uncommon
and impossible to predict. Neither the time of progression to cir-
rhosis nor the transformation to biliary carcinoma are predictable.
Secondary sclerosing cholangitis is rare and affects patients treated
with hepatic arterial chemotherapy with 5-fluorodeoxyuridine for
metastatic colon cancer, or accidental leak of scolicidal agents into
intrahepatic bile ducts during infusion into echinococcal cysts.
Predilection of dominant biliary strictures to the hilar
region can be treated successfully with intrahepatic Roux-Y
bilio-enterostomy after partial central hepatectomy (segments 4
and 5). Progression to cirrhosis in PSC is treated with liver trans-
plantation. The chemical injury induced by hepatic arterial che-
motherapy can be minimized by prophylactic use of steroids. The
chemical toxicity of anti-echinococcal scolicidal agents leading
to secondary sclerosing cholangitis may be treated with bypass
alone, if the stricture is confined to the hilum; extensive intra-
hepatic involvement can be combined with hemi-hepatectomy or
use of liver transplantation.
Answer: The common major risk factors which predispose to
biliary strictures are iatrogenic bile duct injuries during biliary and
pancreatic surgery. Clinical evidence indicates that laparoscopic
cholecystectomy is associated with twofold higher rate of injuries
than open cholecystectomy. Other risk factors leading to bile duct
stenosis include inborn anatomic anomalies such as choledochal
cysts, autoimmune syndromes especially PSC, chronic inflamma-
tory diseases such as alcoholic pancreatitis, extrinsic compression
by cystic or neoplastic lesions, and abdominal trauma. (Grade C
recommendation)
2. Can IOC prevent or minimize bile duct injuries?
The routine or selective performance of IOC during open or
laparoscopic cholecystectomy has been debated ever since its
PMPH_CH49.indd 395
Benign Biliary Strictures ■ 395
introduction by P. L. Mirizzi in 1937. The rapid dissemination of
laparoscopic biliary surgery without the customary review and
scientific validation and the initial suboptimal technology has lead
to doubling of bile duct injuries, in comparison to open cholecys-
tectomy. The need of IOC to define the surgical anatomy during
laparoscopic surgery has risen substantially.15 The acquisition of
skills necessary to perform IOC during laparoscopic cholecystec-
tomy was included in the guidelines of the consensus conference
of the National Institutes of Health in 1993.16
A retrospective nationwide cohort study of nearly 1.6 million
cholecystectomies (laparoscopic 76%) was derived from records of
a Medicare Database over a period of 7 years (1992–1999). Overall
bile duct injuries amounting to 0.5% were defined as “reoperation
to repair the biliary injury within 1 year from cholecystectomy”.
IOC was performed in 39% of all patients. The use of IOC reduced
bile duct injuries to 0.39%, compared with 0.58% in those without
IOC (p < .001). The authors concluded that routine use of IOC may
decrease the rate of bile duct injury.4
A retrospective population-based study in Western Austra-
lia was based on hospital records and postoperative endoscopic
retrograde cholangio-pancreatographies (ERCPs) for bile leaks.
Of 19,187 colecystectomies, open and laparoscopic, 456 patients
with intraoperative intestinal, vascular, and bile duct injuries
were identified. After the introduction of laparoscopic cholecys-
tectomy in 1991, the percentage of iatrogenic injuries doubled
from 0.67 in 1988–1990 to 1.33 in 1993–1994. The odds ratio for
laparoscopic to open cholecystectomy was 1.79. In this impor-
tant population study, intraoperative cholangiographic imaging
lowered substantially the risk of all injuries. IOC reduced the
rate or injuries from 2.7 to 1.0/1,000 cases comparing laparo-
scopic with open cholecystectomy. Laparoscopic cholecystec-
tomy combined with IOC lowered the number of injuries from
4.3 to 2.1, and from 16.9 in patients with acute cholecystitis,
pancreatitis, jaundice, or cholangitis, to 2.2 in patients with-
out severe comorbidities. The authors estimated that combin-
ing surgery with routine IOC might have prevented one-third
of bile duct injuries.12
A respectable study of IOC published in 1995, did not find
beneficial protective effect from IOC.17
The sequence in the performance of IOC during laparo-
scopic colecystectomy offers certain protective advantages:
(a) trans-cystic cholangiography is performed before transecting
the cystic duct and dissection around the gallbladder; (b) biliary
anomalies can be detected before deeper dissection; (c) cholan-
giographic imaging is clearer as the continuous flow of contrast
fi lls sequential segments of the biliary system under C-arm fluo-
roscopy; and (d) the early detection of injury, which is critical.
The time for performance of the IOC and the low cost are trivial
in comparison with the gain of anatomic surgical precision and
prevention of injuries, especially in severe cholecystitis and coex-
isting morbidities.
Answer: IOC is a highly valuable tool in biliary surgery and
in operations adjacent to the biliary system, such as pancreatic,
duodenal, or liver surgery. The C-arm fluoroscopic cholangiog-
raphy has vastly improved the accurate interpretation of cho-
langiograms, compared with the cumbersome and less precise
suboptimal radiography of the past. On the other hand, the
current preoperative imaging offers a great deal of information
regarding the biliary anatomy and the extent of inflammatory
5/22/2012 5:34:45 PM
 396 ■ Surgery: Evidence-Based Practice
changes surrounding the bile duct. The national trend appears to
favor selective use of IOC; however, the threshold for use of IOC
must be substantially low and the special equipment immediately
available. (Grade C recommendation)
3. How accurate is the differential diagnosis of benign and
malignant biliary strictures?
Progress in the distinction between benign biliary strictures and
cholangiocarcinoma has been significant, but not spectacular.
The history and clinical findings, the prior surgical, endoscopic or
percutaneous interventions, and conventional plus scintigraphic
imaging are the hallmarks of differential diagnosis. Tumor mark-
ers in the serum, cytology of bile, and fine needle tissue aspirations
(percutaneous or intraoperative) have not yielded major advance-
ments. The severe desmoplastic response in cholangiocarcinoma
often precludes cytologic or histologic diagnosis.
PSC is often indistinguishable radiographically from cholan-
giocarcinoma. Choledochal cysts also have the potential of malig-
nant transformation. After resection of a choledochal cyst, the
reconstruction is similar to that of iatrogenic strictures. Long-term
close follow-up of these premalignant syndromes is essential.
Bile samples collected during ERCP, percutaneous transhe-
patic and intraoperative were studied for methylation profi le of
6 of 19 tumor suppressor genes, assays of Ki-ras gene point muta-
tions and brush cytology in bile and lumen of the stricture yielded
only qualitative trends.18-20 Fine needle aspiration (FNA) cytology
of percutaneously accessible strictures has been recommended to
only strengthen concomitant diagnostic data.21
Table 49.1 shows an overview of the features of the two enti-
ties. A history of biliary or pancreatic surgery, endoscopic or
percutaneous transhepatic interventions, chronic cholelithiasis or
choledocholithiasis, chronic pancreatitis, surgery for choledochal
cyst, abdominal trauma, radiotherapy, human immunodeficiency
viral (HIV) cholangiopathy, and cystic or neoplastic diseases
compressing the bile duct should raise suspicion of benign stric-
ture. The presence of paraneoplastic symptoms, pruritus, episodic
cholangitis, chronic or autoimmune pancreatitis, and cholangitis,
augmented by a precise history, facilitate the distinction between
benign and malignant biliary disease. Bacterial cholangitis is
absent in cholangiocarcinoma unless there was endoscopic, per-
cutaneous, or surgical intervention.
Imaging, noninvasive and invasive, is critical in differentiating
benign from malignant biliary strictures. Computed tomography
in 50 patients with strictures (32 malignant) showed length of 17.9
mm in malignant versus 8.9 mm in benign strictures (p < .001),
upstream bile duct caliber of 22.0 versus 17.8 mm (p = .003), thick-
ness >1.5 mm in 26 malignancies, and greater enhancement during
arterial and portal venous phases in malignancies compared with
those with benign strictures.22
Intraductal ultrasonography (IDUS) utilizes a cholangio-
scope combined with an ultrasound probe. The 4.9-mm instru-
ment is inserted through the duodenal ampulla or percutaneous
transhepatic route. This endoscopic approach was used in 93
patients with biliary strictures (38 cholangiocarcinoma, 23 pan-
creatic cancer, 7 gallbladder malignancy, 9 benign structure,
6 chronic pancreatitis, 6 autoimmune pancreatitis, and 4 scle-
rosing cholangitis). In 42 patients with malignant stricture, the
diagnosis was confirmed by examination of the surgical speci-
men. The diagnosis of 26 malignant strictures and 9 benign
PMPH_CH49.indd 396
strictures was made from the histology of biopsy specimens. The
sensitivity and specificity were 89.7% and 84%, respectively, for
the differential diagnosis of biliary strictures. Direct visualiza-
tion of the biliary mucosa using the percutaneous transhepatic
endoscopic approach facilitated the distinction between benign
and malignant disease. Untreated autoimmune pancreatitis and
the intrapancreatic bile duct proved difficult in distinguishing
benign from malignant strictures.23
Magnetic resonance cholangiopancreatography (MRCP) was
compared with ERCP. Fift y patients with strictures (23 benign, 27
cholangiocarcinoma) were retrospectively reviewed after definitive
diagnosis with surgical biopsy. Irregular margins and asymmetric
narrowing were present in 89% of cholangiocarcinomas and in
30% in benign strictures. The sensitivity, specificity, and accuracy
were 81 versus 74, 70 versus 70 and 76 versus 72 for MRCP versus
ERCP, respectively. The mean length of cholangiocarcinomas was
30 mm and for benign strictures 13.6 (p < .001). The conclusion
from this small retrospective study was that a long stricture with
irregular margins and asymmetric stenosis suggests the presence
of cholangiocarcinoma.24
Rare entities which must be differentiated from benign bil-
iary strictures are primary and secondary sclerosing cholangitis
and polycystic liver disease.
Answer: The distinction between benign and malignant biliary
strictures is not difficult. The history of previous surgery or abdom-
inal trauma, the absence of paraneoplastic symptoms, the presence
of episodic cholangitis, combined with the imaging characteris-
tics permit the differentiation in the majority of cases. Short sym-
metrical strictures especially on cholangiographic images strongly
support the diagnosis of benign disease. Serum tumor markers,
cytology, and molecular and genetic studies of bile have not yielded
sufficient diagnostic power. (Grade C recommendation)
4. What is the optimal surgical treatment of benign biliary
strictures?
The gold standard for evaluation of biliary stricture is cholang-
iography. MRCP offers a diagnostic overview of the biliary and
pancreatic duct integrity or disruption. ERCP will confirm the site
and degree of stenosis or occlusion of the bile duct. If the proximal
biliary system is not visualized with retrograde contrast injection,
percutaneous transhepatic cholangiography (PTC) is necessary to
define the site and extent of discontinuity of the bile ducts.
The types of surgical reconstruction include transduodenal
sphincteroplasty for ampullary stricture, supraduodenal chole-
docho-duodenostomy for ampullary or intrapancreatic strictures
and Roux-Y hepatico-jejunostomy. The reconstruction of the bile
duct with duct-to-duct anastomosis is limited to cases when the
loss of duct is <1 cm.
In both choledochoduodenostomy and transduodenal
sphincteroplasty, the choledocho-duodenal anastomosis should
be at least 2.5 cm. The requisite for successful patency for cho-
ledocho-duodenostomy is a bile duct caliber of at least 10 mm,
and 3 cm distal common duct above the fi rst portion of the duo-
denum. The transduodenal sphincterotomy should not be longer
than 2.5 cm from the ampulla to avoid duodenal perforation.
The suture material must be absorbable.
The technique of constructing a Roux-Y hepatico-jejunostomy
is using a segment of proximal jejunum with sufficient mesen-
teric length to reach the hilum of the liver through retrocolic path.
5/22/2012 5:34:45 PM
 Benign Biliary Strictures ■ 397

A side-to-side anastomosis avoids excessive mobilization of the
normal bile duct remnant above the stricture and the risk of devas-
cularization, or injury to the hepatic artery or portal vein. For bilio-
enteric anastomosis above the confluence of the two hepatic ducts
it may be possible to join the two ducts and perform a technically
easier 2-cm intrahepatic reconstruction. The length of the biliary
limb should measure 40 to 50 cm to prevent reflux of gastroduode-
nal contents beyond the anastomosis and into intrahepatic ducts.
Postoperative peri-hilar strictures (Bismuth Types III and IV,
Strasberg Types E3 and E4) are technically the most challenging.
Peri-hilar or hemi-hepatectomy may be necessary to restore bilio-
enteric continuity but the incidence of recurrent strictures is in
the range of 12% to 45%.25
In the remote prelaparoscopic era covering the period from
1930 to 1960 biliary and bilio-enteric reconstructions were mostly
duct-to-duct and duct-to-duodenum. Three large series from
premier academic institutions in New York (Presbyterian and
Memorial Hospitals),26 Massachusetts General in Boston,27 and
Minnesota (Mayo Clinic)28 performed only 17% Roux-Y hepatico-
jejunostomies in 331 reconstructions. The duct-to-duct recon-
structions were successful only in 56% of the 331 operations.
The Roux-Y hepatico-jejunostomy has become the gold
standard for restoration of bilio-enteric continuity for strictures
reaching the proximal common hepatic duct and peri-hilar
region. Lillemoe et al.1 reported successful immediate and long-
term outcome in 98% of 156 patients covering a 10-year period
from 1990 to 1999. Similar successful outcomes have been
reported by Sikora et al.9 in 300 patients with postcholecys-
tectomy biliary strictures (open 262, laparoscopic 38) with low
surgical mortality of 1.3%, excellent 5-year outcome and failure
rate of 5.4%. Millis et al.29 used two types of bilio-enteric recon-
structions, Roux-Y choledocho-jejunostomy in 101 patients and
hepatico-jejunostomy in 45 patients over the period from 1955
to 1990. Recurrent strictures developed in 22% of the patients
during the 3-year follow-up.29
The superiority of Roux-Y hepatico-jejunostomy for high bilio-
enteric anastomosis was proven by Tocchi et al.30 in both early
and late outcomes. Fift y-four patients treated with Roux-Y recon-
struction by Schmidt et al.31 yielded high success rate (93%) with a
mean follow-up of 62 months (range 2.6–154).31
Answer: The surgical gold standards for benign biliary
strictures are Roux-Y hepatico-jejunostomy for proximal and
choledocho-duodenostomy (supra- or transduoenal) for distal
strictures. With the exception of the rare supra-hilar intrahepatic
strictures, the success rate of these surgical approaches is about 90%.
(Grade C recommendation)

Clinical Question Summary

Question Answer Level of Grade of References
Evidence Recommendation
1 What predisposes Biliary surgery, laparoscoic more than open. Surgery 3 C 1-12
to benign biliary in the pancreatic head. Surgical or endoscopic
strictures? interventions in the duodenal ampulla. Gallstones,
cysts or tumors compressing the bile duct. Chronic
pancreatitis. Primary or secondary sclerosing
cholangitis.
2 Can IOC prevent or Selective rather than routine IOC appears to be the 3 C 4, 7, 12,
minimize bile duct national trend. This attitude of surgeons has been 15-17
injuries? greatly influenced by strong reliance on endoscopic
diagnosis and treatment of choledocholithiasis and
iatrogenic injuries. Precise preoperative imaging,
familiarity with and low threshold of performance of
IOC are protective of injuries
3 How accurate is A history of biliary or pancreatic surgical, endoscopic 3 C 18-24
the differential or transhepatic interventions, episodic bacterial
diagnosis of benign cholangitis, absence of paraneoplastic symptoms and
and malignant biliary associations with inflammatory, autoimmune and
strictures? inherited syndromes strongly favor benign disease.
Imaging (conventional, endoscopic) depicting short
homogeneous strictures reinforce the diagnosis
of benign entity. Differentiation from primary or
secondary sclerosing cholangitis is difficult.
4 What is the optimal Duct-to-duct anastomosis should be avoided if 3 C 1, 9, 25-31
surgical treatment the segmental loss of bile duct is greater than
of benign biliary 1 cm. Choledocho-duodenostomy (supra- or
strictures? transduodenal) and Roux-Y hepatico-jejunostomy
are the surgical gold standards for distal and
proximal strictures, respectively.

PMPH_CH49.indd 397 5/22/2012 5:34:45 PM

 398 ■ Surgery: Evidence-Based Practice
REFERENCES
1. Lillemoe KD, Melton GB, Cameron JL, et al. Postoperative bile
duct strictures; Management and outcome in the 1990s. Ann
Surg. 2000;232:430-441.
2. A prospective analysis of 1518 laparoscopic cholecystectomies.
The Southern Surgeons Club. N Engl J Med. 1991;324:1973-1078.
3. Windsor JA, Pong J. Laparoscopic biliary surgery: More than a
learning curve problem. Aust NZ Surg. 1998;68:186-189.
4. Flum DR, Cheadle A, Prelac C, et al. Bile duct injury during
cholecystectomy and survival in medicare beneficials. JAMA.
2003;290:2168-2173.
5. Roslyn JJ, Bins GS, Hughes EF, et al. Open cholecystectomy. A
contemporary analysis of 42,474 patients. Ann Surg. 1993;218:
129-137.
6. Dolan JP, Diggs BS, Sheppard BC, Hunter JG. Ten-year trend
in the national volume of bile duct injuries requiring operative
repair. Surg Endosc. 2005;19:967-973.
7. Lillemoe KD. Repair of common bile duct injuries. uptodate.com/
contents/repair-of-common-bile-duct-injuries, September 2010.
8. Kahn MH, Howard TJ, Fogel EL, et al. Frequency of biliary com-
plications after laparoscopic cholecystectomy detected by ERCP:
Experience in a large tertiary referral center. Gastrointest Endosc.
2007;65:247-252.
9. Sikora SS, Pottakkat B, Srikanth G, et al. Postcholecystectomy
benign biliary strictures: Long-term results. Dig Surg. 2006;23:
304-312.
10. Cantwell CP, Pena CS, Gervais DA, et al. Thirty years experience
with balloon dilatation of benign postoperative biliary strictures:
Long-term outcomes. Radiology. 2008;249:1050-1057.
11. Pitt HA, Miyamoto T, Parapatis SK, et al. Factors influencing
outcome in patients with postoperative biliary strictures. Am J
Surg. 1982;144:14-21.
12. Fletcher DR, Hobbs MST, Tan P, et al. Complications of chole-
cystectomy: Risks of the laparoscopic approach and protec-
tive effects of operative cholangiography. Ann Surg. 1999;229:
449-457.
13. Jarnagin WR, Blumgart LH. Benign biliary strictures. In: Blum-
gart LH, ed. Surgery of the Liver, Biliary Tract, and Pancreas. 4th
ed. Philadelphia, PA: Saunders; 2007:634.
14. Strasberg SM, Hertl M, Soper NJ. An analysis of the problem of
biliary injury during laparoscopic cholecystectomy. J Am Coll
Surg. 1995;180:101-105.
15. Massarweh NN, Flum DR. Role of intraoperative cholangiography
in avoiding bile duct injury. J Am Coll Surg. 2007;204:656-664.
PMPH_CH49.indd 398
16. National Institutes of Health. Consensus Development Confer-
ence Statement on gallstones and laparoscopic cholecystectomy.
Am J Surg. 1993;165:390-396.
17. Lorimer JW, Fairfull-Smith RJ. Intraoperative cholangiography
is not essential to avoid duct injuries during laparoscopic chole-
cystectomy. Am J Surg. 1995;169:344-347.
18. Zhang Y, Yang B, Du Z, et al. Identification and validation of spe-
cific methylation profile in bile for differential diagnosis of malig-
nant biliary stricture. Clin Biochem. 2010;43:1340-1344.
19. Saurin J-C, Joly-Pharoboz M-O, Pernas P, et al. Detection of
Ki-ras gene point mutations in bile for differential diagnosis of
malignant and benign biliary strictures. Gut. 2000;47;357-361.
20. Mansfield JC, Griffin SM, Wadehra V, et al. A prospective
evaluation of cytology from biliary strictures. Gut. 1997;40:
617-677.
21. Desa LA, Acosa AB, Lazzara S, et al. Cytodiagnosis in the
management of extrahepatic biliary stricture. Gut. 1991;32:
1188-1191.
22. Choi SH, Han JK, Lee JM, et al. Differentiating malignant from
benign common bile duct stricture with multiphasic CT. Radiol-
ogy. 2005;236:178-183.
23. Inui K, Yoshino J, Miyoshi H. Differential diagnosis and treat-
ment of biliary strictures. Clin Gastroenterol Hepatol. 2009;7:
579-583.
24. Park MS, Kim TK, Kim KW, et al. Differentiation of extrahepatic
bile duct cholangiocarcinoma from benign stricture: Findings at
MRCP versus ERCP. Radiology. 2004;233:234-240.
25. Larghi A, Tringal A, Lecca PG, et al. Management of hilar biliary
strictures. Am J Gastroenterol. 2008;103:458-473.
26. O’Malley RD, Auses AH, Jr., Whipple AO. Benign extrahepatic
biliary tract obstruction. Ann Surg. 1951;134:797-807.
27. Donaldson GA, Allen AW, Bartlett MK. Postoperative bile-
duct strictures: their etiology and treatment. N Engl J Med.
1956;254:50-56.
28. Walters W, Ramsdell JA. Study of three hundred eight opera-
tions for stricture of bile ducts. JAMA. 1959;171:872-276.
29. Millis JM, Tompkins RK, Zinner, et al. Management of bile
duct strictures: An evolving strategy. Arch Surg. 1992;127:
1077-1084.
30. Tocchi A, Costa G, Lepre L, et al. The long-term outcome of
hepatico-jejunostomy in the treatment of benign bile duct stric-
tures. Ann Surg. 1996;224:162-167.
31. Schmidt SC, Langrehr JM, Hintze RE. Long-term results and
risk factors influencing outcome of major bile duct injuries fol-
lowing cholecystectomy. Brit J Surg. 2005;92:76-82.
5/22/2012 5:34:45 PM

INTRODUCTION
Gallstone ileus is a rare complication of cholelithiasis character-
ized by small bowel obstruction from a biliary calculus migrated
through a biliary enteric fistula. Bowel obstruction from an enter-
olith accounts for 1% to 3% of all bowel obstructions, but may
account for 25% of bowel obstructions in those above age 65 years
of age. The most common locations for obstructing enteroliths
are: the ileum (60.5%), followed by the jejunum (16.5%), stomach
(14.2%), colon (4.1%), and duodenum (3.5%).1 Bouveret’s syndrome
is a clinical entity described as impaction of a stone within the
duodenal bulb and thus leads to gastric outlet obstruction.
Although gallstone ileus was first described by Erasmus Bar-
tholin in 1654, current morbidity and mortality figures remain
high due to the often vague, nonspecific symptoms, delayed diag-
nosis, and elderly preponderance. Less than 50% of patients have
a known history of biliary disease.1,2 With current diagnostic and
management strategies, mortality from gallstone ileus remains as
high as 12% to 27% in most published studies. Questions remain
regarding optimal diagnosis and treatment for this clinical entity.
1. Is enterolithotomy alone sufficient treatment for gallstone
ileus?
Operative strategies for gallstone ileus are controversial. Current
surgical options include: (1) one-stage procedure involving entero-
lithotomy to relieve bowel obstruction, cholecystectomy, and repair
of chole-enteric fistula; (2) two-stage procedure involving entero-
lithotomy and interval cholecystectomy; and (3) Eenterolithotomy
alone. To date, there are no randomized or prospective clinical tri-
als comparing the various treatment strategies.
In 1993, Reisner and Cohen conducted a review of 1001 cases
of surgically treated gallstone ileus in the literature.1 They reported
significantly less mortality in those patients treated with entero-
lithotomy alone versus a one-stage procedure (11.7% vs. 16.9%).
More recently, several smaller retrospective have been published
comparing the two modalities (Table 50.1).
399
PMPH_CH50.indd 399
CHAPTER 50
Gallstone Ileus
David W. Smith and Ara J. Feinstein
Although it is difficult to make conclusions about morbid-
ity and mortality due to the poor quality and small sample sizes
of these studies, the complication rate of one-stage procedures
involving enterolithotomy, cholecystectomy, and repair of chole-
enteric fistula appears to be higher than enterolithotomy alone.
Th is is likely due to a longer operative time in these series. Mor-
tality figures are small, but also seemingly higher in the one-stage
procedures.
The incidence of biliary complications after the enteroli-
thotomy alone was low in all studies, and most resolved with
conservative or endoscopic management. Although follow-up
time was variable, there was only one case that required interval
cholecystectomy.3
Answer: Recent retrospective case series show that gallstone
ileus continues to have a substantial complication rate, likely due
to significant comorbidities of the affected population. In the
past, it was argued that, in addition to enterolithotomy, a chole-
cystectomy and fistula repair should be performed at the initial
procedure or later due to the subsequent risk of biliary compli-
cations. In more recent series, however, the incidence of biliary
complications in patients who received enterolithotomy alone was
quite low. The risks of cholecystectomy and fistula repair seem-
ingly outweigh the benefits. Enterolithotomy alone should be the
treatment of choice, especially in older, less stable patients with
significant comorbidities. (Grade C recommendation).
2. Can gallstone ileus be treated laparoscopically?
Laparoscopic management of gallstone ileus is a variation of a
staged procedure or enterolithotomy alone. Ideally, laparoscopic
techniques would minimize the physiologic burden and high mor-
bidity and mortality figures associated with an open procedure.
The use of laparoscopy to treat gallstone ileus was first pub-
lished by Montgomery in 1993.13 In a subsequent case series by
Soto et al.,14 two patients underwent laparoscopic management for
gallstone ileus. An obstructing stone in the proximal jejunum was
identified and laparoscopically brought through an extended port
5/22/2012 5:35:18 PM
 400 ■ Surgery: Evidence-Based Practice

Table 50.1 Operative Strategies

Author Procedure Number of Complications Mortality Level of
Patients (%) (%) Evidence
Yakan et al.3 Open enterolithotomy 11 1 (9.1) 2 (18.2) 4
One-stage 2 0 (0) 0 (0)
Moberg and Montgomery4 Laparoscopic-assisted 19 6 (31.5) 0 4
enterolithotomy
Open enterolithotomy 13 5 (38.5) 0
Lobo et al. 5 Open enterolithotomy 14 5 (35.7) 0 4
One-stage 1 1 (100) 1 (100)
Ayantunde and Agrawal6 Open enterolithotomy 20 12 (60) 4 (20) 4
One-stage 2 2 (100) 1 (50)
Pavlidis et al.7 Open enterolithotomy 3 1 (33.3) 0 (0) 4
One-stage 6 2 (33.3) 1 (16.7)
Doko et al.8 Open enterolithotomy 11 3 (27.3) 1 (9.1) 4
One-stage 18 15 (83.3) 2 (11.1)
Tan et al.9 Open enterolithotomy 7 4 (57.1) 0 (0) 4
One-stage 12 7 (58.3) 0 (0)
Muthukumarasamy et al.10 Open enterolithotomy 10 3 (30.0) 0 (0) 4
One-stage 3 1 (33.3) 0 (0)
Riaz et al.11 Open enterolithotomy 5 3 (60.0) 0 (0) 4
One-stage 5 1 (20.0) 0 (0)
Martínez Ramos and Enterolithotomy (Open and 27 13 (48.1) 5 (18.5) 4
Daroca José12 laparoscopic)
One-stage 4 2 (50.0) 1 (25.0)

site. Extracorporeal enterolithotomy was completed with the small
bowel defect closed in two layers. The second patient underwent
laparoscopic decompression of the stone into the large bowel. The
biliary enteric fistula was not addressed in either case and both
patients subsequently discharged on the 4th and 6th postopera-
tive day, respectively. There was no morbidity or mortality noted
in either of the patients.
Total laparoscopic management has been cited in recent lit-
erature. Ferraina et al.15 retrospectively reviewed six patients who
underwent video-assisted laparoscopic enterolithotomy. Four out
of the six patients were treated with extracorporeal enterolitho-
tomy and enterorrhaphy via a mini mini-incision after laparo-
scopic identification. One patient underwent total laparoscopic
enterolithotomy and enterorrhaphy. The remaining patient under-
went laparoscopy alone, as the enterolith had subsequently passed
into the large bowel. The overall complication rate was 33% with
a mortality of 16.6%. Owera et al.16 reported three patients who
underwent total laparoscopic enterolithotomy without intraop-
erative or postoperative complications. The authors reported no
morbidity or mortality at follow-up.
In the largest study to date addressing laparoscopic manage-
ment, Moberg and Montgomery4 retrospectively compared laparo-
scopically assisted and open enterolithotomy on 32 consecutive
patients with gallstone ileus. Once the impacted stone was identi-
fied laparoscopically, it was delivered extracorporeally for subse-
quent enterolithotomy through an extended port site or separate
lower abdominal incision. Two out of 19 patients treated initially
with laparoscopy were converted to open due to technical difficul-
ties. No significant difference in patient demographics, duration of
operation, length of hospitalization, morbidity, or mortality was
identified between the two groups.
Answer: Current literature supporting feasibility and suc-
cess of laparoscopic enterolithotomy comes from small retrospec-
tive case series. Technical feasibility has been demonstrated with
similar morbidity and mortality in the largest retrospective study
to date. With careful patient selection and laparoscopic exper-
tise, laparoscopy with enterolithotomy alone may be a treatment
option in gallstone ileus. (Grade C recommendation).
3. What is the best diagnostic modality?
Abdominal radiographs were initially the diagnostic modality of
choice for gallstone ileus. Radiographic criteria included pneu-
mobilia, presence of an ectopic gallstone, and mechanical bowel
obstruction. Review of retrospective studies reveals the presence
of this classic Rigler’s triad in less than 50% of cases of surgically
proven gallstone ileus with sensitively at a modest 70%.1,2,17 Ultra-
sonography and computed tomography have been reviewed as sepa-
rate diagnostic modalities or in combination with plain abdominal

PMPH_CH50.indd 400 5/22/2012 5:35:18 PM

 Gallstone Ileus ■ 401

radiographs. To date, there are no prospective trials comparing
abdominal radiographs, ultrasound, or computed tomography in
accurately diagnosing gallstone ileus.
Yakan et al.3 retrospectively reviewed 12 patients with surgi-
cally confirmed gallstone ileus. Correct preoperative diagnosis by
imaging was made in five patients. Four patients had CT imaging
correctly identifying gallstone ileus, while and the remaining indi-
vidual had an ultrasound finding of ectopic stone. The remaining
seven patients were taken to the operating room without pre-
operative imaging due to clinical presentation requiring urgent
exploration. Plain fi lms were obtained in all 12 patients with the
authors noting nonspecific findings in all 12 to suggest a correct
preoperative diagnosis of gallstone ileus.
Lassandro et al.18 retrospectively studied the radiologic find-
ings of 27 patients with gallstone ileus and found air fluid levels
and dilated bowel loops were the most common findings with
abdominal plain fi lm, ultrasound, and computed tomography.
The complete Rigler’s triad was found 4 times (15%) with plain
abdominal fi lm, 3 times (11%) with ultrasound, and 21 times (78%)
with CT. The study suggests that plain abdominal films and ultra-
sound may be adequate screening tools, but CT is clearly superior
for identifying gallstone ileus. Reimann et al.19 also showed the
usefulness in CT scanning to evaluate gallstone ileus. In a retro-
spective review of three patients, all had the complete triad identi-
fied on CT scan prior to operative intervention.
Diagnostic sensitivity with separate or combined radiologic
approaches with abdominal radiographs and ultrasonography was
retrospectively reviewed by Ripollés et al.20 Alone, ultrasonogra-
phy had a statistically significant increased sensitivity in definitive
diagnosis of gallstone ileus over plain abdominal radiographs. The
sensitivity of ultrasonography alone or in combination with plain
abdominal radiographs still only approached 74%. Combined
imaging results were also reported by Ayantunde and Agrawal.6
A 77% preoperative diagnosis of gallstone imaging was achieved
with various combinations of abdominal plain fi lm, ultrasonogra-
phy, and computed tomography. Sensitivity of individual imaging
modalities were not reported, but the addition of CT imaging in
combination or alone achieved 100% sensitivity in preoperative
diagnosis of gallstone ileus.
Yu et al.21 retrospectively reviewed 151 patients with small
bowel obstruction with 14 patients in that group known to have sur-
gically confirmed gallstone ileus. Thirteen had correct preoperative
CT diagnosis of gallstone ileus, one false positive case, and no false
negatives. Lassandro et al.22 in their retrospective review showed
that in 40 patients, correct preoperative diagnosis was made in 35
patients based on clinical and CT findings on presentation. The
remaining five patients had stones found at surgery.
Answer: Prompt definitive diagnosis of gallstone ileus is rarely
from clinical history and physical examination alone. Used solely
or in combination with ultrasound and plain films, computed
tomography may add to a higher diagnostic sensitivity, specificity,
and accuracy essential to early diagnosis and surgical management.
CT may also add location, size, and presence of additional stones.
This may warrant a CT scan in all elderly patients with small bowel
obstructions or in patients in whom there is a clinical suspicion of
gallstone ileus. (Grade C recommendation).
4. Can gallstone ileus be treated with other techniques?
Endoscopy and novel lithotriptic techniques alone or in combina-
tion with endoscopy have been successfully utilized in extract-
ing impacted stones. Various lithotriptic techniques have been
described and include laser lithotripsy, extracorporeal shockwave
lithotripsy, intracorporeal electrohydraulic lithotripsy, and endo-
scopic mechanical lithotripsy. Current literature reveals several
case studies of endoscopic removal of proximally located gas-
tric stones as well as those located in small and large bowel.23,24
One report utilized shockwave lithotripsy before endoscopic
removal,25 two cases reported using a YAG laser to assist in stone
fragmentation prior to removal,26,27 and one case utilized both.28
Some authors have utilized various combinations of lithotriptic
modalities to assist in stone disintegration for subsequent endo-
scopic removal. There are case studies which have shown spon-
taneous passage of disintegrated stones as well. The technique of
lithotripsy fragmentation for endoscopic retrieval or spontane-
ous passage may avoid exposure of the aged patient with medical
comorbidities to invasive operations and general anesthesia.
Answer: Less invasive techniques to treat gallstone ileus
have been described in several case reports. These reports dem-
onstrate success in various modalities of lithotriptic procedures
alone or in combination with endoscopy. Less invasive modalities
to treat gallstone ileus await further investigation, but may be an
option in patients too ill to undergo abdominal surgery. (Grade D
recommendation).

Clinical Question Summary

Question
1 Is enterolithotomy alone
sufficient?
2 Can gallstone ileus be
treated laparoscopically?
3 What is the best diagnostic
modality?
4 Can gallstone ileus be
treated with different
techniques?
Answer Grade of References
Recommendation
Yes, operating times are shorter and the risk of subsequent C 1-11
biliary complications is low.
Yes, it is technically feasible with similar morbidity and C 12-16
mortality to open enterolithotomy.
CT scan, due to improved sensitivity in preoperative C 17-23
diagnosis compared to with plain films and ultrasound.
Possibly. The use of endoscopy and lithotripsy has been D 24-28
successful in selected patients but larger studies are
needed.

PMPH_CH50.indd 401 5/22/2012 5:35:18 PM

 402 ■ Surgery: Evidence-Based Practice
REFERENCES
1. Reisner RM, Cohen JR. Gallstone ileus: A review of 1001 reported
cases. Am Surg. 1994;60(6):441-446.
2. Clavien, PA, Richon J, Burgan S, Rohner A. Gallstone ileus. Br J
Surg. 1990;77:737-742.
3. Yakan S, Engin O, Tekeli T. Gallstone ileus as an unexpected
complication of cholelithiasis: Diagnostic difficulties and treat-
ment. Ulus Travma Acil Cerrahi Derg. 2010;16(4):344-348.
4. Moberg AC, Montgomery A. Laparoscopically assisted or open
enterolithotomy for gallstone ileus. Br J Surg. 2007;94(1):53-57.
5. Lobo DN, Jobling JC, Balfour TW. Gallstone ileus: Diagnostic
pitfalls and therapeutic successes. J Clin Gastroenterol. 2000;
30(1):72-76.
6. Ayantunde AA, Agrawal A. Gallstone ileus: Diagnosis and man-
agement. World J Surg. 2007;31(6):1292-1297. Epub 15 April, 2007.
7. Pavlidis TE, Atmatzidis KS, Papaziogas BT. Management of gall-
stone ileus. J Hepatobiliary Pancreat Surg. 2003;10(4):299-302.
8. Doko M, Zovak M, Kopljar M. Comparison of surgical treatments
of gallstone ileus: Preliminary report. World J Surg. 2003;27(4):
400-404.
9. Tan YM, Wong WK, Ooi LL. A comparison of two surgical strat-
egies for the emergency treatment of gallstone ileus. Singapore
Med J. 2004;45(2):69-72.
10. Muthukumarasamy G, Venkata SP, Shaikh IA. Gallstone ileus: Sur-
gical strategies and clinical outcome. J Dig Dis. 2008;9(3):156-161.
11. Riaz N, Khan MR, Tayeb M. Gallstone ileus: Retrospective review
of a single centre’s experience using two surgical procedures.
Singapore Med J. 2008;49(8):624-626.
12. Martínez Ramos D, Daroca José JM. Gallstone ileus: Manage-
ment options and results on a series of 40 patients. Escrig Sos J,Rev
Esp Enferm Dig. 2009;101(2):117-120, 121-124.
13. Montgomery A. Laparoscopic-guided enterolithotomy for gall-
stone ileus. Surg Laparosc Endosc. 1993;4:310-314.
14. Soto DJ, Evan SJ, Kavic MS. Laparoscopic management of gall-
stone ileus. JSLS. 2001;5:279-285.
15. Ferraina P, Gancedo MC, Elli F. Video-assisted laparoscopic
enterolithotomy: New technique in the surgical management of
gallstone ileus. Surg Laparosc Endosc Percuntan Tech. 2003;13(2):
83-87.
PMPH_CH50.indd 402
16. Owera A, Low J, Ammori BJ. Laparoscopic enterolithotomy
for gallstone ileus. Surg Laparosc Endosc Percuntan Tech. 2008;
18(5):450-452.
17. Maglinte DD, Reyes BL, Harmon BH, et al. Reliability and role
of plain fi lm radiography and CT in the diagnosis of small-bowel
obstruction. Am J Roentgenol. 1996;167:1451-1455.
18. Lassandro F, Gagliardi N, Scuderi M. Gallstone ileus analysis of
radiologic findings in 27 patients. Eur Radiol. 2004;50:23-29.
19. Reimann AJ, Yeh, BM, Breiman RS. Atypical cases of gallstone ileus
evaluated with multidetector computed tomography. J Comput
Assist Tomogr. 2004;28(4):523-527.
20. Ripollés T, Miguel-Dasit A, Errando J. Gallstone ileus: Increased
diagnostic sensitivity by combining plain fi lm and ultrasound.
Abdom Imaging. 2001;26:401-405.
21. Yu CY, Lin CC, Shyu RY, Hsieh CB. Value of CT in the diagnosis
and management of gallstone ileus. World J Gastroenterol. 2005;
11(14):2142-2147.
22. Lassandro F, Romano S, Ragozzino A. Role of helical CT in the
diagnosis of gallstone ileus and related conditions. AJR. 2005;
185:1159-1165.
23. DePalma, GD, Mastrobuoni G, Benassai. Gallstone ileus: Endo-
scopic removal of a gallstone obstructing the lower ileum. Dig
Liver Dis. 2009;41:446.
24. Heinzow, HS, Meister T, Wessling J. Ileal gallstone obstruction:
Single-balloon enteroscopic removal. World J Gastrointest Endosc.
2010;2(9):321-324.
25. Zielinski MD, Ferreira LE, Baron TH. Successful endoscopic treat-
ment of colonic gallstone ileus using electrohydraulic lithotripsy.
World J Gastroenterol. 2010;15(12):1533-1536.
26. Alsolaimana MM, Chrisoph R, Nawras AT. Bouveret’s syndrome
complicated by distal ileus after laser lithotripsy using Holmium:
YAG laser. BMC Gastroenterol. 2002;2(15).
27. Goldstein EB, Savel RH, Pachter HL. Successful treatment of Bou-
veret Syndrome using holmium: YAG laser Lithotripsy. Am Surg.
2005;71(10):882-885.
28. Gemmel C, Weikert U, Eickhoff A. Successful treatment of
gallstone ileus (Bouveret’s syndrome) by using extracorporeal
shock wave lithotripsy and argon plasma coagulation. Gastroin-
test Endosc. 2007;65(1):173-175.
5/22/2012 5:35:18 PM

Bile Duct and Gallbladder Tumors
T. Peter Kingham and Michael D’Angelica
Bile duct and gallbladder tumors are rare. Traditionally these have
been thought of as diseases with poor prognoses. This viewpoint
exists because these diseases frequently present late in their dis-
ease course and often with disseminated disease. Furthermore,
chemotherapy has traditionally had limited successes. In late
stage bile duct and gallbladder cancer this pessimism is warranted
given the low survival rates. Surgical treatments, however, have
been shown to be effective in some well selected patients. In these
patients, given improvements in staging, imaging, and surgical
resections, long-term disease-free survival is now possible.
1. How do patients with biliary tract tumors commonly present?
Gallbladder cancer and bile duct tumors have distinct risk factors
that can help raise suspicion of their diagnosis. The risk factors for
gallbladder cancer are cholelithiasis, chronic inflammation, cal-
cification in the wall of the gallbladder, and gallbladder polyps.
Cholelithiasis exists in 75% to 90% of patients with gallbladder
cancer.1,2 Gallstones and gallbladder cancer may, however, simply
have similar risk factors instead of a cause-and-effect relationship.
Although most (close to 90%) gallbladder cancer specimens con-
tain stones, the incidence of gallbladder cancer in the population
of patients with stones is only 0.3% to 3%. Longstanding inflamma-
tion (porcelain gallbladder) traditionally has been associated with a
higher risk of gallbladder cancer, but modern series have shown an
incidence of less than 10%.3,4 There is some suggestion of an ade-
noma to carcinoma progression in the development of gallbladder
cancer. There is often severe dysplasia and carcinoma in situ adja-
cent to gallbladder carcinomas.1 Most small gallbladder polyps,
however, are pseudopolyps with no increased risk of malignancy.
Adenomatous gallbladder polyps are distinctly uncommon. 5,6
Current practice recommendations are to perform cholecystec-
tomy for gallbladder polyps >1 cm in size because of a small but
significantly increased risk of malignancy.
Although the great majority of cholangiocarcinoma cases in
the United States have no underlying risk factors, there are sev-
eral conditions associated with an increased incidence of cho-
langiocarcinoma. In the United States, the most common risk
403
PMPH_CH51.indd 403
CHAPTER 51
factor for cholangiocarcinoma is primary sclerosing cholangi-
tis (PSC). In a Swedish series of 305 patients with PSC followed
up for more than 5 years, 8% of patients eventually developed
cancer while occult cholangiocarcinoma has been reported in
40% of autopsy specimens and 36% of liver explants from
patients undergoing orthotopic liver transplantation for PSC.7
The incidence of bile duct cancer in patients with congenital
biliary cystic disease is also substantial (15–20%), especially in
patients who are not treated until after age 20 years.8 Biliary
para sites (Clonorchis sinensis, Opisthorchis viverrini) are endemic
in parts of Asia and are also associated with an increased risk
of cholangiocarcinoma.9
There are three common clinical scenarios for gallbladder
cancer: (1) final pathology after routine cholecystectomy iden-
tifies gallbladder cancer; (2) gallbladder cancer is discovered
intraoperatively; and (3) gallbladder cancer is suspected prior to
surgery.10 Gallbladder cancer is notorious for being asymptomatic
in its early stages. Careful history taking often shows a history of
constant right-upper quadrant pain rather than the typical pain
of biliary colic. The diagnosis of gallbladder cancer should be
considered in an elderly patient with constant right-upper quad-
rant pain with weight loss or anorexia, or both. The presence of
a palpable mass or jaundice is an ominous fi nding and predicts a
high rate of unresectability. In a report by Hawkins et al.,11 82 of
240 patients (34%) presented with jaundice. Of these 82 patients,
only 6 (7%) were resectable, and all 6 of these patients experi-
enced recurrence or died of disease within 2 years. The early
symptoms of cholangiocarcinoma are nonspecific. Abdominal
pain, anorexia, weight loss, and pruritus are the most common,
but are seen only in about one-third of patients. Fever is rarely
seen at initial presentation, but is common once biliary manip-
ulation is initiated. Ultimately, most patients come to medical
attention with the development of jaundice. Intrahepatic cholan-
giocarcinomas are often diagnosed after an intrahepatic mass is
found on abdominal imaging.
Laboratory examination often is not helpful except for the typ-
ical signs of advanced disease, such as anemia, hypoalbuminemia,
leukocytosis, and elevated alkaline phosphatase or bilirubin.12,13
5/22/2012 5:35:55 PM
 404 ■ Surgery: Evidence-Based Practice
The only tumor markers studied that are of any potential value
with gallbladder cancer are carcinoembryonic antigen (CEA) and
CA 19-9. An elevated CEA tends to be specific for gallbladder
cancer (90%), but lacks sensitivity (50%) when used as a screen-
ing test in cancer patients compared with patients with benign
gallbladder diseases.14 CA 19-9 is more consistent as a marker for
gallbladder cancer with sensitivities and specificities of approxi-
mately 75% at a level greater than 20 U/mL.15 Many cholangio-
carcinomas express CEA and CA 19-9 as well. CA 19-9 can be
falsely elevated in a jaundiced patient. Serum levels of these mark-
ers, although elevated in some patients, have had little diagnostic
value, but can be helpful in follow-up after complete resection and
normalization.9 In jaundiced patients, the total bilirubin level may
suggest an etiology. In patients with obstruction from cholangio-
carcinoma, the serum bilirubin level often achieves levels greater
than 10 mg/dL and averages 18 mg/dL, whereas patients with
obstruction from choledocholithiasis have bilirubin levels 2 to
4 mg/dL and rarely greater than 15 mg/dL; however, there is likely
to be considerable overlap.
2. What are the optimal diagnostic tests to evaluate patients
with biliary tract masses?
It is important to try to establish the diagnosis and the extent of
disease with imaging to minimize the number of patients who have
to undergo a nontherapeutic surgical exploration. In addition to
the modalities available for examining the liver, chest radiographs,
or computed tomography (CT) scan should be obtained during
the complete staging work-up to rule out pulmonary metastases.
It is, however, rare to find pulmonary metastases without locally
advanced or intra-abdominal metastatic disease.16 Percutane-
ous biopsy is generally only used to provide a tissue diagnosis in
patients who have metastatic or unresectable disease.
Ultrasonography is an excellent first imaging modality for
the gallbladder and liver. Findings such as discontinuous mucosa,
echogenic mucosa, and submucosal echolucency are more com-
mon in early gallbladder malignancy compared with benign
gallbladder disease. Doppler assessment of blood flow can help
to differentiate early malignancy from benign disease.17 One ret-
rospective study reported that in 203 patients with gallbladder
cancer, a mass was identified in 177 (87%) of patients on preop-
erative ultrasound (US).18 US was limited, however, in identify-
ing regional lymph node metastases. For cholangiocarcinomas,
experienced ultrasonagraphers can show the level of biliary ductal
obstruction, but also may be able to provide information regard-
ing tumor extension within the bile duct and in the periductal
tissues.
Cross-sectional imaging with CT or magnetic resonance imag-
ing (MRI) is an important part of the preoperative assessment
of biliary tumors. These techniques provide crucial information
about the local extent of disease and whether distant metastases
are present. In patients with gallbladder cancer, the most com-
mon finding on CT is a mass involving all or part of the gallblad-
der. Extension into local organs, particularly the liver, usually can
be discerned. In one study of patients with gallbladder masses,
asymmetrical wall thickening was found in 45% of patients, a
mass replacing the gallbladder was found in 35% of patients, and
an intraluminal mass was found in 20% of patients.19 Assessment
of regional and distant lymph nodes is important and can be done
with CT. CT is also an important study for evaluating patients with
PMPH_CH51.indd 404
biliary obstruction. A high-quality CT scan can provide valuable
information regarding level of obstruction, vascular involvement,
and liver atrophy.
The utility of MRI for evaluating patients with biliary tract
tumors has increased in recent years. Invasive diagnostic cholan-
giography has largely been replaced by MRI cholangiography in
most high-volume centers.20 Analyses of MRI for the assessment
of gallbladder cancer have shown sensitivities of 70% to 100% for
hepatic invasion and 60% to 75% for lymph node metastases.20,21
MRI cholangiopancreatography (MRCP) is a powerful investiga-
tive tool for initial preoperative assessment of hilar cholangio-
carcinoma. Several studies have shown its utility in evaluating
patients with biliary obstruction.22 MRCP not only may identify
the tumor and the level of biliary obstruction, but also may reveal
obstructed and isolated ducts not appreciated at endoscopic or
percutaneous study. MRCP also provides information regarding
the patency of hilar vascular structures, the presence of nodal or
distant metastases, and the presence of lobar atrophy.
Most gallbladder cancers are positron emission tomography
(PET)-avid, so theoretically PET imaging can help differentiate
between benign and malignant tumors and diagnose extra-hepatic
spread.23 PET is more accurate in diagnosing metastatic disease
than CT scan. In 41 patients with gallbladder cancer at Memo-
rial Sloan-Kettering Cancer Center (MSKCC) PET results altered
surgical management in 23% of patients during preoperative stag-
ing (for either the initial operation or reresection after incidental
finding of cancer after cholecystectomy) compared with 10% in
patients evaluated for recurrent disease.24
Endoscopic retrograde cholangiopancreatography (ERCP) is
a useful tool for assessing biliary tract strictures in patients who
require biliary interventions, as it permits visualization of the bili-
ary tree with the opportunity for treatment and collection of speci-
mens for cyto- and histopathologic evaluation. Obstruction of the
mid–bile duct with occlusion of the cystic duct on endoscopic cho-
langiography all suggest gallbladder carcinoma. The finding of a
smooth, tapered stricture on cholangiography suggests a benign
stricture. Biliary drainage should not be routinely performed in
patients who are surgical candidates.
3. How does staging of biliary tract tumors affect preoperative
planning and treatment options?
When a biliary tract malignancy is suspected on clinical and radio-
graphic grounds, patient evaluation should turn toward an assess-
ment of tumor resectability and assessment of hepatic and overall
physiologic reserve. The presence of significant comorbid condi-
tions, chronic liver disease, or portal hypertension generally pre-
cludes resection. Over the years, a variety of staging systems for
gallbladder cancer have been proposed based on prognostic clinical
and pathologic factors. The American Joint Committee on Cancer
(AJCC) tumor depth nodal status metastases (TNM) staging (6th
edition) of gallbladder cancer is the standard reporting mechanism
for gallbladder cancer studies in the literature. In 2010, the 7th edi-
tion was published and is the preferred staging system clinically.
Preoperative staging assists the surgeon in deciding optimal sur-
gical management. The standard resection for most patients with
resectable gallbladder cancer is an extended cholecystectomy that
includes segments 4b and 5 with a regional portal lymphadenec-
tomy. In some cases major hepatic resection or bile duct resection
may be necessary due to the location of the tumor.
5/22/2012 5:35:55 PM

For gallbladder cancer, the AJCC 6th edition uses TNM to
place patients into four stages based on pathologic and radiographic
findings. The 7th edition was issued in 2010 with stage groupings
that were changed to correlate with resectability and patient out-
come. Locally unresectable T4 tumors are classified as Stage IV and
the N classification has changed. N1 nodes are lymph nodes adja-
cent to the cystic duct, bile duct, hepatic artery, and portal vein.
Regional (N2) nodes are celiac, periduodenal, and peripancreatic
nodes. Lymph node metastasis is now classified as Stage IIIB (N1)
or stage IVB (N2) disease.
For cholangiocarcinoma, historically there was no clinical
staging system available that stratifies patients preoperatively
into subgroups based on potential for resection. This preoperative
stratification is important for intraoperative planning, because
intrahepatic cholangiocarcinomas are generally treated with liver
resections, hilar cholangiocarcinomas are treated with liver and
bile duct resections, and distal cholangiocarcinomas are treated
with a pancreaticoduodenectomy. AJCC TNM stage system is
based largely on pathologic criteria and has little relevance to pre-
operative staging since it can only be determined after resection.
Jarnagin et al. proposed a system to predict resectability, one that
improves characterization of tumor extent by taking into account
all of the available preoperative data related to local tumor extent,
as follows: (1) extent of tumor within the biliary tree, (2) vascular
involvement, and (3) lobar atrophy.25 Using such an approach, it
is possible to stage tumors preoperatively in a way that correlates
with resectability and outcome.
This preoperative clinical staging system has been compared
with the AJCC classification in a series of 87 patients with cholan-
giocarcinoma, with no correlation seen between AJCC stage and
resectability or median survival.25 By contrast, the proposed stag-
ing system correlated closely to resectability, which was highest in
the T1 group (59%) and decreased progressively to 0 in the T3
group. The clinical T stage grouping was an independent predic-
tor not only of resectability, but also of the likelihood of achieving
an R0 resection.
Patients with hilar cholangiocarcinoma almost always require
major liver resection, so their preoperative management must be
optimized carefully. Obstructive jaundice associated with perihi-
lar cholangiocarcinoma differs from that associated with middle or
distal bile duct cancer, as it often requires multiple biliary drainage
catheters of the future liver remnant (FLR). For both endoscopic
and percutaneous biliary drainage, the intrahepatic bile duct of
the predicted FLR is intubated or punctured and subsequently
drained. Preoperative biliary drainage improves cholestatic liver
disease and affords safer performance of hepatectomy for hilar
cholangiocarcinoma; especially when the FLR is small.
Portal vein embolization (PVE) has become an important
consideration in the presurgical management of patients who are
to undergo extensive liver resection. The ultimate goal of PVE is
to minimize postoperative liver dysfunction by inducing com-
pensatory hypertrophy in the FLR. In right PVE, the volume of
the left lobe increases by 130 cm3 on average within 2 weeks after
embolization, and the estimated resection volume decreases by
an average of approximately 10%.26 Biliary drainage is required
prior to PVE if the biliary tree is obstructed on the side to be
embolized. A single prospective trial in nonjaundiced patients
undergoing right hemi-hepatectomy demonstrated a benefit in
patients with chronic liver disease, but no benefit in patients with
normal livers.27
PMPH_CH51.indd 405
Bile Duct and Gallbladder Tumors ■ 405
4. What are the results for resection of biliary tract tumors?
If the diagnosis of gallbladder cancer is made by frozen section
in the operating room the operating surgeon should prepare for a
curative resection or arrange for transfer of the patient to an experi-
enced hepatobiliary surgeon. Although not ideal management, this
situation may not affect outcomes, as a study at MSKCC reported
outcomes after prior noncurative resection were similar to out-
comes from primary curative resections.28 Ouchi et al. reported on
498 patients diagnosed with gallbladder cancer after laparoscopic
cholecystectomy. They found 34% had T1a tumors, 14% had T1b,
41% had T2, 8% had T3, and 2% had T4 tumors.29
T1 GALLBLADDER TUMORS
T1 tumors typically are diagnosed incidentally in cholecystectomy
specimens because they are usually not obvious on imaging stud-
ies. By definition, they do not penetrate through the muscular layer,
and because a simple cholecystectomy dissects the perimuscular
layer, this operation theoretically should be curative. With T1a
tumors, if margins are negative, standard cholecystectomy cures
85% to 100% of patients.30,31 Controversy exists with T1b tumors.
Principe et al. demonstrated a 50% 1-year survival in patients with
T1b gallbladder cancers after simple cholecystectomy.31,32 Other
series, however, report cure rates for T1b tumors as 90% to 100%
at 5 years.33 These results are similar to the published results for
extended cholecystectomies for T1b tumors, with survival rates
above 90% at 5 years. In a fit patient, it is recommended to treat
T1b tumors with a segment 4b,5 liver resection with portal node
dissection given the association of liver resection with improved
survival in some retrospective series.
T2 TUMORS
T2 tumors are those most likely to benefit from an extended resec-
tion of the liver and porta hepatis lymph nodes. Because these tumors
also are difficult to diagnose preoperatively, they also are commonly
diagnosed incidentally at cholecystectomy. The dissection plane of
a simple cholecystectomy in the subserosal plane is often involved
with tumor, resulting in a positive margin for many T2 tumors. In
addition, approximately one-third of patients with T2 tumors have
nodal metastases, reinforcing the need for a regional lymphadenec-
tomy for diagnostic and potentially therapeutic purposes.34 Based
on retrospective comparisons survival is significantly improved in
patients undergoing an extended cholecystectomy and this opera-
tion is standard of care for patients with T2 tumors.
T3/T4 TUMORS (LOCALLY ADVANCED)
The most controversial aspect of the surgical treatment of gallblad-
der cancer involves patients with nonmetastatic locally advanced
tumors. Since the 1990s, numerous small series have documented
that with varying levels of extended resections, long-term survival
is possible in highly selected patients. Japanese surgeons liberally
use extensive surgical procedures, including vascular resection,
bile duct resection, extended hepatectomy, and hepatopancreat-
icuoduodenectomy.35-37 When extensive lymph node dissections are
5/22/2012 5:35:55 PM
 406 ■ Surgery: Evidence-Based Practice
performed routinely and survival results may be a reflection of
stage migration and better staging. Western series also have begun
to show similar results with an aggressive surgical approach. In
our own series from MSKCC, approximately 25% of patients with
locally advanced disease had long-term survival; usually accounted
for by the significant fraction of patients with lymph node negative
disease.28 These results, however, must be interpreted in the proper
context. Overall, most patients with locally advanced disease have
metastatic disease, and resection is usually not possible. The most
important associated prognostic factor in every series is the status
of lymph nodes. Long-term survival is rarely found with distant
lymph node disease and is uncommon with hepatoduodenal lymph
node metastases.
Long-term survival can be achieved with an acceptable opera-
tive mortality in patients with cholangiocarcinoma as well.25
For distal cholangiocarcinomas a pancreaticoduodenectomy
required for adequate resection. For hilar cholangiocarcinomas
and intrahepatic cholangiocarcinomas a liver resection is requ-
ired to obtain an R0 resection. Five-year survival rates range
from 25% to 40%. The status of the resection margins is crucial to
obtaining such results. Several studies have shown that patients
resected with negative histologic margins survive significantly
longer than patients with involved margins.25,38 Hepatic resec-
tion is often critical to obtain negative margins. In addition to
the status of the resection margin, many other variables have
been shown to have an impact on outcome, including tumor
involvement of regional lymph nodes, tumor grade or differen-
tiation, and tumor morphology (e.g., papillary versus nodular-
sclerosing). 25 The issue of lymph node metastases, their impact
on outcome, and extent of lymphadenectomy remain points of
some controversy.
5. What is the role of adjuvant therapies for biliary tract tumors?
The rarity of biliary tract cancers has precluded large randomized
trials, and the literature abounds in small case series and retro-
spective comparisons that attempt to address whether adjuvant
chemotherapy or radiation or both are beneficial after complete
resection. In a study from MSKCC, it was found that 85% of gall-
bladder cancer recurrences included distant sites, 39 highlighting
the importance of systemic therapies.
There is only one randomized trial that examined the role
of adjuvant chemotherapy in patients with biliary tract tumors.
Takada et al.40 reported a phase III multi-institutional trial of
adjuvant chemotherapy performed in Japan. This trial included
508 patients with biliary and pancreatic cancers. On subset analy-
sis, this study included 140 gallbladder cancer patients who were
randomized to receive surgical resection alone or resection plus
adjuvant mitomycin C and 5-fluorouracil (5-FU). In considering
only the gallbladder cancer patients, the actuarial 5-year disease-
free survival favored the adjuvant chemotherapy group (20.3%)
when compared with the surgery alone group (11.6%, p = .02).
Data regarding the extent of surgical resection and histologic
staging were lacking, making it difficult to interpret these encour-
aging results. Th is study found no benefit of adjuvant systemic
5-FU and mitomycin compared with surgery alone for patients
with bile duct carcinoma.
There are several retrospective studies that have examined
the outcomes of patients treated with adjuvant chemotherapy
after resection for gallbladder cancer. One such series from Mayo
PMPH_CH51.indd 406
Clinic analyzed 73 patients, 25 of whom received adjuvant chemo-
radiotherapy.41 Adjuvant chemoradiotherapy was a significant
predictor of improved overall survival after adjusting for prognos-
tic factors (T and N stage, histologic findings). In general, the use
of adjuvant chemotherapy and or radiation after complete resec-
tion of gallbladder or biliary cancers is unproven and used on an
individualized basis.
6. What palliative options are available to treat patients with
unresectable biliary tract tumors?
A common problem in patients with biliary tract cancers is pallia-
tion, because most patients are unresectable at presentation. The
most common symptoms to palliate include pain, jaundice, and
bowel obstruction. In the past, operative approaches provided
the most effective relief of obstruction in well-selected pati-
ents. In patients who are symptomatic from obstructive jau ndice
with pruritus or cholangitis, endoscopic or percutaneous inter-
ventions are the preferred approach for palliation and mini-
mizing morbidity.42-44 Saluja et al.45 randomized 44 patients
with gallbladder cancer and obstructive jaundice to percuta-
neous or endoscopic stenting. They found successful stenting
occurred in 89% of patients in the percutaneous group com-
pared with 41% in the endoscopic group (p < .001). Cholangi-
tis was also significantly higher (48%) in the endoscopic stent
group compared with the percutaneous group (11%; p = .002).
The mortality rates were similar between the two groups, but
percutaneous stenting in this trial offered better palliation than
endoscopic stenting. Radiation therapy may also be an effec-
tive palliative therapy for locally advanced disease. Radiation
therapy is generally well tolerated, may have an impact on
local symptoms, and is usually combined with chemotherapy.46
Operative biliary-enteric bypass, either open or laparoscopic,
will provide excellent relief of jaundice and can be performed
with an acceptably low morbidity and mortality. Patients who
are found to have unresectable disease at the time of operative
exploration should be considered for a biliary-enteric bypass if
technically feasible.
When considering biliary drainage in patients with malignant
biliary obstruction in the proximal biliary tree the overall prog-
nosis, specific symptoms and complexity of the stricture must be
considered. If symptoms are manageable and the overall prognosis
is poor, management without drainage should be considered. In
general, patients in need of palliative procedures for symptom-
atic proximal biliary tract cancers have high rates of complica-
tions and early death due to disease after palliative procedures. A
prospective study from MSKCC included 109 patients undergoing
percutaneous biliary drainage for malignant obstruction.47 There
was a 58% rate of major complication and two procedure-related
deaths. The 8-week postprocedure mortality rate was 28%; largely
due to progressive malignancy. These palliative procedures were
successful in alleviating pruritus, but quality of life measures con-
tinued to decline.
Recently, gemcitabine-based regimens, often combined with
a platinum agent, have become the drug of choice for oncologists
in treating patients with unresectable and metastatic gallblad-
der or biliary cancer. A recently published randomized Phase III
study of gemcitabine compared with gemcitabine with cisplatin
for metastatic gallbladder and bile duct cancer has established
the combination therapy as standard of care.48 Four hundred and
5/22/2012 5:35:55 PM
 Bile Duct and Gallbladder Tumors ■ 407

ten patients with locally advanced or metastatic gallbladder can- SUMMARY

cer, cholangiocarcinoma, or ampullary cancers were randomized
with overall survival as the primary endpoint. After a median
follow-up of 8 months, there was a significant difference in overall
survival, with a hazard ratio of 0.57 to 0.61 for in patients with
gallbladder cancer, intrahepatic cholangiocarcinoma, and extra-
hepatic cholangiocarcinomas favoring the gemcitabine-cisplatin
combination.48 Another smaller randomized controlled trial of
gemcitabine combined with oxaliplatin (GEMOX) showed a simi-
lar benefit when the gemcitibine regimen was compared with 5-FU
or best supportive care in patients with unresectable or metastatic
gallbladder cancer. Median overall survival was 9.5 months in the
GEMOX group (n = 27), compared with 4.6 months in the 5-FU
group (n = 28; p = .039).
Improvements in high-resolution cross-sectional imaging have
permitted better patient selection and preoperative planning and
preparation prior to the safe performance of operations for hilar cho-
langiocarcinoma. Long-term disease-free survival, rather than pal-
liation, is now the primary goal of operative resection. Judicious use
of adjunctive preoperative interventions including biliary drainage
and PVE may help to improve outcomes especially when major peri-
and postoperative complications are anticipated. Selection of appro-
priate nonoperative therapies for palliation of unresectable tumors
arising from the proximal and distal bile ducts should be tailored
according to the patient’s expected longevity and technical expertise of
the multi-disciplinary team charged with treating bile duct cancer.

Clinical Question Summary

Question
1 How do patients with
biliary tract tumors
commonly present?
2 What are the optimal
diagnostic tests to
evaluate patients with
biliary tract masses?
3 How does staging of
biliary tract tumors
affect preoperative
planning and treatment
options?
4 What are the results
for resection of biliary
tract tumors?
5 What is the role of
adjuvant therapies for
biliary tract tumors?
6 What palliative options
are available to
treat patients with
unresectable biliary
tract tumors?
Answer Level of Grade of References
Evidence Recommendation
Early symptoms are nonspecific. Jaundice, 3 B 1-15
weight loss, and abdominal pain are all
presenting symptoms.
US is a useful first imaging study. This can 3 B 16-25
be followed by CT scan or MRI. MRCP
has replaced ERCP for diagnostic imaging.
Biopsy of resectable tumors is not
necessary.
Staging determines which patients are 3 C 26, 27
candidates for surgical resection.
Staging tests can provide information to
determine the need for PVE or biliary
drainage.
For patients with resectable gallbladder 3 B 28-38
cancers, median survival is approximately
13 months. Lymph node positivity is an
important prognostic factor. For hilar
cholangiocarcinomas and intrahepatic
cholangiocarcinomas a liver resection is
required to obtain an R0 resection. Five-
year survival rates after resection range
from 25% to 40%.
There are limited data to recommend 1B C 39-41
adjuvant therapy. One randomized
trial showed a benefit with adjuvant
chemotherapy. Several retrospective
series suggest an association between
adjuvant therapy and improved survival.
Gemcitabine-based regimens, often 1B A 42-48
combined with a platinum chemotherapy,
have shown an improved overall survival
in patients with metastatic biliary tract
tumors. There are endoscopic and
percutaneous biliary drainage procedures
that can successfully palliate most
patients.

PMPH_CH51.indd 407 5/22/2012 5:35:55 PM

 408 ■ Surgery: Evidence-Based Practice
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Bile Duct and Gallbladder Tumors ■ 409
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5/22/2012 5:35:55 PM
 CHAPTER 52
Obstructive Jaundice: Transhepatic
and Endoscopic Interventions
Brian J. Dunkin
INTRODUCTION
A large variety of biliary and pancreatic pathologies cause jaun-
dice. Gallstones, pancreatic malignancy, and biliary malignancy
are the most common reasons for obstructive jaundice and this
chapter focuses on the nonsurgical management of these diseases.
It is estimated that 6 per 100,000 people in the United States are
afflicted with common bile duct (CBD) stones and that over 57,000
people per year are diagnosed with malignancy of the pancreas or
biliary tree.1
Percutaneous transhepatic cholangiography (PTC) was des-
cribed as early as 1937 by Huard-Du, but did not gain widespread
use until the introduction of the Chiba needle by Okuda of Japan
in 1973.2 In 1968 McCune, Shorb, and Moskovitz performed the
first endoscopic retrograde cholangiopancreatography (ERCP).3
The procedure was done intraoperatively using a modified endo-
scope with an external channel taped to the side. Their cannula-
tion success rate was 25%. Since these initial reports both PTC and
ERCP have evolved into sophisticated diagnostic and therapeutic
procedures. This chapter reviews the best evidence for using these
modalities to manage jaundice from obstruction of the biliary tree.
It is divided into three sections: CBD Stones, benign CBD strictures,
and malignant CBD strictures.
CBD STONES
Stones in the CBD are the most common cause of obstructive
jaundice. ERCP has become a mainstay of management with suc-
cessful clearance of the CBD approaching 100% in experienced
programs. Questions that arise around CBD stone management
center on how to predict their presence, discerning effective non-
invasive and invasive modalities for visualizing them, and when
to apply endoscopic or surgical therapies.
1. What is the best way to predict CBD stones?
In patients with symptomatic cholelithiasis it would be useful to
have a noninvasive way to predict the presence of CBD stones to help
410
PMPH_CH52.indd 410
guide therapy. Patients with no CBD stones could proceed directly
to cholecystectomy, while those with stones could have preop-
erative ERCP. An accurate prediction strategy would assure that
patients who do not require ERCP will not get it and those that
do have CBD stones are not inadvertently missed or discovered
incidentally during surgery.
Single-risk factors examined to predict CBD stones focus on
individual factors such as elevated liver function tests (LFTs) or a
dilated CBD on ultrasound. Elevated bilirubin alone as a risk fac-
tor has a 31% to 56% sensitivity, 48% to 99% specificity, with a pos-
itive predictive value (PPV) of 42% to 95%.4-12 Studies vary as to
what is considered an abnormal bilirubin ranging from anything
above the normal limits as listed by a laboratory to greater than
three times normal. In general, the sensitivity of an elevated bili-
rubin is low, specificity higher, and PPV relatively high. Abnormal
LFTs other than bilirubin have also been studied and sensitivities,
specificity, and PPV values vary. A tradeoff is noted between sen-
sitivity and specificity with cutoff values chosen for high specific-
ity decreasing sensitivity. Dilated CBD (range >5 to >10 mm) on
ultrasound has a sensitivity of 28% to 94%, specificity of 72% to
98%, and PPV of 28% to 91%.12,13
Four studies have looked at multivariable risk factors for
predicting CBD stones with one of the four testing their model
prospectively.10,12-14 This prospective evaluation by Trondsen et al.
demonstrated 94% sensitivity and 84% specificity.12 Despite the
apparent excellent performance of multivariable risk-factor models
for predicting CBD stones, they have not become widely integrated
into clinical practice.
Studies have also investigated the ability to predict the
absence of CBD stones by studying whether or not an absence
of any of the previously mentioned factors predicts no CBD
stones.9,11-16 In the absence of any abnormality in LFTs or CBD
dilation by ultrasound there is 0.25% to 7% chance of having
a CBD stone which is comparable with the 0% to 17% negative
predictive value of ERCP.
Answer: The best method of predicting CBD stones based on
laboratory and ultrasound evidence is to look for an absence of
abnormality (i.e., normal LFTs and no CBD dilation on ultrasound).
5/22/2012 5:36:36 PM
 Obstructive Jaundice: Transhepatic and Endoscopic Interventions
This strategy has a negative predictive value comparable with diag-
nostic ERCP. Multivariable risk-factor formulas also have good
accuracy, but have not been widely adopted in clinical practice.
Univariate factor analysis has the least accuracy. (Level 2 evidence;
Grade B recommendation).
2. How does diagnostic ERCP compare with noninvasive imaging
modalities?
Understanding the accuracy of diagnostic ERCP in identify-
ing CBD stones serves as a comparison with other noninvasive
modalities. However, most studies compare various diagnostic
modalities with ERCP making it impossible to know the real
performance of ERCP itself. Sugiyama et al.17 compared diag-
nostic ERCP with ERCP with endoscopic sphincterotomy (ES)
and balloon sweep of the CBD in the same patient when a stone
was thought to be found, and demonstrated a 100% sensitivity
of ERCP to discover stones. This compares with 90% sensitivity
for magnetic resonance cholangiopancreatography (MRCP) and
endoscopic ultrasound (EUS), and 71% for computed tomographic
cholangiography (CTC).17-31
Answer: Because of the excellent performance of MRCP and
EUS in detecting CBD stones, ERCP should not be used as a diag-
nostic tool alone particularly given its associated higher rate of
potential complications. CTC is not as accurate as MRCP and
EUS. (Level 2 evidence; Grade B recommendation).
3. What is the optimal treatment of suspected CBD stones: pre/
postoperative ERCP or intraoperative cholangiogram (IOC)
and CBD exploration?
There are essentially three options for managing patients with a
possible CBD stone: (1) preoperative ERCP and duct clearance
followed by cholecystectomy; (2) IOC with laparoscopic com-
mon bile duct exploration (LCBDE) if stones are found; and
(3) IOC with cholecystectomy and postoperative ERCP if CBD
stones are found.
Chung et al.32 investigated preoperative ERCP versus post-
operative ERCP in gallstone pancreatitis patients who had CBD
stones identified on IOC. Both strategies were successful at clear-
ing CBD stones in all patients, but over half of the patients having
preoperative ERCP had a negative study. Hospital length of stay
(LOS) and costs were higher in the preoperative ERCP group.
Cuschieri et al. 33 prospectively studied preoperative ERCP
versus IOC and LCBDE. Both techniques were successful in
clearing the CBD stones 84% of the time, but hospital LOS
was shorter in the LCBDE group. Interestingly, more patients
were converted to open surgery in the LCBDE group com-
pared with preoperative ERCP, but this did not reach statistical
significance.
Rhodes et al. compared LCBDE with postoperative ERCP on
those patients with CBD stones identified on IOC.36 Both tech-
niques had similar success in clearing the CBD of stones, but the
LOS was three times longer for the postoperative ERCP group.
Answer: The efficacy to clear CBD stones and procedure-
related morbidity are essentially equal among the three strategies.
However, IOC followed by LCBDE is more cost effective with
shorter LOS. Given that both ERCP and LCBDE are operator-
dependent procedures, the strategy employed at any single insti-
tution must take into account the available expertise. (Level 2
evidence; Grade B recommendation).
PMPH_CH52.indd 411
■ 411
4. What is the expected success rate of ERCP to clear CBD stones
and can it serve as definitive therapy?
The success rate to clear CBD stones using ERCP and sphinc-
terotomy plus balloon or basket extraction is operator depen-
dent. Carr-Locke et al. 34 reported a greater than 90% success
rate with a 5% complication rate and 1% mortality. Other stud-
ies reported 75% to 100% initial success with a 93% to 100% final
clearance rate. 33,35,36 The National Institutes of Health (NIH)
state-of-the-science statement on ERCP reports that success-
ful ERCP and CBD clearance should be achieved 90% of the
time. 37
Some have investigated if ERCP, ES, and clearance of the CBD
alone can serve as definitive therapy without having to remove the
gallbladder in patients that are at high surgical risk. Targarona
et al.38 compared ERCP with open cholecystectomy and CBDE
and found that ERCP had a higher initial failure rate, readmission
rate, and more complications from biliary disease, but the LOS
and immediate morbidity was lower in the ERCP group. Trias
et al.39 compared ERCP with laparoscopic cholecystectomy in the
same cohort of high-risk patients and found more long-term bil-
iary complications, readmissions, and need for repeat surgery in
the ERCP group. LOS and immediate morbidity were similar
in both groups.
Answer: ERCP for removal of CBD stones should be success-
ful at least 90% of the time (Level 2 evidence; Grade B recom-
mendation). There is limited data on the use of ERCP alone for
definitive management of CBD stones, but the available studies
indicate that open or laparoscopic cholecystectomy can be per-
formed in these high-risk patients with acceptable short-term
morbidity and equivalent mortality to that of ERCP with less
recurrence of biliary symptoms or need for hospital readmission.
It is reasonable to choose ERCP for definitive therapy in patients
deemed too ill to tolerate cholecystectomy understanding that
some studies put the 5-year risk of serious biliary complications
leading to cholecystectomy at 10% to 15%.40 (Level 3 evidence;
Grade C recommendation).
5. Can ERCP with ES and/or stent placement be used to palli-
ate pregnant women with CBDS until after delivery?
Gallstone disease is common during pregnancy with acute
cholecystitis being the second most common nonobstetric
emergency in pregnant women. Given that there is an increased
risk for complications to the fetus when these patients undergo
general anesthesia and abdominal surgery, it may be advanta-
geous to clear the CBD using ERCP and rely on ES and/or biliary
stenting to protect the patient from further attacks of choledo-
cholithiaisis or gallstone pancreatitis until after delivery of the
baby. There are no prospective studies examining this question
and the literature reports only institution case series. However,
there is some data on using ERCP with ES and stone extrac-
tion versus placement of a biliary stent to manage CBD stones
in high-risk, nonpregnant patients that may support using these
techniques during pregnancy. Chopra et al.41 compared biliary
stent placement to ES and stone extraction in patients with CBD
stones that were at high risk for surgery because of advanced
age or debilitating dementia. The rate of immediate complica-
tions was similar in each group, but the ES group had less bil-
iary complications at 20 months compared with the stent group
(14% vs. 36% p < .03).41
5/22/2012 5:36:36 PM
 412 ■ Surgery: Evidence-Based Practice
Since ERCP uses ionizing radiation, which can lead to chro-
mosomal mutations, neurologic abnormalities, mental retarda-
tion, and increased risk of childhood leukemia, exposure to the
fetus must be minimized. Fetal mortality is greatest when expo-
sure occurs in the first week of conception and it is recommended
that the cumulative radiation dose to the conceptus during preg-
nancy be less than 5 to 10 rads.42 Multiple studies report that
ERCP can be accomplished using little to no radiation at minimal
risk to the fetus.43
Answer: There is no high-level data investigating the use of
ERCP with ES and/or stent placement to palliate CBD obstruc-
tion from stones until after pregnancy. Case series data on man-
aging nonobstetric high-risk surgery patients with ERCP and ES
or stenting report a significant rate of biliary complications at 20
months with less from ES than stenting. When performing ERCP
in pregnant patients, radiation exposure should be kept below
10 rads which can be easily accomplished in experienced hands.
(Level 3 evidence; Grade C recommendation).
6. What is the best method of gaining access to the CBD
following Roux-en-Y gastric bypass?
The rise of the surgical management of morbid obesity has resulted
in an increase in the number of patients with CBD pathology that
have altered foregut anatomy. The Roux-en-Y gastric bypass is the
most common procedure for morbid obesity and gaining endo-
scopic access to the ampulla of Vater after this procedure is chal-
lenging. There is no consensus as to the best approach to manage
these patients with the literature reporting only case reports and
small case series.
There are four approaches to gaining access to the biliary
system post Roux-en-Y gastric bypass. Intraoperative ERCP with
laparoscopic access to either the gastric remnant or the pancreati-
cobiliary limb is perhaps the most common method. The surgeon
gains access to the gastric remnant, creates a gastrotomy, and then
works with the endoscopist to introduce the duodenoscope across
the gastric wall, through the gastrotomy, and into the duodenum.
A similar approach can be used via the jejunum either at a de novo
jejunostomy or through an opening created in the entero-entros-
tomy. In nonemergent conditions, percutaneous access to the gas-
tric remnant has also been described with placement of a temporary
gastrostomy tube. Over a number of weeks, the tube is upsized
until the opening is large enough to accommodate a pediatric
duodenoscope. ERCP is then performed working through the
gastrostomy tube tract.44 Another method of access is via PTC.
A skilled interventional radiologist can often gain access even to
nondilated bile ducts, but is limited in the therapy that can be
delivered for managing CBD stones. Finally, enteroscopy can be
used to gain retrograde access to the ampulla of Vater. Th is may
be performed with a pediatric colonoscope, push enteroscope,
balloon enteroscope, or with the assistance of an overtube
device. Th is method is limited not only by the difficulty in navi-
gating the entero-enterostomy and traveling retrograde up to
the second portion of the duodenum, but also by the limitation
of ERCP tools that can be introduced through a colonoscope or
enteroscope.
Answer: There is no consensus in the literature about the best
approach to the papilla of Vater after Roux-en-Y gastric bypass.
The choice of approach depends on available expertise and equip-
ment. (No Level 1, 2, or 3 evidence; no recommendation).
PMPH_CH52.indd 412
BENIGN CBD STRICTURES
Benign strictures of the CBD may occur from a variety of causes,
but most frequently from chronic pancreatitis with compression
of the intrapancreatic portion of the CBD or from anastomotic
strictures related to bilio-enteric or bilio-bilio anastomosis.
This section explores the endoscopic management of these
strictures.
7. Can biliary strictures from chronic pancreatitis be relieved
with dilation and stenting?
Bile duct strictures from chronic pancreatitis can be difficult to
manage endoscopically with long-term success rates as low as
10%.45,46 Calcifications in the pancreatic head predicts an even
worse outcome of 7.7% at 1 year.46 Results can be improved if mul-
tiple stents are placed side-by-side and left in place for up to 14
months.47 Using this technique with up to five stents placed simul-
taneously, Catalano et al.47 were able to achieve 100% success in
normalizing LFTs with no episodes of cholangitis at 4.2 years mean
follow-up. More recently, self-expanding metal stents (SEMS) have
been used to treat benign biliary strictures. These stents may be
uncovered, partially covered, or fully covered. Published data
using SEMS for benign biliary strictures is limited to small single-
institution series and case reports. However, based on this available
data, plastic stents appear to be more efficacious than uncovered
SEMS, and partially or fully covered SEMS seem to be equivalent
to multiple plastic stents in patency and require less endoscopic
interventions.48-50
Answer: Benign biliary strictures from chronic pancreatitis
can be successfully managed with endobiliary stenting, but require
placement of multiple plastic stents left in place for up to 14 months.
The data is evolving on the use of partially or fully covered SEMS
for this purpose, but preliminary reports are encouraging. Calci-
fications at the head of the pancreas may predict worse outcomes.
(Level 2 evidence; Grade B recommendation).
8. How does management of biliary strictures from primary
sclerosing cholangitis (PSC) and anastomotic stenosis compare
with chronic pancreatitis?
Biliary strictures from PSC respond well to endoscopic management
and seem less refractory to treatment than those from chronic pan-
creatitis. They may be treated with dilation alone or in combination
with stenting. Limited published data is available on the optimal
approach, but it appears that balloon dilation alone is most effective
with stent placement increasing the risk of complications and cho-
langitis.51 Dilation of dominant strictures from PSC may improve
survival, but does not delay liver transplant.52 These strictures should
also be brushed or biopsied to ensure they are not malignant.53
Benign postoperative anastomotic bile duct strictures are also
amenable to endoscopic management and are less refractory to
treatment than those from chronic pancreatitis. Long-term clinical
success rates range from 55% to 88% overall.54 Bile duct strictures
after liver transplant may be successfully managed with dilation
and stenting with reports as high as 91% to 100% success early after
transplant; however, late postoperative strictures may be less ame-
nable to this mode of treatment with as low as 8% success.55-57
Answer: Biliary strictures from PSC are more amenable to
dilation alone when compared with strictures from chronic pan-
5/22/2012 5:36:36 PM
 Obstructive Jaundice: Transhepatic and Endoscopic Interventions
creatitis, and placement of a stent in these patients is not necessary
and may increase the risk of cholangitis. Postoperative anasto-
motic biliary strictures are also amenable to a combination of
dilation and stenting with early strictures responding better than
late. (Level 3 evidence; Grade C recommendation).
MALIGNANT CBD STRICTURES
Approximately 30,000 new cases of pancreatic cancer and 7000
cases of biliary tract cancer are diagnosed each year in the United
States. Many of these patients are not candidates for surgery and
decompression of the biliary tree may be an important factor in
their palliation. This chapter explores issues related to stenting of
the bile duct in the face of malignant obstruction.
9. Should a patient with jaundice from pancreas cancer undergo
biliary drainage prior to surgical resection?
Patients with pancreatic cancer often present with obstructive
jaundice. Radiologic imaging is the first step in evaluation to
determine if they have a lesion in the head of the pancreas. If so,
and if they are surgical candidates, will preoperative ERCP and
biliary decompression improve their outcome? Seven studies in
the literature examine this question, four nonrandomized and
three randomized.58-64 Some of the evidence is of poor method-
ologic quality, but all data fail to show a benefit of preoperative
ERCP and stenting. The technical success of gaining decompres-
sion appears to be high at 87% to 94% with all studies showing a
significant decrease in hyperbilirubinemia.64 Hospital LOS either
overall or pre/postoperatively is not clearly impacted by preopera-
tive biliary decompression. Perioperative mortality is not impacted
either. Van der Gaag et al.63 demonstrated that total complications
(pre/postoperative, endoscopic, surgical) were increased in the
preoperative stent group (47% vs. 37%). Sewnath et al.59 reported
no difference in postoperative complications, but a 6% stent com-
plication rate. Heslin et al.61 reported only postoperative compli-
cations with a higher rate in the stent group (59% vs. 34%).
Answer: There is no benefit to preoperative stenting of the
obstructed biliary tree in pancreatic cancer patients who are sur-
gical candidates. In fact, the data suggest that preoperative stent-
ing may result in more perioperative complications and should
not be performed routinely, but only in those cases with acute
cholangitis or intense pruritis in whom surgery may be delayed.
(Level 2 evidence; Grade B recommendation).
10. What is the best method of biliary decompression in hilar
cholangiocarcinoma: ERCP or PTC?
Primary cholangiocarcinoma is an uncommon malignancy in
the United States with poor prognosis. Hilar cholangiocarcino-
mas (Klatskin’s tumor) account for up to half of these cases and
are often inoperable. As a result, treatment centers on decompres-
sion of the obstructed biliary tree to improve liver function and
relieve pruritis so as to improve quality of life. Biliary decom-
pression may be complex in these patients because of the high
location of the lesion and potential involvement of intrahepatic
ducts. Endoscopic retrograde biliary drainage (ERBD), exter-
nal percutaneous transhepatic biliary drainage (EPTBD), and
internal biliary stenting via the PTBD tract (IPTBD) are the
PMPH_CH52.indd 413
■ 413
strategies commonly reported in the literature and all have been
used successfully. The optimal method of drainage, however, is
not universal, but rather depends on the Bismuth classification
of the tumor involvement.65 Lee et al.66 investigated the outcomes
of these three drainage techniques based on the Bismuth clas-
sification of tumor. Th is retrospective review did not include any
patients with Bismuth Type I tumors. Overall, 91% of patients
gained relief from their jaundice with no differences among the
procedures or Bismuth types (II–IV) for Bismuth Type II lesions.
There was no difference in patency rates among the three meth-
ods of drainage. ERBD and IPTBD were superior to EPTBD for
Bismuth Type III, and IPTBD was best for Bismuth Type IV, par-
ticularly when factoring quality of life and patency of drainage
in comparison to EPTBD. The authors recommend ERCP with
stent as the first line of therapy for Bismuth Types II and III and
IPTBD for Bismuth Type IV.
There is debate in the literature on whether bilateral or uni-
lateral drainage is better for Klatskin’s tumor. The worst outcomes
are in patients who have cholangiographic opacification of both
lobes of the liver, but drainage of only one side leading to cho-
langitis.67 If care is taken to drain ducts that have been opacified
on cholangiography, the data do not show a clear superiority to
placement of more than one stent. As a result, it has been argued
that unilateral stent placement using the easiest duct that can be
accessed for drainage should be selected.68
Answer: The best method of drainage of the biliary tract in
Klatskin’s tumor is dependent on the Bismuth classification. Bis-
muth Type II lesions are equally amenable to endoscopic or percu-
taneous transhepatic drainage. Bismuth Type III lesions are best
managed with either endoscopic drainage or a hybrid approach
using both PTC and ERCP to place an endobiliary stent. Bismuth
Type IV lesions do best with the hybrid approach. (Level 3 evidence;
Grade C recommendation).
11. Are plastic or metal stents best for biliary decompression
in malignancy?
Two randomized controlled trials have investigated this question.
Davids et al.69 randomized 115 patients with distal CBD obstruc-
tion from malignancy to receive plastic stents or SEMS. Prat et al.70
randomized 101 patients into three arms: SEMS, plastic stent with
scheduled changes, and plastic stent with change as needed based
on LFTs and symptoms. Both studies report excellent results in
all arms in placing the stents and gaining initial relief of jaundice.
Both studies demonstrated longer patency rates with SEMS ver-
sus plastic with Davids et al.69 reporting SEMS remaining patent
twice as long (9.1 vs. 4.2 months). Periprocedure mortality related
to biliary complications was similar in both groups as was sur-
vival and stent exchange as needed versus on a scheduled basis
did not seem to increase morbidity or mortality. Use of SEMS also
required less ERCPs than plastic and less hospital days with Prat
et al.70 reporting lower cost.
Answer: Use of SEMS for CBD obstruction from malignancy
results in longer patency rates, less procedures, hospital days,
and cost, and similar periprocedure morbidity and long-term
mortality when compared with routine plastic stent exchange.
Change of plastic stents on an as needed basis seems to be equiva-
lent to scheduled exchange with the potential for fewer proce-
dures and hospital days and lower cost. (Level 1 evidence; Grade A
recommendation).
5/22/2012 5:36:36 PM
 414 ■ Surgery: Evidence-Based Practice

12. Is per oral choledochoscopy helpful in defining CBD
strictures of unclear etiology?
Per oral choledochoscopy is a method of directly visualizing the
lumen of the CBD during ERCP. A choledochoscope is introduced
through the working channel of the ERCP duodenoscope and
passed under direct and fluoroscopic vision across the papilla of
Vater and into the CBD. In this configuration the duodenoscope
is called the “mother” scope and the choledochoscope the “daugh-
ter” scope. Traditionally this has been a demanding procedure
requiring two expert endoscopists and use of a daughter scope
that is expensive and fragile. Recent technologic developments
have enabled the procedure to be performed by one endoscopist
with a more functional choledochoscope which even enables
pinch biopsy.
The ability to directly examine the lumen of the CBD has led some
to investigate whether this approach could help better define stric-
tures of unknown etiology. Choledochoscopy with biopsy, brush-
ing, and even augmented visualization using chromoendoscopy
and narrow-band imaging have all been utilized to evaluate CBD
strictures.71 Unfortunately, all reports in the literature about cho-
ledochoscopy are case reports or small case experience series with
no comparative data.
Answer: Although per oral choledochoscopy is feasible, can be
performed safely, and holds promise as a better method of evaluat-
ing CBD strictures of unclear etiology, there is no high-level com-
parative data that proves it is superior to other any other modality.
(No Level 1, 2, or 3 evidence; no recommendation).
SUMMARY
This chapter examined the literature around 12 important questions
related to managing CBD obstruction and jaundice from either
stone disease or stricture. It should serve as a guide to managing
patients with these disease processes and as a basis for identifying
gaps in the literature where further study is needed.

Clinical Question Summary

Question
1 What is the best way to
predict CBD stones?
2 How does diagnostic
ERCP compare with
noninvasive imaging
modalities?
3 What is the optimal
treatment of suspected
CBD stones: pre/
postoperative ERCP
or IOC and CBD
exploration?
4 What is the expected
success rate of ERCP
to clear CBD stones
and can it serve as
definitive therapy?
5 Can ERCP with ES and/
or stent placement
be used to palliate
pregnant women
with CBDS until after
delivery?
Answer Level of Grade of References
Evidence Recommendation
Look for an absence of abnormality 2 B 4-16
(i.e. normal LFTs and no CBD dilation
on ultrasound). Negative predictive
value comparable to diagnostic ERCP.
Multivariable risk-factor formulas also
have good accuracy. Univariate factor
analysis has the least accuracy.
Because of the excellent performance of 2 B 17-31
MRCP and EUS in detecting CBD stones,
ERCP should not be used as a diagnostic
tool alone particularly given its associated
higher rate of potential complications.
CTC is not as accurate as MRCP and EUS.
IOC followed by LCBDE is more cost 2 B 32-33
effective with shorter lengths of stay than
pre/postoperative ERCP. Given that both
ERCP and LCBDE are operator-dependent
procedures, the strategy employed at any
single institution must take into account
the available expertise.
ERCP for removal of CBD stones should 2, 3 B, C 33-39
be at least 90% successful. Open or
laparoscopic cholecystectomy is preferred
in high-risk patients because of acceptable
short-term morbidity and equivalent
mortality to that of ERCP with less
recurrence of biliary symptoms or need
for hospital readmission.
Data limited to case reports. ERCP can 4 C 41-43
be done safely in pregnant women with
minimal risk to the fetus.

(Continued)

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 Obstructive Jaundice: Transhepatic and Endoscopic Interventions ■ 415

(Continued)
Question Answer Level of Grade of References
Evidence Recommendation
6 What is the best method There is no consensus in the literature about 4 C 44
of gaining access to the the best approach to the papilla of Vater
CBD following Roux- after Roux-en-Y gastric bypass. The choice
en-Y gastric bypass? of approach depends on available expertise
and equipment.
7 Can biliary strictures Benign biliary strictures from chronic 2 B 45-50
from chronic pancreatitis can be successfully managed
pancreatitis be relieved with endobiliary stenting but require
with dilation and placement of multiple plastic stents left in
stenting? place for up to 14 months. Calcifications
at the head of the pancreas predict worse
outcomes.
8 How does management Biliary strictures from PSC are more 3 C 51-57
of biliary strictures amenable to dilation alone when
from PSC and compared to strictures from chronic
anastomotic stenosis pancreatitis, and placement of a stent in
compare with chronic these patients may increase the risk of
pancreatitis? cholangitis. Postoperative anastomotic
biliary strictures are also amenable to a
combination of dilation and stenting
with early strictures responding better
than late.
9 Should a patient There is no benefit to preoperative stenting 2 B 58-65
with jaundice from of the obstructed biliary tree in pancreatic
pancreas cancer cancer patients who are surgical
undergo biliary candidates.
drainage prior to
surgical resection?
10 What is the best Bismuth type II lesions are equally 3 C 65-68
method of biliary amenable to endoscopic or percutaneous
decompression in hilar transhepatic drainage. Bismuth type III
cholangiocarcinoma: lesions are best managed with either
ERCP or PTC? endoscopic drainage or a hybrid
approach using both PTC and ERCP to
place an endobiliary stent. Bismuth IV
lesions do best with the hybrid
approach.
11 Are plastic or metal Metal stents result in longer patency 1 A 69, 70
stents best for biliary rates, less procedures, hospital days,
decompression in and cost, and similar periprocedure
malignancy? morbidity and long-term mortality
when compared to routine plastic
stent exchange.
12 Is per oral Per oral choledochoscopy is feasible, N/A N/A 71
choledochoscopy can be performed safely, and holds
helpful in defining CBD promise as a better method of
strictures of unclear evaluating CBD strictures of unclear
etiology? etiology. There is no high-level
comparative data that proves it is
superior to other any other modality.

PMPH_CH52.indd 415 5/22/2012 5:36:36 PM

 416 ■ Surgery: Evidence-Based Practice
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PMPH_CH52.indd 418 5/22/2012 5:36:36 PM
 PART VIII

THE PANCREAS

PMPH_CH53.indd 419 5/22/2012 5:37:13 PM

PMPH_CH53.indd 420 5/22/2012 5:37:13 PM

Acute Pancreatitis
Acute pancreatitis (AP) is responsible for approximately 250,000
hospital admissions per year in the United States alone and its
incidence is rising.1 The spectrum of disease can range from a
self-limiting process to one that may be life-threatening and
require therapeutic intervention. Recurrent disease can occur
on the basis of two less common disorders: Sphincter of Oddi
dysfunction (SOD) and pancreas divisum (PD). 2 These entities
are often difficult to assess, diagnose and treat. Further, results
of endoscopic and surgical intervention for these diseases are
often less than enviable and thus it is imperative that patient
selection for therapeutic intervention be defi ned as precisely as
possible.
Severe pancreatitis defi ned as organ failure persisting
beyond 72 h and/or complications, such as pseudocyst formation
or necrosis occurs in 10% to 20%, may require surgical interven-
tion and is associated with substantial morbidity and mortality. 3,4
Early therapeutic intervention in this cohort is imperative to
stabilize the patient physiologically, mitigate infectious compli-
cations and maintain metabolic needs. Although management
relative to the early resuscitative phase of severe AP has been well
delineated, other treatment algorithms have more recently been
challenged.
1. What is the role of early endoscopic retrograde cholang-
iopancreatography (ERCP) in acute biliary pancreatitis?
The need for, and timing of ERCP in biliary pancreatitis has been
a subject of controversy. The vast majority of stones will pass
spontaneously into the duodenum and thus will neither worsen
the degree of pancreatitis nor present a risk for the development
of concurrent cholangitis. Indeed, early ERCP may exacerbate
pancreatitis. However, cholangitis developing in the face of severe
AP would most certainly contribute to morbidity and mortality
favoring early endoscopic evaluation. Perhaps more controversial
is the role of early ERCP in ameliorating the degree of pancreatitis
and the ensuing inflammatory cascade. Several randomized con-
trolled studies and meta-analyses have addressed these issues that
are key in the management of these often critically ill patients.
421
PMPH_CH53.indd 421
CHAPTER 53
Stephen W. Behrman
In an early study, Neoptolemos et al.5 prospectively random-
ized 121 patients with presumed biliary pancreatitis to early (< 72 h
from admission) ERCP with sphincterotomy and stone extraction
if necessary versus conservative management alone with selec-
tive ERCP “if it was indicated.” The severity of pancreatitis was
assessed via the modified Glascow criteria with severe disease
defined as a score of 3 or higher. Interpretation of the data in this
study is somewhat clouded by the fact that gallstones could not be
confirmed in 18 patients despite the availability of ultrasound and
computed tomography. With this limitation in mind, early ERCP
was successful in 52 of 59 (88%) patients and choledocholithiasis
was confirmed in 19 (32%) (vs. 3 of 14 (21%) in the conservative
group) and successful stone extraction was accomplished in all.
Early ERCP was associated with a statistically significant decrease
in disease-related complications (pseudocyst, organ failure) and a
reduction (not significant) in mortality in those with severe, but
not mild, pancreatitis.
Fan et al.6 studied the role of ERCP in AP of all causes (pre-
dominantly biliary) in a prospective randomized trial of 197
patients. The purpose of this study was to compare the efficacy
of early (<24 h) ERCP with papillotomy if stones were identified
versus initial conservative treatment with ERCP ± papillotomy
reserved for those with clinical deterioration defi ned as fever,
tachycardia, worsening leukocytosis and/or an increase in bili-
rubin. Outcome was assessed on the basis of local and systemic
complications as well as death. Severe pancreatitis was defined
as a Ranson score of 4 or higher. Impacted stones were found in
37 of 97 (38%) patients having early ERCP. In contrast, 27 of 98
patients initially followed conservatively required ERCP for dete-
rioration, with stones found in the common bile duct or ampulla
in only 12 (12%) confirming that the vast majority of stones pass
spontaneously. Complications were higher in those with initial
conservative treatment (29% vs. 18%), but this difference was not
significant. With the exception of those developing cholangitis in
the conservative group (8 vs. 0 patients), other complications did
not differ dramatically. Mortality was higher in those treated con-
servatively (9 vs. 5 patients), but did not reach statistical signifi-
cance. All deaths occurred in those with severe pancreatitis—the
5/22/2012 5:37:13 PM
 422 ■ Surgery: Evidence-Based Practice
vast majority of who had no stone found on endoscopic evalu-
ation. Early ERCP did not seem to either worsen or improve
the progression of pancreatitis. The authors, surprisingly, con-
clude that emergency ERCP is indicated in all patients with AP
although their data seems to suggest otherwise.
Folsch et al.7 conducted a prospective, randomized, multi-
center study comparing early ERCP (<72 h) versus conservative
management in those with acute biliary pancreatitis without evi-
dence of obstructive jaundice. Disease severity was measured by
the modified Glasgow criteria (>3 severe). Indications for ERCP in
the conservatively managed group were similar to those described
by Fan et al. Fift y-eight of 126 patients undergoing early ERCP had
documented bile duct stones versus 13 of 112 in the conservative
group. Of note, 22 of 112 patients in the conservatively managed
group developed indications for ERCP and the incidence of cho-
ledocholithiasis in this cohort was 60 percent. Overall, morbidity
and mortality did not differ between groups including the risk of
developing pancreatic-related complications such as pseudocyst
and necrosis. The authors conclude that early ERCP is not indi-
cated in those with acute biliary pancreatitis in the absence of
clinical evidence of biliary obstruction or sepsis.
In a more recent study, Oria et al.8 examined the role of early
(<48–72 h) ERCP in those presenting with acute gallstone pan-
creatitis and evidence of biliopancreatic obstruction defined as a
common bile duct >8 mm or serum bilirubin >1.2 mg/dL. Impor-
tantly, patients with clinical evidence of cholangitis (Charcot’s
triad) were excluded as this condition was felt to mandate early
ERCP in this randomized, prospective study. Severe pancreatitis
was defined as an APACHE II score >6. The specific aims of this
study were to determine if early ERCP could reduce the severity
of pancreatitis and thereby limit organ failure and complications
of pancreatitis. The safety of early endoscopy was also assessed.
Fift y-one of 103 patients were randomized to early ERCP with
choledocholithiasis noted on 47 (72%) successful cannulations
with minimal complications. When comparing the two groups,
early clearance of the common duct did not reduce organ failure,
local complications of the pancreas or mortality in either mild or
severe pancreatitis. The authors concluded that early ERCP did
not alter the course of acute gallstone pancreatitis and was not
indicated in the absence of cholangitis. Two recent meta-analyses
have yielded the same conclusions while recognizing the hetero-
geneity of patient populations, enrollment criteria, the arbitrary
assignment of mild and severe pancreatitis and the definition of
“early” ERCP.9,10
A slightly contrasting conclusion was reached in a group of
patients with severe AP (Apache II score > 8) reported by van
Santvoort et al.11 in a prospective multicenter observational study
where the decision to perform early ERCP (within 72 h) was at the
discretion of the treating physician. Patients with frank cholangi-
tis were excluded. Those with “cholestasis” (defined as bilirubin
>2.3 mg/dL and/or dilated common bile duct with a temperature
<38.6°C) were compared with those without. Although overall
complications were significantly reduced in the early ERCP group
with cholestasis, organ failure, infected pancreatic necrosis, the
need for operation, and hospital length of stay were no different.
This study was a subset analysis of a previous report from these
institutions on the utilization of probiotics in AP that demon-
strated a negative outcome. This author’s conclusion that compli-
cations are reduced with early ERCP in severe AP associated with
cholestasis is somewhat misleading.
PMPH_CH53.indd 422
In conclusion, ERCP has proven to be safe when performed
in the face of acute biliary pancreatitis. If performed early, the
incidence of choledocholithiasis is substantially higher than if
ERCP is performed selectively when there is evidence of persis-
tent biliary obstruction based on routine radiologic and chemi-
cal analysis. However, in studies to date, early clearance of the
common bile duct has not correlated with a reduction in organ
failure, pancreatic-related complications or mortality. For these
reasons, in the absence of cholangitis or evidence of persistent bil-
iary obstruction, early ERCP in gallstone pancreatitis is not rec-
ommended. (Grade A recommendation)
2. What is the role of prophylactic antibiotics in severe AP?
Severe pancreatitis, by any grading system, is associated with a
substantial risk for the development of pancreatic fluid collections
and/or pancreatic necrosis as defi ned by the Atlanta Classifica-
tion.3 If these processes remain sterile, there is a good probability
that patients will recover without the need for operative inter-
vention. In contrast, secondary pancreatic infections mandate
the need for operative drainage and debridement, markedly
increase hospital length of stay and are associated with signifi-
cant morbidity and mortality.12 In theory, prophylactic antibiot-
ics in those with severe AP might prevent the progression of a
sterile process into an infected milieu. Questions remain if this
mode of therapy is chosen. When should antimicrobial therapy
be initiated and for how long? In addition, there may be a price
to pay for such a strategy including antibiotic associated colitis
and the potential selection of resistant or fungal organisms given
prolonged therapy that may increase, rather than protect against,
the risk for mortality.13 The fluoroquinolones and carbapenems
have formed the basis of clinical studies investigating the role
of antimicrobial prophylaxis in severe pancreatitis due to their
superior concentrations in the pancreatic bed likely on the basis
of their liposolubility.14,15
In an early, small multicenter, nonblinded trial, Penderzoli
et al.16 randomized 74 patients with pancreatic necrosis noted on
CT scan within 72 h of admission to medical management alone
versus the addition of prophylactic imipenem-cilastin for 14 days
(41 patients). Mean Ranson criterion for all patients was 3.7 and
about one-half had pancreatitis on the basis of biliary disease.
More patients receiving prophylaxis had >50% necrosis (14 vs. 2).
Only five patients receiving antimicrobial prophylaxis developed
pancreatic sepsis (confirmed by culture) statistically different than
those medically managed. However, mortality and the need for
surgical debridement of the pancreas did not differ. Curiously, in
addition to the five septic patients in the prophylaxis group, seven
additional patients had laparotomy for reasons not stated. Culture
data on those with pancreatic sepsis suggests that prophylaxis did
not select out resistant organisms.
Isenmann et al.17 performed a multicenter, randomized,
placebo-controlled, double-blind study on the effect of ciprofloxa-
cin and flagyl, administered for a minimum of 14 days, in prevent-
ing infected pancreatic necrosis and thereby reducing mortality.
One hundred and fourteen patients with severe AP defi ned as a
C-reactive protein level (CRP) >150 mg/L and or the presence of
pancreatic necrosis on contrast-enhance CT and entering within
72 h of admission were analyzed. Study patients were converted
to open antibiotic therapy if extra or de novo pancreatic sepsis
was documented, multiple organ failure developed or CRP levels
5/22/2012 5:37:13 PM

increased. The etiology of pancreatitis was predominantly biliary
and alcohol related. Of the 58 patients randomized to antibi-
otic prophylaxis, only 16 required conversion to open anti-
microbial administration versus 26 in the placebo group—a
significant difference. However, the incidence of secondary and
extra-pancreatic infections was not different nor was the mortal-
ity rate. Approximately one-half of the isolates in both groups
with infected necrosis were gram positive organisms. However,
it was not noted how these isolates were obtained—open ver-
sus percutaneous. Thus, because empiric antibiotic treatment
did not lead to development of resistant or fungal organisms, it
failed to prevent pancreatic and systemic infections and it did
not reduce mortality in this study. It should be noted, however,
that the initial power analysis called for a study population of 200
patients assuming an incidence of pancreatic infection of 40%.
Surprisingly, this study was terminated after an interim analysis
because, the authors state, infected pancreatic necrosis occurred
in 7/53 treated patients versus 5/52 receiving placebo and this was
a reverse trend. Certainly it could be argued that study recruit-
ment should have continued.
Dellinger et al.18 reported a multicenter similarly designed
study and patient population to that of Isenmann comparing
prophylactic meropenem infusion to placebo in 40 patients each
within 5 days of onset of severe AP and delivered for 7 to 21 days.
In contrast to the study by Isenmann, most patients in this study
had >30% pancreatic necrosis documented by CT consistent with
severe disease. The incidence of pancreatic infection, the number
of operative interventions on the pancreas and the mortality rate
was not different between groups. The utilization of prophylaxis
did not increase the incidence of resistant organisms with gram
positive and negative flora predominating. The authors concluded
the antibiotic prophylaxis did not reduce septic pancreatic infec-
tions in those with severe AP. This study again did not reach its
desired power analysis assuming an incidence of pancreatic infec-
tion of 40% and it was not continued to reach the desired number
of patients due to a “restriction of resources.”
Two small, randomized controlled studies yielded conclu-
sions similar to Dellinger et al. Garcia-Barrasa et al.19 random-
ized 46 antibiotic naive patients with severe AP (defined by the
Atlanta criteria3) and CT documented pancreatic necrosis to cip-
rofloxacin (within 10 days) for a 10-day treatment versus placebo
in a double-blind, placebo-controlled trial. Of the 41 patients
completing study protocol-infected necrosis, organ failure, the
need for operation and mortality was not different between
groups. Fourteen patients crossed over to open antibiotic therapy
due to established infected necrosis or progressive organ dysfunc-
tion diminishing meaningful results in this study. Xue et al.20
randomized 56 well-matched patients with severe AP defined as
>30% necrosis by CT criteria reaching study entry within 72 h of
presentation to imipenem-cilastin for 7 to 14 days or placebo. The
incidence of pancreatic infection, the need for operative debri-
dement, organ failure, and mortality were not different between
groups. Recent meta-analyses have yielded similar findings that
antibiotic prophylaxis does not reduce the morbidity and mortal-
ity of severe AP.21-23
To summarize, the utilization of prophylactic antibiotics
in severe necrotizing pancreatitis is well tolerated and may alter
the flora recovered if infection ensues, but is not associated with
the development of resistant organisms. Randomized, double-
blinded, placebo-controlled studies to date have failed to recruit
PMPH_CH53.indd 423
Acute Pancreatitis ■ 423
enough patients to establish a statistically significant difference, if
it exists, between prophylaxis and placebo. It is unlikely that given
the low incidence of severe pancreatitis as well as the heteroge-
neity of patients and the treatment they receive that future stud-
ies might improve on those reported to date. Given the inherent
morbidity and mortality associated with infected necrosis, anti-
microbial prophylaxis could be considered in those with severe
pancreatitis and significant necrosis if there is evidence of organ
failure or hemodynamic instability, but studies to date would sug-
gest otherwise. (Grade B recommendation)
3. Is gastric feeding safe and equivalent to jejunal feeding
in AP?
Nutritional support in severe AP is vital due to the local and sys-
temic inflammatory response that increases metabolic demands
resulting in hypercatabolism.24 In an attempt to “rest” the pan-
creas and not worsen its severity, hyperalimentation has tradition-
ally provided the backbone of therapy. It has long been recognized
that enteral nutrition is superior to the parenteral route in terms
of immune competence, metabolic homeostasis and reducing the
overall cost of therapy.25 Most recently, the paradigm that enteral
feeding in severe pancreatitis exacerbates the disease or will not
be tolerated has been challenged. The utilization of this mode of
nutritional support, however, must not present its own set of com-
plications and it must demonstrate superior outcomes to standard
therapy with TPN. Nasojejunal tube placement typically requires
either radiologic or endoscopic advancement, and bedside place-
ment can be utilized but is cumbersome and time consuming.26
When compared with TPN, careful utilization of jejunal feedings
is well tolerated, reduces the inflammatory response of AP, reduces
infectious morbidity and is less expensive. Clinical improvement
with respect to the need for operative intervention, a shorter hos-
pital length of stay and disease-related mortality remains sparse
but promising due to the small number of patients reported in
comparative studies to date.27-30 With the aforementioned benefits
of jejunal feedings a reasonable extrapolation would be to sim-
plify the limitations of tube placement by feeding directly into
the stomach. Several clinical trials have compared these routes of
administration.
Eatock et al.31 randomized 49 well-matched patients with
severe AP defi ned as an Imrie score >3, and APACHE II score >6
or a CRP >150 mg/dl to nasogastric (NG) versus endoscopically
placed nasojejunal (NJ) feedings beginning within 72 h of onset
of symptoms. All but one patient tolerated the enteral route and
the majority of patients in both groups were receiving at least
75% of goal calories within 48 h of initiation of feedings. Groups
did not differ with respect to follow-up APACHE II scores, CRP
levels or pain analog scales and mortality was not statistically
different (24.5% of study population). Gastrointestinal compli-
cations were equivalent between groups. One patient required
repeat endoscopy to replace an NJ tube. The authors conclude
that NG feeding is simpler, less expensive and equivalent to the
NJ route.
Kumar et al.32 randomized 31 evenly matched patients with
severe AP defined as organ failure and an APACHE II score >8 or
Balthazar score >7 to NG (n = 15) or NJ (placed endoscopically)
feedings. Importantly, patients in shock (systolic blood pressure
< 90 mmHg) were appropriately excluded and feedings were
gradually increased over a 7-day period. Patients were assessed for
5/22/2012 5:37:13 PM
 424 ■ Surgery: Evidence-Based Practice
study accrual up to 4 weeks after onset of symptoms—a delay in
initiation that might allow better tolerance of feedings. No patient
required TPN once the goal rate of feeding was achieved (day 7).
When compared with the NJ route, NG feedings were associated
with similar rates of pancreatic infection and operative interven-
tion and the LOS and mortality was not different between groups.
Anthropometric and nutritional parameters declined regardless of
route of administration and complications were similar. Neither
modality exacerbated pancreatitis. The authors conclude that both
routes of administration when gradually delivered are well toler-
ated but fail to reverse the catabolism associated with the disease.
Eckerwall et al. 33 compared NG feedings with TPN in 48
well-matched patients with severe AP defined as an APACHE II
score >8 and/or a CRP level >150 mg/dL. The goal of the study
was to assess the impact of nutrient delivery on the inflamma-
tory response of AP during the first 10 days of illness. Nutri-
tional support was started within 24 h of admission with a target
goal reached in 66% of the entire population with no difference
between groups. No patient receiving NG feeds had aspiration.
EndoCab concentrations decreased equally in both groups during
the study period. Only one patient in the entire series required
operative pancreatic surgery. The authors concluded that NG
feedings were tolerated well in those with predicted severe AP, but
did not attenuate the inflammatory response associated with the
disease when compared with TPN.
In summary, these preliminary studies suggest that NG
feeding seems to be tolerated as well as NJ feeding in those with
severe AP in the hemodynamically stable patient without exacer-
bating the disease process provided close assessment of tolerance
is made. Tube placement is easier and less costly. The relationship
of NG feedings to a decline in secondary pancreatic infections
and disease-related mortality has yet to be ascertained. (Grade B
recommendation)
4. Can preoperative testing accurately predict the success of
biliary sphincteroplasty and pancreatic septoplasty in sphinc-
ter of Oddi dysfunction?
SOD is defi ned as a benign outflow obstruction of the ampulla
of Vater resulting in episodic abdominal pain mimicking more
common biliary and pancreatic pathology. The derangements
associated with the sphincter may be anatomic (stenosis) or
physiologic (incomplete relaxation) in nature. The exact etiology
is unknown but commonly implicated factors include choledo-
cholithiasis, instrumentation of the ampulla and pancreatitis to
name a few. The discomfort may be accompanied by abnormal
Table 53.1 Contemporary Classification of Sphincter of Oddi Dysfunction
Type Biliary SOD
Type I 1. Biliary type pain (lasting 30 min and occurring at least
once per year)
2. Elevated AST/ALT on two occasions
3. Dilated CBD (>12 mm), or delayed biliary drainage
(>45 min)
Type II Biliary type pain and at least one additional factor above
Type III Biliary type pain alone
PMPH_CH53.indd 424
laboratory and radiologic fi ndings such as elevated liver function
tests or amylase and dilation or delayed drainage of the biliary
or pancreatic ductal system. A classification of SOD based on
clinical and radiologic paramenters was proposed by Hogan and
Geenen (Table 53.1).34 Sphincter of Oddi manometry (SOM) is
invasive and has a defined rate of iatrogenic induced pancreati-
tis of 10% to 25%, but is the most accurate tool for diagnosis. A
variety of provocative tests have been studied as potential less
invasive substitutes for SOM. Because the diagnosis can be elu-
sive, it is crucial that a methodical preoperative assessment uti-
lizing discrete clinical, laboratory, radiologic, and manometric
findings be undertaken prior to consideration of therapeutic
intervention. If not, results will be less than satisfactory and
recurrent pain—predictable.
CLINICAL ASSESSMENT
Sherman et al.35 assessed the accuracy of clinical parameters in
diagnosing pancreatic SOD when compared with manometric
findings defined as a sphincter pressure greater than 40 mmHg.
In 168 patients with idiopathic pancreatitis, abnormal manom-
etry correlated with Type 1 pancreatic clinical parameters in 92%.
In contrast, Type II and III cohorts had abnormal measurements
in only 58% and 32% of patients, respectively, suggesting this pro-
cedure was an important adjunct in directing therapy in these
groups. Although the results of therapeutic intervention were not
reported, these data suggest that in those patients meeting type 1
criteria for SOD—manometry is unnecessary prior to proceeding
with therapeutic intervention.
PROVOCATIVE ASSESSMENT
Noninvasive testing has been utilized in an attempt to diagnose
SOD and predict the success of therapeutic intervention while
reducing the need of SOM and its inherent risk of pancreatitis.
The morphine neostigmine provocative (Nardi) test was assessed
in 290 of 446 patients having surgical sphincteroplasty by Madura
et al.36 A positive test was defined as reproduction of symptoms or
a fourfold increase in enzyme levels. In this study, postinjection
symptoms occurred in 91%, but only 47% had lipase levels elevated
fourfold or greater. Of the 71 patients having repeat testing post-
operatively, enzyme levels were reduced significantly from base-
line. While a subset analysis specific to those having the Nardi test
Pancreas SOD
1. Recurrent pancreatitis or pain suspected of pancreatic
origin
2. Elevated amylase or lipase
3. Dilated pancreatic duct or delayed emptying of the
pancreatic duct
Presumed pancreatic pain and at least one additional factor
above
Pancreatic type pain alone
5/22/2012 5:37:13 PM

was not performed, overall 83% of the patients in this series had
an excellent or good result following surgical decompression. In
a study by Geenen et al.,37 only 7 of 35 patients with type II SOD
documented by manometry had a positive Nardi test—four of
who had normal manometric pressures suggesting that this study
may be inaccurate in this cohort.
The accuracy of secretin-stimulated magnetic resonance pan-
creatography (MRP) defined as pancreatic duct dilation ≥1 mm
from baseline when compared with SOM to accurately diagnose
SOD was assessed by Aisen et al.38 Thirty patients with type II and
III classification had both MRP and SOM. MRP was unreliable in
predicting SOD and demonstrated poor sensitivity and specificity
when compared with SOM. Although data with respect to thera-
peutic intervention in those with SOD in this study was lacking,
these findings suggest that secretin-stimulated MRP is not helpful
in the assessment of this disease.
Cholecystokinin scintigraphy has been utilized to assess pos-
tcholecystectomy pain. Parameters analyzed have included hepatic
hilum to duodenal transit time and percentage of common bile
duct emptying. Craig et al.39 studied 29 patients with type II and III
criteria following cholecystectomy subjected to both scintigraphy
and SOM. When compared with the eight with positive SOM, scin-
tigraphy lacked sensitivity and specificity. The authors concluded
that scintigraphy was not useful in the diagnosis of SOD.
MANOMETRIC ASSESSMENT
The ability of abnormal manometry to predict success following
endoscopic sphincterotomy for SOD was assessed by Geenen et al. 37
Entry criteria for this prospective, randomized, double-blind
study included type II SOD criteria, previous cholecystectomy,
abdominal pain, and clinical evidence suggestive of biliary
obstruction. Patients received endoscopic retrograde cholan-
giopancreatography (ERCP) and either true or sham biliary
sphincterotomy and most were followed for 4 years. Sphinc-
terotomy resulted in improvement in pain scores in 10 of 11
patients with elevated pressures. In contrast, only 3 of 12 with
elevated pressure receiving the sham procedure improved. Th is
latter group of patients crossed over to formal sphincterotomy
at 1 year. At study completion, 17 of 18 with SOD verified by
manometry remained pain-free. In patients with normal sphinc-
ter pressure, sphincterotomy offered no advantage over those
receiving placebo. These data suggest that SOM is effective at
distinguishing those that will and will not improve following
endoscopic sphincterotomy.
In conclusion, provocative testing in those with suspected
SOD cannot reliably differentiate those that will and will not ben-
efit from therapeutic intervention. In those meeting type I criteria
for this disease, endoscopic or surgical sphincter disruption may
be comfortably recommended without further diagnostic test-
ing. In contrast, those meeting type II and III criteria should have
therapy guided by results of SOM. (Grade B recommendation)
5. Endoscopic versus surgical management of sphincter of
Oddi dysfunction: Which is superior?
Once the diagnosis of SOD has been established, options for
management include endoscopic sphincterotomy versus surgical
sphincteroplasty. Proponents of sphincterotomy site the relative
PMPH_CH53.indd 425
Acute Pancreatitis ■ 425
ease of the outpatient procedure, rapid recovery, and durable early
results. Detractors note the complications of perforation, bleed-
ing, and pancreatitis (reduced with empiric stent placement),
the potential for sphincter fibrosis and recurrent disease and the
lack of reliable long-term follow-up studies. Those favoring sur-
gical intervention promote the durability of the patulous drain-
age provided. Critics observe the invasiveness of the procedure,
the potential for duodenal leak and the extended recovery. There
are no randomized controlled trials of endoscopic versus surgi-
cal treatment of SOD. Indeed, randomized trials to address the
efficacy of one form of treatment or another are difficult to define,
execute and interpret.40 Despite these limitations, scrutiny of the
literature helps balance and better delineate the therapeutic man-
agement of SOD.
In the previously noted study by Geenen et al.,37 17 of 18 with
SOD and abnormal manometry had a good outcome following
endoscopic biliary sphincterotomy alone with the majority fol-
lowed up for 4 years postprocedure.
In a carefully performed study, Park et al.41 reviewed 313
patients having dual pancreaticobiliary sphincterotomy for type II
and III SOD following manometric confirmation of the disease
in at least one sphincter during a 5-year time period with a mean
length of follow-up of 43 months. Patients with prior sphincter
intervention were excluded and dual sphincterotomy was per-
formed in a single session with the placement of a prophylactic
pancreatic stent for 10 to 14 days to prevent postprocedure pan-
creatitis. The purpose of this study was to assess the impact of rou-
tine dual sphincterotomy on the need for re-intervention due to
recurrent symptoms versus biliary sphincterotomy alone. Impor-
tantly, over one-half of these patients in this series had elevated
pressures in both the biliary and pancreatic sphincters Forty-five
patients had immediate postendoscopic pancreatitis that was
severe in three patients. Seventy-seven patients (25%) required
re-intervention (defined as the need for repeat ERCP) due to recur-
rent symptoms and this did not differ between SOD types. The
majority underwent repeat sphincter ablation. Of the 77 patients
having re-intervention, 26 (33%) had further ERCP procedures.
When compared with historical controls from this same institu-
tion having biliary sphincterotomy alone, dual sphincterotomy
had a lower rate of re-intervention.
Similar observations were noted by Wehrmann42 in a series
of 37 patients with manometrically documented SOD and acute
relapsing pancreatitis followed at least 10 years postintervention.
At least one episode of recurrent pancreatitis occurred in 19 (51%)
patients. When analyzed relative to single (biliary or pancreatic)
versus dual sphincterotomy, those receiving the latter therapeutic
intervention had significantly fewer episodes of recurrent pancre-
atitis (12/13 vs. 7/24).
Toouli et al.43 reported a series of 26 patients having surgical
sphincteroplasty and septectomy for recurrent idiopathic pancre-
atitits followed for a median of 24 months including 7 with failed
prior sphincterotomy. SOD was confirmed by manometry but
subtype analysis was not performed. Dual duct sphincteroplasty
resolved further pain in 23 and was recommended by the authors
as important for optimal results.
Madura et al.36 assessed the results of surgical sphinctero-
plasty in 372 patients with SOD—100 of who had undergone
previous sphincter ablation by either endoscopic (73) or surgical
(27) means. Stratification according to SOD type was not done in
this retrospective review of a 25-year experience. Intraoperative
5/22/2012 5:37:13 PM
 426 ■ Surgery: Evidence-Based Practice
manometry was performed pre- and postprocedure and both
sphincters were surgically disrupted in the majority. Long-term
(not defined) outcome was considered excellent or good in 86.8%
with a trend toward improved results in the procedure naïve
cohort. Manometric pressures of both ducts were significantly
reduced. Patency of the major ampulla was uniformally observed
but re-stenosis of the pancreatic duct requiring re-intervention
was an “occasional problem.”
Morgan et al.44 evaluated results of dual duct sphinctero-
plasty in 51 patients during a recent 5-year time period when
classification of SOD type existed and endoscopic therapy with
sphincterotomy predominated. Unfortunately, if preoperative
manometry was performed, these results were not reported rel-
ative to SOD types (predominantly II and III). Those patients
with an accessible ampulla all had at least one prior endoscopic
sphincterotomy (median 2, range 1–10) prior to surgical refer-
ral. In those with an inaccessible ampulla due to prior gastric
surgery, SOD was evaluated preoperatively with magnetic reso-
nance cholangiopancreatography. The morbidity rate in this
group of predominantly type II and III SOD was 10% includ-
ing one patient with pancreatic necrosis and two patients with
intraabdominal abscess. One patient required re-do sphinc-
teroplasty. Follow-up surveys were completed in two-thirds at a
median length of 3.5 years. Sixty-six percent reported favorable
outcomes with a trend toward better results in those without
prior endoscopic intervention.
In conclusion, surgical studies are hindered by poor report-
ing of preoperative manometric findings with regard to SOD
subtypes. Patients are often referred for surgery as a salvage pro-
cedure frequently resulting in outcomes inferior to those reported
in endoscopic cohorts. Studies to date suggest that surgery is equal
to endoscopic therapy if performed as the index procedure. Endo-
scopic sphincterotomy is associated with a higher rate of recidi-
vism versus sphincteroplasty. Data from both the endoscopic
and surgical literature favors up-front ablation of both the bil-
iary and pancreatic sphincters when therapeutic intervention
is performed. A randomized trial is sorely needed, stratified for
type of SOD and manometric findings, to better identify patients
that may benefit from one form of therapy or the other. (Grade B
recommendation)
6. Can preoperative testing accurately assess those that will
benefit from surgical intervention in pancreas divisum?
Pancreas divisum (PD) occurs in 5% to 10% of the population,
based on autopsy studies, but is associated with pathology in
only a minority. The pain and recurrent episodes of pancreatitis
are felt to originate from impedence to flow of pancreatic secre-
tions at the minor papilla leading to elevated ductal pressures.
In addition, a significant proportion of those with symptomatic
PD harbor genetic mutations associated with chronic pancreatit-
is.45 Therapeutic intervention on the minor papilla is technically
more demanding than its sister the ampulla of Vater. Further,
some reports in both the endoscopic and surgical literature sug-
gest therapeutic results for PD are inferior to those performed for
SOD. Thus, patient selection is paramount if meaningful proce-
dure-related success is to be anticipated.
PMPH_CH53.indd 426
RADIOLOGIC EVALUATION
Warshaw et al.46 examined the utility of the ultrasound-secretin
test in accurately predicting the success of surgical sphinctero-
plasty in 100 patients with PD—the majority of who were followed
for at least 4 years. Outcomes were evaluated relative to whether
patients presented with recurrent AP (49) or pain alone (51) with
results globally favoring the former group. Ninety-two percent
of 72 patients with a positive ultrasound-secretin test had a
good outcome following sphincteroplasty versus only 42% with
a negative test. In the subset with pain but not pancreatitis and a
negative secretin provocative test, only 21% had a good result.
This study suggests that provocative testing, in conjunction with
clinical presentation, is a helpful adjunct in predicting surgical
success.
ENDOPROSTHETIC ASSESSMENT
Lans et al.47 performed a prospective, nonblinded, randomized
controlled trial of 19 patients with PD and at least two prior epi-
sodes of AP comparing dorsal duct stenting (10) to control (9).
Mean follow-up was approximately 30 months and pancreatic
stents were removed at 1 year. In those with an endoprosthesis in
place, symptomatic improvement, emergency room visits, hos-
pitalizations, and documented episodes of AP were significantly
reduced as compared with control. Four patients in the control
arm crossed over to stenting of the minor papilla with no epi-
sodes of hospitalization or AP at follow-up ranging from 6 to 53
months. No patient in this study had either endocopic or sur-
gical sphincteroplasty. It should be noted that stenting of either
pancreatic duct has been associated with the early development
of chronic pancreatitis and/or ductal strictures on follow-up
imaging.48
Siegel et al.49 studied 31 consecutive patients with symptom-
atic PD including 5 with prior surgical sphincteroplasty found
to have postoperative stenosis. Minimal criteria for study entry
included pain, either serum amylase or lipase values greater
than three times normal and/or evidence of pancreatitis via CT
scan.49 Twenty-six patients (84%) had symptomatic improve-
ment following stent placement though data relative to any
further episodes of AP was not reported. During an average
follow-up of 2 years the authors noted progressive stricturing
and ductal dilation of the minor duct suggesting that the stent
itself induced chronic pancreatitis if left for prolonged periods.
Seventeen patients ultimately had surgical intervention includ-
ing dual duct sphincteroplasty (11) or resection with 15 having
a good outcome.
In summary, PD should be considered an incidental finding
unless accompanied by documented episodes of AP. Both secre-
tin provocative testing and temporary stent placement though the
minor papilla are predictive of success following surgical or endo-
scopic sphincteroplasty though neither is firmly recommended
prior to proceeding to therapeutic intervention. Long-term endo-
prosthesis placement should be avoided to prevent deterioration
to chronic pancreatitis. (Grade B recommendation)
5/22/2012 5:37:13 PM

Clinical Question Summary
Question Answer
1 What is the role of ERCP in acute Only if evidence of cholangitis or
biliary pancreatitis? biliary obstruction exists
2 What is the role of prophylatic Studies do not show a benefit.
antibiotics in severe AP? May be reasonable in severe AP
3 Is gastric feeding safe and equivalent Safe in hemodynamically stable
to jejunal feeding in AP? patients if tolerated
4 Can the success of intervention for Yes, when correlated with SOD
SOC be predicted? type
5 Is therapeutic endoscopy or surgery Equal early results, surgery may
superior for SOD? reduce recidivism
6 Can the success of intervention for Yes, when correlated with AP
PD be predicted?
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16. Penderzoli P, Bassi C, Vesentini S, et al. A randomized multicenter
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18. Dellinger EP, Tellado JM, Soto NE, et al. Early antibiotic treat-
ment for severe necrotizing pancreatitis: A randomized, double-
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infected pancreatic necrosis and mortality in acute necrotizing
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22. Hart PA, Bechtold ML, Marshall JB, et al. Prophylactic antibi-
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23. Jafri NS, Mahid SS, Idstein ST, et al. Antibiotic prophylaxis is not
protective in severe acute pancreatitis: A systematic review and
meta-analysis. Am J Surg. 2009;197:806-813.
24. Dickerson RN, Vehe KL, Mullen JL, et al. Resting energy exp-
enditure in patients with pancreatitis. Crit Care Med. 1991;19:
484-490.
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 428 ■ Surgery: Evidence-Based Practice
25. Kudsk KA. Beneficial effect of enteral nutrition. Gastrointest
Endosc Clin N Am. 2007;17:647-662.
26. Zaloga GP. Bedside method for placing small bowel feeding
tubes in critically ill patients. A prospective study. Chest. 1991;
100:1643-1646.
27. Windsor A, Kanwar S, Li A, et al. Compared with parenteral
nutrition enteral feeding attenuates the acute-phase response
and improves disease severity in acute pancreatitis. Gut. 1998;
42(3):431-435.
28. McClave SA, Greene LM, Snider HL, et al. Comparison of the
safety of early enteral vs parenteral nutrition in mild acute pan-
creatitis. J Parenter Enter Nutr. 1997;21(1):14-20.
29. Kalfarentzos F, Kehagias J, Mead N, et al. Enteral nutrition is
superior to parenteral nutrition in severe acute pancreati-
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84(12):1665-1669.
30. Petrov MS, Kukosh MV, Emelyanov NV. A randomized con-
trolled trial of enteral versus parenteral feeding in patients with
predicted severe acute pancreatitis shows a significant reduction
in mortality and in infected pancreatic complications with total
enteral nutrition. Dig Sug. 2006;23(5-6):336-345.
31. Eatock F, Chong P, Menezes N, et al. A randomized study of early
nasogastric versus nasojejunal feeding in severe acute pancreati-
tis. Am J Gastroenterol. 2005;100(2):432-439.
32. Kumar A, Singh N, Prakash S, et al. Early enteral nutrition in
severe acute pancreatitis: A prospective randomized controlled
trial comparing nasojejunal and nasogastric routes. J Clin Gas-
troenterol. 2006;40(5):431-434.
33. Eckerwall G, Axelsson J, Andersson R. Early nasogastric feed-
ing in predicted severe acute pancreatitis: a clinical randomized
study. Ann Surg. 1006;244(6):959-967.
34. Hogan WJ, Greenen JE. Biliary dyskinesia. Endoscopy. 1988;
20(Suppl 1):179-783.
35. Sherman S, Iroiano FP, Hawes RH, et al. Frequency of abnor-
mal sphincter of Oddi manometry compared with the clinical
suspicion of sphincter of Oddi dysfunction. Am J Gastroenterol.
1991;86:586-590.
36. Madura JA, Madura JA, II , Sherman S, et al. Surgical sphinctero-
plasty in 446 patients. Arch Surg. 2005;140:504-512.
37. Geenen JE, Hogan WJ, Dodds WJ, et al. the efficacy of endo-
scopic sphincterotomy after cholecystectomy in patients with
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38. Aisen AM, Sherman S, Jennings SG, et al. Comparison of
secretin-stimulated pancreatography and manometry results in
patients with suspected sphincter of ODDI dysfunction. Acad
Radiol. 2008;15:601-609.
39. Craig AG, Peter D, Saccone GTP, et al. Scintigraphy versus
manometry in patients with suspected biliary spincter of Oddi
dysfunction. Gut. 2003;52:352-357.
40. Cotton PB, Durkalski V, Orrell KB, et al. Challenges in planning
and initiating a randomized clinical study of sphincter of Oddi
dysfunction. Gastrointest Endosc. 2010;72:986-991.
41. Parks SH, Watkins JL, Fogel EL, et al. Long-term outcome of
endoscopic dual pancreatobiliary sphincterotomy in patients
with manometry-documented sphincter of Oddi dysfunc-
tion and normal pancretogram. Gastrointest Endosc. 2003;57:
483-491.
42. Wehrmann T. Long-term results (≥10 years) of endoscopic
therapy for sphincter of Oddi dysfunction in patients with acute
recurrent pancreatitis. Endoscopy. 2011;43:202-207.
43. Toouli J, diFrancesco V, Kollias SJ, et al. Divison of the sphincter
of Oddi for treatment of dysfunction associated with recurrent
pancreatitis. Br J Surg. 1996;83:1205-1210.
44. Morgan KA, Ramognuolo J, Adams DB. Transduodenal sphinc-
teroplasty in the management of sphincter of Oddi dysfunc-
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2008;206:901-914.
45. Garg PK, Khajuria R, Kabra M, et al. Association of SPINK
1 gene mutation and CFTR gene polymorphisms in patients with
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46. Warshaw AL, Simeone JF, Schapiro RH, et al. Evaluation and
treatment of the dominant dorsal duct syndrome (pancreas
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47. Lans JI, Geenen JE, Johanson JF, et al. Endoscopic therapy in
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1992;38:430-434.
48. Attasaranya SA, Abdel Aziz AM, Lehman GA. Endoscopic man-
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results in 31 patients. Endoscopy. 1990;22:129-133.
5/22/2012 5:37:13 PM
 Commentary on
Acute Pancreatitis
Wayne H. Schwesinger
As illustrated in this excellent review, acute pancreatitis covers a
broad clinical spectrum: from common and straightforward to
rare and esoteric. In each case, optimal management requires a
multidisciplinary approach often involving gastroenterology, radi-
ology, and surgery. Continuing advances in technology in each of
these specialties has generally promoted less invasive method-
ologies, often with minimal supportive evidence. Increasingly,
the role of surgery has been relegated to the prevention of recur-
rence (laparoscopic cholecystectomy) or the treatment of major
complications (pancreatic necrosectomy). Accordingly, few open
sphincterotomies are currently performed and even the volume of
necrosectomies has dramatically decreased. Whether the fledg-
ling enthusiasm for laparoscopic retroperitoneal necrosectomy
429
PMPH_CH53.indd 429
will alter the latter experience is far from clear. Much more opera-
tive experience with this apparently demanding procedure is nec-
essary. Meanwhile, improvements in radiological and endoscopic
methods are regularly reported.
It seems clear that the potentially lethal nature of acute pan-
creatitis will continue to stimulate re-newed attempts at improved
diagnosis and control. Surgeons are integral to these efforts
and must remain active members of the management and
research teams. Ongoing critical assessments such as the current
review represent an important step in our evolving understand-
ing of acute pancreatitis and will ultimately help us to select
the most appropriate and efficacious of the new management
strategies.
5/22/2012 5:37:13 PM
 CHAPTER 54
Infected Pancreatic Collections
Nader N. Massarweh and Karen D. Horvath
INTRODUCTION
In the United States, acute pancreatitis is among the three most
common gastrointestinal diseases requiring hospitalization, with an
annual cost of over USD 2 billion.1,2 The majority (75%) of patients
have a mild form of acute pancreatitis and resolve their symptoms
without event. The rest may go on to develop a more severe form of
acute pancreatitis with consequent organ failure and/or the devel-
opment of organ necrosis. Despite modern medical advances, severe
acute pancreatitis is still currently associated with significant rates
of morbidity and mortality approaching 15% to 30%.3
While management of mild acute pancreatitis has changed
little in the past decade, appropriate management of patients
with severe acute pancreatitis and its associated complications
has undergone significant changes. Sterile peripancreatic collec-
tions can usually be treated conservatively. However, secondary
infection of peripancreatic collections occurs in about 33% of
patients—generally 3 to 4 weeks after the onset of disease. With-
out timely and effective treatment of these patients, mortality
approaches 100%.4
A body of data is currently emerging to help clarify some of
the questions regarding the optimal management of patients with
severe acute pancreatitis who develop infectious complications. A
potential source of much of the uncertainty surrounding man-
agement has been the use of different terminology in the litera-
ture and amongst clinicians over the last 20 years. For example,
the term “pancreatic abscess” may be used by some clinicians to
describe a process others might refer to as “infected necrosis” and
yet others might call an “infected pseudocyst.” Although the dis-
tinction may seem subtle, these differences can markedly affect
the selection of proper management algorithms and thus treat-
ment outcomes. The current confusion surrounding severe acute
pancreatitis nomenclature developed over time as we have come to
understand more about this disease. The Atlanta Symposium Con-
sensus Conference5 terminology, which provided a key advance
in 1993, is now outdated. In this regard, an international work-
ing group has updated the Atlanta classification system to create
a common framework for discussing the hierarchy and severity
430
PMPH_CH54.indd 430
Pancreatitis
IEP Necrotizing
Early Late Early Late
*APFC *Pseudocyst *APNC *WON
Figure 54.1 Updated Atlanta classification
Note that the term “pancreatic abscess” is not used in this classification.
Early is <4 weeks. Late is >4 weeks.
*Each of these entities can be infected or noninfected.
IEP—Interstital edematous pancreatitis; APFC—Acute peripancreatic fluid
collection; APNC—Acute postnecrotic collection; WON—Walled-off
necrosis.
of pancreatitis-associated complications.6 It is anticipated that the
uniform adoption of the new classification will both aid and sim-
plify clinical management, research methodology, and provider-
to-provider communication. For these reasons, we describe the
updated terminology below and use these terms throughout the
remainder of this chapter (Figure 54.1).
NOMENCLATURE
1. How should infectious complications associated with pan-
creatitis be described?
Throughout the inflammatory phase, fluid collections may develop
within or around the pancreas. In the early stage of the disease
(<4 weeks), the pancreatitis can be morphologically characterized
as interstitial edematous pancreatitis (IEP), or an acute peripancre-
atic fluid collection (APFC) when a separate collection is present.
By comparison, if the computed tomography (CT) morphology
demonstrates necrotizing pancreatitis (with necrosis of the gland
and/or the peripancreatic tissues), the collection is referred to as
an acute postnecrotic collection (APNC) of the pancreatic paren-
chyma and the peripancreatic tissues, the pancreatic parenchyma
5/22/2012 5:38:02 PM

alone, or the peripancreatic tissue alone. In all cases, the APNC
contains variable amounts of both fluid and necrotic pancreatic
or peripancreatic tissue.
In the later stages of the disease (≥4 weeks), an APFC may
develop a defined inflammatory wall and now be considered a
pseudocyst. An APNC may also develop a defined wall at which
point it is classified as walled-off necrosis (WON). In all cases
(early/late, APFC/APNC, or pseudocyst/WON), these collec-
tions may be considered sterile or infected. The term “pancreatic
abscess,” as it has been traditionally used, is not specific enough to
adequately characterize the infectious complications. For exam-
ple, under the prior Atlanta Classification, the term referred to
a purulent fluid collection in the absence of significant necrotic
tissue (an uncommon finding). Therefore, the term was not incor-
porated into the new classification and will not be used herein.
Answer: To provide a more uniform framework for the clas-
sification of infectious sequelae associated with pancreatitis and
to facilitate communication between providers caring for these
patients and better standardization of research terminology, the
New International Working Group Consensus Classification sys-
tem (an update of the former Atlanta Classification) should be
used. (Grade D recommendation).
DIAGNOSIS
2. Should fine-needle aspiration biopsy (FNAB) be used?
Early and accurate identification of infection in a pancreatic or
peripancreatic collection is crucial for providing patients with
timely and appropriate care since patients with severe acute pan-
creatitis who have infectious complications have a significantly
higher mortality rate. Although the use of modern, contrast-
enhanced imaging has greatly facilitated the diagnosis and classi-
fication of severe acute pancreatitis and its associated complications,
imaging modalities alone are not always sufficient for establishing
the diagnosis of infection. The presence of gas in a peripancreatic
collection is considered pathognomonic for the presence of infec-
tion, but in its absence a practitioner must rely on clinical judg-
ment and physiologic parameters to establish the diagnosis of
infection. However, this can be challenging since common signs
of infection may be elusive or absent or may simply indicate the
presence of other sources of infection (urinary tract infections,
pneumonia, bacteremia from line sepsis, etc.), which are common
in this patient population. In these cases tissue/fluid sample with
subsequent gram stain and bacterial culture can be very useful.
Although there is a lack of high-level evidence to direct the
use of image-guided fine-needle aspiration biopsy (FNAB), there
is general consensus that when the presence of infection is sus-
pected, but not clearly demonstrated on imaging, FNAB is indi-
cated to help direct therapy. In the past decade, only one study
has provided data regarding the sensitivity and specificity of
FNAB. Evaluating 98 patients with necrotizing pancreatitis using
ultrasound-guided FNAB, Rau et al.7 described an 88% and 90%
sensitivity and specificity, respectively. Although CT-guided
approaches are likely more common, there are no contemporary
studies that have evaluated this method of tissue sampling. How-
ever, one would suspect the sensitivity/specificity would at least
be similar to (if not better than) the ultrasound-guided method.
Endoscopic methods introduce the potential for iatrogenic infec-
tion by gut flora and should be avoided.
PMPH_CH54.indd 431
Infected Pancreatic Collections ■ 431
Answer: Despite a lack of high-level evidence, there is gen-
eral consensus that FNAB has a role in establishing the diagnosis
of infection when imaging alone is not adequate. When FNAB is
used, it has high sensitivity/specificity and can be repeated mul-
tiple times in the same patient with a very low risk of iatrogenic
infection. (Grade C recommendation).
NUTRITION
3. Should enteral or parenteral feeding be used?
Enteral nutrition (via the nasoenteral route or through direct
enteric access) is an integral tool in the management of critically
ill general surgical patients. But, in patients with severe acute pan-
creatitis, there exists a longstanding dogma that enteral nutrition
has the potential to stimulate exocrine pancreatic function thereby
exacerbating the peripancreatic inflammatory process. There is,
however, little evidence to suggest that this actually occurs. To the
contrary, there are data demonstrating that these patients are ben-
efited when enteral nutrition is used.
Several randomized controlled trials (RCTs) have been per-
formed comparing the use of enteral and parenteral nutrition
among patients with pancreatitis. Various measures of morbidity
and mortality have been evaluated, including the occurrence of
infectious complications. Data from these trails have been ana-
lyzed in three meta-analyses—all of which found statistically
significant reductions in the risk of systemic and pancreatic infec-
tious complications. Marik et al.8 found the use of enteral nutri-
tion to be associated with a significantly lower risk of infectious
complications, need for surgical intervention, and length of hos-
pital stay, but failed to identify a decreased risk of mortality or
noninfectious complications. However, this study had two impor-
tant limitations to consider. First, the study had a relatively small
sample size and a small number of mortality events, which likely
underpowered the analysis. Second, the study included patients
who were heterogenous in terms of the severity of acute pancrea-
titis, which may have biased the assessment of mortality toward
the null.
In a subsequent analysis, Petrov et al. restricted their inclu-
sion criteria to only those studies evaluating patients with severe
acute pancreatitis.9 When patients with mild pancreatitis were
excluded (limiting the analysis to a more homogeneous group of
patients with severe acute pancreatitis), use of enteral nutrition
was associated with statistically significant reductions in the risk
of total and pancreatic infectious complications, need for surgi-
cal interventions, and mortality (without significant heterogene-
ity across the included studies). Similarly, in a recent Cochrane
review updating the analysis performed by Marik et al., Al-Omran
et al.10 included three additional studies which increased the sam-
ple size from 263 to 348 patients. While the prior analysis failed
to identify a decreased risk of mortality, these additional patients
may have provided adequate power to allow identification of a
statistically significant reduction in the risk of mortality associ-
ated with enteral nutrition. However, since some of the studies
included in these analyses were performed prior to the current
emphasis placed on the prevention of sepsis associated with tem-
porary central lines, it is possible that these data may be biased
in favor of enteral nutrition. Nonetheless, providing supplemental
nutrition in a manner that minimized possible routes of infection
is an appealing general principle of treating critically ill patients.
5/22/2012 5:38:02 PM
 432 ■ Surgery: Evidence-Based Practice
Given that enteral nutrition appears to provide consistent
and measurable benefit, another important question to consider is
whether the route of enteral administration (i.e., gastric vs. jejunal)
makes a difference? Two small randomized studies have addressed
this issue. First, Eatock et al.11 sought to evaluate whether naso-
gastric feeding is equivalent to the nasojejunal route in terms of
safety, effectiveness, complications, and exacerbation of inflam-
mation and pain. Because the authors did not use a noninferior-
ity design, this study was underpowered to establish equivalence.
However, nasojejunal feeding was not found to be superior when
compared with nasogastric feeding in terms of clinical and physi-
ologic parameters. In a second pilot study, the authors again did
not find evidence that jejunal feeding was superior to intragastric
feeding.12 Although the results of these two studies are compel-
ling and appear to support the conclusion that jejunal feeding is
not superior to nasogastric feeding, both suffer from small sample
size, which may have unpowered these analyses to detect signifi-
cant differences in the primary outcome or in other meaningful
complications such as aspiration (which is a highly relevant issue
in this patient population). Future work will, therefore, be neces-
sary to confirm these findings. In the meantime, it seems prudent
to advise that nasogastric tube feeding be considered in patients
with severe acute pancreatitis who either are capable of protecting
or have a protected airway.
Answer: There exists consistent evidence that using enteral,
as compared with parenteral, nutrition results in clinically and
statistically significant decreases in the risk of pancreatitis-
associated morbidity and mortality. Furthermore, there currently
does not appear to be evidence that jejunal administration of
enteral nutrition offers any significant advantage over the gastric
route. As such, enteral feeding should be the preferred method
of providing nutrition to patients with pancreatitis and the route
(jejunal vs. gastric) should be tailored to each patient and/or dic-
tated by the practitioner’s best clinical assessment and judgment.
(Grade A recommendation).
4. Should feeding begin early or be delayed?
The management paradigm for patients with pancreatitis has tra-
ditionally included “resting the gastrointestinal tract” and pro-
viding intravenous fluids until the initial signs and symptoms of
pancreatic inflammation, such as lab markers (amylase and lipase)
and abdominal pain subside. The rationale for this approach has
been to minimize passage of food through the duodenum and
past the pancreas which was thought to stimulate pancreatic exo-
crine function and potentially drive the inflammatory response.
Although this form of management may be appropriate for the
75% of patients who present with a self-limited attack of “gar-
den variety” mild acute pancreatitis, for patients diagnosed with
severe acute pancreatitis, more aggressive management is needed.
In these patients prolonged fasting can have important negative
ramifications for the patient including bacterial overgrowth in the
small bowel with atrophy of the mucosal barrier increasing the
risk of bacterial translocation leading to infectious complica-
tions, progressive and profound protein calorie malnutrition, and
immune compromise. As the enteral route, when tolerated, is the
preferred method for providing nutrition to patients with severe
acute pancreatitis, remaining questions are what to feed patients
and when to begin feeding (immediately vs. delayed)?
The inflammatory process associated with severe acute pancre-
atitis can create a profound, chronic, catabolic state in a patient who
PMPH_CH54.indd 432
is generally unable to consistently consume enough calories to keep
up with their caloric needs, so nutritional supplementation through
the use of tube feeding will often be required. However, selecting
from the many and varied nutritional formulations can be challeng-
ing. A recent meta-analysis performed by Petrov et al.13 compared
the use of (semi)elemental with polymeric formulations in terms of
infectious complications and mortality. The authors found no iden-
tifiable difference in the risk of mortality, feeding intolerance, or
infectious complications associated with either formulation.
To date, only one randomized trial has compared an early with
a delayed approach to feeding.14 In this study, Eckerwall et al.14
randomized 60 patients with mild acute pancreatitis to an early
feeding strategy where patients received immediate oral feeding
(as tolerated) or a delayed feeding approach where patients under-
went immediate fasting with administration of intravenous flu-
ids. They found no differences in pain, inflammatory markers, or
gastrointestinal symptoms. However, those randomized to imme-
diate oral feeding spent shorter periods of time on intravenous
fluids, reintroduced solid food much earlier, and had a signifi-
cantly shorter length of hospital stay. There are several important
considerations when reflecting on the results of this trial. First,
and most importantly, this study only included patients with mild
pancreatitis. Because it is very likely the severity of the inflam-
matory process that influences a patient’s ability to tolerate oral
intake, the results of this work may not necessarily generalize to
those with severe acute pancreatitis. Second, this study was pow-
ered to detect a difference in length of stay. Therefore, although
there were potentially important differences between the early
and delayed feeding strategies (e.g., in many cases, the proportion
of gastrointestinal symptoms in the early feeding group was lower,
but not statistically significant) the small sample size may not have
been sufficient. Finally, the authors did not evaluate whether one
strategy resulted in more infectious complications.
Answer: For patients who either have or are predicted to have
severe acute pancreatitis, it is advised that supplemental, enteral
nutrition through an appropriate nasoenteric route (tailored to
the patient) begin in those not expected to resume adequate oral
intake within approximately 3 days. There does not appear to be
any clinical difference between using a (semi)elemental or a poly-
meric formulation. For patients who can tolerate oral nutrition and
who are able to consume the required number of calories, a liber-
alized diet (beyond normal step-wise advancement) may result in
a shorter length of hospital stay. (Grade B recommendation).
5. Should probiotics be used?
The idea of using of probiotics as a nutritional supplement for the
purpose of reducing bacterial overgrowth, protecting the integ-
rity of the barrier function of the bowel, and modulating immune
function has gained in popularity. However, two important stud-
ies reporting results from the PROPATRIA trial conducted by the
Dutch Acute Pancreatitis Study Group have helped to clarify the
role for probiotics.15 In the first, 296 patients predicted to have a
severe course of acute pancreatitis were randomized to a blinded
28-day course of either a multispecies probiotic preparation or a
placebo.16 All patients received concurrent nasojejunal tube feed-
ing. Although the results of this trial did not suggest probiotic
prophylaxis resulted in any reduction in the risk of infectious com-
plications, the authors unexpectedly found higher rates of organ
failure, bowel ischemia, and mortality in the probiotic group.
In a second study, the authors evaluated a subgroup of patients
5/22/2012 5:38:02 PM

from the PROPATRIA trial in whom assessments of enterocyte
damage, intestinal permeability, and bacterial translocation were
made.17 Probiotic administration was associated with decreased
bacterial translocation and increased enterocyte damage in
the overall cohort. However, when the subgroup with organ failure
was evaluated, probiotics appeared to increase bacterial translo-
cation and enterocyte damage. Thus, it appeared that the adverse
effect of probiotics on mortality was limited to patients with organ
failure. Although the mechanism responsible for the unexpected
findings in both studies is unclear, probiotics should be avoided
until the reason for these adverse outcomes is resolved or until
subgroups in whom probiotics are beneficial can be identified.
Answer: Probiotics should not be used in the management of
patients with severe pancreatitis because they appear to be associ-
ated with an increased risk of organ failure, bowel ischemia, and/
or mortality. (Grade A recommendation).
MANAGEMENT
6. Are prophylactic antibiotics recommended?
Local and/or systemic infections are common complications in
patients with severe acute pancreatitis. Early infections, such as
pneumonia or bacteremia, usually develop within the first week
following hospital admission while infected pancreatic necro-
sis develops later (a median of 26 days following symptoms).3
Whether “early” or “late,” the mortality of infectious compli-
cations in severe acute pancreatitis portends a worse prognosis.
Clinicians may, therefore, perceive antibiotic prophylaxis as a rea-
sonable method of decreasing the risk of infectious complications
thereby lowering the risk of death.
However intuitive this reasoning may seem, current data do
not appear to support the use of prophylactic antibiotics in patients
who have, or are predicted to have, severe acute pancreatitis. A
recent Cochrane review evaluated the effectiveness of prophylac-
tic antibiotics in the setting of severe necrotizing pancreatititis.18
The results did not indicate any significant benefit (in terms of
mortality or infection) associated with the use of prophylactic
antibiotics. There are several important issues to consider. First,
these seven trials evaluated various types of antibiotics, some of
which are uncommonly used for pancreatitis (i.e., quinolones), so
the lack of a significant benefit may have been a function of the
disparate types of antibiotics used. Of the seven trials included in
this study, five assessed the use of β-lactam antibiotics (commonly
used for pancreatitis); however, the combined data did not identify
a significant difference. A second important consideration is that
only the two most recent trials included in this analysis were
double-blind. Finally, in the overall analysis and the subgroup
analyses, the use of antibiotics was associated with notably lower
rates of each outcome assessed (mortality [8.4% vs. 14.4%]; infected
pancreatic necrosis [19.7% vs. 24.4%]; nonpancreatic infection
[23.7% vs. 36.0%]; all sites of infection [37.5% vs. 51.9%]). There-
fore, although there may not have been a statistically significant
decrease in the risk of infectious complications and mortality, this
meta-analysis simply may not have been adequately powered to
evaluate the effectiveness of a current and appropriate prophy-
lactic antibiotic regimen. However, a recently updated systematic
review and meta-analysis including seven additional randomized
studies (with a total of 841 patients) provides similar results that
appear to confirm these findings.19
PMPH_CH54.indd 433
Infected Pancreatic Collections ■ 433
Answer: There is insufficient evidence to support routine use
of antibiotics as a means of preventing infectious complications
in patients with necrotizing pancreatitis. The use of antibiotics
for targeted therapy should be based on a thorough assessment of
clinical and laboratory data. (Grade A recommendation).
7. How should infected pancreatic collections be managed?
Traditionally, the presence of an infected pancreatic or peripan-
creatic collection has been an indication for open necrosectomy.
However, the different methods for open surgical necrosectomy
in these often moribund patients are associated with a high rate
of morbidity and mortality,20-22 so less invasive interventions are
increasingly being utilized with quality data supporting their
use. However, there may be instances where immediate surgical
intervention is still required because percutaneous drainage alone
is either inadequate or not feasible (e.g., multi-loculated fluid col-
lections; mixed fluid and solid components of the collection; no
direct path for placement of a drainage catheter; and a patient
with visceral ischemia). In these cases, an open transabdominal
necrosectomy affords ample access to the pancreatic bed and sur-
rounding tissues and allows drains to be properly positioned. For
these reasons, open necrosectomy techniques should not disap-
pear from the armamentarium of the general surgeon.
The use of percutaneous drains for infected pancreatic collec-
tions was first described in the mid-1980s. Drains are usually placed
percutaneously using ultrasound or CT guidance; however, translu-
minal catheters can also be placed by an endoscopist via the trans-
gastric or transduodenal route. Once considered only an adjunctive
therapy or a temporizing measure to delay surgical intervention, there
is evidence that drains alone may represent adequate therapy and in
many cases and may be the only therapeutic intervention needed.
For example, a recent systematic review of 11 nonrandomized stud-
ies suggested that catheter drainage might be the only treatment
needed in up to 55% of patients with necrotizing pancreatitis.23
Even when percutaneous drainage is not successful, the drain
tract can be used as roadmap for minimally invasive necrosectomy.
The best studied approach for minimally invasive necrosectomy is
known as the “Step-Up” approach. This involves placement of per-
cutaneous drains followed by a minimally invasive necrosectomy
procedure when drainage alone is unsuccessful. Step-Up has been
classically paired with the technique of video-assisted retroperi-
toneal debridement (VARD), a simple, low-tech technique requir-
ing minimal resource utilization, which involves a 4- to 5-cm left
flank incision with debridement through a 10-mm laparoscopic
port followed by postoperative lavage.24,25 In a recent multicenter,
prospective Phase II study of 40 patients with infected necrosis,26
the Step-Up approach was associated with an excellent safety pro-
fi le (7.5% bleeding complication rate, a 17.5% enteric fistula rate
and a 2.5% mortality) and a high success rate (60% of patients who
required intervention were successfully managed by percutane-
ous drains with/without a VARD and 23% of patients were man-
aged with percutaneous drains alone). In another case-matched
study of open necrosectomy with continuous postoperative lavage
compared with retroperitoneal debridement with continuous
postoperative lavage, the authors found no difference in the rate of
postoperative complications, but a lower rate of in-hospital mor-
tality and a significantly lower rate of organ failure in the retro-
peritoneal debridement group.27
A recent trial performed by the Dutch Pancreatitis Study group
(the PANTER trial) provides data comparing the Step-Up approach
5/22/2012 5:38:02 PM
 434 ■ Surgery: Evidence-Based Practice

with open necrosectomy.28 In this RCT, 88 patients with infected 8. What is the optimal timing for surgical intervention in
pancreatic or peripancreatic tissue were randomized to either patients with infected necrosis?
open necrosectomy (45 patients) or a minimally invasive Step-Up
Over the past 50 years, the timing of surgical intervention for
approach (43 patients). Patients randomized to the Step-Up arm had
patients with infected necrosis has changed significantly. From
a lower rate of incidence of postoperative organ failure, a lower rate
the 1960s to the mid-1990s, surgeons performed radical, open
of major complications, and a lower risk of death or complications
necrosectomies or even total pancreatectomies on patients within
(primarily attributable to the decreased complication rate). Post-
the first few days of presentation with mortality rates approach-
operatively, the Step-Up arm had fewer incisional hernias (7% vs.
ing 70%. The use of percutaneous drains in combination with
24%), less diabetes (16% vs. 38%), less exocrine insufficiency with
significant improvements in intensive care unit (ICU) care dur-
need for pancreatic enzyme supplementation (7% vs. 33%), and
ing the mid-1980s, introduced a new paradigm of delaying surgi-
lower healthcare utilization and medical costs (12% cheaper as
cal intervention and led to a decrease in mortality rates. Among
compared with open necrosectomy). In addition, surgical inter-
patients with necrotizing pancreatitis, an “early” (within 72 h of
vention (other than drain placement) was avoided in one-third of
admission) interventional approach has been compared with a
patients in the Step-Up arm. These results provide compelling data
“late” approach (after 12 days) in an RCT.33 This study terminated
in favor of the minimally invasive Step-Up approach.
prematurely due to a significant difference in mortality (58% for
Although Step-Up offers a clear advance in the management of
early necrosectomy vs. 27% for late). Although a major criticism
patients with infectious complications of pancreatitis, there are other
of this study is that all patients underwent necrosectomy (not just
minimally invasive options that can be considered. Another widely
those who were infected), it nonetheless instituted a new era of
used minimally invasive approach also associated with decreased
“delayed” intervention.
mortality as compared with open necrosectomy is minimal access
In 2007, Besselink et al.34 reported a systematic review of
percutaneous retroperitoneal necrosectomy (MAPRN).29 This tech-
11 studies including 1136 patients correlated mortality rate with
nique involves dilating a percutaneous drainage tract (to approxi-
timing of first intervention. The authors found a median time to
mately 30 F) and use of an operating nephroscope to accomplish
first surgical intervention of 26 days with a 25% mortality rate.
debridement. Postoperative lavage is then used with repeated necro-
Most striking, the authors found a statistically significant inverse
sectomies at 7 to 10 day intervals using local anesthetic. If VARD
association between mortality (decreasing) and time to surgical
or MAPRN is not feasible, a transluminal endoscopic approach
intervention (delayed). Although the data only allowed an evalua-
(NOTES) can be considered.30-32 Although early results seem prom-
tion of intervention out to 30 days, there may have been a contin-
ising, the lack of wide availability of this technique and the need for
ued trend past this time point.34
randomized data should argue against its routine use at this time.
It is postulated that the delay in intervention permits the acute
Pending the results of randomized comparisons, patients
inflammatory process associated with the initial SIRS (Systemic
with severe acute pancreatitis should likely be referred to centers,
Inflammatory Response Syndrome) response to abate, the wall
or treated by practitioners, that can confidently offer the full gam-
of the collection to encapsulate and the tissues to demarcate mak-
bit of multidisciplinary therapeutic options and have experience
ing the surgery safer. Exceptions to the delayed approach should
making the complex management decisions so often associated
be considered when patients manifest hemodynamic instability
with this complicated disease process.
despite aggressive resuscitation for 24 h or those patients for whom
Answer: Infected pancreatic collections should be managed
an intra-abdominal catastrophe cannot be ruled. Otherwise, cur-
using a Step-Up approach, which involves the placement of percu-
rent International Association of Pancreatology guidelines advise
taneous or transluminal drains with or without subsequent mini-
against operating in the acute phase of the disease.35
mally invasive necrosectomy. When compared with traditional
Answer: Delaying surgical intervention to at least 30 days
open necrosectomy, minimally invasive approaches can be as effi-
from onset of symptoms, when feasible, is likely associated with a
cacious with lower rates of complications and healthcare utiliza-
decreased risk of mortality. (Grade B recommendation).
tion. (Grade A recommendation).

Clinical Question Summary

Question Answer Level of Grade of References
Evidence Recommendation
1 How should infectious The new International Working Group 5 D 6
complications Consensus Classification system should be
associated with used.
pancreatitis be
described?
2 Should fine-needle Yes, in cases where imaging alone cannot 4 C 7
aspiration biopsy establish a diagnosis of infection.
(FNAB)be used?
3 Should enteral or Enteral nutrition decreases the risk of 1a A 8-12
parenteral feeding morbidity and mortality and should be the
be used? preferred method of nutritional support.

(Continued)

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 Infected Pancreatic Collections ■ 435

(Continued)
Question Answer Level of Grade of References
Evidence Recommendation
4 Should feeding begin Supplemental tube feeding should begin early 1b B 13-14
early or be delayed? in patients who have or are predicted to
have severe acute pancreatitis. Either
(semi)elemental or polymeric formulations
can be used.
5 Should probiotics be No. 1b A 15-17
used?
6 Are prophylactic No. 1a A 18-19
antibiotics
recommended?
7 How should infected Drain placement ± subsequent minimally 1b A 23-28
pancreatic collections invasive interventions (VARD) appears
be managed? to be an efficacious and safe approach to
the management of infected pancreatic
collections.
8 What is the optimal Delaying surgical intervention to at least 2a B 33-34
timing for surgical 30 days from symptom onset, when feasible,
intervention in is likely associated with a decrease in the
patients with infected risk of mortality.
pancreatic necrosis?

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Camargo CA, Jr. Direct medical costs of acute pancreatitis hos-
pitalizations in the United States. Pancreas. 2007;35(4):302-307.
2. Shaheen NJ, Hansen RA, Morgan DR, et al. The burden of gas-
trointestinal and liver diseases, 2006. Am J Gastroenterol. 2006;
101(9):2128-2138.
3. Besselink MG, van Santvoort HC, Boermeester MA, et al. Tim-
ing and impact of infections in acute pancreatitis. Br J Surg. 2009;
96(3):267-273.
4. Banks PA, Freeman ML. Practice guidelines in acute pancreati-
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5. Bradley EL, 3rd. A clinically based classification system for acute
pancreatitis. Summary of the International Symposium on Acute
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Surg. 1993;128(5):586-590.
6. Banks PA, Bollen T, Dervenis C, et al. Revision of the Atlanta
Classification of Acute Pancreatitis. Ongoing.
7. Rau B, Pralle U, Mayer JM, Beger HG. Role of ultrasonographically
guided fine-needle aspiration cytology in the diagnosis of infected
pancreatic necrosis. Br J Surg. 1998;85(2):179-184.
8. Marik PE, Zaloga GP. Meta-analysis of parenteral nutrition versus
enteral nutrition in patients with acute pancreatitis. BMJ. 2004;
328(7453):1407.
9. Petrov MS, van Santvoort HC, Besselink MG, et al. Enteral nutrition
and the risk of mortality and infectious complications in patients
with severe acute pancreatitis: A meta-analysis of randomized
trials. Arch Surg. 2008;143(11):1111-1117.
10. Al-Omran M, Albalawi ZH, Tashkandi MF, Al-Ansary LA. Enteral
versus parenteral nutrition for acute pancreatitis. Cochrane Data-
base Systematic Reviews. 2010(1):CD002837.
11. Eatock FC, Chong P, Menezes N, et al. A randomized study of early
nasogastric versus nasojejunal feeding in severe acute pancreatitis.
Am J Gastroenterol. 2005;100(2):432-439.
12. 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):431-434.
13. Petrov MS, Loveday BP, Pylypchuk RD, et al. Systematic review
and meta-analysis of enteral nutrition formulations in acute pan-
creatitis. Br J Surg. 2009;96(11):1243-1252.
14. Eckerwall GE, Tingstedt BB, Bergenzaun PE, Andersson RG.
Immediate oral feeding in patients with mild acute pancreatitis is
safe and may accelerate recovery—a randomized clinical study.
Clin Nutr. 2007;26(6):758-763.
15. Besselink MG, Timmerman HM, Buskens E, et al. Probiotic
prophylaxis in patients with predicted severe acute pancreatitis
(PROPATRIA): Design and rationale of a double-blind, placebo-
controlled randomised multicenter trial [ISRCTN38327949].
BMC Surg. 2004;4:12.
16. Besselink MG, van Santvoort HC, Buskens E, et al. Probiotic pro-
phylaxis in predicted severe acute pancreatitis: A randomised,
double-blind, placebo-controlled trial. Lancet. 2008;371(9613):
651-659.
17. Besselink MG, van Santvoort HC, Renooij W, et al. Intestinal bar-
rier dysfunction in a randomized trial of a specific probiotic com-
position in acute pancreatitis. Ann Surg. 2009;250(5):712-719.
18. Villatoro E, Mulla M, Larvin M. Antibiotic therapy for prophy-
laxis against infection of pancreatic necrosis in acute pancreati-
tis. Cochrane Database Systematic Reviews. 2010;(5):CD002941.
19. Wittau M, Mayer B, Scheele J, et al. Systematic review and meta-
analysis of antibiotic prophylaxis in severe acute pancreatitis.
Scand J Gastroenterol. 2011;46(3):261-270.

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20. Besselink MG, de Bruijn MT, Rutten JP, et al. Surgical interven-
tion in patients with necrotizing pancreatitis. Br J Surg. 2006;
93(5):593-599.
21. Rau B, Bothe A, Beger HG. Surgical treatment of necrotizing pan-
creatitis by necrosectomy and closed lavage: Changing patient
characteristics and outcome in a 19-year, single-center series.
Surgery. 2005;138(1):28-39.
22. Rodriguez JR, Razo AO, Targarona J, et al. Debridement and
closed packing for sterile or infected necrotizing pancreatitis:
Insights into indications and outcomes in 167 patients. Ann Surg.
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23. van Baal MC, van Santvoort HC, Bollen TL, et al. Systematic
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for necrotizing pancreatitis. Br J Surg. 2011;98(1):18-27.
24. Horvath KD, Kao LS, Wherry KL, Pellegrini CA, Sinanan MN.
A technique for laparoscopic-assisted percutaneous drainage of
infected pancreatic necrosis and pancreatic abscess. Surg Endosc.
2001;15(10):1221-1225.
25. van Santvoort HC, Besselink MG, Horvath KD, et al. Video-
scopic assisted retroperitoneal debridement in infected necrotiz-
ing pancreatitis. HPB (Oxford). 2007;9(2):156-159.
26. Horvath KD, Freeny P, Escallon J, et al. Safety and efficacy of
video-assisted retroperitoneal debridement (VARD) for infected
pancreatic collections: A multicenter, prospective, single-arm
phase II study. Arch Surg. 2010;145(9):817-825.
27. van Santvoort HC, Besselink MG, Bollen TL, et al. Case-matched
comparison of the retroperitoneal approach with laparotomy for
necrotizing pancreatitis. World J Surg. 2007;31(8):1635-1642.
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28. van Santvoort HC, Besselink MG, Bakker OJ, et al. A step-up
approach or open necrosectomy for necrotizing pancreatitis.
N Engl J Med. 2010;362(16):1491-1502.
29. Raraty MG, Halloran CM, Dodd S, et al. Minimal access retro-
peritoneal pancreatic necrosectomy: Improvement in morbid-
ity and mortality with a less invasive approach. Ann Surg. 2010;
251(5):787-793.
30. Papachristou GI, Takahashi N, Chahal P, Sarr MG, Baron TH. Per-
oral endoscopic drainage/debridement of walled-off pancreatic
necrosis. Ann Surg. 2007;245(6):943-951.
31. Seifert H, Biermer M, Schmitt W, et al. Transluminal endoscopic
necrosectomy after acute pancreatitis: A multicentre study with
long-term follow-up (the GEPARD Study). Gut. 2009;58(9):
1260-1266.
32. Voermans RP, Bruno MJ, van Berge Henegouwen MI, Fockens P.
Review article: Translumenal endoscopic debridement of orga-
nized pancreatic necrosis—the first step towards natural orifice
translumenal endoscopic surgery. Aliment Pharmacol Ther. 2007;
26(Suppl 2):233-239.
33. Mier J, Leon EL, Castillo A, Robledo F, Blanco R. Early versus
late necrosectomy in severe necrotizing pancreatitis. Am J Surg.
1997;173(2):71-75.
34. Besselink MG, Verwer TJ, Schoenmaeckers EJ, et al. Timing of
surgical intervention in necrotizing pancreatitis. Arch Surg. 2007;
142(12):1194-1201.
35. Uhl W, Warshaw A, Imrie C, et al. IAP guidelines for the surgi-
cal management of acute pancreatitis. Pancreatology. 2002;2(6):
565-573.
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 CHAPTER 55

Pancreatic Pseudocysts
Olga N. Tucker and Raul J. Rosenthal

INTRODUCTION A classification system for acute pancreatitis was published in

1993 following the International Symposium on Acute Pancreatitis
A pancreatic pseudocyst is a collection of pancreatic secretions in Atlanta, Georgia in September 1992.7,15 This was an attempt at
enclosed in a fibrous tissue layer in the absence of a lining epithe- reaching an international agreement to create a uniform set of
lium.1 In the majority of cases, pancreatic pseudocysts arise as a accepted clinically based definitions for acute pancreatitis, and
complication of acute or chronic pancreatitis. Pancreatic pseudo- associated local complications including pancreatic pseudocysts.
cysts are caused by pancreatic ductal disruption due to pancreatic (Level 5 evidence).
parenchymal necrosis or injury, or following increased pancreatic Definitions of local complications of acute pancreatitis accord-
ductal pressure due to obstruction of the pancreatic ductal system ing to the Atlanta Criteria (Level 5 evidence)7 are as follows:
by calculi, protein plugs, stenosis or localized fibrosis usually com-
plicating chronic pancreatitis leading to extravasation of pancre- • Acute fluid collections (Figure 55.1): Occur early in the course
atic secretions.2-5 Pancreatic pseudocysts, therefore, communicate of acute pancreatitis, are located in or near the pancreas, and
either indirectly through the injured pancreatic parenchyma or always lack a wall of granulation of fibrous tissue. Spontaneous
directly with the pancreatic ductal system.
There are several important issues to consider in the man-
agement of pancreatic pseudocysts including exclusion of other
causes of pancreatic cystic lesions by appropriate clinical and
radiological features, consideration of the optimal management
approach, determination of the optimal timing for intervention,
and awareness and management of potential complications.

1. What is the definition of acute fluid collections, pancreatic

necrosis, pancreatic abscess, and pancreatic pseudocyst?
Accurate definition of a pancreatic pseudocyst with differentiation
from other local complications of pancreatitis, including pancre-
atic and peripancreatic fluid collections, pancreatic necrosis, and
pancreatic abscess, is essential for optimal management and out-
come. Expert opinion from a number of international conferences
and published guidelines from specialty groups have attempted
to clarify the terminology for acute pancreatitis and its compli-
cations, including the international conferences in Marseilles
(1963), Cambridge (1983), Marseilles (1984), Marseilles-Rome
(1988), and Atlanta (1992), and guidelines of the Intractable Pan-
creatic Disease Investigation and the Research Group of the Japa-
nese Ministry of Health, and Welfare (1987), the British Society
of Gastroenterology 1998), the Japanese Working Group (2006),
and most recently the Japanese guidelines for the management of Figure 55.1 CECT demonstrating an acute peripancreatic fluid
acute pancreatitis Working Group (2010).6-14 collection in a patient with acute pancreatitis.
437

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 438 ■ Surgery: Evidence-Based Practice
Figure 55.2 CECT demonstrating pancreatic necrosis, acute
peripancreatic fluid collection and ascites in a patient with acute
pancreatitis.
regression occurs in approximately 50% of cases. In the other
50%, an acute fluid collection progresses to a pancreatic abscess
or pseudocyst.
• Pancreatic necrosis (Figure 55.2): Diff use or focal area(s) of non-
viable pancreatic parenchyma, typically associated with peri-
pancreatic fat necrosis. Nonenhanced pancreatic parenchyma
>3-cm diameter or involving >30% of the area of the pancreas
is required.
• Acute pancreatic pseudocyst (Figure 55.3): (1) A collection of
pancreatic juice enclosed by a wall of fibrous or granulation tis-
sue, which arise as a consequence of acute pancreatitis, pancreatic
trauma, or chronic pancreatitis. (2) Their formation requires 4 or
more weeks from onset of pancreatitis. (3) Pseudocyst contents
should consist of clear pancreatic fluid with no pus or necrotic
debris. (4) Pseudocyst are round or ovoid and most often ster-
ile. In the presence of pus the lesion is termed a “pancreatic
abscess.”
• Pancreatic abscess: Circumscribed, intra-abdominal collection
of pus, usually in proximity to the pancreas, containing little or
no pancreatic necrosis, which arises as a consequence of acute
pancreatitis or pancreatic trauma. Usually arises >4 weeks after
onset of symptoms.
However, in 2008, a review by Bollen et al.16 on 447 articles retri-
eved using a Medline literature search on studies published after
1993 on the use of the Atlanta Criteria in the defi nition and
management of acute pancreatitis, including 3 meta-analysis,
34 randomized controlled trials, 12 guidelines, and 82 reviews,
suggested the existence of a large variation in the utilization
and interpretation of the Atlanta defi nitions of local compli-
cations including pancreatic pseudocysts. (Level 2 evidence)
Alternative or nonuniform definitions were frequency used.
The authors suggested the need for a revision of the criteria.16
In 38 reviewed articles, pseudocysts were defi ned as collections
containing both fluid and solid necrotic debris.16 According to
Bradley,17 the defi nition of a pancreatic pseudocyst should be an
PMPH_CH55.indd 438
Figure 55.3 CECT demonstrating a large pancreatic pseudo-
cyst causing external compression of the stomach anteriorly.
encapsulated homogenous fluid collection without necrotic con-
tents, and should be carefully distinguished from a peripancreatic
acute fluid collection to determine appropriate management. The
authors concluded that treatment outcome in many published
studies could not be interpreted with accuracy due to the incon-
sistencies in reporting techniques of distinctions between acute
fluid collections and pancreatic pseudocysts, and acute and
chronic pseudocysts.16
In 2010, a revised edition of the Japanese guidelines for the
management of acute pancreatitis was published. The publication
of revised guidelines so soon after the previous guidelines in 2006
was justified on the basis of a summary of activities and reports of
shared studies conducted in 2008. The revised guidelines included
a new severity classification and clinical indicators (pancreatitis
bundles) to improve the quality of management, and new termi-
nology was proposed for pancreatitis and its complications.14
Definitions of local complications of acute pancreatitis accord-
ing to the revised Japanese guidelines are as follows:14
• Acute fluid collections: Exudate collection that often occurs
within the pancreas or in the parapancreatic tissue in the early
phase of the disease. It may progress as far as the anterior
paraphrenic cavity, the mesocolon, and beyond the inferior
renal portion. It is also characterized by lack of the fibrous wall.
Pleural fluid, ascites, and fluid collection as far as the cavity of the
omental bursa occur as a reaction against inflammation, so these
features are not defined as acute exudate collection.
• Pancreatic necrosis: Diff use or localized necrosis of the pancre-
atic parenchyma and is differentiated from necrosis occurring
around the pancreas and that of extrapancreatic adipose tissue.
The detection of a poorly visualized area by contrast-enhanced
computed tomography (CECT) does not necessarily suggest the
presence of necrosis in all the cases involved and that detection
of an area that is not visualized, particularly in the acute phase,
may suggest the presence of temporary ischemia, which can be
reversible.
• Acute pancreatic pseudocyst: The type of pseudocyst with a wall
structure of granulation or fibrotic tissue. It is accompanied
5/22/2012 5:38:38 PM

by the collection of pancreatic juice and the tissue of liquefac-
tion necrosis, and often occurs 4 weeks after the onset of acute
pancreatitis. It may resolve spontaneously, although it may
persist for a long time. It may be complicated by infections or
bleeding.
• Pancreatic abscess: An abscess accompanied by localized pus
collection in the pancreas and adjacent organs. However, there is
usually no necrosis within the pancreas, or there is only a small
amount if any. Because pancreatic abscess consists of necrotic
tissue as well as liquid components, there are indications that it
is induced by the liquefaction of tissue necrosis.
Answer: The Atlanta Classification system provides a defini-
tion for pancreatic pseudocyst and local complications of acute
pancreatitis. (Level 5 evidence; Grade D recommendation) The
revised Japanese guidelines provide further definitions of termi-
nology associated with acute pancreatitis. However, neither of the
systems has been validated, or used uniformly or consistently, to
allow accurate comparison of management outcome between cen-
ters. (Level 2 evidence; Grade C recommendation).
2. What is the true incidence of pancreatic pseudocysts?
The reported incidence of pancreatic pseudocysts is low at 0.5 to
1 per 100,000 adults per year or 1.6% to 4.5%.18,19 However, the true
incidence of pancreatic pseudocysts is unknown due to inconsis-
tencies in the application of a uniform definition, the timing of
diagnosis, differing techniques of clinical monitoring, the use
of varying diagnostic modalities, the use of varying clinical and
radiological severity grading systems, the complexity and variety
of the underlying pathology, and the wide use of multiple inter-
ventional techniques with poor reporting of treatment outcomes.
Incidence rates of pseudocyst formation after acute pancreatitis,
trauma, iatrogenic injury, and autoimmune pancreatitis have been
reported in case reports, multiple case series, and review articles.
(Level 4 evidence).
Many reported case series on the incidence and management
of pseudocysts are limited by population heterogeneity, small
patient numbers, and mixed data on patients with mild acute
nonnecrotizing and severe acute pancreatitis, and/or the inclu-
sion of patients with varying etiology, including acute and chronic
pancreatitis. Mild acute and severe acute pancreatitis represent
contrasting ends of a wide spectrum of disease severity with sig-
nificant differences in complication and survival rates. In addition,
there are many cases of severe acute pancreatitis, which are not
found until autopsy.18,19 The incidence of pancreatic pseudocysts
in patients with chronic pancreatitis is probably grossly underesti-
mated as long-term follow-up is poor. In contrast to patients with
acute pancreatitis, those with chronic pancreatitis have a greater
potential to develop local complications over the prolonged period
of their illness.
The majority of acute fluid collections complicating acute
nonnecrotizing pancreatitis will resolve spontaneously with
pseudocyst formation in a minority.20 The incidence of acute
pancreatic pseudocysts is higher after severe acute pancreatitis,
with higher morbidity and mortality rates related to a higher
incidence of complications.21 The use of inaccurate and impre-
cise defi nitions of acute pancreatic pseudocysts has resulted in
inaccurate representation of data. One of the most common dif-
ficulties is the differentiation of organized pancreatic and peri-
pancreatic necrosis with associated fluid sequestration from an
PMPH_CH55.indd 439
Pancreatic Pseudocysts ■ 439
acute pancreatic pseudocyst with pancreatic necrosis.22 These
clinical entities are very different in terms of treatment approach
and prognosis.
Answer: The true incidence of pancreatic pseudocyst is
unknown, due to the heterogeneity of published reports and incon-
sistencies in the published literature. (Level 4 evidence; Grade C
recommendation).
3. Does the etiology of pancreatitis influence the likelihood of
pancreatic pseudocyst formation?
Pancreatic pseudocyst formation is more commonly seen in
patients with chronic pancreatitis compared with acute pan-
creatitis with a reported incidence of 30% to 40% and is more
common after alcohol-induced than nonalcohol-related panc-
reatitis.4,5,18,19,23-25 Alcohol-related pancreatitis is the major cause
documented in most series and is responsible for a reported 59%
to 78% of all pseudocysts.4,18,23 Patients with chronic pancreati-
tis who develop acute exacerbations have a higher incidence of
pseudocyst formation than patients with acute pancreatitis,
whereas patients with gallstone-related acute pancreatitis appear
to have a lower incidence. (Level 4 evidence). However, pancreatic
pseudocysts can occur with any condition that results in pancre-
atic ductal disruption or injury, or following increased pancre-
atic ductal pressure due to obstruction of the pancreatic ductal
system.26 In the case of acute pancreatitis, approximately 20% of
patients develop a severe form with local and systemic complica-
tions. Pancreatic enzymatic activation leads to the formation of
pancreatic and peripancreatic fluid collections. These fluid col-
lections represent an exudative or serous reaction to pancreatic
injury and occur in approximately 50% of patients with mod-
erate to severe pancreatitis. Approximately 50% of these collec-
tions spontaneously resolve within 6 weeks of acute presentation.
In approximately 5% to 15% a profound inflammatory response
along the serosal surfaces of the adjacent organs results in the for-
mation of a fibrous pseudocapsule and a pseudocyst develops.4,25,27
Approximately 20% to 40% of pancreatic pseudocysts develop in
patients with chronic pancreatitis related to chronic and pro-
gressive ductal obstruction, dilation, and disruption.4,25 Other
causes of pancreatic pseudocyst formation include blunt trauma,
penetrating trauma, iatrogenic surgical pancreatic injury, pan-
creatic ductal adenocarcinoma, very rarely hemorrhagic pancre-
atic pseudocysts associated with autoimmune pancreatitis, and
idiopathic.28-32
Answer: Pancreatic pseudocyst formation is more commonly
seen in patients with chronic pancreatitis compared with acute
pancreatitis, and is more common after alcohol-induced than
nonalcohol-related pancreatitis. However, pancreatic pseudocysts
can occur with any condition that results in pancreatic ductal dis-
ruption or injury, or following increased pancreatic ductal pres-
sure due to obstruction of the pancreatic ductal system. (Level 4
evidence; Grade C recommendation).
4. Can an increased risk of pancreatic pseudocyst formation be
predicted at admission in patients presenting with pancreatitis?
A small number of published retrospective and prospective cohort
studies and case series have suggested that the presence of ascites,
pleural eff usion, a high Ranson score, and pancreatic necrosis
increases the risk of acute pancreatic pseudocyst formation.33-35 In
a retrospective cohort study, Diculescu et al.36 examined predictive
5/22/2012 5:38:38 PM
 440 ■ Surgery: Evidence-Based Practice
factors for pancreatic pseudocyst formation in 62 patients admit-
ted over a 1-year period with acute pancreatitis.36 A predomi-
nance of alcoholic acute pancreatic was seen in 58.1%, followed
by biliary (22.6%), hypertriglyceridemia (8.1%), following endo-
scopic retrograde cholangiopancreatography (ERCP) (3.2%) and
unknown etiology (8%). Splenic or portal vein thrombosis was
present in 5%, 30.6% had surgical intervention, and two patients
(3.2%) died. Twenty-two patients (35.5%) developed pancreatic
pseudocysts, which were multiple in 12 patients. Alcoholic eti-
ology of acute pancreatitis was the only categorical variable in
univariate analysis significantly associated with pseudocyst pres-
ence. Multivariate analysis demonstrated alcoholic etiology and
lower values of serum alkaline phosphatase predicted the occur-
rence of pseudocysts.36 Acute pseudocyst formation could be pre-
dicted with a specificity of >90% if serum alkaline phosphatase
was less than a cutoff value of two times the upper normal limit
(UNL = 185 U/L). Lower levels of serum alkaline phosphatase
were seen as a risk factor for pseudocyst formation in patients
with nonalcoholic etiology. However, 48.4% of the patients had
concomitant chronic liver disease with either fatty liver disease or
cirrhosis on imaging.36
In a recent publication, Poornachandra et al.37 prospecti-
vely analyzed clinical, biochemical, and radiologic parameters
at admission in 65 of 75 recruited patients with acute pancrea-
titis. Twenty-four (36.9%) patients had alcohol-related, whereas
18 (27.7%) had gallstone-related acute pancreatitis. CECT dem-
onstrated pancreatic necrosis in 38 (58.46%) patients, and acute
fluid collections in 34 (52.3%). Thirty-four (52.3%) patients devel-
oped an acute pancreatic pseudocyst, with multiple pseudocysts
in the majority (52.9%) after 4 weeks of follow-up. Identified
factors associated with pseudocyst formation after acute pan-
creatitis on univariate analysis included male sex, a palpable
mass, blood sugar >150 mg%, presence of necrosis, acute fluid col-
lection, ascites, pleural eff usion, a high grade of pancreatitis, sep-
sis, elevated C-reactive protein, acute fluid collection at 2 weeks,
and a high CT severity index (CTSI) score. The etiology of the
acute pancreatitis was not significantly associated with pseudo-
cyst development. On multivariate logistic regression analysis, it
was shown that male sex, a palpable abdominal mass, ascites, and
a high CTSI score were significantly associated with formation the
an acute pseudocyst.37
Answer: There is limited published data on the factors at
admission that predict the development of a pseudocyst follow-
ing acute pancreatitis. Male sex, a palpable abdominal mass,
ascites, and a high CTSI score on admission may predict pseudo-
cyst development in acute pancreatitis. (Level 2 evidence; Grade C
recommendation).
5. What is the risk of nonoperative expectant management of a
pancreatic pseudocyst?
Current evidence supports intervention in patients who are symp-
tomatic or who develop a pseudocyst-related complication (Levels
3 and 4 evidence). Controversies exist with regard to the need for
intervention in those pseudocysts that are asymptomatic. In these
patients, factors such as the diameter, location, persistence of the
pseudocyst during follow-up and the length of time the pseudo-
cyst has been present have been used as indicators to determine
the need for intervention because of a potential higher risk of
complications. Some authors advocate elective intervention in
all patients with uncomplicated acute pancreatic pseudocysts
PMPH_CH55.indd 440
greater than 6 cm in size, which persist for longer than 6 weeks
regardless of symptoms due to reduction in the possibility of
spontaneous resolution and a reported increase in complications
(rupture, abscess, jaundice, and hemorrhage) during extended
periods of observation.21,38,39 Complications can arise in the pres-
ence of a pancreatic pseudocyst including pseudocyst infection with
abscess formation, intracystic hemorrhage, rapid expansion with
increasing abdominal pain, extrinsic compression, and obstruction
of adjacent organs including the esophagus, stomach, duodenum,
jejunum, colon, biliary tree, or retroperitoneal structures.21,40,41 If
the pseudocyst extends into the mediastinum, patients may present
with dyspnea, chest pain, palpitations, dysphagia, hemoptysis, acute
respiratory compromise, or cardiogenic shock depending on the
location and size of the lesion. Cyst rupture can occur into an adja-
cent hollow viscus such as the stomach, duodenum, or colon, or an
adjacent body cavity.21,41,46 Rupture into the peritoneal cavity results
in pancreatic ascites, while rupture into the pleural space results in
a pleural effusion or haemothorax.42-44 In addition, rupture into the
pericardium, or bronchus with fistula formation can occur.45
Abdominal wall pseudocyst fluid collection have been
reported in isolated case series due to a slow leak or rupture of
a pancreatic pseudocyst.47 Pseudocysts may erode into an adja-
cent major artery, more commonly the splenic artery, resulting
in a pseudoaneurysm and/or hemorrhage.48 A massive gastroin-
testinal bleed can occur if the pseudoaneurysm communicates
with the main pancreatic duct, a condition known as hemosuc-
cus pancreaticus. Portal and splenic vein thrombosis have been
reported in patients with pancreatic pseudocysts with a persistent
inflammatory response with development of gastric varices. Rarer
complications including pancreatic pseudocyst-inferior vena cava
fistula, pancreaticorenal fistula, pancreaticocholedochal fistula,
gastric necrosis, and perforation have been described.49-52
In a series by Vitas et al.53 of 114 patients with the diagnosis
of a pancreatic pseudocyst followed up over a period of 5 years, 46
patients had primary surgical intervention, with 13% requiring
emergency operative treatment for pseudocyst-related compli-
cations. The remaining 68 patients were managed expectantly.
Of these, severe life-threatening complications developed only
in six patients (9%) over a mean period of 46 months. Nineteen
patients required elective surgery over a 5-year period related to
the pseudocyst or pancreatitis-associated complications. Of 24
patients treated conservatively with satisfactory radiological follow-
up, spontaneous resolution was seen in 57%, with 38% resolving
more than 6 months following initial diagnosis.53 Operative inter-
vention was more common in large pancreatic pseudocysts >6.9-cm
diameter; however, no serious complications occurred in seven
patients with pseudocysts >10-cm diameter treated expectantly.53
Cooperman et al.54 advocated expectant management of asym-
ptomatic pseudocysts due to the natural history of spontaneous
resolution. Yeo et al.46 also support a conservative approach in
asymptomatic patients able to tolerate oral intake, with a reported
spontaneous resolution rate of 60% at 1 year with stability or size
reduction in 40% treated nonoperatively in the absence of pseudo-
cyst-related mortality. Again, large pseudocyst size predicted the
need for surgical intervention, with operative drainage required
in 67% of those greater than 6-cm diameter, whereas only 40% less
than 6-cm diameter required operative intervention.46
Answer: Nonoperative expectant management of asymptom-
atic pseudocysts is feasible due to the natural history of sponta-
neous resolution and the low incidence of severe life-threatening
complications. (Level 4 evidence; Grade C recommendation).
5/22/2012 5:38:38 PM

6. What is the incidence of complicated pancreatic pseudocysts?
Although the occurrence of complications is uncommon, no accu-
rate figures are available from the published literature on the true
incidence of morbidity associated with pancreatic pseudocysts.
Available data has been extracted from multiple case series, case
reports, and review articles.18,21,38,46,47,49-52,55-60 (Level 4 evidence).
The incidence of complicated pseudocysts is higher in patients
following severe acute pancreatitis, as the majority of acute fluid
collections in patients with mild acute nonnecrotizing pancrea-
titis resolve without pseudocyst formation.20 Ocampo et al.,21
reported complications in 43 (59%) of 73 patients over a 10-year
period with an acute pancreatic pseudocyst following severe acute
pancreatitis including infection in 74%, perforation in 21%, and
bleeding in 4.6%.
Answer: Complications of pancreatic pseudocysts are uncom-
mon; however, no accurate figures of the true incidence are
available in the published literature. (Level 4 evidence; Grade C
recommendation).
7. What is the optimal time for intervention once the diagnosis
of pancreatic pseudocyst has been confirmed?
Once identified, the timing of intervention for pancreatic pseudo-
cysts remains controversial.18-20,38,39,46,53,54,61,62 Experimental studies
by Warren et al.63 suggest a minimum period of 6 weeks to allow
cyst wall maturation. As it is not always possible to date the onset
of pseudocyst formation a wait period of 6 weeks from the time
of diagnosis has been recommended.38,64 Intervention is indicated
in the presence of symptoms directly attributable to the pancre-
atic pseudocyst and in the presence of pseudocyst-related com-
plications. Others advocate a nonoperative, noninterventional
approach in selected patients.46,53,54
Warshaw et al.39 defi ned clinical and biochemical criteria in
a series of 42 patients, of whom 28 had underlying chronic pan-
creatitis, to guide the time of optimal drainage in patients with
pancreatic pseudocyst. They observed differences in the natural
history and treatment requirements dictated by etiology. Sponta-
neous resolution occurred in only three patients following ante-
cedent acute pancreatitis, although it was not seen in any patient
with chronic pancreatitis. They suggested that a pseudocyst is
unlikely to resolve when persistent for greater than 6 weeks, in the
presence of chronic pancreatitis, a thick cyst wall on ultrasound,
and a pancreatic duct abnormality other than communication
with the pseudocyst.39 In the setting of chronic pancreatitis, the
authors concluded that internal drainage procedures should be
performed at the time of diagnosis to avoid unnecessary addi-
tional expense and potential increased complications. 39 Serum
levels of old amylase may help guide the optimal drainage time
indicating a mature pseudocyst.39 In a small series of study of
37 patients with chronic pancreatitis and pancreatic pseudo-
cysts by Talar-Wojnarowska et al.65 spontaneous regression was
observed in seven pseudocysts (18.9%). The mean size of the
pancreatic pseudocysts in the series was 7.8 cm (range 2–16 cm).
Stable lesions in terms of diameter and absence of symptoms were
reported in nine patients (24.3%). Therapeutic intervention was
required in 21 patients (56.8%) involving percutaneous drainage
in 10.8%, endoscopic drainage in 27.1%, and surgical interven-
tion in 18.9%. The overall recurrence rate in the series was high
at 33.3%. Again the size of the primary pseudocyst was a statis-
tically significant factor determining outcome where the mean
size for those patients requiring interventional management was
PMPH_CH55.indd 441
Pancreatic Pseudocysts ■ 441
9.6 cm compared with 4.2cm for patients undergoing successful
conservative management.65
Answer: There are no published randomized controlled
trials in the literature that defi ne the optimal time of interven-
tion for pancreatic pseudocysts. Evidence from highly selected
multiple case series, case reports, and review articles support an
expectant approach in patients with asymptomatic pseudocysts
following acute pancreatitis regardless of size for a minimum
of 6 weeks after diagnosis. In the setting of chronic pancreati-
tis, immediate intervention to drain the cyst is feasible and may
reduce postoperative complications. (Level 3 evidence; Grade C
recommendation).
8. What are the optimal imaging modalities for diagnosis of a
pancreatic pseudocyst?
A variety of radiological techniques are utilized in diagnosis,
monitoring, and planning of therapeutic intervention for pan-
creatic pseudocysts, including transabdominal ultrasonography
(USS), CECT, magnetic resonance imaging (MRI), and magnetic
resonance cholangiopancreatography (MRCP); combined radio-
logical and endoscopic modalities include ERCP and endoscopic
USS (EUS). Prospective data from randomized controlled trials
and large patient series comparing currently available imaging
modalities is lacking. CECT is the preferred and most com-
monly utilized modality to facilitate the accurate diagnose,
define extent of disease, and plan percutaneous intervention if
appropriate.66,67 Balthazar’s CTSI, based on combined assess-
ments of peripancreatic inflammatory collections and degree of
pancreatic necrosis, can be used to predict morbidity and mor-
tality in patients with severe acute pancreatitis.68 However, the CT
appearances cannot characterize the local complications of acute
pancreatitis, and in the acute phase cannot predict the development
or extent of pseudocyst formation. Controversies exist regarding
interobserver variability in interpretation of CECT, and the vary-
ing definitions used to define acute peripancreatic fluid collections
including pancreatic pseudocysts. A recent study performed to
assess the interobserver agreement of categorizing peripancreatic
collections on CECT using the Atlanta Classification in patients
with acute necrotizing pancreatitis, who underwent surgery from
2000 to 2003, involving five radiologists from 11 hospitals dem-
onstrated poor concordance despite the radiologists’ awareness
of the clinical condition of the patient and the timing of the scan.
All five radiologists agreed in only 4% of 70 cases, four of the five
agreed in 19%, and three agreed in 60% using terminology defined
by the Atlanta Criteria to define CECT findings.69 In most of the
published series, the differentiation between an acute fluid col-
lection and a pseudocyst was determined 4 weeks from onset of
disease; however, different time periods have been described from
3 to 8 weeks.35,70-72 In further publications, pseudocysts have been
defined as collections containing fluid and necrotic debris.73-75 As
previously stated pseudocysts should be devoid of solid necrotic
debris. Controversy also exists in correct differentiating pseudo-
cysts and pancreatic abscesses as CECT has a low sensitivity in the
detection of necrotic debris in collections predominantly containing
fluid, and poor discriminatory ability between sterile and infected
collections.22,66,76-78 Misinterpretation of CECT findings may result
in instrumentation of sterile collections causing infection, or a delay
in appropriate intervention. MRI and EUS can more accurately
detect the presence of necrotic debris, and may be of additional
benefit in guiding appropriate intervention (Figure 55.4).66,76,79
5/22/2012 5:38:38 PM
 442 ■ Surgery: Evidence-Based Practice
Figure 55.4 MRCP demonstrating a large pancreatic pseudo-
cyst with no communication with the pancreatic ductal system
and normal biliary tree.
Demonstration of communication with the pancreatic ductal
system at ERCP is thought to differentiate a pancreatic cystic neo-
plasm from a pseudocyst. However, pitfalls can occur as reported
by Ellis et al.,80 who reported two cases of mucinous cystadenomas
with main pancreatic duct communication. Upper gastrointestinal
endoscopy can be performed to plan endoscopic or surgical drain-
age (Figure 55.5). EUS is an excellent diagnostic and therapeutic
tool due to its high resolution and the proximity of the transducer
to the pancreas.81,82 However, it has limited efficacy in diagno-
sis and management of lesions in the distal body and tail of the
pancreas. Additional limitations include the operator-dependent
nature of the investigation. Radial and linear EUS, elastography,
contrast-enhanced EUS, and fine-needle aspiration (FNA-EUS)
can be performed, where diagnostic dilemmas exist to differenti-
ate a focal pancreatic mass.81
Answer: There are no published randomized controlled tri-
als in the literature to directly compare currently available imag-
ing modalities in the diagnosis and management of pancreatic
pseudocysts. Evidence from multiple case series, case reports,
reviews, and nonrandomized trials support CECT as the imaging
modality of choice. Prior to anticipated intervention, an MRI scan
or an EUS should be performed to exclude necrotic debris in the
collection. (Level 3 evidence; Grade C recommendation).
9. What is the optimal method of therapeutic intervention for
symptomatic pancreatic pseudocysts?
Indications for intervention include symptomatic, large (>6-cm
diameter), enlarging, and complicated pseudocysts, and where
there is a suspicion of an underlying malignancy.25,38,39,62 Thera-
peutic intervention takes the form of internal or external drain-
age, or surgical resection. Options include percutaneous external
PMPH_CH55.indd 442
Figure 55.5 Upper gastrointestinal endoscopy demonstrating
protrusion of a large pancreatic pseudocyst into the posterior
wall of the stomach.
drainage, ERCP with transpapillary pancreatic duct stenting,
endoscopic internal drainage, laparoscopic, laparoscopic-assisted,
or open surgical internal drainage and/or resection.74,83-90 To
date, no prospective randomized trials have directly compared
percutaneous, endoscopic, and surgical approaches. The manage-
ment is therefore usually based on the existing local or regional
expertise. Clinical decisions are based on available clinical evi-
dence from retrospective cohort studies, case series, and iso-
lated case reports. (Level 2 evidence) Factors that determine the
approach and timing of intervention include etiology, maturity of
the cyst wall, cyst location, the presence or absence of complica-
tions, and the availability of local expertise.38,39,63,64,85 The optimal
approach and timing of intervention should be determined in a
multidisciplinary setting incorporating the experience of radiolo-
gists, gastroenterologists, and surgeons.
Percutaneous external drainage can be achieved using a
transabdominal USS– or CT-guided approach. A drainage pigtail
catheter is placed percutaneously under local anaesthetic into the
fluid cavity of the pseudocyst and left in situ until confirmation of
minimal output and/or cavity resolution. Contrast material can be
injected into the cyst cavity to confirm resolution. This approach
is associated with a low risk of mortality, but a complication rate
of 16% in some series with a risk of hemorrhage in 1% to 2%,
infection in 9%, traversing of viscera/pleural space in 1% to
2%, and pancreaticocutaneous fistula formation. Percutaneous
external drainage is contraindicated in patients with cysts con-
taining solid or bloody material, and in patients with an obstructed
ductal system.84,91 Three-dimensional USS and color Doppler can
be used to visualize structures such as blood vessels, small bowel
and colon, and guide the accurate placement of the catheter. Per-
cutaneous drainage is generally performed under CT guidance,
5/22/2012 5:38:39 PM

with successful outcomes reported in the diagnosis and drainage
of sepsis in infected pancreatic pseudocysts, and in patients with
symptomatic or complicated pseudocysts that are too unwell to
undergo a more definitive procedure.21,87 In a series by Ocampo
et al.,21 CT-guided percutaneous and endoscopic drainage were
successful in controlling sepsis in 11 of 13 patients (85%) with
severe organ failure and facilitated subsequent definitive surgical
management.21,87
Open surgical drainage as an initial therapeutic option has
been largely replaced by minimally invasive techniques includ-
ing endoscopic and laparoscopic approaches.83,85,92-98 Endoscopic
drainage can be performed transmurally through the wall of
the stomach or duodenum, or transpapillary via the pancreatic
duct.74,59,99,100 Transpapillary drainage is performed when the
pancreatic pseudocyst is demonstrated to communicate with
the main pancreatic duct at ERCP, or in the presence of a distal
pancreatic duct stricture. In some reported series endoscopic
transmural drainage has been associated with a higher success
rate, with lower morbidity, mortality, and recurrence rates than
surgery.73,99 Cavallini et al.100 recently reported a retrospectively
analyzed case series of 55 patients who underwent endoscopic
drainage of symptomatic pancreatic pseudocysts with proven
direct contact between the pseudocyst itself and the gastric wall
following pancreatitis or pancreatic resection from January
1999 to June 2008.100 In this study, a postprocedural CTET was
performed at 1 week, and an USS or CECT at 1 and 6 months,
with an annual USS thereafter. Of the 55 patients studied, 28
had a pseudocyst complicating acute and two complicating
chronic pancreatitis. The overall technical success rate was
73.3% in the patients with pseudocyst following pancreatitis
compared with 84% in those following pancreatic resection. The
procedure complication rate was much higher in the pancrea-
titis group at 23.3% compared with 8% in the resection group.
Six patients in the pancreatitis group developed a pseudocyst
infection and underwent surgical intervention within 2 weeks.
Two deaths occurred due to major hemorrhage with a mortal-
ity rate 1.8%. Pseudocyst recurrence was seen in 6 of 43 treated
patients (13.9%) all of whom were in the pancreatitis group. Th is
study demonstrated the high technical success rate of transmu-
ral endoscopic drainage, but a high rate of procedure-related
complications and recurrences particularly in patients with
pancreatitis-associated pseudocysts.100 Baron et al.101 previously
reported a higher resolution rate in with chronic (92%) than
acute pseudocysts (74%) or necrosis (72%) with endoscopic
drainage, with a higher rate of complications in patients with
necrosis (37%) than chronic (17%) or acute pseudocysts (19%).
Recurrence rates at a median follow-up of 2.1 years were 16%,
and were more commonly seen in patients with necrosis (29%)
than acute (9%) or chronic pseudocysts (12%).These fi ndings sug-
gest outcome differences following endoscopic drainage depen-
dent on the nature of the pseudocyst.101 The role of concomitant
transpapillary duct stenting at endoscopic drainage is unclear
and benefit has only been demonstrated in one study.102
The use of EUS-guided pseudocyst drainage with improved
visualization of the contact area between the pseudocyst and
the gastric wall on EUS and delineation of anatomy with avoid-
ance of injury to major vessels or bowel has been advocated over
conventional endoscopy Two small randomized controlled tri-
als demonstrated a significantly higher success rate in patients
PMPH_CH55.indd 443
Pancreatic Pseudocysts ■ 443
randomized to EUS.93,103 In a study by Varadarajulu et al.103 100%
of patients randomized to EUS-guided drainage underwent suc-
cessful drainage compared with 33.3% randomized to drainage
guided by esophagogastroduodenoscopy (EGD). Based on as-
treated analysis, treatment was successful in 23 patients man-
aged by EUS and in four patients treated by EGD (80%) with
no significant difference in rates of treatment success between
EUS and EGD after stenting. Although not statistically signifi-
cant, EUS was associated with less complications than EGD.103
Park et al., randomized 60 consecutive patients with pancreatic
pseudocysts to undergo either EUS- (n = 31) or EGD-guided
(n = 29) drainage of pancreatic pseudocysts.93 The technical suc-
cess rate was higher for EUS (94%) than EGD (72%). Complica-
tions occurred in 7% of the EUS compared with 10% of the EGD
group. Long-term follow-up showed no significant difference in
clinical outcomes between EUS and EGD.103 The major limita-
tions in these studies is small patient numbers with inclusion of
only 29 patients and 60 patients, respectively.93,103
Laparoscopic techniques include endogastric, transgastric,
or exogastric cystgastrostomy, Roux en Y or loop cystjejunos-
tomy.83 A review of the published literature on laparoscopic
and endoscopic approaches to internal drainage of pancreatic
pseudocysts from 1974 to 2005 was published by Aljarabah
et al.83 Forty-four cohort series were identified. No random-
ized control or comparative studies were identified. Laparo-
scopic procedures were performed in 118 patients in 19 reports,
and endoscopic procedures in 583 patients in 25 reports. The
reporting of data related to the underlying etiology, patient
demographic data, pseudocyst size, duration of the procedure,
procedural complications including estimated blood loss, and
hospital stay was better in the laparoscopic group. The endo-
scopic approach was more widely employed with fivefold
greater number of reported patients. The mean cyst diameter
was significantly smaller in the endoscopic group with a mean
cyst diameter of 7 cm compared with 13 cm in the laparoscopic
group. In three reports, pancreatic pseudocysts as small as 1.5- to
2-cm diameter were drained endoscopically.104-106 The success rate
in achieving pseudocyst drainage and resolution was higher
after the laparoscopic (98.3%) compared with the endoscopic
(80.8%) approach. Postprocedural complications were observed
in 4.2% of patients after laparoscopic versus 12% after endo-
scopic drainage. Two patients died after endoscopic drainage
resulting in a mortality rate of 0.35%, with no deaths after lap-
aroscopic drainage. The mean follow-up period was longer at
24 months (range 0.5–70) after endoscopic than laparoscopic
drainage at 13 months (range 1–59) with reported recurrence in
14.4% and 2.5%, respectively.83
Answer: The optimal approach to pancreatic pseudocyst
drainage remains controversial. Minimally invasive internal
drainage techniques by endoscopic and laparoscopic approaches
are commonly employed. These two approaches are safe with
minimal morbidity and mortality. Although laparoscopic drain-
age has a higher success rate in achieving pseudocyst drainage
and resolution, a lower postprocedural complication rate, and a
lower recurrence rate, reported follow-up periods are significantly
shorter. The heterogeneity of the published reports and the lack of
consistency in the reporting of data limit direct comparison bet-
ween the two techniques. Only two small randomized controlled
trails have been performed comparing EUS- with EGD-guided
5/22/2012 5:38:39 PM
 444 ■ Surgery: Evidence-Based Practice

drainage of pancreatic pseudocysts. (Level 2 evidence; Grade C
recommendation).
10. Do delays in surgical intervention affect outcome?
Initial interventions in the management of pancreatic pseudocysts
are increasingly directed toward nonsurgical therapies includ-
ing percutaneous external drainage or endoscopic approaches
due to the perceived benefits of reduced invasiveness, and lower
morbidity and mortality rates. However, these techniques can be
associated with significant failure rates and complications.75,107,108
Subsequent surgical intervention is often required as a salvage
procedure to treat persistent or recurrent pseudocysts, or compli-
cations such as infection following percutaneous drainage.75,107,109
Some authors have suggested that primary nonoperative inter-
vention with delayed surgery is associated with a higher inci-
dence of postoperative complications, readmission, morbidity,
and mortality.107,110 Rao et al.107 retrospectively reviewed outcome
in 52 patients who underwent early surgical intervention com-
pared with 18 who underwent delayed surgery after failed CT and
endoscopic drainage. Perioperative morbidity was twice as fre-
quent in the delayed surgery group (33% vs. 14%), with increased
time to pancreatic pseudocyst resolution from the initial drain-
age attempt.107 In a study by Ito et al.,110 284 consecutive patients
admitted with pancreatic pseudocysts over a 15.5-year period
were identified retrospectively, of which 46 underwent initial
operative intervention.110 Percutaneous drainage was performed
in 89 patients of whom 42 required subsequent surgical interven-
tion for failure, while endoscopic drainage was performed in 73
patients of whom 33 required subsequent surgical intervention
for failure. There was no significant difference in patient demo-
graphics, etiology of pancreatitis, location, number, and diam-
eter of pseudocysts, or morphology of the main pancreatic duct
in patients treated with initial surgery versus those undergoing
delayed surgery. However, the median time from diagnosis to
surgery was three times longer in the delayed surgery group. The
main indication for intervention in the delayed group was pseudo-
cyst infection in 43% versus 13% in the early group. The delayed
surgery group had a significantly higher incidence of postopera-
tive pancreatic complications, infectious complications, periop-
erative morbidity, and readmission rates. Five patients died in the
postoperative period, of whom two died secondary to sepsis and
three due to organ failure. On univariate analysis failure of non-
surgical intervention was associated with pseudocyst diameter
>6 cm, main pancreatic duct stricture >2, nonsurgical interven-
tional procedures, and pseudocyst infection.110
Answer: Surgical intervention after failed nonoperative drain-
age procedures is associated with higher incidences of postopera-
tive infection, pancreatic complications, morbidity, mortality, and
readmission rates. (Level 3 evidence; Grade C recommendation).

Clinical Question Summary

Question
1 What is the definition of acute fluid
collections, pancreatic necrosis,
pancreatic abscess, and pancreatic
pseudocyst?
2 What is the incidence of pancreatic
pseudocysts?
3 Does the etiology of pancreatitis influence
the likelihood of pancreatic pseudocyst
formation?
4 Can an increased risk of pancreatic
pseudocyst formation be predicted at
admission?
5 What is the risk of nonoperative
management?
6 What is the incidence of complicated
pancreatic pseudocysts?
7 What is the optimal time for intervention
for pancreatic pseudocyst?
8 What are the optimal imaging modalities
for diagnosis of a pancreatic pseudocyst?
9 What is the optimal method of therapeutic
intervention?
10 Do delays in surgical intervention affect
outcome?
Answer Grade of References
Recommendation
There is a lack of uniformity and consistency C 7, 14
in the use of terminology to define
pancreatitis-related local complications
The true incidence of pancreatic pseudocyst C 4, 20-22
is unknown
Pancreatic pseudocysts can occur with C 4, 26
any condition that causes pancreatic
ductal disruption or injury, or following
increased pancreatic ductal pressure
Male sex, palpable mass, ascites and high C 36, 37
CTSI score on admission may predict
pseudocyst development
Nonoperative expectant management of C 46, 53, 54
asymptomatic pseudocysts is feasible
The true incidence of complicated pancreatic C 21, 55
pseudocyst is unknown
The optimal time for intervention is C 39, 65
unknown
CECT is the imaging modality of choice C 68, 111
The optimal approach to pancreatic C 83
pseudocyst drainage remains controversial
Yes C 107, 110

PMPH_CH55.indd 444 5/22/2012 5:38:39 PM

 Pancreatic Pseudocysts ■ 445

Levels of Evidence
Subject Year References Level of Strength of Findings
Evidence Recommendation
1 What is the definition of 1993 7, 14 2 C Widespread adoption of an
acute fluid collections, 2010 uniform terminology for
pancreatic necrosis, local complications of acute
pancreatic abscess, and pancreatitis is required
pancreatic pseudocyst?
2 What is the incidence of 1999 4, 20-22 4 C The true incidence is unknown
pancreatic pseudocysts? 2007
2008
3 Does the etiology of 1988 4, 26 4 C Pancreatic pseudocysts can be
pancreatitis influence the 1990 caused by multiple pathologies
likelihood of pancreatic
pseudocyst formation?
4 Can an increased risk of 2005 36, 37 2 C Male sex, palpable mass, ascites and
pancreatic pseudocyst 2010 high CTSI score on admission
formation be predicted may predict pseudocyst
at admission? development
5 What is the risk 46, 53, 54 4 C Expectant management of
of nonoperative asymptomatic pseudocysts is
management? feasible
6 What is the incidence of 2001 21, 55 4 C The true incidence is unknown
complicated pancreatic 2007
pseudocysts?
7 What is the optimal 1985 39, 65 3 C Timing of intervention is determined
time for intervention of 2011 by etiology, symptoms, and
pancreatic pseudocyst? complications
8 What are the optimal 1990 68, 111 3 C CECT is the imaging modality of
imaging modalities for 2010 choice. Prior to intervention, an
diagnosis of a pancreatic MRI or EUS should be performed
pseudocyst? to exclude necrotic debris
9 What is the optimal 2007 83 2 C Minimally invasive internal drainage
method of therapeutic by endoscopic and laparoscopic
intervention? approaches are safe
10 Do delays in surgical 1993 107, 110 3 C Surgical intervention after failed
intervention affect 2007 nonoperative drainage is
outcome? associated with a worse outcome

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Chronic Pancreatitis
Katherine A. Morgan and David B. Adams
INTRODUCTION
It is the merit of the common law that it decides the case first
and determines the principle afterwards. The life of the law
has not been logic; it has been experience.
Oliver Wendell Holmes
Chronic pancreatitis is a disorder whose pathogenesis is poorly
understood. Most likely, chronic pancreatitis does not have a single
causative agent but is multifactorial, related to genetic, anatomic,
and environmental factors. The disease itself has protean mani-
festations, and when we consider surgical treatment of chronic
pancreatitis we are speaking of more than one disease entity.
Peripancreatic fibrosis and inflammation may result in obstruc-
tion of the biliary tree, the duodenum, the transverse colon, the
splanchnic vasculature, as well as the pancreatic duct. Erosion of
peripancreatic vessels may cause life-threatening hemorrhage.
The number one indication for surgery in chronic pancreatitis
remains, however, intractable pain, and the complex splanchnic,
peripheral, and central pathways involved in chronic pancreatitis
pain is a promising focus of future research.
Surgical management of chronic pancreatitis is steeped in history
and tradition. Eponyms for pancreatic tumor resection procedures—
Kausch, Whipple, Longmire—have their counterparts in the 20th
century eponyms of pancreatic resection and drainage procedures
for chronic pancreatitis—Duval, Puestow, Gillesby, Partington,
Rochelle, Frey, Beger. The eponymic status of chronic pancreatitis
surgery points to the fact that though chronic pancreatitis is an
increasingly common cause of hospitalization, surgery for chronic
pancreatitis is not. The life of pancreatic surgery has not been
evidence, it has been experience. Individual surgeon and center-
based experiences dominate the literature, and because surgery for
chronic pancreatitis is uncommon compared with other abdominal
operations, large cohorts of randomized and case-controlled series
are hard to find. The merit of the conventional wisdom regarding
pancreatic surgery is that surgeon experience decides the case first
and the evidence is found afterwards.
449
PMPH_CH56.indd 449
CHAPTER 56
Nevertheless, insight, intuition, and individual surgeon inno-
vation have brought us to the modern era of pancreatic surgery,
and the future of surgery for chronic pancreatitis remains exciting
and challenging as we move the field forward with careful exami-
nation of the science of chronic pancreatitis and the published
evidence of its surgical management.
1. What is the current understanding of the underlying patho-
physiology of chronic pancreatitis?
The underlying pathophysiology of chronic pancreatitis is not well
defined. Although risk factors, most notably excessive alcohol con-
sumption, are recognized, direct causation has not been delineated.
A more complex etiologic mechanism likely exists involving the
interaction of multiple factors including environmental stressors,
genetic predisposition, and individual immunologic response. Sev-
eral theories on the pathophysiologic sequence of chronic pancrea-
titis have been proposed. The necrosis–fibrosis hypothesis contends
that pancreatic injury from repeated bouts of acute pancreatitis
results in fibrosis and chronic pancreatitis.1 An alternate modern
theory is the Sentinel Acute Pancreatitis Event (SAPE) hypothesis,
described by Whitcomb. In this model, it is theorized that a signifi-
cant acute pancreatitis event results in an inflammatory response.
This inflammatory injury incites an immune response that then
effects the development of fibrosis and pain.2
A genetic basis for susceptibility to pancreatitis is recognized.
In 1996, Whitcomb et al.3 described the cationic trypsinogen gene
(PRSS1), which is the mutational locus responsible in several fam-
ily cohorts of hereditary pancreatitis. The mutated genes code
for a trypsin that is inappropriately activated.3 Hereditary pan-
creatitis is an autosomal dominant disorder with incomplete pen-
etrance (80–93%) and phenotype. Approximately, half of patients
affected develop chronic pancreatitis and 40% of those develop
pancreatic cancer. Importantly, the discovery of PRSS1 led to
an understanding of the potential for genetic polymorphisms
as a mechanism for susceptibility to pancreatitis. It also led to
the concept that inappropriate activation of trypsin or failure to
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 450 ■ Surgery: Evidence-Based Practice
eliminate activated trypsin is a primary cause of acute and chronic
pancreatitis.3-6
Other susceptibility genes have been recognized, including the
anionic trypsinogen gene (PRSS2), serine protease inhibitor Kazal 1
(SPINK1; pancreatic secretory trypsin inhibitor), cystic fibrosis
transmembrane conductance regulator (CFTR), chymotrypsino-
gen C (CTRC), and calcium-sensing receptor (CASR).
The anionic trypsinogen gene (PRSS2) has been associated
with a loss of function mutation resulting in a form of trypsin that
is rapidly eliminated by autolysis. This mutation, found more com-
monly in healthy controls than in pancreatitis patients, is felt to be
protective against the development of pancreatitis.7
SPINK1 is an acute phase protein, upregulated during pancre-
atic inflammation, which plays an inhibitory role toward trypsin
by competitively binding to its active site. Its mutation is associated
with increased risk of pancreatitis.8 The cystic fibrosis transmem-
brane conductance regulator gene (CFTR) is thought to play a duct
flushing role in the prevention of pancreatitis. Mutation conveys a
loss of this protective function.9
Chymotrypsin C (CTRC) destroys prematurely activated
trypsin, protecting against pancreatitis. Its mutation is found in
4.8% to 12% of pancreatitis versus 0.7% to 1.1% of healthy controls,
translating to an increased risk of pancreatitis of fivefold.10,11 The
CASR is a membrane-bound G protein coupled receptor that is
involved in calcium homeostasis, mutation of which has been asso-
ciated with chronic pancreatitis. The hypercalcemic state favors
trypsin activation and inhibits trypsin autolysis.12
An altered immune response has been noted in the develop-
ment of chronic pancreatitis. HLA antigens have been examined
at length with inconclusive results. HLAA1 and HLABw39 are
expressed more frequently in cases of chronic pancreatitis.13
On a cellular level, pancreatic stellate cells (PSCs) have been
implicated in chronic pancreatitis. PSCs are homologous to
hepatic stellate cells and in the quiescent state are involved in fat
storage. In response to pancreatic injury, however, PSCs alter their
phenotype to extracellular matrix-producing cells, contributing
to the fibrotic parenchymal changes characteristic of chronic
pancreatitis.14
More complete understanding of the pathophysiology of pan-
creatitis on a genetic and cellular level is ongoing. This develop-
ing knowledge in the context of the SAPE hypothesis promises
to unveil potential points of early intervention in the future. For
example, understanding and avoidance of certain environmental
stressors can prevent triggering of the acute inf lammation.
Enzyme pathway inhibition could potentially allow for interven-
tion in the case of the presence of a known genetic susceptibility
and minimize an inflammatory response. Modulation of the
immune response may potentially prevent the development of
fibrosis (Level 5 evidence).
2. What is the etiology of pain in chronic pancreatitis?
The clinical hallmark of chronic pancreatitis is severe intractable
abdominal pain. Pain is reported by 80% to 94% of chronic pancre-
atitis patients.15 Unfortunately, the mechanisms of pain in chronic
pancreatitis are poorly understood. The pain is complex, likely mul-
tifactorial, and certainly of disparate causes in individual patients.
Pancreatic ductal hypertension has been implicated as an
etiology of pain in some patients with chronic pancreatitis.
PMPH_CH56.indd 450
Intraoperative measurements of main pancreatic duct pressures
have been shown to be significantly elevated in patients with
dilated duct pancreatitis. The ductal hypertension is theorized
to result from exocrine secretion against a proximal obstruction
due to stricture or stone. In theory, the pain results from ductal
distention. Th is theory is supported in part by successful pain
relief after lateral pancreaticojejunostomy (LPJ) for dilated duct
pancreatitis.16
Pancreatic tissue hypertension, analogous to extremity or
abdominal compartment syndrome, occurs when gland fibrosis
is constricting, notably during times of glandular exocrine secre-
tion. Elevated pancreatic tissue pressures have been observed and
reported (>30 vs. 7 mm Hg in normal gland). This compartment
syndrome is evidenced by a decreased pain with pancreatectomy
during surgical pancreaticojejunostomy.17
Strong evidence exists that neural mechanisms, both periph-
eral nociceptive neural pathways and neuroplastic/neuropathic
pathways, are fundamental to the pain of chronic pancreatitis.
Peripancreatic neurons are clearly involved in the inflammatory
process of pancreatitis.18 Histologically, there are focal disrup-
tions of the perineural sheath with infi ltration of inflammatory
cells within and around the pancreatic tissue.19 The degree of this
inflammatory neuritis is directly related to the frequency and
intensity of the pancreatitis pain.20
There is an increase in the number and diameter of intral-
obular and interlobular pancreatic nerve bundles in patients
with chronic pancreatitis, likely due to the activation of multiple
neurotrophic factors.19 Nerve growth factor (NGF) and its high-
affinity receptor tyrosine kinase A (TrkA) are overexpressed in
chronic pancreatitis and the degree of TrkA expression correlates
to pain intensity.21 Similarly, brain-derived neutrotrophic fac-
tor (BDNF)22 and the glial cell-line–derived neurotrophic factor
artemin are upregulated in chronic pancreatitis and relate directly
to pain levels.20
There is upregulation of several of the nociceptive neuropep-
tides such as Substance P and calcitonin gene-related peptide in the
pancreatic tissue of pancreatitis patients.23 Substance P is a tachy-
kinin involved in nociception and is a component in both the neu-
ral and immune systems. There is increased Substance P mRNA
expression in chronic pancreatitis. Substance P receptors NK-1R,
NK-2R, and PPT-A are also upregulated in chronic pancreatitis
tissue. NK-2R expression correlates with intensity and duration of
pain and NK-1R levels relate to the degree of pancreatic fibrosis.24,25
The Substance P degradation enzyme neutral endopeptidase
(NEP) is not upregulated in pancreatitis and may exacerbate the
associated pain syndrome. Interestingly, after pancreatic resec-
tion, the majority of chronic pancreatitis patients have decreased
Substance P serum levels.24
In addition to these histologic and biochemical neural changes
in pancreatitis, there are alterations in the overall autonomic inner-
vation and glial cell activation response, resulting in general neural
remodeling.26 This neuroplastic effect represents pancreatic neu-
ropathy. These changes are certainly consistent with the clinical
pattern of chronic pancreatitis pain, with its degree of recidivism
despite many therapies.
Although much has been elucidated about pain mechanisms
in pancreatitis, they are still incompletely understood. A clearer
definition of the pain mechanisms at work would better direct
therapeutic efforts (Level 5 evidence).
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3. What is the role of endoscopic intervention for chronic
pancreatitis?
Medical therapies, including ethanol abstinence, nutritional
optimization, oral pancreatic enzyme supplementation, and
analgesics are the initial approaches to chronic pancreatitis. In
patients with continued symptomatology, endoscopic assessment
and management are warranted. Therapeutic endoscopic inter-
ventions for chronic pancreatitis are aimed at improving drain-
age in obstructive pancreatopathy, and include sphincterotomy,
stone extraction with possible lithotripsy, stricture dilation, and
stenting.
In practice, the endoscopic approach is generally exhausted
prior to committing a patient to surgery, given the perceived risks
and increased potential morbidity of surgical intervention. This
algorithm holds in most centers despite now two randomized-
controlled trials demonstrating an increased effectiveness of pain
relief in patients after surgical intervention versus therapeutic
endoscopy. Dite et al.27 in the Czech Republic reported on 72
patients with pancreatic duct obstruction and pain who were ran-
domized to endoscopic or surgical therapy. Endoscopic therapy
included 52% sphincterotomy and stenting or 23% stone removal,
whereas operative management consisted of drainage (20%)
and resective (80%) procedures. At 5-year follow-up, the surgi-
cal group had a greater number of patients who were pain-free
(34% vs. 15%), whereas the rate of partial pain relief was equiva-
lent between the groups (52% surgery, 46% endotherapy).27 Cahen
et al.28 in 2007 reported on 39 patients with dilated duct (>7 mm
main pancreatic duct) pancreatitis randomized to surgery (pan-
creaticojejunostomy) versus endoscopic therapy (sphinctero-
tomy/stent) for the management of pain. At 2-year follow-up,
surgically managed patients had significantly lowered Izbicki
pain scores (25 vs. 51) as well as better quality of life as measured
by their SF-36 physical health scores. Pain relief was achieved in
32% of endoscopically managed patients as compared with 75% of
patients who underwent surgery (p = .007). Complications, hos-
pital stay, and pancreatic exocrine and endocrine function were
equivalent between groups. The endoscopically managed group
required a median of eight procedures versus three for the surgi-
cal group (p < .001).28
Endoscopic evaluation and intervention remain an essential
component to the management of chronic pancreatitis. In some
patients, early surgical intervention may be beneficial rather than
repeated endocopic procedures (Level 1 evidence).
4. What are the indications and outcomes in the surgical man-
agement of chronic pancreatitis?
The primary indication for surgery in patients with chronic pan-
creatitis is intractable pain, unresponsive to medical or endoscopic
therapies. Less common indications include anatomic complica-
tions, including duodenal or biliary obstruction or concern for
malignancy. In all, approximately half of patients with chronic
pancreatitis meet the criteria for surgery at some point in their
disease process.
As described earlier in this chapter, the mechanisms for
pain in pancreatitis are poorly understood, thus making surgical
decision-making for chronic pancreatitis challenging. The goals
of surgery are to effectively and durably relieve pain, to minimize
morbidity and mortality, and to preserve endocrine and exocrine
PMPH_CH56.indd 451
Chronic Pancreatitis ■ 451
function when possible. In general, the main pancreatic duct
anatomy is the most essential determinant of surgical planning.
Patients with a large main pancreatic duct (greater than 6–7mm
in size) are suited to a drainage procedure. Those with a small
pancreatic duct do less well with drainage and are better managed
with resection.29 If a portion of the organ is primarily affected,
this part can be resected with expected benefit. An inflammatory
mass in the head of the pancreas or a densely fibrotic tail can be
resected by partial pancreatectomy with good results. If however,
the gland is diff usely involved, total pancreatectomy (TP) may be
indicated. This operation has received new enthusiasm given the
development of islet autotransplantation.
LATERAL PANCREATICOJEJUNOSTOMY
In 1957, at the Western Surgical Association, Puestow and Gillesby16
presented their series of 21 patients with chronic pancreati-
tis who underwent pancreaticojejunostomy. Their technique
included a splenectomy and pancreatic tail resection followed by
opening of the main pancreatic duct along its length. The pan-
creas was then mobilized to the level of the superior mesenteric
vessels, and the gland was invaginated into a defunctionalized
limb of jejunum.16 In 1960, Partington and Rochelle30 presented
their modification of Puestow’s procedure, with exposure of the
anterior aspect of the pancreas and a lateral side-to-side anasto-
mosis between the fibrotic parenchymal edge of the pancreatic
duct and the opened small bowel Roux limb. Since these initial
descriptions, multiple series have examined the outcomes of LPJ
for dilated duct pancreatitis.31-38 Pain relief is achieved in 48%
to 91% of patients on follow-up. Morbidity is reported on aver-
age to be 20%, and preservation of endocrine and exocrine pan-
creatic function is optimized.39 LPJ remains the procedure of
choice in dilated duct pancreatitis (duct diameter >7 mm), with-
out an inflammatory mass in the head of the pancreas (Level 4
evidence).
With LPJ, a secondary failure rate exists. The primary mecha-
nism for failure of the Puestow procedure, marked by recurrent
pain, is likely related to the disease within the head of the pancreas.
Some of this disease represents intraductal stone disease and can
be addressed with the addition of intraoperative pancreatoscopy
with electrohydraulic lithotripsy. In selected patients, this proce-
dure decreases re-admissions and pain recurrence from 9% to 0%.
Pain relief rates of 90% are reported.40 Alternatively, in patients
with dilated duct disease with an inflammatory pancreatic head,
drainage alone may be doomed to failure and a localized pan-
creatic head resection combined with a pancreaticojejunostomy
(LR-LPJ) is an option.
LOCAL RESECTION OF THE PANCREATIC
HEAD WITH LONGITUDINAL
PANCREATICOJEJUNOSTOMY
In 1987, Frey et al.41 described a localized pancreatic head resec-
tion with a longitudinal pancreaticojejunostomy (LR-LPJ). The
goal of this surgery is pain relief due to both ductal drainage and
resection of damaged and poorly drained tissue in the head of the
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 452 ■ Surgery: Evidence-Based Practice

pancreas, at the same time preserving the duodenum and main-
taining pancreatic function. Certainly, this addresses the issue of
late failure of LPJ due to residual disease in the head of the pan-
creas. Frey reported initially on 50 patients, describing a morbid-
ity of 22% and a pain relief rate of 84%.41 In modern series, pain
relief rates of 62% to 88% are reported, with morbidity of 20% to
30% (Level 1 evidence).42-45
PANCREATICODUODENECTOMY
Pancreaticoduodenectomy (PD) for chronic pancreatitis was descri-
bed as early as 1946 by Whipple, and thus has greater history than
any other procedure in the management of chronic pancreatitis.46
Despite this, the enthusiasm for PD for benign disease was limited
really until the 1970s, given a prohibitive mortality rate around
30%. In the modern era, with acceptable operative morbidity
and mortality, patients with chronic pancreatitis pain and an
inflammatory mass in the head of the pancreas benefit from this
operation. In these patients, the head acts as the described “pace-
maker” of disease. Outcomes for PD include pain relief in 70% to
89% of patients, morbidity in 16% to 53%, and mortality in less than
5% in high volume centers.38,47-50
In an effort to maintain the potential physiologic benefits of
a functional pylorus, the pylorus preserving pancreaticoduodec-
tomy (PPPD) was popularized by Traverso and Longmire51 in 1978.
This modification has been well adopted into pancreatic surgery.
Disappointingly, the postulated nutritional benefits have not been
evidenced, with similar long-term weight status being reported
between the two techniques.48,52-54 PPPD may have a higher
rate of delayed gastric emptying postoperatively, particularly
in patients with chronic pancreatitis. Long-term pain relief
rates and the development of postoperative diabetes mellitus are
equivalent.48 Some studies have reported improved professional
rehabilitation53 and improved quality of life after PPPD (Level 1
evidence).55
DUODENAL PRESERVING PANCREATIC
HEAD RESECTION
In an effort to limit the associated long-term morbidity of duo-
denal resection, the duodenal preserving pancreatic head resec-
tion (DPPHR) was developed by Beger et al.56-58 in the 1970s. In
this surgery, the afflicting inflammatory mass in the head of the
pancreas is resected, leaving the bile duct and duodenum intact
and decompressed. Morbidity and mortality are acceptable at
28.5% and 1%, respectively. Pain relief is reported in 77% to 88%
of patients, with professional rehabilitation rates of 63% to 69%
(Level 1 evidence).56-59
COMPARATIVE RANDOMIZED CLINICAL
TRIALS OF PANCREATIC HEAD
RESECTION
Over the past several years, there has been great interest from
multiple surgical groups, particularly in Europe, in methodically
evaluating the comparative efficacy of the various approaches to
pancreatic head resection in chronic pancreatitis.60-66 The results
of the Level 1 studies are summarized in Table 56.1.

Table 56.1 Level 1 studies comparing techniques of pancreatic head resection

Study Comparison n Morbidity (%) Mortality (%) Pain Relief (%)
Klempa et al.60 PD 21 51 0 70
DPPHR 22 54 5 100

Buchler et al.61 PPPD 20 20 0 77

DPPHR 20 15 0 94

Muller et al.*62 PPPD 14

DPPHR 15

Farkas et al.63 PPPD 20 40 0 100

DPPHR 20 0 0 100

Izbicki et al.64 DPPHR 20 20 0 70

LR-LPJ 22 9 0 70

Izbicki et al.65 LR-LPJ 31 19 3 80

PPPD 30 53 0 75

Strate et al.**66 LR-LPJ 31 82

PPPD 30 81

*Long-term follow-up of Buchler’s study.

**Long-term follow-up of Izbicki’s study.

PMPH_CH56.indd 452 5/22/2012 5:39:16 PM


DISTAL PANCREATECTOMY
In patients with chronic pancreatitis with disease localized to
the body and tail of the pancreas or in patients with obliteration
of the pancreatic duct in the neck or body, distal pancreatec-
tomy (DP) is an effective means of pain relief. Pain relief rates
of 57% to 84% are reported with occupational rehabilitation in
29% to 73%. Morbidity and mortality are reasonable, reported
in 15% to 32% and 2% to 2.2% of cases, respectively.37,67-69 The
postoperative pancreatic fistula remains a challenge and appears
to be related to patient-specific factors rather than operative
technique.70 In the modern era, some cases can be performed
safely laparoscopically, with expected decreased length of hos-
pital stay and at least equivalent morbidity.71,72 DP appears to be
applicable in approximately 9% to 25% of patients in larger series
of patients undergoing surgery for chronic pancreatitis (Level 4
evidence).37,73
TP WITH ISLET AUTOTRANSPLANTATION
In selected patients with chronic pancreatitis, TP is a good option
for pain relief. Specifically, patients with diff use small duct pan-
creatitis, patients who have failed lesser surgeries, and those with
hereditary pancreatitis are good candidates for TP. TP was first
performed in 1894 by Theodore Billroth and in 1944 for pancrea-
titis by Clagett. Excellent pain relief rates of 72% to 100% have
been described, with morbidity rates of 22% to 54% and mortal-
ity 0% to 14%. There is a requisite pancreatogenic diabetes that
accompanies TP; however, with severe diabetic control problems
in 15% to 75% of patients, and in one series half of late postopera-
tive deaths were due to hypoglycemia.74-76 The problem is not only
a loss of insulin, but also of the counter-regulatory islet hormones,
such as glucagon and pancreatic polypeptide. As a result, patients
have wide swings in blood glucose, an unpredictable response
to insulin therapy, and importantly may develop hypoglycemic
unawareness, which increases morbidity sixfold.77 The largest
modern series of TP is from the Mayo Clinic. There were three late
deaths from hypoglycemia and 26% of patients were rehospital-
ized for glycemic control.76 Thus, it seems that TP is a good option
for pain relief, but the resultant diabetes is exceptionally morbid.
In the 1970s, the concept arose at the University of Minne-
sota for the autotransplantation of islet cells immediately after
pancreas resection, in order to preserve endocrine function and
allow for the analgesic benefits of extensive pancreatectomy. In
1978, Sutherland reported the first TP with islet autotransplanta-
tion (TPIAT) in a young woman with hereditary pancreatitis.78
Since that time, the science of islet harvest has progressed, and
over the past decade, the procedure has received new interest with
now multiple centers offering this therapy.
Pain relief rates of 72% to 86% have been reported with TPIAT,
with 47% to 55% morbidity and 1.4% to 6% mortality, and insulin
independence in 10% to 40% after islet transplant.74,79-82 Improved
posttransplant endocrinologic function correlates with the number
of islet equivalents per kilogram harvested74,81,82 and transplanted
islet function appears to be durable, with outcomes reported for
greater than 13 years.83 Although this therapy holds promise, long-
term pain relief data are currently lacking (Level 4 evidence).
PMPH_CH56.indd 453
Chronic Pancreatitis ■ 453
LAPAROSCOPIC SURGERY FOR
CHRONIC PANCREATITIS
Laparoscopic pancreatic surgery began as early as 1911 when
Bernkeim described the use of “organoscopy,” which involved a
headlight and a proctoscope to evaluate for metastatic disease in
pancreatic cancer. Modern laparoscopic staging for pancreatic
cancer was introduced by Cuschieri in Europe in 1978 and War-
shaw in the United States in 1986. It was not until the develop-
ment of laparoscopic stapler technology in the early 1990s that
more complex procedures could be undertaken. In 1996, Gagner
reported on five patients with benign tumors on which he per-
formed a laparoscopic DP.84 Currently, laparoscopic DP is the
most commonly reported laparoscopic pancreatic surgery. The
largest single-institution experience is from the Mayo Clinic,
with 100 laparoscopic DPs compared with 100 open historical
controls. The authors reported lower blood loss and length of
stay postoperatively in the laparoscopic group, but equivalent
operative time and morbidity including pancreatic fistula rate.
Importantly, only one of the laparoscopic cases was for chronic
pancreatitis.71 The largest multicenter group included 667 DPs
with 159 (24%) laparoscopic. Fourteen (9%) were for chronic
pancreatitis. The authors reported lower blood loss, length of
stay and morbidity with laparoscopy, and equivalent operative
times and pancreatic fistula rates.72 Laparoscopic DP is a tech-
nique in progress, rapidly approaching the standard in benign
or low-grade neoplasms. Given the difficult dissection and loss
of planes in chronic pancreatitis, its application in this patient
group is still currently in evolution. Laparoscopic LPJ has been
described by several authors and is technically feasible.85 Suc-
cess rate for the minimally invasive approach in this operation
increases as the size of the pancreatic duct increases. The laparo-
scopic PD is being performed at a few centers, mostly for malig-
nant disease, but in a few with chronic pancreatitis. The authors
report reasonable operative times (median 357–368 min), blood
loss (75–240 mL), morbidity (26.7–42%), and pancreatic fistula
rates (6.7–18%).86,87 The limitations of laparoscopic PD in chronic
pancreatitis are similar to those with laparoscopic DP, with loss
of planes and distortion of anatomy due to the fibrotic changes
of disease (Level 3 evidence).
CONCLUSIONS
The British physicist Sir Ernest Rutherford quipped that all sci-
ence is either physics or stamp-collecting. The evidence behind
the surgical science of chronic pancreatitis management is
clearly more akin to stamp-collecting than physics. Level 1 evi-
dence, when uncovered, is handicapped by confounders related
to surgeon experience and selection, difficult to measure out-
come variables, and time which grows old in itself. Yet, large
advances have been made in the standardization of operations
for chronic pancreatitis and in defi ning the salient outcome
measurements. Therefore, it cannot be long before we have bet-
ter understanding of the disease of chronic pancreatitis and new
surgical science to continue to improve the safety and efficacy
of surgical treatments.
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 454 ■ Surgery: Evidence-Based Practice
Clincial Question Summary
Question
1 What is the current
understanding of the
underlying pathophysiology
of chronic pancreatitis?
2 What is the etiology of pain in
chronic pancreatitis?
3 What is the role of endoscopic
intervention for chronic
pancreatitis?
4 What are the indications and
outcomes in the surgical
management of chronic
pancreatitis?
5 Lateral pancreaticojejunostomy
(LPJ)
6 Pancreaticoduodenectomy (PD)
7 Duodenal preserving pancreatic
head resection (DPPHR)
8 Local resection of the head
of the pancreas with lateral
pancreaticojejunostomy
(LR-LPJ)
9 Distal pancreatectomy
10 Total pancreatectomy with
islet autotransplantation
11 Laparoscopic pancreas surgery
PMPH_CH56.indd 454
Answer Level of Recommendation References
Evidence
There is an interaction of multiple 5 D 1-14
factors including environmental
stressors, genetic predisposition,
and individual immunologic
response.
Neural mechanisms, both peripheral 5 D 15-26
nociceptive neural pathways and
neuroplastic/neuropathic pathways,
are fundamental to the pain of
chronic pancreatitis.
Endoscopic evaluation and 1 A 27-28
intervention remain an essential
component to the management
of chronic pancreatitis. In patients
with obstructive pancreatopathy,
early surgical intervention may be
beneficial rather than repeated
endocopic procedures.
LPJ remains the procedure of choice 4 C 30-39
for pain relief in dilated duct
pancreatitis (duct diameter >7 mm),
without an inflammatory mass in
the head of the pancreas.
PD is an effective means of pain relief 1 A 60-63, 65-66
in patients with an inflammatory
mass in the head of the pancreas
and debilitating pain from chronic
pancreatitis.
DPPHR is an effective means of 1 A 60-64, 66
pain relief in patients with an
inflammatory mass in the head of
the pancreas and debilitating pain
from chronic pancreatitis.
LR-LPJ achieves pain relief in chronic 1 A 64-66
pancreatitis by both ductal
drainage and resection of damaged
and poorly drained tissue in the
head of the pancreas.
Distal pancreatectomy is an effective 4 C 37, 67-70
means of pain relief in patients with
disease localized to the tail of the
pancreas.
Total pancreatectomy is an effective 4 C 74, 79-82
means of pain relief in selected
patients with chronic pancreatitis.
Laparoscopy is a safe and effective 3 B 71, 72
approach in selected cases of
pancreatic resection.
5/22/2012 5:39:16 PM

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 CHAPTER 57
Pancreatic Adenocarcinoma
Jamii St. Julien, Alexander A. Parikh, and Nipun B. Merchant
INTRODUCTION
Pancreatic cancer remains a major healthcare problem. In 2010,
there were an estimated 43,140 new cases and 36,800 deaths
from pancreatic cancer, making it the 10th most common cause of
cancer and the 4th most common cause of cancer-related death in
the United States.1 Over the past four decades, we have made min-
imal impact on survival outcomes for this disease, with overall
1- and 5-year relative survival rates for all stages combined being
25% and 6%, respectively.
The nonspecific symptoms associated with early pancreatic
cancer and the aggressiveness of the tumors make it one of the most
challenging diseases to treat. Numerous studies have attempted to
guide treatment strategies and improve outcomes. However, due
to the lack of standardized approaches for diagnosis, staging, sur-
gery, and multimodality therapy, it has been challenging to inter-
pret data from clinical trials in a meaningful way.
This chapter will discuss pretreatment assessment and
combined-modality therapy for pancreatic cancer through a
review of the current data and with the goal of clarifying and
standardizing the important components of pancreatic cancer
management.
DIAGNOSIS
1. What is the optimal pretreatment staging assessment of
patients with pancreatic adenocarcinoma?
COMPUTED TOMOGRAPHY
Accurately staging and selecting the appropriate patients for surgical
therapy is crucial to minimize nontherapeutic surgical exploration.
Computed tomography (CT) remains the primary method for stag-
ing pancreatic malignancy and determining tumor resectability.2-4
The current state-of-the-art system uses a 64-slice multidetec-
tor CT scanner, which allows for very thin (3–5 mm) collimation,
458
PMPH_CH57.indd 458
providing high-image resolution and fast image acquisition. The
optimal protocol for imaging includes injection of 100–120 mL
of nonionic iodinated contrast, with image acquisition in both an
arterial and a venous phase to visualize the relationship of the pri-
mary tumor to the mesenteric vasculature, as well as the detec-
tion of metastatic deposits as small as 3–5 mm. The addition of
CT angiography with 3D reconstruction of the mesenteric ves-
sels has been shown to markedly improve the ability to predict
resectability.5
ENDOSCOPIC ULTRASONOGRAPHY
Endoscopic ultrasound (EUS) is accurate for local tumor (T) stag-
ing and in predicting vascular invasion of the tumor. Compared
with CT imaging, EUS has been found to be as accurate in deter-
mining resectability, and is more sensitive for detecting vascular
invasion.5,6 This assessment may, however, be less accurate when
a biliary stent is present.7 The accuracy of this staging modality
depends largely upon the experience of the operator and results
may vary. In addition, EUS is not routinely available at all hospi-
tals and therefore has not been widely adopted as a routine test for
staging pancreatic cancer.
However, EUS is an essential tool for patients enrolled in neo-
adjuvant therapy trials because it provides relatively easy access to
the pancreas for tissue diagnosis by fine-needle aspiration (FNA).
Lymph nodes, liver lesions, and ascites can all be sampled via
EUS-FNA.
The three modalities most commonly utilized for preoperative
tissue diagnosis are endoscopic retrograde cholangiopancreatog-
raphy (ERCP) with cytologic brushing, image-guided percutane-
ous FNA, or EUS-guided FNA. Of these, EUS-FNA has the highest
sensitivity (96%), specificity (100%), and diagnostic accuracy (98%)
for pancreatic cancer (especially for tumors ≤25 mm), and has
been shown to be the most cost-effective approach.8-10 If indicated,
celiac ganglion blockade can also be performed under EUS guid-
ance for pain control. In patients requiring stent placement, EUS
and ERCP can be performed during the same sedation.
5/22/2012 5:39:55 PM

Diagnostic adjuncts, such as magnetic resonance imaging
(MRI) and positron emission tomography (PET) scanning, may
play a role in select instances when results from CT or EUS are
not definitive.3
STAGING LAPAROSCOPY
The major limitation of CT and EUS is their low sensitivity for
detecting occult liver metastases or peritoneal implants, which
may lead to unnecessary laparotomy. The value of staging laparos-
copy (SL) remains controversial. Proponents argue that SL is quick
and efficient, does not affect subsequent resection, and imparts
minimal morbidity. Further supporting the use of SL, hospital
stays, costs, and morbidity are reduced when unnecessary laparo-
tomies are avoided.11 Opponents argue that with the current high
quality of noninvasive imaging, only a small minority of patients
actually benefits, and the cited value of SL is overestimated.
A comprehensive review pointed out that the literature on SL
for pancreatic cancer was difficult to interpret due to the incon-
sistent use of high-quality CT, poor definitions of surgical resec-
tability, inclusion of nonpancreatic periampullary malignancies
and benign disease, inclusion of patients with locally advanced
disease, and poor analysis of surgical margins after resection,
making it impossible to correlate laparoscopic findings with R0/
R1/R2 resection rates.12 However, they concluded that due to the
high accuracy of CT imaging for predicting resectability based on
objective criteria, the proportion of potentially resectable patients
in whom SL may prevent unnecessary laparotomy is only 4% to
13%. Based on the results of this study and two subsequent retro-
spective analyses, selective use of SL at the time of planned lapa-
rotomy for potentially resectable patients should be reserved for
patients at higher risk for occult metastatic disease. These include
patients with (1) primary tumors >3 cm, (2) lesions in the neck,
body, or tail, (3) equivocal radiographic findings suggestive of
occult M1 disease (low volume ascites, possible carcinomatosis,
small liver lesions not amenable to biopsy), or (4) CA 19-9 levels
>100 U/mL.12-14
SL may be beneficial in patients with locally advanced disease
without evidence of distant metastases by CT imaging by helping
to determine the need for radiation therapy. In this group, up to
34% of patients have been found to have occult metastatic disease
by SL, thereby avoiding the inappropriate use of radiotherapy.15
Answer: CT imaging with a specific “pancreas protocol” with
thin cuts (3–5 mm) through the pancreas is the optimal preop-
erative diagnostic and staging tool to determine resectability in
all patients with suspected pancreatic adenocarcinoma. Objective
criteria to determine resectability based on CT imaging should
be utilized (see next section). For potentially resectable pancreatic
adenocarcinoma, SL may be used selectively in patients considered
high risk for occult metastatic disease: (1) primary tumors >3 cm,
(2) all tumors of the neck, body, and tail, (3) equivocal findings on
MDCT, (4) or high CA 19-9 levels (>100 U/mL). SL may also be used
in patients with locally advanced (Stage III) pancreatic adenocarci-
noma without evidence of distant metastases on CT imaging to rule
out occult metastatic disease and avoid unnecessary radiotherapy.
Patients being considered for neoadjuvant therapy require a
preoperative tissue diagnosis. EUS-FNA is the best modality for
obtaining a tissue diagnosis, and can add additional staging infor-
mation to CT imaging.
PMPH_CH57.indd 459
Pancreatic Adenocarcinoma ■ 459
2. What defines resectable, borderline resectable, and locally
advanced pancreatic adenocarcinoma?
Most patients with pancreatic adenocarcinoma present with advanced
disease at the time of diagnosis, and only 15% to 20% are candidates
for potentially curative resection.16-18 Surgical resection remains the
only potentially curative option. Therefore, accurate disease staging
and selection of appropriate patients for surgical therapy are crucial
to maximizing the benefits of surgery and minimizing nontherapeu-
tic surgical explorations.
The definition of resectable disease has been an area of con-
troversy. Several efforts have been made to utilize cross-sectional
imaging to objectively classify pancreatic adenocarcinoma as resec-
table, borderline resectable, or locally advanced, unresectable. Each
classification emphasizes the distinction between potentially resec-
table tumors, where a negative margin resection can reasonably
be expected, and locally advanced and metastatic disease, where
a curative resection is unlikely. These definitions are based upon
properly performed CT imaging (as detailed above).
Varadhachary et al.19,20 from MD Anderson Cancer Center
(MDACC), in an attempt to standardize inclusion criteria into
clinical trials for neoadjuvant chemotherapy, proposed the fol-
lowing definitions (of tumors without evidence of metastatic dis-
ease): resectable tumors (Stage I/II) were those with normal tissue
planes between the tumor and the superior mesenteric artery
(SMA) and celiac axis, and a patent superior mesenteric vein
(SMV)/portal vein (PV) confluence; locally advanced, unresect-
able tumors (Stage III) were those with encasement (>180° of the
vessel circumference) of the SMA or the common hepatic artery,
or an occluded SMV/PV confluence with no technical option
for reconstruction; borderline resectable tumors were defined as
those with tumor abutment (≤180° of the circumference) of the
SMA, abutment or short-segment encasement of the common
hepatic artery, or short-segment occlusion of the SMV/PV conflu-
ence with patent vessel above and below the occlusion suitable for
venous reconstruction.19,20
The National Comprehensive Cancer Network (NCCN)
defines a tumor in the head or in the body of the pancreas as bor-
derline resectable if there is abutment (i.e., ≤180°) of the SMA,
reconstructible abutment or encasement of the hepatic artery,
severe impingement of the PV and/or SMV, or reconstructible
SMV occlusion.21
In the 2009 American Hepato-Pancreato-Biliary Association
(AHPBA)/Society of Surgical Oncology (SSO) Consensus Report
on pretreatment assessment of resectable and borderline resect-
able pancreatic cancers, borderline resectable tumors differ from
potentially resectable tumors anatomically by having either venous
involvement (abutment with or without impingement and nar-
rowing of the SMV) or limited involvement of the gastroduodenal
artery, hepatic artery, or SMA.22
Answer: Tumor resectability must be based on objective cri-
teria from multidetector CT imaging. Resectable disease should
be arrowly defined as the absence of tumor extension to the SMA,
celiac, or common hepatic arteries, and the absence of any tumor-
induced unilateral shift or narrowing of any aspect of the PV-
SMV confluence. 23,24 A “surgery fi rst” approach is acceptable in
these patients.
Borderline resectable disease is defined as tumors with abut-
ment (≤180° of the circumference) of the SMA, abutment or short-
segment encasement of the common hepatic artery, tumor-induced
unilateral shift or narrowing of the PV-SMV, or short-segment
5/22/2012 5:39:55 PM
 460 ■ Surgery: Evidence-Based Practice
occlusion of the SMV/PV confluence with patent vessel above
and below the occlusion suitable for venous reconstruction.20,22,23
These patients should be treated with neoadjuvant therapy prior
to surgery, preferably within a clinical trial to enhance the pos-
sibility of a negative margin resection.
Locally advanced tumors are those with encasement (>180°
of the circumference) of the SMA or common hepatic artery, or
an occluded SMV/PV confluence with no technical option for
reconstruction.20,21
MANAGEMENT
3. What is the role of adjuvant therapy after resection for pan-
creatic adenocarcinoma?
Despite attempted curative resection, the majority of patients with
pancreatic adenocarcinoma will recur and ultimately die of their
disease, presumably due to the presence of micrometastatic disease
present at the time of diagnosis. As a result, significant research has
been devoted to evaluating adjuvant treatment strategies includ-
ing systemic chemotherapy, radiation therapy, and combined
chemoradiation therapy (CRT).
HISTORICAL PERSPECTIVE
In the United States, the standard of care for adjuvant therapy
in pancreas cancer has been based largely on a number of rela-
tively small trials, the first being the Gastrointestinal Tumor
Study Group (GITSG) trial published in 1985. This small trial
of 49 patients showed a survival benefit for fluorouracil (5-FU)–
based CRT followed by 5-FU chemotherapy versus surgery alone
(median survival 20 vs. 11 months, p = .035) and established adju-
vant CRT and chemotherapy as the standard of care for resected
pancreas cancer.25
Unfortunately, most subsequent trials have been limited
due to size or other methodologic problems. The European
Organization for Research and Treatment of Cancer (EORTC)
trial published in 1999 consisted of 218 patients with pancreatic
and periampullary tumors randomized to adjuvant 5-FU–based
CRT alone or observation.26 Although there was a trend for sur-
vival in the adjuvant group, for the entire cohort, as well as for
the subset with pancreatic cancer, this did not reach statistical
significance.
MODERN TRIALS
Since that time, several large studies have been published in hopes
of better defining the role of adjuvant therapy in pancreatic cancer.
The European Study Group of Pancreas Cancer (ESPAC-1) trial
published their complex trial over several years starting in 1997.
This trial utilized a 2 × 2 factorial design to compare adjuvant
CRT, adjuvant chemotherapy (6 mos), both of these, or observa-
tion.27 The median survival for the chemotherapy and no-chemo-
therapy groups was 20.1 and 15.5 months, respectively (p = .009),
with 5-year survival rates of 21% and 8%, respectively (p = .05). The
median survival for the CRT and no CRT groups was 16 and 18
months, respectively (p = .05), with 5-year survival rates of 10%
PMPH_CH57.indd 460
and 20%, respectively (p = .05). The authors concluded that adju-
vant chemotherapy was beneficial, whereas adjuvant CRT was
actually detrimental. Criticisms of this trial include possible sub-
optimal CRT regimen, poor compliance, a lack of quality control,
and the complex 2 × 2 design of the trial. Despite these limitations,
this trial helped establish a clear role for systemic chemotherapy in
the adjuvant setting, but introduced controversy regarding the role
of radiation therapy.
In 2009, composite data from the ESPAC-1, ESPAC-1 Plus,
and the ESPAC-3(v1) trial were reported, which recapitulated the
results reported in 2004.28 The ESPAC-1 Plus trial was a cohort of
192 patients from ESPAC-1 that were entered into a direct ran-
domized comparison between 5-FU and observation alone (with
clinician’s choice of background CRT if indicated). The ESPAC-
3(v1) trial was initially a three-arm study of adjuvant 5-FU versus
gemcitabine versus observation alone. Following the publication
of the results of the larger ESPAC-1 trial, 27 the observation
arm was dropped. The eligibility criteria and treatment sched-
ules were identical for all three studies. A meta-analysis of the
pooled data again showed the benefit of adjuvant chemotherapy,
with a superior overall survival in patients randomized to 5-FU
compared with observation (hazard ratio [HR] = 0.70, p = .003).
The composite 2- and 5-year survival rates were 49% and 24%
for the 5-FU arm, compared with 37% and 14% for the observa-
tion arm. 28 A direct comparison between the gemcitabine and
5-FU arms was recently reported as well and showed no differ-
ence in the median overall survival (23.6 vs. 23 months, respec-
tively; p = .39).
The CONKO-001 trial compared adjuvant gemcitabine che-
motherapy (six cycles) to observation alone in 368 patients.29 Esti-
mated disease-free survival was 13.4 months in the gemcitabine
arm compared with 6.9 months in the control arm (p = .001),
regardless of margin status, tumor size, or nodal involvement.
Updated results presented at the American Society of Clinical
Oncology (ASCO) meeting in 2008 showed estimated 5-year sur-
vival rates of 21% in the gemcitabine arm, and 9% in observation
arm (p = .005), further establishing the role of adjuvant gemcit-
abine chemotherapy in resected pancreatic cancer.30
The Radiation Therapy Oncology Group (RTOG 97-04) trial
was a large intergroup trial of 451 patients randomized to either
5-FU- or gemcitabine-based chemotherapy followed by identical
5-FU–based CRT regimens. The final analysis revealed no dif-
ference in overall or disease-free survival between the treatment
groups.31 A subgroup analysis of patients with tumors in the head
of the pancreas showed a nonsignificant trend toward improved
survival with gemcitabine, with a median survival of 20.5 months
and a 3-year survival rate of 31% in the gemcitabine group versus
16.9 months and 22% in the 5-FU group (HR = 0.82, p = .09). How-
ever, after adjusting for prespecified stratification variables of nodal
status, tumor diameter, and surgical margin status, the treatment
effect yielded an HR of 0.80 (p = .05). Although this trial was well
designed and adequately powered, it did not clearly demonstrate an
advantage for gemcitabine over 5-FU in the adjuvant setting, and
certainly did not address the more pressing issue of whether or not
CRT added any benefit to adjuvant chemotherapy.
A new EORTC randomized Phase II trial (40013) comparing
gemcitabine alone to gemcitabine with radiation using modern
CRT techniques was reported at the 2009 ASCO annual meeting.
Ninety patients were randomized to either chemotherapy or CRT.
There was a significant improvement in the local control with the
5/22/2012 5:39:55 PM

use of CRT, but the overall survival was the same for both arms
(24 months).32
RETROSPECTIVE STUDIES
Several retrospective reviews have also attempted to investigate the
role of adjuvant therapy in pancreatic cancer. Although they suffer
from the inherent biases of retrospective studies, they do provide
additional evidence for the use of adjuvant therapy in resected
pancreatic cancer. A study from the Mayo Clinic showed a signifi-
cant survival benefit with the use of adjuvant CRT.33 In this study,
274 patients received adjuvant CRT, most receiving concomitant
5-FU, whereas 180 were observed after surgical resection. Radia-
tion doses varied widely from 13.8 to 60 Gy. Those receiving CRT
had improved median survival (25.2 vs. 19.2 months, p = .001)
with improved 2- and 5-year overall survival.
Another review from Johns Hopkins Hospital compared 271
patients who received adjuvant 5-FU–based CRT with 345 patients
who underwent surgery alone.34 Patients who received CRT had an
improved median, 2- and 5-year survival compared with surgery
alone (21.2 vs. 14.4 months; 43.9% vs. 31.9%, and 20.1% vs. 15.4%,
respectively, for adjuvant CRT vs. no CRT; p < .001). The beneficial
effect of CRT remained even after adjustment for prognostic fac-
tors including tumor size, grade, margin, and nodal status. A sub-
set analysis suggested that lymph node-positive patients showed a
benefit, whereas node-negative patients did not.
Finally, a recent retrospective, multicenter study from the
Central Pancreas Consortium (CPC) compared 374 patients who
had surgery alone with 299 patients who underwent adjuvant
CRT (predominantly 5-FU–based).35 Patients receiving CRT after
surgery had significantly improved survival (20 vs. 14.5 months,
p = .001). On subset and multivariate analysis, patients with lymph
node-positive disease had a significantly improved survival with
adjuvant CRT (19.4 vs. 10.4 months, p < .01), whereas patients that
were lymph node-negative did not show any benefit from CRT
(22.9 vs. 24.2 months, p = .774) regardless of margin status (R0
or R1).
Answer: Randomized trials have clearly established a role for
adjuvant systemic chemotherapy in the treatment of resected pan-
creatic cancer. Both adjuvant 5-FU and gemcitabine have led to a
survival advantage compared with surgery alone, though neither
agent has conclusively been shown to be superior. The role of adju-
vant radiation therapy is less clear. Although randomized trials
have failed to show a clear benefit, well-designed retrospective stud-
ies have suggested a role for adjuvant CRT in high-risk patients—
that is, patients with lymph node-positive disease. Well-designed
randomized trials are therefore needed to better establish the
role of adjuvant CRT. Furthermore, as these trials are designed,
it will be important to stratify patients by high-risk features such
as lymph node status to better define which patients may benefit
the most.
4. What is the role of neoadjuvant therapy in the management
of pancreatic adenocarcinoma?
Another option in the treatment of resectable pancreatic cancer
is systemic and locoregional therapy prior to resection. The use of
neoadjuvant therapy has several potential advantages over adju-
vant strategies including (1) downsizing of the tumor leading to
PMPH_CH57.indd 461
Pancreatic Adenocarcinoma ■ 461
improved margin-negative resection and local recurrence rates;
(2) the ability to identify patients who would most benefit from
pancreatectomy and avoid unnecessary surgery in patients with
progressive disease; (3) the ability to deliver treatment to better
perfused and oxygenated tissues prior to surgical manipulation,
thereby enhancing the effects of chemotherapy and/or radiation;
(4) improved patient tolerance and a decrease in complication
rates; and (6) the early delivery of systemic therapy to treat occult
metastases.
The use of neoadjuvant therapy also has potential disadvan-
tages. For example, to receive neoadjuvant therapy, a pathologic
confirmation of pancreatic adenocarcinoma is required. This often
requires invasive techniques such as EUS-FNA, which is not with-
out risk, highly operator-dependent, and not available at all hospi-
tals. In addition, patients who are jaundiced require preoperative
biliary drainage such as stenting prior to receiving chemotherapy.
The use of preoperative stents, however, has been associated with
increased perioperative complications.36,37 Also, ineffective neo-
adjuvant strategies may lead to local progression of an initially
resectable tumor.
HISTORICAL PERSPECTIVE
The first reported trials utilizing neoadjuvant therapy for resect-
able pancreatic cancer were published in the early 1990s. Initial
experience involved the use of 5-FU–based CRT. Most patients
tolerated these regimens well, and approximately 60% ultimately
underwent successful resection with median survival of approxi-
mately 2 years.38-40 It is important to note that the reported survival
was only for the patients who subsequently underwent successful
resection. Two other trials included neoadjuvant regimens of con-
tinuous infusion (CI) 5-FU, mitomycin C (MMC), and concurrent
radiotherapy.39,41 They both included patients with both resectable
and locally advanced disease, and one also included duodenal as
well as pancreatic cancer. Their results were unimpressive, but
these studies highlighted the importance of designing trials that
separate patients by well-defined resectability criteria as discussed
earlier.
MODERN TRIALS
A French single-institution trial of 101 patients with resectable
or borderline resectable pancreatic adenocarcinoma undergoing
neoadjuvant 5-FU-cisplatin-CRT reported a resectability rate
of 62% (92% R0) and a median survival of 23 months for those
who underwent resection versus 11 months for those who did not
(p = .002).42 This group has also published a Phase II trial of 34
patients with resectable or borderline resectable pancreatic ade-
nocarcinoma who underwent docetaxel-based CRT. This regimen
resulted in a 50% resectability rate (100% R0) and a median sur-
vival of 32 months for those resected compared with 11 months
for those who were not (p < .001). 43
Gemcitabine has also been used in combination with radia-
tion in the neoadjuvant setting. The group at MDACC published a
Phase II trial of preoperative gemcitabine-based CRT in 86 patients
with Stage I/II pancreatic head adenocarcinoma. Although 41%
required hospital admission, 74% were successfully resected (89%
5/22/2012 5:39:55 PM
 462 ■ Surgery: Evidence-Based Practice

R0). Of the patients whose disease progressed, all developed meta-
static disease rather than local progression. The median survival for
resected patients was 34 months, compared with 7 months for those
who were not resected (p < .001). The 5-year survival was 36% and
0% for those who did and did not undergo resection, respectively.44
These results led to gemcitabine-based CRT being considered the
preferred neoadjuvant approach for pancreatic cancer.
The MDACC group also reported on the addition of sys-
temic cisplatin to the gemcitabine-based chemoradiation regi-
men in a Phase II trial of 90 patients with Stage I/II pancreatic
adenocarcinoma. A total of 79 patients (88%) completed the pre-
operative regimen and 52 (58%) were successfully resected (96%
R0). Median overall survival was 17.4 months for all 90 patients,
and 31 months for the patients successfully resected compared
with 10.5 months for those who were not (p < .001).45 Although
these results were also encouraging, the authors noted that the
addition of systemic gemcitabine and cisplatin did not appear to
improve survival when compared with gemcitabine-based CRT
alone.
Answer: Neoadjuvant CRT, regardless of the regimen, is well
tolerated and can lead to excellent margin-negative resection rates
and significantly improved survival in patients eligible for resec-
tion. A minority of patients will have disease progression during
therapy, with the majority of these being due to distant metasta-
ses rather than local progression alone suggesting that patients
with biologically aggressive disease may be spared from unneces-
sary surgery. The applicability of neoadjuvant strategies outside of
major academic centers is unclear. Randomized-controlled trials
are needed to determine whether neoadjuvant therapy offers any
advantage over the adjuvant approach.

Clinical Question Summary

Question
1 What is the optimal
pretreatment staging
assessment of patients with
pancreatic adenocarcinoma?
2 What defines resectable,
borderline resectable, and
locally advanced pancreatic
adenocarcinoma?
Answer Level of Grade of References
Evidence Recommendation
CT with “pancreas protocol” 2c C 2, 4-6
is the preferred method for
diagnosis, staging, and determining
resectability.
EUS-FNA is the best modality for 2c B 11, 13-15
obtaining a tissue diagnosis.
SL should be used selectively in 2b, 3a B 7-10
patients at high risk for occult
metastatic disease, and in those
with Stage III disease to avoid
unnecessary radiotherapy.
Resectable disease is defined as the 2c, 5 D 19-24
absence of tumor extension to the
SMA, celiac, or common hepatic
arteries, and the absence of any
tumor-induced unilateral shift or
narrowing of any aspect of the
PV-SMV confluence.
Borderline resectable disease is
defined as tumors with abutment
of the SMA, abutment or
short-segment encasement of
the common hepatic artery,
tumor-induced unilateral shift
or narrowing of the PV-SMV,
or short-segment occlusion of
the SMV/PV confluence with
patent vessel above and below
the occlusion suitable for venous
reconstruction.
Locally advanced tumors are those
with encasement of the SMA or
common hepatic artery, or an
occluded SMV/PV confluence
with no technical option for
reconstruction.

(Continued)

PMPH_CH57.indd 462 5/22/2012 5:39:55 PM

 Pancreatic Adenocarcinoma ■ 463

(Continued)
Question
3 What is the role of adjuvant
therapy after resection for
pancreatic adenocarcinoma?
4 What is the role of neoadjuvant
therapy in the management of
pancreatic adenocarcinoma?
Answer Level of Grade of References
Evidence Recommendation
Adjuvant chemotherapy is clearly 1b
beneficial.
The role of adjuvant CRT is unclear, 2c B 37-45
though may benefit the subset of
patients with nodal involvement.
Gemcitabine should be used with 2b
adjuvant CRT regimens.
Neoadjuvant CRT is well tolerated
and results in excellent margin-
negative resection rates and
significantly improved survival in
patients who undergo resection. 2b B 31-34
It can also identify the subset of
patients with aggressive disease
who will not benefit from surgical
therapy.

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5/22/2012 5:39:55 PM
 Commentary on
Pancreatic Adenocarcinoma
Matthew H. G. Katz, Jason B. Fleming, Jeffrey E. Lee, Peter W. T. Pisters
The first multi-institutional trial of multimodality therapy for
localized pancreatic adenocarcinoma, published over 25 years ago,
demonstrated that the overall survival duration of patients who
received chemoradiation after resection was longer than that of
patients who underwent surgery alone.1 Although numerous tri-
als have since evaluated novel pre- and postoperative therapy regi-
mens for patients with pancreatic cancer, no meaningful further
improvement in survival has been achieved. The median overall
survival duration of patients with resectable pancreatic tumors—
just under 2 years—has essentially stagnated.2-4 In this chapter,
Dr. St. Julien and colleagues provide a concise, thoughtful over-
view of four critical, yet controversial issues in the multimodal-
ity care of patients with localized pancreatic cancer and highlight
several reasons for our incredibly slow progress. In doing so, the
authors suggest several key areas for improvement in the design
and conduct of future clinical trials of novel therapies for local-
ized pancreatic cancer.
Although adjuvant therapy maximizes oncologic outcomes
following surgery for localized pancreatic cancer, the only treat-
ment that has been proven to be curative itself is the complete
resection of the primary tumor and regional lymph nodes. To
the extent that microscopically complete (R0) resection has been
associated with longer survival times than either macroscopi-
cally complete (R1) or incomplete (R2) resection,5 fundamental
components of a multidisciplinary approach to treating patients
with resectable pancreatic cancer include accurate staging of the
disease to properly identify patients for whom complete resection
is feasible, use of a meticulous surgical technique with specific
attention given to oncologically critical soft tissue margins, and
precise histopathologic analysis of the surgical specimen prior to
(or, if neoadjuvant therapy is used, following) adjuvant therapy.
Unfortunately, as Dr. St. Julien and colleagues note, no
standard system of staging localized pancreatic cancer exists.
Although most institutions use computed tomography images
to determine whether a tumor can be technically resected, the
interpretation of such images to differentiate “potentially resect-
able,” “borderline resectable,” and “unresectable” primary cancers
varies among institutions, radiologists, pancreatic surgeons, gen-
eral surgeons, and other oncologists. Over the past decade, the
National Comprehensive Cancer Network,6 the Society of Surgi-
cal Oncology-American Hepatopancreaticobiliary Association,7
and The University of Texas MD Anderson Cancer Center8 have
developed systems of classifying localized pancreatic cancer that
465
PMPH_CH57.indd 465
focus on the primary cancer’s radiographic relationship to the
superior mesenteric vein and superior mesenteric artery. However,
none of these systems have been validated or uniformly adopted,
and all are open to subjectivity with regard to their use in clinical
practice.
After disease stage and tumor resectability have been precisely
determined, a meticulous technical operation must be performed
to achieve a macroscopically and microscopically complete resec-
tion. Several studies have reported high rates of microscopic resid-
ual disease at the SMA margin, suggesting that surgeons need to
pay critical attention to this margin during pancreaticoduodenec-
tomy. However, in a recent analysis of patients enrolled in an
American College of Surgeons Oncology Group (ACOSOG) trial
who received chemoradiation following presumably complete
pancreaticoduodenectomy performed by experienced pancreatic
surgeons at high-volume sites, the ACOSOG found that only a
minority of surgeons may actually utilize a standard operation
that is designed to minimize residual cancer at the SMA margin.9
At least 60% of patients analyzed in that study may have under-
gone an operation in which the retroperitoneal tissues were incom-
pletely resected, suggesting that residual cancer may be left in
many patients in the United States who undergo tumor resection—
an outcome that might be prevented or reduced with a more thor-
ough, standardized operation.
Finally, a systematic histopathologic analysis of the surgical
specimen is critical, particularly proper stratification of patients
by margin status. The College of American Pathologists10 suggests
using a standardized method to examine and report the status of
the surgical margins. However, as anatomic nomenclature varies,11
many centers may not routinely evaluate the oncologically signifi-
cant SMA margin,9 and many surgeons dispute the definition of a
positive margin (tumor cells at the margin vs. tumor cells within
1 mm of the margin), which leads to inconsistency in documenta-
tion.12 Determining the role of specific therapies based on surgical
margin status is therefore difficult, if not impossible.13
The variability or absence of quality control in disease stag-
ing, surgical methods, and pathologic analysis may thus cause
significant heterogeneity in patient populations in clinical trials
of multimodality therapy for pancreatic cancer. Notwithstanding
the limitations and methodological problems that Dr. St. Julien
and colleagues note are inherent to previous trials—the inclusion
of patients with varied periampullary diagnoses, the use of com-
plicated study designs, the use of suboptimal treatment regimens,
5/22/2012 5:39:55 PM
 466 ■ Surgery: Evidence-Based Practice
etc.—the absence of standardization and quality control specifi-
cally related to the selection and conduct of surgery suggests that
past trials have enrolled a heterogenous group of patients who had
a variety of disease stages, underwent variable operations that
needlessly left many with residual cancer, and were subsequently
stratified by margin status by variable methods. Is it any wonder,
then, that we have not been able to come to a consensus on the
use of adjuvant chemoradiation, let alone refine the staging sys-
tem, define the precise role (or absence thereof) of preoperative
therapy, or demonstrate the efficacy of novel targeted therapeutics
in pancreatic cancer?
The pancreatic research community must give considerable
thought to these critical issues, as well as to the general research
strategy that we pursue for this disease. Although large, phase III
randomized trials have been appropriately encouraged in other
solid tumors in support of evidence-based decision making, it
must be recognized that in the setting of localized pancreatic can-
cer, large phase III trials take years to accrue, cost millions of dol-
lars, and utilize valuable patient resources that might be directed
instead to a more efficient—and perhaps more effective—research
strategy. For example, the last American phase III trial, RTOG
9704, took 4 years to accrue 388 patients with pancreatic cancer
and the outcome data were published a decade after the trial was
opened.4 The current phase III trial, RTOG 0848 has a sample size
of 856 patients and will take more than 5 years to complete accrual
at the protocol specified accrual rate of 14 patients per month.
These valuable patient resources might instead be invested in nine
phase II trials enrolling 100 patients each, each designed to evalu-
ate the efficacy of novel targeted agents administered preopera-
tively, and each coupled with basic and translational correlative
research studies. It is quite possible that by adopting this alternate
strategy we would make more progress in understanding the biol-
ogy and potential therapeutic efficacy of the broad spectrum of
targeted agents that will come to market in the time that we are
locked into a national commitment to a phase III trial that is very
unlikely to yield much gain on the less than 2-year median sur-
vival outlined by St. Julien and colleagues.
Dr. St. Julien and colleagues highlight the limitations of the
limited number of high-level studies that provide the data we use
as the basis for the multidisciplinary care of patients with local-
ized pancreatic cancer. To accelerate progress, we must recognize
the opportunity costs of continuing an expensive and resource-
intensive research strategy that has failed to yield a meaningful
improvement in patient outcome over the last 25 years. Focus on
a more efficient program of smaller and better-designed clinical
trials—with attention to the methodological problems described
by Dr. St. Julien and colleagues and described above—would be a
major step forward.
PMPH_CH57.indd 466
REFERENCES
1. Kalser MH, Ellenberg SS. Pancreatic cancer. Adjuvant combined
radiation and chemotherapy following curative resection. Archives
of surgery. 1985;120(8):899-903.
2. Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy
and 5-fluorouracil after curative resection of cancer of the pan-
creas and periampullary region: phase III trial of the EORTC gas-
trointestinal tract cancer cooperative group. Annals of surgery.
1999;230(6):776-782; discussion 782-784.
3. Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with
gemcitabine vs observation in patients undergoing curative-
intent resection of pancreatic cancer: a randomized controlled
trial. JAMA: the journal of the American Medical Association.
2007;297(3):267-277.
4. Regine WF, Winter KA, Abrams RA, et al. Fluorouracil vs Gem-
citabine Chemotherapy Before and After Fluorouracil-Based
Chemoradiation Following Resection of Pancreatic Adenocarci-
noma. A Randomized Controlled Trial. JAMA: the journal of the
American Medical Association. 2008;299(9):1019-1026.
5. Katz MH, Hwang R, Fleming JB, et al. Tumor-node-metastasis
staging of pancreatic adenocarcinoma. CA Cancer J Clin. 2008;
58(2):111-125.
6. Pancreatic adenocarcinoma. NCCN Clinical Practice Guidelines
in Oncology. 2009.
7. Callery MP, Chang KJ, Fishman EK, et al. Pretreatment assessment
of resectable and borderline resectable pancreatic cancer: expert
consensus statement. Ann Surg Oncol. 2009;16(7):1727-1733.
8. Katz MH, Pisters PW, Evans DB, et al. Borderline resectable pan-
creatic cancer: the importance of this emerging stage of disease.
J Am Coll Surg. 2008;206(5):833-846; discussion 846-848.
9. Katz MH, Merchant NB, Brower S, et al. Standardization of sur-
gical and pathologic variables is needed in multicenter trials of
adjuvant therapy for pancreatic cancer: results from the ACO-
SOG Z5031 trial. Ann Surg Oncol. 2011;18(2):337-344.
10. Pancreas (exocrine) [College of American Pathologists Cancer Pro-
tocols web site]. 2009. Available at: http://www.cap.org/apps/docs/
committees/cancer/cancer_protocols/2009/PancreasExo_09
protocol. pdf. Accessed March 25, 2011, 2010.
11. Raut CP, Tseng JF, Sun CC, et al. Impact of resection status on
pattern of failure and survival after pancreaticoduodenectomy for
pancreatic adenocarcinoma. Annals of surgery. 2007;246(1):52-60.
12. Verbeke CS, Menon KV. Variability in reporting resection mar-
gin status in pancreatic cancer. Annals of surgery. 2008;247(4):
716-717.
13. Neoptolemos JP, Stocken DD, Dunn JA, et al. Influence of resec-
tion margins on survival for patients with pancreatic cancer
treated by adjuvant chemoradiation and/or chemotherapy in
the ESPAC-1 randomized controlled trial. Annals of surgery.
2001;234(6):758-768.
5/22/2012 5:39:55 PM
 CHAPTER 58

Unusual Pancreatic Tumors

David W. Rittenhouse, Charles J. Yeo, and Samuel D. Gross

INTRODUCTION neoplasms which arise from a different progenitor cell than the
pancreatic ductal cell, share mixed histology or are a result of
With greater quality and availability of cross-sectional imaging, metastasis from another organ.2 Cystic tumors comprise up to
more patients with pancreatic neoplasms are being found than 15% of pancreatic neoplasms and present many challenges with
in the past. Pancreatic ductal adenocarcinoma (PDA) is the 10th diagnosis and management.1 Neuroendocrine tumors, both func-
most commonly diagnosed cancer in the United States and the tional (Table 58.2) and nonfunctional, account for approximately
4th leading cause of cancer-related death. Much work is currently 1% to 2% of pancreatic tumors.3 Adenosquamous carcinoma,
being done to develop biomarkers that are both prognostic and acinar cell carcinoma, lymphoma, rare sarcomas, pancreatoblas-
predictive for adjuvant therapy. Th is work will help to identify toma, metastatic disease, and others make up the remaining rare
which populations carry the highest risk for the development of neoplasms of the pancreas. The relative rarity of these tumors has
PDA, which patients will benefit from early screening, and which made it difficult to gather substantial epidemiologic data. Their
therapies will be optimal for any specific patient. However, PDA scarcity has also made it challenging to develop any guidelines
only comprises approximately 85% of all pancreatic neoplasms.1 on the best diagnostic and management strategies. In this chap-
The remaining pancreatic neoplasms (Table 58.1) consist of other ter, we discuss key elements of many of the unusual pancreatic
tumors.
Table 58.1 Unusual Pancreatic Tumors
Pancreatic Endocrine Neoplasms
A. Neuroendocrine tumors
Nonfunctional tumors Insulinoma
Functional tumors
Insulinoma 1. Is endoscopic ultrasound (EUS) the most sensitive test used
VIPoma for preoperative localization of insulinoma and other pancre-
Gastrinoma atic neuroendocrine neoplasms?
Glucagonoma
Insulinomas occur with an annual incidence in the general pop-
Somatostatinoma
ulation of approximately one to four cases per 1,000,000.4 They
B. Cystic tumors comprise the majority of functional neuroendocrine tumors and
Serous cystadenoma typically occur sporadically.4,5 Patients can present with the clas-
Serous cystadenocarcinoma sic Whipple’s triad: (1) symptoms of hypoglycemia during fasting,
Mucinous cystadenoma (2) documentation of hypoglycemia, with a serum glucose level
Mucinous cystadenocarcinoma below 50 mg/dL, and (3) relief of hypoglycemic symptoms fol-
Intraductal papillary mucinous neoplasm lowing administration of exogenous glucose. The typical symp-
C. Adenosquamous carcinoma toms include neuroglycopenic symptoms (confusion, personality
D. Acinar cell carcinoma change, and coma) and catecholamine surge symptoms (trem-
bling, diaphoresis, and tachycardia). The classic diagnostic test is
E. Solid pseudopapillary tumor a monitored fast, done under supervision, where blood is drawn
F. Pancreatoblastoma for glucose and insulin levels at the time of symptoms. Fasting glu-
cose and insulin measurements aid in the diagnosis of insulinoma,
G. Metastases from a nonpancreatic primary
but do not help in the localization. Insulinomas occur with an even

467

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 468 ■ Surgery: Evidence-Based Practice

Table 58.2 Symptoms, Diagnostic Tests and Anatomic Localization of Functional Neuroendocrine Neoplasms of
the Pancreas
Insulinoma Gastrinoma VIPoma Glucagonoma
Symptoms Neuroglycopenia causes Peptic ulcer disease Watery diarrhea Necrolytic migratory
confusion, personality erythema
change, coma
Catecholamine surge Diarrhea Weakness Stomatitis
causes trembling,
diaphoresis, tachycardia
Anabolic state: weight gain Esophagitis Lethargy Angular chelosis, glossitis
Nausea Catabolic state: weight loss
Diagnostic tests Monitored fast Serum gastrin Hypokalemia Hyperglycemia
measurement
Insulin-to-glucose ratio Gastric acid analysis Achlorhydria Hypoproteinemia
Secretin stimulation test Metabolic acidosis Serum glucagon measurement
Elevated serum Serum amino acid profile
VIPoma
Anatomic localization Evenly distributed through Duodenum and head of Most in body and Most in body and tail of
pancreas pancreas (gastrinoma tail of pancreas, pancreas, with liver
triangle) with liver metastases
metastases
Source: Ref. [19].

distribution throughout the head, body, and tail of the pancreas.
Approximately, 90% of insulinomas are less than 2 cm in diameter,
and 30% are less than 1 cm in diameter.
Localization techniques include noninvasive studies or inva-
sive studies. Noninvasive cross-sectional imaging such as com-
puted tomography (CT) scanning and magnetic resonance imaging
(MRI) is commonly performed. CT scanning has a sensitivity of
detecting insulinomas ranging only from 30% to 66%.6 Much of
this variability comes from the differences in imaging quality,
interpreter variability, and also is related to the small size of many
insulinomas. CT scanning can be helpful in staging the tumor, in
the case of local spread or metastasis.7 MRI is another form of
cross-sectional imaging that has been used to localize insulinomas.
Druce et al. studied the accuracy of MRIs in correctly identifying
tumors that were preoperatively presumed to be insulinoma.8 Of
the 28 patients who had preoperative MRIs, the correct diagnosis
was made in 75% of patients.
Invasive tests occasionally used for localization are angiog-
raphy or transhepatic portal-venous sampling (THPVS). For the
latter, a catheter is placed percutaneously through the liver into
the portal vein. Insulin levels are measured from blood samples
that are collected from the splenic vein, superior mesenteric vein,
and portal vein.9 Another invasive procedure, the EUS uses a 7.5 to
10 MHz transducer and detects lesions as small as 5 mm.9 Zimmer
et al. prospectively evaluated the sensitivity and specificity of EUS
in localizing insulinomas and gastrinomas.10 EUS identified 13 of
14 insulinomas in 10 patients that were expected to have the diag-
nosis of insulinoma based on clinical characteristics. All patients
underwent resection. Sensitivity of detecting the insulinoma was
93%. Rosch et al. compared the sensitivities of EUS with angiog-
raphy in identifying pancreatic endocrine neoplasms.11 Thirty-
seven patients with 39 CT negative pancreatic neuroendocrine
neoplasms (31 insulinomas) were analyzed by EUS and angiogra-
phy. EUS had a sensitivity of 85% and a specificity of 95%, whereas
angiography had a sensitivity of only 27%.
Answer: Yes. EUS has a greater sensitivity than CT scan-
ning and MRI and should be used in the localization of suspected
insulinomas.
VIPoma
2. Are somatostatin analogs (octreotide) helpful in control-
ling symptoms in patients with VIPoma (vasoactive intestinal
polypeptide-oma)?
VIPoma, first described by Verner and Morrison in 1958, occurs
with a frequency of 1 in 10 million people.12,13 Synonyms for VIPoma
include the Verner–Morrision syndrome, pancreatic cholera, and
the WDHA syndrome (watery diarrhea, hypokalemia, and achlo-
rhydria/acidosis). VIPomas secrete high levels of VIP, a neuropep-
tide that activates adenylate cyclase and cAMP on the intestinal
lumen, inhibiting absorption and stimulating intestinal secretion.
Patients frequently present with intermittent voluminous watery
diarrhea. Laboratory analysis typically reveals hypokalemia, gas-
tric achlorhydria, metabolic acidosis, and elevated serum VIP lev-
els. Ghaferi et al.14 reviewed three patients at a single institution
and the world literature and found that the mean serum VIP levels
were 683 pg/mL (range 293–1500 pg/mL). The differential diagno-
sis can include a host of gastrointestinal diseases from infectious
to malignant (Table 58.3). Over 90% of VIPomas are confined to
the pancreas (Fig. 58.1), with less than 10% occurring in the ret-
roperitoneum or in the chest. The body or tail of the pancreas is
the most common location of the primary VIPoma. More than
60% of VIPomas have metastasized (typically to lymph nodes or
to liver) by the time of diagnosis.13 Fluid replacement and elec-
trolyte correction are critical, given the severe dehydration that
can occur with the voluminous diarrhea. In addition to surgery to
remove the tumor, treatment with somatostatin analogs (typically
octreotide 50–250 μg SQ q8 h) has shown excellent results in ame-
liorating the diarrhea. Oberg et al.15 reported a tumor response
(diminution in size) in less than 5% of patients, but symptomatic

PMPH_CH58.indd 468 5/22/2012 5:40:30 PM

 Unusual Pancreatic Tumors ■ 469

relief from diarrhea in more than 60% of patients. Maton et al.16
reported less than 20% of patients having a response in tumor
size, with 83% of patients experiencing symptomatic relief. The
inhibitory effect of somatostain analogs has been hypothesized to
act by reducing tumor blood flow or by a direct hormonal inhibi-
tory effect.17
Answer: Yes. Management of VIPoma patients with long-
acting somatostatin analogs can be effective at controlling symp-
toms, but should not be anticipated to affect tumor size or bulk.

Table 58.3 Differential Diagnosis of the Gastrinoma

Verner–Morrison Syndrome (VIPoma)
3. Should you ever electively operate on a gastrinoma patient
Entity Workup without first controlling their gastric acid secretion?
Villous adenoma Lower GI endoscopy Gastrinomas are the second most common functional pancre-
Laxative abuse Stool examination for atic neuroendocrine tumor (Fig. 58.2). These gastrin-producing
phenolphthalein tumors typically present with peptic ulcer disease and diarrhea.
Approximately, 75% of tumors are sporadic, with nearly 25%
Celiac disease Fecal fat measurement
occurring as part of the multiple endocrine neoplasia-1 syndrome
D-xylose tolerance test
Small bowel biopsy (MEN1). MEN1 is an autosomal dominant inherited disorder
HLA typing that consists of parathyroid hyperplasia, pituitary neoplasms,
and pancreatic neuroendocrine neoplasms (most commonly gas-
Parasitic and Stool culture trinoma). More than 90% of gastrinoma patients have abdomi-
infectious diseases Ovum and parasite analysis nal pain and some form of upper gastrointestinal ulceration. The
Clostridium difficile toxin assay fi nding of a serum gastrin level elevated to more than 1000 pg/mL
Inflammatory bowel Lower GI endoscopy (far above the upper limit of normal which is 100 pg/mL) is nearly
disease Upper GI and small bowel series pathognomonic for gastrinoma in a patient with gastric acid
Carcinoid syndrome Urinary 5'-HIAA excess. Other causes of ulcerogenic hypergastrinemia (Table 58.4)
Upper GI and small bowel series include antral G-cell hyperplasia/hyperfunction, gastric outlet
Abdominal CT obstruction, renal insufficiency, and retained excluded gastric
Serum serotonin measurement antrum (a surgical mishap).18 Patients with gastrinoma have ele-
vated acid secretion with a basal acid output (BAO) above 15 mEq/h
Gastrinoma Serum gastrin measurement
or a ratio of BAO to maximal acid output (MAO) exceeding
Gastric acid analysis
0.6. One common mistake is to falsely consider the diagnosis of
Secretin stimulation test
gastrinoma in a patient on proton pump inhibitors (PPIs) with
CT, computed tomography; GI, gastrointestinal; 5'-HIAA, mildly elevated serum gastrin levels. As PPIs cause reduced acid
5'-hydroxyindoleacetic acid secretion, the gastrin elevation is a result of the achlorhydria and
Source: Ref. [19]. does not indicate a neoplastic process. Provocative testing can
be done to differentiate the causes of ulcerogenic hypergastrine-
mia. An intravenous bolus of secretin is given after a baseline

Figure 58.2 An abdominal CT scan of a 69-year-old man pre-

Figure 58.1 An abdominal MRI of a 64-year-old female pre-
sented with voluminous watery diarrhea and hypokalemia. The
MRI reveals a 5.1 × 5.8 cm mass (arrow) with central necrosis
in the head and uncinate process of the pancreas. The serum
VIP level was markedly elevated. The patient underwent a pylo-
rus preserving pancreaticoduodenectomy, and the pathology
revealed a pancreatic endocrine neoplasm. Immunohistochemi-
cal staining for VIP was strongly positive.
sented with abdominal pain and peptic ulcer disease. The patient
had an elevated serum gastrin level of greater than 1000 pg/mL.
The CT scan shows a 2.0 × 2.4 cm hypervascular mass in the
body of the pancreas (arrow) with a dilated pancreatic duct in the
tail of the gland. The patient underwent a distal pancreatectomy
and splenectomy. The pathology revealed a pancreatic endocrine
neoplasm, with the immunohistochemical stain for gastrin being
strongly positive.

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 470 ■ Surgery: Evidence-Based Practice
Table 58.4 Disease States Associated with
Hypergastrinemia
Nonulcerogenic causes (normal to low gastric acid secretion)
Atrophic gastritis
Pernicious anemia
Previous vagotomy
Renal failure
Short-gut syndrome
Ulcerogenic causes (excess gastric acid secretion)
Antral G-cell hyperplasia or hyperfunction
Gastric outlet obstruction
Retained excluded gastric antrum
Zollinger–Ellison syndrome
Source: Ref. [19].
level of gastrin is drawn and gastrin levels are collected at 5-min
intervals for 30 min. An increase by more than 200 pg/mL above
the basal level is indicative of the diagnosis of gastrinoma.19
Answer: No. Gastric acid should be suppressed with appro-
priate (often high dose) PPIs prior to elective exploration for gas-
trinoma. To operate without controlling the ulcer diathesis risks
problems with perioperative gastrointestinal ulceration.
Glucagonoma
4. In patients with glucagonoma, does resection of advanced
local disease or metastases increase overall survival?
Glucagonomas have a characteristic clinical presentation of a skin
rash (necrolytic migratory erythema), glossitis, angular chelosis,
diabetes, and a catabolic state resulting in weight loss. Laboratory
analyses reveal hyperglycemia and elevated fasting levels of serum
glucagon. The disease is also accompanied by a dramatic amino
acid profi le disruption. Most glucagonomas are in the body or tail
of the pancreas. Compared with other neuroendocrine tumors of
the pancreas, these tumors are often large (>4 cm) at the time of
diagnosis.18 The rate of malignancy in glucagonomas is 60%
to 80% in tumors that are larger than 5 cm. Thus, the majority
of patients have lymph node or hepatic metastases at the time of
diagnosis.18 There are data to support resection for patients for
locally advanced and metastatic disease.
Wermers et al.20 performed a large single institution review
of 21 patients with glucagonoma. All of the patients had meta-
static disease at presentation. Twelve patients underwent surgi-
cal debulking via distal pancreatectomy and splenectomy with
or without resection of hepatic metastases. Eight of the patients
had major reduction in serum glucagon levels from preoperative
levels. Serum glucagon levels decreased by a mean of 1442 pg/mL.
Six patients had remission of the necrolytic migratory erythema.
Chu et al.21 reviewed 12 patients that had resection of a gluca-
gonoma at a single institution. Eight of the patients underwent
surgical exploration. Three of the eight had diff use metastatic
spread to the liver. Of those with metastatic disease found at
operation, only one underwent a hepatic resection (left lateral
segmentectomy) after extensive tumor embolization procedures.
Sarmiento et al.22 reviewed 170 patients that had hepatic metas-
tases from neuroendocrine tumor (9 glucagonomas, 5.3%) and
found that hepatic resection of metastases was associated with a
5-year survival of 61%. The authors further reviewed the literature
and found 5-year survival of 47% to 76% after hepatic resection
PMPH_CH58.indd 470
for neuroendocrine metastases.22 Hill et al.23 analyzed the SEER
database to look for a survival advantage with surgery in all pan-
creatic neuroendocrine tumors, including glucagonoma. Patients
with all stages of disease showed a survival advantage with sur-
gery compared with no surgery.
Answer: Large prospective multi-institutional trials are lack-
ing, but there is some evidence to suggest that aggressive resection
of a locally advanced primary tumor and metastatic deposits can
improve survival in patients with glucagonoma.
Adenosquamous Carcinoma
5. Are there any means to preoperatively differentiate between
adenosquamous carcinoma and adenocarcinoma?
Pancreatic adenosquamous carcinoma (PASC) is a rare morpho-
logic variant of PDA which comprises only 1% to 4% of exocrine
pancreatic tumors. PASC is distinguished from PDA on a histo-
logic basis by having more than 30% squamous cell carcinoma
mixed with the underlying ductal adenocarcinoma.24 It has been
thought that PASC carries a worse prognosis than PDA.25 Katz
et al.26 sought to look for differences in clinical features between
PASC and PDA by performing a historical analysis of cases in the
California Cancer Registry Database. A total of 14,746 cases of PDA
and 95 cases of PASC were included in the analysis. Median age at
diagnosis, gender, race, socioeconomic status, and clinical stage of
patients were all similar between the PDA and PASC patients. More
than 50% of patients from both groups had metastatic disease at
the time of diagnosis. Patients with locoregional PASC were more
likely to undergo resection (61.9%) than those patients with PDA
(35.6%); however, the two groups had similar rates of adjuvant ther-
apy. The two cohorts had a similar median survival (approximately
4 months) when examined by a Cox proportional hazard model.
PASC and PDA have been compared on a molecular level.
Brody et al.27 examined the molecular characteristics of eight cases
of PASC and found that these patients had similar molecular alter-
ations to that of PDA in KRAS2, tp53, and DPC4. However, p63
staining was helpful in identifying those cases of adenosquamous
differentiation with an acantholytic growth pattern.27 However,
this is not helpful in preoperatively differentiating between the
two tumors, due to the paucity of tissue retrieved by standard
needle biopsy techniques.
It would be ideal to have a radiologic method of distinguishing
between PASC and PDA. Currently, no such method exists. Izuishi
et al.28 published a case report of a patient with PASC. The patient
underwent a fluorodeoxyglucose positron emission tomography
(FDG-PET), which showed strong FDG uptake with a maximum
standardized uptake volume (SUV) of 15.8. The mean SUV of PDA
is somewhat lower at 4.7 ± 2.5. Yet, as most patients with resectable
pancreatic tumors are not recommended to undergo PET scanning,
its value in differentiating PASC from PDA remains unproven.
Answer: There is currently no evidence to support any
means of effectively differentiating between PASC and PDA
preoperatively.
6. Are there molecular markers for adenosquamous cancers
that can be used for prognosis or the prediction of response to
adjuvant therapy?
A better understanding of biomarkers is critical as we prog-
ress toward the goal of personalized cancer therapy. It has been
shown that adjuvant chemoradiation therapy (typically either
5/22/2012 5:40:30 PM

gemcitabine or 5-FU with radiation) is associated with a slight
improvement in overall survival in patients with resected PDA.
Voong et al.24 showed that the proportion of squamous differentia-
tion (<30% vs. >30%) was not a factor which influenced the median
overall survival.24 It would be helpful if we could identify biomark-
ers that could be prognostic or be predictive in patients with PASC.
One biomarker that is currently used is carbohydrate antigen 19-9
(CA19-9). CA19-9 has been used to preoperatively help to distin-
guish between benign disease and PDA, with a sensitivity rang-
ing from only 41% to 86%, and a specificity ranging from 33% to
100%.29 Another emerging biomarker is the mRNA binding protein
HuR. High expression levels of HuR have been shown to carry a
poor prognosis in patients with PDA and other cancers. However,
high cytoplasmic levels of HuR have been shown to be predictive
of a favorable response to gemcitabine-based adjuvant therapy in
patients with PDA.30,31 Patients with higher levels of HuR expres-
sion had a seven fold increase in survival after gemcitabine treat-
ment, when compared with patients with low HuR expression.
Answer: There is no evidence currently available that shows
that molecular markers for PASC can predict response to adjuvant
therapy.
Acinar Cell Carcinoma
7. Are there clinical measures to preoperatively differentiate
between acinar cell carcinoma of the pancreas and adenocarci-
noma of the pancreas?
Pancreatic acinar cell carcinoma (ACC) is a rare cancer that
accounts for only 1% of the non-neuroendocrine pancre-
atic tumors, despite approximately 80% of the pancreas volume
being composed of acinar cells. Matos et al.32 performed a multi-
institutional study looking at the clinical characteristics of 17
patients with pathologically confirmed ACC between the years
1988 and 2008.32 Patients with ACC did not present with the typi-
cal symptoms of painless obstructive jaundice, but rather they
presented with pain and weight loss (Fig. 58.3). None of the ACC
patients had elevated CA19-9 levels on preoperative laboratory
analysis, a tumor marker which is commonly elevated in PDA.
Schmidt et al.33 reviewed 865 patients with ACC and 367,999
patients with PDA in the National Cancer Database from 1985
to 2005. Patients with ACC were more likely to be male, white,
have a larger tumor size (>4 cm), no nodal involvement, and to
have pancreatic tail tumors. Wisnoski et al.34 reviewed the Sur-
veillance, Epidemiology, and End Results (SEER) database and
compared 672 patients with ACC with 58,526 patients with PDA.
Patients with ACC were more likely to be younger at diagnosis
(56 vs. 70 years), white and male when compared to patients with
PDA. Another institutional review looked at 14 patients with ACC
and reported a median age of diagnosis of 57 years.35
Answer: Large retrospective database reviews have shown
that patients with ACC tend to be white, male, and present at
an earlier age as compared with PDA patients. However, these
demographic features lack accuracy in predicting the ultimate
pathology in patients with pancreatic neoplasia.
8. Is the overall prognosis worse for patients with acinar cell
carcinoma of the pancreas when compared with adenocarci-
noma of the pancreas?
Schmidt et al.33 reported that stage-specific 5-year survivals were
significantly better for resected ACC versus resected PDA with
PMPH_CH58.indd 471
Unusual Pancreatic Tumors ■ 471
Figure 58.3 MRI showing a dilated pancreatic duct (arrow) in a
34-year-old white female who presented with a history of seven
bouts of pancreatitis in 1 year. Her CA19-9 level was normal at
28 U/mL. The patient underwent a distal pancreatectomy and
splenectomy. Pathology revealed a multifocal acinar cell car-
cinoma (T2N0M0) with positive surgical margins. The patient
returned for a completion right-sided pancreatectomy 2 months
later, with the second pancreatectomy specimen also revealing a
scattered multifocal acinar cell carcinoma.
Stage I: 52.4% versus 28.4%, Stage II: 40.2% versus 9.8%, Stage III:
22.8% versus 6.8%, and Stage IV disease: 17.2% versus 2.8%. By
multivariate analysis, age less than 65 years, well-differentiated
tumors, and negative resection margins were the independent
favorable prognostic markers for ACC. Wisnoski et al.34 also
reported overall better survivals for patients with ACC when
compared with PDA, as their overall 5-year survival was 42.8%
(median, 47 months) for ACC and only 3.8% for PDA (median,
4 months). When analyzing only those patients who did not
undergo resection, the 5-year survival rates were 22% for ACC
and 2% for PDA. When comparing only patients that underwent
surgical resection, the 5-year survival rates were 72% for ACC
and only 16.3% for PDA.
Answer: Large retrospective database reviews have shown
that patients with ACC have a better overall prognosis when com-
pared with similarly treated and staged patients with PDA.
Mucinous Cystic Neoplasm (MCN)
9. What is the most important element, between surgery and
pathology, in ensuring the proper diagnosis of MCN? What
information is essential to predict prognosis?
MCN are cystic tumors of the pancreas that are characterized
by an ovarian-like stroma underlying the cyst epithelium.36 It is
hypothesized that this ovarian-like tissue arises from the rest of
the embryologic ovarian tissue in the pancreas.1 Patients with these
tumors have an average age at diagnosis of 48 years, and a female
to male ratio that exceeds 20:1. MCNs most commonly arise in the
body and tail of the pancreas and consist of uni- or multilocular
components that typically do not communicate with the pancre-
atic ductal system (Figs. 58.4A and B).36 Microscopically, the wall
may have velvety papillations with trabeculations.1 Less than 20%
of MCNs harbor an invasive component consisting of elements
that resemble PDA, or even rarer forms such as undifferentiated
5/22/2012 5:40:30 PM
 472 ■ Surgery: Evidence-Based Practice
Figure 58.4A An abdominal CT scan from a 32-year-old female
presented to the hospital 4 days after her first episode of severe
left upper quadrant pain. The patient was treated for pancreatitis
and diagnosed as having a “pseudocyst” of the pancreas, as this
CT scan showed a 3.3 × 3.9 cm cystic lesion in the tail of the
pancreas (arrow).
Figure 58.4B The lesion failed to disappear after 1 year of
follow-up, at which time the patient sought a second opinion.
Repeat CT scanning showed an increased size cystic lesion in
the tail of the pancreas, now 4.5 × 4.5 cm (arrow). The patient
underwent a distal pancreatectomy and splenectomy with the
final pathology on the entirely submitted specimen revealing a
mucinous cystic neoplasm with a low-grade dysplasia.
carcinoma with osteoclast-like giant cells, adenosquamous carci-
noma, choriocarcinoma, or sarcoma.36 Zamboni et al.37 studied
the clinicopathologic features of 56 patients with MCNs. Malig-
nancy correlated with multilocularity and presence of papillary
projections or mural nodules, loss of ovarian-like stroma, and
p53 immunoreactivity. Complete pathologic analysis should
be done on all MCNs given their malignant potential and the
PMPH_CH58.indd 472
variable and difficult identification of small malignant areas in
large neoplasms.
Answer: The most important aspect in managing the pathol-
ogy specimen in patients with MCN is the clear communication
between the surgeon and the pathologist about the importance
of a complete pathologic analysis of the tumor, given the propen-
sity of MCNs to undergo scattered malignant transformation. We
recommend that all MCNs be completely submitted and entirely
pathologically examined.
Intraductal Papillary Mucinous Neoplasm (IPMN)
10. Should you perform a partial or a total pancreatectomy for a
main duct intraductal papillary mucinous neoplasms (IPMN)?
IPMNs, which account for 10% of pancreatic tumors, consist of
cystic dilatation of the main and/or branch pancreatic ducts in
which intraductal proliferation of neoplastic mucin-producing
cells project as papillations.1 These tumors, which typically pres-
ent in the 7th to 8th decade of life, are most commonly found in
the head and uncinate process of the pancreas. 38 Macroscopi-
cally, an IPMN communicates with the ductal system. Micro-
scopically, the cystic lesions will consist of papillae with three
distinct patterns: intestinal, pancreatobiliary, and gastric.1
Branch duct IPMNs are more commonly found in younger
patients and those resected have lower rates of malignancy,
ranging from 6% to 46%.39 Resected main duct IPMNs have
been shown to harbor malignancy in 58% to 92% of tumors.38
Given the increased risk for malignancy, especially in main
duct IPMNs, it is imperative to develop clearly defi ned treat-
ment strategies. Sohn et al.40 reviewed 60 patients that under-
went pancreatic resections for IPMNs and compared them with
702 concurrent patients with PDA. The mean age at presenta-
tion was 67.4 years in patients with IPMNs. Most IPMNs were in
the head of the pancreas or diff usely throughout the gland. Of
the operations for IPMN, 70% underwent pancreaticoduodenec-
tomy, 22% underwent total pancreatectomy, and 8% underwent
distal pancreatectomy. Infi ltrating adenocarcinoma was found
in association with 37% of the IPMNs. Adsay et al.41 examined
the clinicopathologic characteristics of 28 IPMN lesions. Four of
these patients died of disease at the follow-up time of 35 months.
Two of the four patients only had borderline atypia with no evi-
dence of invasive carcinoma. One of the patients had intraduc-
tal carcinoma extending to the distal pancreatic ductal margin.
It is unclear whether this was a missed disease at the original
operation or inadequate analysis because the entire tumor
specimen was not analyzed. Chari et al.42 analyzed 113 IPMNs
and categorized them based on the presence of an invasive
component. Forty patients had an element of invasive carci-
noma, whereas 73 patients did not. Recurrence rates were similar
after partial pancreatectomy (18/27; 67%) when compared with
total pancreatectomy (8/13; 62%). Recurrence occurred within
3 years of resection in 91% of the patients. Among the patients
with noninvasive IPMNs, 5 of 60 (8%) recurred after partial pan-
createctomy and 0 of 13 had recurrence after total pancreatec-
tomy. Of those noninvasive IPMNs that recurred, the median
time to recurrence was 40 months.
Answer: At this time, there is no evidence to support a rou-
tine total pancreatectomy over a partial resection (typically right-
sided) for an isolated main duct IPMN. Total pancreatectomy
5/22/2012 5:40:31 PM

renders the patient an obligate insulin-dependent diabetic. If par-
tial pancreatectomy is performed, the remnant pancreas needs to
be kept under radiographic surveillance.
11. What is the appropriate surveillance for patients who have
undergone resection for IPMN?
The question of surveillance arises when dealing with IPMNs.
Sohn et al.40 in a review of 60 patients found that 37% of patients
had an associated infi ltrating IPMN and that the 5-year survival
rate for all patients with IPMNs was 57%. Chari et al.42 reported
that 91% of the patients that had resection for an IPMN with
an invasive component recurred within 3 years, whereas recur-
rence was seen at a mean of 3.25 years in resected IPMNs that
did not have an invasive component. Verbesey et al. 38 suggested
re-evaluation every 6 months with radiologic imaging.
Answer: There is no Level 1 evidence to suggest the exact
timing of surveillance screening for patients who have had an
IPMN resected. Patients who have had a main duct IPMN are
at an increased risk for recurrence; so we believe they should be
screened more frequently than those with branch duct IPMNs.
We recommend yearly or every other year MRI/MRCP for such
surveillance.
Serous Cystic Neoplasm (SCN)
12. Can you reliably differentiate preoperatively between SCN,
MCN, and IPMN?
SCNs are benign tumors of the pancreas that are composed of
uniform small cysts containing serous fluid.1 These tumors are
seen with a female to male ratio of 3:1 and present at a mean age of
61 years. SCNs often present as large masses in the body and tail
of the pancreas with either a microcystic or a macrocystic appear-
ance. Microcystic forms contain multiple small cysts fi lled with
a clear fluid in a characteristic honeycomb pattern that can have a
central stellate scar. Macrocystic SCNs form unilocular cystic
structures with fewer but larger loculi.
Lee et al.43 retrospectively reviewed the CT scans of 52 patients
to try to determine the preoperative accuracy of CT scanning in
correctly identifying SCNs. The accuracy varied based on the
structure of the cysts. The accuracy of CT scanning in predicting
unilocular macrocystic SCNs was only 35.7%. However, the accu-
racy of CT scanning in correctly predicting honeycombed micro-
cystic SCNs and multilocular macrocystic SCNs was 81% and
87.5%, respectively. Shah et al.44 reported the frequency of which
certain characteristic SCN features appear on CT imaging. Of the
28 patients reviewed who had SCN, 22 (78%) had a microcystic
appearance, 25 (89%) had surface lobulations, and 9 (32%) had the
presence of a central scar. Based on a stepwise logistic regression
analysis, a microcystic appearance was the only finding statisti-
cally predictive for the diagnosis of SCN.
Cyst fluid can also be used to help diagnose SCN and to
help to differentiate it from MCNs and IPMNs. Frossard et al.
reviewed 113 patients who had cystic tumors of the pancreas who
underwent EUS-FNA.45 The cyst fluid analysis and EUS results
were compared with the final pathology from surgery or post-
mortem examination. EUS appearance alone correctly diagnosed
SCNs, MCNs, and IPMNs with a sensitivity/specificity of
43%/76%, 65%/84%, and 100%/100%, respectively. FNA cyst fluid
analysis correctly diagnosed SCNs, MCNs, and IPMNs with a
PMPH_CH58.indd 473
Unusual Pancreatic Tumors ■ 473
sensitivity/specificity of 100%/98%, 94%/100%, and 100%/98%,
respectively. Allen et al.46 reported using a biomarker panel for
the analysis of cyst fluid. When comparing SCN, MCN, and
IPMN, there was an error in classification of tumors in 27% of
cases; however, this number fell to only 8% when only comparing
SCN with IPMN.
Answer: Preoperative differentiation of cystic tumors of the
pancreas is a challenge. The literature is lacking in large random-
ized prospective trials. The use of cross-sectional imaging with
CT scanning, along with EUS visualization and cyst fluid analysis,
can provide information to differentiate between these tumors;
however, the accuracy is not 100%.
13. Do serous cystic neoplasms ever undergo malignant
transformation?
Unlike MCNs (up to 20% can harbor malignancy), SCNs are usu-
ally benign. Galanis et al.47 reviewed 158 patients with SCN that
underwent surgical resection at a single institution. Two percent of
the patients had the final diagnosis of serous cystadenocarcinoma.
Strobel et al.48 reviewed the literature from 1989 to 2003 and found
673 cases of SCN with 19 cases reporting malignant transforma-
tion, for an overall malignant prevalence of 3%. Nine of the 19
patients were diagnosed as a malignant SCN because of the infil-
trative pattern of tumor growth, whereas three of the patients pre-
sented with metastatic disease.
Answer: Although of low risk, SCNs do have malignant
potential, with the capacity for infi ltrative tumor growth and
metastatic disease.
Solid Pseudopapillary Tumor (SPT)
14. Are there genetic markers that can predict phenotype and
prognosis for solid pseudopapillary tumors (SPTs)?
SPTs account for less than 1% of pancreatic tumors. They are
usually benign, are commonly found in young women, and have
a nearly 95% to 100% 5-year survival after surgical resection.49
Nearly 20% of the tumors examined in a review by Papavramidis
et al.49 had some element of invasion or metastases suggesting a
capacity of these tumors to have a malignant component. Prog-
nosis is much better than other pancreatic tumors, given that the
5-year survival is 95%. Kim et al.50 reviewed the medical records
of patients with pathologically confirmed SPTs over a 12-year
period in search for clinical predictors of malignancy. Clini-
cal fi ndings that suggested malignancy were metastasis at the
first operation, invasion of adjacent structures, large tumor size
(>13 cm), younger age at presentation, tumor rupture, and inad-
equate resection.50 Even though patients with malignant SPTs
do better than patients with other pancreatic tumors, it would
be beneficial to identify biomarkers that could possibly predict
phenotype or prognosis of disease. SPTs show diff use nuclear
and cytoplasmic staining for β-catenin. Tanaka et al.51 examined
18 patients and found all of them to have diff use nuclear and
cytoplasmic staining for β-catenin, and suggested that nuclear
accumulation of β-catenin with consequent overexpression of
cyclin D may lead to cell arrest and a more favorable phenotype
of disease.
Answer: There is some evidence to suggest that measuring
the differential subcellular expression of β-catenin and cyclin
D may be useful in elucidating which patients will have a more
5/22/2012 5:40:31 PM
 474 ■ Surgery: Evidence-Based Practice

favorable phenotype. Greater evidence is needed before tissue or
serum biomarkers can be used for accurate prediction of progno-
sis in SPTs.
Pancreatoblastoma
15. What is the most common age and presentation of pan-
creatoblastoma?
Pancreatoblastomas are rare pancreatic tumors that usually arise
in children, although some tumors present in adulthood. Those
affected typically present with vague gastrointestinal symptoms
of weight loss and abdominal pain.52 On gross examination, these
lesions are typically large and globular, consisting of discrete
masses with pseudocapsules of compressed tissue.53 Histologically,
these tumors resemble fetal tissue. Dhebri et al.54 searched the lit-
erature for all cases of pancreatoblastoma and found 158 patients
with a median age at presentation of 5 years (range from <1 to
60 years). Seventeen of the patients had metastatic disease at the
time of diagnosis and the median survival was 48 months. Factors
associated with a worse prognosis were synchronous (p = .05) or
metachronous metastases on presentation (p < .001), unresectable
disease at presentation (p < .001), and age >16 years at diagnosis
(p = .02). Rajpal et al.53 reviewed the literature for adult patients
with pancreatoblastoma. Of the 15 adult patients, ages ranged
from 19 to 78 years. Thirteen of the 15 patients underwent surgical
resection. Eight of the patients died with recurrent disease with a
mean survival of only 12 months.
Answer: The median age at presentation of patients with
pancreatoblastoma is 5 years; however, this disease can present in
adults as well. Increased age at the time of diagnosis carries a poor
prognosis. Patients typically present with weight loss and abdo-
minal pain.

Clinical Question Summary

Question
1 Is endoscopic ultrasound the most
sensitive test used for preoperative
localization of insulinoma and
other pancreatic neuroendocrine
neoplasms?
2 Are somatostatin analogs (octreotide)
helpful in controlling symptoms in
patients with VIPoma (vasoactive
intestinal polypeptide-oma)?
3 Should you ever electively operate
on a patient with a gastrinoma
without first controlling their
gastric acid secretion?
4 In patients with glucagonoma, does
resection of advanced local disease
or metastases increase overall
survival?
5 Are there any means to
preoperatively differentiate
between adenosquamous
carcinoma and adenocarcinoma?
6 Are there molecular markers for
adenosquamous cancers that
can be used for prognosis or the
prediction of response to adjuvant
therapy?
7 Are there clinical measures to
preoperatively differentiate
between acinar cell carcinoma of
the pancreas and adenocarcinoma
of the pancreas?
Answer Grade of References
Recommendation
Yes. EUS has a greater sensitivity than CT scanning B 4-11
and MRI and should be used in the localization
of suspected insulinomas.
Yes. Management of VIPoma patients with long- B 12-17
acting somatostatin analogs can be effective
at controlling symptoms, but should not be
anticipated to affect tumor size or bulk.
No. Gastric acid should be suppressed with B 18, 19
appropriate (often high dose) PPIs prior to
elective exploration for gastrinoma. To operate,
without controlling the ulcer diathesis risk
problems with perioperative gastrointestinal
ulceration.
Large prospective multi-institutional trials are C 18, 20-23
lacking, but there is some evidence to suggest
that aggressive resection of a locally advanced
primary tumor and metastatic deposits can
improve survival in patients with glucagonoma.
There is currently no evidence to support any D 24-28
means of effectively differentiating between
PASC and PDA preoperatively.
There is no evidence currently available that shows D 24, 29-31
that molecular markers for PASC can predict
response to adjuvant therapy.
Large retrospective reviews of databases have C 32-35
shown that patients with ACC tend to be
white, male, and present at an earlier age
as compared with PDA patients. However,
these demographic features lack accuracy in
predicting the ultimate pathology in patients
with pancreatic neoplasia.

(Continued)

PMPH_CH58.indd 474 5/22/2012 5:40:31 PM


(Continued)
Question
8 Is the overall prognosis worse for
patients with acinar cell carcinoma
of the pancreas when compared
with adenocarcinoma of the
pancreas?
9 What is the most important
element, between surgery
and pathology, in ensuring the
proper diagnosis of MCN? What
information is essential to predict
prognosis?
10 Should you perform a partial or a
total pancreatectomy for a main
duct IPMN?
11 What is the appropriate
surveillance for patients who have
undergone resection for IPMN?
12 Can you reliably differentiate
preoperatively between SCN,
MCN, and IPMN?
13 Do serous cystic neoplasms ever
undergo malignant transformation?
14 Are there genetic markers that can
predict phenotype and prognosis
for solid pseudopapillary tumors?
15 What is the most common
age and presentation of
pancreatoblastoma?
PMPH_CH58.indd 475
Unusual Pancreatic Tumors ■ 475
Answer Grade of References
Recommendation
Large retrospective database reviews have shown B 33, 34
that patients with ACC have a better overall
prognosis when compared with similarly treated
and staged patients with PDA.
The most important aspect in managing the C 1, 36, 37
pathology specimen in patients with MCNs is
the clear communication between the surgeon
and the pathologist about the importance of a
complete pathologic analysis of the tumor, given
the propensity of MCNs to undergo scattered
malignant transformation. We recommend that
all MCNs be completely submitted and entirely
pathologically examined.
At this time, there is no evidence to support a B 1, 38-42
routine total pancreatectomy over a partial
resection (typically right-sided) for an isolated
main duct IPMN. Total pancreatectomy renders
the patient an obligate insulin-dependent
diabetic. If partial pancreatectomy is performed,
the remnant pancreas needs to be kept under
radiographic surveillance.
There is no level 1 evidence to suggest the exact C 38, 40, 42
timing of surveillance screening for patients
who have had an IPMN resected. Patients who
have had a main duct IPMN are at an increased
risk for recurrence; so we believe they should
be screened more frequently than those with
branch duct IPMNs. We recommend yearly
or every other year MRI/MRCP for such
surveillance.
Preoperative differentiation of cystic tumors of the D 1, 43-46
pancreas is a challenge. The literature is lacking
in large randomized prospective trials. The use
of cross-sectional imaging with CT scanning,
along with EUS visualization and cyst fluid
analysis, can provide information to differentiate
between these tumors; however, the accuracy is
not 100%.
Although very low risk, SCNs do have malignant B 47, 48
potential with the capacity for infiltrative tumor
growth and metastatic disease.
There is some evidence to suggest that measuring D 49-51
the differential subcellular expression of
ß-catenin and cyclin D may be useful in
elucidating which patients will have a more
favorable phenotype. Greater evidence is needed
before tissue or serum biomarkers can be used
for accurate prediction of prognosis in SPTs.
The median age at presentation of patients with B 52-53
pancreatoblastoma is 5 years; however, this
disease can present in adults as well. Increased
age at the time of diagnosis carries a poor
prognosis. Patients typically present with weight
loss and abdominal pain.
5/22/2012 5:40:31 PM
 476 ■ Surgery: Evidence-Based Practice
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Papavramidis T, Papavramidis S. Solid pseudopapillary tumors
of the pancreas: Review of 718 patients reported in English litera-
ture. J Am Coll Surg. 2005;200(6):965-972.
Kim CW Han D, Kim J, Kim YH, Park JB, Kim SC. Solid pseudo-
papillary tumor of the pancreas: Can malignancy be predicted?
Surgery. 2011;149(5):625-634.
Tanaka Y, Kato K, Notohara K, et al. Frequent beta-catenin
mutation and cytoplasmic/nuclear accumulation in pancreatic
solid-pseudopapillary neoplasm. Cancer Res. 2001;61(23):8401-
8404.
Levey JM, Banner BF. Adult pancreatoblastoma: A case report
and review of the literature. Am J Gastroenterol. 1996;91(9):1841-
1844.
Rajpal S, Warren RS, Alexander M, et al. Pancreatoblastoma in
an adult: Case report and review of the literature. J Gastrointest
Surg. 2006;10(6):829-836.
Dhebri AR, Connor S, Campbell F, et al. Diagnosis, treatment and
outcome of pancreatoblastoma. Pancreatology. 2004;4(5):441-451;
discussion 452-453.
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PMPH_CH58.indd 478 5/22/2012 5:40:31 PM
 PART IX

THE SPLEEN

PMPH_CH59.indd 479 5/22/2012 5:41:03 PM

PMPH_CH59.indd 480 5/22/2012 5:41:03 PM

Hematologic Indications
for Splenectomy
INTRODUCTION
Traumatic injury to the spleen, including both external and iatro-
genic injuries, accounts for the most common indication for sple-
nectomy. Of the remaining indications for splenectomy, staging
for Hodgkin’s lymphoma has historically been the most common
reason for splenectomy.1 More recently, idiopathic thrombocy-
topenic purpura (ITP) has become the most common indication
for elective splenectomy.2,3 This chapter discusses the evidence for
splenectomy in various hematologic diseases, both malignant and
benign. A discussion of the evidence regarding the role of laparo-
scopic splenectomy in hematologic diseases is also included.
1. What are the indications for splenectomy in chronic myeloid
leukemia?
Chronic myeloid leukemia (CML) is a disorder of pluripotent
bone marrow stem cells, and is characterized by the presence of
a chromosomal translocation resulting in a fusion between the
abl gene on chromosome 22 and the bcr gene on chromosome 9.
This “Philadelphia chromosome” encodes for a tyrosine kinase
implicated in the leukemic transformation.4 As the disease pro-
gresses, patients may experience splenomegaly with subsequent
sequestration of platelets and erythrocytes. Patients may also
experience mechanical symptoms directly related to the spleno-
megaly, including left upper quadrant pain and early satiety. The
role of splenomegaly has been investigated in both early- and late-
stage CML. A prospective trial of 189 patients in the early indo-
lent phase of CML randomized them to either splenectomy or no
surgery, and all of the patients underwent the same chemotherapy
regimen. Splenectomy did not influence either disease progression
or survival, but patients in the splenectomy group had a higher
incidence of both thrombotic and hemorrhagic complications.5
Based on this data, the authors conclude that splenectomy is not
indicated in the early stage of CML. A retrospective review of 53
patients with CML in either the accelerated phase or the blastic
phase found that patients with transfusion-dependent thrombo-
cytopenia has a significant reduction in both red cell and platelet
481
PMPH_CH59.indd 481
CHAPTER 59
Mark T. Muir
transfusions over six months, and patients with pain related to
splenomegaly also had symptomatic improvement.6 Splenectomy
had no impact on survival. Sadamori and Sandberg studied a
cohort of 53 subjects in blastic phase and divided them according
to karyotype.7 They report that splenectomy improved survival as
well as increased the response to chemotherapy in subjects with
certain chromosomal abnormalities in addition to the Philadel-
phia chromosome. A large retrospective review of 358 patients
undergoing allogeneic bone marrow transplant, 68 of whom had
previously undergone splenectomy, found no effect of splenec-
tomy on acute or chronic graft-versus-host disease or infectious
complications.8 There was a significant increase in the rate of leu-
kemic relapse in the splenectomy group, but splenomegaly is likely
the major risk factor for relapse rather that the splenectomy itself.
Finally, there is anecdotal evidence that splenectomy following
bone marrow transplant may hasten engraftment.9 In a series of
four patients with splenomegaly and poor engraftment following
allogeneic bone marrow transplant, all four patients had rapid
hematologic recovery and ceased to require transfusions within a
month of splenectomy.
RECOMMENDATIONS
1) In the early indolent stage of CML, splenectomy does not
provide a survival benefit and is associated with thrombotic and
hemorrhagic complications. This recommendation is supported
by a randomized controlled trial. (Grade A recommendation)
2) In the accelerated or blastic phase of CML, patients with
transfusion-dependent thrombocytopenia, anemia, or sympto-
matic splenomegaly experienced symptomatic relief but no survi-
val benefit after splenectomy. (Grade B recommendation)
2. What are the indications for splenectomy in nonleukemic
chronic myeloid disorders?
Myelofibrosis with myeloid metaplasia (MMM) refers to a group
of related bone marrow disorders including agnogenic myeloid
5/22/2012 5:41:04 PM
 482 ■ Surgery: Evidence-Based Practice
metaplasia, postthrombocythemic myeloid metaplasia (advanced-
stage essential thrombocythemia), and postpolycythemic myeloid
metaplasia (advanced-stage polycythemia vera). MMM is asso-
ciated with varying degrees of splenomegaly, as extramedullary
hematopoiesis increases to compensate for the diminished mar-
row hematopoiesis caused by progressive fibrosis of the bone
marrow.10 Splenectomy in patients with MMM has been reserved
for those patients experiencing significant sequelae of splenom-
egaly, including thrombocytopenia, transfusion-dependent ane-
mia, and pain. All of the literature in support of splenectomy for
MMM comes in the form of case series. In the largest published
series, the results of 314 patients undergoing splenectomy over a
28-year period were described.11 Indications for splenectomy in
this group of patients included pain (49%), transfusion-dependent
anemia (25%), symptoms related to portal hypertension (15%),
and thrombocytopenia (11%). The authors report that for those
patients undergoing splenectomy within the most recent decade,
76% of patients experienced symptomatic improvement for a
median duration of 12 months. Twenty-eight percent of patients
experienced postoperative morbidity, including infection (10%),
thrombosis (10%), and bleeding (14%), as well as a 7% mortality. Of
the factors evaluated by the authors, only preoperative thrombo-
cytopenia had a statistically significant association with decreased
survival. Another series of 71 patients undergoing splenectomy
for MMM found similar rates of morbidity (39%) and mortality
(8%).12 The authors report that hemorrhagic and/or thrombotic
complications occurred in 17% of patients, and rapidly pro-
gressive hepatomegaly occurred in 24% of patients. They report
improved survival in younger patients (<45 years) and in patients
with a baseline leukocyte count <10 × 106/mL count. There is some
evidence that patients undergoing splenectomy for MMM may
have a higher incidence of leukemic transformation.12-14 However,
there does not seem to be any decrease in the survival for sple-
nectomized patients with leukemic transformation compared to
splenectomized patients without transformation.15 It is important
to note that while the literature with regard to splenectomy in the
setting of MMM results in a high rate of symptomatic improve-
ment, splenectomy has not been shown to increase survival.16
Essential thrombocythemia (ET) and polycythemia vera (PV)
are myeloproliferative disorders of the megakaryocyte and eryth-
rocyte cell lineages, respectively.10 Splenomegaly may occur dur-
ing the course of either disease, but splenectomy has not been
recommended in the early phase of these diseases due to a risk
hemorrhage.17,18 However, in the limited number of subjects with
either ET or PV who progress to myeloid metaplasia (postthrom-
bocytocythemic myeloid metaplasia for ET and postpolycythemic
myeloid metaplasia for PV), progressive splenomegaly may
accompany bone marrow fibrosis.19 Since both of these conditions
are extremely rare, and progression to the myeloid metaplasia
stage even more uncommon, there is little evidence evaluating the
role of splenectomy. It is generally agreed that splenectomy plays
no role in the early course of either ET or PV, but may be consid-
ered for relief of symptoms due to splenomegaly in the myeloid
metaplasia phase.20
RECOMMENDATIONS
1) Splenectomy in the setting of MMM is recommended only for
palliation of symptoms attributable to splenomegaly, as there
PMPH_CH59.indd 482
is no evidence for survival benefit following splenectomy. The
decision regarding whether to perform elective splenectomy
for any of the above symptoms of splenomegaly should be
individualized, based on a discussion of the patient’s degree
of symptoms and preoperative surgical risk factors. (Grade B
recommendation)
2) The results of small series of patients suggest that splenectomy
is contraindicated in the early course of PV and ET. (Grade C
recommendation)
3. What are the indications for splenectomy in non-Hodgkin’s
lymphoma (NHL) and nonmyeloid leukemia?
Historically, laparotomy (including splenectomy) was performed
as a routine part of the staging evaluation for patients with
Hodgkin’s lymphoma.1 More recently, laparotomy and sple-
nectomy were applied selectively in those cases in which intra-
abdominal or splenic involvement would change the planned
therapy.21 Recent advances in imaging technology, most notably
the use of PET scans, have relegated splenectomy and staging
laparotomy to historical significance only.22-24 Current recom-
mendations do not include a role for splenectomy in the staging of
Hodgkin’s lymphoma.
NHL is the term encompassing all malignancies of lymphoid
origin exclusive of classical Hodgkin’s lymphoma. Two 10-year
retrospective reviews totaling 81 patients with NHL undergoing
splenectomy identified the indications as diagnostic (5 patients),
hematologic abnormalities (28 patients), painful splenomegaly
(8 patients), and combined hematologic abnormalities and sple-
nomegaly (40 patients).25,26 The authors report postsplenectomy
response rates for leukopenia, thrombocytopenia, and anemia
of 82% to 94%, 68% to 89%, and 50% to 64%, respectively. These
studies show a mortality rate of 3% to 9% and morbidity of 21%
to 37%, primarily infectious complications. The introduction of
rituximab (anti-CD20 monoclonal antibody) has changed the
indications for splenectomy in patients with responsive vari-
ants of NHL, including diff use large B-cell CD20-positive NHL,
follicular or low-grade CD20-positive B-cell NHL, and splenic
marginal zone B-cell NHL.27,28 Where previously splenectomy
was indicated for the B-cell lymphomas for the indications dis-
cussed above, rituximab has been shown to induce response
rates of 88% to 100% and sustained responses of 60% to 88%.28,29
Currently splenectomy is reserved for patients with symptom-
atic splenomegaly or cytopenias not responsive to rituximab.
There are, however, no direct comparisons of rituximab and
splenectomy.
Chronic lymphocytic leukemia (CLL) and hairy cell leu-
kemia (HCL) are malignancies of the lymphocyte cell lineage.
The traditional indications for splenectomy in CLL and HCL are
similar to those discussed for NHL, namely to correct refractory
cytopenia or to treat symptomatic splenomegaly. Indications for
splenectomy in a retrospective review of 77 patients with CLL
over a 24-year period included hypersplenism (51%), immune
thrombocytopenia (21%), hemolytic anemia (20%), and miscel-
laneous (9%).30 Hematologic response was most pronounced
in those patients with the lowest baseline values, with 69% of
subjects with baseline hemoglobin < 10 g/dL having an excel-
lent response, and 61% of subjects with platelet counts < 50 ×
106 per mL also having an excellent response. The authors also
identified a survival advantage for splenectomized patients with
5/22/2012 5:41:04 PM

hemoglobin < 10 g/dL or platelets < 50 × 106 per mL. But like
many forms of NHL, CD20-positive B-cell forms of CLL are now
routinely treated with rituximab as fi rst-line therapy, with sple-
nectomy reserved for treatment failures.27 HCL is an uncommon
B-cell lymphocytic leukemia, and like CLL retrospective stud-
ies have shown splenectomy to be effective in alleviating symp-
toms of splenomegaly and improving cytopenias in 40% to 70%
of patients.31,32 The introduction of purine nucleoside analogs
has since transformed the treatment of HCL with many patients
achieving a durable response, such that splenectomy is rarely
indicated.33
RECOMMENDATIONS
1) Multiple retrospective studies demonstrate splenectomy to result
in a durable improvement in cytopenia in patients with NHL.
However, in patients with CD20-positive B-cell NHL, rituximab
is the first-line therapy and splenectomy should be reserved for
treatment failures. (Grade C recommendation)
2) Consistent retrospective data demonstrate an improvement in
cytopenia following splenectomy for CLL or HCL. But similar
to NHL, immuno- or chemotherapy are considered first-line
treatments for most patients with CLL or HCL, and splenectomy
is reserved for treatment failures. (Grade C recommendation)
4. What are the indications for splenectomy in immune
thrombocytopenia?
Immune thrombocytopenia (ITP) is an uncommon disorder, so it
has only been within the past decade that rigorous evidence has
emerged directly comparing the effectiveness of various treat-
ment regimens. Since the widespread use of glucocorticoids began
in the 1960s, steroids have been the standard first-line therapy for
ITP, and splenectomy has been the standard therapy for patients
who fail to have an adequate response to steroids.34 The introduc-
tion of rituximab (monoclonal antibody to CD20), and even more
recently the thrombopoietin-mimetics (romiplostim and eltrom-
bopag), have provided additional medical alternatives for those
patients who fail steroid therapy. As opposed to glucocorticoids
and the thrombopoietin-mimetic agents, which require ongo-
ing maintenance therapy, both rituximab and splenectomy are
capable of inducing complete remission. Splenectomy was the first
treatment for ITP, and remains the most effective. A systematic
review of splenectomy for ITP spanning 58 years and including
2623 patients demonstrated a partial or complete response of 86%.
Two-thirds of patients underwent complete remission (essentially
cured) and recurrences were rare.35 There are also data demon-
strating that the risk of severe infection is no greater in patients
with ITP after splenectomy than in ITP patients who have not had
a splenectomy.36 A recent international consensus report on the
management of ITP gives splenectomy a Grade C recommenda-
tion regarding the level of evidence.37
RECOMMENDATIONS
Splenectomy is effective in achieving a lasting improvement in
thrombocytopenia in ITP, but given the extensive evidence (includ-
ing multiple RCTs) in favor of medical treatment as first-line therapy,
PMPH_CH59.indd 483
Hematologic Indications for Splenectomy ■ 483
splenectomy should be reserved for patients who have failed treat-
ment with at least two classes of medication. Unfortunately, little
data exist comparing splenectomy to the newer therapeutic agents
as second- or third-line therapy. (Grade C recommendation)
5. What are the indications for splenectomy in thrombotic
thrombocytopenic purpura?
Thrombotic thrombocytopenic purpura (TTP) is a rare but seri-
ous disorder characterized by microangiopathic hemolytic ane-
mia, consumptive thrombocytopenia, neurological deficits, and
renal insufficiency.38 First-line therapy is plasma exchange with
fresh frozen plasma, and both rituximab (anti-CD20 monoclonal
antibody) and splenectomy have been recommended as second-
line for plasma-refractory or relapsing cases.39 A recent system-
atic review of the literature identified 18 studies with 87 subjects
undergoing splenectomy for relapsing TTP, and 15 studies with
74 subjects undergoing splenectomy for refractory TTP.40 Patients
undergoing splenectomy for relapsing TTP had a lower mortality
(1.2% vs. 5%) and morbidity (6% vs. 10%). The relapse rate follow-
ing splenectomy was low in both groups, but relapsing patients
had a higher rate of recurrence (17% vs. 8%) than patients with
refractory TTP.
RECOMMENDATIONS
Although there are multiple retrospective reviews demonstrating
the effectiveness of splenectomy in relapsing or refractory TTP,
there are no data comparing splenectomy directly to rituximab
in this setting. (Grade D recommendation)
6. What are the indications for splenectomy in hemolytic
anemia?
Sickle cell disease (SCD) is an inherited disorder of hemoglo-
bin, and results in polymerization of deoxygenated hemoglobin
molecules and subsequent “sickling” of the erythrocyte. Splenic
sequestration of erythrocytes and resultant splenomegaly are
typical, and many patients eventually undergo splenic infarction
and autosplenectomy.41 In three retrospective reviews includ-
ing a total of 343 patients with sickle cell anemia undergoing
splenectomy, indications for splenectomy were major seques-
tration crisis or recurrent minor sequestration crises (60–77%),
hypersplenism (13–36%), splenic abscess (5–11%), and massive
splenic infarction (1–2%).42-44 All three studies demonstrated
improvement in hemoglobin level following splenectomy in
those patient with hypersplenism, in addition to eliminating
the risk of future splenic sequestration crises. There were no
recorded mortalities and the rate of postoperative complica-
tions was 6% to 9%, confi rming the safety of splenectomy in
this patient population.
Thalassemias are a group of inherited disorders of hemoglobin
production resulting in microcytic anemia, and in the homozy-
gous form (β-thalassemia major) require regular transfusion to
maintain hemoglobin levels above 10 g/dL.45 The data regard-
ing the role of splenectomy in thalassemia are largely retrospec-
tive in nature, and much of it arises from the Arabian Peninsula
and southeastern Asia due to the high prevalence of thalas-
semia (the “thalassemia belt”). A retrospective study of 24 chil-
dren with β-thalassemia major who had undergone splenectomy
5/22/2012 5:41:04 PM
 484 ■ Surgery: Evidence-Based Practice
demonstrated a significant increase in mean hemoglobin level
in those patients who were not transfusion-dependent preopera-
tively, and a significant decrease in transfusion requirements in
those patients who were transfusion-dependent prior to surgery.46
Among three other retrospective reviews involving a total of 67
patients with β-thalassemia major, the indications for splenec-
tomy were increased transfusion requirements (> 200 mL/kg/
year) with or without massive splenomegaly in all patients, except
for one patient presenting with splenic abscess.42,44,45 These studies
all demonstrated a significant increase in postsplenectomy hemo-
globin level and a significant decrease in postsplenectomy transfu-
sion requirements. Vaccines against encapsulated organisms were
administered when available, and prophylaxis with oral penicillin
was given in the absence of vaccines. There were no mortalities
and no cases of postsplenectomy sepsis. This demonstrates that
splenectomy is effective in increasing mean hemoglobin concen-
tration in β-thalassemia major without significant morbidity. One
prospective cross-sectional study found a significant association
between prior splenectomy and pulmonary hypertension in thal-
assemia patients (75.8% of patients with pulmonary hypertension
had splenectomy vs. 25.6% of patients without pulmonary hyper-
tension, 95% confidence interval 3.0–27.7).47 The study design pre-
cludes a determination of causality; however, splenectomy may
simply be an indicator of more advanced disease.
Hereditary spherocytosis (HS) is an inherited disorder of the
erythrocyte membrane resulting in hemolytic anemia and subse-
quent splenomegaly.48 A systematic review of the literature con-
cluded that the evidence supports splenectomy in patients with
severe HS (hemoglobin < 8 g/dL), and that splenectomy should be
considered on an individual basis in patients with moderate HS
(hemoglobin 8–12 g/dL and reticulocyte count > 6%).49 Splenec-
tomy is not recommended in patients with mild HS (hemoglobin
> 11 g/dL and reticulocyte count < 6%). Patients with symptomatic
cholelithiasis should undergo splenectomy at the time of cholecys-
tectomy. Patients with cholelithiasis but without symptoms may
be considered for stone removal rather than cholecystectomy.
There is also increasing data on the role of partial splenectomy,
but the level of evidence at this time is poor.
Autoimmune hemolytic anemia (AIHA) is an autoantibody-
mediated hemolytic anemia that frequently presents with splenom-
egaly as well. Initial treatment is typically with corticosteroids,
with IVIG as second-line treatment. 50 Splenectomy may be
considered for patients who have failed medical therapy, as
the spleen both produces the autoantibodies and sequesters
the coated erythrocytes.51 The data in support of splenectomy
for AIHA are derived from small case series, demonstrating a
response to splenectomy ranging from 54% to 100%.42,44,50,52,53
RECOMMENDATIONS
1) Splenectomy is safe and results in significant improvement
in hemoglobin levels in sickle cell patients with recurrent
splenic sequestration crises or hypersplenism. (Grade C
recommendation)
2) Splenectomy leads to increases in hemoglobin level and
decreased transfusion requirements in β-thalassemia, and is
indicated in patients receiving blood transfusion greater than
200 mL/kg/year. (Grade C recommendation)
PMPH_CH59.indd 484
3) Splenectomy should be performed in patients with severe HS
and avoided in patients with mild HS. Patients with concurrent
cholelithiasis should have surgical intervention at the same
time as splenectomy. (Grade B recommendation)
4) Data for the benefit of splenectomy in AIHA come from small
case series but are consistent. (Grade C recommendation)
7. What are the benefits of splenectomy for Felty’s syndrome
(rheumatoid arthritis, splenomegaly, and neutropenia)?
Felty’s syndrome comprises a well-known triad of rheumatoid
arthritis, splenomegaly, and neutropenia, although it occurs in
less than 1% of patients with rheumatoid arthritis.54 The splenom-
egaly of Felty’s syndrome may result in portal venous hypertension
and its sequelae, including bleeding complications from varices.
Splenectomy in patients with portal hypertension and esopha-
geal varices has been shown to reduce portal venous pressure
and prevent future episodes of variceal bleeding.55,56 In patients at
higher risk of surgical complications, the risks of serious adverse
events from variceal hemorrhage must be weighed against the risk
of splenectomy. For this reason, some authors advocate medical
management alone in elderly patients or those with significant
surgical risk factors.57
RECOMMENDATIONS
Splenectomy can reduce portal venous pressure and prevent epi-
sodes of variceal bleeding, but this data is based on small case
series. (Grade C recommendation)
8. What is the role of laparoscopic splenectomy in hematologic
disease?
There are no randomized trials comparing the safety and effec-
tiveness of laparoscopic and open splenectomy in hematologic
disorders. The data therefore are either in the form of retrospec-
tive reviews or prospective cohort studies. A retrospective review
of data from the Italian Registry of Laparoscopic Surgery of the
Spleen (IRLSS) identified 309 patients undergoing laparoscopic
splenectomy since 1993.58 The size of spleens removed ranged from
85 to 4500 g, and they experienced a 7% conversion rate, 0.6% rate
of perioperative mortality, and 18% morbidity (fever, pleural eff u-
sion, and hemorrhage), with 2% of patients undergoing re-operation
for bleeding. They conclude that laparoscopic splenectomy may
represent the new gold standard, but this is difficult to support
without comparison to an open splenectomy group. Another
retrospective review of 186 patients undergoing laparoscopic
splenectomy for hematologic disease focused on long-term hema-
tologic outcomes.59 The study had a mean follow-up period of 35
months, and the most common indications for splenectomy were
ITP, followed by hematologic malignancy, HS, and autoimmune
hemolytic anemia. The authors report a remission rate of 89% for
ITP, 100% for HS, and 70% for autoimmune hemolytic anemia.
Mortality was 22% in the malignancy group and 5% for the other
disorders. These results are comparable to those for open sple-
nectomy. In an attempt to compare results between laparoscopic
and open splenectomy, Sapucahy et al. compared a prospectively
studied group undergoing laparoscopic splenectomy (n = 30) to a
retrospective group undergoing open splenectomy (n = 28).60 The
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 Hematologic Indications for Splenectomy ■ 485

conversion rate was 13%, and laparoscopic procedures took signif-
icantly longer to complete (261 ± 83 vs. 184 ± 71 min, p = 0.0004),
but there was no significant difference in postoperative hospital
stay, amount of blood transfused, or postoperative complications.
Rate of recurrence of the original disorder was similar in the two
groups. In another series of 137 patients undergoing splenec-
tomy for hematologic disease (63 laparoscopic and 74 open), the
authors similarly found a longer operative time for laparoscopic
procedures, but they also noted a significantly decreased postop-
erative hospital stay in the laparoscopic group (3.5 ± 2.3 vs. 6.7 ±
3.1 days, P < 0.01), as well as significantly increased blood transfu-
sions in the open group.61 Complications were again similar in the
two groups. Two additional retrospective studies including 258
patients undergoing laparoscopic splenectomy for hematologic
disease evaluated the impact of preoperative diagnosis on postop-
erative outcomes.3,62 Both studies found that patients undergoing
laparoscopic splenectomy for ITP, and perhaps for hemolytic ane-
mia, had significantly shorter hospital stays compared to other
indications. The larger study also found significantly shorter
operative times, less intraoperative blood loss, and lower conver-
sion rates for patients with ITP.3
RECOMMENDATIONS
Laparoscopic splenectomy may result in shorter hospital stays,
and has similar rates of complications compared to open splenec-
tomy. More data are needed to determine if laparoscopic or open
splenectomy is preferred for certain hematologic diseases. Lap-
aroscopic splenectomy is an acceptable approach for hematologic
disease, including patients with massive splenomegaly. (Grade B
recommendation)

Clinical Question Summary

Question
1 What are the indications
for splenectomy
in chronic myeloid
leukemia?
2 What are the indications
for splenectomy in
nonleukemic chronic
myeloid disorders?
3 What are the indications
for splenectomy in
non-Hodgkin’s lymphoma
and nonmyeloid
leukemia?
4 What are the
indications for
splenectomy in immune
thrombocytopenia?
5 What are the indications
for splenectomy
in thrombotic
thrombocytopenic
purpura?
6 What are the indications
for splenectomy in
hemolytic anemia?
7 What are the benefits of
splenectomy for Felty’s
syndrome?
8 What is the role of
laparoscopic splenectomy
in hematologic disease?
Abbreviations: Hgb, hemoglobin; SCA, sickle cell anemia.
Answer Grade of
Recommendation
1. Splenectomy is not indicated during the early indolent phase A
2. Splenectomy is indicated for symptomatic splenomegaly (pain, B
thrombocytopenia, or anemia) in the accelerated or blastic phase
1. MMM—Symptomatic splenomegaly (persistent pain, thrombocytopenia, B
or anemia)
2. PV/ET—No role for splenomegaly until spent phase, then treat as MMM C
1. NHL—Symptomatic splenomegaly or refractory cytopenia in non C
CD20-positive patients
2. CLL/HCL—Symptomatic splenomegaly or refractory cytopenia in non C
CD20-positive patients (CLL) or medically refractory disease (HCL)
Splenectomy should be reserved for patients that have failed at least C
two medical treatments (corticosteroids and either rituximab or a
thrombopoietin-mimetic agent)
Splenectomy or rituximab may be used in relapsing or plasma exchange- D
refractory thrombotic thrombocytopenic purpura
1. SCA—Hypersplenism or recurrent splenic sequestration crises C
2. β-Thalassemia major—Transfusion > 200 mL/kg/year C
3. HS—Severe disease (Hgb < 8 g/dL), or patients undergoing B
cholecystectomy for symptomatic cholelithiasis
4. AIHA—Medically refractory disease C
Splenectomy reduces portal venous pressure and future variceal bleeding in C
patients with portal hypertension
Laparoscopic splenectomy is an acceptable approach for hematologic disease, B
including patients with massive splenomegaly

PMPH_CH59.indd 485 5/22/2012 5:41:04 PM

 486 ■ Surgery: Evidence-Based Practice
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11. Mesa R, Nagorney D, Schwager S, et al. Palliative goals, patient
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361-370.
12. Barosi G, Ambrosetti A, Buratti A, et al. Splenectomy for patients
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14. Akpek G, McAneny D, Weintraub L. Risks and benefits of sple-
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tive analysis of 26 cases. J Surg Oncol. 2001;77:42-48.
15. Tefferi A, Mesa R, Nagorney D, et al. Splenectomy in myelofibro-
sis with myeloid metaplasia: A single-institution experience with
223 patients. Blood. 2000;95:2226-2233.
16. Benbassat J, Gilon D, Penchas S. The choice between splenec-
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genic myeloid metaplasia. Am J Hematol. 1990;33:128-135.
17. Jacobs P, Wood L, Dent D. Splenectomy in the chronic myelopro-
liferative syndromes. A retrospective risk-versus-benefit analy-
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18. Ravich R, Gunz F, Thompson I, Reed C. The dangers of surgery
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19. Wang J, Wang A. Plasma soluble interleukin-2 receptor in patients
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23. Juweid M. Utility of positron emission tomography (PET) scan-
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24. Podoloff D, Advani R, Allred C, et al. NCCN task force report:
Positron emission tomography (PET)/computed tomography (CT)
scanning in cancer. J Natl Compr Canc Netw. 2007;5(Suppl 1):
S1-S22.
25. Lehne G, Hannisdal E, Langholm R, et al. A 10-year experience
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26. Kehoe J, Daly J, Straus D, DeCosse J. Value of splenectomy in
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29. Bennett M, Schechter G. Treatment of splenic marginal zone
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30. Cusack J Jr, Seymour J, Lerner S, et al. Role of splenectomy in
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31. Golomb H, Vardiman J. Response to splenectomy in 65 patients
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32. Magee M, McKenzie S, Filippa D, et al. Hairy cell leukemia. Dura-
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36. Thomsen R, Schoonen W, Farkas D, et al. Risk for hospital con-
tact with infection in patients with splenectomy: A population-
based cohort study. Ann Intern Med. 2009;151:546-555.
37. Provan D, Stasi R, Newland A, et al. International consensus
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39. Kremer Hovinga J, Meyer S. Current management of throm-
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445-450.
40. Dubois L, Gray D. Case series: Splenectomy: Does it still play a
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41. Schwartz S. Role of splenectomy in hematologic disorders. World
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43. Al-Salem A. Indications and complications of splenectomy for
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saemia major: Experience at Madina Maternity and Children’s
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46. Hoe T, Lammi A, Webster B. Homozygous beta-thalassaemia: A
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50. Hill J, Walsh R, McHam S, et al. Laparoscopic splenectomy for
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Hematologic Indications for Splenectomy ■ 487
52. Bowdler A. The role of the spleen and splenectomy in autoim-
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5/22/2012 5:41:04 PM
 CHAPTER 60
Tumors, Cysts, and Abscesses
of the Spleen
Robert Benjamin
INTRODUCTION
Over the past 20 years, medical management has evolved to the
point where splenectomy is no longer the first line therapy or a
diagnostic tool for many disorders involving the spleen. In addi-
tion, the laparoscopic approach has supplanted open splenectomy
as the procedure of choice. But there are disorders in which a
splenectomy is still a relevant therapy. This chapter explores the
changing medical and surgical management of malignant and
infectious diseases involving the spleen.
There are many questions which remain controversial when
discussing the surgical management of splenic diseases: (1) Is
splenectomy as effective as medical therapy? (2) Is percutaneous
drainage the preferred therapy for splenic abscess? and (3) How
does splenic size affect surgical approach?
MALIGNANCIES
1. Is splenectomy as effective as medical therapy?
Splenic tumors are divided into nonlymphoid and lymphoid tumors.
Malignant nonlymphoid tumors are rare and most commonly vas-
cular hemangiosarcomas. Clinical features include splenomegaly,
left upper quadrant pain, sequestration, pleural effusions, and hyper-
splenism. These spleens can be massive and weigh over 3000 grams.
When diagnosed, splenectomy is indicated, but these patients present
with advanced disease and have a poor prognosis.1,2
Metastatic disease to the spleen is usually from the lung, breast,
and melanoma.3 Retroperitoneal and pancreatic tumors can directly
extend into the spleen.4 These patients can present with splenom-
egaly or splenic ruptures. In these patients, splenectomy is palliative
due to their advanced disease.1
Recommendations
These recommendations are based on retrospective Class III data:
1. Level 2 evidence—Many retrospective articles confirm that
splenectomy is indicated for primary splenic malignancy
despite poor outcomes for advanced disease.
488
PMPH_CH60.indd 488
2. Level 3 evidence—For metastatic disease to the spleen, retros-
pective studies show splenectomy is palliative.
SPLENIC ABSCESS
2. Is percutaneous drainage the preferred therapy for splenic
abscess?
Splenic abscess is a rare condition that is manifested in immuno-
deficiency disease, intravenous drug use, trauma, use of steroids,
immunosuppressive therapy, diabetes mellitus, and an infective
endocarditis.5,6 Computer tomographic-guided drainage with cath-
eter placement has proven safe and efficacious with 70% to 100%
resolution.7,8 Catheters will initially resolve up to 70% of the abscess
with the rest being drained for up to two weeks. In addition, failure
at drainage can mean multiple attempts will be performed because
of the low rates of morbidity and mortality associated with the pro-
cedure.8 In infective endocarditis, splenic abscess occur as a result
of septic emboli that produce a splenic infarct which over time
becomes an abscess. Patients with severe valve disease will need
expedited heart valve replacement when the infection is cleared.
Percutaneous drainage of a splenic abscess will be effective in 75%
of patients and fails to be definitive in patients who need a prosthetic
heart valve.9 The consequence of continuous infection with heart
valve replacement was described by Robinson et al., who reported
a retrospective study of 27 patients with endocarditis and splenic
abscess. Ten patients did not have a splenectomy and of those ten,
five received prosthetic heart valves. This group’s mortality rate was
100%. The remaining 17 patients had a splenectomy and after valve
replacement sustained a survival rate of 82%.10 This study confirms
the findings by Johnson et al.11 who studied 37 patients with infec-
tive endocarditis and splenic abscess. They reported 100% mortality
in those patients not treated with splenectomy.11
Recommendations
These recommendations are based on retrospective Class III data:
1. Level 3 evidence—Retrospective studies show that retained
splenic infection in the face of prosthetic valve replacement has
5/22/2012 5:41:36 PM
 Tumors, Cysts, and Abscesses of the Spleen ■ 489

a 100% mortality rate. Splenectomy is recommended prior to
valve replacement.
2. Level 2 evidence—prospective and retrospective studies show
that computer tomographic-guided drainage of a splenic abscess
is safe and efficacious. Drains can be placed and used until
resolution of the abscess.
SPLENOMEGALY: DOES SIZE MATTER?
3. How does splenic size affect the surgical approach?
The laparoscopic approach has gained wide acceptance as the pro-
cedure of choice for splenectomy. Compared with open splenec-
tomy, laparoscopic splenectomy has demonstrated decreased pain,
shorter length of hospital stay, and similar rates of morbidity and
mortality.12 However, some authors allude to increased morbid-
ity and higher conversion rates in patients with large spleens.13,14
Massive splenomegaly refers to a spleen weighing >600 g or with a
craniocaudal length >17 cm. Super massive spleens weigh >1600 g
and have a length >22 cm.15 A significant portion of malignancies
involve massive and super massive splenomegaly and need a larger
orifice to remove the specimen intact in order to maintain onco-
logic principles.16 Heniford et al.17 performed a prospective study on
142 patients who underwent laparoscopic splenectomy. One group
included 82 patients with normal-sized spleens, whereas the second
group included 60 patients with splenomegaly and 58% of those
were due to a malignancy. Ten patients with a malignancy had super
massive splenomegaly and needed laparoscopy via a hand-assisted
technique. The only significant factor between the two groups was
operative time and blood loss. The groups had similar conversion to
laparotomy, length of stay, and complication rates.17 Another pro-
spective study by Kercher et al. evaluated 177 patients who under-
went laparoscopic splenectomy. Forty-nine patients (28%) had
massive splenomegaly, and 12 patients had super massive splenom-
egaly. These 12 patients underwent laparoscopic splenectomy with a
hand-assisted technique. The majority of massive splenomegaly was
due to malignancies. There were no conversions to laparotomy.15
Recommendations
These recommendations are based on retrospective Class II data:
1. Level 2 evidence—Laparoscopic splenectomy is the standard of
care and leads to less pain and morbidity for patients.
2. Level 2 evidence—Splenomegaly is amendable to laparoscopic
splenectomy. Many authors use a lateral approach to aid in the
dissection.
3. Level 2 evidence—Super massive spleens have similar morbidity
rates and conversion rates to open splenectomy as normal sized
spleens. Super massive spleens (>22 cm) are removed with
hand-assisted techniques.

Clinical Question Summary

Question Answer Level of Evidence References
1 Is splenectomy as Splenectomy is indicated for primary splenic malignancy despite poor 2 and 3 1-4
effective as outcomes for advanced disease (LoE 2). For metastatic disease
medical therapy? splenectomy is palliative (LoE 3).
2 Is percutaneous Retained splenic infection after prosthetic valve replacement has 100% 2 and 3 5-11
drainage the mortality. Splenectomy is recommended before valve replacement
preferred therapy (LoE 3). Computer tomographic-guided drainage of a splenic abscess is
for splenic abscess? safe and efficacious (LoE 2).
3 How does splenic Laparoscopic splenectomy is the standard of care. Splenomegaly is amenable 2 12-17
size affect surgical to laparoscopic splenectomy. Super massive spleens (>22 cm) have similar
approach? morbidity and conversion to open splenectomy rates as normal spleens.

REFERENCES abscess and infective endocarditis. Ann Thorac Surg. 2003;75:

1. Katz S, Pachter HL. Indications for splenectomy. Am Surg. 2006;
72:565-579.
2. Morgenstern L, Rosenberg J, Geller SA. Tumors of the spleen.
World J Surg. 1985;9:468-476.
3. Berge T. Splenic metastases: Frequency and patterns. Acta Pathol
Microbiol Scand A. 1974;82:499-506.
4. Marymount JH, Gross S. Patterns of metastatic carcinoma in the
spleen. Am J Clin Pathol. 1963;40:58-64.
5. Kim HS, Cho MS, Hwan S, et al. Splenic abscess associated with
endocarditis in a patient on hemodialysis: A case report. J Korean
Med Sci. 2005;20(2):313-315.
6. Fotiadis C, Lavranos G, Patopis P, et al. Abscesses of the spleen:
Report of three cases. World J Gastroenterol. 2008;14(19):3088-3091.
7. Nelken N, Ignatlus J, Skinner M, et al. Changing clinical spec-
trum of splenic abscess: A multicenter study and review of the
literature. Am J Surg. 1987;154:27-34.
8. Thanos L, Dailiana T, Papaioannou G, et al. Percutaneous CT-
guided drainage of splenic abscess. Am J Roen. 2002;179:629-632.
9. Simsir SA, Cheeseman SH, Lancey RA, et al. Staged lap-
aroscopic splenectomy and valve replacement in splenic
1635-1637.
10. Robinson SL, Saxe JM, Lucas CE, et al. Splenic abscess associated
with endocarditis. Surgery. 1992;112:781-787.
11. Johnson JD, Raff MJ, Barnell PA, et al. Splenic abscess complicat-
ing infectious endocarditis. Arch Intern Med. 1983;143:906-912.
12. Kucuk C, Sozuer E, Ok E, et al. Laparoscopic versus open sple-
nectomy in the management of benign and malign hematologic
diseases: A ten-year single-center experience. J Laparo Adv Surg
Tech. 2005;15:135-139.
13. Park A, Gagner M, Pomp A. The lateral approach to laparoscopic
splenectomy. Am J Surg. 1997;173:126-130.
14. Rege RV, Merriam LT, Joehl RJ. Laparoscopic splenectomy. Surg
Clin North Am. 1996;3:459-468.
15. Kercher KW, Matthews BD, Walsh RM, et al. Laparoscopic sple-
nectomy for massive splenomegaly. Am J Surg. 2002;183:192-196.
16. Rosen M, Brody F, Ponsky MJ. Outcome of laparoscopic sple-
nectomy based on hematologic indication. Surg Endosc. 2002;16:
272-279.
17. Heniford BT, Park A, Walsh RM, et al. Laparoscopic splenec-
tomy in patients with normal-sized spleens versus splenomegaly:
Does size matter? Am Surg. 2001;67(9)854-858.

PMPH_CH60.indd 489 5/22/2012 5:41:37 PM

 CHAPTER 61
Splenic Salvage
Dror Soffer and Daniel Abraham
INTRODUCTION
The spleen is the intraabdominal organ most frequently injured
in blunt trauma. Because the spleen is a highly vascular organ, an
injury could have devastating consequences. This fear led to the
universal belief that most splenic injuries should be managed with
splenectomy, a practice that began in the early 19th century and
continued up until four decades ago. The mortality risk associated
with not operating was said to be 90%, compared with 30% to 40%
following an uncomplicated removal. Over the last few decades,
however, the influx of data concerning the disadvantages of sple-
nectomy and its relation to overwhelming sepsis has led to a more
conservative approach. Today, nonoperative management (NOM)
is considered safe in selected patients. More than 70% of all stable
patients are being treated by means of a nonoperative approach.1
The movement toward a nonoperative scheme has exposed a whole
new set of questions. This chapter highlights the questions that
have arisen from this new trend and attempt to present the cur-
rent state of NOM of the patient that presents with blunt splenic
injury (BSI) using up-to-date clinical data.
1. Is there a way to predict the success of NOM?
Physicians are progressively opting for splenic preservation pro-
cedures in a patient that presents with a BSI. In contrast to the
alternative, a more conservative approach raises several issues
which make appropriate patient care more challenging. The
Organ Injury Scaling Committee of the AAST released a set of
criteria in 1989 for the grading of a splenic injury that would
help facilitate clinical investigation and treatment.2 The grading
ranges from I to V and can be based on computed tomography
(CT) scan fi ndings. While the intention of the AAST grading sys-
tem is to standardize the description of the injury, many physi-
cians will use these grading systems to direct their clinical plan.3
The actual ability of these grading systems in predicting the need
for intervention, however, is a controversial topic. Radiologists
evaluating abdominal CT scans demonstrate poor accuracy and
490
PMPH_CH61.indd 490
reliability in grading the injury.4 An appropriate screening test is
crucial to help the physician decide which patients will succeed
on NOM. However, until one is decided upon, most physicians
have come to rely on predictors of NOM success as seen in the
literature.
In 1995, Schurr et al.5 published a retrospective study review-
ing 309 BSI patients to better characterize failures of NOM. Results
showed that contrast blush was noted in 8 of 12 (67%) patients
who failed NOM and in 5 of 77 (6%) of those managed success-
fully (p < .0001). These results suggest that contrast blush is an
important indicator of NOM failure. In 2000, Peitzman et al.6
from 27 trauma centers published a large retrospective study
evaluating 1488 patients with BSI, 61.5% of which were admit-
ted for NOM. Among patients that were treated conservatively,
the failure rate was 10.8%, with the failure rate increasing with
increasing graded splenic injuries. The failure rates were 5% for
grade I, 10% for grade II, 20% for grade III, 33% for grade IV, and
75% for grade V. Most (61%) of the failures occurred in the first 24 h
and were correlated with the quantity of hemoperitoneum pres-
ent. Successful NOM was correlated with a higher blood pressure
and hematocrit. The success of lesser injuries was based on ISS,
GCS, grade of injury, and quantity of hemoperitoneum.6 In 2009,
Cohn et al.7 published a paper proposing a new grading system
for splenic injuries in an attempt to create a better predictor of
the need for intervention. Results showed that the following were
highly predictive of the need for intervention: devascularization
of half or more of the splenic parenchyma, contrast blush that
could be attributed to active extravasation or pseudoaneurysm
(PSA), and a large hemoperitoneum.7
Recommendations: There are no set criteria to predict the suc-
cess of NOM. While the AAST grading scale for splenic injury is
commonly used as a predictor, there is sufficient Level 2 and 3 evi-
dences to demonstrate that it can be inconsistent. Although there
are no official predictors of NOM success, contrast extravasation,
amount of hemoperitoneum, and grade of injury might assist in
making a decision about the need for intervention. (Level 3 evi-
dence; Grade C recommendation)
5/22/2012 5:42:30 PM

2. When is splenic angiographic embolization recommended?
While NOM has become the current gold standard of practice for
most splenic injuries, there is still no set protocol for a physician
treating a patient with BSI. The procedure of splenic artery embo-
lization (SAE) has emerged as an exciting adjunct to the practice
of NOM. It is therefore vital that there exists a set of screening cri-
teria for the use of SAE for patients with BSI. A PubMed search of
“splenic angiographic embolization” over the past 30 years yielded
several studies, mostly with Level 2 and 3 evidences.
In the 1980s, Sclafani8 introduced a novel treatment of splenic
angiographic embolization in the management of splenic trauma.
Subsequently, his group described the use of admission CT to char-
acterize splenic injury, and its value as a screening tool for SAE.9 In
1995, Sclafani et al.10 prospectively evaluated 172 patients with BSI.
SAE was performed in the hemodynamically stable patients that
had any CT-graded splenic injury or stable patients that demon-
strated angiographic extravasation. Fift y-six of the 60 treated by
embolization had a successful outcome.10
Hagiwara et al.,11 who followed the study design set out by
Sclafani et al., led their own group of studies. The first one, in 1996,
was a prospective study that included 228 patients. Their protocol
called for a CT on all BSI patients and subsequent SAE performed on
all patients that showed contrast extravasation and/or an (arterio-
venous) AV fistula. The study reported a 93% salvage rate with
these criteria.11 A second prospective study by Hagiwara et al.,12
published in 2005, involved 104 patients. SAE was performed
on patients with CT-graded injuries of III or higher and patients
with contrast extravasation. The results demonstrated that even
patients that present with hemodynamic instability, a parameter
typically used as an indication for laparatomy, could be amenable
to SAE if they respond to fluid resuscitation.12
In 2001, Haan et al.13 conducted a retrospective study that
demonstrated 92% effectiveness in the 40 patients who under-
went SAE. They concluded that CT-graded injuries were a useful
predictor of SAE success.13 In a larger retrospective study con-
ducted in 2004 involving 140 patients, Haan et al.14 demonstrated
a splenic salvage rate of 87%, which decreased with increasing
injury grade. Over 80% of the splenic injury grades IV and V,
however, were successfully managed nonoperatively.14 In 2005,
Haan et al.15 retrospectively evaluated 132 patients who underwent
SAE. The authors established a 90% splenic salvage rate using SAE
in patients with CT-graded injuries of level IV and V, patients
with hemoperitoneum and contrast extravasation, and in patients
with a splenic artery PSA.15
In 2004, a prospective observational study by Liu et al.16 dem-
onstrated an 89% success rate using SAE in patients with hemo-
peritoneum, CT extravasation, and CT- graded IV and V injuries.
In 2006, Bessoud et al.17 published a retrospective study involv-
ing 67 NOM patients, 37 of whom underwent proximal splenic
embolization (PSE). Splenic injuries were notably more severe in
the NOM PSE group than in the NOM group without emboliza-
tion with regards to the mean splenic injury CT grade (3.7 vs. 2,
respectively; p < .0001), active contrast extravasation or blush (38%
[14/37] vs. 3% [1/30], respectively; p = .0005), and hemoperitoneum
grade (1.6 vs. 0.8, respectively; p = .0006). Secondary splenectomy
rate was lower in the nonoperative management PSE group (2.7%
[1/37] vs. 10% [3/30]).17
Most recently, Sabe et al.18 retrospectively looked at all patients
presenting with BSI over 16 years. They found a 97% success rate
PMPH_CH61.indd 491
Splenic Salvage ■ 491
for NOM and a 90% success rate for SAE management. Their cri-
teria for SAE included contrast extravasation, PSA, and level III
and IV CT-graded injuries.18
Recommendations: There is sufficient Level 2 and 3 data to
suggest that SAE might be considered as an adjunct to conser-
vative treatment in stable patients, where no other indication for
laparotomy exists. It is recommended in patients with contrast
material extravasation (Blush on CT); in patients with a PSA;
and it might also be recommended in patients with high CT-
graded splenic injuries (Levels III–V). (Level 3 evidence; Grade C
recommendation)
3. Should postsplenic angiographic embolization patients need
to be vaccinated against Pneumococus and Hemophilus influ-
enza infections?
The spleen has historically been linked with its connection to
the immune system, and more recently, upon total splenectomy,
with overwhelming sepsis. Unfortunately, the immune function
in patients that have undergone SAE has not been well studied. A
PubMed search of “immune function and splenic embolization”
yielded only four retrospective studies.
In 2007, Bessoud et al.19 published a retrospective study, eval-
uating 24 patients that had undergone SAE with an objective of
ascertaining the impact it had on immune function. The study
looked at the presence of Howell–Jolly bodies, and serum anti-
body titer determinations (Pneumococcus and H. influenzae B).
All patients who were assessed for exposure-driven immunity
against H. influenza B had sufficient immunity. Seventeen of the
18 patients (94%) assessed for exposure-driven immunity against
Pneumococcus had sufficient immunity.19
In 2009, Tominaga et al. 20 conducted a retrospective study
on 17 patients who underwent SAE and compared results with
controls (blunt abdominal trauma patients with negative abdomi-
nal CT scans) and splenectomy patients. The objective was to
define any immunologic differences by comparing levels of IgM,
IgG, C3 complement, complement factor B, helper T cells (CD3,
CD4), suppressor T cells (CD8), complete blood counts, and HIV
status. Their results show that the immune capability tested 3
months following SAE was preserved in embolized patients.20 In
2009, Nakae et al.21 conducted a large retrospective study involv-
ing seven trauma centers, which focused on the immunocom-
petence of patients who underwent splenic salvage procedures
compared with patients who underwent splenectomy. Eighty-one
of the patients underwent SAE. The study group did not show a
discernible advantage over the group who underwent splenec-
tomy according to immunologic indices, which included IgM and
14 serotypes of anti-S. pneumonia antibodies, suggesting that pro-
phylactic measures and close follow-up are necessary after both
treatments.21
In 2010, Shih et al.22 conducted a study that compared a
group of five BSI patients who had undergone SAE with 11
patients that were closely monitored. The study followed the
endotoxin responses of peripheral blood mononuclear cells in
the two groups. The results demonstrate that SAE may induce
alterations of immune response and culminate in infectious
vulnerability.22
Recommendations: There is not yet enough data to support
any recommendation against vaccination in patients who under-
went SAE. (Level 4 evidence; Grade C recommendation)
5/22/2012 5:42:31 PM
 492 ■ Surgery: Evidence-Based Practice
4. What is the role of repeated splenic imaging in conserva-
tively treated patients and what should the preferred imaging
technique be in such patients?
While it has become a gold standard to use a CT scan upon admis-
sion of BSI, the use of follow-up repeated imaging is a controversial
topic. Delayed splenic hemorrhage is theorized to be associated
with latent PSA formation, which may not be picked up on admis-
sion CT, and can subsequently lead to late rupture.
In 2007, Weinberg et al.23 conducted a retrospective study
evaluating 341 patients on NOM. The purpose of the study was
to re-evaluate the practice of serial CT imaging in the clinical set-
ting. They discovered that close to one-half of the PSAss identified
in this study were captured on a follow-up CT scan performed
24 to 48 h after the initial scan.23 In 2008, a study by Savage et al.24
included 637 patients with BSI retrospectively reviewed with atten-
tion to their follow-up CT scans. The purpose of the study was
to document the progression of splenic recovery using CT scans.
The results indicate that most tissue healing occurred within
2 months but about 20% had not healed after 3 months. Using
these results, they concluded that a close observation of patients
with BSI, which could include serial CT scanning, should con-
tinue until healing can be confirmed, although the clinical signifi-
cance of such a survey is not clear.24
Despite the various studies that have demonstrated the value
of serial CT scanning, there are equally as many conflicting arti-
cles. In 2005, Fata et al.25 published a retrospective study on sur-
geons’ practices that confirm the schism. They found that 85.5%
of surgeons would not usually perform predischarge abdominal
CT scans in the absence of clinical deterioration, extravasation
on initial CT, or high-grade injury.25 In 1996, Allins et al.26 pub-
lished a retrospective study on 99 NOM patients with an objec-
tive of determining the utility of a second CT scan. None of the
follow-up scans showed any major progression of injury, and scan
findings had no influence over decisions for additional opera-
tions in any patients.26 Thaemert et al.’s27 retrospective study in
1997 focused on 62 follow-up abdominal CT scans obtained in
49 patients. Information that affected management was evident
on only one follow-up CT scan performed in the absence of clini-
cal indications.27 In a more recent retrospective study by Sharma
et al.,28 NOM was undertaken in 221 patients with spleen/liver
trauma, with 65 patients having an additional CT scan after their
admission scan. NOM failed in 11 patients. Only 4.9% of repeat
scans, which accounted for four patients, were done prior to sur-
gery. Two of these patients had hemodynamic instability and, in
the other two, there were clinical signs of peritonitis. The remain-
ing seven patients who failed NOM had delayed surgery due to
hemodynamic instability.28
There are thus proponents on both sides of the serial CT scan
issue with regards to its use for NOM patients. Major arguments
from those that oppose repeat CT scans include unnecessary
radiation, contrast material complications, and expensive costs.
This has driven surgeons to adopt different means of imaging for
identification of PSA, potential delayed splenic rupture, and docu-
mentation of healing.
In 1996, Goletti et al.29 conducted a trial with 10 patients to
determine the efficacy of Doppler ultrasound (DUS) on patient
follow-up and its ability to detect splenic PSA. Echo Doppler and
echo color Doppler evaluations were scheduled at 24 h and at 3
and 6 days after trauma. In eight cases, no complications were
PMPH_CH61.indd 492
observed; in two cases, PSAs were diagnosed.29 In 2005, Doody
et al.30 conducted a review of the practices in their hospital and
found that ultrasound is an important modality in assessing
success of embolization and in evaluating for recurrence during
follow-up. Within the review, they also documented what a PSA
might look like when imaged by DUS.30 In 2007, in a retrospec-
tive study by Bessoud et al.19 of 24 embolized patients, DUS was
also used to follow-up after the procedure and demonstrates that
splenic size and measurements were in the normal range. Within
this paper, they documents the size and measurements seen on
a DUS after an embolization with no complications.19 More
recently, Soffer et al. conducted a prospective study on 38 patients
using DUS to follow-up. Grading of splenic injury demonstrated
19 (50%) patients with grade I, 16 (42%) with grade II, and three
patients (8%) with grade III injuries. Two patients (5%) had
PSAs. Splenic injury was detected by ultrasound in 35/38 (92%);
hence, the DUS examination had a sensitivity of 94.6% with a
positive predictive value of 100%.31 While DUS has shown some
promise as an adjunct to NOM, it is extremely user-dependent
and therefore has limitations.
Recommendations: There is not enough data to support the
need for repeated imaging in patients with BSI after conserva-
tive treatment. Repeated imaging might be considered in patients
with high-grade injuries. DUS might be a safer, cheaper, and easily
repeated modality to be used in such patients. (Level 3 evidence;
Grade C recommendation)
5. Which technique is preferred, proximal SAE or distal selec-
tive embolization?
Proximal SAE involves inserting embolic coils to the splenic
artery at a point proximal to branching. Selective embolization,
also known as distal embolization, involves inserting embolic
coils closer to locations of vascular injury, thereby limiting the
fraction of the spleen that will be ischemic. Recent studies have
started to tease apart the advantages of using proximal emboliza-
tion, and some have even reported fewer complications than the
distal approach.
In 2004, in his letter to the editor, Bessoud reported an inva-
sive intrasplenic arterial pressure monitoring during main SAE in
two patients in order to demonstrate the effects of this technique
on splenic blood pressure. Patients experienced a pressure reduc-
tion of 47% and 58% within the splenic artery. He concluded that
main SAE significantly reduces the intrasplenic blood pressure,
a condition that may help the clot to organize in splenic injuries
and permit the conservative management of the patient.32 Sclafani
et al.’s10 1995 prospective study involving 60 embolized patients set
out to determine if coil embolization of the proximal splenic artery
provides effective hemostasis. The results showed that emboliza-
tion decreased the splenic blood flow and arterial blood pressure
by occluding the main arterial channel to the spleen. The rich
network of collateral circulation provided sufficient blood flow
to the spleen, thus maintaining the viability of the spleen, which
explained the absence of splenic infarction after SAE. Therefore,
Sclafani et al.10 concluded that coil embolization of the proximal
splenic artery is an effective method of hemostasis in stabilized
patients with splenic injury. Bessoud et al.17 conducted another
study that mirrored this sentiment in 2006. This retrospective
study included 67 NOM patients, 37 of whom underwent PSE. No
procedure-related complications were encountered during early
5/22/2012 5:42:31 PM

and delayed clinical follow-up.17 In 2009, Zmora et al.33 published a
prospective observational study that included 11 patients. Their aim
was to assess the efficacy of PSE in the cessation of bleeding without
the formation of PSAs. The results showed that after embolization,
splenic parenchymal blood flow was found on Doppler sonography
in 82% of the patients and no PSAs were demonstrated. During fol-
low-up, no patient underwent surgery or repeated embolization.33
There are also some studies that have tried both emboliza-
tion approaches. In 2006, Smith et al. 34 conducted a trial of 38
embolized patients and found that selective distal embolization
failed in 3 of 9 (33%) patients whereas proximal SAE failed in
about 6 of 27 (22%) patients. Another study conducted in 2001
by Killeen et al.35 using 80 embolized patients found that splenic
infarcts occurred in 63% of patients after main SAE and in 100%
of patients after selective distal embolization. Infarcts after distal
embolization were larger, whereas infarcts after proximal embo-
lization were smaller.35
In 2004, Haan et al.14 published a retrospective study where
they used combined therapy embolization. In patients that were
candidates for combined embolization therapy, the largest vascu-
lar injuries were selectively embolized and the smaller injuries were
treated with a proximal coil. Although only nine patients in this
trial were treated with combined therapy, it was found that failure
rates were higher when compared with main coil or distal embo-
lization, though it never reached statistical significance (p = .057).14
Most recently in 2011, a systematic review and meta-analysis
was released by Schnuriger et al.36 to assess the impact of the dif-
ferent embolization techniques. Pooled outcomes from 15 evalu-
ated studies totaling 479 embolized patients were compared based
on proximal and distal embolizations. The overall failure rate of
angioembolization was 10.2%. Although rebleeding was the most
common reason for failure, it did not differ statistically between
the two techniques. Minor complications, which included rebleed-
ing, infarction, and infection not requiring splenectomy, occurred
statistically and clinically more often after distal than after proxi-
mal embolization. Major complications, which included rebleed-
ing, infarction, and infection requiring splenectomy, had an
equivalent rate in both techniques.36
Recommendations: There is insufficient Level 1 and 2 data sup-
porting the use of a particular embolization technique. Therefore,
proximal artery embolization cannot be stated to be preferred to
distal embolization. There are, however, some clues which show
that PSE might be an easier, more feasible approach associated
with less splenic tissue damage, despite adequate data to support
its success over distal embolization. (Level 3 evidence; Grade C
recommendation)
6. What is the natural history of traumatic splenic PSAs?
PSAs of splenic artery branches after blunt abdominal trauma
are commonly considered as the most probable cause of delayed
splenic rupture, and therefore its detection is crucial.31 This detec-
tion is the basis of the argument for serial imaging in a patient that
presents with splenic injury. The association with PSA formation
and delayed splenic rupture has never been properly studied, and
as a result, little is known about the natural progression of a splenic
PSA. Thus, the recommended approach to any detected PSA is by
angiographic embolization or by surgery. Spontaneous obliteration
and resolution of a post-traumatic splenic PSA was described in a
case report by Dror et al.37
PMPH_CH61.indd 493
Splenic Salvage ■ 493
In 2010, Soffer et al.31 conducted a prospective study regard-
ing the use of DUS as a tool for follow-up and reported a spontane-
ous obliteration and resolution of two out of two detected splenic
PSAs. Further, it was showed that PSA formation is an unexpected
phenomenon—one that can form regardless of grade of injury.31
Recommendation: There is insufficient data to support any
assumption regarding the natural history of traumatic splenic
PSAs. While some consider them to be infrequent and benign, they
might present with a significant risk if ruptured. (Level 4 evidence;
Grade D recommendation)
7. How long should one follow a conservatively treated BSI
patient?
The importance of follow-up observation for the nonsurgically
treated patient has already been expressed. Successful inpatient
management of splenic injuries leads to an outpatient follow-up
dilemma. The debate over serial imaging is only one facet of this
matter. Another equally important and equally debated topic is
the length of follow-up time, which begs the question: how long
is long enough?
In 2008, Savage et al.24 released a study which was based on
637 patients with BSI. The purpose of their study was to determine
the time course and natural progression of BSI. Ninety-seven
patients discharged with BSI had outpatient CT scans. Nine of the
discharged patients had worsening of BSI as outpatients and two
required splenectomies. Thirty-three outpatients were followed
up to complete healing. Lesser injuries had a shorter mean healing
time compared with severe injuries (12.5 vs. 37.2 days, p < .001).
Most healing occurred within 2 months but approximately 20% of
each group (mild vs. severe injury) had not healed after 3 months.
The results thus elucidated that the majority of those who will heal
from their injury will do so within 2 to 2.5 months, regardless of the
severity at presentation. These findings led to the conclusion that
close outpatient follow-up for at least 8 to 10 weeks after presen-
tation should be considered.24 In 2008, McCray et al.38 released a
retrospective study involving 449 NOM patients with the purpose
of finding out what is an appropriate length of time is safe for obser-
vation of the injured spleen. The protocol for the study called for
serial hemoglobin measurements until stable measurements war-
ranted discharge. Using this protocol, the study had a 96% success
rate. They found that hospital stay was reduced to 3 days ± 0.8 days,
and believed that late failures were rare and did not justify inpatient
observation beyond the point when their hemoglobin stabilizes.38
Recommendation: Not enough Level 1 and 2 evidences exist
regarding the length of follow-up time in a splenic injury patient.
Because many hospitals follow their own protocol, there are no set
criteria to ascertain how long a conservatively treated patient should
be followed up. (Level 5 evidence; Grade D recommendation)
8. When can full physical activity be resumed?
Regardless of the management that is used to treat blunt splenic
trauma, full splenic recovery is an end point that all physicians
have in mind. This point, however, comes with a necessary amount
of activity restriction for the patient. Limited activity is an impor-
tant concern in a young and otherwise healthy population, espe-
cially for individuals whose quality of life and return to work may
be compromised by such limitations. While most physicians fol-
low their hospital protocol when it comes to activity restriction,
5/22/2012 5:42:31 PM
 494 ■ Surgery: Evidence-Based Practice

there is no national standard for these considerations, and little
research in the literature regarding it.
In 1987, Dulchavsky et al.39 published a study evaluating
canine and porcine wound healing and breaking strength fol-
lowing splenorrhaphy postsplenic injury. The results showed that
there was no difference in the wound breaking strength after
observant therapy in pigs after 3 weeks, and in both species after
6 weeks. These results suggest that prolonged rest following splenic
injury appears unjustified.39 In 2005, Fata et al.25 released a study
that used membership of the EAST, drawing on answers compiled
from a survey constructed to collect data on surgeons’ current
practices related to NOM of isolated blunt trauma to the spleen. It
was found that 62.9% of the sample chose to allow patients with
grade I and II injuries to return to light activity (defined as light
house work, office work, or low impact aerobic activity) within
2 weeks of their initial trauma. For grade III injury, 29.6% of
respondents chose to allow light activity at 2 weeks. For grades IV
and V, 22.4% of the sample chose to lift light activity restriction as
early as 2 weeks from the start of their injury. Two-thirds of the
sample chose to allow patients with grades III or higher to return
to light activities within 4 weeks to 2 months of their injury. For
full activity including contact sports, no detectable patterns
emerged. For grade I and II injuries, 37.6% reported less than 6
weeks restriction, 39.9% reported less than 3 months, and 19.7%
between 4 and 6 months. For grades IV and V, 45.8% reported 2 to
3 months full activity restriction, 31% reported 4 to 6 months, and
5% for longer than 6 months.25
In 2008, Savage et al.24 published a study with 637 splenic
injury patients, intent on finding out more information on the pro-
gression and resolution of splenic injury. The results showed that
by 2 to 2.5 months, over 80% of patients with blunt spleen injuries
had improved or healed their injury. This represented a starting
point for their recommendations and they therefore optioned to
limit physical activity for at least 8 to 10 weeks.24
Recommendation: There is not enough evidence concerning a
return to full physical activity after blunt splenic trauma. While
there is a similarity across protocols offered within different hos-
pitals, there is not enough data to support these recommendations.
Therefore, no recommendations based solely on the literature can
be made. (Level 5 evidence; Grade D recommendation)

Clinical Question Summary

Question
1 Is there a way to predict the
success of NOM?
2 When is splenic angiographic
embolization recommended?
3 Should postsplenic angiographic
embolization patients need
to be vaccinated against
Pneumococus and Hemophilus
influenza infections?
4 What is the role of
repeated splenic imaging in
conservatively treated patients
and what should the preferred
imaging technique be in such
patients?
5 Which technique is preferred,
proximal SAE or selective
embolization?
6 What is the natural history of
traumatic splenic PSAs?
7 How long should one follow
a conservatively treated BSI
patient?
8 When can full physical activity
be resumed?
Answer Grade of References
Recommendation
Although there are no set criteria to predict the C 2-7
success of NOM, contrast extravasation, amount
of hemoperitoneum, and grade of injury might
assist in making a decision about the need for
intervention.
It is recommended in patients that are C 8-18
hemodynamically stable with no other indications
for laparotomy; in patients with CT extravasation
or blush; in patients with a PSA; and might be
recommended in patients with high CT-graded
splenic injuries (levels III–V).
There are not yet enough data to support any C 19-22
recommendation against vaccination in patients
who underwent SAE.
There is no set role or set modality for repeat imaging C 19, 23-31
in conservatively treated BSI patients. Common
practices include using CT to grade injuries upon
admission. Some physicians use CT to follow up
or to detect PSA formation. Doppler US might be
used for follow-up in contrast to CT.
There are not enough data to support the use or C 10, 14, 17,
benefit of either approach. 32-36
Little is known about the natural history of traumatic D 31, 37
splenic PSA because there are not enough data
regarding its progression.
There are not enough data to suggest how long D 24, 38
follow-up should be in a patient with BSI, if at all.
There are not enough data to suggest when a patient D 24, 25, 39
with BSI can return to full physical activity.

PMPH_CH61.indd 494 5/22/2012 5:42:31 PM


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38. McCray VW, Davis JW, Lemaster D, Parks SN. Observation
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5/22/2012 5:42:31 PM

Sherry Sixta, John B. Holcomb, and Jack H. Mayfield
In Chapter 61 entitled “Splenic Salvage”, the authors have thor-
oughly reviewed the recent debates and controversies surround-
ing nonoperative management (NOM) of blunt splenic injury
(BSI). NOM, whether simple observation or angioembolization
(AE) followed by observation, has become the standard of care
for hemodynamically stable patients with BSI. BSI management
has changed significantly over the past 30 years. It was not until
the middle of the 20th century that we began to understand the
immunologic risks associated with splenectomy. Prior to that
time, splenectomies were performed with impunity as the spleen
was felt to serve no function. Historically, there was a notion that
the spleen did not have the ability to heal, and if injured it would
ultimately bleed, resulting in lethal hemorrhage. The management
subsequently transitioned to laparotomy and splenorraphy. Even
up until the 1980s and the early 1990s, the term “splenic salvage,”
which now refers to observation ± AE, referred to splenorraphy.
The practice of splenorrhaphy was fraught with its own issues
including technical difficulty, rebleeding, splenic abscesses, and
morbidity. Once the CT scanner emerged and imaging became
more accurate, management evolved toward observation and AE.1
In 2000, a multicenter trial was published through EAST, which
documented the evolution of NOM of BSI. The percentages of adult
trauma patients admitted for observation of BSI increased from
48% in 1993 to 61% in 1997. Given the rapid transition in practice
patterns, this was the first large study to document outcomes in
correlation with splenic injury grade, ISS, hemoperitoneum, ini-
tial hematocrit, and blood pressure.2 By 2008, the transition was
profound. Data from the NTDB documented that over a 5-year
span, in 23,532 adult patients with BSI, only 10.3% were taken for
laparotomy within the first 2 h of hospital arrival.3 As manage-
ment trends, including practice patterns associated with AE, have
evolved so quickly, historical reviews are difficult to meaningfully
analyze. Some of the literature is cohort in nature but all is retro-
spective. As the pendulum swung toward NOM, an entirely new
group of clinical problems evolved.
In 2008, Moore et al.4 from WTA published a consortium
statement as well as an algorithm for treatment of BSI and AE
based on a review of the literature, all Level 2 and 3 data, as well as
expert opinion. Management is dependent on hemodynamic insta-
bility (Graded 1–5), response to resuscitation, FAST examination,
and CT findings as available. Although the grade of splenic injury
does correlate with successful outcomes of NOM, it is not accu-
rate enough to predict outcomes in individual patients. Therefore,
the CT may contribute to the decision-making process, but it is in
496
PMPH_CH61.indd 496
Commentary on
Splenic Salvage
no way an absolutely reliable indication for either method. Hemo-
dynamic response to initial resuscitation always takes precedence.
If the patient is a transient responder, AE can be considered; how-
ever, the surgeon must consider site-specific availability of AE,
balancing transfusion requirements/risks with immediate opera-
tive intervention. Nonresponders should proceed to the operat-
ing room for splenectomy. If the patient is normotensive and a
blush is seen on the CT scan, angiography is recommended. The
use of angiography is variable. There is a controversy over the
optimal use of AE due to the labor intensity, and multiple studies
have denoted a surprisingly high rate of complications. The WTA
multi-institutional data reported 140 patients who underwent
arterial embolization, of which 27 (20%) suffered major complica-
tions including 16 (11%) failure to control bleeding (requiring nine
splenectomies and seven repeat AE), 4 (3%) missed injuries, 6 (4%)
splenic abscesses, and 1 (1%) iatrogenic vascular injury. However,
more aggressive use of angiography is associated with the highest
rates of NOM (>80%) and the lowest rates of failure (2–5%).4
The evidence regarding the technique of AE, proximal versus
distal embolization, is inconclusive. The Schnuriger meta-analysis
referenced in the chapter claims that both methods were equiva-
lent in respect to complications that ultimately led to failure of
AE, defined as splenectomy. However, complications that did not
ultimately lead to failure, such as rebleeding, infection, and infarc-
tion, were more often seen in distal embolizations. There is also a
concern that distal embolizations are more time consuming and
resource intensive. Moreover, the incidence of pseudoaneurysm
(PSA) after proximal embolization is unknown. Unless improved,
prospective studies can better elucidate the best technique,
local expertise and consensus, should dictate which AE technique
is utilized.
The mechanism behind delayed splenic bleeding is thought
to be a PSA or a pericapsular hematoma that subsequently rup-
tures. Delayed splenic bleeding is usually categorized as early or
late (>48 h). There is a small incidence of late bleeding (2–4%),
and most tend to occur within 4 to 8 days of injury. There have
been reports of hemorrhage weeks removed from injury.4 The
Weinberg data referenced in the chapter found that 7% (25/341)
of their patient population had PSAs on CT imaging: 4% were
seen on initial imaging and 3% were seen on follow-up CT scans
(24–48 h after admission). They also found that PSAs were associ-
ated with splenic injury grade: 24% were in grade I and II injuries
and 76% were in high-grade injuries. Once identified, PSAs can
then be managed by AE. This is an area where prospective studies
5/22/2012 5:42:31 PM

would be extremely helpful in clinical decision-making. However,
given the thought process of correlation of grade of injury with
development of PSA, regardless of the small incidence, it may be
worth repeating follow-up imaging depending upon the clinical
scenario.
The evidence of whether or not to vaccinate after AE is mixed.
The majority of the studies, other than the Nakae et al. paper, are
underpowered, and all are retrospective in nature. Although rare,
the lifetime risk of overwhelming postsplenectomy sepsis is 1% to
2% with a mortality rate of 33%,5 versus the very low risk of vacci-
nations. The current recommendation is to vaccinate AE patients
for encapsulated organisms. Large prospective controlled trials
are needed prior to alteration of vaccination recommendations.
Most trauma center protocols for NOM BSI call for serial mon-
itoring of hemoglobins as well as continuous noninvasive hemody-
namic monitoring for 24 to 48 h. The average stay from McCray
et al.’s study is 3 ± 0.8 days, though other reported observation rates
vary widely and range from 4.1 to 12 days.3 Smith et al. reported
that 95% of patients who fail NOM will do so within the first 3 days
post injury, and 2 more days of monitoring only identifies another
1.5%.3 Therefore, it seems reasonable to discharge the patient once
hemoglobins remain stable.
Savage et al. helped to delineate splenic healing times, reveal-
ing that lower grade injuries healed faster than higher grade inju-
ries. Though the study was underpowered, it did help to defi ne an
average timeframe of 2 to 2.5 months for healing of 80% of inju-
ries. Therefore, an outpatient following of 8 to 10 weeks seems rea-
sonable. Patients can be followed clinically and symptomatically
without any need for further radiographic imaging. In general,
outpatient CTs are not usually necessary or helpful unless being
used to confirm healing for patients with high-risk activities such
as contact sports.4
Evidence supporting the notion that restriction of activity
after NOM prevents delayed splenic rupture is also lacking. How-
ever, it seems intuitive that there should be some timeframe of
activity limitation. The American Pediatric Surgical Association
PMPH_CH61.indd 497
Splenic Salvage ■ 497
recommendations are based on the grade of BSI. (Grade I: 3 weeks
restriction, Grade II: 4 weeks, Grade III: 5 weeks, and Grade IV:
6 weeks).6 In a survey of EAST surgeons, 95% of surgeons who
responded limited activity of NO-SBI patients, with the major-
ity requiring 2 to3 months, but >20% mandating 4 to 6 months
restriction.7
This review points out the lack of quality data in this field,
and although recommendations are made the grade of those rec-
ommendations never rises above a “C.” For such a common injury,
this lack of quality data represents an outstanding opportunity for
a young surgeon to perform extremely important, high-quality
clinical research.
REFERENCES
1. Peitzman, Andrew B. MD; Richardson, J. David MD. Surgical treat-
ment of injuries to the solid abdominal organs: A 50-year perspec-
tive from the Journal of Trauma. J Trauma. 2010;69(5):1011-1021.
2. Peitzman AB, Heil B, Rivera L, et al. Blunt splenic injury in adults:
Multi-institutional study of the Eastern Association for the Sur-
gery of Trauma. J Trauma. 2000;49:177-189.
3. Smith J et al. Blunt splenic injuries: Have we watched long enough?
J Trauma. 2008;64:656-665.
4. Moore FA, Davis JW, Moore EE, Jr., Cocanour CS, West MA, McIn-
tyre RC, Jr. Western Trauma Association critical decisions in trauma:
Management of adults splenic trauma. J Trauma. 2008;65:1007-1011.
5. Davies JM, Barnes R, Milligan D; British Committee for Stan-
dards in Haematology. Update of guidelines for the prevention and
treatment of infection in patients with an absent or dysfunctional
spleen. Clin Med. 2002;2(5):440-443.
6. Zarzaur BL, Vashi S, Magnotti LJ, Croce MA, Fabian TC. The real
risk of splenectomy after discharge home following nonoperative
management of blunt splenic injury. J Trauma. 2009;66(6):1531-1538.
7. Fata P, Robinson L, Fakhry SM. A survey of EAST member prac-
tices in blunt splenic injury: A description of current trends and
opportunities for improvement. J Trauma. 2005;59:836-842.
5/22/2012 5:42:31 PM
 CHAPTER 62
Postsplenectomy Sepsis
Regan J. Berg and Kenji Inaba
INTRODUCTION
Over the first half of the 20th century, understanding of the spleen
shifted from its classical perception as an organ of relative incon-
sequence to one of key immunologic function, whose removal
risks rare but devastating infectious sequelae.1 In 1919, Morris
and Bullock 2 first recognized the spleen’s immunologic role after
noting high rates of fatal infection in splenectomized rats. King
and Shumacker3 reported the first case series of severe postsple-
nectomy sepsis in 1952, describing five infants with congenital
hemolytic anemia and concluding, “the subsequent development
of serious infection was so constant as to suggest a cause-effect
relationship.” In 1969, Diamond4 coined the term “overwhelm-
ing postsplenectomy infection” (OPSI) to describe an increasingly
noted syndrome of rapidly progressive and often fatal sepsis in
children. The syndrome was subsequently demonstrated in the
adult population.5-8 Growing awareness of this rare but devastat-
ing complication has prompted increasingly conservative surgi-
cal management of splenic disorders, particularly in traumatic
injury and malignant disease.9 Although diagnostic acceptance
of postsplenectomy sepsis is well established, the condition’s rar-
ity makes the determination of its true incidence, precipitants,
associated features, prevention, and management difficult,
despite considerable literature. Th is chapter reviews the cur-
rent evidence regarding postsplenectomy sepsis, addressing key
questions of epidemiology, clinical presentation, treatment, and
prophylaxis.
1. Who is at risk for postsplenectomy sepsis, what is the magni-
tude of risk and what factors affect it?
Singer published the first major review of the literature in 1973,
reporting 2795 patients from 24 series, defining the condition
as “septicaemia, meningitis, or pneumonia” days to years after
splenectomy.10 The overall incidence of sepsis and mortality was
4.3% and 2.5%, respectively. Subsequent studies have reported
incidence rates both higher and lower. Significant methodologic
498
PMPH_CH62.indd 498
differences account for this variation including variable disease
definition, follow-up duration, population size and age distribu-
tion, prevalence of underlying disease, and time-related changes
in antibiotic and immunoprophylaxis utilization.
O’Neal and McDonald11 reported a 2.7% incidence of lethal
sepsis in a 10-year, retrospective matched cohort study, a rate
similar to Singer’s, but they did not report nonlethal infec-
tions. Schwartz et al.12 reviewed 193 splenectomy patients from
the Mayo Clinic over 25 years, reporting incidence of mortality,
fulminant sepsis, and severe infection requiring hospitalization.
Mortality was 0.9 per 1000 person-years of follow-up, whereas the
rates of fulminant sepsis and severe infection were 0.18 and 7.16
per 100 person-years, respectively. The authors contrast their low
mortality rate with that reported by O’Neal (7.3 per 1000 person-
years), attributing this to unspecified differences in the two popu-
lations. An Australian study noted a 2.2% incidence of severe, late
postsplenectomy infection (0.42 per 100 person-years) and overall
mortality rate of 0.4% in 1490 patients over a 13-year period. This
risk of septicemia was 12.6 times that of an age-matched, nonsple-
nectomized cohort.13
Since Singer’s initial review, two more recent studies have
extensively examined the literature. Holdsworth et al.14 generated
a cohort of 12,514 patients from 59 series between 1952 and 1987.
Using only those series with full documentation (5902 patients),
they found the overall severe infection and mortality rates to be
2.9% and 1.5%. Similarly, Bisharat15 found an invasive infection
rate of 3.2% and a mortality rate of 1.4% in a review of 19,680 post-
splenectomy patients (78 series) reported in the literature between
1966 and 1996. More recently, Kyaw et al.16 reviewed 1648 splenec-
tomy patients, aged 1 to 94 years, during an 11-year period with
a mean follow-up of 4.5 years. Twenty-one percent developed a
severe infection requiring hospitalization, an overall incidence
of 7.0 per 100 person-years. Overwhelming infection (defined as
septicemia or meningitis) occurred at an incidence of 0.89 per 100
person-years. Variable inclusion of less severe infections as “post-
splenectomy sepsis” is one factor responsible for the disparity in
incidence noted across the literature.
5/22/2012 5:43:51 PM

INTERVAL BETWEEN SPLENECTOMY
AND ONSET OF SEPSIS
The risk of postsplenectomy sepsis appears greatest in the first
2 to 3 years postsurgery in pediatric patients.4,17-19 Adult popu-
lations demonstrate a similar peak in early incidence.14 O’Neal
reported average onset of lethal sepsis at 26 months (range
1–72).11 Schwartz found that the greatest risk of severe infection
occurred in the fi rst year.12 Holdsworth’s extensive literature
review found 32% of cases occurred within the fi rst year and
52% within the second year. Additionally, younger patients at
the time of splenectomy had a shorter interval to infection. One-
third of all cases, however, still occurred at least 5 years after
splenectomy.14
In Bisharat’s more recent review, mean time to infection was
22.6 months. Patients with spherocytosis and thalassemia had the
shortest mean time to infection (15 and 18 months, respectively)
and traumatically injured patients the longest (49.7 months).15 In
Kyaw’s clinical series, more than 50% of severe infections pre-
sented within the first year and 84% within 3 years. The interval
to first infection was also shorter in patients with malignancy,
both hematologic and nonhematologic.16 Although these studies
suggest an early peak in incidence, multiple case reports docu-
ment infection 10 to 50 years postsplenectomy, suggesting lifelong
risk.20-23 Waghorn collected 40 cases of postsplenectomy sepsis
through microbiologic surveillance. The interval from operation
to infection ranged from 24 days to 64 years; 60% of these cases
occurred 10 to 30 years postsurgery.24 Cullingford noted that
42% of cases occurred more than 5 years after splenectomy.13 It is
unclear whether the often cited early peak in incidence is biased
by studies with shorter follow-up durations or over-representation
of pediatric populations. The risk appears to extend across the
lifespan.
EFFECT OF AGE GROUP ON RISK
Most series demonstrate a higher risk of infection in children
relative to adults.19,25,26 The youngest pediatric age group (<5
years) appears particularly vulnerable. Splenectomy in patients
below 4 years of age conferred a 2.5 time greater risk of infec-
tion than seen in older patients.27 Similarly, Walker et al.17 found
significantly increased risk in patients younger than 5 years.
Holdsworth also found a higher incidence of postsplenectomy
infection (4.4%) and mortality (2.2%) in children generally as
compared with adults (0.9% and 0.8%, respectively).14 Incidence
of infection did not differ between children and adults in Bish-
rat’s collective review (3.3 vs. 3.2%), but pediatric mortality was
slightly higher (1.7% vs. 1.3%). Children with thalassemia major
and sickle cell anemia suffered significantly higher mortality
than similarly affected adults (7.3% and 6.1% vs. 3.7% and 3.8%,
respectively).15
In contrast, one review found the risk of severe infection
highest in those who are older than 50 years of age (9–14 per
100 person-years). These patients were also more likely to have
second and third episodes of severe infection. Severe infec-
tion risk correlated with advancing age.16 These results may be
confounded by a very small number of patients (six) less than
5 years old.
PMPH_CH62.indd 499
Postsplenectomy Sepsis ■ 499
RISK RELATED TO UNDERLYING
PATHOLOGY
Underlying pathology, as well as concomitant therapies, may influ-
ence the risk of sepsis. Risk of infection is higher in pediatric patients
after splenectomy for thalassemia major, portal hypertension, and
malignancy when compared with traumatic injury or nonmalignant
conditions.4,10,17,28 In adults, the presence of underlying hematologic
or malignant disease doubled the rate of fatal sepsis.11 Underlying
malignancy has been associated with five times greater risk of severe
postsplenectomy infection than of traumatic injury.12 The same
study also found that splenectomy for malignant disease or inciden-
tal to other abdominal surgery had significantly higher cumulative
risk of infection at 1 year, compared with splenectomy secondary
to trauma or nonmalignant hematologic and primary splenic dis-
orders. Other studies have also found higher risk for severe infec-
tion with malignancy (hematologic or otherwise) and lower rates for
trauma.15,16 The increased incidence in malignant conditions likely
reflects both immunosuppressive aspects of the underlying dis-
ease and the impact of concomitant therapy. Schwartz found that
chemotherapy increased the relative risk of infection by a factor of
3.7, immunosuppressive therapy by a factor of 3.2, and radiation
treatment by a factor of 2.3.12 Many have also conjectured that the
decreased rates with traumatic splenectomy might reflect retained
immunologic function secondary to splenosis.9,13,29
RISK IN TRAUMA PATIENTS
The risk of severe infection after traumatic splenectomy is lower
than in patients with underlying disorders.10,12,14,25 Cullingford
determined an incidence of 0.21 per 100 person-years exposure.13
Despite a lower incidence, postsplectomy sepsis after trauma
has significant clinical consequence. A review of 47 published
case reports of severe infection following traumatic splenec-
tomy described a mortality rate of 59%, 84% dying within 48 h of
symptom onset.30 Green et al. prospectively followed 18 patients
less than 15 years old undergoing splenectomy for trauma over
a mean duration of 5.8 years (range 1–12). They reported an 11%
incidence of overwhelming late infection (septicemia or meningi-
tis), a rate four- to twentyfold greater than previous reports and
150 times that of the general pediatric population.31 The same
group prospectively followed 144 adults undergoing splenectomy
for trauma or intraoperative injury for a mean duration of 61
months (12–114). Major infection occurred in 5.9% of those suf-
fering trauma and 18.5% of those with splenectomy secondary to
intraoperative injury. The overall rate of major infection was 8.3%,
166 times that expected in the general population.32 These are the
only prospective studies to date but are weakened by small sample
size, in the first study, and loss of a significant number of patients
to follow-up (37%) in the latter.
SUMMARY
Despite considerable literature, the true incidence of postsplenec-
tomy sepsis remains unknown due to considerable heterogeneity
across published studies. The literature suggests an incidence of
1.4% to 4.3% with an associated mortality incidence of 0.4% to
5/22/2012 5:43:51 PM
 500 ■ Surgery: Evidence-Based Practice
2.5%. (Grade B recommendation) Risk may be greater in the first
2 to 3 years postsplenectomy, particularly in children <5 years of
age, but extends across the lifespan. (Grade B recommendation)
Risk is also higher in those with underlying malignant or hemato-
logic disease, or those undergoing immunosuppressive therapies,
and is lowest in trauma patients. (Grade B recommendation)
2. What are the typical pathogens involved and are there emerg-
ing pathogens?
The encapsulated bacteria Streptococcus pneumoniae, Hemophilius
influenzae, and Neisseria meningitidis are traditionally most fre-
quently implicated in overwhelming postsplenectomy sepsis.9,10,33
A major component of the reticuloendothelial system, the spleen,
is important in both the specific and the nonspecific immune
response.29,34 Splenic recognition of carbohydrate antigens, early
IgM production, and removal of poorly opsionized particles likely
account for the increased rate of sepsis due to encapsulated bacte-
ria in asplenic individuals.9,35,36 These polysaccharide-coated bac-
teria resist antibody binding and subsequent clearance by hepatic
kupffer cells, increasing the relative importance of splenic seques-
trative and phagocytic function.35,37-39 The importance of intact
splenic function is increased in infants and very young children,
who lack specific antibody function, or in adults with concomi-
tant disease or therapy modifying immune response.
Pathogen frequency varies between series, and may be altered
by increasing utilization of immunoprophylactic strategies, but
S. pneumoniae historically accounts for 50% to 90% of postsple-
nectomy infection.9,10,24,37,40,41 In the two most recent large collective
reviews, examining 349 and 356 episodes of postsplenetomy infec-
tion, S. pneumoniae accounted for 56.7% and 66%, respectively.14,15
H. influenza is the second most frequent pathogen, although far
less common, accounting for 5% to 6% of infections.13,14 N. menin-
gitidis is cited as the third most common, although rare. Less com-
monly thought of as an encapsulated bacterium, Escherichia coli,
which possesses an acidic polysaccharide microcapsule, may be
more frequent than usually recognized. An Australian review of
1490 splenectomized patients found that E. coli accounted for 26%
of positive cultures and S. pneumoniae only 32%.13 Not all stud-
ies support such frequency; Holdsworth’s review of 349 reported
episodes of infection found E. coli far less common (3.7%) but still
equal in incidence to N. meningitidis.14 A Danish population-based
review of 40 bacteremias, in 538 splenectomized patients between
1983 and 1994, also found E. coli to be the most common single
pathogen, accounting for 25% of infections. Gram-negative rods
as a group comprised 45% of all bacteremias, whereas traditional
encapsulated bacteria were infrequent.42 Sixty percent of this pop-
ulation was vaccinated against S. pneumoniae but direct associa-
tion between immunoprophylaxis and the evolving bacteriology
of postsplenectomy sepsis has not been clearly demonstrated.
Although encapsulated bacteria predominate in most studies,
postsplenectomy sepsis can occur secondary to any bacterial, viral,
fungal, or protozoan organism. Other implicated bacterial species
include Pseudomonas aeruginosa, B-hemolytic strep, Strep sanguis,
Salmonella species, Staphylcoccus aureus, bacteroides species, and
Plesiomonas shigelloides.9,13,14,23,33,37,43,44
Capnocytophaga canimorsus and Bordetella holmesii are two
more recently recognized pathogens. Capnocytophaga canimorsus
(formerly DF2) is a gram-negative rod found primarily in dog, but
also in cat saliva, first reported as a human pathogen in 1976.45 Rarely
PMPH_CH62.indd 500
virulent in healthy hosts, as many as 90% of affected patients have
underlying immunosuppression, most often secondary to asple-
nia or to alcohol use.45-47 Bordetella holmseii, a gram-negative rod
first characterized in 1995, is a cause of bacteremia, endocarditis,
and respiratory illness in children and adults.48,49 Eighty-five per-
cent of affected patients in one series were functionally or anatomi-
cally asplenic.50
Splenic function is also important in defense against pro-
tozoal disease. Babesiosis is a zoonotic infection transmitted by
the Ixodes tick that produces mild or subclinical infections in
healthy hosts but severe and potentially fatal disease in asplenic
individuals.51,52 A review of 22 reported cases of babesiosis in
splenectomized patients, from 1957 to 1984, found an overall
mortality rate of 27%.53 Splenectomized patients accounted for
18% of clinical and subclinical infections in one review, 41% of
clinical infections in another.54,55 The role of the spleen in defense
against malaria is less clear. Animal and human studies indicate
splenic importance in the removal of parasitized erythrocytes and
the generation and maintenance of immune response.56 It is still
unclear, however, if splenectomized patients have an increased
risk of infection or disease severity.56,57
Increased susceptibility of asplenic patients to viral infec-
tions is not well documented. Influenza, however, is important as
a precipitant of secondary bacterial infection and sepsis in this
population.8
SUMMARY
Encapsulated bacteria, S. pneumoniae (55–66%), H. Influenza (3–5%),
and N. meningitidis (3–4%), have traditionally accounted for the
majority of postsplenectomy infections. (Grade B recommenda-
tion). The effect of immunnoprophylaxis on subsequent pathogen
frequency is unclear. Increasing evidence, however, indicates grow-
ing importance of gram-negative rods, particularly E. coli. (Grade B
recommendation). Capnocytophaga canimorsus and B. holmesii are
important emerging pathogens. (Grade C recommendation). Tick-
borne babesiosis can result in severe and fatal disease in asplenic
patients. (Grade C recommendation)
3. What are the clinical presentations and outcomes of post-
splenectomy sepsis?
The classic presentation is based on Singer’s initial categoriza-
tion of the syndrome as a fulminant bacteremia, meningitis, or
pneumonia following splenectomy. A brief nonspecific prodrome
may occur, variably followed by headache, photophobia, nausea,
emesis, diarrhea, malaise, fever, rigors, and confusion.9,5,40,41,58
Adults typically present without an obvious septic focus whereas
meningitis is the predominant presentation in children.14,19,37,43
Rapid progression to septic shock occurs and death can ensue
within 24–48 h. Disseminated intravascular coagulation (DIC),
adrenal hemorrhage (Waterhouse–Friderichsen syndrome), pur-
pura fulminans, and bilateral extremity gangrene accompany
severe cases.5,8,30,38,59-62 Patients demonstrate massive bacteremia
(greater than 106/mL), in contrast to nonsplenectomized indi-
viduals who rarely show more than 103 organisms per mL.40 Cap-
nocytophaga canimorsus sepsis can present a similar fulminant
course but is also associated with arthritis, meningitis, and endo-
carditis.45 Peripheral extremity gangrene and purpura fulminans
5/22/2012 5:43:51 PM

are common.45,47,63 Severe abdominal pain can occur, mimicking
peritonitis.46,64,65 Bortedella holmseii is associated with bacteremia,
endocarditis, and pneumonia but tends to have a milder course,
even in asplenic patients.48,50
Outcomes
Although a rare complication, the true significance of postsplenec-
tomy sepsis derives from associated mortality rates of 50% to 70%
despite appropriate antibiotic therapy.9,37 Singer’s initial study con-
cluded that death from sepsis was 200 times more likely in asplenic
individuals.10 Subsequent reviews suggested rates of lethal sepsis
300 to 540 times greater in splenectomized patients compared with
the general population11,13 Mortality rates are influenced by the age
of the patient, the presence of underlying disease, and the etiologic
agent. Patients with hematologic or malignant disease demonstrate
mortality rates from postsplenectomy sepsis nearly double those
without underlying illness.11 Waghorn found postsplenectomy
sepsis highest in those with coexistent hematologic malignancy
(69%), lower in trauma patients (46%), and lowest in patients with-
out traumatic injury, hematologic disease or malignancy (38%).24
Thalassemia major and sickle cell anemia are also associated with
higher morality rates than trauma or spherocytosis.15
Patient age is also a factor. Mortality incidence among thalas-
semia major and sickle cell anemia pediatric patients is significantly
higher than in similarly affected adults (7.3% and 6.9% vs. 3.7% and
3.8%, respectively).15 Holdsworth found a significantly higher inci-
dence of postsplenectomy sepsis mortality in children (2.2%) com-
pared with adults (0.9%).14 This study also suggests a more complex
interaction between age, clinical presentation, and mortality. Pure
meningitis without bacteremia had a relatively low (22%) mortality
rate and 83% of these cases occurred in patients younger than 15.
Bacteremia alone produced 65% mortality and occurred in all age
groups. Bacteremia and meningitis, however, occurred primarily
in adult patients, associated with a 76% mortality rate.
The type of pathogen may also affect survival. Bisharat found
slight mortality rate variation between S. pneumoniae (55%),
gram-negative bacteria (62%), and N. meningitidis (59%).14 More
convincingly, E. coli and N. meningitidis produced greater mortal-
ity rates than S. pneumoniae and H. influenzae (77% and 78% vs.
57% and 32%, respectively).14 The factors contributing to mortal-
ity in postsplenectomy sepsis likely interact in a complex manner
that has not been adequately assessed.
SUMMARY
Severe postsplenectomy infection is associated with fatality rates of
50% to 70% despite antibiotic treatment. (Grade B recommenda-
tion). Young children, particularly those less than 5 years old, have
increased mortality, as do those with coexistent malignant or hema-
tologic disease or those undergoing concomitant immunosuppressive
therapy. (Grade B recommendation). Traumatic splenectomy is asso-
ciated with the lowest mortality rates. (Grade B recommendation)
4. What is the role of antibiotics in preventing postsplenec-
tomy sepsis?
The use of prophylactic antibiotics in splenectomized or function-
ally asplenic patients is widely advocated but good evidence to
PMPH_CH62.indd 501
Postsplenectomy Sepsis ■ 501
support efficacy is scarce. The PROPS study, a multicenter, ran-
domized, double-blind, placebo-controlled trial, reported an 84%
reduction in the rate of infection in children with sickle cell disease
given daily oral penicillin. Three deaths occurred in the placebo
but none in the treatment group and the trial terminated early, after
an average of 15 months follow-up.66 A Cochrane review has since
supported the efficacy of penicillin prophylaxis in this patient pop-
ulation.67 Sickle cell disease is associated with functional asplenia
but no prospective trial has specifically examined splenectomized
pediatric patients or adult populations. A more recent retrospec-
tive review of 318 patients (mean age 14 years; range 5–26), who
underwent splenectomy between 1985 and 1997, suggested a sig-
nificant difference in infection between those taking regular peni-
cillin (2.7%) and those who did not (20%) over a median follow-up
of 10.5 years. The overall incidence of postsplenectomy infection in
this patient group was 5.7%.68 Oral penicillin or amoxicillin is the
traditionally advocated prophylactic agent but growing pneumo-
coccal antibiotic resistance has prompted the utilization of broader
spectrum drugs such as fluroquinolones, macrolides, amoxicillin/
clavulanate, and trimethoprim/sulframethoxazole.37,39
The appropriate duration of antibiotic prophylaxis is also
uncertain. In a follow-up to the original PROPS study, the
authors concluded that prophylaxis could be safely discontinued
by 5 years of age. However, this recommendation was directed
at patients with sickle cell disease, receiving concomitant vac-
cination and regular medical care, who did not have a surgical
splenectomy or a prior severe episode of pneumococcal sepsis.69
Prophylaxis in pediatric patients, particularly those younger than
5, for at least 2 years following surgery is frequently advocated,
reflective of the perceived increased risk during this period.44,70,71
The American Academy of Pediatrics suggest continuation until
at least age 5.72 Some suggest continuation into adulthood for
high-risk patients.73
The use of prophylactic antibiotics in adult populations has
not been prospectively studied and is controversial. Given the risk
of lifelong sepsis, some authors advocate continual prophylaxis.74-76
Short duration (2–3 years) prophylaxis, particularly in high-risk
patients, has also been suggested.9,77-79 Others contend that no pro-
phylaxis is needed.80,81
Failures of antibiotic prophylaxis have been reported.82-85
Patient adherence to daily prophylaxis can be problematic in both
children and adults.77,86,87 The variable contributions of patient
adherence, evolving resistance patterns, and changing frequency
of causative pathogens to these cases of failure are unclear. In one
review of 77 cases of postsplenectomy sepsis, 14% of cases were
taking regular prophylaxis at the time of infection.24
The use of “stand-by” antibiotics, for early patient-initiated
treatment, is also widely advocated.9,41,43 This practice has not been
studied but is consistent with known benefits of early antibiotic
therapy in the setting of sepsis.88 However, no evidence exists to
suggest that outcomes are improved or that benefit exists over
patient education and prompt presentation to medical attention,
at first sign of illness, alone.
SUMMARY
Antibiotic prophylaxis benefits pediatric patients with functional
asplenia secondary to sickle cell disease. (Grade A recommenda-
tion). The use in anatomically asplenic children and adults has not
5/22/2012 5:43:51 PM
 502 ■ Surgery: Evidence-Based Practice
been studied but recommendations for prophylaxis in the first
2 years following splenectomy in all pediatric patients until adult-
hood and long-term use in high-risk populations are common
despite clear evidence of efficacy. (Grade C/D recommendation).
Similarly, patient-initiated “stand-by” antibiotics therapy is often
advocated, although efficacy and risk benefit have not been estab-
lished by trials. (Grade D recommendation)
5. What vaccines should be given, and when, and how effective
are they in preventing postsplenectomy sepsis?
Vaccines exist for three of the pathogens implicated in postsple-
nectomy sepsis: S. pneumoniae, H. influenzae type b, and N. menin-
giditis. Ninety known different serotypes of S. pneumoniae exist.34
In the U.S., two vaccines are available. A 23-valent polysaccharide
vaccine (PPSV23) covers 85% to 90% of serotypes responsible for
invasive pneumococcal infection.89 A new 13-valent conjugate
vaccine (PCV13), approved by the FDA in 2010, replaces the pre-
vious 7-valent vaccine for pediatric use. PCV13 is approved for
all children aged 2 to 59 months and in those up to 18 years with
conditions increasing the risk of invasive disease.90,91
Six serotypes (A–f) of H. influenzae cause invasive disease.
The current conjugated vaccine covers serotype B (HiB), known to
cause 95% of invasive disease in children younger than 5.92 Vacci-
nation is recommended for all asplenic children and adults.93 Both
pneumococcal and the HiB vaccine have been shown immuno-
genic in asplenic patients.94
Neiserria meningitidis has 13 serotypes, with 90% of infec-
tions worldwide caused by serotypes A, B, and C.34 Two current
U.S. vaccines protect against serotypes A, C, Y and W-135, a tet-
ravalent polysaccharide vaccine (MPSV) and a newer tetrava-
lent conjugate vaccine (MCV4).95 MCV4 is approved for patients
between 11 and 55 years old. Children 2 to 10 years of age, or
persons older than 55, should receive MPSV. Asplenic individuals
should receive a two-dose primary series, administered 2 months
apart, and a booster dose every 5 years.95
Although asplenic individuals are not known to be at increa-
sed risk for influenza, yearly immunization is widely recom-
mended due to the disease’s association with secondary bacterial
infection.8,96,97
Optimal timing of vaccination has been debated. Serum
IgM antibodies become detectable around 9 days following a
novel antigen exposure, leading to wide recommendation for
vaccination at least 2 weeks prior to elective splenectomy. 34,96,98
The timing of vaccination after emergent splenectomy has
been addressed in two prospective, randomized trials by Shatz
et al.99,100 Trauma patients undergoing splenectomy demon-
strated greatest functional antibody response to pneumo-
coccal polysaccharide vaccine given 14 days postoperatively
when compared with days 1 or 7. Antibody response was not
improved by delaying vaccination to 28 days. A Danish study
examined pneumococcal antibody levels in a population of
remotely splenectomized patients.101 Need for re-immunization
was more likely in those vaccinated less than 14 days before
or after splenectomy, lending support to these parameters for
timing vaccination in both elective and emergent cases. Vac-
cination is generally performed 6 months after treatment for
patients undergoing chemo- or radiotherapy to allow reconsti-
tution of adequate immune response.96,102
PMPH_CH62.indd 502
Revaccination is required as antibody levels diminish with
time.98 Antibody concentrations decreased linearly by 24% to
32% from peak levels in splenectomized adults and children in
the fi rst year following vaccination.103 In patients with splenec-
tomy for trauma or Hodgkin’s disease, antibody levels declined
to prevaccination levels over 3 years.104 Revaccination has been
shown to be safe and effective.105,106 The U.S. Advisory Commit-
tee on Immunization Practice (ACIP) currently recommends
pneumococcal revaccination at 5 years for adult patients with
functional or anatomic asplenic but does not currently support
multiple revaccinations without further evidence of clinical
benefit.90
Few studies have examined the efficacy of vaccination in
splenectomized patients. A recent Cochrane meta-analysis
of 15 randomized controlled trials and 7 observational stud-
ies suggested an overall pneumococcal vaccine efficacy of 74%
but did not specifically address asplenic patients.107 An ear-
lier indirect cohort analysis of 2837 pneumococcal infections,
however, found 77% vaccine efficacy in anatomically asplenic
individuals.108 Observational studies in splenectomized chil-
dren and adults also suggest benefit for immunoprophylactic
strategies.73,109
Despite considerable efficacy in preventing invasive disease,
vaccination failure occurs.82,110-112 Vaccine failure may reflect wan-
ing antibody response, coexistent immunosuppressive conditions,
or rare infection with a serotype not covered by the vaccine.24,98 Also
contributing to the persistent risk of infection is evidence of highly
variable adherence to immunoprophylaxis guidelines among cli-
nicians and minimal patent awareness of infectious risks following
splenectomy. A review of 70 cases of postsplenectomy infection,
87% secondary to S. pneumoniae, found only a 31% vaccination
rate against this organism.113 Other studies report pneumococcal
vaccination rates from 11% to 88% with much lower overall rates for
H. influenzae and meningococcus.79,114-117 Splenectomy for trau-
matic or intraoperative injury was associated with far lower vac-
cination rates compared with splenectomy for other etiologies
in one study.118 A survey of North American surgeons found
wide variation in immunization practice, particularly regarding
revaccination.119
Patient education and awareness of risk have been found
deficient in multiple studies, a potentially correctable barrier to
immunoprophylactic strategy adherence and early detection and
treatment of disease.68,115,116,120-122
SUMMARY
Pneumoccocal vaccine is effective in asplenic patients and vac-
cination against S. pneumoniae, H. influenzae type b, and N. men-
ingitidis should be performed at least 2 weeks prior to elective
splenectomy. (Grade C recommendation). Vaccination adminis-
tration at 14 days after emergent splenectomy appears optimal.
(Grade A recommendation). Antibody levels in asplenic patients
diminish over time and re-immunization with meningococcal
and pneumococcal vaccine at 5 years is recommended. (Grade C
recommendation). Yearly influenza vaccine may have benefit in
preventing secondary bacterial infection and sepsis in asplenic
patients. (Grade C/D recommendation)
5/22/2012 5:43:51 PM

6. What role do splenosis, autotransplantation, conservative
splenic surgery, and splenic embolization have in preventing
postsplenectomy sepsis?
Splenosis, ectopic tissue found in patients following splenic rupture,
has been proposed as an explanation for the lower rates of post-
splenectomy sepsis seen after traumatic injury.34 In 1978, Pearson
et al.123 found that 59% of 22 children with traumatic splenectomy
had low counts of pitted erythrocytes, similar to eusplenic individ-
uals, in contrast to the much higher counts seen in patients splenec-
tomized for hematologic indications. One study found increased
tuftsin activity and decreased pitted erythrocytes in patients under-
going traumatic rather than elective splenectomy, felt suggestive
of residual splenic function attributed to splenosis.124 One patient
found to have post-traumatic splenosis incidentally, at subsequent
abdominal surgery, had some residual spleen-associated phago-
cytic and immunologic activity.125 This concept of the “born again
spleen” has persisted in the literature despite lack of strong evidence
of its efficacy in preventing infection. In one series of 47 cases of
severe postsplenectomy infection following trauma, four fatal cases
were found to have ectopic splenic tissue at autopsy.9 Another series
noted the presence of splenosis or accessory splenic tissue in 26%
of 39 fatal infections.126 Multiple case reports and series describe
fatal infection despite the presence of splenic nodules or accessory
splenic tissue, weighing as much as 92 gm.9,127-129 Although there is
a definite publication bias in favor of failed cases of splenosis, one
large review of the literature to date concluded that little evidence
exists of any protective benefit.130
Re-implantation of splenic tissue at the time of operation, auto-
transplantation, is also thought to preserve some degree of immune
function. Initial animal models suggested more rapid bacterial
clearance and improved survival than in splenectomy, but required
omental as opposed to subcutaneous, intramuscular, or intraperi-
toneal placement.131-133 Regeneration of autotransplanted splenic tis-
sue was also better in young rats compared with old rats, suggesting
a possible requisite developmental window.134 Re-implantation of at
least 50% of original splenic tissue was necessary to produce benefit
in rodent models, but linear increases in immunologic function to
a maximal 80% were observed.132,135 In contrast, a porcine model
found that the size of implants or mass of grafted tissue has no effect
on the regenerated splenic mass at 6 months.136
In humans, splenic reticuloendothelial function was prospec-
tively assessed in 51 trauma patients with suspected splenic injury
over 2 to 5 years. Splenorrhaphy or partial splenectomy was associ-
ated with lower levels of pocked erythrocytes and greater clearance
of antibody-labeled autologous cells than splenectomy, suggesting a
maintained splenic function. Autotransplantation resulted in better
function than splenectomy though not as good as when the spleen
was conserved.137 A comparison of 10 autotransplanted patients
with 14 patients undergoing splenectomy alone, found significantly
greater rises in antibody titers (both IgM and IgG) in response to
pneumococcal vaccination, suggesting potential immunologic ben-
efit.138 This study, however, lacked a control group. Subsequently,
the same authors found a similar antibody increase (in response to
23-valent pneumococcal vaccine) in autotransplanted and sham-
operated rats, compared with a significantly lower rise in those
splenectomized.139 The capacity of splenic autotransplants to restore
immunologic and phagocytic function has been questioned in two
more recent animal models.140,141
PMPH_CH62.indd 503
Postsplenectomy Sepsis ■ 503
Failure of autotransplantation has been documented in
human case reports.142,143 Determining the significance of these
rare events is difficult and there is clearly a relevant publication
bias. In one case, implantation occurred in the anterior rectus and
in the other, less than 2 gm of tissue was implanted. One study
examined 90 postsplenectomy patients with scintigraphy and red
cell microscopy, suggesting 20 to 30 cm3 of retained splenic tissue
necessary for immunologic function but no human trial has ade-
quately assessed this issue.144 Moore et al.145 reviewed 43 splenic
autotransplantation patients over a 6-year period, noting one
death from postsplenectomy sepsis. The most recent systematic
review of the autotransplantation literature, published in 1994,
concluded that the procedure was relatively safe and easy to per-
form with some normalization of the measured immunologic and
reticuloendothelial function but with unknown effect on morbid-
ity and mortality.146 Although the bulk of evidence hints potential
benefit, this has been established or quantified in any large, well-
designed trial.
Immunologic function appears retained in animals under-
going partial splenectomy.133,147-149 In children with hereditary
spherocytosis, partial splenectomy preserved immunologic and
phagocytic function when assessed by peripheral blood smear,
red blood cell microscopy, immunoglobulin levels, and specific
antibody titers.149 A group of 12 thalassemia patients with par-
tial splenectomies did not suffer any fatality due to sepsis over a
4-year follow-up period in contrast to five deaths in a group of
30 patients having total splenectomy. These patients did not have
access to immunoprophylaxis.150 In both these studies, partial
splenectomy provided adequate control of the underlying dis-
ease. In trauma patients, subtotal splenectomy was associated
with the absence of Howell–Jolly bodies and normal antibody
levels. No early complications occurred specifically related to
the splenic surgery but clinical correlation of the observed func-
tional parameters was limited by the lack of follow-up beyond
the late postoperative period.151
Although not studied by any large prospective trials, a small
body of evidence suggests that splenic artery embolization pre-
serves immunologic function. Thirty-seven adult trauma patients
successfully managed with proximal splenic artery embolization
retained normal splenic size, homogeneity, and immunologic
function, as measured by the exposure-driven antibody responses
to H. influenza and S. pneumoniae.152 Splenic volume and a vari-
ety of cellular counts, complement, and immunoglobulin levels
were evaluated in patients with abdominal trauma who either had
a CT scan without evidence of significant injury, a splenectomy,
or had a splenic artery embolization. No significant difference
was found between these groups.153 Other authors have reported
similar preservation of immunologic function.154,155 These studies
have been variably subject to criticism for retrospective methodol-
ogy, lack of appropriate controls, lack of tests able to discriminate
the asplenic state, or utilization of tests examining organ viabil-
ity rather than immunologic function. To address these limita-
tions, Malhotra et al.156 examined CD4+ T cell counts and specific
CD4+ subpopulations in patients having embolization comparing
them with control groups of splenectomized and normal individ-
uals. Splenic embolization preserved immunologic function, as
measured by the T cell subset, tests that allowed the detection of
asplenic individuals.156
5/22/2012 5:43:51 PM
 504 ■ Surgery: Evidence-Based Practice

SUMMARY CONCLUSION

Evaluation of a protective benefit for splenosis and splenic autotrans-
plantation is hampered by the lack of large studies and a publication
bias favoring failed cases. A benefit for post-traumatic splenosis is
not established by the literature to date. (Grade D recommenda-
tion). Autotransplantation of splenic tissue may preserve some
immunologic capability, but demonstration of reduced infectious
risk has not clearly been shown and the amount of tissue required
to preserve function is unclear. (Grade C recommendation). Partial
splenectomy, in suitable patients, appears to preserve immunologic
function and is associated with reduced infection risk. (Grade C
recommendation). Similarly, immune function appears preserved
after splenic embolization, although a reduction in the subsequent
risk of infection has not been studied. (Grade C recommendation)
A paucity of high-quality evidence exists to aid in the preven-
tion and management of postsplenectomy sepsis, largely due
to the inherent difficulty of studying a rare clinical condition.
Although the true incidence is unknown, the risk clearly extends
across the lifespan, is influenced by underlying disease and con-
comitant therapy, and produces high mortality. The efficacy of
immunoprophylactic strategies may improve with greater clini-
cian adherence to management guidelines and patient education.
Particularly in trauma, where the limits of nonoperative manage-
ment of splenic injury are being continually tested, a real under-
standing of this disease is necessary to balance its risk with the
equally real, and potentially greater, risks of failure of nonopera-
tive management.157

Clinical Question Summary

Question Answer Level of Grade of References
Evidence Recommendation
1 What is the True incidence remains unknown but ranges 2b–3 B 10-17
epidemiology of from 1.4% to 4.3% with mortality incidence
postsplenectomy of 0.4% to 2.5% are reported.
sepsis (PSS)? Age-related incidence of overwhelming 2b–4 B 12, 16
infection ranges 0.18 to 0.89 per
100 person-years.
Risk may be higher in the first 2 to 3 years B 4, 11-14, 17-19,
postsplenectomy but persists lifelong and is 20-25
higher after splenectomy for malignant and
hematologic disease compared with trauma.
2 What pathogens Streptococcus pneumoniae (55–66%), 2b–4 B 13-15, 42
cause PSS? H. influenzae (3–5%), and
N. meningitidis (3–4%) are traditionally the 2b, 2c B 13, 42
most frequently implicated pathogens.
Gram-negative rods (particularly E. coli)
may be implicated more frequently than
often recognized.
C. canimorsus and B. holmesii are important 3b, 4 C 45-51
emerging pathogens.
3 What mortality is Morality ranges from 50% to 70% despite 2b, 2c B 11, 15, 24
associated with PSS? treatment.
Young children (less than 5) may have higher 2b B 14, 15
mortality.
Coexistent malignant and hematologic disease 2a, 3b B 11, 15, 24
increase mortality.
4 Do antibiotics prevent Antibiotic prophylaxis benefits functionally 1a, 1b A 66, 67, 69
PSS? asplenic, sickle cell pediatric patients.
Use in pediatric patients, or in all patients 4–5 C/D 9, 70-79
during the 2-year period following
splenectomy, and long-term use in high-
risk populations are frequently advocated
despite lack of clear evidence for benefit.
Patient-initiated “stand-by” antibiotic 5 D 9, 41, 43
treatment for early infection is often
advocated but efficacy has not been
examined.

(Continued)

PMPH_CH62.indd 504 5/22/2012 5:43:51 PM

 Postsplenectomy Sepsis ■ 505

(Continued)
Question Answer Level of Grade of References
Evidence Recommendation
5 What vaccinations Vaccination appears effective in asplenic 2b–5 C 34, 71, 90, 108,
should be given and patients. Meningococcal, pneumococcal, 109
when? and H. influenzae B vaccines should be
given at least 2 weeks prior to elective
splenectomy.
Vaccination following emergent splenectomy 1b A 99, 100
appears optimal at 14 days.
Re-immunization at 5 years is recommended 2b–5 C 90, 95, 98, 103,
for pneumococcal and meningococcal 104
vaccines as antibody levels diminish with
time.
Yearly influenza vaccination is recommended 4, 5 C/D 96, 97
to reduce the risk of secondary bacterial
infection and sepsis.
6 Does splenosis, A protective benefit of post-traumatic 2b–5 D 30, 123-130
splenic splenosis is not supported by the current
autotransplantation, literature.
partial splenectomy, Splenic autotransplantation may preserve 2b–4 C 137, 138, 145,
or splenic some residual immunologic function but 146
embolization prevent subsequent risk reduction for sepsis or
infection? mortality has not been established.
Partial splenectomy retains some immunologic 2b, 3b C 137, 138, 149-151
function and may reduce the risk of sepsis.
Splenic embolization appears to preserve 2b, 3b C 152-156
immunologic function but long-term clinical
impact has not been studied.

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110. Chaikof EL, Goodson JD, McCabe CJ. Postsplenectomy pneumo-
coccemia in a healthy vaccinated adult. Am J Emerg Med. 1984;
2(2):141-143.
111. Gonzaga RA. Fatal post-splenectomy pneumococcal sepsis
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113. Waghorn DJ. Overwhelming infection in asplenic patients:
Current best practice preventive measures are not being
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115. Meerveld-Eggink A, de Weerdt O, Rijkers GT, van Velzen-
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spleen in the Netherlands. Vaccine. 2008;26(52):6975-6979.
116. Kind EA, Craft C, Fowles JB, McCoy CE. Pneumococcal
vaccine administration associated with splenectomy: Missed
opportunities. Am J Infect Control. 1998;26(4):418-422.
117. Kinnersley P, Wilkinson CE, Srinivasan J. Pneumococcal
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118. Bruni L, Bayas JM, Vilella A, Conesa A. Vaccination coverage
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120. Lammers AJ, Veninga D, Lombarts MJ, Hoekstra JB, Speelman
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122. Kotsanas D, Al-Souffi MH, Waxman BP, King RW, Polkinghorne
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retrospective review. ANZ J Surg. 2006;76(7):542-547.
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124. Zoli G, Corazza GR, D’Amato G, Bartoli R, Baldoni F, Gas-
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125. Hathaway JM, Harley RA, Self S, Schiffman G, Virella G. Immu-
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128. Reay DT, Nakonechny D. Sudden death and sepsis after
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Overwhelming infection after splenectomy in spite of some
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131. Livingston CD, Levine BA, Sirinek KR. Preservation of splenic
tissue prevents postsplenectomy pulmonary sepsis following
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133. Patel JM, Williams JS, Naim JO, Hinshaw JR. The effect of site
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clearance from the blood. J Pediatr Surg. 1986;21(10):877-880.
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function after splenectomy, spleen repair, and spleen auto-
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138. Leemans R, Manson W, Snijder JA, et al. Immune response
capacity after human splenic autotransplantation: Restoration
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139. Leemans R, Harms G, Rijkers GT, Timens W. Spleen auto-
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140. Smith E, J De Young N, Drew PA. Decreased phagocytic capacity
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141. Tang WH, Wu FL, Huang MK, Friess H. Splenic tissue auto-
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implants to protect against fatal postsplenectomy infection. Am
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156. Malhotra AK, Carter RF, Lebman DA, et al. Preservation of splenic
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Coll Surg. 2005;201(2):179-187.
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 PART X

HERNIA

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PMPH_CH63.indd 512 5/22/2012 5:44:24 PM

George Kasotakis and Marc A. de Moya
INTRODUCTION
Inguinal hernia repair represents the most commonly performed
procedure by General Surgeons in the United States with more
than 770,000 repairs performed annually according to the National
Center for Health Statistics.1 These figures have significant socio-
economic ramifications, as both the condition and the operation
are associated with significant costs, morbidity, and afflict caregiv-
ers with a nontrivial burden. Until recently, a belief commonly held
among surgical training programs worldwide purported that all
inguinal hernias be repaired at diagnosis. The reasoning behind
this principle was twofold: early intervention helped prevent com-
plicating events with unacceptably high morbidity and mortal-
ity and allowed a less technically challenging operation later on.
However, a growing body of evidence suggests that the incidence
of long-term complications after herniorrhaphy might be higher
than previously thought, whereas little is known about the natu-
ral history of hernias in men who elect to not have an operation.
Other controversial issues surrounding inguinal hernias include
the routine use of mesh and neurectomies to prevent recurrences
and postoperative groin pain, respectively; the role of laparoscopy
in unilateral, bilateral, and recurrent hernias; optimal anesthesia
selection for elective herniorrhaphies; as well as factors predispos-
ing recurrence are among the topics discussed in this chapter.
1. Should asymptomatic hernias be repaired?
Although the question of whether to intervene in a patient with a
symptomatic hernia is easily answered, defining whether asymp-
tomatic or minimally symptomatic patients warrant herniorrhaphy
is much more difficult to tackle. The difficulty in this undertaking
lies in estimating the incidence of potentially life-threatening her-
nia accidents, which appears to be lower than initially thought.2,3
Two prospective-randomized controlled clinical trials have
been published in the past few years testing the hypothesis that a
strategy of watchful waiting is an acceptable alternative to routine
repair at diagnosis of an asymptomatic or minimally symptom-
atic hernia in men.4,5
513
PMPH_CH63.indd 513
CHAPTER 63
Inguinal Hernias
Fitzgibbons et al.4 followed prospectively 720 men with reduc-
ible, minimally symptomatic or asymptomatic inguinal hernias
after randomizing them to watchful waiting versus a Lichtenstein
tension-free repair with a prosthetic mesh. Primary outcome mea-
sures included worsening pain that interfered with daily activities at
2 years and a change in quality of life metrics. Both groups developed
pain interfering with activities in equal proportions (5.1% for the
watchful waiting group vs. 2.2% for the surgically treated, p = .52)
in the intention-to-treat analysis. However, 23% of watchful waiting
patients had crossed over to the intervention group by 2 years, citing
worsening symptomatology, whereas 17% of the men assigned to
hernia repair crossed over to watchful waiting. Acute hernia acci-
dents (bowel obstruction without strangulation) were very rare at
a cumulative accident rate of 0.0018 events per patient year, and the
patients that presented with those were managed successfully with
urgent or semielective repairs without significant complications.
Contrary to popular belief, there appears to be no “penalty”
for delaying operation in the men with minimally symptomatic
or asymptomatic hernias. A follow-up study on the same cohort
of patients assessed a range of objective measures after grouping
patients in an “immediate” (<6 months) or “delayed” (>6 months)
repair group.6 Operative time (64 vs. 67 min, p = .382), complica-
tion (17% vs. 21.5%, p = .375), and recurrence rates (1% vs. 3.1%),
as well as patient satisfaction scores were similar between the
two groups. Watchful waiting also appears to be a cost-effective
approach in managing minimally symptomatic patients with her-
nias7 that does not overburden patients’ caregivers.8
The second trial took place in the United Kingdom and
included 160 males over the age of 55 years with asymptom-
atic inguinal hernias.5 The primary outcome was pain at 1 year
and was similar between the two groups. Twenty-three of the
80 observation patients crossed over to repair due to pain or
increase in size. Hernia-related adverse events occurred only in
three of those, and those were successfully managed with either
an urgent or an elective herniorrhaphy after reduction. When
the same cohort of watchful waiting patients were followed for a
period of 8 years, more than half (46 of 80, 57.5%) elected to have
their hernias repaired, with most citing pain or increase in size as
5/22/2012 5:44:24 PM
 514 ■ Surgery: Evidence-Based Practice

an indication.9 Over the course of the 8 years, only two patients laparoscopic surgery in the 1990s, minimally invasive attempts
presented with acute hernia accidents, but neither required bowel at tension-free repairs yielded encouraging results. The dominat-
resection. ing techniques for laparoscopic inguinal hernia repair include the
Given the aforementioned data, it appears that watchful wait- transabdominal preperitoneal (TAPP) and the totally extraperito-
ing can be safely offered as an option in asymptomatic or mini- neal (TEP) approaches.
mally symptomatic men with inguinal hernias. This is a Grade A In an attempt to answer what patient population might ben-
recommendation. efit the most from a laparoscopic approach, multiple prospective
clinical trials have been conducted. The EU Hernia Trialists Col-
2. Are mesh repairs better than native tissue repairs? laboration meta-analysis16 included 41 prospective-randomized
trials, comparing laparoscopic with open tension-free herniorrha-
Since the late 19th century, when Bassini introduced the muscu-
phies. This meta-analysis, which included a total of 7294 patients,
loaponeurotic approximation for inguinal hernias,10 the primary
demonstrated no significant difference in the recurrence rates
tissue repair dominated the general surgical circles with multi-
between the laparoscopic and the open approach (2.2% vs. 1.7%;
ple variations (Shouldice, McVay) for over a century. However, it
OR 1.26, 95% CI 0.76−2.08), but showed a benefit in chronic groin
was unacceptably high recurrence rates in the 10% to 15% that
pain in the former (OR 0.64, 95% CI, 0.52−0.78, p < .001).
prompted surgeons to look for new approaches. The concept of
Another meta-analysis,17 which included 29 prospective-
“tension-free” repair that was first introduced by Lichtenstein in
randomized trials comprising a total of 5588 patients, concluded
the 1980s11 attracted attention early on, as the addition of a mesh
that short-term hernia recurrence was higher in the laparoscopi-
allowed reconstruction without the need to pull layers of tissue
cally managed by about 50%, although this result was not sta-
under tension. This technically easier approach continued to gain
tistically significant (OR 1.51, 95% CI, 0.81−2.79). Postoperative
ground and multiple prospective-randomized trials demonstrated
complications were fewer in the laparoscopic group (OR 0.62,
its advantages over the more traditional native tissue approaches,
95% CI, 0.46−0.84), discharge from the hospital occurred ear-
including a significant reduction in recurrence, the ability to per-
lier (3.43 h, 95% CI, 0.35−6.5 h) and patients returned sooner to
form under local anesthesia, less pain and more rapid return to
normal activity by about 5 days (95% CI 3.51−5.96). The down-
work, and routine physical activities.
side was a slightly longer operative time (15.2 min longer; 95% CI
In 2001, the Cochrane Collaboration identified 20 prospec-
7.78−22.63 min).
tive-randomized or quasi-randomized clinical trials comparing
The Veterans Affairs cooperative trial,18 one of the most com-
open mesh with nonmesh repairs.12 Of these, 17 used a flat mesh,
monly cited trials in the United States, included 1983 patients
two plug-and-mesh, and one a mesh placed preperitoneally. The
that were randomized to a tension-free open versus a laparo-
control groups in all studies included a variety of primary tissue
scopic repair and had some contradictory findings: recurrence at
repairs. Despite the marked heterogeneity of the studies included,
2 years was lower in the open group (10.1% vs. 4.9%; OR 2.2; 95%
it appeared that tension-free approaches required on average 7 to
CI, 1.5−3.2), but when surgeon experience was taken into account
10 min less to perform than Shouldice repairs, but 1 to 4 min lon-
(>250 laparoscopic hernia repairs) the recurrence was low and
ger than the Bassini or McVay approach. There was no statistically
below 5% with either approach. Complication rate was slightly
significant difference in minor postoperative complications, such
higher in the laparoscopic group (39% vs. 33.4%; OR 1.3, 95% CI,
as hematoma and seroma formation, or wound infections. Serious
1.1−1.3). The laparoscopically treated patients reported less groin
complications, including femoral neurovascular bundle, spermatic
pain at 2 weeks postoperatively and were able to return to their
cord, and visceral injuries were rare in both groups. Hospital stay
usual activity 1 day earlier than the open group.
was slightly shorter in the mesh-based repairs (OR −0.28, 95%
A more recent meta-analysis from Dedemadi and associ-
CI −0.35 to −0.22), but significant heterogeneity was noted, likely
ates19 that comprised 1542 patients undergoing laparoscopic
reflecting variability in the local discharge practices. Return to
versus Lichtenstein repair reported similar postoperative com-
usual activities/work was also shorter in the mesh-repair group
plications and recurrence risk, but noted more recurrences when
(OR 0.81, 95% CI 0.73–0.91), and persisting pain or numbness in
the TAPP group was compared with the TEP (RR 3.25, 95%
the genitofemoral area also favored the tension-free approach (OR
CI 1.32–7.9, p = .01).
0.68, 95% CI 0.47–0.98 and OR 0.7, 95% CI 0.29–1.72, respectively).
With regard to the optimal approach for managing recurrent
Most importantly, recurrence after mesh repair was consistently
hernias, the Danish Hernia Database analysis,20 which included
less frequently reported and overall was reduced by between 50%
a total of 67,306 prospectively recorded herniorrhaphies, demon-
and 75% (OR 0.37, 95% CI 0.26–0.51).
strated a reduced re-reoperation rate if a laparoscopic approach
Subsequent prospective trials reported similar findings, favor-
was used for the first recurrence (1.3%, 95% CI 0.4−3.0) compared
ing mesh-based repairs over primary herniorrhaphies.13-15 Given
with Lichtenstein (11.3%, 95% CI 8.2−15.2). Another random-
the aforementioned data, we conclude that the use of mesh during
ized trial comparing laparoscopic with open repairs for recurrent
open inguinal hernia repair is associated with a significant reduc-
inguinal hernias21 demonstrated no difference in operative time
tion in the recurrence risk and may act favorably in reducing post-
or recurrence rates at 5 years (18% for TAPP vs. 19% for Lichten-
operative groin pain and numbness and allowing earlier return to
stein), but postoperative pain and time to return to work were less
preoperative functioning status. We therefore recommend routine
with the former.
application of mesh-based tension-free inguinal herniorrhaphy.
In summary, laparoscopic repairs offer an equivalent recur-
This is a Grade A recommendation.
rence risk and a slightly earlier return to normal activity com-
pared with open repairs, at the expense of longer operative times,
3. Open or laparoscopic repair for inguinal hernias?
a greater equipment cost, and the need for general anesthesia.
With the improved outcomes and subsequent popularization of Laparoscopic hernia repairs may offer an advantage for managing
the Lichtenstein herniorrhaphy in the 1980s and the explosion of recurrent hernias. This is a Grade A recommendation.

PMPH_CH63.indd 514 5/22/2012 5:44:24 PM


4. Risk factors for hernia recurrence.
Inguinal hernia recurrence is estimated at <5% with either a Lich-
tenstein or a laparoscopic repair when performed by experienced
surgeons. Using a mesh to re-approximate the tissues in a tension-
free fashion is one of the best known methods employed to signifi-
cantly reduce recurrence; however, other risk factors for hernia
recurrence are not clearly delineated.
Mayagoitia et al.22 looked at 551 open hernia repairs per-
formed with either a flat mesh (Licthenstein), a Prolene Hernia
System, or a Mesh-Plug and concluded that recurrence was greater
with the latter (2.5%, RR 4.35, 95% CI 0.85–22.23); yet the differ-
ence was not statistically significant. Previous herniorrhaphy, an
internal ring >4.5 cm, and postoperative complications were also
found to be predictive of future recurrence.
Data from the Veterans Affairs trial23 demonstrated that inde-
pendent predictors of recurrence in the open repair group were
recurrent hernia, lack of a caregiver, and operating time <72 min.
Among the patients treated laparoscopically, low surgeon volume,
active lifestyle, and a BMI <25 were the independent predictors.
While the aforementioned data provide an idea for what
might contribute to a hernia recurrence, larger studies designed
to detect risk factors for recurrence should be performed. This is a
Grade C recommendation.
5. Should neurectomy for prevention of postoperative groin
pain be done routinely?
Inguinodynia or chronic groin pain is one of the most dreaded
complications following inguinal hernia repair and one that
affects the quality of life significantly.24 It is usually attributed to
intraoperative nerve damage or postoperative mesh-related fibro-
sis. Although traditional surgical teaching holds that the nerves
(ilioinguinal, iliohypogastric, and genitofemoral) should be iden-
tified and preserved during repair, recent cohort studies demon-
strate that routine ilioinguinal nerve sacrifice is associated with
less chronic groin pain, whereas subjective paresthesia is usually
only temporary.25-27 In addition, ilioinguinal neurectomy appears
to be the effective treatment for chronic groin pain relief after open
herniorrhaphy.28,29 However, results of prospective-randomized
clinical trials comparing the preservation versus routine ilioin-
guinal neurectomy during open tension-free herniorrhaphies are
conflicting.30-33 In light of the contradictory evidence and while a
Cochrane review is underway, preservation or routine resection of
the inguinal nerves should be left to the discretion of the treating
surgeon. This is a Grade D recommendation.
6. What is the optimal approach for bilateral hernias: open or
laparoscopic?
Concurrent repair of bilateral hernias may best be accomplished
laparoscopically. Long-term data demonstrate no difference in
recurrence between bilateral open compared with bilateral lap-
aroscopic repairs34 and it appears that overall recurrence (0.63%
vs. 0.42%), postoperative complications (1.9% vs. 1.4%), need for
reoperation (0.5% vs. 0.43%), and time to return to previous activ-
ity (14 vs. 14 days) are the same for unilateral versus bilateral lap-
aroscopic hernia repair.35
Postoperative complications, operative time, length of stay,
and groin pain appear to favor the laparoscopic approach com-
pared with a Licthenstein repair in three prospective-randomized
trials.36-38 With these data in mind, and given the easier concurrent
PMPH_CH63.indd 515
Inguinal Hernias ■ 515
access to both groins with the laparoscopic approach, we recom-
mend the TAPP or the TEP for bilateral inguinal hernias if the
operating surgeon is expert in laparoscopic repairs, otherwise the
open repair is acceptable.
7. Is a plug necessary for mesh repairs?
Due to the rising popularity of tension-free herniorrhaphies over
the last few decades, plug-and-patch prostheses, which consist
of a “plug” covering the abdominal wall defect and a flat mesh
reinforcing the inguinal canal floor, were developed. The unique
feature of these repairs is that they require minimal dissection,
theoretically allowing for shorter operating times, reducing post-
operative pain, and affording earlier recovery. However, these
claims were not confirmed in rigorous clinical trials.
Dalenbäck et al.39 randomized 472 men undergoing tension-free
herniorrhaphy to a Lichtenstein, Prolene Hernia System, or plug-
and-patch repair and followed them for 3 years. Although opera-
tive time was slightly shorter in the latter two groups (40.4 ± 1 min
vs. 37.4 ± 1 min, and 35.5 ± 1 min, respectively), the difference was
not clinically significant. Postoperative complications, groin pain,
return to full functional ability, and incidence of recurrence did not
differ between the groups. Similarly, Nienhuijs et al.40 randomized
334 patients to the same procedures, and assessed the quality of life
and pain with the SF-36 and the visual analog scale at 2, 12, and
60 weeks after surgery. There were no differences noted in either.
When the plug-and-patch repair was compared against the
Lichtenstein herniorrhaphy 595 patients undergoing a total of 700
primary or recurrent herniorrhaphies by Frey et al., no differences
were noted in recurrence rates or postoperative complications.41
Similarly, postoperative pain and time to recovery did not differ in
141 individuals studied by Kingsworth and colleagues.42 Operative
time was significantly shorter in the plug-and-patch group (32 vs.
37.6 min, p = .01), but the difference was not clinically significant.
Based on the above findings, mesh type selection should be left
to the surgeon’s discretion. This is a Grade B recommendation.
8. Local versus general anesthesia: does one confer a better out-
come than the other?
There have been several case series that have described the feasibil-
ity and safety of performing inguinal hernia repairs utilizing local
anesthesia.43,44 Other larger database retrospective series have also
suggested that local anesthesia is underutilized as a method for
inguinal hernia repair.45 This has been extended to include lap-
aroscopic hernia repairs,46 as well as open. We focus our question
on the use of local anesthesia versus general anesthesia in open
hernia repairs.
In 2001, Gonullu et al.47 performed a randomized clinical
trial directly comparing the use of local anesthesia with the use of
general anesthesia with a primary outcome of pulmonary effects,
postoperative pain and fatigue, morbidity, and patient satisfac-
tion. They demonstrated a significant difference in pain relief but
only at one time point (8 h postop) but significantly improved
CO2 clearance and oxygenation in the local anesthesia group.
There was no significant difference in patient satisfaction. They
concluded that local anesthesia provided slightly better pain con-
trol and improve pulmonary function.
In 2003, O’Dwyer et al. performed a randomized trial com-
paring local and general anesthesia on 279 patients with ulti-
mately 138 in each group. They found that intraoperative pain led
to patient dissatisfaction but postoperative pain was better at 6 h
5/22/2012 5:44:24 PM
 516 ■ Surgery: Evidence-Based Practice
than the general anesthesia group. In addition, they noted that
open repair using general anesthesia was 4% more in cost than
local anesthesia. They concluded that there were no major dif-
ferences in patient recovery after local or general anesthesia and
patients could be presented with both options.48
Th is was followed by a randomized clinical trial compar-
ing local, regional, and general anesthesia in Sweden. There were
approximately 200 patients in each arm of this multi-institutional
trial. The investigators seemed to standardize methods across the
institutions with favorable outcomes for those undergoing local
anesthesia. There was a significant decrease in admission dura-
tion, less immediate postoperative pain, and fewer problems with
urinary retention. However, there was no difference in pain after
the first day and no difference in time to normal activity. This
study suggested that local anesthesia should be utilized more fre-
quently for open inguinal hernia repairs.49
There is currently a meta-analysis being performed by the
Cochrane Collaboration to evaluate the randomized trials con-
cerning this question. However, after review of the evidence, it
appears as though the use of local anesthesia is safe and effec-
tive and in some patients may be a better alternative to general
anesthesia. However, there is no compelling data that suggest that
local anesthesia is superior to general anesthesia. This is a Grade B
recommendation.
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13. Miedema BW, Ibrahim SM, Davis BD, Koivunen DG. A prospec-
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18. Neumayer L, Giobbie-Hurder A, Jonasson O, et al. Open mesh
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19. Dedemadi G, Sgourakis G, Radtke A, et al. Laparoscopic versus
open mesh repair for recurrent inguinal hernia: A meta-analysis
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20. Bisgaard T, Bay-Nielsen M, Kehlet H. Re-recurrence after opera-
tion for recurrent inguinal hernia. A nationwide 8-year follow-up
study on the role of type of repair. Ann Surg. 2008;247:707-711.
21. Eklund A, Rudberg C, Leijonmarck CE, et al. Recurrent inguinal
hernia: Randomized multicenter trial comparing laparoscopic
and Lichtenstein repair. Surg Endosc. 2007;21:634-640.
22. Mayagoitia JC, Prieto-Diaz Chavez E, Suarez D, Cisneros HA, Tene
CE. Predictive factors comparison of complications and recur-
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23. Matthews RD, Anthony T, Kim LT, et al. Factors associated with
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25. Zieren J, Tsigris C, Menenakos C. Open tension-free hernia repair
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26. Dittrick GW, Ridl K, Kuhn JA, McCarty TM. Routine ilioingui-
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188:736-740.
27. Tsakayannis DE, Kiriakopoulos AC, Linos DA. Elective neurec-
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28. Loos MJ, Scheltinga MR, Roumen RM. Tailored neurectomy
for treatment of postherniorrhaphy inguinal neuralgia. Surgery.
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29. Aasvang EK, Kehlet H. The effect of mesh removal and selective
neurectomy on persistent postherniotomy pain. Ann Surg. 2009;
249:327-334.
30. Malekpour F, Mirhashemi SH, Hajinasrolah E, Salehi N, Kho-
shkar A, Kolahi AA. Ilioinguinal nerve excision in open mesh
repair of inguinal hernia—results of a randomized clinical trial:
Simple solution for a difficult problem? Am J Surg. 2008;195:
735-740.
31. Mui WL, Ng CS, Fung TM, et al. Prophylactic ilioinguinal neurec-
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32. Picchio M, Palimento D, Attanasio U, Matarazzo PF, Bambini
C, Caliendo A. Randomized controlled trial of preservation or
elective division of ilioinguinal nerve on open inguinal hernia
repair with polypropylene mesh. Arch Surg. 2004;139:755-758;
discussion 759.
33. Ravichandran D, Kalambe BG, Pain JA. Pilot randomized con-
trolled study of preservation or division of ilioinguinal nerve
in open mesh repair of inguinal hernia. Br J Surg. 2000;87:
1166-1167.
34. Kald A, Fridsten S, Nordin P, Nilsson E. Outcome of repair of
bilateral groin hernias: A prospective evaluation of 1,487 patients.
Eur J Surg. 2002;168:150-153.
35. Wauschkuhn CA, Schwarz J, Boekeler U, Bittner R. Laparoscopic
inguinal hernia repair: Gold standard in bilateral hernia repair?
Results of more than 2800 patients in comparison to literature.
Surg Endosc. 2010;24:3026-3030.
36. Feliu X, Claveria R, Besora P, et al. Bilateral inguinal hernia
repair: Laparoscopic or open approach? Hernia. 2011;15:15-18.
37. Sarli L, Iusco DR, Sansebastiano G, Costi R. Simultaneous repair
of bilateral inguinal hernias: A prospective, randomized study of
open, tension-free versus laparoscopic approach. Surg Laparosc
Endosc Percutan Tech. 2001;11:262-267.
38. Mahon D, Decadt B, Rhodes M. Prospective randomized trial
of laparoscopic (transabdominal preperitoneal) vs open (mesh)
repair for bilateral and recurrent inguinal hernia. Surg Endosc.
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39. Dalenback J, Andersson C, Anesten B, et al. Prolene Hernia System,
Lichtenstein mesh and plug-and-patch for primary inguinal her-
nia repair: 3-year outcome of a prospective randomised controlled
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lay with plug for inguinal hernia repair. Hernia. 2009;13:121-129;
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PMPH_CH63.indd 517
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40. Nienhuijs S, van Oort I, Keeners-Gels M, Strobbe L, Rosman C.
Randomized clinical trial comparing the Prolene Hernia System,
mesh plug repair and Lichtenstein method for open inguinal
hernia repair. Br JSurg. 2005;92:33-38.
41. Frey DM, Wildisen A, Hamel CT, Zuber M, Oertli D, Metzger
J. Randomized clinical trial of Lichtenstein’s operation versus
mesh plug for inguinal hernia repair. Br J Surg. 2007;94:36-41.
42. Kingsnorth AN, Porter CS, Bennett DH, Walker AJ, Hyland
ME, Sodergren S. Lichtenstein patch or Perfi x plug-and-patch
in inguinal hernia: A prospective double-blind randomized con-
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43. Callesen T, Bech K, Kehlet H. Feasibility of local infi ltration
anaesthesia for recurrent groin hernia repair. Eur J Surg. 2001;
167:851-854.
44. Makuria T, Alexander-Williams J, Keighley MRB. Comparison
between general and local anaesthesia for repair of groin hernias.
Ann Roy Coll Surg Engl. 1979;61:291-294.
45. Kehlet H, Nielsen M. Anaesthetic practice for groin hernia repair – a
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221-224.
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5/22/2012 5:44:24 PM
 CHAPTER 64
Recurrent Inguinal Hernia
H. R. Nanda Kumar and Kent R. Van Sickle
INTRODUCTION
Approximately, 770,000 inguinal hernia repairs are performed
annually in the United States.1 An analysis in Sweden noted that 15%
of all inguinal hernia repairs were performed to treat recurrence.2
Although recurrence has been regarded as the most important mea-
sure of success of an inguinal hernia repair, newer measures also
focus on the quality of life and return to normal activities. Recurrent
inguinal hernia repairs are technically more difficult than primary
repairs because of inflammation and scarring from prior repair.
1. What is the rate of recurrence for inguinal hernia?
Primary Repair
The rate of recurrence following primary repair of an inguinal her-
nia has been variable and is reported between <1% and 17%.2-4 This is
attributable to the multiple techniques of repair involving open versus
laparoscopy, tissue versus prosthetic repairs, and so on. Recurrence
after primary inguinal hernia repair is higher in females compared
with males,2,3 mainly due to occurrence of femoral hernias.
Recurrence rates of tissue-based repairs vary according to pro-
cedure. The Shouldice repair has been regarded as the most superior
by large-scale analyses. Surgeons who perform a large volume of the
Shouldice repair are able to demonstrate recurrence rates around
1%.5 In less experienced hands, such low recurrence rates have
not been demonstrated. However, recurrence rates for the Shoul-
dice repair are consistently lower than those of the Bassini or
McVay repair. A multicenter controlled trail of 1578 patients from
France demonstrated that the Shouldice repair, even with a recur-
rence rate near 6%, is superior to the Bassini repair (8.6% recurrence
rate) and McVay repair (11.2%).6
The introduction of prosthetic repairs reduced recurrence
rates to a consistently low level. In a multi-institutional series, 3019
inguinal hernias were repaired using Lichtenstein tension-free
repair with a reported recurrence rate of 0.2%.7 In another series
of 3175 inguinal hernias repaired by Lichtenstein tension-free
repair, the recurrence rate was 0.5% with a follow-up period of up
to 5 years.8 Consistently low recurrence rates led to the acceptance
518
PMPH_CH64.indd 518
of Lichtenstein tension-free repair as the gold standard for open
anterior approaches. Lichtenstein tension-free repair is the most
commonly used prosthetic repair by open technique.1
There are limited prospective, randomized data compar-
ing the recurrence rate of open prosthetic repairs versus open
nonprosthetic (i.e., primary tissue) repairs. A review of 26,000
inguinal hernia repairs from Denmark found that mesh repairs
had a lower reoperation rate than conventional open repairs.3
Meta-analysis studies have also demonstrated that mesh repair
was associated with fewer overall recurrences with 1.4% in mesh
group and 4.4% in nonmesh group9,10 and a reduction in the risk
of recurrence by 50–75%.
Laparoscopic versus Open Repairs
In the early 1990s, the application of laparoscopic surgery to the
repair of inguinal hernias gained interest. Evidence available to
date has not been definitive while comparing laparoscopic with
open methods of repair. A meta-analysis of 41 randomized tri-
als in 2000 found no significant difference in the risk of recur-
rence between the two approaches.11 In 2004, the results of the
VA cooperative study, a multicenter randomized trial that ana-
lyzed long-term hernia results in over 2000 patients in 14 Veterans
Affairs hospitals, were published. A total of 1983 patients under-
went either a laparoscopic (TAPP or TEP) or an open (Lichten-
stein tension-free) operation. It showed a significantly increased
recurrence rate of primary unilateral hernias at 2 years within the
laparoscopic group versus the open group (10.1% vs. 4.0%). How-
ever, a posthoc evaluation of the surgeons’ self-reported experi-
ence compared with recurrence rates demonstrated a statistically
significant reduced recurrence rate (5.1%) for those that had per-
formed >250 laparoscopic procedures. It has been suggested that
the recurrence rates noted in this study may be more reflective of
the general population outside of specialty centers. In the hands
of very experienced laparoscopic surgeons, with more than 250
cases, the recurrence rates may approach that of open technique.
However, other studies including a systematic review published in
2000 have shown equivalent recurrence rates in both groups.12-18
5/22/2012 5:44:59 PM

Recurrent Inguinal Hernia Repair
The recurrence rate for repair of a recurrent inguinal hernia varies
depending on the method of primary hernia repair and method of
the recurrent hernia repair. Bisgaard et al. reported in 2008 that the
re-recurrence rate after a primary open hernia repair ranged from
1% to 2% and 7% to 17% with a laparoscopic technique and open
repair for recurrence, respectively.4 In other randomized trials
including a total of 337 recurrent groin hernias, the re-recurrence
rate ranged from 8% to 19% and 2% to 18% in patients undergo-
ing laparoscopic and open repair, respectively.22-24 The follow-up
ranged from 2.5 to 5 years but again no information on the tech-
nique of previous repair was provided. Two of the trials23,24 showed
no significant differences whereas one trial22 reported significantly
lower re-recurrence rate after open repair (Stoppa) compared with
a laparoscopic repair (2% vs. 13%).
Answer: Operations using mesh result in fewer recurrences
than nonmesh techniques. (Grade A) The recurrence rate following
Lichtenstein repair of primary inguinal hernia is around 4%. There
is a significantly higher recurrence rate with laparoscopic repair of
inguinal hernias. Highly experienced surgeons may have a recurrence
rate which approaches that seen with the open repair. (Grade B)
2. What is the pattern of recurrence?
Studies suggest that most hernia recurrences are medial22,24 and
around 10% of them are femoral.4 There is a higher incidence of
recurrence in the form of a femoral hernia in women. In a very large
Swedish hernia registry, where around 7000 women with inguinal
hernias were followed prospectively, 42% of women with a recur-
rent groin hernia were noted to have a femoral hernia at the time of
reoperation. This number was less than 5% in men. It is important
that surgeons are aware of the incidence of femoral hernia, espe-
cially in women and make appropriate considerations while plan-
ning the operation for recurrent inguinal hernias.25
Answer: Women have a higher incidence of recurrence fol-
lowing the repair of inguinal hernia due to occurrence of femoral
hernias. (Grade C)
3. Is there a role for nonoperative management of recurrent
inguinal hernias?
Recurrent inguinal hernias on presentation are most often asymp-
tomatic or minimally symptomatic. The traditional teaching has
been to repair these hernias considering the risk of incarceration
or strangulation. However, the risk of incarceration of an asymp-
tomatic inguinal hernia is low (estimated to be 0.3–3% per year).26
An emergency operation due to a strangulated inguinal hernia
has a higher associated mortality than an elective operation (>5 vs.
<0.5%).3,27 A large randomized multicenter clinical trial published
in 2006 compared patients with primary or recurrent inguinal her-
nias with a minimum follow-up of 2 years.28 They were randomized
to watchful waiting versus Lichtenstein repair. The rate of her-
nia accident (defined as a strangulation or bowel obstruction) for
all patients (both primary and recurrent) was calculated at 0.0018
events/patient/year in that study. The main conclusions after 2 years
of follow-up were 23% crossover rate from watchful waiting to oper-
ation, one acute incarceration without strangulation within 2 years,
and one incarceration with bowel obstruction within 4 years. There
were no significant differences between the two groups in pain inter-
fering with activities or performance on the physical component of
the SF-36. There were no consequences for delaying operation, and
PMPH_CH64.indd 519
Recurrent Inguinal Hernia ■ 519
outcomes were the same when compared with those randomized
to receive immediate operation. In another trial,29 in which 80 men
(over 55 years of age) were randomized to operation and 80 to watch-
ful waiting, the main conclusions after 1 year of follow-up were 29%
of patients crossed over to operation and three serious hernia-related
adverse events occurred in the watchful waiting. The results dem-
onstrated no difference in outcomes or costs between groups and
concluded that surgery can be safely delayed and watchful waiting is
an acceptable option for men who are asymptomatic.
Answer: Watchful waiting is an acceptable option for men
with minimally symptomatic or asymptomatic hernias. (Grade A)
4. What is the preferred method of repair for recurrent ingui-
nal hernias?
Recurrence following a repair of an inguinal hernia can occur
early within days of or late after a few years after the initial repair.
It is advisable to delay the repair of a reducible recurrent inguinal
hernia for at least 6 weeks after the primary repair whenever fea-
sible to allow for the inflammatory process to subside.
Recurrent inguinal hernias can be repaired via an open or
a laparoscopic approach. The method of the initial hernia repair
should be given due consideration before deciding the type of
repair for the recurrent inguinal hernia. The operative report
should be obtained and any other intervening procedures like ret-
ropubic prostatectomy and pelvic fi xation should also be consid-
ered. The goal of repair of a recurrent inguinal hernia should be
to identify the failure in coverage of the myopectineal orifice from
the initial repair, and attempt to provide a definitive coverage.
Open Approach for a Recurrent Inguinal Hernia
The open approach for repair of a recurrent inguinal hernia is
currently based on prosthetic repairs. The conventional nonpros-
thetic repairs are out of favor for recurrent inguinal hernias.2
If the initial repair was a prosthetic repair, then the repair
of the recurrent hernia should be approached via a virgin plane.
An anterior approach should be used following a failed posterior
repair and a posterior approach should be used following a failed
anterior repair.30
The choice of the procedure will also depend on the individual
experience of the surgeon. The most common open anterior mesh
procedure is the Lichtenstein repair. Orchiectomy should be dis-
cussed with the patient although it is rarely necessary. Attempts to
remove the mesh are discouraged but the anatomy should be care-
fully delineated to include the femoral canal and repair performed
adhering to the principles as discussed earlier. When a femoral
hernia is encountered, the mesh should be anchored to Cooper’s
ligament. This technique has also been modified by the addition
of a mesh plug into the hernia defect after reduction of the hernia
sac, prior to placement of the mesh onlay.
Multiple trials have demonstrated the effectiveness of open
anterior mesh repair for recurrent inguinal hernias. Open pre-
peritoneal repair can be performed by posterior approach. It
requires the placement of a mesh posterior to transversalis fascia.
This approach is less popular than the other repairs, but some
studies have reported low recurrence and complication rates.22
Many recent randomized controlled trails have shown
advantages with laparoscopic approach for the repair of recurrent
inguinal hernias and are more commonly used when a posterior
approach is being considered.
5/22/2012 5:45:00 PM
 520 ■ Surgery: Evidence-Based Practice

Laparoscopic Approach for a
Recurrent Inguinal Hernia
Laparoscopic repair offers the benefit of visualizing the myo-
pectineal orifice and thereby all the potential defects. The two
most common types of laparoscopic repair for an inguinal hernia
are the transabdominal preperitoneal repair (TAPP) and totally
extraperitoneal repair (TEP).
There are no multicenter randomized controlled trails com-
paring TEP and TAPP repairs. Most studies show equivalent
results in terms of outcomes (pain, recovery, complications, and
recurrence). Some groups favor the TEP repair, as it does not
violate the peritoneum and a reported lower incidence of serious
complications.11,31,32
Open versus Laparoscopic Repair
The debate of open versus laparoscopic repair for recurrent ingui-
nal hernias has been addressed by randomized controlled trials22-24
over the last few years. The majority of these studies have excluded
patients with prior mesh repair. They have shown equivalent results
in terms of recurrence when mesh repair has been used in the open
approach. The laparoscopic approach has certain advantages mainly
with reduced complications like seroma, early postoperative pain,
analgesic consumption, and return to activities.2,4,21-24,33,34
Some of the relative contraindications for laparoscopic repair
are similar to that of a primary inguinal hernia. A large scrotal
hernia and patients with ascites are also better served with an
open repair.
Answer: A recurrent inguinal hernia after conventional open
repair should be repaired by an open or a laparoscopic preperito-
neal approach. (Grade A). The preperitoneal approach (open or
laparoscopic) is recommended for the repair of recurrent inguinal
hernia following previous open Lichtenstein repair. (Grade B). An
open anterior approach is recommended for a recurrent inguinal
hernia after previous posterior approach. (Grade D)
5. What is the incidence of chronic pain following repair of
primary and recurrent inguinal hernias?
Chronic postoperative groin pain syndromes have emerged as the
major complication being faced by hernia surgeons today. Sys-
tematic reviews of prospective studies of inguinal hernia repair
report the incidence of moderate to severe chronic pain to be
around 10–12%.35-37 A study of 226 patients found that there was
a fourfold increase in the risk of developing chronic pain for an
operation of recurrent inguinal hernia as compared with a pri-
mary inguinal hernia.37,38 Also, a Danish prospective study of 419
patients noted a higher risk of moderate or severe pain after repair
of recurrent than primary hernias (14% vs. 3%).39 There are no ran-
domized controlled trials comparing the incidence chronic pain
following open versus laparoscopic repairs of recurrent inguinal
hernias. However, studies have reported higher incidence of pain
with open as compared with laparoscopic repair of initial ingui-
nal hernias.35,36,40
Answer: The overall incidence of moderate to severe pain
after hernia surgery is around 10–12%. There is a fourfold increase
in the rate of moderate to severe chronic pain following surgery
for recurrent inguinal hernia. (Grade B)

Randomized controlled trials comparing laparoscopic versus open repairs

Study Year Intervention No. of Pts Follow-up Recurrence Comments
Eklund et al.19 2009 TEP vs. TFR 1365 5 years TEP: 3.5% * PIH only
TFR: 1.2% When one surgeon with a
33% recurrence rate in the
TEP group was excluded,
the cumulative recurrence
rate dropped to 2.4% in the
TEP group (not significant
statistically)
Hallen et al.12 2008 TEP vs. TFR 80: TEP 1 year TEP: 4.3% PIH & RIH
87: TFR TFR: 5.1 %
Lau et al.13 2006 TEP vs. TFR 100: TEP 1 year None in both PIH only
100: TFR groups
Arvidsson et al.20 2005 TAPP vs. 1183 5 years TAPP: 6.6% PIH only
Shouldice Shouldice: 6.7%
Neumayer et al.21 2004 TFR vs. TEP/ 756: TFR 2 years TFR: 4.9%* PIH (4%, 10.1%)
TAPP 781: TEP TEP/TAPP: 10.1% RIH (14.1%, 10%)
and Difference in recurrence rate
TAPP between TEP and TAPP not
reported. Recurrence rate
in lap group was 5.1 % in
experienced surgeon group
(self-reported experience of
>250 repairs)

(Continued)

PMPH_CH64.indd 520 5/22/2012 5:45:00 PM

 Recurrent Inguinal Hernia ■ 521

(Continued)
Study Year Intervention No. of Pts Follow-up Recurrence Comments
Liem et al.14 2003 TEP vs. 487: TEP 2 and 2 years PIH and RIH
Conventional 507: open 4 years TEP: 3.8 Open Bassini and Non-Bassini
open anterior Open: 6.3 (Including Mesh)
repair 4 years
TEP: 4.9*
Open: 10
Douek et al.15 2003 TAPP vs. TFR TAPP: 122 5 years TAPP: 1.6% PIH and RIH
TFR: 120 TFR: 2.5%
Colak et al.16 2003 TEP vs. TFR TEP: 67 1 year TEP: 2.9% PIH and RIH
TFR: 67 TFR: 5.9%
Bringman et al.17 2003 TEP vs. Mesh TEP: 92 19.8 ± 8.6 TEP: 2.2 PIH and RIH
plug vs. TFR M-P: 104 months M-P: 1.9
TFR: 103 TFR: 0
Andersson et al.18 2003 TEP vs. TFR TEP: 76 1 year TEP: 2.6% PIH and RIH
TFR: 85 TFR: 0
TAPP, Transabdominal Preperitoneal Patch; TEP, Totally Extraperitoneal Patch; TFR, Tension-Free Repair; PIH, Primary Inguinal Hernia;
RIH, Recurrent Inguinal Hernia.

Summary Table
Question
1 What is the rate of recurrence
for repair of an inguinal hernia?
2 What is the pattern of
recurrence?
3 Is there a role for non-
operative management of
recurrent inguinal hernias?
4 What is the preferred method
of repair for a recurrent
inguinal hernia?
5 What is the incidence of
chronic pain following repair of
primary or recurrent inguinal
hernia?
Recommendation Grade
Operations using mesh result in fewer recurrences than nonmesh techniques. A
The recurrence rate following Lichtenstein repair of primary inguinal hernia is around B
4%. There is a significantly higher recurrence rate with laparoscopic repair of
inguinal hernias. Highly experienced surgeons may have a recurrence rate similar to
that seen with open repair.
Women have a higher incidence of recurrence following repair of inguinal hernia due C
to occurrence of femoral hernias.
Watchful waiting is an acceptable option for men with minimally symptomatic or A
asymptomatic hernias.
A recurrent inguinal hernia after conventional open repair should be repaired by an A
open or laparoscopic preperitoneal approach.
The preperitoneal approach is recommended for repair of recurrent inguinal hernia B
following previous open Lichtenstein repair.
An open anterior approach is recommended for a recurrent inguinal hernia after D
previous posterior approach.
The overall incidence of moderate to severe pain after hernia surgery is around B
10–12%.
There is a fourfold increase in rate of moderate to severe chronic pain following C
surgery for recurrent inguinal hernia.

REFERENCES 4. Bisgaard T, Bay-Nielsen M, Kehlet H. Re-recurrence after opera-

1. Rutkow IM. Demographic and socioeconomic aspects of hernia
repair in the United States in 2003. Surg Clin North Am. 2003;
83(5):1045-1051, v-vi.
2. Haapaniemi S, Gunnarsson U, Nordin P, Nilsson E. Reopera-
tion after recurrent groin hernia repair. Ann Surg. 2001;234(1):
122-126.
3. Bay-Nielsen M, Kehlet H, Strand L, et al. Quality assessment of
26,304 herniorrhaphies in Denmark: A prospective nationwide
study. Lancet. 2001;358(9288):1124-1128.
tion for recurrent inguinal hernia. A nationwide 8-year follow-up
study on the role of type of repair. Ann Surg. 2008;247(4):707-711.
5. Glassow F. The Shouldice Hospital technique. Int Surg. 1986;
71(3):148-153.
6. Hay JM, Boudet MJ, Fingerhut A, et al. Shouldice inguinal hernia
repair in the male adult: The gold standard? A multicenter con-
trolled trial in 1578 patients. Ann Surg. 1995;222(6):719-727.
7. Shulman AG, Amid PK, Lichtenstein IL. The safety of mesh repair
for primary inguinal hernias: Results of 3,019 operations from five
diverse surgical sources. Am Surg. 1992;58(4):255-257.

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 522 ■ Surgery: Evidence-Based Practice
8. Kark AE, Kurzer MN, Belsham PA. Three thousand one hun-
dred seventy-five primary inguinal hernia repairs: Advantages of
ambulatory open mesh repair using local anesthesia. J Am Coll
Surg. 1998;186:447-455; discussion 456.
9. Scott NW, McCormack K, Graham P, Go PM, Ross SJ, Grant AM.
Open mesh versus non-mesh for repair of femoral and inguinal her-
nia. Cochrane Database Systematic Reviews. 2002(4):CD002197.
10. Grant A. Mesh compared with non-mesh methods of open
groin hernia repair: Systematic review of randomized con-
trolled trials. Br J Surg. 2000;87(7):854-859.
11. Grant A. Laparoscopic compared with open methods of groin
hernia repair: Systematic review of randomized controlled trials.
Br J Surg. 2000;87(7):860-867.
12. Hallen M, Bergenfelz A, Westerdahl J. Laparoscopic extraperi-
toneal inguinal hernia repair versus open mesh repair: Long-
term follow-up of a randomized controlled trial. Surgery. 2008;
143(3):313-317.
13. Lau H, Patil NG, Yuen WK. Day-case endoscopic totally extraperi-
toneal inguinal hernioplasty versus open Lichtenstein hernioplasty
for unilateral primary inguinal hernia in males: A randomized
trial. Surg Endosc. 2006;20:76-81.
14. Liem MS, van Duyn EB, van der Graaf Y, van Vroonhoven TJ. Recur-
rences after conventional anterior and laparoscopic inguinal hernia
repair: A randomized comparison. Ann Surg. 2003;237(1):136-141.
15. Douek M, Smith G, Oshowo A, Stoker DL, Wellwood JM. Pro-
spective randomised controlled trial of laparoscopic versus open
inguinal hernia mesh repair: Five year follow up. Br Med J. 2003;
326(7397):1012-1013.
16. Colak T, Akca T, Kanik A, Aydin S. Randomized clinical trial com-
paring laparoscopic totally extraperitoneal approach with open
mesh repair in inguinal hernia. Surg Laparosc Endosc Percutan
Tech. 2003;13(3):191-195.
17. Bringman S, Ramel S, Heikkinen TJ, Englund T, Westman B,
Anderberg B. Tension-free inguinal hernia repair: TEP versus
mesh-plug versus Lichtenstein: A prospective randomized con-
trolled trial. Ann Surg. 2003;237(1):142-147.
18. Andersson B, Hallen M, Leveau P, Bergenfelz A, Westerdahl J.
Laparoscopic extraperitoneal inguinal hernia repair versus open
mesh repair: A prospective randomized controlled trial. Surgery.
2003;133(5):464-472.
19. Eklund AS, Montgomery AK, Rasmussen IC, Sandbue RP, Bergkvist
LA, Rudberg CR. Low recurrence rate after laparoscopic (TEP) and
open (Lichtenstein) inguinal hernia repair: A randomized, multi-
center trial with 5-year follow-up. Ann Surg. 2009;249(1):33-38.
20. Arvidsson D, Berndsen FH, Larsson LG, et al. Randomized clini-
cal trial comparing 5-year recurrence rate after laparoscopic ver-
sus Shouldice repair of primary inguinal hernia. Br J Surg. 2005;
92(9):1085-1091.
21. Neumayer L, Giobbie-Hurder A, Jonasson O, et al. Open mesh
versus laparoscopic mesh repair of inguinal hernia. N Engl J Med.
2004;350(18):1819-1827.
22. Beets GL, Dirksen CD, Go PM, Geisler FE, Baeten CG, Kootstra G.
Open or laparoscopic preperitoneal mesh repair for recurrent
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inguinal hernia? A randomized controlled trial. Surg Endosc.
1999;13(4):323-327.
23. Dedemadi G, Sgourakis G, Karaliotas C, Christofides T, Kourak-
lis G. Comparison of laparoscopic and open tension-free repair
of recurrent inguinal hernias: A prospective randomized study.
Surg Endosc. 2006;20(7):1099-1104.
24. Eklund A, Rudberg C, Leijonmarck CE, et al. Recurrent inguinal
hernia: randomized multicenter trial comparing laparoscopic
and Lichtenstein repair. Surg Endosc. 2007;21(4):634-640.
25. Koch A, Edwards A, Haapaniemi S, Nordin P, Kald A. Prospec-
tive evaluation of 6895 groin hernia repairs in women. Br J Surg.
2005;92(12):1553-1558.
26. Gallegos NC, Dawson J, Jarvis M, Hobsley M. Risk of strangula-
tion in groin hernias. Br J Surg. 1991;78(10):1171-1173.
27. Nilsson H, Stylianidis G, Haapamaki M, Nilsson E, Nordin P.
Mortality after groin hernia surgery. Ann Surg. 2007;245(4):
656-660.
28. Fitzgibbons RJ, Jr., Giobbie-Hurder A, Gibbs JO, et al. Watchful
waiting vs repair of inguinal hernia in minimally symptomatic
men: A randomized clinical trial. JAMA. 2006;295(3):285-292.
29. O’Dwyer PJ, Norrie J, Alani A, Walker A, Duff y F, Horgan P.
Observation or operation for patients with an asymptomatic
inguinal hernia: A randomized clinical trial. Ann Surg. 2006;
244(2):167-173.
30. Simons MP, Aufenacker T, Bay-Nielsen M, et al. European Hernia
Society guidelines on the treatment of inguinal hernia in adult
patients. Hernia. 2009;13(4):343-403.
31. Ramshaw BJ, Tucker JG, Mason EM, et al. A comparison of trans-
abdominal preperitoneal (TAPP) and total extraperitoneal app-
roach (TEPA) laparoscopic herniorrhaphies. Am Surg. 1995;61(3):
279-283.
32. Felix EL, Michas CA, Gonzalez MH, Jr. Laparoscopic hernio-
plasty. TAPP vs TEP. Surg Endosc. 1995;9(9):984-989.
33. Felix EL. A unified approach to recurrent laparoscopic hernia
repairs. Surg Endosc. 2001;15(9):969-971.
34. Kumar S, Nixon SJ, MacIntyre IM. Laparoscopic or Lichtenstein
repair for recurrent inguinal hernia: one unit’s experience. J Roy
Coll Surg Edinb. 1999;44(5):301-302.
35. Aasvang E. Chronic postoperative pain: The case of inguinal
herniorrhaphy. Br J Anaesth. 2005;95(1):69-76.
36. Nienhuijs S, Staal E, Strobbe L, Rosman C, Groenewoud H, Ble-
ichrodt R. Chronic pain after mesh repair of inguinal hernia: A
systematic review. Am J Surg. 2007;194(3):394-400.
37. Poobalan AS, Bruce J, Cairns W, et al. A review of chronic pain
after inguinal herniorrhaphy. Clin J Pain. 2003;19:48-54.
38. Poobalan AS, Bruce J, King PM, Chambers WA, Krukowski
ZH, Smith WC. Chronic pain and quality of life following open
inguinal hernia repair. Br J Surg. 2001;88(8):1122-1126.
39. Callesen T, Bech K, Kehlet H. Prospective study of chronic pain
after groin hernia repair. Br J Surg. 1999;86(12):1528-1531.
40. Eklund A, Montgomery A, Bergkvist L, Rudberg C. Chronic pain
5 years after randomized comparison of laparoscopic and Lich-
tenstein inguinal hernia repair. Br J Surg. 2010;97(4):600-608.
5/22/2012 5:45:00 PM
 Commentary on
Recurrent Inguinal Hernia
Thomas E. Knuth
Considering that 24% of all males and 2% of females will develop
an inguinal hernia in their lifetime1 and considering that 750,000
inguinal hernia repairs are performed each year in the United
States, even a low recurrence rate, if a second operation is needed,
represents a significant medical and economic concern. The authors
in this chapter take a critical look at the literature related to the
two best measures of a successful hernia repair—recurrence rates
and chronic postoperative pain—and offer some best-evidence-
based insight into one of the most commonly performed general
surgery procedures.
Unfortunately, despite a steady evolution in repair tech-
niques and hernia repair products,2 not much has changed since
the father of “modern inguinal hernia surgery,” Edoardo Bassini
(1844–1924), recognized these same issues over 150 years ago.
Even then, he understood that there was something intrinsically
wrong with the tissue of patients who required repeated hernia
repairs. We now understand that connective tissue disorders,3
malnutrition, steroid use, chronic renal failure, and smoking4
contribute to recurrences. We are getting closer to understand-
ing the DNA of “poor protoplasm.” Someday soon, we may have
the ability to regenerate a strong, healthy native tissue in an area
of injury or tissue breakdown and finally achieve the ideal hernia
repair. Meanwhile, there is still no agreement on the best way to
initially repair an inguinal hernia or to repair its recurrence after
repair. By addressing relevant questions and outlining the current
best-evidence-based data, this chapter is an essential reading for
every hernia surgeon.
The authors point out that the rate of recurrence follow-
ing primary repair of an inguinal hernia varies depending on
technique. It is anywhere from 1% to 17% and slightly higher in
females who have more concomitant femoral hernias. In compar-
ing tissue-based or tension repairs (Bassini, Shouldice, and McVay
repairs) to mesh or tension-free repairs (Lichtenstein repair), the
authors are clear: recurrence rates are lower with the use of mesh.
Th is fi nding has been generally accepted since the 1990s but
perhaps now the question can be put to rest. The continuing debate,
however, is which tension-free mesh technique is best. The Lich-
tenstein repair is the current gold standard against which others
are measured but the Plug and Patch repair popularized by
Rutkow5 and the Prolene Hernia System (PHS) repair popularized
by Gilbert6 deserve mention. Gilbert’s claim that his bilayer poly-
propylene mesh device (BPMD) reduces recurrence rates to one-
tenth that of other common repairs is significant. He claims that
523
PMPH_CH64.indd 523
the PHS has the practical advantage over other products, in that
it covers the entire myopectineal orifice and that the dual layers
above and below the abdominal wall with a connector traversing
the defect will not move. Because recurrence rates are known to be
so low with all of these mesh techniques, head-to-head random-
ized controlled trials of sufficient size may not be feasible. For the
time being, we may have to accept that any one of these techniques
is best in the personal experience of any given surgeon.
In comparing open mesh repairs to laparoscopic mesh repairs,
the authors find no significant difference in risk of recurrence. This
is surprising when considering the inherent benefit of preperito-
neal reinforcement versus extraperitoneal. Several common sense
explanations are offered to explain laparoscopic recurrences—
the mesh can fold during evacuation of insufflation, the mesh
may shrink or migrate, or there may be incomplete reduction of
a hernia sack. The authors point out that the overall laparoscopic
recurrence rate is significantly higher than that of open repairs
but, in the hands of surgeons who have performed more than 250
cases, recurrence rates approach those of open repairs. This of
course emphasizes errors in technique. The take-home message
may be alluded to in the brief mention of the Shouldice Clinic
experience. The fact that very low Shouldice recurrence rates have
not been duplicated elsewhere makes a point that has become the-
matic at the Harvard Business School as the concept of “Focused
Factory” whereby a best practice may be “the practice of perfect-
ing one, clearly defined process and pursuing it to the point or
excellence.”7
Next, the authors address a pattern of inguinal hernia recur-
rence and state that most are medial, at the pubic tubercle.
Three related conditions are undoubtedly responsible for these
recurrences. First is the insufficient underlap in a laparoscopic
repair or an overlap in a Lichtenstein repair—an error in tech-
nique. Second, as the mesh shrinks in the process of inflam-
mation and scar formation, it can pull away from its anchor—a
problem with product. Th ird is the inherent deficiency in tissue
that contributed to hernia formation in the first place—problem
with the patient. The fi nding that 10% of recurrent hernias are
femoral carries an important lesson although it would be helpful
to know how many of the 42% of femoral recurrences in women
and the 10% in men were actually missed concomitant hernias
or whether the fi rst repair somehow contributes to the develop-
ment of the femoral hernia. Nevertheless, the important lesson is
that the entire myopectineal orifice, including the femoral canal,
5/22/2012 5:45:00 PM
 524 ■ Surgery: Evidence-Based Practice
should be covered in the initial repair. The Lichtenstein, Plug and
Patch, and Bassini repairs cover only medial and lateral inguinal
triangles but laparoscopic and open PHS techniques cover the
femoral triangle as well.
The question always arises as to whether a coincidentally
found recurrent hernia needs to be fi xed. The authors point out
that one-quarter to one-third of these patients needed an operation
within 1–2 years and that only 1–2 per thousand cases developed a
potentially catastrophic event requiring emergency surgery. Given
the exceedingly small risk of incarceration, the authors conclude
that watchful waiting is acceptable for asymptomatic patients. On
a more practical level, active patients who frequently run, jump,
or lift heavy weights may need to be repaired sooner while it may
be prudent to watch very sedentary patients and those at high
surgical risk due to comorbidities. The take-home message is that
recurrences probably do need to be fi xed—but selectively.
Finally, the authors discuss chronic pain after inguinal her-
nia repair, typically defined as lasting longer than 3 months after
surgery. The authors quote a 10–12% incidence of chronic pain
after initial repair that rises fourfold after a recurrent repair.
While recurrences can be asymptomatic or relatively easily fi xed,
chronic pain can be debilitating and difficult to treat. Various fac-
tors including age, body habitus, preoperative pain, use of mesh,
and workman’s compensation have been examined to predict
who will develop postoperative pain but numerous scoring algo-
rithms have not been found to be reliable.8 Prevention remains
the key and this involves a meticulous technique to avoid inadver-
tent injury to the ilioinguinal, genitofemoral, and iliohypogastric
nerves in the open repair and the lateral femoral cutaneous nerve
in the laparoscopic repairs. Reports that some surgeons routinely
sacrifice the ilioinguinal nerve in open repairs and tuck the cut
ends in soft tissue away from the surgical field where it will not
become entrapped in scar tissue9 suggest that this is also the solu-
tion for a neuroma after inadvertent injury.10 This point may be
of particular importance in recurrent hernia surgery where dis-
section through distorted tissue planes increases the risk to small
nerves that are already trapped in scar tissue. Again, prevention is
PMPH_CH64.indd 524
the key and warrants consideration for approaching through the
undisturbed planes—anterior for a previous laparoscopic repair,
and laparoscopic for a previous open anterior repair.
In conclusion, the best evidence is that recurrent inguinal her-
nias should be repaired with the benefit of mesh. The question of
which technique to use for recurrent inguinal hernia repair remains
unanswered although the authors point out that the Lichtenstein
and Plug and Patch techniques are the most popular. The conven-
tional wisdom is that an approach through virgin, uninterrupted
planes is best for minimizing the risk of injury to cord structures
and nerves and thereby avoid chronic postoperative pain.
REFERENCES
1. Abramson JH, Golin J, Hopp C, et al. The epidemiology of ingui-
nal hernia. A survey in western Jerusalem. J Epidemiol Commu-
nity Health. 1991;27:300.
2. DeBord JR. The historical development of prosthetics in hernia
surgery. Surg Clin North Am. 1998;78(6):973-1006.
3. Uden A, Lindhagen T. Inguinal hernia in patients with congeni-
tal dislocation of the hip. A sign of general connective tissue dis-
order. Acta Orthop Scand. 1988;59:667.
4. Cannon DJ, Read RC. Metastatic emphysema: A mechanism for
acquiring inguinal herniation. Ann Surg. 1981;194:270.
5. Robbins AW, Rutkow IM. The mesh-plug hernioplasty. Surg Clin
North Am. 1993;73:501-512.
6. Gilbert AI, Young j, Graham MF, et al. Combined anterior and
posterior inguinal hernia repair: Intermediate recurrence rates
with three groups of surgeons. Hernia. 2004;8:203-207.
7. Shouldice Hernia Clinic website: www.shouldice.com
8. Dickinson KJ, Thomas M, Fawole AS, et al. Predicting chronic
post-operative pain following laparoscopic inguinal hernia
repair. Hernia. 2008;12:597-601.
9. Dittrick GW, Ridl K, Kuhn JA, et al. Routine ilioinguinal nerve
excision in inguinal hernia repairs. Ann Surg. 2004;188:736-740.
10. Ferzli GS, Edwards ED, Khoury GE. Chronic pain after inguinal
herniorrhaphy. J Am Coll Surg. 2007;205(2):333-341.
5/22/2012 5:45:00 PM

Epigastric and Umbilical Hernia
Rachel Beard and Steven D. Schwaitzberg
Umbilical hernias and epigastric hernias comprise 10% of all
primary hernias.1 Umbilical hernias develop at the site of the
umbilical ring, the fascial defect via which the umbilical vessels
pass. This defect is physiologic and the vast majority will close
spontaneously during childhood. A minority, however, remains
open and becomes symptomatic, requiring repair in childhood or
adulthood.2 Umbilical hernias can also be acquired in adulthood
when herniation occurs through an umbilical canal, defined by
the umbilical fascia posteriorly, the linea alba anteriorly, and the
medial edge of the two rectus sheaths on either side. Epigastric
hernias protrude through the midline of the linea alba, most com-
monly above the level of the umbilicus. Whether they are con-
genital or acquired remains a topic of controversy. They occur in
3–5% of the population and 20% of patients have multiple hernias.
They are usually repaired at the time of diagnosis because smaller
defects are likely to become incarcerated or strangulated with
preperitoneal fat, whereas larger defects tend to become unsightly
and symptomatic.1
Spigelian hernias are protrusions of fat or abdominal organs,
usually small bowel or colon, through a defect in the spigelian
aponeurosis, defined as the aponeurosis of the transverse abdomi-
nal muscle limited by the linea semilunaris laterally and the lateral
edge of the rectus muscle medially.3 It was first described by Josef.
T Klinkosh in 1764 and named after Adrian van der Spieghel.
Affected patients are primarily in the fift h and sixth decades of
life, and obesity, multiple pregnancies, COPD, chronic constipa-
tion, ascites, trauma, and prior surgeries are all significant risk
factors. They are rare, affecting less than 1% of the population4
and comprising only 1–2% of all hernia repairs. The majority
occur in 6 cm wide transverse zone above the interspinal plane,
known as the spigelian hernia belt.3 The weakness of this area is
secondary to the intersection of the fibers of the transverse and
internal oblique muscles, the transition below the arcuate line of
the anterolateral abdominal wall becoming anterior and only the
external oblique muscle fibers maintaining their firmness, and
the penetration of the epigastric artery through the transversalis
fasia at the lateral border of the rectus sheath muscle.4
525
PMPH_CH65.indd 525
CHAPTER 65
Lumbar hernias are a rare defect in the posterior abdominal
wall defined as a protrusion of the preperitoneal or intra-abdominal
contents that occur in the lumbar region, which is defined supe-
rior by the 12th rib, medically by the erector spinae muscle, inferi-
orly by the iliac crest, and laterally by the external oblique. These
hernias were first suggested by Barbette in 1672 and first described
in publication in 1731 by Garangeot. Lumbar hernias may be con-
genital, appearing initially during infancy, or acquired. Acquired
lumbar hernias are usually primary and associated with strenu-
ous physical activity. Predisposing factors to spontaneous lumbar
hernias include extremes of weight, older age, chronic coughing,
debilitating disease, muscle atrophy, and sepsis. All these factors
lead to a loss of fatty tissue that leads to a rupture of the neurovas-
cular orifices which penetrate the lumbodorsal fascia. The most
common location for spontaneous lumbar hernias is the supe-
rior lumbar triangle, dubbed the Grynfeltt–Lesshaft triangle by
Macready in 1890 after Grynfeltt described the superior spaced
in 1866. It is an inverted space defined by the base of the 12th rib,
the lower edge of the serratus posterior inferior muscle, posteri-
orly by the sacrospinal muscle, anteriorly by the internal oblique
muscle with a roof formed by the external oblique and latissmus
dorsi, and the floor formed by the transversalis fascia and aponeu-
rosis of the transversalis muscle. Another common location for
herniation is the Petit triangle, after Petit who described the infe-
rior space in 1783. It is smaller and bordered by the crest of the
iliac, laterally by the external oblique, medially by latissmus dorsi
and the lumbodorsal fascia which forms the floor. Secondary
acquired lumbar hernias can be caused by blunt injury, iliac crest
fractures, infection, or abscesses, all of which alter the integrity
of the lumbodorsal fascia. Previous surgery can also lead to inci-
sional acquired lumbar hernias, particularly after lumbotomy,
nephrectomy, abdominal aortic aneurysm surgery iliac bone
donation, and latissmus dorsi flaps.5 Traumatic acquired lumbar
hernias have also been described after seatbelt injuries after motor
vehicle crashes.6
Obturator hernias were first described by Amaud de Ronsil in
1724 with the first repair having been done by Obre in 1851.7 They
5/22/2012 5:45:41 PM
 526 ■ Surgery: Evidence-Based Practice
are rare pelvic hernias that account for less than 1% of all abdom-
inal hernias8 though high incidences, 1.6%, have been reported
in Asian populations.7 The obturator foramen lies between the
ischium and the pubis. It is defined by the superior pubic ramus as
the upper margin, the body and inferior pubic ramus as the infe-
rior margin, the ramus of the ischium as the lower margin, and
the anterior margin is the body of the ischium. Obturator hernias
protrude through the obturator canal through which the obtu-
rator vessels and nerve pass to reach the hip and the sac usually
contains small bowel, particularly ileum.7 The patient population
tends to be women greater than 70 years of age8 and slight build,
multiparity, cachexia, chronic lung disease and constipation and
kyphoscoliosis are all risk factors.7 Occurrences are more often on
the right than on the left and presenting symptoms include groin
pain radiating down the medial side of the thigh to the knee due
to compression of the obturator nerve (the Howship–Romberg
sign), small bowel obstruction and strangulation.8 Occasionally,
a palpable mass can be appreciated on rectal or vaginal exami-
nation.7 Diagnosis is often delayed and presentation is often of
acute or of recurrent obstruction, bowel incarceration or per-
foration, with high mortality rates from 12% to 70%.7 Unlike
most other hernias, CT is generally utilized for diagnosis of obtu-
rator hernias.9
1. What do we know about the natural history of umbilical her-
nias in adults and children?
All children possess a defect in the abdominal wall at the time
of birth through which the umbilical vessels pass. Closure of
the umbilical ring is spontaneous and affected by genetics, with
African Americans and African children having higher rates of
umbilical hernias, as well as patients with genetic disorders such
as Beckwith–Wiedemann and Downs syndrome. Closure rates are
variable and closure can become arrested, resulting in an umbili-
cal hernia which may become clinically significant. Incarceration
and symptoms such as pain or obstruction are clear indications
for repair. As children grow, umbilical hernias which remain open
are less likely to close, though studies from Nigeria have demon-
strated that closure does continue to occur until the age of 14.10
However, repair is generally undertaken for lesions greater than
1.5 cm in diameter after 2–3 years of age, defects greater than
1.0 cm which fail to decrease in size of 6–12 months, and defects
that persist after the age of 5.2 In adults, 10% of umbilical hernias,
as persistent from childhood and the other 90% are acquired,
represented an indirect herniation through an umbilical canal.
Factors that increase intra-abdominal pressure predispose adults
to umbilical hernias, such as obesity, multiple pregnancies, and
large abdominal tumors.1 Umbilical hernias are more likely to
occur in patients who are obese, as well as those with cirrhosis
and ascites, and early repair is often endorsed to prevent later
complications.11
Answer: The majority of umbilical hernias in children will
close spontaneously, yet those that fail to close by adolescence
are likely to remain open. In adults, the vast majority of umbili-
cal hernias are acquired rather than persistent from childhood.
2. Do umbilical and epigastric hernia repairs require mesh?
Although there are multiple options for open repair of umbilical
and epigastric hernias, there is a widespread agreement on the
PMPH_CH65.indd 526
need for tension-free repair, regardless of the technique used.
The simplest open technique utilizes simple interrupted sutures.
Another option is the Mayo technique which involves placing
two rows of sutures and overlapping the upper edge with the
lower edge by 2–3 cm. Another method, the Keel technique, is
a two-layered interrupted closure method in which the medial
1.5–2 cm of the rectus sheath is on either side.12 Mesh repair
techniques, which utilize either a flat mesh or a mesh plug, are
increasingly popular. Possible locations for mesh placement
include preapneurotic placement using an onlay technique, fi xa-
tion to the ring on the fascial layer, on the retromuscular prefasi-
cal space or on the preperitoneal space.13 There are many options
for the types of mesh to use. Unprotected synthetic lightweight
mesh is appropriate for open repairs with no exposure of mesh to
viscera. Tissue-separating mesh is appropriate for repairs with a
high risk of dehiscence and exposure of the viscera to prevent in-
growth into the mesh. Polypropylene prosthetic mesh is overall
the most commonly used.14 Biologic meshes are another option
which are becoming more widely used, particularly when con-
tact with bowel is unavoidable. Long-term data are still pending
but studies have demonstrated fewer bowel adhesions to repair
sites in comparison with polypropylene mesh (8% vs. 70%) with
similar strength.15 Reported recurrence rates after umbilical
hernia repair are variable and have been reported to exceed 40%
for repairs done without mesh. Studies have consistently shown
lower recurrence rates after mesh repair. One single center ret-
rospective study reported a recurrence rate at 6 years of 7.7% in
patients undergoing open suture repair and 3% in those who had
undergone mesh repair.16 Another randomized controlled trial
reported even more disparate recurrence rates of 1% for mesh
repairs and 11% for suture repairs at 5 years.17 Yet another series
showed a recurrence rate at 5 years of 14.7% after suture repair
and 3.1% after repair with mesh.18 A meta-analysis reported a
10-fold decreased recurrence rate in mesh repair patients com-
pared with suture repair patients with similar rates of compli-
cation.19 Disadvantages of the use of mesh include increased
cost and higher infection rates reported in some studies, which
can require reoperation for mesh removal. A single center study
specifically examined differences in infection rates between
mesh and suture repair and reported an overall infection rate
of 19% with higher rates of infection in the mesh group, though
they did fi nd lower recurrence rates with the mesh group (1.5%
vs. 9.2%).20 Other studies, however, have reported similar infec-
tion rates.17
Answer: Utilizing mesh in the repair of umbilical and epigastric
hernias clearly decreases recurrence rates, though increased infec-
tious risks and subsequent complications need to be considered.
3. Is there a role for laparoscopic repair of umbilical and epi-
gastric hernias?
Laparoscopic repair of ventral hernias has been described for
many years as a feasible and safe option. Initial studies described
it as an option for recurrent ventral hernias, including those with
failed open mesh repairs.21 Studies that followed demonstrated
low conversion rates (0–1.9%), low rates of recurrence (3–3.4%),
low rates of complication (13–14%) and quick recovery times,
and recommended it as a reasonable option for repair of primary
hernias.22,23 Subsequent studies specifically examined its role in the
repair of umbilical hernias and found similarly acceptable results,
5/22/2012 5:45:42 PM

particularly for larger umbilical hernias. Shorter hospital stays,
faster operative times, and lower recurrence rates were demon-
strated, particularly for those with previous repairs and hernias
larger than 3 cm.24 Subsequent prospective studies have consistently
demonstrated shorter hospital stays, less postoperative pain, fewer
wound complications, and no recurrence rates with laparoscopic
onlay patch hernioplasty for umbilical hernias compared with
open techniques including Mayo repair, suture herniorrhaphy,
and mesh hernioplasty.25 Open repair remains the technique of
choice, however, for smaller defects (<2 cm), as these can be per-
formed under local anesthetic, rather than the general anesthe-
sia required for laparoscopic repair.26 Retrospective reviews have
demonstrated shorter operative times and lower costs for open
repair of small defects as compared with laparoscopic repairs,
though prospective series comparing the techniques for umbilical
and epigastric hernia repairs have not yet been done.26
Answer: Laparoscopic repair of umbilical and epigastric her-
nias is an acceptable alternative to open repair and can be consid-
ered the procedure of choice for larger defects.
4. Is there an optimal method for repairing spigelian, lumbar,
and obturator hernias?
The most widespread repair of Spigelian hernias utilizes an open
anterior herniorraphy with approximation of the muscle and
mesh placement into the preperitoneal space.3 Th is approach
offers good results but can require wide dissection of the muscle
layers, general anesthesia, and postoperative admission. Recently,
a new technique has been described involving preperitoneal and
subfascial prosthetic repair using Prolene Hernia System (PHS)
mesh. In this repair, the bottom underlay portion of the PHS mesh
lies flat in the preperitoneal space, the connector portion obliter-
ates the hernia orifice, and the overlay covers the internal oblique
with four cardinal sutures placed to secure the connection por-
tion. Studies have shown a quicker recovery time and this repair
can more often be done with local, rather than general anesthesia.4
Laparoscopic repair has also been done using a transabdominal
approach with preperitoneal mesh placement 27 as well as utilizing
the scroll technique, wherein the mesh is rolled and attached to
the anterior abdominal wall prior to being unrolled. Laparoscopic
suture repair has also been reported as feasible and safe.28
There are multiple options for repair of lumbar hernias. The
anterior approach requires a major dissection but allows for a com-
plete parietal reconstruction. Laparoscopic approach has become
more popular for its obvious benefits of less pain and shorter
hospital stays. Benefits include improved visualization and exact
localization of the hernia lesion; however, laparoscopic repair does
not permit parietal reconstruction. A transabdominal approach
can also be used. One study reviewed the literature and recom-
mended an anterior approach or extraperitoneal laparoscopy on
small defects with extraperitoneal contents, a transabdominal
approach for moderate defects with paraperitoneal or intraperi-
toneal hernias, and an anterior repair with double mesh for cases
PMPH_CH65.indd 527
Epigastric and Umbilical Hernia ■ 527
of recurrences or diff use hernias larger than 15 cm.5 Small series
have reported open anterior repair with mesh to be easy and safe
with no recurrences, with a recovery to normal function in about
2 weeks for most patients.29 Laparoscopic repairs of acquired and
traumatic lumbar hernias have been reported in small series to be
safe and feasible with no recurrences and a faster return to nor-
mal function and the majority of these cases can be done on an
outpatient basis.30-32
Surgical repair of obturator hernias, particularly primary
repair, is difficult because the tissues around obturator hernias
are not easily mobilized.33 Because the presenting symptoms are
often bowel obstruction or incarceration, many repairs are done
on an urgent or on an emergent basis. Open repair has tradi-
tionally been done, most frequently with a lower midline lapa-
rotomy incision. Retropubic, obturator, and inguinal approaches
have also been described. After the hernia is reduced and bowel
viability is confirmed, the repair can either be performed pri-
marily34 or with mesh.7 There are many case reports of success-
ful laparoscopic repairs, both elective and emergent, of obturator
hernias, 35-37 but prospective and retrospective comparisons have
not been done.
Answer: Anterior repair with mesh is the most widely uti-
lized technique for spigelian hernias, though laparoscopic repair is
becoming more widespread. Anterior, transabdominal, and lap-
aroscopic repairs are all acceptable options for lumbar hernia
repairs, and the choice is most dependent on the size of the defect.
Open repair of obturator hernias is traditional but successful lap-
aroscopic repair has been reported, though large trials have not
yet been done.
5. Does umbilical or epigastric hernia repair require preopera-
tive antibiotics?
There is controversy over whether preoperative antibiotics are
useful for prevention of infection prior to repair of umbilical
and epigastric hernias. Some authors assert that hernias are
clean cases and should therefore not require preoperative antibi-
otic dosing. 38 One randomized control trial showed significantly
lower infection rates of both umbilical (11% vs. 40%) and inci-
sional (0% vs. 50%) hernia repairs after a one-time preopera-
tive dose of cefonicid. 39 There are ample studies which examine
preoperative antibiotic dosing for repair of inguinal hernias,
some of which demonstrate a decreased wound infection after
antibiotic dosing,40 whereas others fail to show a difference in
outcomes.41,42 More studies are needed, however, to determine
if preoperative antibiotics for umbilical and epigastric her-
nias are necessary, though postoperative antibiotics have been
shown to decrease the incidence of cellulitis in patients who
developed seromas after laparoscopic ventral hernia repair (40%
vs. 100%).43
Answer: Though more studies are needed, small series have
demonstrated decreased wound infections with preoperative anti-
biotics for umbilical and epigastric hernia repair.
5/22/2012 5:45:42 PM
 528 ■ Surgery: Evidence-Based Practice

Clinical Question Summary

Question
1 What do we know about
the natural history of
umbilical hernias in adults
and children?
2 Do umbilical and epigastric
hernia repairs require
mesh?
3 Is there a role for
laparoscopic repair of
umbilical and epigastric
hernias?
4 Is there an optimal method
for repairing spigelian,
lumbar, and obturator
hernias?
5 Does umbilical or
epigastric hernia repair
require preoperative
antibiotics?
Answer Grade of Level of References
Recommendation Evidence
The majority of umbilical hernias in children Grade C 2c, 4 1, 2, 10, 11
will close spontaneously, yet those that
fail to close by adolescence are likely to
remain open. In adults, the vast majority of
umbilical hernias are acquired rather than
persistent from childhood.
Utilizing mesh in the repair of umbilical Grade B 1b, 2b, 4 12-20
and epigastric hernias clearly decreases
recurrence rates, though increased
infectious risks and subsequent
complications need to be considered.
Laparoscopic repair of umbilical and epigastric Grade B 2b, 4 21-26
hernias is an acceptable alternative to open
repair and can be considered the procedure
of choice for larger defects.
Anterior repair with mesh is the most widely Grade C 4 2, 4, 27, 28
utilized technique for spigelian hernias,
though laparoscopic repair is becoming
more widespread.
Anterior, transabdominal, and laparoscopic Grade C 4 5, 29-32
repairs are all acceptable options for
lumbar hernia repairs, and the choice is
most dependent on the size of the defect.
Open repair of obturator hernias is traditional Grade C 4 7, 33-37
but successful laparoscopic repair has been
reported, though large trials have not yet
been done.
Though more studies are needed, small series Grade B 1b, 4 38-43
have demonstrated decreased wound
infections with preoperative antibiotics for
umbilical and epigastric hernia repair.

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5/22/2012 5:45:42 PM
 CHAPTER 66
Incisional and Ventral Hernias
Rachel Beard and Steven D. Schwaitzberg
INTRODUCTION
Incisional hernias occur through a scar from a prior surgery and
are a serious complication of abdominal wall surgery. Occurrence
rates have been reported in up to 11% of patients undergoing
abdominal wall surgery and up to 23% in those who develop post-
operative wound infections.1 Studies have been done to compare
the rate of herniation between different abdominal incisions. One
review of 11 studies found that midline incisions had the highest
rate of ventral hernias at 10.5%, followed by transverse incisions
at 7.5% and paramedian incisions at 2.5%.2 Another study, per-
formed in the prelaparoscopic era of the late 1970s, randomized
150 patients to undergo cholecystectomy either via a midline or via
a transverse incision, and demonstrated lower rates of incisional
hernias when utilizing a transverse incision, 2% versus 14%.3 Inci-
sional hernias are fraught with complications. Even hernias which
are initially small and asymptomatic can enlarge overtime and
lead to pain, bowel obstruction, and ultimately life threatening
complications such as incarceration or strangulation. Risk fac-
tors for developing incisional hernias include suture technique,
wound infection, increased abdominal wall tension from obesity
or pregnancy, and connective tissue disorders.4 Minimizing the
occurrence and recurrence of incisional hernias is not only in
the interest of the patients, but also in the interest of the health-
care system overall. There are numerous options available for
repair of such hernias, including open or laparoscopic techniques,
suture hernioplasty, mesh repair, and component separation. Each
technique has benefits and drawbacks, and familiarity with such
repairs is an essential knowledge for the general surgeon.
1. What are the available data on recurrence rates (>2 years)
for hernias repaired with biologic versus synthetic mesh?
Aside from very small incisional and ventral hernias, the major-
ity of ventral hernia repairs require the use of a mesh to prevent
recurrence. The recurrence rates after open suture repair have
been found to be unacceptably high, reported at 31–49%.1 Of
note, one recent paper advocated utilizing a two-layered suture
530
PMPH_CH66.indd 530
repair which consisted of closing the anterior and posterior rec-
tus sheaths separately along with the associated rectus muscles.
They reported a recurrence rate of 4.5%.5 Current practice sug-
gests that mesh repair decreases recurrence rates to 0–9%.1 There
are many different ways to perform a mesh repair, including pre-
fascial onlay, subfascial or preperitoneal sublay or inlay, in which
the fasica is not approximated but a mesh is used to bridge the
gap. There are various different types of synthetic mesh which can
be used. Type I mesh is a macroporous prosthesis consisting of
a monofilament or a double fi lament polypropylene. Type II is a
completely microporous prosthesis, such as expanded polytetra-
fluoroethylene (PTFE) whereas Type III is a macroporous prosthe-
sis with microporous prosthesis, such as PTFE mesh.4 Recurrence
rates with prosthetic mesh have been reported as high as 24% over
a 3 year period for primary hernia and 20% for a recurrent her-
nia.6 A number of studies have looked at the differences in the
recurrence based on the type of mesh used. One study from 2005
reported improved recurrence rates at 2 years (7% vs. 17%) when
using a standard polyester or a polypropylene mesh as opposed to
the lightweight composite mesh.7 Another study from 2002 com-
pared polypropylene mesh repair with skin autograft repair in
both simple and complex hernias, with complex hernias defined
as those larger than 10 cm in diameter or a re-recurrence. Both
methods utilized an onlay technique and results demonstrated
a recurrence rate of 8.6% for the mesh group and 12.3% for the
skin autograft group.8 A study published in 2003 prospectively
looked at patients undergoing open intraperitoneal underlay
repair with a bilayer prosthetic mesh and found no recurrences
at a median follow-up of 28 months.9 Another option is the use
of a biologic mesh. A recent study published in 2011 looked at a
group of 57 patients who underwent ventral hernia repair with
an underlay of XenMatrix biologic porcine mesh. Their overall
recurrence rate was 7.2% and all recurrences occurred within the
first 3 weeks, with no additional recurrences at 1 year.10 Another
study published in 2011 examined the differences between vari-
ous biologic meshes used in repair of ventral abdominal defects,
and demonstrated lower rates of infection (37.9%) but higher rates
of hernia recurrence (28.6%) when using human-derived mesh
5/22/2012 5:46:16 PM

as compared with porcine cross-linked meshes, which demon-
strated a 60% infection rate and 20% hernia recurrence rate. Por-
cine noncrosslinked meshes had the worst outcome with 29.4%
recurrence rates and 54.2% infection rates.11
Answer: Recurrence rates following mesh repair depend not
only on the type of mesh but also on the technique. Truly long-
term data do not exist comparing biologic and synthetic meshes,
but there is a likely trend toward higher recurrence rates with bio-
logic meshes (Grade C recommendation).
2. Are there any data available on “watchful waiting” for inci-
sional hernias?
Conventional teaching is that once an incisional hernia occurs, it
should be repaired as soon as possible to prevent complications
such as bowel obstruction, strangulation, or loss of abdominal
domain. Over time, the lateral abdominal muscles retract and
become fibrotic, thereby enlarging the hernia and increase the
complexity of future repairs, as well as the risk of recurrence after
repair. The only recommended delay in the repair of an incisional
hernia is to allow for weight loss in obese patients.12 In a review
of the literature, there are plentiful data on “watchful waiting”
and the natural history of other types of hernias. Several random-
ized clinical trials have been done studying “watchful waiting” of
patient with asymptomatic or minimally symptomatic inguinal
hernias. These studies have concluded that delaying repair has no
adverse effect on the eventual operation and no statistically sig-
nificant increased complications in the interim.13-15 A recent study
examined “watchful waiting” in the case of traumatic lumbar
hernia and reported good outcomes with two patients who were
managed with just an observation for several months.16 Watchful
waiting of abdominal wall hernias has been studied in the preg-
nant population and delay of repair until the postpartum period
has been shown to be a safe management strategy.17 However,
similar studies have not been done on patients with incisional or
with ventral hernias.
Answer: There are no data available to promote or reject
the “watchful waiting” concept for incisional hernias (Grade D
recommendation).
3. What is the recurrence rate for repairing hernias where the
rectus cannot be closed comparing component separation ver-
sus bridging the defect with mesh?
When an abdominal wall hernia is so large and there is such a
loss of domain that the fascia cannot be approximated, often the
mesh is used to close the gap.18 A recent study published in 2007
looked at a series of patients with incisional hernias at least 20 cm
in length that could not be closed primarily and randomized them
to either component separation repair or PTFE repair using the
mesh to bridge the fascial gap. They found similar recurrence rates,
56% versus 58%, between the component separation and the mesh
group, respectively, at 1 year, and recurrences occurred at a mean
of 7 months postoperatively.19 An earlier study in 2005, however,
compared two different methods of bridging a fascial gap. Patients
with large recurrent ventral hernias either underwent repair with
an onlay polypropylene mesh or double mesh intraperitoneal
repair in which a Vicryl and polypropylene mesh were sutured
together and placed intraperitoneally with the closure of the her-
nia sac over the mesh. They reported a recurrence rate of 27% in the
onlay group and 0% in the double mesh group at 1 year.20 A recent
retrospective review published in 2011 attempted component
PMPH_CH66.indd 531
Incisional and Ventral Hernias ■ 531
separation of 133 ventral hernia repair patients over 4 years with
placement of a mesh underlay when the fascia could not be closed.
They reported a recurrence rate of 16% in patients undergoing
component separation alone and 8% in those undergoing compo-
nent separation with the mesh bridging the fascial gap, with the
median recurrence occurring at 10.4 months.21 A small case series
published in 2010 described a novel method of repair of complex
incisional hernias in which a laparoscopic component separa-
tion was performed to facilitate a Rives–Stoppa repair with mesh
placement in the retromuscular position without skin flaps. They
reported no recurrences in short-term follow-up.22
Answer: Intraperitoneal mesh repair and combined com-
ponent separation and mesh repair yield the lower recurrence
rates when compared with component separation alone (Grade C
recommendation).
4. Are there available data comparing open hernia repairs to
laparoscopic repairs with respect to recurrence?
Laparoscopic repair has been demonstrated to be a safe and feasi-
ble option for incisional hernias, with recurrence rates reported at
0–9%.1 There are plentiful data comparing open and laparoscopic
repairs, particularly with respect to complications and recur-
rence rates. One meta-analysis of randomized controlled trials
in the literature demonstrated no difference in recurrence rates
between techniques, but a shorter mean hospital stay with lap-
aroscopic repair. This study also showed that laparoscopic repair
was associated with fewer wound infections and fewer hemor-
rhagic complications.23 Another prospective study demonstrated
similar findings, namely shorter postoperative stays, less pain,
fewer complications, and lower recurrence rates (2% vs. 10%) with
patients undergoing laparoscopic repair with the mesh for ventral
hernias as compared with open repair with the mesh.24 A mul-
ticenter cohort study published in 2010 concluded that underlay
mesh technique, regardless of whether or not it is performed open
or laparoscopically, leads to lower recurrence rates after several
years than suture repairs, inlay, or only mesh techniques.25 How-
ever, another randomized trial demonstrated higher recurrence
rates at 2 years with patients undergoing laparoscopic repairs for
ventral hernias as compared with open, 12.5% vs. 8.2%, though
laparoscopic repair was associated with fewer complications and
faster recovery.26 The majority of studies comparing recurrence
rates have a follow-up time of 2–3 years. One retrospective study
followed up 331 patients for 5 years and found similar recur-
rence rates between laparoscopic and open repairs. With respect
to surgical technique, the only patients in the study that demon-
strated higher recurrence rates were those who underwent lap-
aroscopic repairs that required conversion to open procedures.
Larger defects demonstrated higher recurrence rates, regardless
of the technique.27 The majority of studies published in the U.S.
seem to demonstrate few complications with laparoscopic repair,
though one study published in 2009 out of Denmark demon-
strated higher rates of major complications (4.8% versus. 2.8%)
and overall morbidity (11.8% vs. 10.1%) with laparoscopic repair
as compared with open.28
Answer: The literature demonstrates similar recurrence rates
with laparoscopic and open repair of incisional hernias. Laparo-
scopic repairs are associated with faster recovery times and lower
rates of wound infection, but some studies have demonstrated
higher rates of major complications and morbidity (Grade C
recommendation).
5/22/2012 5:46:17 PM
 532 ■ Surgery: Evidence-Based Practice

5. What influence does technique have on wound infection rates than those who underwent repair with an onlay technique
rate? with the same prosthetic mesh.29 In patients where the risk of sur-
gical site infection is thought to be high, biologic mesh may be
In addition to hernia recurrence, wound infection is one of the
used in place of synthetic mesh. These materials are more resistant
most important complications of hernia repair. Studies have dem-
to infection, and, should infection occur, remain intact without
onstrated certain comorbidities which independently increase the
requiring mesh removal.30,31 Some case-controlled studies have
rate of wound infection following hernia repair, including steroid
demonstrated higher rates of wound infection with open ventral
use, diabetes, obesity, advanced age, chronic obstructive pulmo-
hernia repair with mesh when compared with laparoscopic repair,
nary disease, coronary artery disease, and poor nutritional status.
22.1% versus 3.4% in one study. Open repairs were also associ-
In addition, long operative times and use of synthetic mesh have
ated with higher blood loss and were more likely to require drain
demonstrated higher wound infection rates. Importantly, infected
placement.32 In addition to overt wound infection, seromas also
fields involving synthetic mesh often require reoperation for mesh
occurred more often with open repair than with laparoscopic
removal, whereas those done with suture repairs can more often
repair, 23.3% versus 6.8%, and were associated with drain place-
resolve with conservative management. There is evidence that the
ment and more preoperative abdominal incisions.18
technique used when utilizing mesh techniques affects the rate
Answer: The risk of wound infection can be lessened by uti-
of occurrence of wound infections. One study from 2010 demon-
lizing a sublay technique for repairs utilizing mesh and laparo-
strated that patients who underwent incisional hernia repair with
scopic techniques when possible (Grade B recommendation).
a prosthetic mesh sublay technique had lower wound infection

Clinical Question Summary

Question
1 What are the available
data on recurrence rates
(>2 years) for hernias
repaired with biologic
versus synthetic mesh?
2 Are there any data
available on “watchful
waiting” for incisional
hernias?
3 What is the recurrence
rate for repairing hernias
where the rectus cannot
be closed comparing
component separation
versus bridging the
defect with mesh?
4 Are there available data
comparing open hernia
repairs to laparoscopic
repairs with respect to
recurrence?
5 What influence does
technique have on
wound infection rate?
Answer Grade of Level of References
Recommendation Evidence
Recurrence rates following mesh Grade C 1a, 1b, 2b, 2c, 3b, 4 1, 4-11
repair depend not only on
the type of mesh but also on
technique. Truly long-term data
do not exist comparing biologic
and synthetic meshes, but there
is a likely trend toward higher
recurrence rates with biologic
meshes.
There are no data available to Grade D 1b, 4, 5 12-17
promote or reject the “watchful
waiting” concept for incisional
hernias.
Intraperitoneal mesh repair Grade C 1b, 2b, 2c, 4 18-22
and combined component
separation and mesh repair
yield the lower recurrence
rates when compared with
component separation alone.
The literature demonstrates Grade C 1a, 1b, 2b, 2c, 3b, 4 1, 22-28
similar recurrence rates with
laparoscopic and open repair of
incisional hernias. Laparoscopic
repairs are associated with faster
recovery times and lower rates
of wound infection, but some
studies have demonstrated
higher rates of major
complication and morbidity.
The risk of wound infection Grade B 1a, 1b, 4 18, 29-32
can be lessened by utilizing a
sublay technique for repairs
utilizing mesh and laparoscopic
techniques when possible.

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REFERENCES
1. Cassar K, Munro A. Surgical treatment of incisional hernias. Br
J Surg. 2002;89:534-545.
2. Carlson MA, Ludwig K, Condon RE. Ventral hernia and other
complications of 1,000 midline incisions. Southern Med J. 1995;
88(4):450-453.
3. Halm JA, Lip H, Schmitz PI, Jeekel J. Incisional hernia after
upper abdominal surgery: A randomised controlled trial of mid-
line versus transverse incision. Hernia. 2009;13(3):275-280.
4. den Hartog D, Dur A, Tuinebreijer WE, Kreis RW. Open surgical
procedures for incisional hernias. Cochrane Database of Systemic
Reviews. 2011;16(3):CD006438.
5. Dur AH, den Hartog D, Tuinebreijer WE, Kreis RW, Lange JF. Low
recurrence rate of a two-layered closure repair for primary and
recurrent midline incisional hernia without mesh. Hernia. 2009;
13(4):421-426.
6. Luijendijk RW, Hop W, van den Tol MP, et al. A comparison of
suture repair with mesh repair for incisional hernia. N Engl J
Med. 2000;343(6):392-398.
7. Conze J, Kingsnorth A, Flament JB, et al. Randomized clini-
cal trial comparing lightweight composite mesh with polyester
or polypropylene mesh for incisional hernia repair. Br J Surg.
2005;92(12):1488-1493.
8. Korenkov M, Sauerland S, Arndt M, Bograd L, Neugebauer EA,
Troidl H. Randomized clinical trial of suture repair, polypropyl-
ene mesh or autodermal hernioplasty for incisional hernia. Br J
Surg. 2002;89(1):50-56.
9. Millikan KW, Baptista M, Amin B, Deziel DJ, Doolas A. Intraperi-
toneal underlay ventral hernia repair utilizing bilayer expanded
polytetrafluoroethylene and polypropylene mesh. Am Surg. 2003;
69(4):287-291.
10. Byrnes MC, Irwin E, Carlson D, et al. Repair of high-risk inci-
sional hernias and traumatic abdominal wall defects with por-
cine mesh. Am Surg. 2011;77(2):144-150.
11. Shah BC, Tiwari M, Goede MR, et al. Not all biologics are equal!
Hernia. 2011;15(2):165-171.
12. Voeller G. Ventral abdominal hernia. In: Fischer JE, ed. Mastery
of Surgery. Philadelphia, PA, Lippincott Williams and Williams;
2006:1947-1957.
13. Thompson JS, Gibbs J, Reda DJ, et al. Does delaying repair of an
asymptomatic hernia have a penalty? Am J Surg. 2008;195(1):89-93.
14. Fitzgibbons RJ, Jr, Giobbie-Hurder A, Gibbs JO, et al. Watchful
waiting vs repair of inguinal hernia in minimally symptomatic
men: A randomized clinical trial. JAMA. 2006;295(3):285-292.
15. Stroupe KT, Manheim L, Lou P, et al. Tension-free repair ver-
sus watchful waiting for men with asymptomatic or minimally
symptomatic inguinal hernias: A cost-effectiveness analysis. J
Am Coll Surg. 2006;203(4):458-468.
16. Bathla L, Davies E, Fitzgibbons RJ Jr., Cemaj S. Timing of trau-
matic lumbar hernia repair: is delayed repair safe? Report of two
cases and review of the literature. Hernia. 2011;15(2): 205-209.
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17. Buch KE, Tabrizian P, Divino CM. Management of hernias in
pregnancy. J Am Coll Surg. 2008;207(4):539-542.
18. Kaafarani HM, Hur K, Hirter A, et al. Seroma in ventral inci-
sional herniorrhaphy: Incidence, predictors and outcome. Am J
Surg. 2009;198(5):639-644.
19. de Vries Reilingh TS, van Goor J, Charbon JA, et al. Repair of
giant midline abdominal wall hernias: “Components separation
technique” versus prosthetic repair. World J Surg. 2007;31(4):
756-763.
20. Afifi R. A prospective study between two different techniques for
the repair of a large recurrent ventral hernia: A double mesh intra-
peritoneal repair versus onlay mesh repair. Hernia. 2005;9(4):
310-315.
21. Hadeed JG, Walsh M, Pappas TN, et al. Complex abdominal wall
hernias: A new classification system and approach to manage-
ment based on review of 133 consecutive patients. Ann Plast Surg.
2011;66(5):497-503.
22. Cox TC, Pearl J, Ritter EM. Rives-Stoppa incisional hernia repair
combined with laparoscopic separation of abdominal wall com-
ponents: A novel approach to complex abdominal wall closure.
Hernia. 2010;14(6):561-567.
23. Forbes SS, Eskicioglu C, McLeod RS, Okrainec A. Meta-analysis
of randomized controlled trials comparing open and laparoscopic
ventral and incisional hernia repair with mesh. Br J Surg. 2009;
96(8):851-858.
24. Lomanto D, Iyer S, Shabbir A, Cheah WK. Laparoscopic versus
open ventral hernia mesh repair: A prospective study. Surg
Endosc. 2006;20(7):1030-1035.
25. Hawn MT, Snyder C, Graham LA, Gray SH, Finan KR, Vick CC.
Long-term follow-up of technical outcomes for incisional hernia
repair. J Am Coll Surg. 2010;210(5):648-655.
26. Itani KM, Hur K, Kim LT, et al. Comparison of laparoscopic and
open repair with mesh for the treatment of ventral incisional
hernia: A randomized trial. Arch Surg. 2010;145(4):322-328.
27. Ballem N, Parikh R, Berber E, Siperstein A. Laparoscopic versus
open ventral hernia repairs: 5 year recurrence rates. Surg Endosc.
2008;22(9):1935-1940.
28. Bisgaard T, Kehlet H, Bay-Nielsen MB, et al. Nationwide study
of early outcomes after incisional hernia repair. Br J Surg. 2009;
96(12):1452-1457.
29. Venclauskas L, Maleckas A, Kiudelis M. One-year follow-up after
incisional hernia treatment: Results of a prospective randomized
study. Hernia. 2010;14(6):575-582.
30. Breuing K, Butler C, Ferzoco S, et al. Incisional ventral hernias:
review of the literature and recommendations regrading the
grading and technique of repair. Surgery. 2010;148(3):544-558.
31. Kim H, Bruen K, Vargo D. Acellular dermal matrix in the man-
agement of high-risk abdominal wall defects. Am J Surg. 2006;
192(6):705-709.
32. Kaafarani HM, Kaufman D, Reda D, Itani KM. Predictors of sur-
gical site infection in laparoscopic and open ventral incisional
herniorrhaphy. J Surg Res. 2010;163(2):229-234.
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 PART XI

ENDOCRINE GLANDS

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PMPH_CH67.indd 536 5/22/2012 5:46:47 PM

Adrenocortical Tumors and
Incidentalomas
INTRODUCTION
In a text of evidence-based surgical practice, summarizing data
and providing recommendations on the relatively uncommon,
diverse collection of diseases encompassing the topic of adrenocor-
tical tumors is challenging. The threat to evidence-based surgery
is the paucity of high-quality evidence to guide decision-making.
Although evidence from randomized controlled trials (RCTs)
provides surgeons with the most confidence in the effectiveness
of an intervention, several challenges limit the ability to perform
RCTs of surgical interventions.1 RCTs commonly include highly
selected patients treated in a highly controlled environment that
limits the applicability of these findings to a broader population.2
In situations where RCTs cannot be performed due to practical
considerations, surgeons must still make decisions and treatment
recommendations based on suboptimal evidence.
The optimal disease to study with an RCT is one which (1) is
common, to allow sufficient accrual in a reasonable amount of
time, (2) has a relatively homogeneous presentation, severity, and
prognosis, (3) has limited treatment options—ideally only two, and
(4) has a predictable, measurable outcome in a short interval. Adre-
nal tumors satisfy none of these requirements. They are uncom-
mon (except for benign incidentalomas), and may be characterized
as benign or malignant, primary or metastatic, functional or non-
functional, and cortical or medullary. Taken together, these per-
mutations represent 16 potential categories of diseases, each with
unique challenges and treatment considerations. Thus, manage-
ment of the patient with an adrenal tumor must be individualized,
incorporating the patient’s expectations, the surgeon’s experience,
and the best available evidence to guide decision-making.
The majority of adrenal tumors are asymptomatic and do
not require treatment, identified in 2.3% of patients at autopsy.3
Despite a consistent prevalence at autopsy over the past several
decades, the annual volume of adrenalectomies has nearly doubled
in the United States from 3241 in 1998 to 5323 in 2006.4 The vast
majority of this increase occurred in patients with benign diseases
of the adrenal, predominantly adenomas. More concerning, the
rate of major postoperative complications increased from 5.9% to
537
PMPH_CH67.indd 537
CHAPTER 67
Paul Karanicolas and Murray Brennan
8.1% during that time frame despite purported improvements in
surgical techniques such as the proliferation of laparoscopic sur-
gery. Given this apparent increase in the use of adrenalectomy for
benign disease and the increase in postoperative complications,
an evidence-based appraisal of the current approach to diagnosis
and management of adrenal tumors is warranted.
We attempt to identify the highest level of evidence available
for each seminal question using a systematic, comprehensive search
of the published literature. Very few RCTs have been performed
directly addressing the issues we consider to be most relevant to the
practicing surgeon managing patients with adrenocortical tumors.
When high-quality evidence is not available, we present the best
available evidence and our recommendations. Finally, we discuss
the opportunities for surgical research to contribute to the evi-
dence that is accumulating for the management of these patients.
EVALUATION OF ADRENAL
INCIDENTALOMAS
As cross-sectional imaging has become increasingly sophisticated
and more patients are investigated for a variety of abdominal
symptoms; incidentally detected adrenal tumors (adrenal inci-
dentalomas) have become a common diagnostic challenge. An
effective management strategy requires the surgeon to consider
four issues: (1) Is the tumor of cortical or medullary origin? (2) Is
the tumor benign or malignant? (3) Is the tumor primary or meta-
static? (4) Is the tumor functional or nonfunctional? If the physi-
cian is able to confidently reconcile these four considerations, a
clear pathway for management may be developed.
1. What are the indications for resection of an adrenal
incidentaloma?
The neglected question is whether the anticipated benefits of
resection outweigh the risks associated with operative interven-
tion. There are two primary indications for adrenalectomy: malig-
nant lesions (or sufficient concern that a tumor is malignant) and
functional tumors.
5/22/2012 5:46:47 PM
 538 ■ Surgery: Evidence-Based Practice
Several single-center series have attempted to identify factors
that can confidently discriminate benign from malignant tumors
of the adrenal, including patient characteristics, laboratory inves-
tigations, and radiographic features. Unfortunately, even with the
most comprehensive evaluation possible, the ability to identify
malignant tumors is poor. A major limitation in interpreting
studies of adrenocortical cancer is the variability in definitions
of malignancy between studies. Histopathology alone is a poor
discriminator of malignancy and the only definitive criteria for
malignancy are the distant metastasis or local invasion. Several
classification systems have been developed based on histopatho-
logic criteria found to be associated with tumors that had metas-
tasized or had locally recurred; the most utilized being the Weiss
system.5 In this classification system, nine criteria are assessed
including nuclear grade, mitotic rate, atypical mitoses, clear cells,
architecture, necrosis, and invasion of venous, sinusoidal, or capsular
structures. Irrespective of the histopathologic characteristics, the
only definitive evidence of malignancy remains the presence of
metastatic disease.
Clinically, patients who present with pain, weight loss, ane-
mia, fever, virilization, or feminization are more likely to have
malignancy.6,7 Patients with these symptoms should be offered
exploration if the adrenal tumor appears resectable on imaging
studies. (Grade C recommendation)
The most consistent radiologic characteristic identified that
correlates with the risk of malignancy is size. In one institutional
series of 51 adrenalectomies for nonfunctional incidentalomas,
adrenocortical carcinoma was identified in only three patients
(6%).8 In this cohort of patients, the size was the only significant
characteristic associated with malignancy. The three carcinomas
in this group measured 3.8, 6.1, and 8.1 cm, whereas the mean
size of the benign adenomas was 3.9 cm. However, malignancy in
these patients was defined by the histopathologic criteria and was
not confirmed by metastatic disease.
Another single-institution series included 342 patients with
incidentalomas of whom 55 underwent adrenalectomy.9 Four
patients were diagnosed with adrenocortical carcinoma based on
histopathology, with the smallest tumor measuring 5 cm. A mini-
mum of 1 year of follow-up was obtained in 88% of patients who
did not undergo operation, with no patients exhibiting signs of
clinical progression to suggest malignancy.
In a multicenter retrospective analysis, the Italian Society of
Endocrinology reported data collected from 26 referral centers
over a 15 year period.10 The study included 1004 patients with
adrenal incidentalomas, including 388 who underwent adrenalec-
tomy. The prevalence of adrenocortical carcinoma based on histo-
pathologic assessment was 12% (47 patients). Although the size of
the tumor was significantly associated with the risk of malignancy,
four adrenocortical tumors in this study measured less than 4 cm.
The authors concluded that a cutoff of 5 cm maximized the area
under the ROC curve; however, this strategy yields a sensitivity
of only 81% with a specificity of 63%. Sensitivity increased to 93%
with a 4 cm cutoff but specificity fell to 42%.
Due to the inability of size alone to accurately discriminate
between benign and malignant tumors, radiologists have exam-
ined other characteristics that may be helpful. The simplest of
these characteristics is the measurement of noncontrast CT atten-
uation (Hounsfield Units). In a series of 290 patients, the mean
value in adenomas or cases of adrenal hyperplasia was 16.2, signif-
icantly less than the mean values in adrenocortical cancers (36.9),
metastases (39.2), and pheochromocytomas (38.6).11 In this group
PMPH_CH67.indd 538
of patients, a management strategy of resecting tumors greater
than 4 cm or with Hounsfield Unit measurement greater than 20
would yield a sensitivity of 100% and a specificity of 42.1% for one
of these three conditions.
Smaller studies have measured the washout characteristics
of tumors at contrast-enhanced CT.12,13 These studies concluded
that the optimal threshold for the relative percentage washout is
40% to 50%, with all malignant lesions demonstrating less than
this and nearly all benign tumors demonstrating more than 50%
enhancement loss. These results have not been validated in larger
studies.
Due to the limited ability of CT scanning to differentiate
between benign and malignant adrenal tumors, other imaging
modalities have been explored. Consistent MRI features of adre-
nocortical carcinoma include internal hemorrhage, central necro-
sis, and peripheral enhancing nodules.14 In a study of 229 adrenal
masses in 204 patients, MRI achieved a sensitivity of 89%, a speci-
ficity of 99%, and an accuracy of 94% at distinguishing malig-
nancy based on the histopathologic criteria.15
In patients with indeterminate tumors after cross-sectional
imaging with CT and MRI, FDG-PET/CT scanning may assist
in better characterizing malignant potential. Among 37 patients
with no personal history of cancer, PET/CT achieved a sensitivity
of 100% and a specificity of 86% for malignancy.16 PET/CT may be
particularly helpful in patients who have a prior history of nonad-
renal malignancy. In a study of 80 adrenal tumors in patients with
prior cancers, PET was 93% sensitive and 96% specific for adrenal
metastases.17 Visual interpretation was as accurate as quantitative
analysis with SUV in both of these studies.
In summary, several single-center studies and one multi-
center study identify a strong association between size of adrenal
tumor and risk of malignancy. Additional imaging characteristics
on CT including noncontrast attenuation and contrast-enhanced
washout appear to provide additional, complementary informa-
tion. MRI and FDG-PET/CT may assist in better characterizing
indeterminate lesions. Tumors greater than 4 cm in size; with
Hounsfield Units greater than 20 or less than 40% to 50% wash-
out at contrast-enhanced CT; with internal hemorrhage, central
necrosis, or peripheral enhancing nodules on MRI; or with visual
adrenal uptake on PET/CT should be considered for resection.
(Grade C recommendation)
Independent of the risk of malignancy, patients with symp-
tomatic, functional adrenal tumors are typically offered resection.
In this group of patients, adrenalectomy offers the only curative
option and is appropriate. The role of adrenalectomy in patients
with asymptomatic, functional adrenocortical tumors is less clear.
One RCT compared surgical with conservative management in
patients with subclinical Cushing syndrome (a cortisol-producing
tumor).18 Patients were eligible for the study if they had an adrenal
incidentaloma, a positive dexamethasone suppression test, and no
clinical signs of hormonal excess. The trial randomized 23 patients
to laparoscopic adrenalectomy and 22 patients to observation, of
whom 3 patients crossed over to the surgical group due to their
adrenal masses increasing in size during follow-up. Urinary cor-
tisol and the dexamethasone suppression test normalized in all
patients who underwent adrenalectomy. Furthermore, patients
who underwent surgery experienced improvements in diabetes
(5 of 8 patients), hypertension (12 of 18 patients), hyperlipidemia
(3 of 8 patients), and obesity (3 of 6 patients). No patients in the
observation group experienced improvements in these comorbid-
ities, and several worsened.
5/22/2012 5:46:48 PM
 Adrenocortical Tumors and Incidentalomas ■ 539

In summary, patients with an adrenal incidentaloma and was a posterior adrenalectomy through the bed of the 11th or 12th
subclinical Cushing syndrome should consider adrenalectomy, rib. Over the past two decades, laparoscopy has emerged as the over-
particularly if they suffer from diabetes, hypertension, hyperlipi- whelmingly preferred approach, supported by several retrospective
demia, or obesity. (Grade B recommendation) single-center comparative studies.23-25 Taken together, these stud-
ies suggest that the laparoscopic approach yields longer operative
2. What is the most cost-effective approach to adrenal time, less blood loss, lower postoperative narcotic requirement,
incidentalomas? shorter postoperative hospital stay, and less overall morbidity than
open adrenalectomy. These findings were replicated in a popula-
Given the paucity of evidence to guide surgeons in the diagnostic
tion-based study from the National Surgical Quality Improvement
evaluation of patients with adrenal incidentalomas and the cur-
Program database.26 Therefore, laparoscopic adrenalectomy is the
rent economic climate, the costs of various approaches should be a
preferred approach for patients with small adrenocortical tumors
consideration to clinicians managing these patients. When several
felt to be benign. (Grade B recommendation)
management strategies appear to yield similar clinical outcomes,
In a small prospective RCT, Tiberio et al.27 compared laparo-
a reasonable approach is to select the strategy that is least costly.
scopic with open adrenalectomy for sporadic pheochromocytoma.
Unfortunately, a dearth of high-quality research exists to deter-
Although the number of patients was small (22 total), no signifi-
mine the relative costs of selected management strategies. Our
cant differences were seen in hemodynamic instability, operative
search for research examining the cost-effectiveness of treatment
time, or morbidity. The laparoscopic procedure yielded less blood
algorithms for adrenal incidentalomas yielded only three publica-
loss and a shorter length of hospitalization. Although patients
tions, all published in nonsurgical subspecialty journals.
with pheochromocytoma must be carefully monitored intraop-
The three decision analyses that we identified reached differ-
eratively for hemodynamic instability, laparoscopy appears to be
ent conclusions, depending on the management strategies com-
a safe operative approach. (Grade B recommendation)
pared, underlying assumptions, and healthcare systems. Kievit
During the development of laparoscopic adrenalectomy,
concluded that in the Dutch system, the most cost-effective strat-
surgeons were appropriately cautious applying these results
egy was to screen patients for medullary secreting tumors using
to patients with malignancies. Over time, some surgeons have
urinary metanephrines, with more extensive investigations such
expanded their indications for this operative approach to selected
as hormonal testing, imaging, and biopsy reserved for subgroups
patients with metastases to the adrenal or primary adrenocortical
of patients.19 In an analysis from Italy, MRI in conjunction with
carcinoma. Strong et al.28 reported their experience with 63 open
image-guided fine needle aspiration biopsy was felt to be most
adrenalectomies and 31 laparoscopic adrenalectomies for isolated
cost-effective in patients with adrenal incidentalomas greater than
metastases to the adrenal. In their series, the laparoscopic approach
2 cm.20 From the American perspective, Dwamena et al.21 con-
yielded shorter operative time, lower blood loss, shorter length of
cluded that a strategy involving one-time evaluation with 131I-6
hospital stay, and fewer total complications than the open approach
beta-iodomethylnorcholesterol (NP-59) scintigraphy yielded the
with no difference in margin status, local recurrence, or overall sur-
optimal combination of high diagnostic accuracy and low cost.
vival. In a multicenter study from Germany, Brix et al.29 compared
These markedly opposing conclusions highlight the limita-
laparoscopic with open resection in 152 patients with stage I–III
tions of cost-effectiveness analyses and the importance of care-
adrenocortical carcinoma less than 10 cm in maximal diameter.
fully defining the context of the decision-maker. Based on the
Laparoscopy was attempted in 35 patients, with 12 patients conver-
existing evidence, no recommendation can be made with respect
ted to an open approach. There was no difference in the recurrence-
to the most cost-effective approach to patients with adrenal inci-
free or in the disease-specific survival in these selected patients. In
dentalomas. However, it is important to emphasize that the 64%
summary, laparoscopic resection is an alternative to open adrena-
increase in the use of adrenalectomy, without proven evidence of
lectomy in selected patients with metastases to the adrenal or to the
function or malignancy, is costly and accompanied by unneces-
early adrenocortical carcinoma. (Grade C recommendation)
sary complications. Common sense dictates that clinicians should
Two approaches to laparoscopic adrenalectomy have been com-
only employ investigations likely to yield clinically useful infor-
pared in a RCT.30 Transperitoneal adrenalectomy yielded similar
mation and that the frequency of surveillance should be kept to
operative time, blood loss, analgesic requirements, hospital stay, and
a minimum. Further contemporary economic analyses of this
complication rate as retroperitoneal adrenalectomy. Transperitoneal
increasingly prevalent diagnostic challenge are needed.
and retroperitoneal laparoscopic adrenalectomy can be performed
With respect to the operative approach, one study compared
safely and effectively. (Grade B recommendation)
the cost of transperitoneal, lateral retroperitoneal, and posterior
laparoscopic adrenalectomy in the American system.22 The aver-
age costs ranged from $2850 to $3219 with no significant differ-
ence between the approaches. ADRENOCORTICAL CARCINOMA

4. What is the role of adjuvant therapy for completely resected

OPERATIVE APPROACH TO
ADRENAL TUMORS
3. What is the optimal operative approach to adrenal tumors?
Once a decision has been made to attempt resection of an adrenal
tumor, the surgeon must select one of several operative approaches
to the adrenal gland. For relatively small (less than 7–8 cm) adreno-
cortical tumors felt to be benign, the historically preferred approach
adrenocortical carcinoma?
Adrenocortical carcinoma is a rare tumor that most commonly
presents with advanced disease precluding complete resection.
For patients with localized disease, surgical resection offers the
only chance of cure, with median survival of 101 months for those
with early stage I or II disease.31 In contrast, patients with incom-
plete primary resection have a uniformly poor prognosis, with
median survival of 12 months.

PMPH_CH67.indd 539 5/22/2012 5:46:48 PM

 540 ■ Surgery: Evidence-Based Practice
Mitotane is an adrenocorticolytic drug that has efficacy in
patients with ACC. For patients with unresectable or incompletely
resected functional adrenocortical carcinoma, primary treatment
with mitotane is indicated. The main benefit in this setting is a
reduction in the excess hormone production and a reduction in the
symptoms of hypercortisolism in up to 75% of patients.32 Unfor-
tunately, the duration of efficacy is limited and survival does not
appear to be improved compared with untreated patients.33 For
the patient with a nonfunctional tumor, mitotane should be con-
sidered. However, many patients experience significant side effects
from higher doses of mitotane, requiring a balance between the
minimal uncertain benefit and the significant side effects.
The role of adjuvant mitotane in patients undergoing complete
resection of adrenocortical carcinoma is controversial, with no
RCTs to guide the clinicians. Several small series have been pub-
lished with conflicting results due to variability in patient charac-
teristics and dosing regimens in individual studies. The strongest
evidence in support of adjuvant mitotane is derived from a multi-
center retrospective analysis including 177 patients treated at 55
centers in Italy and Germany.34 The authors compared 47 patients
who received adjuvant mitotane in Italy for stage I–III carcinoma
with 55 Italian patients and 75 German patients who did not. The
groups were relatively well balanced with the exception of a higher
frequency of older patients with earlier stage disease in the Ger-
man group than in the other two groups. Treatment with adjuvant
mitotane was associated with prolonged recurrence-free survival
(median recurrence-free survival 42 months compared with 10 to
25 months in the control groups). Mitotane treatment was well tol-
erated with a temporary dose reduction needed in 13% of patients.
This study is limited by the inherent selection bias in a retrospec-
tive study, however, given the poor prognosis in patients with
adrenocortical carcinoma and the lack of other efficacious agents;
this study recommends adjuvant mitotane therapy to patients who
have undergone resection of adrenocortical carcinoma, regardless
of stage or completeness of resection. (Grade B recommendation)
Several investigators have explored the role of mitotane in
combination with other agents, but none have demonstrated con-
sistent improvements in outcomes.
The role of adjuvant radiation therapy in patients undergoing
complete resection of adrenocortical carcinoma is controversial.
Polat et al.35 reviewed 10 studies published between 1960 and 2008
including 64 patients. Rates of local control varied widely from
0% to 86% without clear indications or complete information on
the completeness of resection in these studies. Given the lack of
evidence, adjuvant radiation therapy is not recommended.
5. What is the optimal treatment of persistent or recurrent
adrenocortical carcinoma?
Recurrent or metastatic adrenocortical carcinoma is common
even for patients who undergo complete resection. Given the pau-
city of evidence to guide the management of primary disease, it is
not surprising that little data exist to support strategies for per-
sistent or for recurrent adrenocortical carcinoma. In the absence
of strong evidence, surgeons who manage patients with adreno-
cortical cancer will be faced with this dilemma and must make
treatment recommendations based on the limited data available.
Treatment modalities including surgery, radiation therapy, radiof-
requency ablation (RFA), and chemotherapy should be tailored
to the individual patient depending on the extent of disease and
goals of therapy.
PMPH_CH67.indd 540
The largest surgical series includes 47 patients who underwent
resection of locally recurrent or distant metastatic adrenocortical
carcinoma at Memorial Sloan-Kettering Cancer Center.31 As in
primary resection, the most important prognostic factor in these
patients was the ability to achieve a complete resection. Patients
who had a complete second resection had a median survival of
74 months, compared with 16 months in patients who underwent
an incomplete second resection. Similar results were observed in
a retrospective comparison of 18 patients treated with chemother-
apy and 15 patients treated with resection plus chemotherapy.36 In
addition to the possible survival benefit, resection provides excel-
lent palliation in patients with symptomatic steroid production
that cannot be controlled with medical therapy.
Other local therapies including external beam radiation and
RFA may have a role in patients with unresectable recurrent dis-
ease, particularly in those with local symptoms. In several small
studies, the administration of mitotane to previously untreated
patients with unresectable disease results in tumor response in up
to one-third of patients, but no improvement in survival has been
consistently reported.
In summary, patients with locally recurrent or metastatic dis-
ease should be offered reoperation if they have potentially com-
pletely resectable disease and are in otherwise good health. (Grade C
recommendation)
METASTASES TO THE ADRENAL
6. What is the optimal management of metastases to the
adrenal?
Adrenal metastases occur most commonly in patients with lung,
renal, breast, and gastrointestinal carcinoma. 37,38 Only 4% of
patients with adrenal metastases develop symptoms, usually due to
large tumors compressing adjacent structures.37 Most patients with
adrenal metastases present with multiple synchronous metastases
at other sites, and in approximately half of patients both adrenal
glands are involved.37 Local therapies have no role in asymptomatic
patients with extra-adrenal synchronous metastases; these patients
may be offered palliative systemic therapy based on the primary
site or supportive care.
When metastatic disease is limited to the adrenal gland,
local treatment may be associated with a survival advantage.
Several small retrospective studies have examined the role of
adrenalectomy in patients with isolated adrenal metastases, most
commonly from nonsmall cell lung cancer.37,39-41 In these highly
selected patients, adrenalectomy could be safely performed with
minimal morbidity and short length of hospital stay. Resection
was associated with an improved survival in these patients com-
pared with patients who underwent nonoperative management,
although patient selection was likely a primary determinant of
this difference. Overall 3-year survival in patients who under-
went adrenalectomy was approximately 30%, compared with no
long-term survivors in patients treated nonoperatively.28,37,39,41 In a
systematic review comparing adrenalectomy for isolated synchro-
nous (6 months or less disease-free interval) versus metachro-
nous (greater than 6 months) metastases from nonsmall cell lung
cancer, the median overall survival was shorter for patients with
synchronous metastasis (12 vs. 31 months, p = .02).42 However, a
durable long-term survival was achieved in approximately 25% of
patients in both groups. Therefore, adrenalectomy is appropriate in
5/22/2012 5:46:48 PM
 Adrenocortical Tumors and Incidentalomas ■ 541

highly selected patients with isolated adrenal metastasis. (Grade C
recommendation)
Several small case series have reported clinicians’ experiences
with less invasive percutaneous ablative techniques for adre-
nal metastasis, including RFA,43 microwave ablation,44 chemical
ablation,45 and RFA combined with arterial chemoembolization
(for hepatocellular carcinoma).46 Although these reports demon-
strate promising early local results, the data are far too limited to
generate meaningful conclusions. Until further evidence emerges,
percutaneous ablation of adrenal metastasis should be viewed as
experimental.
For patients with unresectable or widely metastatic symp-
tomatic adrenal metastasis, radiotherapy may improve pain. In
one study of 16 symptomatic patients treated with external beam
radiotherapy, the overall response rate was 75% and all patients
who responded experienced moderate to complete pain relief.47 In
eight of these patients, the pain relief persisted until death. External
beam radiation is an option for patients with unresectable or
widely metastatic symptomatic adrenal metastasis. (Grade C
recommendation)
SUMMARY
Management of patients with adrenocortical tumors provides
many challenges to surgeons due to the rarity and paucity of
evidence to guide decision-making. Treatment must be individ-
ualized, with patients fully aware of the uncertainty and explic-
itly involved in the decision-making. Further research is sorely
needed, particularly in the areas of cost-effectiveness and in the
assessment of new technologies including percutaneous abla-
tion. Until then, surgeons must rely on the combination of scant
evidence, clinical intuition, and biologic rationale to guide their
patients with adrenocortical tumors.

Clinical Question Summary

Question
1 What are the indications
for resection of an
adrenal incidentaloma?
2 What is the most cost-
effective approach to
adrenal incidentalomas?
3 What is the optimal
operative approach to
adrenal tumors?
Answer Levels of Grade of References
Evidence Recommendation
Patients who present with pain, weight loss, 4 C 6, 7
anemia, fever, virilization, or feminization
should be offered exploration if the
adrenal tumor appears resectable.
Tumors greater than 4 cm in size; with 3–4 C 8-17
Hounsfield Units greater than 20 or less
than 40% to 50% washout at contrast-
enhanced CT; with internal hemorrhage,
central necrosis, or peripheral enhancing
nodules on MRI; or with visual adrenal
uptake on PET/CT should be considered
for resection.
Patients with an adrenal incidentaloma and 2 B 18
subclinical Cushing syndrome should
consider adrenalectomy, particularly if
they suffer from diabetes, hypertension,
hyperlipidemia, or obesity.
No Level 1–3 evidences exist.
Laparoscopic adrenalectomy is the preferred 2 B 23-26
approach for patients with small
adrenocortical tumors felt to be benign.
Although patients with pheochromocytoma 3 B 27
must be carefully monitored
intraoperatively for hemodynamic
instability, laparoscopy appears to be a
safe operative approach.
Laparoscopic resection is an alternative to 4 C 28, 29
open adrenalectomy in selected patients
with metastases to the adrenal or small
suspected adrenocortical carcinoma.
Transperitoneal and retroperitoneal 2 B 30
laparoscopic adrenalectomy can be
performed safely and effectively.

(Continued)

PMPH_CH67.indd 541 5/22/2012 5:46:48 PM

 542 ■ Surgery: Evidence-Based Practice

(Continued)
Question Answer Levels of Grade of References
Evidence Recommendation
4 What is the role of Patients who have undergone resection of 2 B 34
adjuvant therapy for proven adrenocortical carcinoma should
completely resected be considered for adjuvant mitotane
adrenocortical therapy.
carcinoma?
5 What is the optimal Patients with locally recurrent or metastatic 4 C 31, 36
treatment of disease should be offered reoperation
persistent or recurrent if they have potentially completely
adrenocortical resectable disease and are in otherwise
carcinoma? good health.
6 What is the optimal Adrenalectomy should be offered to 4 C 28, 37, 39-42
management of selected patients with isolated adrenal
metastases to the metastasis.
adrenal? External beam radiation is an option for 4 C 47
patients with locally unresectable solitary
or multisite metastatic symptomatic
adrenal metastasis.

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5/22/2012 5:46:48 PM
 CHAPTER 68
Pheochromocytoma
Raymon H. Grogan and Quan-Yang Duh
INTRODUCTION
Pheochromocytomas are tumors that arise in neuroectodermal
chromaffin cells within the adrenal medulla that cause excess
catecholamine secretion. When these tumors develop in neu-
roectodermal cells outside the adrenal gland, they are known
as paragangliomas. Studies from the Swedish National Cancer
Registry and the Mayo Clinic are the most commonly quoted
studies on pheochromocytoma incidence. They show that pheo-
chromocytomas occur with an incidence of two to eight people
per million per year.1,2 Pheochromocytoma is considered to be a
rare disease in the United States according to the Office of Rare
Diseases Research at the National Institutes of Health. Studying
and making any evidence-based recommendations for pheochro-
mocytoma is difficult because it is such a rare disease.
New developments in genetic analysis, laboratory science,
imaging technology, and surgical techniques over the last 2
decades have significantly altered our approach to the diagnosis,
management, and treatment of these tumors. In 2001, it was dis-
covered that mutations of the succinate dehydrogenase subunit B
gene (SDHB) were associated with pheochromocytoma forma-
tion.3 This lead to a complete redefinition of our understand-
ing of the genetics of pheochromocytomas that is still ongoing.
Laboratory techniques have continually improved over the last 10
years and newer assays have been developed that are more sensi-
tive and specific than those that used to be considered the gold
standard. Similarly, imaging technology has evolved, particularly
in the ability to detect functional catecholamine-producing tis-
sues. Laparoscopic resection of adrenal tumors was first reported
in 1992, and since that time it has become the standard of care
for the majority of adrenal tumors.4 Laparoscopic adrenalectomy
represents a paradigm shift in the way adrenal tumors, and pheo-
chromocytomas, are treated because the postoperative recovery
time and pain are significantly shorter than with open surgery.
A quick PubMed search reveals over 11,500 studies that address
pheochromocytoma or paraganglioma. In comparison with that,
based on current population data, there are likely no more than
6800 new cases of pheochromocytoma worldwide per year. The
544
PMPH_CH68.indd 544
high ratio of studies to cases demonstrates how interesting the
physiology of these tumors is to physicians, and bodes well for
the future of evidence-based medical practice for this rare, but
fascinating disease.
GENETICS
1. What genetic mutations are associated with pheochromo-
cytoma development, and how often are pheochromocytomas
caused by inherited mutations?
Until recently, it has always been accepted that 10% of pheo-
chromocytomas are caused by a hereditary genetic mutation.
This presumption was based on multiple case series observa-
tions (Level 4 evidence) starting in the 1960s that found 10% of
pheochromocytomas were diagnosed in patients who had one of
three genetic syndromes: von-Hippel Lindau (VHL) caused by
mutations in the VHL gene, Multiple Endocrine Neoplasia Type
2 (MEN 2) caused by mutations in the RET gene, and neurofi-
bromatosis type 1 (NF1) caused by mutations in the NF1 gene.
This dogma was challenged in 2001 when a germline mutation
in the SDHB gene was found to be associated with pheochromo-
cytoma development in the absence of one of these three genetic
syndromes.3 Since 2001, at least seven more gene mutations
(SDHA, SDHAF1, SDHAF2, SDHC, SDHD, TMEM127, and KIF1-
BBeta) have been linked to pheochromocytoma formation in
patients with no obvious personal or family history of a genetic
syndrome other than pheochromocytoma formation.5,6 Debate
remains as to the exact prevalence of germline mutations associ-
ated with pheochromocytoma. Shortly after the discovery of the
association between SDHB mutations and pheochromocytoma, a
nonconsecutive cohort study (Level 3b evidence) of 271 patients
from a German cancer registry found that 24% of nonsyndromic,
apparently sporadic pheochromocytoma patients, had germline
mutations that were responsible for pheochromocytoma devel-
opment.7 Similar studies from other European cancer registries
have found varying results. Apparent sporadic pheochromocytomas
5/22/2012 5:47:22 PM

were found to have causative germline mutations with a fre-
quency of 7.5% in the Netherlands8 (Level 3b evidence), 10.8% in
Italy 9 (Level 1b evidence), 11.9% in France10 (Level 3b evidence),
and 14% in Spain11 (Level 3b evidence). All of these studies
attempted to exclude patients with a genetic syndrome or fam-
ily history of pheochromocytoma. The variation in mutation
frequency is likely caused by the ethnic and geographic popula-
tion differences in the studies as well as in the inclusion of some
patients with genetic syndromes that were clinically unrecogniz-
able at the time of initial presentation. Regardless of the variation
in the frequency of mutations found, all these studies support
the fi nding that the prevalence of germline, inheritable genetic
mutations that cause pheochromocytoma, is much higher than
the originally identified 10% prevalence. Combining the pheo-
chromocytomas caused by genetic syndrome mutations with
apparently sporadic pheochromocytomas caused by germline
mutations, the overall rate of inheritable genetic mutations in
pheochromocytoma patients ranges from 17.5% to 34%. Th is
does not take into account the more recently identified mutations
SDHA, SDHAF1, SDHAF2, TMEM127, and KIF1BBeta because
these mutation rates have yet to be studied.
Answer: Pheochromocytomas are caused by inherited genetic
mutations in the RET, VHL, NF1, SDHB, SDHC, or SDHD genes
between 17.5% and 34% of the time (Grade B recommendation).
However, the overall rate of inherited mutations in pheochromo-
cytoma patients is likely to be higher because the incidence and
prevalence of SDHA, SDHAF1, SDHAF2, TMEM127, and KIF1B-
Beta mutations are unknown.
DIAGNOSIS/IMAGING
2. What is the best laboratory test to diagnose pheochromo-
cytoma?
Excess catecholamine production is the hallmark of pheochro-
mocytomas, and is responsible for the morbidity and mortality
associated with these tumors. Catecholamines are amine com-
pounds that have a catechol group attached to them. The three
most common catecholamines in the human body are epineph-
rine, norepinephrine, and dopamine. The production and metab-
olism of catecholamines is a complex process that is not specific
to the adrenal medulla and this complexity and nonspecificity has
resulted in the development of multiple serum and urine tests for
both the parent catecholamines and their metabolites.
Production of catecholamines occurs in the sympathetic
nervous system neurons as well as in the adrenal medulla. Mea-
surement of plasma or urine catecholamines was one of the first
diagnostic tests for pheochromocytoma. However, both sympa-
thetic neurons and the adrenal medulla contribute to the circulat-
ing levels of these parent catecholamine compounds with only a
minor percentage of the normal levels being contributed by the
adrenal medulla. Excess catecholamine production by the adrenal
medulla increases the amount of circulating catecholamines dra-
matically and is what allows catecholamine secretion to be used as
a diagnostic tool. But the contribution of sympathetic neurons to
the circulating levels of catecholamines reduces the sensitivity and
specificity of this test for diagnosing pheochromocytoma. Once
this was understood, tests were developed to detect the down-
stream metabolites of the parent catecholamines. Catecholamine
metabolites that can be used to diagnose pheochromocytoma are
PMPH_CH68.indd 545
Pheochromocytoma ■ 545
vanillylmandelic acid (VMA), free plasma metanephrines, and
fractionated urine metanephrines.
Metabolism and conversion of the parent catecholamines into
downstream metabolites occur by deamination, O-methylation,
and/or sulfate conjugation. These processes occur in multiple loca-
tions including the sympathetic neurons, adrenal medulla, liver,
kidney, and/or the gastrointestinal tract. However, the majority of
catecholamine metabolism occurs within the tissue where the cat-
echolamines are produced, that is, the sympathetic neurons and
adrenal medulla.12 These two tissues metabolize catecholamines
via two distinct processes and that is what accounts for the dif-
ferences in sensitivity and specificity of the various tests that are
currently used to diagnose pheochromocytoma.
Sympathetic neurons deaminate the parent catecholamines to
an intermediate compound 3,4 dihydroxyphenolglycol (DHPG)
using the enzyme monoamine oxidase. Deamination by sym-
pathetic neurons accounts for the majority of DHPG found in
the circulation. The liver converts DHPG in the circulation into
other intermediate compounds and eventually into VMA. Thus,
the majority of VMA normally found in the circulation and in
the urine is a reflection of the sympathetic neuronal production
of catecholamines, rather than catecholamine production from
the adrenal medulla. Circulating catecholamines that have been
secreted by the adrenal medulla can also be converted to DHPG
and eventually VMA by the liver, and is the likely source of
elevated levels of VMA that are associated with pheochromocy-
tomas. Similar to the tests that measure parent catecholamines,
the sensitivity and specificity of VMA to diagnose pheochromo-
cytoma are decreased because VMA is a downstream metabolite
of catecholamines from both the sympathetic neurons and the
adrenal medulla.
The adrenal medulla metabolizes catecholamines by O-
methylation of the parent catecholamine compound, a process that
produces metanephrine (from epinephrine), normetanephrine
(from norepinephrine), and methoxytyramine (from dopamine).
The adrenal medulla contains high concentrations of membrane
bound catechol-O-methyltransferase, the enzyme required for
O-methylation of catecholamines. The adrenal medulla is respon-
sible for 94% of elevated levels of metanephrines in the circulation.
O-methylation of catecholamines in the adrenal medulla occurs
continuously and independently of fluctuations in catecholamine
release. This causes a steady state of elevated plasma metanephrines
even if catecholamine production fluctuates. Because the majority
of plasma free metanephrines are continuously produced by the
adrenal medulla, this makes plasma-free metanephrines a highly
sensitive and specific test for pheochromocytoma diagnosis.
Catecholamines and metanephrines are cleared from the cir-
culation by the kidney only after they undergo sulfate conjugation.
The sulfate conjugates remain in the circulation for an extended
period of time before the kidney excretes them. This build-up
makes them a poor serum test for the diagnosis of pheochromo-
cytoma because levels can be very high in the normal circulation.
However, they are excreted in urine at a constant rate that changes
as serum concentration increases, thus making metanephrine
sulfate conjugates an ideal urine test. In humans, sulfotransferase
isoenzyme is responsible for the majority of sulfate conjugation.
The highest concentrations of this enzyme are found in the human
small intestine. Thus, metanephrines are released by the adrenal
medulla into the circulation, undergo sulfate conjugation in the
small intestine, and are then excreted in the urine. Measurement
of urinary fractionated metanephrine sulfate conjugates (urinary
5/22/2012 5:47:23 PM
 546 ■ Surgery: Evidence-Based Practice
fractionated metanephrines) is also a highly sensitive and spe-
cific test for pheochromocytoma formation. The sulfate conjuga-
tion step by the small intestine might make it slightly less reliable
than plasma-free metanephrine measurements because of the tem-
porary changes in gut physiology and sulfate conjugation of
nonadrenal catecholamines. These biochemical pathways suggest
that levels of plasma-free metanephrines are the best diagnostic
choice for pheochromocytoma because the adrenal medulla con-
tains high levels of the enzyme catechol-O-methyltransferase and
thus produce metanephrines. In contrast, the sympathetic neu-
rons contain high levels of monoamine oxidase and almost no
catechol-O-methyltransferase and produce DHPG and VMA.
This theory is supported by clinical studies.
Multiple clinical studies on the sensitivity and specificity of
assays for VMA, catecholamines, plasma-free metanephrines,
and urinary fractionated metanephrines have been conducted,
and have repeatedly shown that plasma-free metanephrines have
the highest sensitivity and specificity of any currently available
single test. A high sensitivity, that is, a low false-negative rate, is
particularly important for any pheochromocytoma diagnostic
test because an undiagnosed pheochromocytoma can be a poten-
tially lethal problem. A rigorous meta-analysis of the literature in
2004 revealed 36 papers that specifically studied the sensitivity
and specificity of plasma-free metanephrines.13 In the final analy-
sis, heterogeneity in methods and statistical analysis excluded
all but three papers.14-16 The meta-analysis found the sensitivity
of plasma-free metanephrines to be 96% to 100% and the speci-
ficity to be 85% to 100% (Level 1a evidence). Plasma-free meta-
nephrine values within the normal range essentially rules out the
diagnosis of pheochromocytoma. This is important in pheochro-
mocytoma because with this test, any patient with normal plasma
metanephrine values can be safely diagnosed as not having a
pheochromocytoma. However, given the lower specificity, that is,
increased false-positive rate, a positive test does not necessarily
rule in the diagnosis of pheochromocytoma, meaning more test-
ing needs to be done if there is any clinical concern or suspicion
for misdiagnosis.
Urinary fractionated metanephrines are the second best
option with a slightly lower sensitivity of 88% to 97% and a slightly
lower specificity of 69% to 95% (Levels 1b and 2b evidence).14,17,18
Again with this test, the sensitivity is so high that a negative test
safely rules out the diagnosis of pheochromocytoma. Although
the literature indicates that serum-free metanephrines have
slightly better sensitivity and specificity compared with fraction-
ated urine metanephrines, there is little evidence in the literature
to support the use of one over the other. In the past, plasma and
urinary metanephrines were measured by high-pressure liquid
chromatography. Newer assays using liquid chromatography-
tandem mass spectrometry are now preferred because they elimi-
nate false-positive results caused by drug interference.19 Both
types of assays have been used in the literature making it diffi-
cult to determine whether plasma-free or urinary fractionated
metanephrines are superior. Direct comparison of the specificity
of plasma-free metanephrines to urinary fractionated metaneph-
rines combined with urinary catecholamines shows that the com-
bination of the two urinary tests has a specificity of 98% compared
with a specificity of 85% for plasma-free metanephrines (Level 1c
evidence).16 It is clear that either plasma or urinary metaneph-
rine tests are superior to plasma or urinary catecholamine tests
PMPH_CH68.indd 546
(sensitivity 84% and 86%, specificity 81% and 88%) or urinary
VMA (sensitivity 64%, specificity 95%) for the diagnosis of pheo-
chromocytoma (Level 1b evidence).14
Answer: Plasma-free metanephrines are the best choice for
diagnosing pheochromocytoma because of their high sensitivity.
(Grade A recommendation). If plasma-free metanephrines are not
available, urinary fractionated metanephrines can be used as an
alternative. (Grade B recommendation). If there is concern over
a possible false-positive plasma-free metanephrine result, then
urinary fractionated metanephrines combined with urinary cat-
echolamines can be considered due to the high specificity of the
combination of the two tests. (Grade B recommendation). Urinary
fractionated metanephrines are now widely available so plasma
or urinary catecholamines and urinary VMA should no longer
be used as the first-line diagnostic tests for pheochromocytoma.
(Grade A recommendation)
3. What is the best imaging study for pheochromocytoma?
There are many types of imaging technologies for pheochromocy-
toma. It is helpful to divide them into two categories, anatomical
and functional. Anatomical studies of pheochromocytoma include
computed tomography (CT) and magnetic resonance imaging
(MRI) and can be used for anatomic evaluation, localization, iden-
tification of metastasis, and preoperative resection planning. Func-
tional imaging techniques take advantage of the catecholamine
synthesis, storage, and secretion pathways of pheochromocytomas.
These techniques include [123/131I]metaiodobenzylguanidine
(MIBG) scintigraphy, 6-[18F]fluoro-L-3,4-dihydroxy-phenylalanine
(DOPA) positron emission tomography (PET), 6-[18F]fluorodop-
amine (FDA) PET, and 2-[18F]fluoro-2-deoxy-D-glucose (FDG)
PET and are superior to anatomical studies in identifying extra-
adrenal sites of metastasis.
Anatomical imaging studies are known to have high sen-
sitivity but low specificity for detecting pheochromocytomas.
Many studies have been done to determine the sensitivity and
specificity of both CT and MRI to detect pheochromocytomas.
Both are better at detecting primary intra-adrenal tumors
than they are at detecting extra-adrenal metastasis. Postop-
erative changes can also hinder their ability to detect recur-
rence in the adrenal bed. The sensitivity of CT for detecting
primary, intra-adrenal pheochromocytomas is between 95%
and 100%, and is decreased to 73% for extra-adrenal loca-
tions (Level 1b evidence).20-22 MRI sensitivity for detecting
primary intra-adrenal pheochromocytomas is similar to CT
and is 91% to 100%, and is decreased to 85% for extra-adrenal
locations (Level 1b evidence). 21,23-25 The specificity of CT and
MRI for detecting pheochromocytoma is poor because they
cannot distinguish functional from nonfunctional adrenal
tumors. The specificity for both CT and MRI to exclude intra-
adrenal primary tumors and extra-adrenal recurrence is 30%
to 50% (Level 1b evidence). 23,25-27 When evaluating pheochro-
mocytomas with CT, a triphasic scan should be used. A clas-
sic pheochromocytoma will show an adrenal nodule with
Hounsfield units of 40 to 50 on the noncontrast image with
an enhancement to over 100 Hounsfield units on the contrast
phase followed by <50% washout on the venous phase. For MRI,
both T1 and T2 weighted images with in- and out-of-phase
sequences and contrast enhancement should be used. A typical
5/22/2012 5:47:23 PM

pheochromocytoma on MRI will be bright on T2 with no signal
dropout on out-of-phase imaging. Many pheochromocytomas
will also show an intense contrast enhancement on MRI.
Functional imaging studies are much more specific than ana-
tomical imaging studies for pheochromocytoma. Their ability
to identify catecholamine-producing tissue makes them ideal at
distinguishing functional from nonfunctional masses. For many
years, MIBG has been the gold standard for functional imaging
of pheochromocytomas with I123 being preferred over I131 for its
higher sensitivity. A recent meta-analysis of 15 studies found a com-
bined specificity of 98% and a sensitivity of 96% in detecting primary
intra-adrenal pheochromocytomas (Level 1a evidence). There were
very little data on extra-adrenal metastasis in this study. A separate
meta-analysis showed that the sensitivity of 123I-MIBG decreases to
79% for metastatic pheochromocytoma (Level 1a evidence). Adre-
nal cortical cancer and infectious lesions can cause false-positive
results, and dedifferentiated malignant pheochromocytomas can
cause false-negative results. Even though MIBG is similar to CT and
MRI in sensitivity, and superior in specificity, it is generally not the
first-line imaging study preferred in patients with a clear biochemi-
cal diagnosis of pheochromocytoma. This is because CT and MRI
provide superior anatomic detail that is necessary for preoperative
planning (Level 5 evidence). Furthermore, in patients with a single
unilateral tumor on anatomic imaging, a clear biochemical diag-
nosis, and no clinical or family history suspicious for metastatic or
multifocal disease, the addition of MIBG to a CT or MRI does not
add any significant information (Level 2b evidence).28
Recent advances in PET technology have allowed for the
development of a number of promising functional studies that may
perform better than MIBG in certain situations. A recent validat-
ing prospective cohort study compared the diagnostic accuracy
of 18F-DOPA PET, 18F-FDG PET, 18F-FDA PET, and 123I-MIBG
in patients with both primary and metastatic pheochromocytoma
(Level 1b evidence).29 There was no statistically significant differ-
ence in sensitivity between any of the functional studies (77–88%)
for primary intra-adrenal lesions. For extra-adrenal metastatic
disease, 18F-FDA had the highest sensitivity (76%), followed by
18F-FDG (74%), 123I-MIBG (57%), and 18F-DOPA (45%). Even
though the sensitivities of 18F-FDA and 18F-FDG are similar,
the specificity of 18F-FDG for pheochromocytoma is much lower
because it is a marker of increased tissue glucose metabolism,
rather than a marker of catecholamine synthesis. The final results
of this study indicate that 18F-FDA is the best functional test for
diagnosing pheochromocytoma metastasis or recurrence (Level 1b
evidence).
Answer: The high sensitivity and anatomic detail of CT or
MRI make them the diagnostic imaging test of choice in biochemi-
cally proven pheochromocytoma in patients with no clinical his-
tory concerning for multifocal or for metastatic disease. (Grade A
recommendation). CT and MRI perform equally well for localizing
pheochromocytomas; however, MRI is preferred in pediatric, preg-
nant, and iodinated-contrast allergic patients. In patients with met-
astatic pheochromocytoma or in patients with genetic syndromes
associated with pheochromocytoma, 123I-MIBG is the functional
test of choice and should be added to the anatomic imaging as part
of the workup. (Grade B recommendation). 18F-FDA PET is a newer
modality that is not widely available at this time, but initial studies
show that 18F-FDA PET may be the functional imaging study of
choice if it is available. (Grade B recommendation)
PMPH_CH68.indd 547
Pheochromocytoma ■ 547
PROGNOSIS/MALIGNANT POTENTIAL
4. Does pheochromocytoma size predict malignant potential?
According to the World Health Organization definition, there is
no single structural or cellular finding that distinguishes malig-
nant from benign pheochromocytoma. The only criterion that
distinguishes malignant pheochromocytoma from benign pheo-
chromocytoma is distant metastasis.30 Even local invasion is not
considered a marker of malignancy in pheochromocytoma. There
are scant evidence-based data on the incidence, prevalence, diag-
nosis, and prognosis of malignant pheochromocytoma. There are
no randomized clinical trials or systematic reviews. Almost all the
data to date come from a collection of retrospective case series
that contain heterogeneous populations of tumor types with lack
of control data.
The malignancy rate of pheochromocytoma ranges between
3% and 36% depending on the genetic background of the tumor as
well as intra- versus extra-adrenal location (Level 4 evidence).31-33
The overall 5-year survival rate of patients with malignant pheo-
chromocytoma is reported to be between 34% and 60% (Level 4
evidence).31,33 Some case reports have also shown that malig-
nant pheochromocytoma may not metastasize for decades, with
the longest reported disease-free interval being 20 years (Level 4
evidence).34,35 The poor survival, difficulty in diagnosis, and the
need for long-term follow-up are all the factors that make it impor-
tant to develop a method of identifying the difference between
benign and malignant pheochromocytomas.
The general consensus has typically been that pheochromo-
cytomas greater than 5 cm in size are at an increased risk for
being malignant. Th is belief was based mostly on data from a
few different single institution case series of roughly 100 patients
each (Level 4 evidence).31,36-39 The majority of these studies were
descriptive in nature and many were focused more on the his-
topathology of malignant pheochromocytoma, rather than on
the size. These studies were further hindered by the inclusion
of intra- as well as extra-adrenal pheochromocytomas, were not
designed as cohort studies, and had no predictive value for sen-
sitivity or specificity.
To address this question more rigorously, investigators at the
University of California San Francisco designed a retrospective
exploratory cohort study of the Surveillance Epidemiology and
End Results database (Level 2b evidence).40 Their study confirmed
the belief that at the time of presentation, malignant pheochro-
mocytomas are larger than benign pheochromocytomas (7.6 vs.
5.3 cm). However, a subgroup analysis showed that there was no
difference in the size between benign and malignant pheochro-
mocytomas that presented initially without distant metastasis. An
analysis of sensitivity and specificity confirmed that pheochromo-
cytoma size could not reliably predict malignancy in the absence
of metastasis at the time of diagnosis.
Answer: Malignant pheochromocytomas are larger than
benign pheochromocytomas at initial presentation. However, the
size difference is not significant in pheochromocytomas that do
not have a distant metastasis at the time of initial presentation.
Size should not be used as a criterion for predicting the malignant
potential of a pheochromocytoma. (Grade C recommendation).
Distant metastasis at the time of presentation remains the only
preoperative criterion for predicting malignancy.
5/22/2012 5:47:23 PM
 548 ■ Surgery: Evidence-Based Practice

TREATMENT of pheochromocytomas made laparoscopic resection unsafe.

5. Is laparoscopic adrenalectomy the procedure of choice for
pheochromocytoma?
Surgical removal is the treatment of choice for pheochromo-
cytoma. Charles Mayo reported the first adrenalectomy in the
United States in 1927.41 Historical records indicate that the mor-
tality of pheochromocytoma resection from that time until the
1950s was as high as 26%.42 The morbidity and mortality of pheo-
chromocytoma resection are a result of uncontrolled surges of
catecholamines causing vasoconstriction, severe hypertension,
cardiovascular shock, and stroke. After the tumor is excised,
patients can experience hypotension and cardiovascular collapse
because of the sudden withdrawal of the excess catecholamines. In
the 1950s, investigators at the Mayo Clinic greatly decreased the
operative mortality of pheochromocytoma resection by introduc-
ing alpha-adrenergic blockade and volume expansion as a routine
part of preoperative preparation of these patients.43 This interven-
tion reduced the operative mortality of open pheochromocytoma
resection to between 0% and 6.7% and the postoperative stay to
approximately 1 week according to multiple case series (Level 4
evidence).44-46
In 1992, Michel Gagner reported the fi rst series of laparo-
scopic transperitoneal adrenalectomies.4 Laparoscopic adrena-
lectomy rapidly became the procedure of choice for the removal
of small, benign adrenal tumors such as aldosteronomas
and cortisol-secreting tumors. Surgeons also began to experi-
ment with laparoscopic techniques for pheochromocytoma
resection. In the beginning, there was a concern that pneu-
moperitoneum, increased operative times, and the larger size
However, by 1996, Gagner had accumulated a case series of 82
laparoscopic adrenalectomies that included 23 pheochromo-
cytoma patients (Level 4 evidence).47 Th is series showed that
in comparison with other adrenal tumors, pheochromocy-
tomas were larger, required longer operative times, had more
intraoperative hemodynamic instability, and were associated
with longer hospital stays. Th is series also showed that in com-
parison with open adrenalectomy, laparoscopic adrenalectomy
was just as safe, but had much shorter postoperative hospital-
izations and much less postoperative pain. A large number of
case series from around the world have since been accumu-
lated showing that laparoscopic adrenalectomy is as safe as
open adrenalectomy (Level 4 evidence). 34,40,48-51 The fi ndings in
these case series have been corroborated by a few prospective
and retrospective cohort studies; however, the small numbers
of patients in these studies mean that most are not sufficiently
powered to detect differences in the populations being studied
(Level 2b evidence). 52-55 There have been no systematic reviews
of the literature on laparoscopic versus open pheochromocy-
toma resection.
Answer: Laparoscopic adrenalectomy is considered superior
to open adrenalectomy for pheochromocytoma resection. (Grade C
recommendation). This is based on the data from multiple case
series and expert opinion that has been generated by these case
series. Because of the low prevalence of pheochromocytoma, most
cohort studies do not have the power to detect significant differ-
ences in outcomes. A high-quality systematic review of what is
already available in the literature needs to be done to improve our
understanding of the safety and efficacy of laparoscopic adrena-
lectomy for pheochromocytoma.

Clinical Question Summary

Question
1 What genetic mutations
are associated with
pheochromocytoma
development, and how often
are pheochromocytomas
caused by inherited mutations?
2 What is the best laboratory
test to diagnose
pheochromocytoma?
Answer Grade of References
Recommendation
Pheochromocytomas are caused by inherited B 3, 5-11
genetic mutations in the RET, VHL, NF1, SDHB,
SDHC or SDHD genes between 17.5% and 34%
of the time. However, the overall rate of inherited
mutations is likely to be higher because the
incidence and prevalence of SDHA, SDHAF1,
SDHAF2, TMEM127, and KIF1B Beta mutations
are unknown.
Plasma-free metanephrines are the best choice A and B 12-19
for diagnosing pheochromocytoma (Grade A).
Alternatively, if these are not available, urinary
fractionated metanephrines can be used
(Grade B). If a false-positive plasma free
metanephrine result seems possible, then urinary
fractionated metanephrines combined with urinary
catecholamines can be considered (Grade B).
Plasma or urinary catecholamines and urinary
VMA should no longer be used as first-line diagnostic
tests for pheochromocytoma (Grade A).

(Continued)

PMPH_CH68.indd 548 5/22/2012 5:47:23 PM

 Pheochromocytoma ■ 549

(Continued)
Question
3 What is the best imaging study
for pheochromocytoma?
4 Does pheochromocytoma size
predict malignant potential?
5 Is laparoscopic adrenalectomy
the procedure of choice for
pheochromocytoma?
Answer Grade of References
Recommendation
CT or MRI are the diagnostic imaging tests of choice in A and B 20-29
biochemically proven pheochromocytoma in patients
with no clinical history concerning multi-focal or
metastatic disease (Grade A). CT and MRI perform
equally well for localizing pheochromocytomas, but
MRI is preferred in pediatric, pregnant, and iodinated-
contrast allergic patients. In patients with metastatic
pheochromocytoma or in patients with genetic
syndromes associated with pheochromocytoma 123I-
MIBG is the functional test of choice and should be
added to the anatomic imaging as part of the workup
(Grade B). 18F-FDA PET is not widely available at this
time, but initial studies show that 18F-FDA PET may
be the functional imaging study of choice when it is
available (Grade B).
Malignant pheochromocytomas are larger than C 30-40
benign pheochromocytomas at initial presentation,
but the size difference is not significant in
pheochromocytomas lacking distant metastasis at
initial presentation. Size should not be used as a
criterion for predicting the malignant potential of a
pheochromocytoma (Grade C). Distant metastasis at
presentation remains the only preoperative criterion
for predicting malignancy.
Laparoscopic adrenalectomy is superior to open C 41-55
adrenalectomy for pheochromocytoma resection
(Grade C). Because of the low prevalence of
pheochromocytoma, most cohort studies cannot
detect significant differences in outcomes.

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2. Stenström G, Svärdsudd K. Pheochromocytoma in Sweden 1958-
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3. Astuti D, Latif F, Dallol A, et al. Gene mutations in the succinate
dehydrogenase subunit SDHB cause susceptibility to familial
pheochromocytoma and to familial paraganglioma. Am J Hum
Genet. 2001;69:49-54.
4. Gagner M, Lacroix A, Bolté E. Laparoscopic adrenalectomy in
Cushing’s syndrome and pheochromocytoma. N Engl J Med. 1992;
327:1033.
5. Hensen EF, Bayley JP. Recent advances in the genetics of SDH-
related paraganglioma and pheochromocytoma. Fam Cancer.
2010;10:355-363.
6. Schlisio S, Kenchappa RS, Vredeveld LC, et al. The kinesin KIF1B-
beta acts downstream from EglN3 to induce apoptosis and is a
potential 1p36 tumor suppressor. Genes Dev. 2008;22:884-893.
7. Neumann HP, Bausch B, McWhinney SR, et al. Germ-line muta-
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2002;346:1459-1466.
analyses of apparently sporadic pheochromocytomas: The Rot-
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9. Mannelli M, Castellano M, et al. Clinically guided genetic screen-
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crinol Metab. 2009;94:1541-1547.
10. Gimenez-Roqueplo AP, Favier J, Rustin P, et al. Mutations in the
SDHB gene are associated with extra-adrenal and/or malignant
phaeochromocytomas. Cancer Res. 2003;63:5615-5621.
11. Cascon A, Ruiz-Llorente S, Fraga MF, et al. Genetic and epi-
genetic profi le of sporadic pheochromocytomas. J Med Genet.
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12. Eisenhofer G, Goldstein D, Kopin I, Richard Crout J. Pheochro-
mocytoma: Rediscovery as a catecholamine-metabolizing tumor.
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13. Sawka AM, Prebtani AP, Thabane L, Gafni A, Levine M, Young WF.
A systematic review of the literature examining the diagnostic
efficacy of measurement of fractionated plasma-free metaneph-
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14. Lenders JW, Pacak K, Walther MM, et al. Biochemical diagno-
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15. Raber W, Raffesberg W, Bischof M, et al. Diagnostic efficacy of
unconjugated plasma metanephrines for the detection of pheo-
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17. Hickman PE, Leong M, Chang J, Wilson SR, McWhinney B.
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gation of phaeochromocytoma. Pathology. 2009;41:173-177.
18. Gardet V, Gatta B, Simonnet G, et al. Lessons from an unpleasant
surprise: A biochemical strategy for the diagnosis of pheochro-
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19. Taylor RL, Singh RJ. Validation of liquid chromatography-
tandem mass spectrometry method for analysis of urinary
conjugated metanephrine and normetanephrine for screening
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20. Quint LE, Glazer GM, Francis IR, Shapiro B, Chenevert TL.
Pheochromocytoma and paraganglioma: Comparison of MR
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21. Neumann HP, Berger DP, Sigmund G, et al. Pheochromocy-
tomas, multiple endocrine neoplasia type 2, and von Hippel-
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22. Lumachi F, Tregnaghi A, Zucchetta P, et al. Sensitivity and posi-
tive predictive value of CT, MRI and 123I-MIBG scintigraphy in
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23. Maurea S, Cuocolo A, Reynolds JC, Neumann RD, Salvatore M.
Diagnostic imaging in patients with paragangliomas. Computed
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24. Varghese JC, Hahn PF, Papanicolaou N, Mayo-Smith WW,
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relaxation times. Clin Radiol. 1997;52:603-606.
25. Timmers HJ, Eisenhofer G, Carrasquillo JA, et al. Use of 6-[18F]-
fluorodopamine positron emission tomography (PET) as
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26. Peplinski GR, Norton JA. The predictive value of diagnostic tests
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27. Maurea S, Cuocolo A, Reynolds JC, et al. Iodine-131-metaiodo-
benzylguanidine scintigraphy in preoperative and postoperative
evaluation of paragangliomas: Comparison with CT and MRI.
J Nucl Med. 1993;34:173-179.
28. Miskulin J, Shulkin BL, Doherty GM, Sisson JC, Burney RE,
Gauger PG. Is preoperative iodine 123 meta-iodobenzylguanidine
scintigraphy routinely necessary before initial adrenalectomy
for pheochromocytoma? Surgery. 2003;134:918-922.
29. Timmers HJ, Chen CC, Carrasquillo JA, et al. Comparison of 18F-
fluoro-L-DOPA, 18F-fluoro-deoxyglucose, and 18F-fluorodopamine
PET and 123I-MIBG scintigraphy in the localization of pheochro-
mocytoma and paraganglioma. J Clin Endocrinol Metab. 2009;94:
4757-4767.
30. DeLellis RA. Pathology and genetics of tumours of endocrine
organs. World Health Organization; 2004.
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31. John H, Ziegler WH, Hauri D, Jaeger P. Pheochromocytomas: Can
malignant potential be predicted? Urology. 1999;53:679-683.
32. O’Riordain DS, Young WF, Grant CS, Carney JA, van Heerden JA.
Clinical spectrum and outcome of functional extraadrenal
paraganglioma. World J Surg. 1996;20:916-921; discussion 922.
33. Mundschenk J, Lehnert H. Malignant pheochromocytoma. Exp
Clin Endocrinol Diabetes. 1998;106:373-376.
34. Tanaka S, Ito T, Tomoda J, Higashi T, Yamada G, Tsuji T. Malig-
nant pheochromocytoma with hepatic metastasis diagnosed 20
years after resection of the primary adrenal lesion. Intern Med.
1993;32:789-794.
35. Shen WT, Grogan R, Vriens M, Clark OH, Duh QY. One hun-
dred two patients with pheochromocytoma treated at a single
institution since the introduction of laparoscopic adrenalec-
tomy. Arch Surg. 2010;145:893-897.
36. Linnoila RI, Keiser HR, Steinberg SM, Lack EE. Histopathology
of benign versus malignant sympathoadrenal paragangliomas:
Clinicopathologic study of 120 cases including unusual histo-
logic features. Hum Pathol. 1990;21:1168-1180.
37. Thompson LD. Pheochromocytoma of the Adrenal gland Scaled
Score (PASS) to separate benign from malignant neoplasms: A
clinicopathologic and immunophenotypic study of 100 cases.
Am J Surg Pathol. 2002;26:551-566.
38. Strong VE, Kennedy T, Al-Ahmadie H, et al. Prognostic indi-
cators of malignancy in adrenal pheochromocytomas: Clinical,
histopathologic, and cell cycle/apoptosis gene expression anal-
ysis. Surgery. 2008;143:759-768.
39. Kimura N, Watanabe T, Noshiro T, Shizawa S, Miura Y. Histolog-
ical grading of adrenal and extra-adrenal pheochromocytomas
and relationship to prognosis: A clinicopathological analysis of
116 adrenal pheochromocytomas and 30 extra-adrenal sympa-
thetic paragangliomas including 38 malignant tumors. Endocr
Pathol. 2005;16:23-32.
40. Shen WT, Sturgeon C, Clark OH, Duh QY, Kebebew E. Should
pheochromocytoma size influence surgical approach? A com-
parison of 90 malignant and 60 benign pheochromocytomas.
Surgery. 2004;136:1129-1137.
41. Mayo CM. Paroxysmal Hypertension With Tumor of Retroperi-
toneal Nerve. JAMA. 1927;89:1047.
42. Welbourn RB. The adrenal glands. The History of Endocrine Sur-
gery. New York: Praeger; 1990:147-215.
43. Kvale WF, Manger WM, Priestley JT, Roth GM. Pheochromocy-
toma. Circulation. 1956;14:622-630.
44. Orchard T, Grant CS, van Heerden JA, Weaver A. Pheochro-
mocytoma—continuing evolution of surgical therapy. Surgery.
1993;114:1153-1158; discussion 1158-1159.
45. Pruszczyk P, Januszewicz W, Feltynowski T, et al. Long term follow-
up after surgical removal of pheochromocytoma—observations
in 61 patients. Clin Exp Hypertens A. 1991;13:1179-1194.
46. Plouin PF, Duclos JM, Soppelsa F, Boublil G, Chatellier G. Factors
associated with perioperative morbidity and mortality in patients
with pheochromocytoma: Analysis of 165 operations at a single
center. J Clin Endocrinol Metab. 2001;86:1480-1486.
47. Gagner M, Breton G, Pharand D, Pomp A. Is laparoscopic
adrenalectomy indicated for pheochromocytomas? Surgery.
1996;120:1076-1079; discussion 1079-1080.
48. Li QY, Li F. Laparoscopic adrenalectomy in pheochromocytoma:
Retroperitoneal approach versus transperitoneal approach. J
Endourol. 2010;24:1441-1445.
49. Perry KA, El Youssef R, Pham TH, Sheppard BC. Laparo-
scopic adrenalectomy for large unilateral pheochromocytoma:
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Experience in a large academic medical center. Surg Endosc.
2010;24:1462-1467.
50. Smith CD, Weber CJ, Amerson JR. Laparoscopic adrenalectomy:
New gold standard. World J Surg. 1999;23:389-396.
51. Cheah WK, Clark OH, Horn JK, Siperstein AE, Duh QY. Lap-
aroscopic adrenalectomy for pheochromocytoma. World J Surg.
2002;26:1048-1051.
52. Kim HH, Kim GH, Sung GT. Laparoscopic adrenalectomy for
pheochromocytoma: Comparison with conventional open
adrenalectomy. J Endourol. 2004;18:251-255.
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53. Mellon MJ, Sundaram CP. Laparoscopic adrenalectomy for pheo-
chromocytoma versus other surgical indications. J Soc Lap Surg.
2008;12:380-384.
54. Inabnet WB, Pitre J, Bernard D, Chapuis Y. Comparison
of the hemodynamic parameters of open and laparoscopic
adrenalectomy for pheochromocytoma. World J Surg. 2000;24:
574-578.
55. Tiberio G, Baiocchi G, Arru L, et al. Prospective randomized
comparison of laparoscopic versus open adrenalectomy for
sporadic pheochromocytoma. Surg Endosc. 2008;22:1435-1439.
5/22/2012 5:47:23 PM
 CHAPTER 69
Thyroid Nodules
Gerard M. Doherty
INTRODUCTION
The risk of malignancy drives the evaluation of a solitary thyroid
nodule; however, selective management is important due to the
preponderance of benign lesions. Between 4% and 7% of the adult
population in the United States have a palpable thyroid nodule,
the vast majority of these patients have benign disease, and do
not require surgical resection. The nodule must be evaluated in
its context, in light of the status of the remainder of the thyroid
gland, and the patient’s overall health and risk factors. The accu-
racy of various diagnostic techniques must be considered in light
of the risk the lesion, to synthesize an overall plan for the patient.
The management of thyroid nodules has been thoroughly
evaluated based on available evidence by the both the American
Thyroid Association and the National Comprehensive Cancer
Network.1,2 In addition, a National Cancer Institute State of the
Science Conference in October 2007 evaluated the available evi-
dence focused specifically on thyroid cytology for diagnostic
evaluation of nodules.3 This chapter summarizes some of the
information available in those more detailed documents.
1. How are thyroid nodules identified?
Thyroid nodules are identified by local symptoms, visible asym-
metry, self-palpation, physical examination, or incidental finding
on unrelated imaging.
The majority of nodules are small (<15 mm) and so do not
typically cause local symptoms nor are they noticed by patients.
However, if they are in a position that is relatively superficial,
then they may be palpated on screening physical examination.
Predominantly, recent increases in the number of imaging tests
performed for unrelated issues in the neck and chest especially,
have led to a large number of incidentally discovered thyroid nod-
ules, and by extension, an increase in the number of small thyroid
cancers discovered.4 Some common imaging scenarios include
carotid duplex examination and magnetic resonance (MR) exam-
inations of the cervical spine, on which previously unsuspected
thyroid nodules can be noted.
552
PMPH_CH69.indd 552
One special circumstance is the discovery of hypermetabolic
nodules in the thyroid on fluorodeoxyglucose-positron emission
tomography (FDG-PET) scan done in patients with an unrelated
cancer. In these patients, the standardized uptake values (SUV)
can be helpful in guiding the evaluation. In general, the higher
the SUV, the more likely the lesion is to be malignant. In general,
however, the nodule is evaluated along the usual algorithm of his-
tory, examination, ultrasound characterization and fi ne needle
aspiration (FNA), to determine the best course of action.1
2. What is the appropriate clinical evaluation for thyroid
nodules?
Evaluation of a nodule in the thyroid gland should begin with a
comprehensive history and physical examination (Figure 69.1).
It is not usually possible to distinguish a benign nodule from a
malignant nodule by palpation; however, there are some clini-
cal findings that are indicative of malignant disease. A history
of a hard and relatively fast-growing nodule is associated with a
higher risk for malignancy when compared with a soft and slowly
growing nodule. Furthermore, the presence of a solitary nodule is
more indicative of malignancy, whereas a multinodular thyroid
is more consistent with benign disease. High-risk aspects of the
patient history include a history of thyroid cancer in one or more
first-degree relatives; history of external beam radiation as a child;
exposure to ionizing radiation in childhood or adolescence; prior
hemithyroidectomy with discovery of thyroid cancer; 18FDG
avidity on PET scanning; or a known activating RET protoonco-
gene mutation.1
The measurement of serum thyroid stimulating hormone
(TSH) to characterize thyroid function is important. The risk of
thyroid carcinoma increases as the serum TSH increases. Though
most patients with thyroid cancer have a normal serum TSH, an
elevated TSH seems to confer increased risk, and a suppressed
TSH level is suggestive of benign pathology, as it is uncommon
for malignant lesions to cause thyrotoxicosis.5 This is an impor-
tant first branch point in any algorithm for thyroid nodule man-
agement. In particular, nuclear scintigraphy of the thyroid gland
5/22/2012 5:47:55 PM
 Thyroid Nodules ■ 553

Patient with a thyroid nodule The ultrasound findings can then be combined with the clini-
cal history, to determine whether the nodule should be aspirated.1,2
History, Physical Examination, TSH level Suspicious ultrasound findings include microcalcifications in the
Characterize personal risk
nodule, hypoechogenicity, increased nodular vascularity, infi ltra-
tive margins and a nodule that is taller than wide on transverse
TSH Low view. These findings must be interpreted in light of the clinical
TSH normal or
high situation of the patient. The ultrasound findings can also be the
baseline study for any subsequent follow-up examinations for
Nuclear scintigraphy– patients who need this. It is very useful to have direct access to the
Characterize nodule by distinguish Graves with
ultrasound nodule from toxic adenoma images from prior examinations for the follow-up studies, rather
than merely the reports.
The combination of the clinical findings and the ultrasound
Treat for hyperthyroidism
observations can be used to recommend which nodules should be
No indication
for tissue biopsied (Table 69.1).
Patient/nodule sampling
meet criteria
for tissue 4. What is the role of FNA thyroid cytology to evaluate thyroid
sampling Interval follow-up by clinical
(Table 1) exam with or without nodules?
ultrasound
FNA cytology is the main evaluative technique available to sep-
FNA (with ultrasound
guidance if available)
arate the many benign thyroid nodules from the few malignant
nodules. FNA has the desirable features of being relatively well-
Repeat Benign
tolerated, inexpensive, and widely available. The negative aspects
Indeterminate
of FNA are the substantial proportion of patients who receive
Malignant
nondefinitive results, either due to insufficient samples in about
Insufficient
sample
15%, or to indeterminate results in about 15% of those who have
sufficient samples.7 These weaknesses are the subject of ongoing
Resection for Cancer Consider diagnostic resection or investigations to try to develop molecular testing approaches
close interval follow-up on the FNA samples that can resolve these issues. The use of
Figure 69.1 Algorithm for the management of a patient with a ultrasound-guided FNA can improve the diagnostic accuracy, but
thyroid nodule. interpretation of the aspirate for definitive diagnosis may still not
be possible.
In patients with follicular neoplasia (follicular adenoma, fol-
is no longer considered useful for the routine management of licular carcinoma), FNA is limited in its ability to distinguish
people with thyroid nodules, except for that subgroup that has a malignant from benign disease, since the diagnosis of follicular
suppressed TSH. carcinoma is based upon histologic features. Specifically, identifi-
The utility of serum measurement of calcitonin in the evalu- cation of capsular or vascular invasion is necessary for diagnosis
ation of thyroid nodules is not clear. This has been proposed as a of malignant disease. This scenario is similar when dealing with
way to detect small medullary thyroid carcinomas, and to select patients who have Hürthle cell neoplasms.
patients for biopsy of otherwise benign appearing nodules. This The 2007 NCI conference regarding thyroid FNA provided
has been evaluated in prospective, nonrandomized trials, and some new guidelines with respect to reporting the results of the
appears to lead to the earlier diagnosis of medullary cancer. How- FNA.3 This should help to standardize the interpretation of thy-
ever, these trials have been done mainly in Europe, and the preva- roid FNA results, and aid the clinician in translating the cytology
lence of medullary thyroid cancer in the US appears to be lower. report into clinical action. The categories expand the usual four
This may diminish the value of such testing in the United States, categories of benign, malignant, indeterminate, and insufficient,
and so it is not generally recommended here.6 to include three intermediate categories representing various
levels of risk of malignancy (Table 69.2). Standardized report-
3. What is the role of thyroid ultrasound to evaluate thyroid ing categories should improve the consistency of communication
nodules? between cytologists and clinicians.
Further evaluation of the solitary nodule is best done by ultra-
5. What is the appropriate nonoperative follow-up for thyroid
sound and selective use of FNA. The ultrasound examination of
nodules?
the thyroid gland allows accurate characterization of the thyroid
nodule and the surrounding thyroid tissue. Characterization of After determination that a thyroid nodule is not at high risk of
the nodule includes the size, shape, vascularity, solid versus cystic being malignant, the clinical course of action may be to follow
nature, the presence of calcifications in the nodule, and the nature the patient and the nodule over time. This is necessary even for
of the borders (smooth, irregular, etc.). Ultrasound examinations nodules that appear to be benign on evaluation, as there is a low
can be performed in a variety of settings, and are now frequently but real rate of false-negative evaluation including FNA cytology.
performed in the outpatient clinic by thyroid specialists. Any Follow-up should generally occur at intervals of 3 to 12 months,
subsequent tissue sampling can then often be performed during t depending on the risk of the nodule being malignant. A common
he same visit in order to compress the patient’s episode of care to paradigm is to re-check the nodule at 6 months, and if still con-
the greatest extent possible. sistent with a benign lesion, to follow-up at 12-month intervals

PMPH_CH69.indd 553 5/22/2012 5:47:55 PM

 554 ■ Surgery: Evidence-Based Practice

Table 69.1 Indications for FNA of a Thyroid Nodule

Patient/Nodule Characteristics Threshold Nodule Size to Trigger Tissue Sampling
ATA Recommendationsa
High-Risk historyb
Nodule with multiple suspicious sonography featuresc >5 mm
Nodule without suspicious sonography >5 mm
Abnormal cervical lymph nodes FNA lymph node and/or thyroid nodule
Microcalcifications in nodule >10 mm
Solid nodule
AND hypoechoic >10 mm
AND isoechoic or hyperechoic >10–15 mm
Mixed cystic-solid nodule
WITH any suspicious ultrasound features >15–20 mm
WITHOUT any suspicious ultrasound features >20 mm
Spongiform nodule >20 mm
Purely cystic nodule FNA not indicated
NCCN Recommendationsd
Solid nodule
With suspicious sonographic features >10 mm
Without suspicious sonographic features >15 mm
Mixed cystic-solid nodule
With suspicious sonographic features >15–20 mm
Without suspicious sonographic features >20 mm
Spongiform nodule >20 mm
Simple cyst FNA not indicated
Suspicious cervical lymph node FNA lymph node and/or thyroid nodule
a
Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer (Ref. [1]).
b
High-risk history: History of thyroid cancer in one or more first-degree relatives; history of external beam radiation as a child; exposure to ionizing
radiation in childhood or adolescence; prior hemithyroidectomy with discovery of thyroid cancer, 18FDG avidity on PET scanning; MEN-2 = FMTC-
associated RET protooncogene mutation, calcitonin >100 pg/mL; MEN, multiple endocrine neoplasia; FMTC, familial medullary thyroid cancer.
c
Suspicious features: microcalcifications; hypoechoic; increased nodular vascularity; infiltrative margins; taller than wide on transverse view.
d
National Comprehensive Cancer Network Guidelines: Thyroid Carcinoma version 1.2011 (Ref. [2]).
e
Suspicious sonographic features: Hypoechoic, microcalcifications, increased central vascularity, infiltrative margins, taller than wide in transverse plane.

Table 69.2 Bethesda System for Thyroid Cytopathology

Diagnostic Category Risk of Malignancy
Nondiagnostic or unsatisfactory 1–4%
Benign 0–3%
Atypical lesion of undetermined significance or follicular lesion of undetermined significance 5–15%
Follicular neoplasm or suspicious for follicular neoplasm 15–30%
Suspicious for malignancy 60–75%
Malignant 97–99%
Source: From the National Cancer Institute State of the Science Conference, Bethesda, Maryland, October 22–23, 2007. 3

PMPH_CH69.indd 554 5/22/2012 5:47:55 PM


thereafter. Follow-up examinations should include the same
modalities as the initial evaluation including sonography.
Benign nodules do enlarge, though often slowly. Thus, enlarge-
ment by itself is not a reason for removal, but rather, enlargement
should prompt repeat FNA cytology. The evaluation is then similar
to the initial decision-making process. The definition of enlarge-
ment used in the ATA guidelines is growth by at least 20% (mini-
mum 2 mm) in two perpendicular dimensions.
6. What is the role of operative management of thyroid nodules?
Thyroid nodules with a significant risk of being malignant after
evaluation, or that are symptomatic, should be treated by thyroi-
dectomy. The most typical procedure is a unilateral diagnostic thy-
roid lobectomy, although a bilateral procedure may be indicated if
there are contralateral abnormalities. The minimum appropriate
procedure for assessing the nature of a potentially malignant thy-
roid lesion is lobectomy and isthmusectomy.8-11 This must include
a gross margin of normal thyroid gland between the line of divi-
sion and the lesion at risk.
Removing one side of the thyroid gland carries complications
that are similar to the complications of total thyroidectomy, with
some important distinctions. First, as a single functional parathy-
roid gland is sufficient to maintain normal parathyroid control
of calcium flux, and there are parathyroid glands on each side of
the larynx, it is not possible to produce permanent hypoparathy-
roidism by thyroid lobectomy. Second, injury to the ipsilateral
recurrent laryngeal nerve can produce permanent voice changes,
but thyroid lobectomy does not carry a risk of bilateral recur-
rent nerve injury and consequent airway occlusion. Finally, most
patients who require only unilateral thyroidectomy have no need
for thyroid hormone replacement therapy, thus eliminating the
possibility of iatrogenic hyper- or hypothyroidism.
7. What operative approaches are available for operative
management?
The most commonly applied standard thyroidectomy is per-
formed under general anesthesia, through a low cervical incision
and encompasses an overnight facility stay. However, each of these
features can be altered. Some surgeons commonly perform this
procedure under local anesthesia as an outpatient, for example.
Others perform the procedure through very small neck incisions
with videoscopic guidance, or even axillary or breast incisions
using video or robotic technology. Any of these approaches are
acceptable as long as the basic principles are respected: the ipsi-
lateral lobe should be completely resected, and the adjacent struc-
tures should be carefully protected.
Currently, improved cosmesis is the only advantage of the
procedures that use new technology to change the standard thy-
roidectomy. There is no advantage in terms of complications, cost,
or recovery time. However, cosmesis is extremely important to
some patients, and in spite of the relatively good cosmesis of most
standard thyroidectomy scars, the additional cost and effort of the
newer approaches may be important to them.
8. What is the operative morbidity of thyroidectomy?
Thyroid operations are generally very safe but not minor surgery.
The risk of death is minimal; however, the risk of life-altering
complications is significant, and as they occur in people with a
long life-expectancy, they can have a lasting effect on quality of
PMPH_CH69.indd 555
Thyroid Nodules ■ 555
life. The potential complications of thyroid operations include
the immediate complication of cervical hematoma, as well as the
more chronic complications of hypoparathyroidism, nerve injury,
and injuries to the aerodigestive tract. Finally, chronic problems
can arise from iatrogenic hyper- or hypothyroidism.
NECK HEMATOMA
Neck hematoma requiring re-operation develops after operation
in about 1 of every 150 thyroidectomies12-16 and nearly always
appears within the initial 6 h after the completion of the proce-
dure. The hematoma is manifest by increasing pain, neck swelling,
and often marked anxiety. It can collect either between the plat-
ysma muscle and the sternohyoid muscles (superficial), or deep to
the strap muscles along the larynx (deep). Deep hematomas are
the more dangerous due to collection on one side of the larynx
causing a shift and compression of the airway.
A minority of patients with postoperative hematomas deve-
lop airway compromise requiring emergent evacuation at the
bedside, but this possibility exists with every neck hematoma.
Patients with a significant hematoma of the neck should not
be left alone until the hematoma has been evacuated. For most
patients, the hematoma is less immediately threatening, and the
patient can be urgently returned to the operating room, placed
under anesthesia, and the hematoma then evacuated and bleed-
ing controlled. Careful hemostasis during the initial operation
is justified, with particular attention to the superior pole vas-
cular pedicle, and the vessels of the ligament of Berry, adjacent
to the recurrent laryngeal nerve insertion, to try to prevent this
complication.
The risk of cervical hematoma has led some to question
the safety of outpatient thyroidectomy, because there would be
some possibility of the hematoma developing after discharge.12-16
The current experience with outpatient thyroid surgery by experts
in the field has demonstrated that this can be done safely, though
postoperative observation for 6 h is routine, to detect this compli-
cation prior to facility discharge.
HYPOPARATHYROIDISM
Permanent hypoparathyroidism can occur after bilateral thyroid
procedures, but is not a risk of unilateral thyroid lobectomy. The
parathyroid glands are small, delicate structures that share a blood
supply with the thyroid gland. Their diminutive size (normal
30–60 mg) and fragile nature make them particularly prone to
damage during thyroidectomy. Patients who have markedly
diminished or absent parathyroid function after thyroidectomy
have severe hypocalcemia that requires replacement. If perma-
nent, this complication can be palliated by calcium supplements,
but this requires multiple doses each day, and uncomfortable
symptoms occur if doses are late or missed. In addition, there is
cumulative bone damage over time.
Temporary hypocalcemia occurs in about 10% of patients
after total thyroidectomy, and permanent hypocalcemia in about
1%.17-23 The temporary hypocalcemia can be severe, and requires
intravenous and oral supplementation for the duration of the
effect. Permanent hypoparathyroidism requires lifelong sup-
port with calcium supplements and vitamin D analogs. Missing
5/22/2012 5:47:55 PM
 556 ■ Surgery: Evidence-Based Practice
doses of the supplements usually produces symptoms of varying
severity, which, although manageable, are quite bothersome for
patients. In addition to the discomfort and inconvenience of the
supplements, patients develop low-turnover bone disease, which
resembles osteomalacia. Though dysmorphic, bone mass is gen-
erally preserved or increased in hypoparathyroidism, and frac-
ture risk is not apparently increased.24 Finally, the calcium and
vitamin D supplements with low parathyroid hormone (PTH)
lead to an increased daily urinary excretion of calcium, and sig-
nificant risk or nephrolithiasis.
The recent availability of pharmacologic PTH for exogenous
administration has opened the opportunity to replace PTH in
patients with postoperative hypoparathyroidism. The experience
with this to date is limited, but early results demonstrate that
PTH delivered subcutaneously twice daily can maintain serum
calcium levels in the same range as oral calcium and vitamin D
supplements, and decreases the amount of hypercalciuria.25,26
Further experience with this strategy will be necessary before the
full long-term effects are clear.
NERVE INJURIES
There are several nerves adjacent to the thyroid gland that can
be deliberately or inadvertently affected during thyroidectomy. These
include the recurrent laryngeal nerve (RLN) immediately adjacent
to the thyroid, and the vagus nerve, which is slightly more removed,
but causes the same symptoms when damaged. The external branch
of the superior laryngeal nerve can be injured during dissection of
the upper pole of the thyroid gland, and the sympathetic chain
and stellate ganglion can be injured near the posterior aspect of
the upper pole of the gland as well.
Damage to the RLN causes unilateral paralysis of the muscles
that control ipsilateral vocal cord tension. Unilateral RLN injury
changes the voice substantially in most patients, and also signifi-
cantly affects the swallowing mechanism. The voice can range
from a soft, whispery voice, with the inability to increase the vol-
ume at all, to a nearly normal-sounding voice which cannot be
raised to a yell. The difference between these is based on the ability
of the contralateral vocal cord to cross the midline and appose the
affected cord. If the cords cannot meet, then the voice will be soft
and breathy. If the cords can meet, then the speaking voice will
be more normal in timbre, but the affected cord prolapses with
increased airway pressure, and the ability to yell is lost. Swallow-
ing is affected also, and the aspiration of liquids is a mark of severe
RLN paresis. This improves with time and can be helped by swal-
lowing training.
Bilateral RLN injury causes paralysis of both cords, and usu-
ally results in a very limited airway lumen at the cords. These
patients usually have a normal-sounding speaking voice, but
severe limitations on inhalation velocity because of upper air-
way obstruction. They often require re-intubation to maintain
ventilation.
RLN paresis is usually temporary, and resolves over days
to months.17-23 There is no known method of aiding or speeding
recovery. If a unilateral paresis proves to be permanent, then pal-
liation of the cord immobility and voice changes can be achieved
with vocal cord injection or laryngoplasty. These procedures
stiffen and medialize the paralyzed cord, to allow the contralateral
cord to appose the paralyzed cord during speech. If both cords
are affected, then the palliative procedures are more limited, and
PMPH_CH69.indd 556
involve creating an adequate airway for ventilation; improvements
in voice quality are not likely, as there is no muscular control of
the cord function.
9. What methods are available to limit the operative morbidity of
thyroidectomy?
As hypoparathyroidism is not a risk of thyroid lobectomy, the
most effective strategy to avoid this complication is to limit pro-
cedures as appropriate. Preservation of each parathyroid on its
native blood supply is critical. In the case of parathyroid glands
that are devascularized during dissection, autograft of the para-
thyroid tissue into the sternocleidomastoid muscle can restore
normal function.27
As with hypoparathyroidism, avoidance of RLN injury is far
superior to palliation. Great care must be taken during the dis-
section of the nerve to protect it. In some clinical situations, the
RLN is sacrificed to allow and adequate tumor resection. Absent
this unusual circumstance, though, careful dissection can gener-
ally preserve cord function. The principles of the dissection are as
follows:
1. Avoid dividing any structures in the tracheoesophageal groove
until the recurrent laryngeal nerve is definitively identified.
Small branches of the inferior thyroid artery may seem like
they can clearly be safely transected; however, the distortion
of tumor, retraction, or previous scar may lead the surgeon to
mistakenly divide a branch of the RLN. The identifying feature
of the RLN is that the more it is dissected, the more it looks
like the correct structure. This is based on the morphologic
appearance and the anatomic course. The nerve can tolerate
manipulation, but not cutting. Once cut, repair of the nerve is
of unproven benefit.
2. Identify the recurrent laryngeal nerve low in the neck, well below
the inferior thyroid artery, at the level of the lower pole of the
thyroid gland, or below. This allows dissection of the nerve at a
site where it is not tethered by its attachments to the larynx or
its relation to the inferior thyroid artery. Traction injuries to
the nerve can occur when the nerve is manipulated near a site
of fi xation.
3. Keep the recurrent laryngeal nerve in view during the subsequent
dissection of the thyroid away from the larynx. Once the nerve
is identified, the dissection can generally proceed from inferior
to superior along the nerve, dividing the inferior thyroid artery
branches and preserving the parathyroid glands. This allows
careful dissection of the tissues with minimal manipulation of
the RLN.
4. Minimize the use of powered dissection posterior to the thyroid.
Although the electrocautery and high-frequency ultrasonic
scalpel are useful tools in dissection, they have some risk of
lateral thermal spread, which can damage adjacent tissues.
Careful cold dissection and hemostasis with ligatures or clips
will avoid this risk. This is particularly important at the entry
of the RLN to the larynx, immediately adjacent to the ligament
of Berry and its vessels.
The use of nerve stimulators and laryngeal muscle potential moni-
tors has recently been investigated as a tool to try to limit or avoid
nerve injuries.28,29 The data do not currently support the manda-
tory use of these devices, as the risk of nerve injury is related to
several factors. 30-32 However, many experienced surgeons now
routinely use a nerve monitoring system intraoperatively. This
5/22/2012 5:47:55 PM
 Thyroid Nodules ■ 557

may be because they merely help to identify the nerve, while the About 10% of patients have some evidence of RLN pare-
portion of the operation most likely to produce damage in experi- sis after thyroidectomy; however, this resolves in most patients.
enced hands is the dissection of the RLN at the fi xed point of the About 1% or fewer patients have permanent nerve injury when
cricopharyngeus. total thyroidectomy is performed by experienced surgeons.

Clinical Question Summary

Question
1 How are thyroid nodules identified?
2 What is the appropriate clinical
evaluation for thyroid nodules?
3 What is the role of thyroid
ultrasound to evaluate thyroid
nodules?
4 What is the role of FNA thyroid
cytology to evaluate thyroid
nodules?
5 What is the appropriate
nonoperative follow-up for thyroid
nodules?
6 What is the role of operative
management of thyroid nodules?
7 What operative approaches are
available for operative management?
8 What is the operative morbidity of
thyroidectomy?
9 What methods are available to
limit the operative morbidity of
thyroidectomy?
Answer Grade of References
Recommendation
By local symptoms, visible asymmetry, self-palpation, C 1, 2, 6
physical examination, or incidental finding on
unrelated imaging.
Comprehensive history and physical examination, A 1-3, 5, 6
TSH measurement, ultrasound evaluation,
possibly FNA as per Fig. 69.1.
Thyroid ultrasound is mandatory for the evaluation A 1-3, 5
of thyroid nodules.
FNA is used selectively for the evaluation of thyroid A 1-3, 5
nodules.
Follow-up should generally occur at intervals of 3 to C 1
12 months, depending upon the risk of the nodule
being malignant.
Thyroid nodules with a significant risk of C 1, 2, 6, 8
being malignant after evaluation, or that
are symptomatic, should be treated by
thyroidectomy.
Standard thyroidectomy is performed under general C 1, 2, 13
anesthesia, through a low cervical incision and
encompasses an overnight facility stay, but can also
be done under local anesthesia as an outpatient,
through very small neck incisions with videoscopic
guidance, or through axillary or breast incisions
using video or robotic technology.
Thyroid operations are generally very safe but not B 1, 12-20
minor. The risk of life-altering complications is
significant, and as they occur in people with a long
life-expectancy, they can have a lasting effect on
quality of life.
Proper surgical technique can limit the risk of C 12-20
morbidity, including liberal use of parathyroid
autograft and consideration of intraoperative
laryngeal nerve monitoring.

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1. Cooper DS, Doherty GM, Haugen BR, et al. Revised American
Thyroid Association management guidelines for patients with
thyroid nodules and differentiated thyroid cancer.[see com-
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2. Tuttle RM, Ball DW, Byrd D, et al. Thyroid carcinoma. J Natl
Compr Cancer Net. 2010;8:1228-1274.
3. Cibas ES, Ali SZ. The Bethesda System for Reporting Thyroid
Cytopathology. Thyroid. 2009;19:1159-1165.
4. Davies L, Welch HG. Increasing incidence of thyroid cancer in
the United States, 1973–2002. JAMA. 2006;295:2164-2167.
5. Kumar H, Daykin J, Holder R, Watkinson JC, Sheppard MC,
Franklyn JA. Gender, clinical findings, and serum thyrotropin
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 558 ■ Surgery: Evidence-Based Practice
9. Mazzaferri EL. An overview of the management of papillary and
follicular thyroid carcinoma. Thyroid. 1999;9:421-427.
10. Hay ID, Grant CS, Bergstralh EJ, Thompson GB, van Heerden
JA, Goellner JR. Unilateral total lobectomy: Is it sufficient
surgical treatment for patients with AMES low-risk papillary
thyroid carcinoma? Surgery. 1998;124:958-964; discussion
964-966.
11. Chen H, Nicol TL, Zeiger MA, et al. Hurthle cell neoplasms of
the thyroid: Are there factors predictive of malignancy? Ann
Surg. 1998;227:542-546.
12. Burkey SH, van Heerden JA, Thompson GB, Grant CS, Schleck
CD, Farley DR. Reexploration for symptomatic hematomas after
cervical exploration. Surgery. 2001;130:914-920.
13. Adler JT, Sippel RS, Schaefer S, Chen H. Preserving function
and quality of life after thyroid and parathyroid surgery. Lancet
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14. Leyre P, Desurmont T, Lacoste L, et al. Does the risk of com-
pressive hematoma after thyroidectomy authorize 1-day surgery?
Langenbecks Arch Surg. 2008;393:733-737.
15. Rosenbaum MA, Haridas M, McHenry CR. Life-threatening
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17. Farrar WB, Cooperman M, James AG. Surgical management of
papillary and follicular carcinoma of the thyroid. Ann Surg. 1980;
192:701-704.
18. Thompson NW, Nishiyama RH, Harness JK. Thyroid carcinoma:
Current controversies. Curr Probl Surg. 1978;15:1-67.
19. Schroder DM, Chambous A, France CJ. Operative strategy for
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20. Clark OH, Levin K, Zeng QH, Greenspan FS, Siperstein A. Thy-
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21. Ley PB, Roberts JW, Symmonds J, et al. Safety and efficacy of
total thyroidectomy for differentiated thyroid carcinoma: A 20-
year review. Am Surg. 1993;59:110-114.
PMPH_CH69.indd 558
22. Tartaglia F, Sgueglia M, Muhaya A, et al. Complications in total
thyroidectomy: Our experience and a number of considerations.
Chirurgia Italiana. 2003;55:499-510.
23. Rosato L, Avenia N, Bernante P, et al. Complications of thyroid
surgery: Analysis of a multicentric study on 14,934 patients oper-
ated on in Italy over 5 years. World J Surg. 2004;28:271-276.
24. Rubin MR, Dempster DW, Zhou H, et al. Dynamic and struc-
tural properties of the skeleton in hypoparathyroidism. J Bone
Miner Res. 2008;23:2018-2024.
25. Winer KK, Ko CW, Reynolds JC, et al. Long-term treatment of
hypoparathyroidism: A randomized controlled study compar-
ing parathyroid hormone-(1-34) versus calcitriol and calcium.
J Clin Endocrinol Metab. 2003;88:4214-4220.
26. Winer KK, Sinaii N, Peterson D, Sainz B, Jr., Cutler GB, Jr. Effects
of once versus twice-daily parathyroid hormone 1-34 therapy in
children with hypoparathyroidism. J Clin Endocrinol Metab.
2008;93:3389-3395.
27. Olson JA, Jr, DeBenedetti MK, Baumann DS, Wells SA, Jr. Para-
thyroid autotransplantation during thyroidectomy. Results of
long-term follow-up.[see comment]. Ann Surg. 1996;223:472-478;
discussion 478-480.
28. Rea JL, Khan A. Clinical evoked electromyography for recurrent
laryngeal nerve preservation: Use of an endotracheal tube elec-
trode and a postcricoid surface electrode. Laryngoscope. 1998;108:
1418-1420.
29. Otto RA, Cochran CS. Sensitivity and specificity of intraopera-
tive recurrent laryngeal nerve stimulation in predicting post-
operative nerve paralysis. Ann Otol, Rhinology & Laryngology.
2002;111:1005-1007.
30. Dralle H, Sekulla C, Lorenz K, Brauckhoff M, Machens A, Ger-
man ISG. Intraoperative monitoring of the recurrent laryngeal
nerve in thyroid surgery. World J Surg. 2008;32:1358-1366.
31. Dralle H, Sekulla C, Haerting J, et al. Risk factors of paralysis
and functional outcome after recurrent laryngeal nerve moni-
toring in thyroid surgery. Surgery. 2004;136:1310-1322.
32. Thomusch O, Sekulla C, Machens A, Neumann H-J, Timmer-
mann W, Dralle H. Validity of intra-operative neuromonitor-
ing signals in thyroid surgery. Langenbecks Arch Surg. 2004;389:
499-503.
5/22/2012 5:47:56 PM

Hyperthyroidism, Thyroiditis,
and Nontoxic Goiter
INTRODUCTION
Hyperthyroidism is a clinical syndrome resulting from excessive
production and release of thyroid hormone into the circulation.
The commonest cause is Graves’ disease, accounting for nearly
60% to 80% of the cases of hyperthyroidism in North America.
Other causes which are common and are relevant to surgeons are
toxic multinodular goiter (MNG) and solitary toxic nodule (STN).
Thyroiditis is defined as an inflammatory disorder of the thyroid
gland. It may result from a myriad of etiologies and is classified
into acute, subacute, and chronic forms, each associated with a
distinct clinical presentation and histology. Nontoxic goiters are
diff use or nodular enlargements of the thyroid. Thyroid nodules
occur in about 4% of the general population; however, most are
benign and do not require any intervention. In this chapter, we
review and provide evidence-based guidelines for the diagnosis
and management of these common conditions, with particular
focus on surgical therapy.
1. What are the appropriate diagnostic tests (laboratories and
imaging) for hyperthyroidism?
A suppressed TSH with or without elevation of free T3 and/or
T4 levels is sufficient to make a diagnosis of hyperthyroidism.1
The presence of eye signs of Graves’ ophthalmopathy (GO, clini-
cally apparent in 20–25% of patients) along with consistent labs
is sufficient to make a diagnosis without further testing. Anti-
thyroglobulin (Tg) and anti-thyroid peroxidase (TPO) antibodies
are present in both Graves’ disease and autoimmune thyroiditis
and are therefore nonspecific. TSH receptor antibodies (TRAb)
are specific to Graves’ disease and elevated levels are diagnostic.
TRAb levels are useful in patients who present with unilateral eye
signs or minimal clinical manifestations of hyperthyroidism. In
the absence of eye signs, an I-123 radioactive iodine scan showing
an elevated uptake with diff use enlargement of the gland confirms
the diagnosis. Either I-123 or technetium-99m pertechnetate
(Tc-99m) may be used for thyroid imaging. There are no ran-
domized studies comparing these modalities; however, Reschini
559
PMPH_CH70.indd 559
CHAPTER 70
Prashant Khullar and Geeta Lal
et al.2 noted good correlation between the studies in a retro-
spective review of 273 patients. (Level 2b evidence) I-123 is both
trapped and organified by the thyroid, has less salivary activity, is
orally administered, and is more effective than Tc-99m at identi-
fying pyramidal lobes and thyroglossal duct remnants. However,
it is more expensive and takes longer to complete. In contrast to
Graves’ disease, thyroid scans typically demonstrate single or mul-
tiple “hot” nodules with suppression of the remaining gland in STN
and toxic MNG, respectively.
Answer: Hyperthyroidism is diagnosed using a combination
of laboratory tests and, in some cases, thyroid scan and uptake
to determine etiology. The latter can be performed with I-123 or
with pertechnetate. (Grade B recommendation)
2. What is the optimal defi nitive treatment of hyperthy-
roidism?
Three treatment options are available for Graves’ disease: (1) anti-
thyroid drug (ATD) therapy, (2) surgery, and (3) RAI ablation.
ATDs (propylthiouracil (PTU) and methimazole) act by decreas-
ing thyroid hormone production by inhibiting the organification
of iodine and the coupling of iodotyrosines. PTU also acts by
inhibiting the peripheral conversion of T4 to T3. ATDs can be used
as both a primary treatment and an adjunct modality in prepara-
tion for RAI or for surgery. When used as primary therapy, they
are given for 6 months to 2 years, till spontaneous remission of
the disease occurs. At the initiation of treatment, higher doses are
used till a clinically euthyroid state is achieved and the dose is
then titrated according to FT4 levels. Drawbacks of ATDs include
a high relapse rate (40–50% by 1 year and 60–70% by 10 years),
once therapy is stopped. Adverse effects include rash, agranulocy-
tosis (less than 0.5%), and possible hepatocellular toxicity. Thus,
ATD treatment is suitable for small glands (<40 g), patients with
mild hyperthyroidism, and those who show substantial decrease
in gland size and remission of symptoms soon after therapy is ini-
tiated. ATDs are often used in conjunction with β-blockers to help
control symptoms related to catecholamine release and have the
added benefit of decreasing peripheral conversion of T4 to T3.
5/22/2012 5:48:26 PM
 560 ■ Surgery: Evidence-Based Practice
RAI therapy is the most common modality used for the
defi nitive treatment of Graves’ disease in the United States. Fre-
quently, patients require pretreatment with ATDs to achieve
a euthyroid state prior to treatment. Euthyroidism is usually
achieved in 70% of patients by 2 months, although it can take
up to 6 months to see the full therapeutic effect. Almost 80%
of adequately treated patients eventually develop hypothyroid-
ism. Advantages of RAI therapy include lower cost, avoidance
of surgery, and long-term drug treatment and their associated
side effects. RAI therapy is contraindicated in pregnant and
breast-feeding patients. Surgery is recommended for treatment of
Graves’ disease when other modalities of treatment are contrain-
dicated. Absolute indications for surgery include patients with
nodules suspicious of or proven to be cancer, pregnant patients
not controlled with ATDs, women desiring pregnancy within 6 to
12 months, patients who had severe allergic/adverse reactions to
ATDs, and patient preference. Large glands are less responsive
to ATDs or RAI are best treated surgically, especially if they are
causing compressive symptoms.
The question of which treatment is optimal has been a mat-
ter of considerable debate. Torring et al.3 attempted to address
this issue and randomized 179 patients with Graves’ disease to
3 groups—ATDs, RAI, or thyroidectomy. (Level 2b evidence) All
modalities normalized the mean serum hormone levels within
6 weeks. The risk of relapse was highest in the medically treated
and lowest in surgically treated patients. The majority of patients
in each group (90%) were satisfied with the treatment received.
Thus, the results from this study did not allow any definitive rec-
ommendations regarding the optimal therapy for Graves’ disease.
Although a recent cost-effectiveness study (Level 3b evidence)
demonstrated that thyroidectomy was the best option compared
with lifelong ATD and RAI (till the cost of surgery exceeds $19,300)
for patients who failed to achieve euthyroidism after initial medi-
cal treatment,4 additional studies are clearly needed in this area.
In contrast, several investigators have evaluated the optimal
therapy in patients with Graves’ disease and GO. In a prospec-
tive, randomized study, Tallstedt et al.5 reported progression of
GO more frequently following RAI when compared with patients
undergoing surgery (32% vs. 16%), respectively. This led to the rec-
ommendation for avoidance of RAI in patients with GO (Level
2b evidence), although later studies showed that glucocorticoid
therapy ameliorates this worsening after either therapy. Another
randomized study (Level 2b evidence) of 60 patients showed that
complete thyroid ablation (with near-total thyroidectomy (TT)
and RAI) was superior to near-TT in terms GO outcomes (0% vs.
25% progression, respectively, at 9 months); however, no long-term
data are available.6 Other case–control studies also show similar
results. In terms of novel therapies, small uncontrolled stud-
ies show that Rituximab (RTX, a monoclonal chimeric human/
mouse antibody directed against the surface molecule CD20)
resulted in significant eye symptom improvement in addition
to reduced relapse rates and that it may be particularly useful in
steroid resistant GO.
There are no prospective randomized studies in the Eng-
lish literature evaluating the various treatment options for toxic
MNG and STN; however, retrospective case series support the
role of both RAI and surgery for these diseases. The doses of RAI
needed in toxic MNG are much higher than those needed for
Graves’ and ATDs may be needed concurrently. The results for
RAI therapy of STNs are variable and larger nodules typically
PMPH_CH70.indd 560
require higher doses, which can lead to hypothyroidism in about
12% of patients. Long-term success rates for RAI ablation have
been reported at 88% for toxic MNG and 100% for STN.7 (Level 4
evidence) Surgery is indicated for large, symptomatic goiters, as
it not only provides rapid control of the hyperthyroidism but also
relieves compressive symptoms. Surgery also provided early and
late cure rates of 99% to 100%.7 (Level 4 evidence) For younger
patients, surgery may also be a more cost-effective option (Level 3b
evidence), provided complication rates are low. 8 Percutaneous
ethanol injection (PEI) has been described in a prospective non-
randomized multicenter trial of 429 patients with STNs and
reported success rates of 67% for patients with toxic nodules
and 83% of patients with pretoxic nodules at 1 year follow-up.9
Another randomized-controlled trial compared US-PEA + RAI
with RAI alone in 22 patients with large STN (>4cm) who were
not operative candidates or refused surgery. The former was
associated with a success rate of 79% versus 57% with the latter,
supporting the adjuvant role of US-PEA in a selected group of
patients.10 (Level 2b evidence) Of note, no studies directly com-
pare this modality with surgery.
Answer: There is insufficient evidence to recommend sur-
gery over RAI or ATDs for Graves’ disease and treatment should
be based on the general guidelines in combination with patient
preference. However, patients with GO are best treated by sur-
gery. (Grade B recommendation) Toxic MNGs and STNs may
be treated with thyroidectomy or RAI. (Grade C recommenda-
tion) PEA may have a role in selected patients with STN. (Grade C
recommendation)
3. What is the optimal extent of surgery for hyperthyroidism?
Graves’ disease may be treated by TT or subtotal (ST) resection
(leaving a 4–7 g remnant). The latter may be accomplished by
bilateral ST or a unilateral total lobectomy combined with a
contralateral ST thyroidectomy (Hartley–Dunhill procedure).
The debate around the extent of surgery is primarily related
to the previously reported higher complication rates with TT.
However, Palit et al.,11 in a meta-analysis of 35 studies includ-
ing 7241 patients, noted that there was no difference in the per-
manent recurrent laryngeal nerve injury rates (0.9% vs. 0.7%) or
hypoparathyroidism (0.9% vs. 1%) between patients undergoing
TT or ST, respectively. (Level 3a evidence) None of the patients
undergoing TT had persistent or recurrent disease, but the recur-
rence rate was 7.9% in the ST group. Witte et al.12 performed a
prospective randomized trial on 150 patients with Graves’ dis-
ease comparing bilateral ST resection-total remnant <4 mL,
unilateral hemithyroidectomy with contralateral ST resection
remnant <4 mL and TT with respect to outcomes. Recurrent
hyperthyroidism occurred in two patients with ST resections,
and although early postoperative hypoparathyroidism was more
frequently detected in patients with TT than in those with ST
resection (28% vs. 12%; p < .002), there was no difference in the
permanent complication rates. (Level 2b evidence) Multiple ret-
rospective case–control studies have also shown equivalent com-
plication rates for TT and ST in Graves’ disease.13-15 (Level 3a
evidence) Of note, small randomized-control studies do not
show any difference in outcomes between the two types of ST
resections.16,17 (Level 2b evidence) Although several retrospec-
tive studies have shown less GO progression with TT, most likely
as a result of removal of the antigenic stimulus, only two small
5/22/2012 5:48:26 PM

prospective, randomized studies (Level 2b evidence) have evalu-
ated this question and did not show any difference between ST
and TT.12,18 There are no Level 1 or 2 studies evaluating the opti-
mal extent of thyroidectomy in the treatment of toxic MNG or
STN although retrospective case series (Level 4 evidence) show
that more limited resections have lower complication rates.7 This
must, however, be balanced with higher recurrence rates. Lugol’s
iodine is often used preoperatively and has been shown to reduce
the rate of blood flow, thyroid vascularity, and blood loss during
thyroidectomy for Graves’ disease in a small randomized, pro-
spective study of 36 patients (Level 2b evidence),19 although other
retrospective studies fail to show any benefit.
Answer: Based on the available evidence regarding cure and
complication rates, TT has become the procedure of choice for
Graves’ disease. (Grade B recommendation) In GO, TT does not offer
any advantage over ST resection and either procedure is appropri-
ate. (Grade B recommendation) Toxic MNG may be treated by TT
or ST resection, whereas lobectomy is preferred for STN. (Grade C
recommendation) Iodine may be used to decrease the vascularity of
the gland. (Grade E recommendation)
4. What are the appropriate diagnostic tests (laboratories and
imaging) for thyroiditis?
Acute suppurative thyroiditis is often characterized by leukocy-
tosis and an elevated ESR. Serial thyroid function studies may
show transient elevations of T3 and T4 as a result of the release of
preformed hormone from the inflamed gland. RAI uptake scans
are usually normal or there is a decreased uptake due to sup-
pression of TSH by the release of thyroid hormones. Ultrasound
is helpful to distinguish solid from cystic lesions. Fine needle
aspiration biopsy (FNAB) for gram stain, culture, and cytology
confirms the diagnosis, helps guide antibiotic therapy, and diag-
nose underlying malignancy. Contrast-enhanced CT scans may
help to identify abscesses and delineate the extent of infection. A
persistent pyriform sinus fistula should always be suspected in
recurrent acute thyroiditis. In a consecutive series of 18 patients,
Kim et al.20 reported that the sensitivity of identification of fis-
tulae in the acute setting was lowest for barium esophagography
(50%) and best for direct endoscopy (100%), with CT scans being
intermediate (80%). In addition, another series of 21 patients
showed that both barium esophagogram and CT scans (espe-
cially if the trumpet maneuver is used) have improved sensitiv-
ity once the acute inflammation has resolved (100% and 83%,
respectively), with CT being better at defi ning the accurate ana-
tomic pathway and its relationship to the thyroid gland.21 (both
Level 3b evidence)
Subacute thyroiditis can occur in the painful (DeQuervain’s
thyroiditis) or painless forms, the latter may occur sporadically or
in the postpartum period. In the early stages, TSH is decreased,
and Tg, T4, and T3 levels are elevated due to the release of preformed
thyroid hormone from destroyed follicles. Thyroid antibody titers
(anti-Tg, anti-microsomal, and TSH receptor antibody) are also
elevated in 10% to 20% of patients. Titers of anti-TPO antibod-
ies are often elevated in painless thyroiditis and these patients
have a risk of recurrence of approximately 70% following a sub-
sequent pregnancy. ESR is typically greater than 100 mm/h in
painful thyroiditis, but is generally normal or only mildly elevated
(<40 mm/h) in painless thyroiditis and the leukocyte counts are
generally normal. RAI uptake is also decreased (<2% at 24 h) in
PMPH_CH70.indd 561
Hyperthyroidism, Thyroiditis, and Nontoxic Goiter ■ 561
subacute thyroiditis. FNAB may be useful in equivocal cases or
to rule out malignancy or acute thyroiditis. Thyroid ultrasound
shows areas of hypoechogenicity which reflect the degree of
inflammation. A recent study showed that RAI uptake (and thy-
roid scintigraphy) was more sensitive than ultrasound (100% vs.
36%) for the diagnosis.22 (Level 2b evidence)
Chronic thyroiditis includes Lymphocytic (Hashimoto’s)
thyroiditis and a rare variant known as Riedel’s struma (inva-
sive fibrous thyroiditis). When Hashimoto’s thyroiditis is sus-
pected clinically, an elevated TSH, reduced T4 and T3 levels,
and the presence of thyroid autoantibodies confi rm the diag-
nosis. Antibodies are directed against three main antigens—Tg
(60 %), TPO (95 %), the TSH-R (60 %), and less commonly to
the sodium/iodine symporter (25%). FNAB is indicated in
patients who present with a solitary suspicious nodule or a rap-
idly enlarging goiter as thyroid lymphoma is a rare but ominous
complication of chronic autoimmune thyroiditis. Reidel’s thy-
roiditis is characterized by the replacement of all or part of the
thyroid parenchyma by fibrous tissue, which also invades into
the adjacent tissues. As fibrosis progresses, an elevated TSH and
hypocalcemia may be apparent. Anti-thyroid antibodies and a
mild eosinophilia may be present. FNAB is generally inadequate
due to the fibrotic nature of the gland.
Answer: Thyroiditis can be diagnosed with a careful exami-
nation of laboratory tests and imaging. Due to the increased risk
of recurrence, screening for anti-TPO antibodies should be con-
sidered in women who are at high risk and pregnant. (Grade B rec-
ommendation) RAI uptake scans, ultrasound (±FNAB), and CT
scans are often necessary (Grade B recommendation) to delineate
the diagnosis and define anatomic abnormalities.
5. What are the indications for surgical intervention in
thyroiditis?
There are no randomized clinical trials directing therapy. Once
the diagnosis of acute suppurative thyroiditis is suspected,
empiric, broad spectrum antibiotic therapy must be initiated.
In the absence of airway complications, surgical intervention is
guided by the presence, persistence, or recurrence of abscesses.
Some case reports suggest that in the absence of an abscess on
CT imaging, acute thyroiditis may be successfully treated with
antibiotics alone or in combination with US surveillance and
drainage of small abscesses. Surgery may include open surgical
drainage or thyroidectomy (lobectomy, near-TT, or TT). In case a
pyriform sinus fistula is identified, complete surgical or nonsur-
gical obliteration is needed to reduce the risk of recurrence.23,24
(Level 3b evidence) Transnasal flexible fiberoptic laryngoscopy
is being increasingly used to identify the internal opening of the
pyriform sinus tract and may also allow electrocauterization of
the tract and success rates similar to open surgery have been
reported.
Subacute thyroiditis is typically self-limited and therefore
treatment is primarily symptomatic. Aspirin and other nonsteroi-
dal anti-inflammatory drugs are used for pain relief, but steroids
may be indicated in more severe cases of deQuervain’s thyroidi-
tis. Short-term thyroid replacement may shorten the duration of
symptoms and is advised for patients with TSH >10 and preg-
nant women as pregnancies in women with subclinical hypothy-
roidism were 3 times more likely to be complicated by placental
abruption (relative risk 3.0, 95% confidence interval [CI] 1.1–8.2)
5/22/2012 5:48:27 PM
 562 ■ Surgery: Evidence-Based Practice
and preterm birth, (relative risk, 1.8, 95% CI 1.1–2.9).25 (Level 2b
evidence) In a retrospective review of 17 patients who under-
went thyroidectomy for deQuervain’s thyroiditis, the most com-
mon indication was an indeterminate thyroid nodule; however,
many of these patients were operated on prior to the era of routine
FNAB.26 (Level 4 evidence)
Thyroid hormone replacement therapy is also indicated in
overtly hypothyroid patients with chronic thyroiditis, with a goal
of maintaining normal TSH levels. The management of patients
with subclinical hypothyroidism (normal T4 and elevated TSH)
is controversial. The condition is typically asymptomatic; how-
ever, a systematic review of cohort studies shows that in age and
sex-adjusted analyses, subclinical hypothyroidism is associated
with a hazard ratio (HR) for coronary heart disease events of 1.89
(95% CI 1.28–2.80, p < .001) and coronary heart disease mortal-
ity of 1.58 (95% CI 1.10–2.27, p = .005) for a TSH level of 10 to
19.9 mIU/L.27 (Level 2a evidence) The data for TSH levels 5 to
10 were less convincing. An evaluation of the 12 randomized-
controlled trials in this area only showed a trend toward improve-
ment of some lipid parameters (Level 1a evidence) and none of the
included trials evaluated overall mortality or cardiac morbidity.28
Patients with anti-TPO antibodies are at highest risk of progres-
sion to overt hypothryodism. When needed, thyroidectomy for
Hashimoto’s thyroiditis can be performed with low complication
rates.29 (Level 4 evidence) Surgery is the mainstay of the treatment
of Reidel’s thyroiditis, with the chief goal being decompression of
the trachea by wedge excision of the thyroid isthmus and for tissue
diagnosis. Corticosteroids, tamoxifen and more recently myco-
phenolate mofetil have been used to attenuate the inflammatory
process and have led to dramatic symptom improvements in small
case series.
Answer: Treatment for thyroiditis is primarily medical and
Levothyroxine is recommended for all patients with TSH levels
>10 uIU/mL and patients with levels of 5 to 10 uIU/mL in the
presence of a goiter or anti-TPO antibodies. (Grade B recommen-
dation) Surgical treatment may be emergently needed in acute
thyroiditis for airway compromise, persistence or progression
of abscess(es) or concern for malignancy. Thyroidectomy is pre-
ferred for poorly defined, multiple abscesses that progress despite
antibiotics or if open drainage fails. A pyriform sinus fistula, if
present, should be obliterated electively by surgical or nonsurgi-
cal means (Grade B recommendation) to avoid recurrence. For
subacute and chronic thyroiditis, thyroidectomy is reserved for
patients with proven cancer/indeterminate nodules. Thyroidec-
tomy is also indicated for the rare patient who has a prolonged
course not responsive to medical measures or for recurrent,
symptomatic disease. (Grade C recommendation) In addition,
open surgical biopsy may be needed to diagnose lymphoma or
Reidel’s thyroiditis.
6. What are the essential diagnostic tests in the workup of a
nontoxic goiter?
A complete history and physical examination is warranted with
specific questions directed toward determining a patient’s risk for
thyroid malignancy. A history of childhood radiation exposure
for head and neck tumors or lymphomas, whole body irradiation
for hematologic malignancy, family history of thyroid cancer or
cancer syndrome and a history of rapid growth, or a hoarse voice
PMPH_CH70.indd 562
at presentation increases likelihood of malignancy. Careful atten-
tion should be paid toward evaluating compressive symptoms
such as dysphagia and dyspnea. Physical examination showing
fi xation, enlarged cervical lymph nodes, and vocal cord palsy also
suggests cancer.
A TSH measurement is indicated as nontoxic goiters may
develop autonomous function. If low or suppressed, free T4
and T3 levels should be measured. High serum TSH is associ-
ated with a higher risk of malignancy in nodular goiters as
reported by Boelaert et al.30 who noted adjusted odds ratios for
cancer ranging from 2.72 to 3.88 for TSH levels >0.4–5.5 mU/L
at presentation in their cohort study of 1500 patients. (Level 2b
evidence) Serum Tg levels can be elevated in many benign thy-
roid conditions and are an insensitive and nonspecific indicator
of malignancy. In contrast, calcitonin levels are a sensitive and
specific marker of medullary thyroid cancer (MTC) with several
prospective, nonrandomized cohort studies indicating that rou-
tine screening results in early detection of MTC and improved
cure rates.31-33 (Level 2b evidence) Another study has also dem-
onstrated the cost-effectiveness of this approach and shown that
screening for MTC in the United States would yield an additional
113,000 life years at a cost increase of 5.3% (Level 3b evidence),
a level which is comparable with mammography and colonos-
copy.34 However, the prevalence estimates in this analysis also
included patients with C-cell hyperplasia/microscopic carcino-
mas which are of unclear clinical significance and the tests may
be falsely positive.
Thyroid ultrasonography is crucial in the evaluation of a
nontoxic goiter and can be used not only to determine the size,
nature, and number of nodules but also to evaluate for cervi-
cal lymphadenopathy. Ultrasound characteristics are also being
increasingly used to predict the risk of malignancy and thus
select nodules for FNAB. In a multicenter study of 831 patients by
Moon et al., 35 statistically significant (p < .05) fi ndings of malig-
nancy were a taller-than-wide shape, a spiculated margin, marked
hypoechogenicity, microcalcification, and macrocalcification
(Level 2b evidence). Similar fi ndings were noted in other studies
which also noted that the absence of a halo and the presence of
suspicious cervical lymphadenopathy also predict a higher risk
of malignancy.36,37 (Level 2b evidence) Ultrasound can also direct
image-guided FNAB and improve diagnostic yield especially in
nonpalpable nodule or nodules with a mixed solid-cystic com-
ponent. It has been shown to alter the management of up to 63%
of patients referred after a palpable abnormality was found on
physical examination.38 (Level 2b evidence) CT scans and MRI
scans may be needed to evaluate for substernal extent, changes
in size, and evidence of tracheal compression. The latter may also
be assessed by pulmonary function tests or by direct laryngos-
copy. Barium esophagograms may be needed for evaluation of
dysphagia. (Level 4 evidence)
Answer: A serum TSH level should be the first laboratory
test obtained in any patient with an apparent nontoxic goiter.39 If
the serum TSH is suppressed, a radionuclide thyroid scan should
be performed to determine whether there are hyperfunction-
ing nodules. (Grade B recommendation) Routine Tg measure-
ments are not recommended, but there is insufficient evidence
for or against routine calcitonin measurement. A diagnostic thy-
roid ultrasound is also recommended in all patients who pres-
ent with MNG. (Grade B recommendation) Additional imaging
5/22/2012 5:48:27 PM

may be obtained to assess for extent or as indicated by symptoms.
(Grade E recommendation)
7. What is the role of FNAB in the diagnosis of nontoxic
goiter?
FNAB has emerged as an accurate and low-cost diagnostic test
in the workup of nontoxic goiters. Several retrospective studies
have shown that ultrasound-guided FNAB has a lower rate of
nondiagnostic and false-negative cytology compared with those
using palpation alone.30,40,41 (Level 2b evidence) Optimum cytol-
ogy specimens should have at least six follicles each containing at
least 10 to 15 cells from at least two aspirates. Patients with mul-
tiple thyroid nodules have the same risk of malignancy as those
with STN and the risk is independent of nodule size.36,38 (Level 2b
evidence) Therefore, ultrasound characteristics can be used for
selection of nodules for FNAB. Of note, the sensitivity of micro-
calcifications as a predictor of malignancy in nodules 1cm or
less in size is lower than that in larger nodules (36.6% vs. 51.4%,
p < .05).35 This finding should prompt the evaluation of lateral
lymph nodes and possibly biopsy as even small papillary cancers
can be clinically significant and prone to recurrence. FNAB is not
needed in patients with nonnodular goiters. Ultrasound elastog-
raphy provides an estimation of tissue stiff ness and has shown
high sensitivity and specificity (92% and 90%, respectively) in pre-
dicting malignancy in thyroid nodules in a recent meta-analysis
(Level 2a evidence) and may be comparable with FNAB.42
Answer: FNAB is the diagnostic procedure of choice in the
evaluation of nodular nontoxic goiters. (Grade B recommenda-
tion) Ultrasound elastography has potential utility as a predictor
of malignancy. (Grade C recommendation)
8. What are the indications for thyroidectomy in nontoxic goi-
ter and is there a role for molecular markers in clinical decision-
making?
Typically, FNAB results are divided into four categories—
malignant (risk of cancer at excision >95%), indeterminate/suspi-
cious for neoplasm, benign or nondiagnostic. A recent NCI state of
the Science conference proposed two additional classifications—
suspicious for malignancy (risk of cancer 50–75%) and follicu-
lar lesion of undetermined significance (risk of cancer 5–10%).
In addition, the term “indeterminate” was replaced by follicular
or Hürthle cell neoplasm (risk of cancer 20–30%). In the latter
situation, the diagnosis of malignancy requires the demonstration
of capsular and/or vascular invasion. Some authors recommend
obtaining a radionuclide scan in patients with a follicular neo-
plasm and low or low-normal TSH (level 5), as the risk of cancer
is lower in this setting. The use of molecular markers can improve
diagnostic accuracy of FNAB, particularly for indeterminate
nodules, as shown in several recent prospective nonrandomized
studies. Bartolazzi et al.43 showed that galectin-3 expression was
78% (95% CI 74–82) sensitive and 93% (95% CI 90–95) specific
for the diagnosis of cancer. Nikiforov et al.44 evaluated mutations
in BRAF, RAS, RET/PTC, and PAX8/PPAR gamma and noted
that any of these mutations was a strong predictor of malignancy
(97%). (Level 2b evidence)
Patients with nodular nontoxic goiter in whom FNAB shows
benign findings do not need additional treatment, but should be
followed up with serial ultrasounds and physical examinations, due
PMPH_CH70.indd 563
Hyperthyroidism, Thyroiditis, and Nontoxic Goiter ■ 563
to the inherent risk of false-negative biopsies (up to 5%),41,45 which
some studies report is higher for nodules larger than 4 cm. (Level 3b
evidence) Nodule growth by itself is not diagnostic of malignancy,
but nodules which increase in size warrant a repeat FNA. There is no
consensus on what constitutes a nodule growth or what thresholds
should be used for a re-biopsy; however, some investigators sug-
gest that a 50% increase in nodule volume is the minimally signifi-
cant and reproducible change in size. Additional studies show that
repeat biopsy increases the diagnostic accuracy of benign lesions to
98%.46 (Level 3b evidence) Biopsies that yield nondiagnostic results
are typically complex nodules, and repeat biopsy under ultrasound
guidance has been shown to yield adequate specimens in 91% series
of patients with initial nondiagnostic biopsy. Up to 7% of nodules
may be “nondiagnostic” despite repeat biopsies and some will be
malignant at excision.47 (Level 4 evidence)
Although RAI has been shown to decrease gland volume
and improve compressive symptoms in some patients with MNG
(Level 4 evidence),48 symptomatic patients are best treated by thy-
roidectomy. The presence of a significant substernal component
is also considered to be an indication for thyroidectomy by many
authors (Level 5 evidence) due to the general inaccessibility of
nodules in this area for FNAB and the ongoing ultrasound sur-
veillance. The extent of surgery has remained a matter of debate;
however, results from a randomized-control study of 600 patients
showed that TT, although associated with higher transient com-
plication rates, leads to significantly lower recurrence and reoper-
ation rates when compared with ST resections (Hartley–Dunhill
or bilateral ST).49 (Level 1b evidence)
Answer: Nontoxic goiters in which the FNAB is diagnostic
or suspicious for malignancy should undergo thyroidectomy.39 If
the FNAB is consistent with a follicular neoplasm (with a normal
TSH) or a Hurthle cell neoplasm, either a lobectomy or a TT may
be performed, depending on lesion size, presence of other nod-
ules, and risk factors.39 Molecular markers may be considered in
selected cases to guide the management of indeterminate cytol-
ogy. (Grade C recommendation) Cytologically benign nodules
should be followed up by serial ultrasounds 6 to 18 months after
initial FNA. Enlarging nodules that are benign on repeat FNA or
those that yield persistently nondiagnostic results should be con-
sidered for surgical removal especially if clinically concerning.
(Grade C recommendation) Symptomatic goiters are best treated
by thyroidectomy, with TT becoming the preferred approach.
(Grade B recommendation)
9. Is there a role for medical therapy in the treatment of non-
toxic nodular goiter?
TSH suppression may have a role in medical management of non-
toxic goiter in areas with a high prevalence of iodine deficiency
and can decrease nodule size and potentially prevent the growth
of new nodules. In iodine-sufficient populations, the data have
been less impressive. Randomized-controlled trial analyses have
shown that less than 25% of benign nodules shrink more than 50%
with TSH suppression in iodine-replete populations.50,51 (Level 1b
evidence) In addition, a meta-analysis of existing randomized-
controlled trials did not show a significant effect of levothyroxine
treatment.52 (Level 1a evidence)
Answer: Routine TSH suppression for nodular nontoxic goi-
ters is not recommended. (Grade A recommendation)
5/22/2012 5:48:27 PM
 564 ■ Surgery: Evidence-Based Practice

Clinical Question Summary

Question Answer Levels of Grade of References
Evidence Recommendation
1 What are the TSH, free T3, T4 levels are the essential tests. Published A* 1
appropriate guidelines
diagnostic tests RAI uptake scan or pertechnetate scans 2b B 2
(laboratories to determine the presence of hot or
and imaging) for cold nodules and delineate etiology of
hyperthyroidism? hyperthyroidism.
2 What is the optimal Insufficient evidence to recommend surgery 2b — 3
definitive treatment over RAI or ATDs for Graves’ disease.
of hyperthyroidism? Patients with GO are best treated by 2b B 5, 6
surgery.
Toxic MNGs and STNs may be treated with 4 C 7
thyroidectomy or with RAI.
PEA may have a role in selected patients 2b C 9, 10
with toxic STN.
3 What is the TT is the procedure of choice in Graves’ 2b and 3a B 11-15
optimal extent disease.
of surgery for Either total or sub-TT may be performed in 2b B 12, 18
hyperthyroidism? patients with GO.
Toxic MNG can be treated with TT or 4 C 7
ST resection, whereas lobectomy is
preferred for STN.
4 What are the CBC, serum TSH, Free T3 and T4, anti- Published A* 1
appropriate thyroid antibodies (particularly anti-TPO), guidelines
diagnostic tests ESR
(laboratories RAI uptake, ultrasound (±FNAB), and CT 2b and 3b B 20-22
and imaging) for scans are helpful for diagnosis and the
thyroiditis? delineation of anatomic abnormalities.
5 What are the Treatment is primarily medical and 1a and 2b B 25, 27, 28
indications Levothyroxine is recommended for all
for surgical patients with TSH levels >10 uIU/mL and
intervention in patients with levels of 5 to 10 uIU/mL
thyroiditis? in the presence of a goiter or anti-TPO
antibodies.
A pyriform sinus fistula, if identified, should 3b B 23, 24
be obliterated surgically or nonsurgically
to reduce recurrence.
Patients with clinico-pathologic features Published A* 1
concerning for malignancy or guidelines
indeterminate nodules should be treated
with surgery thyroidectomy, which may
also be needed to diagnose Reidel’s
thyroiditis or lymphoma.
Thyroiditis refractory to prolonged medical 4 C 26, 29
treatment or recurrent, symptomatic
thyroiditis may be treated with
thyroidectomy.
6 What are the Serum TSH is recommended for all patients. Published A* 39, 30
essential diagnostic guidelines
tests in the workup A radionuclide scan should be performed in 2b B 30
of a nontoxic patients with a low-normal TSH.
goiter? Neck ultrasound should be performed in all 2b B 35-38
patients to evaluate for any nodularity
and assess its characteristics.

(Continued)

PMPH_CH70.indd 564 5/22/2012 5:48:27 PM

 Hyperthyroidism, Thyroiditis, and Nontoxic Goiter ■ 565

(Continued)
Question Answer Levels of Grade of References
Evidence Recommendation
7 What is the role FNAB is the diagnostic procedure of choice 2b B 40, 41
of FNAB in the for thyroid nodules.
diagnosis of Ultrasound elastography may have potential 2a C 42
nontoxic goiter? utility in predicting malignancy.
8 What are the Thyroid nodules with cytopathologic Published A* 39
indications for evidence diagnostic or concerning for guidelines
thyroidectomy in malignancy, Hurthle cell neoplasm, or
nontoxic goiter and follicular neoplasm (with a normal TSH)
is there a role for should be treated with thyroidectomy.
molecular markers Molecular markers can be useful in decision- 2b C 43, 44
in decision-making? making for selected patients with
indeterminate nodules; however, the
exact combination of markers remains to
be determined.
Cytologically benign nodules increasing 3b C 41, 45
in size (benign by repeat FNA) may be
considered for thyroidectomy based
on clinical concern (due to risk of false-
negative biopsy).
Nodules with persistent “nondiagnostic” 4 C 47
cytology should be considered for
excision.
Symptomatic nontoxic goiters are best 1b B 49
treated by thyroidectomy in patients who
are surgical candidates, with TT being the
procedure of choice.
9 Is there a role for Routine TSH suppression with levothyroxine 1a and 1b A 50-52
medical therapy in is not recommended for benign nodules.
the treatment of
nontoxic nodular
goiter?
* This does not necessarily imply Level 1 evidence but rather the recommendation is based on accepted practice and published guidelines regarding
these conditions.

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Diagnostic accuracy of conventional versus sonography-guided
fine-needle aspiration biopsy of thyroid nodules. Thyroid. 1998;8:
15-21.
41. Carmeci C, Jeff rey RB, McDougall IR, Nowels KW, Weigel RJ.
Ultrasound-guided fine-needle aspiration biopsy of thyroid
masses. Thyroid. 1998;8:283-289.
42. Bojunga J, Herrmann E, Meyer G, Weber S, Zeuzem S, Friedrich-
Rust M. Real-time elastography for the differentiation of benign
and malignant thyroid nodules: A meta-analysis. Thyroid;20:
1145-1150.
43. Bartolazzi A, Orlandi F, Saggiorato E, et al. Galectin-3-expression
analysis in the surgical selection of follicular thyroid nodules with
indeterminate fine-needle aspiration cytology: A prospective
multicentre study. Lancet Oncol. 2008;9:543-549.
44. Nikiforov YE, Steward DL, Robinson-Smith TM, et al. Molecu-
lar testing for mutations in improving the fine-needle aspiration
diagnosis of thyroid nodules. J Clin Endocrinol Metab. 2009;94:
2092-2098.
45. Ylagan LR, Farkas T, Dehner LP. Fine needle aspiration of the
thyroid: A cytohistologic correlation and study of discrepant
cases. Thyroid. 2004;14:35-41.
46. Oertel YC, Miyahara-Felipe L, Mendoza MG, Yu K. Value of
repeated fine needle aspirations of the thyroid: An analysis of over
ten thousand FNAs. Thyroid. 2007;17:1061-1066.
47. Yeh MW, Demircan O, Ituarte P, Clark OH. False-negative fine-
needle aspiration cytology results delay treatment and adversely
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5/22/2012 5:48:27 PM
 CHAPTER 71
Hyperparathyroidism
Jason D. Prescott and Robert Udelsman
INTRODUCTION
Hyperparathyroidism is the result of excessive serum parathyroid
hormone (PTH) production and the resultant hypercalcemia.
The multiorgan pathologic effects of hyperparathyroidism were
first recognized in the 1950s and include neuropsychiatric and
neuromuscular disturbances, osteoporosis, peptic ulcer disease,
pancreatitis, nephrolithiasis, nephrocalcinosis, and cardiovascu-
lar disease.1-4 Three major causes of hyperparathyroidism have
been identified. Primary hyperparathyroidism (1° HPT) is due
to an intrinsic abnormality of one or more parathyroid glands. It
is caused by (1) adenomas, (2) four-gland parathyroid hyperpla-
sia, or (3) parathyroid carcinoma. Single adenomas account for
approximately 85% of cases, whereas hyperplasia is responsible
for 15%. Parathyroid carcinoma is extremely rare.
Secondary hyperparathyroidism (2° HPT) results from four-
gland hyperplasia. Unlike 1° HPT, 2° HPT occurs in response
to continuous stimulation of normal parathyroid cells by chronic
hypocalcemia, most commonly in the context of chronic renal failure
(CRF). Tertiary hyperparathyroidism (3° HPT) is a rare condition
in which chronically overstimulated parathyroid tissue associated
with 2° HPT becomes autonomous, continuing to overproduce
PTH despite correction of underlying hypocalcemia . Patients with
3° HPT almost always have four-gland enlargement although one of
these glands is almost always asymmetrically enlarged.5
1. How is hyperparathyroidism diagnosed?
Calcium-mediated negative feedback inhibition normally main-
tains a tight inverse relationship between serum PTH and calcium
levels. Disruption of this relationship produces hyperparathy-
roidism. The diagnosis of hyperparathyroidism is thus biochemi-
cal, hinging on the presence of inappropriately elevated intact
parathyroid hormone (iPTH) levels (normal 10–65 pg/mL) in the
context of persistent hypercalcemia (normal 8.5–10.5 mg/dL). Signs
and symptoms of hyperparathyroidism help to confirm the diag-
nosis, but are not required, as some patients are asymptomatic.
568
PMPH_CH71.indd 568
Several familial syndromes predisposing individuals to para-
thyroid hyperplasia have been described, the most common of
which are multiple endocrine neoplasias type 1 and type 2A. In
addition to hyperparathyroidism, these genetic syndromes pre-
dispose affected kindreds to additional syndromic manifestations.
Careful assessment of family history is thus crucial in the workup
of suspected hyperparathyroidism and genetic testing should pre-
cede treatment in suspicious cases.
Familial hypocalciuric hypercalcemia (FHH) is a mild hyper-
calcemic condition. Affected patients present with mild hypercal-
cemia, hypocalciuria, and normal or slightly elevated serum
iPTH levels.6 This condition is rarely symptomatic and does not
generally require treatment. FHH can be distinguished from con-
ventional 1° HPTH by careful assessment of family history and by
the measurement of 24-h urinary calcium level, which is almost
always less than 30 mg in FHH.
Hypocalcemia is a cardinal feature of CRF. It is largely due
to impaired vitamin D production and virtually all patients with
a glomerular fi ltration rate of less than 60 mL/min/1.73 m2 will
develop some degree of four-gland parathyroid hyperplasia.7 The
severity of 2° HPT is linearly related to the degree of renal dys-
function and thus the frequency of hyperparathyroidism screen-
ing in CRF patients depends on the degree of renal disease. Stage 3
chronic renal disease patients (GFR 30–59 mL/min/1.73 m2) should
undergo annual biochemical testing for 2° HPTH whereas more
advanced renal dysfunction merits screening every 3 months.8
3° HPT is diagnosed when hypercalcemia and hyperparathyroid-
ism develop after definitive treatment of 2° HPT. It can also occur
following renal transplantation.
Answer: Hyperparathyroidism is diagnosed when serum
iPTH levels are persistently elevated or inadequately suppressed in
the context of persistent hypercalcemia. (Grade A recommenda-
tion). The subtype of hyperparathyroidism, for example, primary,
secondary, or tertiary, is determined on the basis of medical his-
tory and biochemical testing. A careful family history is required
in all hyperparathyroidism patients and suspicious findings man-
date genetic evaluation. A 24-h urinary calcium screen can help
5/22/2012 5:49:54 PM

rule out FHH, which may mimic the biochemical features of con-
ventional 1° HPTH. (Grade B recommendation)
2. What are the optimal treatments for hyperparathyroidism?
Surgical resection of hyperfunctioning parathyroid tissue is the
only means of curing 1° HPT and cure rates greater than 95%
are common when parathyroid surgery is performed by an expe-
rienced endocrine surgeon.9,10 Thus, virtually all symptomatic
patients should undergo either resection of causative parathyroid
adenoma(s) or, if four-gland disease is present, subtotal parathyroi-
dectomy. En bloc parathyroidectomy is indicated in rare cases of
parathyroid carcinoma. In contrast, the benefits of surgery remain
unclear in patients having biochemically proven 1° HPT but for
whom symptoms and additional signs of hyperparathyroidism
are absent. Expert consensus regarding such cases was recently
refined at the third international workshop on asymptomatic pri-
mary hyperparathyroidism. This workshop identified a high prob-
ability of benefit from surgery in all asymptomatic 1° HPT patients
less than 50 years old, those unable or unwilling to comply with
biannual biochemical surveillance, in those having a total serum
calcium greater than 1.0 mg/dL above the upper limit of normal, a
creatinine clearance of less than 60 mL/min, a bone mineral density
T score is less than −2.5 at any site, or for whom a history of fragility
fracture was present.11 Asymptomatic 1° HPT patients meeting one
or more of these criteria should be referred for surgery.
Recent data indicate that the majority of supposedly asymp-
tomatic 1° HPT patients actually experience symptoms, most
com monly resorptive bone disease and subtle neurocognitive
disturbances, and that these symptoms often improve following
parathyroid surgery.12-15 Further, progression to symptomatic dis-
ease is common and approximately 27% of asymptomatic patients
eventually undergo parathyroid surgery.16 All asymptomatic, non-
operative cases of 1° HPT therefore merit biannual re-evaluation
for both disease progression and the need for surgery. Bone densi-
tometry should be performed annually in these cases.
Medical therapy for 1° HPT offers inferior disease control rela-
tive to surgical resection and is only indicated in those few patients
who cannot tolerate surgery.17 Bisphosphonates and hormone
replacement therapy can decrease bone turnover and improve
bone mineral density in 1° HPT patients, although these findings
have not been correlated with decreased fracture rates.18,19 Calci-
mimetics can decrease serum calcium and iPTH levels in 1° HPT,
although these medications do not improve bone mineral density
or bone turnover.20 Studies examining the effects of these medi-
cations on the other pathologic features of hyperparathyroidism
have not been reported.
Management of 2° HPT focuses on re-establishing normocal-
cemia. This involves the correction of the underlying disease when
possible, or medical therapy to normalize serum calcium levels
when it is not. Oral activated vitamin D analogs and calcimimet-
ics provide good control of serum calcium and iPTH levels in the
majority of CRF patients, although the optimal therapy for such
patients remains renal transplantation.21,22 Surgery for 2° HPT is
rarely indicated, being reserved for symptomatic cases refractory
to medical therapy and for patients developing calciphylaxis. The
optimal operative intervention for those 2° HPT patients who
do require surgery remains controversial. Subtotal (3.5 gland)
parathyroidectomy and total parathyroidectomy with autotrans-
plantation are associated with recurrence rates of up to 33%.
PMPH_CH71.indd 569
Hyperparathyroidism ■ 569
Although some groups have employed total parathyroidectomy
without autotransplantation, this technique has not gained wide
acceptance.23,24 Long-term prospective outcome data comparing
these three techniques have not been reported and the choice of
surgical procedure continues to depend on surgeon preference.
Calciphylaxis is a rare, life-threatening complication of hyper-
parathyroidism characterized by progressive calcification of cuta-
neous tissues. This process manifests as painful purpuric skin
lesions that respond poorly to local wound care, become chroni-
cally infected, and lead to sepsis and death in up to 92% of cases.25
Although data supporting parathyroid surgery for calciphylaxis
are mixed, the absence of effective alternative therapies mandates
aggressive surgical intervention.
Surgery for asymptomatic 2° HPT patients demonstrating
persistent biochemical evidence of hyperparathyroidism despite
medical therapy remains controversial. Although several reports
describe biochemical indications for surgery in 2° HPT patients,
no long-term data evaluating outcomes, with and without surgery,
have been reported.26 It is thus reasonable to apply the same criteria
established for the surgical management of asymptomatic 1° HPT
when assessing asymptomatic 2° HPT patients for surgery.11
The management of 3° HPT is similar to that of 1° HPT, as
resection of parathyroid adenoma(s) or subtotal/total parathyroi-
dectomy, when four-gland disease is present, offers the only oppor-
tunities for cure.27,28 Indications for surgery among asymptomatic
3° HPT patients are controversial for the same reasons associated
with the surgical management of asymptomatic 1° HPT. Thus,
it is reasonable to apply the same recommendations guiding the
surgical management and surveillance of asymptomatic 1° HPT
patients to asymptomatic 3° HPT patients.11
Answer: Symptomatic 1° HPT and 3° HPT patients should be
referred for surgery (Grade A recommendation), whereas 2° HPT
patients should undergo parathyroid resection if medical manage-
ment fails (Grade A recommendation) or if calciphylaxis devel-
ops. (Grade B recommendation) Medical therapy for 1° HPT and
3° HPT should be limited to patients unable to tolerate parathyroid
surgery. Asymptomatic 1° HPT patients should be evaluated for
surgery according to the guidelines published by the third interna-
tional workshop on asymptomatic primary hyperparathyroidism.11
(Grade A recommendation) These same guidelines may be extrapo-
lated to asymptomatic 3° HPT or medically refractory asymptom-
atic 2° HPT patients, because no evidence-based recommendations
specifying surgical management in such cases have been reported.
3. What is the preoperative management of hyperparathy-
roidism?
The depth of the surgeon’s operating experience is the most impor-
tant determinant in maximizing the probability of cure and min-
imizing morbidity in patients requiring endocrine surgery.29-31
Although data comparing surgical outcomes to case volume fol-
lowing parathyroid surgery have not yet been reported, the clear
association between experience and surgical outcome following
thyroid surgery merits referral of these patients to an experienced
endocrine surgeon.
Optimal surgical outcomes require careful preoperative eva-
luation of all hyperparathyroidism patients. In addition to a
thorough history and physical examination, all cases should be
biochemically verified. Previous medical management should be
reviewed with the referring endocrinologist for all 2° HPT patients
5/22/2012 5:49:54 PM
 570 ■ Surgery: Evidence-Based Practice
and cases in which medical treatment options remain should not
undergo surgery. Surgical indications should be reviewed for
asymptomatic patients and surgery should be deferred in favor of
careful surveillance when these indications are absent.11 Preop-
erative laryngoscopy can help stratify surgical risk by alerting the
surgeon to preexisting recurrent laryngeal nerve (RLN) dysfunc-
tion. Laryngoscopy should be considered for all uncomplicated
hyperparathyroidism patients and is mandatory when the risk of
operative RLN injury is high, as in reoperative cases. Preoperative
localization imaging must be obtained when minimally invasive
parathyroidectomy (MIP) is planned and when reoperative sur-
gery, which involves a distorted and scarred reoperative field, is
necessary.
Answer: All hyperparathyroidism patients requiring surgery
should be referred to an experienced endocrine surgeon. (Grade B
recommendation) Preoperative evaluation should include a com-
plete history and physical examination as well as biochemical
confirmation of hyperparathyroidism. Failure of medical man-
agement should be confirmed preoperatively in cases of 2° HPT.
Preoperative laryngoscopy should be considered for all patients
and is mandatory in reoperative cases. (Grade D recommenda-
tion) Preoperative localization imaging is required when MIP or
reoperative surgery is planned.
4. Which imaging studies should be used preoperatively for
localization of abnormal parathyroid tissue?
The purpose of preoperative imaging in hyperparathyroidism is
to localize hyperfunctioning parathyroid tissue to create a road
map for the surgeon. Such a preoperative knowledge allows the
surgeon to restrict the extent of neck exploration to area(s) har-
boring abnormal parathyroid tissue, which minimizes operative
morbidity. Therefore, cases in which the scope of neck exploration
cannot be focused (e.g., four-gland disease) do not generally ben-
efit from preoperative imaging. Imaging studies should never be
employed for diagnostic purposes, as available imaging modali-
ties lack the sensitivity and specificity of biochemical tests used to
detect hyperparathyroidism.
Initial preoperative imaging for hyperparathyroidism should
be noninvasive and inexpensive. Invasive and/or costly tech-
niques should be reserved for reoperative cases in which initial
imaging is nonlocalizing. Cervical ultrasound (US) and sestamibi
scintigraphy (MIBI) are relatively inexpensive, readily available,
and safe modalities that are suitable first-line imaging choices.
Computed tomography (CT) scanning, 4-dimensional CT (4D
CT) scanning, and magnetic resonance imaging (MRI) are more
expensive studies and CT scanning necessitates exposure to ion-
izing radiation. Positron emission tomography (PET) and com-
bined PET-CT scanning are additional imaging options, although
both studies are more expensive than either MRI or CT alone.
Selective arteriography with venous blood iPTH sampling (SVS)
is expensive and invasive. Arteriography with SVS should thus
be reserved for reoperative cases in which adequate preoperative
localization cannot be obtained using less invasive and less expen-
sive imaging techniques. Individual imaging studies often fail to
adequately localize causative hyperfunctioning parathyroid tissue
and sequential imaging, employing multiple different modalities,
should be employed in such cases.
The quality of preoperative imaging is highly variable. Vari-
ables include the quality of the imaging study, the patient’s body
habitus as well as his or her ability to tolerate the study, the presence
PMPH_CH71.indd 570
of implants or prostheses, and the quality of the interpreting radi-
ologist. Consequently, reported positive-predictive values for each
preoperative imaging modality are extremely variable and diffi-
cult to compare.32 Given such variability, the potential for accu-
rate preoperative imaging should be optimized by performing
these studies at experienced centers.
Answer: Multiple preoperative imaging studies can accu-
rately localize causative hyperfunctional parathyroid tissue, thus
allowing the surgeon to limit the extent of operative exploration.
Nonetheless, preoperative imaging accuracy is highly variable
among institutions and no gold standard modality has been iden-
tified. The choice of preoperative imaging study is therefore based
on the morbidity and cost associated with each technique. (Grade
A recommendation) US and MIBI are inexpensive, benign, and
often accurate. Either test is appropriate for the initial preopera-
tive evaluation of hyperparathyroidism. CT, MRI, and PET scans
are progressively more expensive studies, with CT and PET scans
necessitating ionizing radiation exposure. These imaging modali-
ties can be considered if US and MIBI fail to localize aberrant
parathyroid tissue. Alternatively, an experienced parathyroid
surgeon can explore nonlocalized patients with a high degree of
operative success. Arteriography with SVS is expensive and should
be reserved for reoperative cases in which less morbid studies fail
to localize causative parathyroid lesions. (Grade A recommenda-
tion) US-guided fine needle aspiration for PTH should also be
considered when feasible in the reoperative patient.
5. What are the surgical approaches for treating hyperparathy-
roidism and what intraoperative adjuncts best facilitate para-
thyroid surgery?
The choice of surgical approach for hyperparathyroidism depends
on the location(s) of causative hyperfunctioning parathyroid tis-
sue. Until recently, identification of aberrant parathyroid glands
required four-gland exploration under general anesthesia. This
approach is still preferred in known cases of four-gland dis-
ease and in patients for whom preoperative localization studies
are inadequate. With the advent of intraoperative serum iPTH
(IoPTH) monitoring, refinements in cervical nerve block tech-
nique, and the development of accurate preoperative imaging
modalities, MIP became possible. This technique involves focused
neck exploration via a small cervical incision under regional anes-
thesia, thus minimizing operative morbidity.10
Hyperfunctional parathyroid tissue is usually cervical and can
be readily excised via an abbreviated Kocher incision. Excellent
exposure can be obtained by either a standard medial approach or
by using a lateral approach. The latter approach involves mobiliza-
tion lateral to the strap muscles and allows the surgeon to avoid
previously explored operative fields in reoperative cases. Because
most hyperfunctioning parathyroid tissue is found at one or more
normal (eutopic) anatomic parathyroid gland positions, the medial
approach generally affords the most direct means of resection. The
selection of operative approach is influenced by multiple factors,
including surgeon preference, preoperative localization, and his-
tory of previous neck surgery. Intraoperative circumstances may
merit the use of both techniques.
Cases in which preoperative localization studies identify
extracervical hyperfunctional parathyroid tissue may necessitate
alternative surgical approaches. Intrathymic or retroesophageal
disease can often be resected via a cervical approach, although
rare patients will require exposure via partial or complete median
5/22/2012 5:49:54 PM

sternotomy and/or by transthoracic techniques, 33,34 including
thorascopic approaches.
Parathyroid adenomas should be excised carefully to avoid
capsule rupture and seeding of the operative field with abnormal
or potentially malignant parathyroid cells. Parathyromatosis, an
iatrogenic form of recurrent hyperparathyroidism, in which para-
thyroid nodules develop in the previous surgical field, can develop
after accidental seeding. Great care must be taken to preserve ade-
quate postoperative parathyroid function. Inferior thyroid artery
branches supplying residual parathyroid tissues must be carefully
protected during surgery. Suspected intraoperative devitalization
of normal parathyroid glands should prompt autotransplantation
of parathyroid tissue.
Intraoperative adjuvant techniques can facilitate identification
of abnormal parathyroid tissue and may help minimize the risk of
injury to the recurrent and superior laryngeal nerves. Intraopera-
tive US has been used successfully to guide parathyroid resection,
although this technique has generally given way to accurate pre-
operative imaging. Intraoperative Geiger counter (gamma probe)
detection of radiolabeled sestamibi, which localizes preferentially
to hyperfunctioning parathyroid tissue, can also be used to guide
cervical exploration. Background signal from normal tissues,
however, can limit the intraoperative sensitivity of this technique
and no data demonstrating additive value, relative to preoperative
MIBI scanning alone, have been reported.
Intraoperative monitoring of serum iPTH levels allows verifi-
cation of disease extirpation by demonstrating a decline in serum
iPTH levels after resection of hyperfunctioning parathyroid tis-
sue. For 1° HPT, IoPTH monitoring is rapid and a serum iPTH
decrease of at least 50% after resection is associated with cure in
up to 99.4% of cases.10 The value of IoPTH monitoring for 2° HPT
and 3° HPT is less clear, because PTH clearance is impaired by
renal dysfunction. Further, the specificity of some commercially
available iPTH assays is insufficient to identify intraoperative cure
in some renal failure patients.35 Finally, the percent decline in pre-
excisional IoPTH level correlating with cure is unclear in the con-
text of renal failure, with some studies demonstrating a need for
at least a 90% drop in IoPTH level.36,37
Used in combination, preoperative imaging studies, intra-
operative adjuncts, and meticulous operative technique allow for
successful identification and resection of hyperfunctioning para-
thyroid tissue in almost all cases. Nonetheless, rare cases occur in
which these techniques fail to achieve a cure. In such instances,
neck exploration may reveal three eutopically localized normal
parathyroid glands, with the fourth gland remaining undiscov-
ered. The surgeon must be cognizant of and capable of explor-
ing both eutopic and ectopic parathyroid locations; these include
retroesophageal, retrophargeal, intrathymic, intrathyroidal, and
carotid sheath locations.
Techniques for minimizing the risk of intraoperative nerve
injury during surgery include real-time intraoperative electro-
myographic nerve monitoring, direct visualization of one or both
RLNs, and direct assessment of nerve function, as measured by
intraoperative voice quality testing in conscious patients receiv-
ing regional anesthesia. A recent prospective study assessing the
protective potential of intraoperative electromyographic nerve
monitoring demonstrated no improvement in nerve injury rates
when this technique was employed for remedial 1° HPT.38 Fur-
ther, recent guidelines for the standardization and application of
this technique suggest a maximum positive- predictive value of
PMPH_CH71.indd 571
Hyperparathyroidism ■ 571
only 76%.39 No data assessing the impact of direct intraoperative
voice quality monitoring on RLN injury risk have been reported.
It is clear, however, that surgical experience is paramount to safe
surgery.
Answer: Surgeon preference, preoperative disease localiza-
tion, and history of previous neck surgery influence the selection
of operative approach and both medial and lateral techniques may
be employed. All patients should be prepped and draped to facili-
tate either operative approach and, when regional anesthesia is
employed, efficient conversion to general anesthesia may be nec-
essary. Resection of extracervical parathyroid tissue may rarely
require partial or complete median sternotomy or transthoracic
exposure. The rapid IoPTH assay appears to be the most useful
intraoperative adjunct facilitating a curative operation and its use
should be considered in all operative 1° HPT patients. (Grade A
recommendation) The value of IoPTH monitoring during para-
thyroid resection in 2° HPT and 3° HPT patients is less clear,
because renal dysfunction alters the kinetics of PTH clearance
and impairs the specificity of some IoPTH assays. In this context,
the use of IoPTH monitoring should be used with caution. Intra-
operative neuromonitoring of recurrent nerve function has not
been demonstrated to protect nerves at risk.
6. How are the common complications of parathyroid surgery
managed?
Complications following parathyroid surgery most commonly
result from injury to the RLN and/or parathyroid devitalization.
The RLNs provide innervation of all laryngeal muscles with the
exception of the cricothyroideus. A unilateral RLN will most
likely compromise the voice quality, although some patients will
be asymptomatic. Bilateral RLN injury results in bilateral vocal
cord medialization, which will severely compromise the airway
and can result in airway obstruction. Unilateral postoperative
RLN dysfunction generally manifests as hoarseness and is usu-
ally temporary, resulting from minor traction or crush injuries.
Permanent RLN injury is rare when parathyroid surgery is per-
formed by an experienced endocrine surgeon, occurring in less
than 1% of cases.10,40
Transient hypocalcemia resulting from temporary postoper-
ative parathyroid dysfunction can occur following either subtotal
parathyroidectomy or total parathyroidectomy with autotrans-
plantation. Normalization of serum calcium level should be veri-
fied in the immediate postoperative period using serial serum
calcium checks and a short course of prophylactic oral calcium
carbonate, with or without activated vitamin D supplementa-
tion.41 Transient hypocalcemia may also develop when exten-
sive exploration of all four glands is required and serum calcium
levels should also be monitored in these patients. Hungry bone
syndrome, which involves rapid absorption of serum calcium by
the chronically demineralized bone after normalization of serum
PTH, is associated with curative parathyroid resection in renal
failure patients and can produce profound hypocalcemia. For
this reason, postoperative 2° HPT and 3° HPT patients must be
carefully monitored for hypocalcemia and must be aggressively
treated when hypocalcemia is discovered. Inadvertent parathy-
roid devitalization resulting in permanent hypocalcemia is rare,
occurring in less than 1% of cases performed by an experienced
surgeon.10,28,40 All cases of permanent postoperative hypocalcemia
require life-long calcium supplementation, with or without vita-
min D administration.
5/22/2012 5:49:55 PM
 572 ■ Surgery: Evidence-Based Practice

Answer: Hypocalcemia following subtotal parathyroidec-
tomy, or following cases involving exploration of all four parathy-
roid glands, is usually transient. Normalization of serum calcium
levels should be verified. (Grade C recommendation) Patients
demonstrating persistent postoperative hypocalcemia may require
life-long calcium and vitamin D supplementation. Postopera-
tive 2° HPT and 3° HPT patients must be carefully monitored for
hungry bone syndrome and hypocalcemia must be aggressively
treated in these patients. The RLN(s) must be identified and care-
fully preserved during surgical exploration.

Clinical Question Summary

Question
1 How is hyperparathyroidism
diagnosed?
2 What are the
causes of primary
hyperparathyroidism?
3 What is the optimal
treatment for symptomatic
primary hyperthyroidism?
4 What is a minimally invasive
parathyroidectomy (MIP)?
5 What are the complications
associated with
parathyroidectomy?
Answer Grade of References
Recommendation
Primary hyperparathyroidism is diagnosed when the serum A 7, 8, 17
PTH level is inappropriately elevated relative to the serum
calcium level in the setting of normal renal function.
Secondary hyperparathyroidism most commonly occurs in
renal failure patients who have elevated serum PTH levels.
Parathyroid adenoma (85%) A 11, 16
Parathyroid hyperplasia (15%)
Parathyroid carcinoma (<1%)
Surgery A 10, 16
It is a focused operation based on preoperative localization A 10
that utilizes an intraoperative adjunct such as an
intraoperative parathyroid hormone assay to confirm the
adequacy of resection.
The overall complication rate should be less than 3%; within A 9, 10
this context complications include recurrent nerve injury,
symptomatic hypocalcemia, and neck hematoma.

REFERENCES 10. Udelsman R, Lin Z, Donovan P. The superiority of minimally

1. Cope O, Culver PJ, Mixter CG, et al. Pancreatitis, a diagnostic
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2. Fitz TE, Hallman BL. Mental changes associated with hyperpara-
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89:547-551.
3. Kretschmer HL. Parathyroid adenoma and renal calculi. J Urol.
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4. St Goar WT. Gastrointestinal symptoms as a clue to the diagno-
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5. Kilgo MS, Pirsch JD, Warner TF, et al. Tertiary hyperparathyroid-
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8. K/DOQI clinical practice guidelines for bone metabolism and
disease in chronic kidney disease. Am J Kidney Dis. 2003;42:
S1-201.
9. Lo Gerfo P. Bilateral neck exploration for parathyroidectomy
under local anesthesia: A viable technique for patients with
coexisting thyroid disease with or without sestamibi scanning.
Surgery. 1999;126:1011-1014; discussion 1014-1015.
invasive parathyroidectomy based on 1650 consecutive pat-
ients with primary hyperparathyroidism. Ann Surg. 2011;253:
585-591.
11. Bilezikian JP, Khan AA, Potts JT, Jr. Guidelines for the manage-
ment of asymptomatic primary hyperparathyroidism: Summary
statement from the third international workshop. J Clin Endo-
crinol Metab. 2009;94:335-339.
12. Ambrogini E, Cetani F, Cianferotti L, et al. Surgery or surveil-
lance for mild asymptomatic primary hyperparathyroidism: A
prospective, randomized clinical trial. J Clin Endocrinol Metab.
2007;92:3114-3121.
13. Rao DS, Phillips ER, Divine GW, et al. Randomized controlled
clinical trial of surgery versus no surgery in patients with mild
asymptomatic primary hyperparathyroidism. J Clin Endocrinol
Metab. 2004;89:5415-5422.
14. Pasieka JL, Parsons LL, Demeure MJ, et al. Patient-based surgical
outcome tool demonstrating alleviation of symptoms following
parathyroidectomy in patients with primary hyperparathyroid-
ism. World J Surg. 2002;26:942-949.
15. Roman SA, Sosa JA, Pietrzak RH, et al. The effects of serum
calcium and parathyroid hormone changes on psychological
and cognitive function in patients undergoing parathyroidec-
tomy for primary hyperparathyroidism. Ann Surg. 2011;253:
131-137.
16. Silverberg SJ, Shane E, Jacobs TP, et al. A 10-year prospective
study of primary hyperparathyroidism with or without parathy-
roid surgery. N Engl J Med. 1999;341:1249-1255.

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17. Khan A, Grey A, Shoback D. Medical management of asymp-
tomatic primary hyperparathyroidism: Proceedings of the third
international workshop. J Clin Endocrinol Metab. 2009;94:
373-381.
18. Khan AA, Bilezikian JP, Kung AW, et al. Alendronate in primary
hyperparathyroidism: A double-blind, randomized, placebo-
controlled trial. J Clin Endocrinol Metab. 2004;89:3319-3325.
19. Grey AB, Stapleton JP, Evans MC, et al. Effect of hormone repla-
cement therapy on bone mineral density in postmenopausal
women with mild primary hyperparathyroidism. A random-
ized, controlled trial. Ann Intern Med. 1996;125:360-368.
20. Shoback DM, Bilezikian JP, Turner SA, et al. The calcimimetic
cinacalcet normalizes serum calcium in subjects with pri-
mary hyperparathyroidism. J Clin Endocrinol Metab. 2003;88:
5644-5649.
21. Block GA, Martin KJ, de Francisco AL, et al. Cinacalcet for sec-
ondary hyperparathyroidism in patients receiving hemodialysis.
N Engl J Med. 2004;350:1516-1525.
22. Jean G, Vanel T, Terrat JC, et al. Prevention of secondary hyper-
parathyroidism in hemodialysis patients: The key role of native
vitamin D supplementation. Hemodial Int. 2010;14:486-491.
23. Hargrove GM, Pasieka JL, Hanley DA, et al. Short- and long-term
outcome of total parathyroidectomy with immediate autograft-
ing versus subtotal parathyroidectomy in patients with end-stage
renal disease. Am J Nephrol. 1999;19:559-564.
24. Chan HW, Chu KH, Fung SK, et al. Prospective study on dialy-
sis patients after total parathyroidectomy without autoimplant.
Nephrology (Carlton). 2010;15:441-447.
25. Lal G, Nowell AG, Liao J, et al. Determinants of survival in pat-
ients with calciphylaxis: A multivariate analysis. Surgery. 2009;
146:1028-1034.
26. Dumasius V, Angelos P. Parathyroid surgery in renal failure
patients. Otolaryngol Clin North Am. 2010;43:433-440, x-xi.
27. Pitt SC, Sippel RS, Chen H. Secondary and tertiary hyperpara-
thyroidism, state of the art surgical management. Surg Clin North
Am. 2009;89:1227-1239.
28. Nichol PF, Starling JR, Mack E, et al. Long-term follow-up of
patients with tertiary hyperparathyroidism treated by resection
of a single or double adenoma. Ann Surg. 2002;235:673-678; dis-
cussion 678-680.
29. Stavrakis AI, Ituarte PH, Ko CY, et al. Surgeon volume as a pre-
dictor of outcomes in inpatient and outpatient endocrine sur-
gery. Surgery. 2007;142:887-899; discussion 887-899.
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30. Gourin CG, Tufano RP, Forastiere AA, et al. Volume-based
trends in thyroid surgery. Arch Otolaryngol Head Neck Surg. 2010;
136:1191-1198.
31. Sosa JA, Bowman HM, Tielsch JM, et al. The importance of sur-
geon experience for clinical and economic outcomes from thy-
roidectomy. Ann Surg. 1998;228:320-330.
32. Prescott JD, Udelsman R. Remedial operation for primary hyper-
parathyroidism. World J Surg. 2009;33:2324-2334.
33. Chae AW, Perricone A, Brumund KT, et al. Outpatient video-
assisted thoracoscopic surgery (VATS) for ectopic mediastinal
parathyroid adenoma: A case report and review of the literature.
J Laparoendosc Adv Surg Tech A. 2008;18:383-390.
34. Gold JS, Donovan PI, Udelsman R. Partial median sternotomy:
An attractive approach to mediastinal parathyroid disease. World
J Surg. 2006;30:1234-1239.
35. Bieglmayer C, Kaczirek K, Prager G, et al. Parathyroid hor-
mone monitoring during total parathyroidectomy for renal
hyperparathyroidism: Pilot study of the impact of renal func-
tion and assay specificity. Clin Chem. 2006;52:1112-1119.
36. de Vos tot Nederveen Cappel R, Bouvy N, de Herder W, et al.
Novel criteria for parathyroid hormone levels in parathyroid
hormone-guided parathyroid surgery. Arch Pathol Lab Med.
2007;131:1800-1804.
37. Kara M, Tellioglu G, Bugan U, et al. Evaluation of intraopera-
tive parathormone measurement for predicting successful sur-
gery in patients undergoing subtotal/total parathyroidectomy
due to secondary hyperparathyroidism. Laryngoscope. 2010;120:
1538-1544.
38. Yarbrough DE, Thompson GB, Kasperbauer JL, et al. Intraop-
erative electromyographic monitoring of the recurrent laryngeal
nerve in reoperative thyroid and parathyroid surgery. Surgery.
2004;136:1107-1115.
39. Randolph GW, Dralle H, Abdullah H, et al. Electrophysiologic
recurrent laryngeal nerve monitoring during thyroid and para-
thyroid surgery: International standards guideline statement.
Laryngoscope. 2011;121(Suppl 1):S1-16.
40. Kebebew E, Duh QY, Clark OH. Tertiary hyperparathyroidism:
Histologic patterns of disease and results of parathyroidectomy.
Arch Surg. 2004;139:974-977.
41. Wang TS, Cheung K, Roman SA, et al. To supplement or not to
supplement: A cost-utility analysis of calcium and vitamin D
repletion in patients after thyroidectomy. Ann Surg Oncol. 2010.
[Epub ahead of print.]
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 PART XII

THE BREAST

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PMPH_CH72.indd 576 5/22/2012 5:50:36 PM

Screening, Breast Biopsy,
Benign Disease
Adora Fou-Cockburn and Mark I. Cockburn
INTRODUCTION
Breast cancer is the second leading cause of cancer death after
lung cancer among women in North America. A woman’s life-
time risk of developing breast cancer is 1 in 8.2, with the incidence
increasing with age. One in 30 will die from their disease. Death
rates finally began to decrease in the 1990s, with larger decreases
in women younger than 50 (3.2% per year) than in women over
50 (2.0% per year).1,2 These death rates are indicative of progress
in screening for earlier detection, treatments, and most recently,
decreased overall incidence.
SCREENING FOR BREAST CANCER
Breast cancer screening is performed on asymptomatic patients
with the goal of early detection. Overall and disease-free survival
is improved in treating an early stage cancer compared with treat-
ing a late stage cancer. Breast cancer screening includes breast
self-examination (BSE), clinical breast examination (CBE) by a
physician, risk assessment, and screening mammography. 3 In
well-selected cases, screening may also include breast ultrasound
or breast MRI. Patient with an existing clinical problem, such as a
new breast mass, needs a diagnostic evaluation and is no longer a
screening candidate.
When investigating population-based screening practices,
the magnitude of benefit should outweigh harms. In breast
cancer screening, absolute risk reduction increases and harm
decreases with increasing age.4 Th is is due to multiple factors.
The accuracy of mammography screening5,6 is affected by age
and density of the breast. There are higher false-positive rates in
the younger screening population because of breast density and
higher rates of BSE practice.7 The younger population appar-
ently also tolerates a higher risk of false-positive results.8 All
patients should be informed of the risks as well as the benefits
of screening.
577
PMPH_CH72.indd 577
CHAPTER 72
Clinical discussion with women about screening must include
accurate risk assessment. There are two broad categories: nor-
mal risk and increased risk. Women at increased risk have dif-
ferent screening regimens that are beyond the investigation of
this discussion. High-risk women include (1) women who have
received thoracic or mantle radiation,9 (2) women aged 35 or
older who have a 5-year risk of invasive cancer >1.7% based on
risk calculation models, such as the Gail model,10 (3) women
with a >20–25% lifetime risk of breast cancer due to family
history, (4) women who are BRCA 1 or 2 carriers, (5) women
with a previous biopsy of atypical ductal hyperplasia (ADH) or
lobular carcinoma in situ (LCIS), and (6) women with a previous
breast cancer.
Routine risk factors for asymptomatic women include age
>50, female gender, ethnicity, family history of premenopausal
breast cancer in a first degree relative, early menarche <12 years,
late menopause >55 years, late age at first full-term pregnancy
(>30 years), nulliparity, breast density, history of breast biopsies
(with ADH, LCIS), no breast feeding, obesity, exogenous hormone
use, and alcohol use.11-13 These risk factors may increase a woman’s
risk up to a RR of 4.0 and must be discussed with her at the time
of screening.
Breast Self–Examination
1. Is the breast self-examination (BSE) a useful screening tool?
The traditional goal of BSE was to detect palpable tumors. The
newer philosophy of BSE is its role in increasing self-awareness
of a woman’s normal breast so that there is improved ability to
detect changes and seek appropriate clinical help.14 Greenwald
et al. in the premammography era showed that those who prac-
ticed BSE had their cancers detected at a smaller size and earlier
stage.15 Interestingly, even among the BSE patients, cancers were
most commonly detected incidentally, giving weight to the asso-
ciation between patients who practice BSE and increased body
awareness.
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 578 ■ Surgery: Evidence-Based Practice
Although there are actual recommendations published
against BSE16 (Level 1b evidence), the American Cancer Society,
American College of Obstetricians and Gynecologists, and The
American Cancer Society still recommend that women practice
BSE especially after age 40. Hackshaw et al.17 (Level 2a evidence)
in a meta-analysis of 20 observational studies and three clinical
trials determined that BSE had no effect on breast cancer mortal-
ity. In a well-conducted RCT of over 200,000 women investigating
whether or not instruction of BSE had an effect on breast cancer
mortality over 10 to 11 years of follow-up in Shanghai, Thomas et al.
showed no reduction of mortality, RR 1.04 (95% CI 0.82–1.33).18
(Level 1b evidence) Although this study was one about the
instruction of BSE rather than about execution and efficacy of
the BSE, one important point to consider is that 40% of the study
population and their matched cohorts were in their 30s. A 10-year
follow-up may not have been enough time to see the true number
of cancer deaths in that population. The Russian study19 (Level 1b
evidence), which included 120,000 women aged 40 to 64 years,
suggested that there were more cancers found in the BSE group
(24% more); however, the risk of dying was, once again, not sig-
nificantly higher in the BSE group. The pooled RR of dying was
1.01 (95% CI .92–1.12, p = .79). Notably, there was an increase in
the number of benign breast biopsies in the BSE group, 53% more
biopsies in the BSE group from data from both trials combined,
RR 1.53 (95% CI 1.44–1.63, P < .001), as well as increased anxiety
among that same group.
Answer: Current evidence indicates that women may practice
BSE knowing the risks as well as benefits. There is insufficient con-
sistent data to recommend for or against BSE. Level 1b evidence
reveals no mortality benefit. More cancers were found in the BSE
groups; however, they were found incidentally and not during the
formal monthly BSE.20,21 (Level 1b evidence) This suggests that
an increase in a woman’s self-awareness may lead her to seek a
clinical follow-up sooner for incidentally found masses. Begin-
ning in their 20s, women should be told about the limitations and
benefits of BSE. Those who want to learn should be instructed,
with regular reinforcements of teaching and counseling. (Grade B
recommendation)
Clinical Breast Examination
2. Is the clinical breast examination (CBE) a useful screening
tool?
The data from randomized controlled trials did not evaluate
CBE as an individual screening tool, but as an adjunct to mam-
mography. There is sparse evidence of CBE independently having
statistically significant effect on breast cancer detection or on mor-
tality. CBE detected only 3% to 45% of breast cancers found that
were missed by screening mammography. Barton et al. reviewed
all controlled trials and case–control studies where CBE was at
least part of the screening modality. Analysis of all the trial data
showed that CBE sensitivity is estimated at 54% (95% CI 48–60%)
and specificity at 94% (95% CI 90–97%) if done systematically and
with training.22 (Level 2a evidence) A randomized trial from Edin-
burgh and one from the United States showed a reduction in mor-
tality with screening with CBE and mammography of 29% and
14%, respectively4 (Level 2a evidence), but could not conclude how
much of that benefit was due to CBE. The randomized trial from
Canada, which studied women 50 to 59 years of age, compared
PMPH_CH72.indd 578
groups with CBE and BSE versus CBE, BSE plus mammography,
without comparing data from a control group who received no
screening. Though mortality rates were not statistically different
between the two groups, the CBE, BSE plus mammography group
detected more smaller and lymph node-negative breast cancers.23
(Level 1b evidence) The likelihood ratios of finding a breast cancer
on physical examination were higher in the carefully controlled
RCT setting compared with community settings (10.6 vs. 2.1),
suggesting that excellent CBE technique is important.
Answer: There is no direct evidence for or against CBE in
screening for breast cancer. However, the high specificity of abnor-
mal findings increases the probability of breast cancer detection.
The American Cancer Society review panel suggested that rather
than discarding the CBE, clinicians use it as another opportunity
to raise awareness about the early detection of breast cancer.24
(Level 2a evidence; Grade B recommendation)
Mammography for Screening
3. When is mammography efficacious as a screening tool?
Breast cancer screening in the United States is estimated to have
reduced the death rate from breast cancer 7% to 23% (median
15%). Screening recommendations for women are divided into
recommendations for 40 to 49 year olds, 50 to 69 year olds, and
>70 year olds. Across the RCTs of mammography, the mortal-
ity reduction parallels the reduction in node-positive cancers.25
(Level 2a evidence) The largest benefit is in the 50 to 69 age group.
Screening the 40 to 49 groups has shown lower mortality benefit.
The power of the studies for this group was low. Mortality benefit
may also be skewed as the incidence of cancers is lower in this
group. However, it is argued that in young women, cancer is usu-
ally more aggressive and women benefit mostly from appropriate
treatment at the earliest stage possible. The 9.8% annual false-
positive rate of mammography should be discussed with the 40 to
49 groups. The >70 age group has limited data. Most of the RCTs
studied patients up to age 65. Mammograms are the most sensi-
tive in this age group and detection rates are better, but the deci-
sion to screen in this elderly age group must take into account
the patient’s overall health, comorbidities, longevity, and their
personal wishes. Mammography may miss up to 30% of cancers;
cancers found by mammography may still have poor prognosis.26
Other downsides to mammography for screening include false
positives, benign breast biopsies, anxiety, and increased repeated
imaging after an abnormal reading.
In the last 10 years, there have been no RCTs for breast can-
cer screening with mammography, CBE, or BSE with death from
breast cancer as the outcome measured. In general, the eight his-
toric RCTs that all occurred before 1981 have shown that mam-
mography screening has significantly reduced breast cancer
mortality.27 (Level 1b evidence) The debate rages on over who
benefits most, and what the true mortality benefit might be. The
eight well-established trials are from the United States, Edin-
burgh, Gothenburg, Stockholm, Malmo, Sweden, and Canada.
The recruitment of patients, mammography protocol, control
groups, size, and follow-up all varied. The ages ranged from 40
to 74. There were flaws in all the studies, which have all been rig-
orously dissected and subsequently defended multiple times in
subsequent years.4,24,28 (Levels 1a and 2a evidence) In 2000, a con-
troversial meta-analysis by Gotzsche and Olsen29 questioned the
5/22/2012 5:50:36 PM

validity of these historic RCTs. This sparked re-analysis and more
meta-analyses of the data to answer these criticisms. Follow-up
data also matured and became available.
In the 50–69 year old group, meta-analyses that included
all the trials demonstrated statistically significant 20% to 35%
reductions in mortality from breast cancer.30 (Level 2a evidence)
Humphrey et al.4 (Level 1a evidence) independently reviewed all
RCTs and concluded that the methodologic flaws in each trial did
not negate the effectiveness of mammography for screening espe-
cially in women 50 to 69. Their newer analyses of the old data sup-
ported breast cancer screening as efficacious in reducing breast
cancer mortality, albeit with a wide range: 7% to 44% overall
studies. Fletcher and Elmore in a similarly exhaustive review of
the literature demonstrated statistically significant reductions in
mortality from breast cancer of 20% to 35% for women 50 to 69
who were routinely screened.30 Blanks et al. in 2000 designed a
highly significant age cohort model (p < .001) in a community-
based screening setting in the UK. Th is study revealed that the
mortality dropped across all ages with mammography for screen-
ing, with the largest drop in mortality seen in the 55–69 groups.
This study attempted to differentiate the effects of screening from
that of improved therapy upon mortality. Their estimate of the
effects of screening is a 6.4% reduction in mortality, and the esti-
mate of the effects of therapy on reduction in mortality is 14.9%.31
(Level 2b evidence)
The benefit of screening women 40 to 49 is slower to appear
as the incidence of cancer is lower in that age group, requiring a
longer follow-up to show benefit or harm. The HIP study out of
the United States showed a possible 25% reduction in mortality
benefit after 10 to 18 years of follow-up.32 (Level 1a evidence) The
data gathered from the eight RCTs in regards to women 40 to 49
were re-analyzed by Smart et al. in 1995 using a Mantel–Haenszel
estimator method to assess the follow-up data. This showed a 16%
benefit from screening mammography without statistical signifi-
cance at the 95% confidence level. However, when the data from
the Canadian trial was excluded, which actually showed no benefit
to this group, the analysis showed 24% benefit with statistical sig-
nificance.33 (Level 1a evidence) Most of the RCTs individually did
not have a statistical power to evaluate 40 to 49 year olds. Hendrick
et al. in 1997 re-analyzed the eight RCTs in another meta-analysis
when follow-up reached 18 years (avg time 12.7 years), and found
a statistically significant 18% mortality reduction among women
screened (RR 0.82; 95% CI 0.71–0.95). When they looked only at
the Swedish trials, the mortality reduction was significant and
even higher at 29% (RR 0.71; 95% CI 0.57–0.89).34 (Level 1a evi-
dence) The USPSTF meta-analysis4 calculated a number needed
to screen of 1385 (Cr I 659–6060) to prevent one death. A histori-
cal prospective cohort study of 4482 women aged 40 to 49, with a
follow-up to 9.9 years (median 4.7 years) examined prognostic dif-
ferences in cancers detected by mammography versus BSE, CBE,
or incidental patient findings. In the mammography group, the
mean tumor size detected was smaller (p < .002), more likely to be
localized (p < .0001), and had better survival even after adjustment
for lead-time bias (p < .0001).21 (Level 1b evidence) The question
of benefit versus harm is important especially in this age group.
Annual mammography of 100,000 women starting at age 40, for
10 consecutive years, will result in at most eight cancer deaths due
to the radiation exposure during the lifetime of these women.35
Denser breast tissue in women under 50 decreases the sensitiv-
ity of mammography leading to higher false-positive rates, more
PMPH_CH72.indd 579
Screening, Breast Biopsy, Benign Disease ■ 579
benign breast biopsies, scarring, and anxiety. In this age group,
there is lower incidence of disease, and faster growing cancers.5
Conversely, in older women, when density decreases, false posi-
tives decrease; cancers are less aggressive and have longer sojourn
times. The point at which the trade-off between harm and benefit
becomes acceptable is subjective and therefore both the benefits
and harms of screening must be discussed with patients.
For women greater than age 70, screening is also controver-
sial. Of the eight RCTs, only two included women 70 and older and
is of limited power for strong screening recommendations. Rela-
tive risk reductions of death from breast cancer in women 65 to 74
years were reported as 0.68 (CI 0.51–0.89) from the Malmo trial,
and 0.78 (CI 0.62–0.99) in women 70 to 74 years in the updated
analysis of the Swedish trial.36 (Level 1b evidence) In 2000, a study
out of California investigated 690,000 women aged 66 to 79 years
and found that in situ, local, and regional breast cancers were
more likely to be detected among women who underwent screen-
ing mammography, with a relative risk of detection in the screened
group of 3.3 (95% CI 3.1–3.5). Overall, the risk of metastatic
disease was reduced by 43% among women who were screened
(p < .0001).37 (Level 2b evidence) Screening in this population
was successful in that cancers were detected at an early stage.
Twenty-four early stage breast cancers were diagnosed for each
metastatic case prevented. However, in this age group, detecting
early stage breast cancer may not have as high an impact on breast
cancer mortality due to comorbidities from which patients are
more likely to succumb. Over-treating early stage breast cancer in
elderly should be avoided. In a small cohort study, 17% of screened
women experienced burden, including false-positive results, fur-
ther workup requirements, anxiety, the need to refuse workup,
and identification of clinically insignificant lesions. Forty-two
percent of women had clinically documented anxiety, pain, and
depressive symptoms after screening.38 (Level 2b evidence) Satari-
ano, in a longitudinal observational study of over 900 women, 40
to 84 years old concluded that trials for appropriate assessment
of the efficacy of screening should include comorbidity measures.
Their results also supported the finding that women with severe
comorbid conditions have uniformly higher mortality rates, in
whom there was no survival advantage in detecting early stage
breast cancers.39 (Level 1b evidence) Annual mammography is
still recommended for women >70 years of age, but individual
decisions to screen must be made carefully for elderly individuals
based on comorbidities and overall life expectancy.
Answer: Current recommendations based on the available
data support starting annual mammographic screening of asymp-
tomatic normal risk women at age 40. CBE and BSE are to be used
with clinical judgment and with appropriate counseling. Annual
mammography for women should continue until age 70. After age
70, screening may continue with consideration of comorbid medi-
cal conditions that may affect the life expectancy and whether
a patient would accept further treatment and procedures after
screening detects abnormalities. Patients need to be aware of the
potential harms associated with breast cancer screening includ-
ing false positives and false negatives, biopsies for benign results,
scarring on future imaging studies after biopsies, and associated
anxiety. When cancers are detected at an earlier stage, there is
the possibility of less aggressive therapy, and more treatment
options.26 At this time, breast ultrasound and breast MRI are not
used for screening asymptomatic average-risk women. (Grade B
recommendations)
5/22/2012 5:50:37 PM
 580 ■ Surgery: Evidence-Based Practice
Percutaneous Breast Biopsies
4. Is the sensitivity and specificity of percutaneous breast
biopsy sufficient to replace open surgical biopsy for initial diag-
nosis of a breast abnormality?
Modern breast care strives to minimize the number of open surgical
biopsies performed for initial diagnosis on patients with abnormal
imaging or with clinically apparent lesions. The goal is to optimize
the accuracy of atypical or malignant diagnoses and minimize
the underestimation rates of the percutaneous procedure of choice,
although taking into account patient comfort, complication rates,
and days until return to work. There are pitfalls of benign diagno-
ses such as false negatives, radiologic–histologic discordance, and
lack of appropriate follow-up, as well as patient anxiety. Percuta-
neous biopsies have increasingly become the alternative to open
surgical biopsy for initial diagnosis of breast abnormality.40 Percu-
taneous biopsy can be obtained stereotactically, with ultrasound
guidance, or with clinical palpation and can be performed with
large core needle biopsy (CNB) usually 14-, 11-, or 8-gauge or with
fine-needle aspiration (FNA), usually 22-gauge.
STEREOTACTIC BIOPSIES
Stereotactic biopsy is based on the principle that “the precise
location of a lesion in three dimensions can be determined based
on its apparent change in position on two angled (stereotactic)
images.”41 Brenner et al. in a multi-institutional prospective trial
showed that stereotactic CNBs have statistically significant con-
cordance with surgical excision for obtaining accurate histo-
pathologic diagnosis of breast lesions.42 (Level 1b evidence) CNBs
on 1003 patients after selection criteria were applied, had results
validated at surgery or clinical and mammographic follow-up
based on the American College of Radiology Breast Imag-
ing Reporting and Data System (BIRADS), as well as a clearly
defined scoring scale for histopathologic samples obtained at
CNB or at surgery. Median follow-up was 24 months. The strict
sensitivity was 91% + 1.9% and the strict specificity was 100%.
Accuracy was 97%, with potential for improvement with care-
ful recommendation of surgery based on image-discordant his-
tology, and for suspected sampling error. Another multicenter,
prospective study from the COBRA group (Core Biopsy after
RAdiologic localization) studied 1029 lesions in five centers for
the assessment of diagnostic accuracy of stereotactic large CNB
in women aged 29 to 85 (mean 58). All patients were offered sur-
gery after biopsy, whereas benign patients who refused surgery
were referred to a nationwide database registry to track them.
Discordant results were cored again or surgically excised. Benign
patients had 24 months of imaging follow-up. High-risk lesions
(ADH, ALH, LCIS) had open surgery. DCIS patients had wide
local excision. Invasive cancers were offered appropriate therapy.
The sensitivity was 97% (95% CI 95–98%) and specificity 99%
(95% CI 97–100%).43 (Level 1b evidence)
Stereotactic biopsies are suitable for mammographic micro-
calcifications or mammographic densities that have no ultrasound
correlate. If there is sonographic correlation of a mammographic
finding, biopsy should be attempted with an ultrasound guidance
and a radiopaque marker placed at the time of biopsy. A comple-
tion mammogram is then warranted to ensure concordance
between the mammographic and the sonographic lesions. If there
PMPH_CH72.indd 580
is no correlation between the sonographically placed marker to
the mammographic finding on the postprocedure film, then ste-
reotactic biopsy must still be undertaken for adequate sampling of
the mammographic finding.
ULTRASOUND-GUIDED BIOPSIES
Ultrasound-guided automated core biopsies have also been studied
and shown to have up to 100% concordance rates compared with
open surgical excision. Dillon et al. in 2005 published the largest ret-
rospective study at that time, which included all patients undergoing
biopsy in a 5-year period with the goal of assessing which method
of core biopsy is the most accurate: ultrasound-guided, stereotac-
tic, or clinical palpation. The study is limited by its 3-year follow-up;
however, the false-negative rate was only 1.7% for ultrasound-guided
biopsies, whereas it was 13% for clinical and 8.9% for stereotactic
biopsies.44 (Level 2b evidence) In addition, studies have also shown
the cost-effectiveness, relative comfort, and safety of ultrasound-
guided biopsies. There is no exposure to ionizing radiation and in
live time, all parts of the breast and axilla are accessible.41
FINE-NEEDLE ASPIRATION
FNA may be used to sample palpable or nonpalpable breast
abnormalities; however, there are higher underestimation rates.
One NCI study determined that physician training was contribu-
tory to the accuracy of fine-needle aspiration biopsies (FNAB).
One thousand and forty-three cases were reviewed and analyzed
over 1 year to show that physicians formally trained in FNAB
had a 2% missed cancer rate and physicians with no training
in FNAB had a 25% missed cancer rate (p < .0001).45 (Level 2b
evidence) The sensitivity of FNAB in the trained group was 98%
versus 75% in the untrained group (p = 00014). In 2001, Pisano
et al. in a large multicentered trial that was double-armed and
randomized to stereotactic CNB versus stereotactic FNAB for
BIRADS 4 or 5 images closed the FNAB arm early because of the
high underestimation rates. Results showed sensitivity of 85% to
88% and specificity of 55% to 91%. FNAB was better for solid
masses than for microcalcifications, accuracy 67% versus 53%
(p = .006). FNAB with ultrasound was better than with stereotac-
tic guidance with accuracy 77% versus 58.9% (p = .002).46 (Level 1b
evidence)
Percutaneous biopsy has documented advantages of being
faster, less costly, causing less mammographic scarring subse-
quently, and has lower complications rates than open surgical
biopsy.41 Because of the smaller needle size, FNAB can be more
suitable for patients that cannot stop anticoagulation or who have
other comorbid conditions that preclude large core biopsies. How-
ever, the practitioner must recognize the high underestimation
rate and convey this to the patient. Approximately, 70% to 80%
of lesions with sufficient concern to warrant biopsy will result in
benign findings. If there is imaging-pathologic concordance, the
patient avoids open surgery. If the diagnosis is malignant, surgical
planning can decrease the number of operations performed on
a patient, 2.01 operations in women with open surgical biopsies ver-
sus 1.25 operations in percutaneously diagnosed cancer (p < .001).47
(Level 2b evidence) Multicentricity of malignancy, proven before
open surgery, improves surgical planning. This allows for more
5/22/2012 5:50:37 PM

accurate recommendations for breast conservation versus total
mastectomy.48
Answer: Yes, use large gauge percutaneous CNB whenever
possible and biopsy using the modality with which the abnormal-
ity was detected. (Grade B recommendations)
SURGICAL MANAGEMENT OF
BENIGN BREAST DISEASES
A literature review of the last 10 years for “surgical management
of benign breast diseases” revealed three benign breast diseases of
importance: lobular neoplasia (LN), radial scars (RSs), and benign
breast papillomas. Because of the overall low incidence of these
lesions, there are many studies that, although well conducted, are
retrospective with small cohorts. Therefore, there is insufficient
power for Grade A recommendations. However, the following
reviews are currently available data.
Radial Scar
5. When is RS diagnosed by percutaneous CNB safe to follow
without complete surgical excision (CSE)?
RS, otherwise known as radial sclerosing lesion, sclerosed elastic
lesion, indurative mastopathy, nonencapsulated sclerosing lesion,
sclerosing papillary proliferative lesion, and if >1 cm, a complex
sclerosing lesion, are often incidental findings on autopsy but also
present as masses, architectural distortions with or without cal-
cifications, and sonographic abnormalities. Strict adherence to
mammographic criteria for RS cannot differentiate between RS
and carcinoma, thus sampling of a suspected RS is still required49
(Level 2a evidence); however, which lesions need CSE is debatable.
Brenner’s retrospective multi-institutional study from 2002, which
included data from 11 institutions, studied 157 RSs diagnosed by
image-guided CNB for nonpalpable mammographically detected
lesions and concluded that RS could be reliably diagnosed on
CNB.49 Furthermore, for RS associated with atypia, 28% of these
patients had malignancy at CSE whereas only 4% had malignancy
in the RS group without atypia (p < .0001). At CSE of this latter RS
group without atypia, carcinoma was missed in 9% of lesions biop-
sied with a spring-loaded device but was missed in 0% of biopsies
performed with a vacuum-assisted device (p = .01); carcinoma was
missed in 8% of lesions sampled with <12 specimens per lesion but
in 0% of lesions sampled by >12 specimens (p = .015). Of the RS
patients that did not proceed to surgery, all 55 cases were followed
up mammographically; none showed progression for a median of
38 months. Brenner concluded that CNB of sufficient specimens
(>12), absence of atypia, and concordant imaging was reliable to
diagnose RS with no expectation of underestimation. Unless all
these criteria are met, surgical excision is still recommended.
Another systematic review of eight studies found 341 RSs and eval-
uated them for malignancy upgrade. None of the RS diagnosed by
11- or larger gauge devices had underestimated the lesion.50 (Level 4
evidence) Becker et al., in 2006 from Canada, had the only other
large single-center retrospective trial on RS which included 144
RS lesions of 15,986 consecutive CBNs. Although there were study
limitations, they paralleled the findings of Brenner et al. in that
large (11- or 8-) gauge biopsies of RS that were imaging concordant
and revealed no atypia or other finding that would independently
PMPH_CH72.indd 581
Screening, Breast Biopsy, Benign Disease ■ 581
require CSE, was safe for interval imaging follow-up to a 2-year
stability endpoint to ensure benignity.51 (Level 2b evidence)
Answer: RS diagnosed by CNB with >12 cores from an 11-
or larger gauge needle, without atypia, with imaging concordance
(pathology discordant to the imaging must proceed to CSE), and
with no other independent finding that would require CSE was
safe for nonoperative management if followed up with imaging
and CBE for 2 years to demonstrate continued stability. (Grade B
recommendation)
Lobular Neoplasia
6. What is the appropriate surgical management of LN?
Definitive management of LN, previously known as Lobular Car-
cinoma In Situ (LCIS), and Atypical Lobular Hyperplasia (ALH)
also have no current Level 1 evidence. The incidence of LN is
unknown in the general population and occurs in up to 2.7% on
biopsy of benign lesions. LCIS confers a lifetime risk of cancer of
30% to 40% in either breast, versus 12.5% in average-risk women.
ALH is defined as a precursor lesion as well as a high-risk marker
conferring a 10% to 20% risk of subsequent carcinoma and a
>3-fold risk of invasive carcinoma (lobular > ductal type) in the
ipsilateral breast.52 (Level 2b evidence) LN found on CNB must
be followed by CSE if the core also yields cancer, DCIS, or other
high-risk lesions (ADH or RS). LN on a CNB alone but performed
for BIRAD 4 or 5 finding needs CSE, as 33% of BIRAD 4 lesions
and 90% of BIRAD 5 lesions yield carcinoma when excised.53
(Level 2b evidence) In a small study from Columbia University
Breast Department, Bauer et al.54 (Level 2b evidence) proposed
that isolated LN with benign fibrocystic changes concordant with
imaging findings, adequately sampled by multiple large CNB
specimens, and with no synchronous or prior breast cancer can
be managed with close follow-up consisting of yearly mammo-
grams with high-risk discussions and biannual CBE. However,
the authors cautioned that larger prospective studies were needed.
Another small prospective study55 (Level 2b evidence) adds to the
above conclusions that LN associated with a mass must be com-
pletely excised, as the LN is likely an incidental finding to the
mass. Brem et al. in 200856 (Level 3b evidence) showed statistically
significant underestimation rates when LN was associated with
a mass (p < .001), with high BIRAD scores (4 or 5) (p < .01), with
small specimen sizes (p < .01), and with fewer than 10 specimens
(p = .0027). They concluded that patients with LN at CNB should
be completely excised. ALH of fewer than three foci with no addi-
tional findings that independently require excision and with no
imaging discordance may be managed nonoperatively with close
follow-up. This was shown in a 2010 study from Johns Hopkins
that found 117 isolated ALH cases of 10,024 breast CNBs done
during the 10-year study period for women 40.6 to 85.5 years with
up to 10-year follow–up.57 (Level 2b evidence) In this study, LN
was defined by the Page criteria58,59 and a “focus” was defined as
“involvement by one or more (up to 3) adjacent lobules.” In the
group with <3 foci of ALH, all patients went on for CSE and none
had higher risk lesions or malignancy. Only two women devel-
oped minimal DCIS at 1.5 and 2.3 years later during follow-up.
Answer: Current practice of CSE of LN found on CNB has
no evidence to support or contradict it. Multiple studies (Level 2b
evidence and worse) recommend CSE, especially when associated
with a mass, associated with BIRADS 4 or BIRADS 5 imaging, or
if there is insufficient sampling (less than 10–12 specimens from a
5/22/2012 5:50:37 PM
 582 ■ Surgery: Evidence-Based Practice

large bore needle). However, careful consideration for risk strati-
fication as well as adherence to imaging concordance is crucial
for surgical decision-making; otherwise close follow-up with CBE
and imaging, as well as the use of chemoprophylaxis, remains
acceptable until larger clinical trials are available. Minimal ALH
may be managed nonoperatively with close clinical and imaging
follow-up. (Grade B–C recommendations)
Benign Papillary Lesions
7. Should all benign papillary lesions diagnosed on breast CNB
be completely excised?
Papillary lesions pose similar management dilemmas, as the
overall incidence is low (5% of breast biopsy specimens). There
are little radiologic signs that distinguish benign from atypical or
malignant papillary lesions. Papillary lesions, also named scleros-
ing papillomas, benign sclerosing lesions, have a 7-fold risk of sub-
sequent development of carcinoma if they demonstrate atypia.60
Atypical lesions are excised due to the atypical finding. No Level 1
data support defi nitive surgical management of nonpalpable
benign papillary lesions found on breast CNB. Jacobs et al.61 (Level 3a
evidence) looked at data from five retrospective studies that
ranged from having 734 to 1327 consecutive CNBs that yielded
12 to 28 benign papillomatous lesions each. They concluded that
there is a “small but definite chance of atypia or malignancy on
CSE.” The incidence of carcinoma or ADH at CSE can be as high
as 36%.62 (Level 2b evidence) Liberman et al.63 (Level 2b evidence)
found malignancy in 14% (5/35, 1 IDC, and 4 DCIS) of concordant
benign papillary lesions in a retrospective study of 3864 lesions,
which yielded 50 papillomas on CNB, 35 of which had CSE or
2-year follow-up. Four DCIS were found at interval follow-up at a
median of 22 months (range 7–25 months), the one invasive can-
cer was found immediately at CSE. The frequency of cancer (14%)
is higher than the <2% frequency of cancer in lesions interpreted
as “probably benign” designated as BIRADS 3. This suggests treat-
ing benign papillomas as a lesion between a BIRAD 3 which could
be managed nonoperatively with a 6-month imaging follow-up,
and BIRADS 4 lesion which requires excision. Th is study also
found 17% high-risk lesions on CSE (ADH, RS, LN) with mul-
tiple versus solitary papillomas giving higher frequency of cancer
(p = .02). Data from Cheng et al. support this and also found statis-
tical significance in age >45 (p = .0008) as a predictor of upgrading
a benign papilloma to malignancy.64 (Level 2b evidence) Renshaw
showed in a study of 62 papillary lesions that the rate of carcinoma
in severely atypical papillomas was greater than in benign papil-
lomas (p < .0001). Also, no upgrades to malignancy were found at
surgery for benign papillomas with florid hyperplasia, and no or
minimal atypia, leading them to be the only study to recommend
that this group be managed nonoperatively.65 (Level 2b evidence)
Answer: Current recommendations are for CSE of benign
nonpalpable papillary lesions found on breast CNB. (Grade B–C
recommendations)
Benign surgical findings found at biopsy of abnormal imag-
ing can be treated according to the above recommendations. The
keys to successful management are accurate tissue sampling,
accurate pathologic assessment, and strict adherence to imaging-
pathologic concordance, and minimum 2-year follow-up with
imaging and CBE for every percutaneously diagnosed benign
breast lesion.

Clinical Question Summary

Questions Answers Grade of References
Recommendation
1 Is the breast self- Although BSE has limitations, and no mortality benefit is B 14-21
examination (BSE) a clearly demonstrated, there is current evidence that women
useful screening tool? who practice BSE have more awareness of their bodies.
Extrapolation from these data leads current decision-
making bodies to continue to recommend that clinicians
continue to teach BSE for those women who wish to pro-
actively participate in their own breast health maintenance.
2 Is the clinical breast The high specificity of the CBE and absence of data B 22-24
examination (CBE) a demonstrating any negative effects of CBE allow us to
useful screening tool? continue to recommend it for breast cancer screening.
3 When is Annual screening mammography should start at age 40 and B 25-39
mammography continue to 70. After 70, it may continue as long as the
efficacious as a clinicians also take into account the patients’ comorbidities,
screening tool? life expectancy, and personal acceptance of possible therapy
that may result from the screening.
4 Is the sensitivity and Yes, using large gauge percutaneous CNB whenever possible B 40-46
the specificity of using the modality with which the abnormality was
percutaneous breast detected.
biopsy sufficient to
replace open surgical
biopsy for initial
diagnosis of a breast
abnormality?

(Continued)

PMPH_CH72.indd 582 5/22/2012 5:50:37 PM

 Screening, Breast Biopsy, Benign Disease ■ 583

(Continued)
Questions Answers Grade of References
Recommendation
5 When is RS RS diagnosed by CNB with >12 cores from an 11- or larger B 49-51
diagnosed by gauge needle, without atypia, with imaging concordance,
percutaneous and with no other independent finding that would require
CNB safe to follow CSE was safe for nonoperative management if followed up
without complete with imaging and CBE for 2 years to demonstrate continued
surgical excision stability.
(CSE)?
6 What is the LN associated with a breast mass, BIRADS 4, or BIRADS B–C 52-59
appropriate surgical 5 imaging must have CSE. LN, if not discordant, may be
management of LN? observed with close follow-up. Chemoprophylaxis may be
discussed with oncologist. “Minimal ALH” may be managed
nonoperatively.
7 Should all benign Yes, all benign papillomas on core should be surgically excised. B–C 60-65
papillary lesions
diagnosed on breast
CNB be completely
excised?

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5/22/2012 5:50:37 PM
 Commentary on
Screening, Breast Biopsy,
Benign Disease
Richelle Williams and David P. Winchester
In the chapter entitled “Screening, Breast Biopsy, Benign Disease,”
Adora Fou-Cockburn and Mark Cockburn provide an excellent
review of the current literature on seven key areas of controversy
in breast cancer screening and the management of certain benign
breast diseases. The questions addressed were (1) Is the Breast
Self-Examination (BSE) a useful screening tool? (2) Is the Clinical
Breast Examination (CBE) a useful screening tool? (3) When is
mammography efficacious as a screening tool? (4) Is the sensitivity
and specificity of percutaneous breast biopsy sufficient to replace
open surgical biopsy for initial diagnosis of a breast abnormality?
(5) When is radial scar (RS) diagnosed by percutaneous core nee-
dle biopsy safe to follow without complete surgical excision (CSE)?
(6) What is the appropriate surgical management of Lobular Neo-
plasia (LN)? and (7) Should all benign papillary lesions diagnosed
on breast core needle biopsy be completely excised?
These are all extremely important topics to discuss and to
provide guidance and education, not only for us as physicians
but also for the public. In fact, several of these same questions
(BSE, when to start mammography, percutaneous vs. open surgi-
cal breast biopsy) have garnered much media attention in recent
years. As the authors highlight in this chapter, the evidence asso-
ciated with many of these issues is quite variable and at times even
conflicting, but they do a great job of sorting through the noise
to find a signal and come up with meaningful recommendations.
Throughout all of this is the idea that while guidelines are help-
ful, there has to be a certain amount of tailoring of one’s care to
address the specific circumstances of the patient in front of you—
the art, not so much the science, of medicine. The chapter focuses
mainly on women at average risk undergoing screening.
Regarding the fi rst question, BSE as a screening tool has
been a subject of great debate over the past 2 years. There have
been recommendations both for and against BSE. Proponents
argue that women who perform BSE had more cancers detected
at a smaller size and earlier stage, which may be due to increased
self-awareness. Despite this, the best evidence shows no effect
on breast cancer mortality.1 Thus, these earlier stage detections
do not seem to translate to improved mortality. Opponents add
that BSE leads to increased numbers of benign breast biopsies
with the attendant increase in unnecessary resource utilization
and patient stress.2,3 The authors highlight the largest study pro-
viding evidence against routine BSE, the Shanghai randomized
585
PMPH_CH72.indd 585
controlled trial of over 200,000 women (their reference 18), and
caution that one of the limitations was that a significant number
of these patients were under 40 and thus the 10–11-year follow-up
period may not be adequate to see the true number of cancer
deaths. While that may be a fair criticism, the Russian study the
authors cite (their reference 19) ultimately followed about 120,000
women aged 40 to 64 years for 15 years and also did not find a
difference in mortality.3 The final analysis of that study, however,
did show a significantly higher detection rate of both benign and
malignant tumors in the BSE group.3 As a result, it is difficult to
advocate against teaching a woman BSE, particularly if she wants
to learn and is aware of the risks outlined above. It seems to us
that a woman’s response may depend on her personality and life
philosophy, and the authors rightly conclude that the decision to
practice BSE should be individualized based on a discussion of
the risks/benefits between patient and physician.
Unlike BSE, CBE has no direct evidence to support a firm
stand either for or against its use in breast cancer screening. The
best studies do not isolate the effect of CBE independent of the
effect of mammography, which has been shown to decrease breast
cancer mortality.3 However, as the authors point out, while CBE is
not very sensitive (54%), it is quite specific (94%) for breast cancer
detection. In addition, since the likelihood of finding an abnor-
mality increases with excellent technique, routine CBE provides an
opportunity for the physician to perfect his/her technique as well
as educate the patient about the importance of early detection.
The third question about when mammography should be uti-
lized as a screening tool has also been hotly debated, especially
after the publication of the U.S. Preventive Services Task Force
report in 2009 recommending biennial mammogram starting at
age 50.3 The controversy is mostly regarding the appropriateness of
screening mammography in 40–49–year-old women. While there
is no doubt that mammography decreases breast cancer mortality
in this group, the reduction is less than for 50–69-year-old women.
Furthermore, it comes at a price since the greater breast density in
younger women results in a greater number of false positives with
increased benign breast biopsies and anxiety. Also, because the
incidence of breast cancer is lower in this age group, the number
of women needing to be screened to prevent one cancer death is
likely higher.3 Given that the point at which the benefit of prevent-
ing breast cancer mortality outweighs these risks is subjective, the
5/22/2012 5:50:37 PM
 586 ■ Surgery: Evidence-Based Practice
authors advocate (and we agree) having the discussion with the
patient. Similarly, but at the other end of the spectrum, screen-
ing mammography in women over 70 is also controversial. In this
group, the issue of life expectancy related to other comorbidities
starts to play a significant role in treatment decisions, and should
therefore also impact decisions about screening.
Regarding the sensitivity and specificity of percutaneous
breast biopsy versus open surgical biopsy, many studies have been
published examining this issue. Percutaneous needle biopsy tech-
niques have improved in accuracy with increased experience and
also utilization of image guidance and vacuum-assisted methods.
Overall, large core needle biopsy seems to have some advantages
over fine-needle aspiration in terms of both sensitivity and speci-
ficity. In a study commissioned by the Agency for Healthcare
Research and Quality, Bruening et al. reviewed several studies
and found that core needle biopsy was as accurate as open surgical
biopsy and also associated with fewer serious complications and
a reduced number of surgical procedures.4 Given these and other
advantages of percutaneous needle biopsy over surgical biopsy
(improved cosmesis, decreased cost, improved patient satisfac-
tion, better treatment planning), we strongly advocate the use of
needle biopsy, and specifically core needle biopsy when possible,
as the initial diagnostic procedure of choice for breast lesions.
Finally, in their analysis of the three controversial benign
lesions they chose to examine, Fou-Cockburn and Cockburn do
an excellent job of outlining the major considerations. For RS,
there is a risk of associated malignancy, which cannot be deter-
mined by imaging characteristics. However, finding no atypia on
at least 12 core needle biopsy specimens taken with 11-gauge or
larger needles was reliable criteria on which to base a surveillance
approach. Absent these, a diagnosis of RS should prompt surgical
excision to rule out an associated malignancy. With respect to the
optimal management of LN, which includes lobular carcinoma in
situ (LCIS) and atypical lobular hyperplasia (ALH), we agree with
the authors that there is not enough evidence to support or refute
PMPH_CH72.indd 586
CSE as the primary management strategy and that close surveil-
lance with chemoprophylaxis may be a reasonable approach to
these benign lesions. Although, since there is no good evidence,
we believe it is best to err on the side of caution and perform CSE
unless contraindicated. This stance is supported by NCCN guide-
lines.5 Lastly, regarding whether all papillary lesions diagnosed on
core needle biopsy should be excised, the authors quote a 7-fold
increase in the risk of subsequent carcinoma. In addition, there is
a high rate of carcinoma or atypical ductal hyperplasia (ADH) at
the time of CSE (somewhere between about 15% and 35%). There-
fore, the most conservative approach is to recommend CSE for
all these lesions until we are better able to distinguish high-risk
from low-risk lesions. From our review of the literature, we are
not there yet.
REFERENCES
1. Kösters JP, Gøtzsche PC. Regular self-examination or clinical
examination for early detection of breast cancer. Cochrane Data-
base of Systematic Reviews. 2003;(2):CD003373.
2. Baxter N; Canadian Task Force on Preventive Health Care. Pre-
ventive health care, 2001 update: Should women be routinely
taught breast self-examination to screen for breast cancer? Can
Med Assoc J. 2001;164(13):1837-1846.
3. Nelson HD, Tyne K, Naik A, Bougatsos C, Chan BK, Humphrey L;
U.S. Preventive Services Task Force. Screening for breast cancer:
An update for the U.S. Preventive Services Task Force. Ann Intern
Med. 2009;151(10):727-737, W237-W242.
4. Bruening W, Fontanarosa J, Tipton K, Treadwell JR, Launders J,
Schoelles K. Systematic review: Comparative effectiveness of core-
needle and open surgical biopsy to diagnose breast lesions. Ann
Intern Med. 2010;152(4):238-246.
5. NCCN Clinical Practice Guidelines in Oncology, Breast Cancer.
Version 2. 2011. Available at: http://www.nccn.org/professionals/
physician_gls/pdf/breast.pdf [Accessed April 15, 2011].
5/22/2012 5:50:37 PM

Breast Cancer: Surgical Therapy
Alyssa Gillego, Manjeet Chadha, Beth Freedman, and Susan K. Boolbol
INTRODUCTION
Breast cancer remains the most common cancer worldwide with
high rates of survival in developed countries. According to the
American Cancer Society there were 232,620 new cases of invasive
breast cancer in the United States in 2011.1 The surgical manage-
ment of invasive breast cancer has evolved from William S. Hal-
stead’s first radical mastectomy in 1882 to today’s skin-sparing
mastectomy (SSM) and breast-conserving therapy. Over the past
several decades, the surgical management of breast cancer has
undergone many advances. This is due to a multitude of national
and international randomized clinical trials that have been per-
formed. This chapter addresses the surgical treatment of invasive
ductal carcinoma and invasive lobular carcinoma of the breast.
Historically, surgery involved excision of the entire breast,
underlying muscles, and axillary lymph nodes. Halstead2 pub-
lished his series from the Johns Hopkins Hospital, in which he
reported a 3% local recurrence rate after 3-year follow-up. He was
a pioneer in both surgical education and technique, and radi-
cal mastectomy remained the standard operation for nearly 100
years. The surgery often resulted in disfigurement, disability,
and morbidity such lymphedema and chronic pain. In the 1940s,
Haagensen3 questioned the appropriateness of Halstead’s radical
mastectomy. In 1948, Patey and Dyson4 reported their technique
of performing a mastectomy with preservation of the pectoralis
major muscle. In 1955, Crile, Jr.5 also challenged the established
practice and explored more conservative operations. Debate over
the appropriate surgical treatment of breast cancer led to a call
for scientific evidence. In 1977, Fisher et al.6 published the initial
results of the National Surgery Adjuvant Breast and Bowel Project
(NSABP) B-04 trial. The NSABP B-04 trial was a randomized trial
which compared radical mastectomy with total mastectomy with
or without radiation. This practice-changing trial showed there
was no survival difference between women who were randomized
to radical mastectomy and those who had a total mastectomy.7 Sur-
gical clinical trials with large numbers of patients continued and
innovators in breast conserving operations emerged. Veronesi8 in
Milan promoted the safety of quadrantectomy and lumpectomy.
587
PMPH_CH73.indd 587
CHAPTER 73
The acceptance of less radical surgery coincided with advances in
breast irradiation and chemotherapy, and multimodality treat-
ment for breast cancer emerged. Trials examining the various
operative techniques in combination with these adjuvant therapies
lay the foundation of modern-day breast cancer management.
Invasive carcinoma is pathologically defined as malignant
cells which have spread beyond the basement membrane of the
ductulobular unit of the breast. The two main histologic types are
invasive ductal carcinoma and invasive lobular carcinoma. Inva-
sive ductal carcinoma is the more common type, and can present
as a radiographic lesion or a palpable mass. Frequently invasive
lobular carcinoma is difficult to detect clinically or radiographi-
cally, leading to an underestimation of size and extent of disease
in the breast. Invasive lobular carcinoma is more likely to be mul-
tifocal. Despite these differences, histologic type does not appear
to be a prognostic factor for overall clinical outcome. Mersin et al.9
performed a retrospective study of 510 women with stage I and II
breast cancer. Rates of hormone positive tumors and lymph node
metastasis were not statistically different between the two histo-
logic subtypes. Five-year overall survival was 90% in patients with
invasive ductal carcinoma and 94% in patients with invasive lobu-
lar carcinoma (p = NS). Multivariate analysis showed histologic
subtype was not an independent risk factor for outcome.
All patients diagnosed with breast carcinoma should have
a complete history and comprehensive physical examination.
The history should pay special attention to associated risk fac-
tors for breast cancer, such as early menarche, nulliparity, age
of first delivery, late menopause, and use of unopposed estrogen
therapy. A thorough breast examination should be performed,
along with careful inspection for skin changes and palpation of
the regional lymph node basins in the axilla and supraclavicular
fossa. Blood tests should comprise of a complete blood cell count,
routine chemistry, liver function tests, and alkaline phosphatase
level. Complete investigation of other suspicious areas in the ipsi-
lateral breast and the contralateral breast should be performed
to exclude synchronous disease. In addition, women diagnosed
with breast cancer who have a strong family history of breast can-
cer or ovarian cancer should be evaluated for a mutation of the
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 588 ■ Surgery: Evidence-Based Practice
breast cancer susceptibility genes, BRCA 1 and BRCA 2. Referral
to a genetic specialist for counseling and testing should follow the
practice guidelines of the National Comprehensive Cancer Net-
work (NCCN).10 Additional workup is indicated in symptomatic
patients with bone pain, abdominal pain, pulmonary complaints,
or neurologic findings. A bone scan should be obtained in any
patient with bone pain or an elevated alkaline phospatase level.
The sensitivity and specificity of alkaline phospatase in detect-
ing bone metastasis is 80% and 98%, respectively.11 The sensitivity
and specificity of bone scan in detecting skeletal metastasis is 92%
and 96%, respectively. Computed tomography (CT) scan of the
chest, abdomen, and pelvis is necessary in patients with abdomi-
nal pain, pulmonary symptoms, or abnormal liver function tests.
Brain MRI is indicated in patients with neurologic symptoms.
In patients with clinical stage IIIA disease or higher, the NCCN
recommends considering preoperative bone scan, abdominal CT
scan, and chest imaging for staging purposes.
1. What is the appropriate management for early-stage (stages
I and II) invasive ductal carcinoma and invasive lobular carci-
noma of the breast?
Answer: Most patients with early-stage breast cancer can be
treated with breast-conserving surgery (BCS) followed by whole-
breast radiation therapy (RT). Numerous large trials have demon-
strated that survival rates of mastectomy and BCS with adjuvant
RT is equivalent. The first important trial was the NSABP B-06,
which randomized patients with invasive breast cancer to receive
mastectomy or partial mastectomy plus radiation.12 The trial ran-
domized 1851 women with tumors up to 4 cm in size. Twenty-year
follow-up demonstrated that women who underwent mastectomy
or partial mastectomy plus radiation had similar rates of sur-
vival. Local recurrence rate in the mastectomy arm was 10.2%,
and local recurrence rate in the partial mastectomy plus radiation
arm was 14.3%. Veronesi et al.13 from the Milan Cancer Institute
also demonstrated equivalent overall survival in women who had
mastectomy compared with women who had partial mastectomy
followed by whole-breast radiation. The Milan trial randomized
women with tumors up to 2 cm in size. Once again, a twenty-year
follow-up reported no difference in overall survival. The European
Organization for Research and Treatment of Cancer (EORTC)
10801 trial similarly reported equivalent survival rates between
the two groups.14 Equivalent long-term survival rates in women
who received mastectomy compared with women who underwent
BCS and RT was also demonstrated in a meta-analysis by the Early
Breast Cancer Trialists’ Collaborative Group (EBCTCG).15
The goal of BCS is removal of the cancer with negative mar-
gins while achieving an acceptable cosmetic result. BCS is removal
of the primary tumor along with a rim of normal breast tissue,
allowing preservation of the gland. BCS has been described in var-
ious terms such as lumpectomy, partial mastectomy, segmentec-
tomy, quadrantectomy, and tumorectomy. Determining whether
a patient is a candidate for BCS involves thorough consideration
of patient factors and careful evaluation of extent of disease. Mul-
tifocal disease, defined as multiple foci of disease in one quadrant,
can be treated with BCS. Multicentric disease, defined as disease
in more than one quadrant of the breast, is a contraindication to
BCS and requires mastectomy. Relative contraindications to BCS
include prior RT to the breast or chest wall, pregnancy, diff use
malignant appearing calcifications, and inability to achieve nega-
tive margins, active connective tissue disease and tumors greater
PMPH_CH73.indd 588
than 5 cm in size. Large tumor to breast ratio is also a relative
contraindication to BCS because of poor cosmetic outcome from
resection of a large breast volume relative to breast size. BCS is
generally performed by making a skin incision above the tumor
to avoid tunneling. The specimen removed should be oriented to
allow for reexcision of close or positive surgical margins. At least
two margins of the breast tissue excised should be oriented, either
with sutures or clips, in order for the pathologist to identify spe-
cific margins. Larger breast defects may require a local advance-
ment flap or an oncoplastic procedure for best cosmetic outcome,
therefore preoperative referral to a plastic and reconstructive sur-
geon is recommended in these cases.
The evaluation of surgical margins when performing BCS
has been reported in numerous studies. The NCCN describes
several requirements for optimal margin evaluation. These are
orientation of the specimen, description of the gross and micro-
scopic margin status, and reporting of the distance to the closest
margin. Margin status is an important predictor of local control.
Lagios et al.16 reported a series of patients who underwent BCS
without radiation. Mean follow-up was only 24 months; how-
ever, local recurrence was 9% in women with negative margins
compared with 45% in women with positive margins. Schnitt
et al.17 examined margins status in women who underwent BCS
followed by whole-breast radiation. Five-year recurrence rate was
0% in women with margins >1 mm, 4% in women with margins
<1 mm, 6% in women with a focally positive margin, and 21% in
women with positive margins. The definition of a negative margin
differs among institutions and differs among the trials examin-
ing impact of margin status in breast cancer. Therefore, the great-
est limitation of the literature examining surgical margins is that
a negative margin is defined differently in these studies. Most
surgeons attempt to achieve a negative margin of 1 to 3 mm of
normal breast tissue around the tumor, while some remove up to
1 cm. Mansfield et al.18 studied the impact of margin status on
local control. In their series of 1070 patients who underwent
lumpectomy and radiation, a positive margins status was a highly
significant risk factor for local recurrence in multivariate analysis.
Smitt et al.19 also reviewed the impact of margins on local control.
The retrospective study reviewed 289 women with 303 invasive
breast cancers. A positive margin was defined as tumor at the
inked surface, a close margin was defined as ≤2 mm, and a nega-
tive margin was >2 mm. The 10-year actuarial local control rate
was 98% in women who had negative margins and 82% in women
with close or positive margins (p = 0.007). Patient and tumor char-
acteristics were analyzed, and final margin status was the most
significant determinant of local recurrence in univariate analysis.
In this series, patients who underwent reexcision for close or posi-
tive margins had a 10-year local control rate of 97%, and patients
who did not have a reexicision had a 10-year local control rate
of 84% (p = 0.0001). Therefore, when performing BCS, reexcision
should be performed for close or positive margins. Orientation of
the original lumpectomy specimen helps facilitate reexcision of
only the involved margin instead of excising the entire cavity. If
margins continue to remain positive, especially if multiple reexci-
sion margins are involved, mastectomy may be required.
2. What is the approach to the axilla in patients with early-
stage breast cancer?
Answer: The current NCCN recommendation for patients with
early-stage breast cancer is sentinel lymph node (SLN) biopsy and
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axillary lymph node dissection (ALND) in a patient with senti-
nel node metastasis.10 Surgical management of the axilla histori-
cally involved routine excision of all draining lymph nodes of
the breast. Morton20 first introduced the use of lymphatic map-
ping and SLN biopsy in the treatment of melanoma. Giuliano
et al.21,22 used methylene blue dye and applied Morton’s technique
to the treatment of breast cancer. The identification of SLNs in the
axilla as the first site of lymphatic drainage of the breast redefined
breast surgery. Krag et al.23 described the use of radioisotope to
help localize the SLNs. The accuracy of identifying the SLNs of
the breast is enhanced by combining the injection of blue dye with
injection of technetium-99m (Tc99) sulfur colloid. Tafra et al.24
reviewed 529 patients who underwent 535 sentinel node biopsies
using peritumoral injection of Tc99 and isosulfan blue. The iden-
tification rate of finding a SLN in this series was 87% and the false-
negative rate was 13%.
In the United States, Guiliano et al.25 reported the safety of
omitting ALND in women with negative SLNs. In Italy, Veronesi
et al.26 further validated the safety and accuracy of performing
and SLN biopsy. Women with breast cancers ≤2 cm were random-
ized to either SLN biopsy with axillary dissection or SLN biopsy
with axillary dissection only if the node was positive for metasta-
sis. The sensitivity of SLN biopsy in this study was 91.2% and the
specificity was 100%. Currently, the American Society of Clinical
Oncology recommends that a positive SLN should be routinely
followed by completion ALND.27
The largest prospective randomized trial examining the role
of SLN biopsy in breast cancer is the NSABP B-32 study.28 The
phase III trial randomized 5611 women with invasive breast can-
cer to sentinel node resection and axillary dissection or to senti-
nel node resection alone with completion dissection for positive
SLNs. Blue dye and radioactive tracer were used to identify the
SLNs. The 8-year overall survival was 91.8% in the group who
underwent sentinel node resection and axillary dissection com-
pared with 90.3% in the group who had sentinel node resection
and dissection only in cases of positive SLN. The hazard ratio was
1.20 (95% confidence interval; p = 0.12). The study concluded that
SLN biopsy is safe and accurate, and no axillary dissection is nec-
essary when the sentinel node is negative. Kim et al.29 published a
review of 69 observational studies, which included 8059 patients
who underwent SLN biopsy followed by ALND. The sentinel node
identification rate was 96%, and the false-negative rate was 7%.
The Axillary Lymphatic Mapping against Nodal Axillary Clear-
ance (ALMANAC) trial had a sentinel node identification rate of
95% and a false-negative rate of 5%.30
The most common mapping agents used when performing
SLN biopsy are 1% lymphazurin (isosulfan blue) dye, methylene
blue dye, and Tc99 sulfur colloid. Blue dye and Tc99 sulfur colloid
are preferentially taken up by the lymphatic system. The Ameri-
can Society of Clinical Oncology (ASCO) recommends using both
blue dye and radioisotope to increase the rate of sentinel node iden-
tification. Typically a dose of 1 mCi of filtered technetium sulfur
colloid is injected into the breast prior to the surgery. Unfiltered
isotope should be used in patients who are injected the day prior
to surgery. Unfiltered radioisotope doses contain larger particles
and result in longer time interval for migration to the axilla. Vari-
ous injection techniques and injection sites have been described
for both blue dye and the radioisotope. Successful lymphatic map-
ping with Tc99 sulfur colloid has been seen with intraparenchy-
mal injection, intradermal injection, subareolar injection, and
peritumoral injection.31,32 Lymphoscintigraphy is not necessary
PMPH_CH73.indd 589
Breast Cancer: Surgical Therapy ■ 589
after injection of radioisotope. Similarly various successful injec-
tions sites for blue dye have also been described. The volume of
blue dye injected is 1 to 3 mL, and the breast is gently massaged for
5 minutes. Montgomery et al.33 examined 2392 patients who under-
went SLN biopsy using isosulfan blue dye and reported a 1.6% rate
of allergic reactions. The incision for SLN biopsy is made at the
inferior aspect of the hair-bearing area of the axilla. This incision
can be readily extended for a completion axillary dissection if the
SLN is positive for metastasis. A hand-held gamma probe placed
within a sterile cover is used to locate the area with the highest
counts. SLNs are stained blue or have the highest counts per unit
(CPU) as indicated by the gamma probe. Following excision of
the node or nodes, ex vivo radioactive counts should be obtained
away from the surgical field to avoid counts from the injection
site of the breast. The CPU should be recorded. The gamma probe
should then be place in the axillary incision and positioned in
multiple directions to identify any additional areas of increased
uptake. Any lymph node with a count more than 10% of the node
with the highest CPU should be excised.34 The axilla should then
be palpated, and any abnormal or suspicious node should also be
excised. The sentinel node or nodes can be examined by touch
prep or intraoperative frozen section. If one cannot identify a
SLN, an axillary dissection should be performed.
Traditionally, the finding of a SLN with metastasis is followed
by a completion axillary dissection. The known morbidities of
axillary surgery, low rates of axillary recurrence, and impact on
overall survival have led clinicians to question the need for axil-
lary dissection in women with positive SLNs. Many studies have
described the short- and long-term complications of both SLN
biopsy and ALND. Complications include paresthesia, chronic
pain, restricted range of motion, and lymphedema. Fleissig et al.35
reported arm swelling in 7% of patients who had an SLN biopsy
compared with 14% of patients who had axillary dissection 18
months after surgery (p = 0.002). Arm numbness was 19% in the
axillary dissection group and 8.7% in SLN biopsy alone group. Sev-
eral studies have attempted to identify a subset of women who may
not benefit from axillary dissection despite having involved senti-
nel nodes. Bilimoria et al.36 retrospectively reviewed the National
Cancer Database and identified women with positive SLNs who
did not undergo completion axillary dissection. Although these
women tended to be older and had smaller tumors, there was no
difference in axillary recurrence compared with women who had
an axillary dissection.
Recently, Guiliano et al.37 published the results of the Ameri-
can College of Surgeons Oncology Group (ACOSOG) Z0011
study. They randomized 891 SLN positive patients who underwent
lumpectomy to completion, ALND, or no dissection. The primary
end point was overall survival. Patients were women with clinical
T1 to T2 N0 M0 invasive breast cancers. Lymph node metasta-
sis was detected by frozen section, touch prep, or hematoxilyn-
eosin stain on permanent section. Exclusion criteria included T3
tumors, clinically positive axillae, multicentric disease, and three
or more positive SLNs. All lumpectomy margins were negative and
all women received whole-breast radiation. In the ALND arm, a
level I and II lymph node dissection was performed, with removal
of at least 10 lymph nodes. Patient and tumor characteristics were
similar between 445 women randomized to axillary dissection
and 446 women with no dissection. Median number of SLNs was
2, and median number of lymph nodes removed in the dissection
group was 17. At a median follow-up of 6.3 years, 5-year overall
survival was 91.8% in women who had an ALND and 92.5% in
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 590 ■ Surgery: Evidence-Based Practice
women who had no dissection. The hazard ratio was 0.87 when
adjusted for age and adjuvant therapy. There was no statistically
significant difference in locoregional recurrence. The locoregional
recurrence was 3.6% in the ALND arm, and the locoregional recur-
rence was 1.8% in the SLND alone arm. Adjuvant systemic therapy
was administered to 96% of the patients in the ALND arm and
to 97% of the patients in the SLND arm. All patients in the study
received whole-breast irradiation with standard tangential fields.
Therefore, it is likely that the axilla in many patients was treated in
both arms of the trial. The Z0011 trial concluded that SLND may
offer local control in early-stage breast cancer patients who undergo
breast conservation with adjuvant therapy, and that perhaps local
control is not improved by ALND.
3. What is the role of RT in the treatment of early-stage inva-
sive breast cancer?
Answer: Multiple randomized trials have demonstrated that RT
following BCS decreases local recurrence and improves overall
survival. As previously mentioned, the NASBP B-06 was a large
phase III trial, which randomized 1851 women with stage I or II
invasive breast cancer into three treatment arms: (1) modified
radical mastectomy; (2) BCS with axillary dissection followed
by whole-breast radiation; and (3) BCS with axillary dissection
without radiation.12 Twenty-year follow-up was published in 2002,
which showed a statistically significant lower rate of recurrence
in the group of women who received BCS plus RT, compared
with BCS without RT. The incidence of ipsilateral breast recur-
rence in the group who had BCS plus RT was 14.3%, and the inci-
dence of ipsilateral breast recurrence in the group who had BCS
without RT was 39.2% (p < 0.001). Among the three arms of the
study, there was no significant difference in disease-free survival,
distant-disease-free survival, and overall survival. The EBCTCG
performed a meta-analysis of 7300 women randomized to receive
either BCS or BCS plus RT.38 In women who had negative lymph
nodes, the 10-year local recurrence rate was 29% in the group who
had BCS, compared with a 10-year local recurrence of 10% in the
group who had BCS plus RT. In women who had positive lymph
nodes, 10-year local recurrence rate was 47% in the group who
had BCS, compared with a 10-year local recurrence rate of 13% in
the group who had BCS plus RT. In women with negative lymph
nodes who had BCS, the mortality was 31% compared with 26%
in those who had BCS plus RT. In women with positive lymph
nodes who had BCS, the mortality was 55% compared with 48%
in those who had BCS plus RT. The 15-year overall death rate was
41% in the group who had BCS, and the 15-year overall mortality
rate was 35% in the group who had BCS plus RT (p = 0.005). The
absolute survival advantage attributable to RT was 5.1% in node-
negative women. The absolute survival advantage attributable to
RT was 7.1% in node-positive women. Therefore, the decrease in
local recurrence associated with the addition of RT translated to
an absolute reduction in death.
Conventional radiotherapy is administered is to the whole
breast using electron beam. The most common complications are
fatigue and local skin changes such as dermatitis, erythema, and
hyperpigmentation. The standard dose is 45 to 50 Gy in 1.8 to
2.0 Gy daily fractions, given over 6 weeks. A boost dose of 10 to
16 Gy is delivered to the lumpectomy site, and radiation of regional
nodal basins is given when indicated. Patients who undergo BCS
with negative SLN biopsy typically do not need radiation to the
regional lymph nodes. Patients who are treated with BCS with
PMPH_CH73.indd 590
four or more positive axillary lymph nodes should receive radia-
tion to regional lymph nodes. Whole-breast radiation following
BCS may also be administered to patients with high risk of locore-
gional recurrence. Radiation is administered after surgery, unless
a patient is recommended chemotherapy. Patients who receive
chemotherapy are scheduled for radiation several weeks after
the last dose. A randomized trial examining the optimal sequence
of chemotherapy and radiation compared patients who received
doxorubicin-based chemotherapy followed by RT with patients
who received RT followed by the same chemotherapy. There was
no difference in local recurrence or overall survival in the two
groups.39
Multiple trials have attempted to identify a subset of patients
undergoing BCS in whom radiation can be omitted. In these
studies, women who did not receive radiation had higher rates
of local recurrence, despite favorable disease characteristics such
as smaller size and positive hormone status. Lim et al.40 prospec-
tively studied patients with tumors 2 cm or less in size. Patients
with extensive lymphovascular invasion or extensive intraductal
component were excluded from the study, and all margins were
1 cm or greater. Patients were randomized to BCS with no RT or
BCS alone. The trial was closed due to high recurrence rates in the
arm that did not receive RT. The local recurrence rate in this arm
was 23% after 86-month follow-up. The possibility of eliminating
the need for RT in a select group of patients with favorable tumor
characteristics was also examined in the NSABP B-21 trial.41 The
study randomized women with estrogen-positive tumors ≤1 cm
to receive tamoxifen alone, placebo, placebo plus RT, or tamoxifen
plus RT after BCS. After 8-year median follow-up, the arm which
received tamoxifen alone had a local recurrence rate of 16.5%. The
arm which received placebo plus RT had a local recurrence rate of
9.3%, and the arm which received tamoxifen plus RT had a local
recurrence rate of 2.8%. This study reinforced the role of com-
bining BCS with RT to decrease local recurrence rate, despite the
addition of hormonal therapy. The elimination of RT in a cohort
of elderly patients with breast cancer was examined in the Cancer
and Leukemia Group B (CALGB) 9343 trial.42 The study enrolled
636 women over age 70 years with clinically negative axilla and
hormone-positive tumors 2 cm or less in size. After lumpectomy,
the women were randomized to receive tamoxifen with radiation
or tamoxifen alone. At 5 years, the group who received tamox-
ifen had a local recurrence rate of 4%, and the group who received
tamoxifen with radiation had a local recurrence rate of 1%
(p < 0.001). However, there was no difference in overall survival in
the two arms of the study. The breast cancer mortality rate was 1%
at 5 years, and the mortality rate from all other causes was 17%.
Careful consideration of comorbidities and risk of disease recur-
rence must be examined to provide the best treatment plan for
the elderly patient with breast cancer. The omission of radiation
in patients receiving breast conserving therapy is best managed
by a multidisciplinary team and reserved for carefully selected
patients.
4. What is the management of locally advanced breast cancer
(LABC)?
Answer: Patients who present with LABC should first undergo
additional imaging to determine stage and resectability. LABCs
include tumors greater than 5 cm (T3) or tumors which extend
to the chest wall (T4a) or skin (T4b). Disease is confined to the
breast and regional lymph nodes. Patients with LABC usually
5/22/2012 5:51:25 PM

present with a large palpable mass, which can be associated with
overlying skin changes, nipple retraction, and lymphadenopathy.
Patients with large tumors or axillary involvement are at high risk
for systemic disease and local recurrence. The National Cancer
Data Base of the American College of Surgeons reported 8.7% of
patients with breast cancer in 2008 presented as stage III disease.43
Neoadjuvant chemotherapy should be considered in all patients
with LABC. Neoadjuvant chemotherapy can be used in patients
with large, fi xed tumors or in patients with bulky lymphadenopa-
thy. In some cases, it can convert a patient with an unresectable
tumor to a patient with operable disease. Workup for metastatic
disease is appropriate in all patients with LABC. Bone scan and
CT scan of the chest, abdomen, and pelvis should be obtained.
Systemic metastasis is detected in up to 30% of patients with
LABC who undergo imaging for staging purposes.44
Work done earlier by Haagensen and Stout45 described their
experience with LABCs treated with radical mastectomy, and
described a 6% 5-year survival rate. Results of the NSABP B-04
trial demonstrate radical mastectomy is not indicated.46 The trial
randomized 1079 women. In the node-negative group, the haz-
ard ratio for death among women treated with total mastectomy
and radiation compared with women treated with radical mas-
tectomy was 1.08 (95% confidence interval, 0.91–1.28; p = 0.38).
In the node-positive group, the hazard ratio for death among
women treated with total mastectomy with radiation compared
with women treated with radical mastectomy was 1.06 (95% con-
fidence interval, 0.87–1.23; p = 0.72). Twenty-five-year follow-up
comparing radical mastectomy, total mastectomy with postop-
erative radiation, and total mastectomy with axillary dissection
for nodal involvement did not show survival advantage of radical
mastectomy.
Most patients with LABC undergo mastectomy. Total or sim-
ple mastectomy involves complete removal of the gland includ-
ing the nipple and areola. The underlying pectoralis muscles are
left intact. Mastectomy is removal of the entire breast to the ana-
tomic borders of the gland. The superior border of the breast is
the clavicle, the medial border is the sternum, the lateral border
is the latissimus muscle, and the inferior border is the inframam-
mary fold. The posterior border is the pectoralis major muscle and
the breast specimen is removed along with the pectoralis major
fascia. Mastectomy flaps can be raised using various techniques
including sharp dissection with a scalpel or scissors, or with elec-
trocautery. The thickness of the mastectomy flaps should ensure
both removal of the entire gland and maintenance of a thin layer
of subcutaneous fat beneath the dermis. Meticulous dissection in
the plane between the gland and this layer of subcutaneous fat
improves the vascular supply of the mastectomy skin flaps, mini-
mizing the risk of flap necrosis. Mastectomy can be performed
with or without reconstruction. In patients who undergo mastec-
tomy with no reconstruction, an elliptical incision is made from
the lateral border of the sternum to the latissimus. The incision
should allow for adequate, tension-free closure of the two wound
edges, while avoiding redundant skin. Redundant skin should be
excised and the chest wall should be flat. Avoiding redundant skin
on the chest wall helps facilitate comfortable wear of a breast pros-
thesis postoperatively. To decrease risk of seroma formation, the
skin should be reapproximated over two closed suction drains.
One drain should be placed beneath the superior mastectomy
flap and the other placed beneath the inferior mastectomy flap. In
cases in which an axillary dissection is also performed, one drain
can be placed on the chest wall and a second placed in the axilla.
PMPH_CH73.indd 591
Breast Cancer: Surgical Therapy ■ 591
Drains are removed when the drainage volume is less that 30 mL
in 24 hours. The deep dermal layer is reapproximated with inter-
rupted sutures and the skin is closed with continuous subcuticu-
lar suture. Possible complications following mastectomy include
surgical site infection, hematoma, seroma, and chronic pain. El
Tamer et al.47 reviewed the National Surgical Quality Improve-
ment Program (NSQIP) data and reported an infection rate of
4.34% after mastectomy. In this analysis, the only significant
independent predictors of wound complications including surgi-
cal site infection were obesity (BMI > 30), preoperative albumin,
and hematocrit level.
5. What is the approach to the axilla in LABC?
Answer: Many patients with LABC are treated with neoadjuvant
chemotherapy, and performing SLN biopsy prior to or after neo-
adjuvant chemotherapy is under debate. There is concern that
SLN biopsy after chemotherapy is inaccurate due to sterilization
of axillary nodes. In addition, some clinicians prefer to know the
status of the axilla prior to chemotherapy when planning adjuvant
radiation. Sabel et al.48 reported a small series of 24 patients who
underwent SLN biopsy prior to neoadjuvant chemotherapy. The
SLN identification rate was 100%, and 10 out of 24 (42%) patients
had sentinel node metastasis. All 10 patients who had positive sen-
tinel nodes underwent a completion axillary dissection at the time
of definitive surgical management after chemotherapy. Three out
of ten (30%) patients had metastasis in additional lymph nodes.
The NSABP B-27 studied the role neoadjuvant chemotherapy in
breast cancer management. In this trial, a subgroup of 428 women
underwent SLN biopsy after receiving chemotherapy. Mamounas
et al.49 reported an SLN identification rate of 85% and a false-
negative rate of 11%. The ACOSOG Z1071 trial is a phase II study
evaluating sentinel node biopsy in patients receiving preoperative
chemotherapy. This is a single-arm study examining patients with
known SLN involvement prior to the start of neoadjuvant chemo-
therapy. Patients enrolled in the trial will undergo sentinel node
biopsy and completion axillary dissection after chemotherapy.
The primary goal of the study is to determine the false-negative
rate of SLN biopsy performed after neoadjuvant chemotherapy.
Results of the study are pending. One of the advantages of doing
SLN biopsy after chemotherapy is that it allows for a single opera-
tive procedure, compared with performing sentinel node biopsy
before neoadjuvant chemotherapy and then performing the final
operative procedure after chemotherapy. Most importantly, SLN
biopsy after chemotherapy may also allow the group of women
with positive SLNs prior to chemotherapy whose axillae are ster-
ilized by chemotherapy to avoid unnecessary axillary dissection
and the morbidity associated with dissection.
If an axillary dissection is to be performed, the NCCN recom-
mends excision of level I and II lymph nodes. Lymph nodes in the
axilla are divided into three levels according to their relationship
to the pectoralis minor muscle. Level I nodes are located lateral
to the muscle, level II nodes are located beneath the muscle, and
level III nodes are located medial to the muscle. The lymph nodes
located between the pectoralis major and pectoralis minor mus-
cles are known as Rotter’s nodes. Rotter’s nodes are not removed
when performing an axillary dissection, unless grossly involved.
When performing an axillary dissection, the clavipectoral fascia
is incised and the axilla is exposed. The pectoralis major and pec-
toralis minor muscles are retracted upward and the axillary vein
is identified. The apex of the axilla is the axillary vein. The axillary
5/22/2012 5:51:25 PM
 592 ■ Surgery: Evidence-Based Practice
content inferior to the vein is excised when performing an axil-
lary dissection, paying close attention to small branches from the
axillary artery and vein. NCCN guidelines state a level III axillary
dissection can be considered in patients who have gross disease of
the level II nodes. The thoracodorsal and long thoracic vessels and
nerves should be identified and preserved.
6. What is the role of postmastectomy radiation in locally
advanced breast cancer?
Answer: Postmastectomy radiation therapy (PMRT) is adminis-
tered to patients with locally advanced breast cancer to improve
locoregional control and survival following mastectomy. Several
studies have demonstrated that these women are at high risk for
local and regional recurrence.50,51 The Danish Breast Cooperative
Group (DBCG) 82b trial randomized 1708 premenopausal women
with Stage II and III breast cancer who underwent mastectomy
to receive chemotherapy or chemotherapy with radiation.52 The
trial demonstrated a local recurrence rate of 9% in patients who
received PMRT with chemotherapy, and a local recurrence rate
of 32% in patients who did not receive PMRT (p < 0.001). Overall
survival in the PMRT group was 45%, compared with 54% in the
group with no PMRT (p < 0.001). The DBCG 82c trial randomized
1375 postmenopausal women undergoing mastectomy to receive
tamoxifen alone or tamoxifen with radiation.53 The trial showed
a local recurrence rate of 8% in the patients who received PMRT
with tamoxifen, and a local recurrence rate of 35% in patients
who received tamoxifen alone (p < 0.001). Overall survival in the
PMRT group was 45%, compared with 38% in the group with no
PMRT (p < 0.03). In 2005, Ragaz et al.54 reported the results of
the British Columbia Trial which examined the role of PMRT in
premenopausal women who received chemotherapy. Median fol-
low-up was 14.5 years, and PMRT was shown to decrease locore-
gional recurrence and improve disease-free survival and overall
survival. PMRT is routinely indicated in patients with tumors
>5 cm, metastasis to four or more lymph nodes, or positive surgi-
cal margins.55 Others factors that increase risk of recurrence such
as extensive lymphovascular invasion and extranodal extension of
disease are also considered when determining if a patient is a can-
didate for PMRT. PMRT can also be considered in women with
one to three involved axillary nodes. Overgaard et al.56 reported
a survival benefit when PMRT was administered to women with
one to three involved axillary nodes.
7. What is the role of neoadjuvant therapy in breast cancer?
Answer: In some cases, neoadjuvant chemotherapy can be used to
convert the operative management of disease from mastectomy to
BCS. Systemic chemotherapy or hormonal therapy prior to surgery
can decrease the size of the tumor, while also providing the clini-
cian the ability to assess tumor response to therapy. The patient
should be assessed periodically during therapy, and surgery is
planned three to four weeks after the last dose of chemotherapy. To
assess response to therapy, repeat breast imaging prior to surgery
is necessary. This is especially useful in patients who will undergo
breast conserving therapy as the imaging can help guide surgical
planning. The current NCCN guidelines recommend perform-
ing SLN biopsy before beginning neoadjuvant chemotherapy. If
the SLN is negative, an axillary dissection at the time of mastec-
tomy is not indicated. If the SLN is positive, a level I and II axillary
dissection is performed at the time of definitive surgery. Com-
plete pathologic response to neoadjuvant chemotherapy has been
PMPH_CH73.indd 592
demonstrated with cases of no residual tumor found in the excised
specimen. Therefore, placement of a marking clip in the primary
tumor should be performed prior to initiation of therapy.
The NSABP B-18 trial examined the use of neoadjuvant che-
motherapy and showed no difference in disease-free survival
and overall survival in patients who received preoperative versus
postoperative chemotherapy.57 In this trial, 1523 patients with
T1-T3N0M0 and T1-T3N1M0 disease were treated preoperatively
or postoperatively with four cycles of doxorubicin and cyclophos-
phamide (AC). All patients over age 50 years received tamoxifen.
The patients treated with preoperative chemotherapy had higher
rates of breast conserving therapy. The survival rates were similar
in the two groups. However, the women randomized to the neo-
adjuvant arm had more lumpectomies compared with the group
who had surgery prior to chemotherapy. The lumpectomy rate was
67% among those who received neoadjuvant therapy, compared
with 60% in those who had adjuvant chemotherapy (p = 0.002).
The clinical response rate in women who received neoadjuvant
chemotherapy was 80% and the complete clinical response rate
was 36%. The complete pathologic response rate was 13%. In the
NSABP B-18 trial, the survival rate of women whose tumor had
a complete pathologic response was 75% at 9 years, compared
with a survival rate of 58% in women who had residual disease.
The study showed no difference between the neoadjuvant and the
adjuvant chemotherapy arms in terms of disease-free survival. The
9-year disease-free survival rate in the neoadjuvant arm was 55%
compared with 53% in the adjuvant arm (p = NS). The study also
showed no difference in overall survival (OS). The overall survival
in the neoadjuvant arm was 69% and the OS in the adjuvant arm
was 70% (p = NS). Another NSABP trial which explored the ben-
efit of neoadjuvant chemotherapy was the NSABP B-27 trial. The
B-27 trial was a randomized phase III study with three arms which
included 2411 women with invasive breast cancer.58 The women
were randomized to receive preoperative doxorubicin and cyclo-
phosphamide (AC) for four cycles followed by surgery, preopera-
tive AC followed by docetaxel for four cycles followed by surgery,
or AC followed by surgery and four cycles of postoperative doc-
etaxel. The highest complete pathologic response rate was seen in
women who received preoperative AC followed by docetaxel prior
to surgery. Approximately 25% of patients in the neoadjuvant arms
were converted from mastectomy to BCS.59 Gianni et al. 60 also
examined the use of neoadjuvant chemotherapy and randomized
1335 patients with invasive breast cancer into three arms. The first
arm involved surgery followed by adjuvant doxorubicin, followed
by cyclophosphamide, methotrexate, and 5-FU (CMF). The sec-
ond arm involved surgery followed by adjuvant doxorubicin and
paclitaxel (AT) followed by CMF. Lastly, the third arm was neoad-
juvant AT followed by CMF, followed by surgery. The lumpectomy
rate in the neoadjuvant arm was 63% compared with 34% in the
adjuvant arms (p < 0.001). Overall survival at 5 years was similar
in the neoadjuvant and adjuvant arms (p = 0.81).
Use of neoadjuvant endocrine therapy for hormone positive
LABC is increasing. Three to four months of therapy is indicated
prior to surgery. Similar to neoadjuvant chemotherapy, periodic
clinical examination and imaging is necessary to assess response
to therapy. One of the initial reports describing the use of neo-
adjuvant endocrine therapy was by Preece et al.61 who prescribed
tamoxifen prior to surgery. Dixon et al.62 recommend administer-
ing an aromatase inhibitor (letrozole, anastrozole, or exemestane)
for 3 months prior to surgery. They report the ability to convert
inoperable tumors to resectable tumors, and performing BCS in
5/22/2012 5:51:26 PM

patients initially thought to require mastectomy. The P024 trial
randomized 337 postmenopausal women with estrogen-positive
breast cancer to receive letrozole (2.5 mg daily) or tamoxifen
(20 mg daily).63 All women at the start of the trial were not can-
didates for BCS and 14% were considered inoperable. The group
who received letrozole had a 55% clinical response rate com-
pared with a 36% clinical response rate in the tamoxifen group
(p < 0.001). The rate of conversion to BCS was 45% in the letrozole
arm and the rate of conversion to BCS was 35% in the tamox-
ifen arm (p = 0.022). The PROACT trial randomized 451 post-
menopausal women to anastrozole for 3 months or tamoxifen for
3 months prior to surgery.64 The rate of BCS was 43% in the anas-
trolze group and 35.4% in the tamoxifen group.
8. What is the role of SSM and nipple- and areola-SSM in breast
cancer?
Answer: SSM is removal of the entire gland, while leaving the
majority of the skin as an envelope for breast reconstruction. If
immediate breast reconstruction is to be performed, the skin
allows coverage over an implant or autologous tissue flap. The pri-
mary concern is the oncologic safety of the procedure. Numerous
studies have established that rates of local recurrence in patients
who had a SSM are similar to those in patients who had a non-SSM.
A series from the MD Anderson Cancer Center with four-year fol-
low-up described a 4.2% rate of recurrence in 95 patients who had
an SSM with immediate reconstruction.65 A series from Emory
with 6-year follow-up reported a local recurrence rate of 5.5% in
patients who had an SSM and immediate breast reconstruction.66
The use of nipple-SSM (NSM) and areolar-SSM is increasing.
Among the various incisions used in nipple-sparing and areolar-
SSM are a single lateral incision, a vertical incision inferior to the
areola, a periareolar incision with lateral extension, an inframam-
mary incision, and a transareolar incision. Similar to the onco-
logic concerns surrounding SSM, there is debate as to the safety of
these procedures because of the concern of leaving breast or duc-
tal tissue behind. When performing a NSM procedure, the nipple
should be inverted and a core of tissue should be sharply excised
and submitted for intraoperative frozen section analysis. If the
frozen section is positive for disease, the nipple–areolar complex
(NAC) should be excised. Crowe et al.67 reviewed 149 NSMs per-
formed on 110 patients. In this series, no cancer was detected in
the cored nipple tissue in patients who underwent prophylactic
mastectomy. In patients who underwent NSM for breast cancer,
11% were found to have involvement of the NAC. Chen et al.68
published a series of 115 consecutive patients at Memorial Sloan
Kettering Cancer Center undergoing NSM or areola-SSM with
immediate tissue expander placement. The nipple was involved
in 5.2% of patients, requiring excision. Rate of nipple loss due to
wound-healing problems was 3.5%. Petit et al.69 reported a series
of 579 NSMs performed at the European Institute of Oncology in
Milan. Intraoperative analysis of the NAC was performed in all
patients. Intraoperative radiotherapy using electron beam (total
dose 16 Gy) was administered to the NAC after mastectomy to
decrease risk of local recurrence. In this series, no local recur-
rences occurred in the area of the NAC and local relapse rate was
0.9% per year. A series of 99 NSMs with 5-year follow-up reported
by Jensen et al.70 from the John Wayne Cancer Center reported
three recurrences and no mortalities.
NSM and areola-SSM procedures are being performed more
frequently. Patients who undergo these procedures should be
PMPH_CH73.indd 593
Breast Cancer: Surgical Therapy ■ 593
counseled on the need to resect the NAC if the cored tissue has
disease. They should be informed of the possible complications of
the procedure, which include partial nipple necrosis and nipple
loss. Appropriate and careful patient selection remains the key
element when performing these procedures.
9. What is the approach to stage IV breast cancer?
Answer: Fewer than 10% of patients with breast cancer will pres-
ent with stage IV disease. The 5-year overall survival is approxi-
mately 15%. The most common sites of breast cancer metastasis
are to the bones, lungs, liver, and central nervous system. Women
with bone metastasis and no visceral involvement have more
favorable prognosis and longer survival. Metastasis to the central
nervous system is more commonly associated with HER-2 positive
cancers.71 Biopsy of a presumed area of metastasis should be per-
formed, and tissue diagnosis established. Hormonal therapy can
be used in patients with estrogen-positive tumors. Chemotherapy
is used in patients with estrogen-negative tumors, extensive vis-
ceral involvement, or rapidly growing tumors. Trastuzumab can
safely be administered to patients with HER-2 positive metastatic
breast cancer. Vogel et al.72 reported trastuzumab therapy is well
tolerated as first-line treatment and described a response rate of
26%. The goals of therapy of stage IV breast cancer are to improve
or stabilize disease, palliate symptoms, and minimize treatment-
related toxicities.
Excision of the primary tumor in patients with metastatic
breast cancer has been examined in several series. Rapiti et al.73
reviewed 300 patients with metastatic breast cancer included in
the Geneva Cancer Registry from 1977 to 1996. Women who
had complete excision of the primary tumor with negative mar-
gins had improved survival compared with women who did not
have surgery. Risk of death was decreased by 40% in the group
who underwent surgery (95% confidence interval, HR 0.6). Khan
et al.74 examined 16,023 patients presenting with stage IV breast
cancer in the National Cancer Data Base between 1990 and 1993.
They reported 42.8% of patients did not have surgery, and 57.2% of
patients had either a partial or total mastectomy. Negative surgical
margins were associated with improved 3-year survival. Women
who had resection of their primary tumor with negative margins
had improved survival compared with women who did not have
resection (HR 0.61). The Eastern Cooperative Oncology Group
(ECOG) 2108 study is an ongoing phase III trial evaluating the
value of early local therapy in patients with metastatic breast can-
cer. Patients enrolled in the study will receive systemic therapy,
and those who demonstrate response to therapy are randomized
to either continued systemic therapy or surgery. Patients random-
ized to the surgery arm will either undergo BCS or mastectomy,
according to patient or physician preference. The trial opened in
2011 and the results will help guide future management of patients
with stage IV disease.
CONCLUSION
There has been a dramatic shift in the surgical management of breast
cancer from radical surgery to BCS. Multiple large prospective ran-
domized trials have established the current treatment modalities
as safe and effective. The treatment of invasive breast carcinoma
requires shared-decision making with the patient, as well as a mul-
tidisciplinary approach to achieve the best clinical outcome.
5/22/2012 5:51:26 PM
 594 ■ Surgery: Evidence-Based Practice

Clinical Question Summary

Question
1 What is the appropriate
management for early-stage
(stages I and II) invasive
ductal carcinoma and
invasive lobular carcinoma
of the breast?
2 What is the approach to the
axilla in early-stage breast
cancer?
3 What is the role of RT in the
treatment of early-stage
invasive breast cancer?
4 What is the management
of locally advanced breast
cancer (LABC)?
5 What is the approach to the
axilla in LABC?
6 What is the role of
postmastectomy radiation
(PMRT) in breast cancer?
7 What is the role of
neoadjuvant therapy in
breast cancer?
8 What is the role of SSM and
nipple- and areola-SSM in
breast cancer?
9 What is the approach to
stage IV breast cancer?
Answer Levels of Grade of References
Evidence Recommendation
The majority of patients can be treated Ia A 15
with BCS. BCS followed by whole- Ib A 8, 14-16
breast irradiation when compared with
total mastectomy has been shown to
have equivalent overall survival.
Current guidelines recommend Ib A 30, 32
performing SLN biopsy, followed IIa B 31
by completion axillary dissection in IIb B 27, 28
patients with positive SLNs. IB A 39
The results of the ACOSOG Z11 trial
indicate ALND may be omitted in
early-stage breast cancer patients who
undergo BCS plus RT.
RT decreases local recurrence and Ia A 15, 40
improves overall survival. Ib A 12
Modified radical mastectomy in patients Ib A 48
with resectable disease. See question 7
Consider neoadjuvant chemotherapy in all
patients with LABC.
ALND.
PMRT improves locoregional control and Ib A 54-56
improves disease free survival and
overall survival.
Neoadjuvant chemotherapy can Ib A 58-60
potentially convert a patient for
mastectomy to BCS.
Several patient series report safety and IV C 67-72
low rates of local recurrence.
Patients with metastasis receive palliative IIa B 74
therapy. IIb B 73
Some series report improved survival with
resection of the primary tumor.

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28. Krag, D. Anderson S, Julian T, et al. Sentinel-lymph-node resec-
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5/22/2012 5:51:26 PM

Breast Cancer: Lymphatic Mapping
and Sentinel Lymph Node Biopsy
Abigail S. Caudle, Elizabeth A. Mittendorf, and Henry M. Kuerer
INTRODUCTION
Great strides have been made toward the goal of personalizing
therapy for breast cancer patients. While this concept is often
mentioned when discussing the evolution of “one size fits all”
cytotoxic chemotherapy to the current standard of tailoring
agents with targeted therapies and endocrine approaches based
on tumor biology and patient characteristics, the same is true
regarding surgical management of the disease. The acceptance of
breast conservation therapy in selected patients is one example of
personalized surgical therapy. Another major milestone in this
effort was the acceptance of sentinel lymph node (SLN) biopsy
for nodal assessment in patients with clinically node-negative
breast cancer. The SLN technique provides accurate staging
while limiting morbidity associated with a complete axillary
lymph node dissection (ALND). Although the concept of SLN
biopsy is straightforward and validated, there remain questions
about its application and interpretation of results. Th is chapter
addresses the clinical questions still debated among surgeons
regarding SLN biopsy in breast cancer and the evidence avail-
able to answer those questions.
SLN surgery is based on the concept that the breast has an
orderly pattern of lymphatic drainage with “sentinel nodes”
being the fi rst nodes to drain the breast followed by the rest
of the nodal basin. The concept was fi rst conceived 100 years
ago by Braithwaite after noticing the lymphatic drainage of
gangrenous appendicitis. After much investigation, the fi rst
clinical application was reported in the 1970s for penile can-
cer; however, the initial technique was cumbersome which
limited its widespread use. SLN biopsy as we know it today
became clinically relevant in 1991 when Morton et al.1 refi ned
the technique for melanoma patients. Th is prompted consider-
able interest from the breast cancer community as ALND with
its inherent morbidities such as lymphedema, pain, and func-
tional limitations was the standard of care at that time. Once
technical aspects were established and results were validated,
SLN biopsy became the standard technique for nodal evaluation
597
PMPH_CH74.indd 597
CHAPTER 74
in clinically node-negative breast cancer patients. Although
its original use was limited to patients presenting with unifo-
cal, small breast cancers, its application has since broadened to
include patients with larger tumors or even those with muti-
centric or multifocal disease. Additionally, the technique has
evolved from one offered only in highly specialized cancer insti-
tutions, to one that is taught to all general surgery residents and
is available in most communities. Thus, all clinicians caring for
breast cancer patients should have an understanding of the prin-
ciples of SLN biopsy and when it is indicated in the management
of breast cancer patients as well as its benefits and limitations.
SLN TECHNIQUE
1. What is the best method for identifying an SLN?
There are basic tenets to SLN biopsy; however, there are many
variations in the materials and techniques used by clinicians. The
guiding principle is that an agent such as dye, radioisotope, or
combination of the two is injected into the breast and allowed to
drain into the nodal basins. At the time of operation, any node
that is blue, “hot” (i.e., has increased radioisotope counts by hand-
held Geiger probe), or is suspiciously palpable is classified as an
SLN and should be removed for pathologic evaluation. A “10%”
rule is applied to determine “hot” nodes—all nodes with counts at
least 10% of the “hottest” node should be removed. If the SLN is
negative for disease, then the remaining lymph nodes can be left
in place. If metastasis is found in the SLN, the standard approach
has been to perform a completion ALND. However, as will be dis-
cussed below, recent studies have shown that this may not always
be necessary in a select group of patients.
In the United States, technetium-99m sulfur colloid is the
radioisotope usually employed if a radioisotope is used. It
can be injected at low doses (0.3–0.5 mCi) perioperatively or
at higher doses (1–2.5 mCi) up to 24 h before surgery. If the
radioisotope is injected prior to arrival to the operating room,
5/22/2012 5:52:01 PM
 598 ■ Surgery: Evidence-Based Practice
lymphoscintigraphy can be performed to confirm drainage and
indicate the site of drainage. However, preoperative injection
can be painful and requires scheduling with nuclear medicine.
Blue dyes used as mapping agents include isosulfan blue, meth-
ylene blue, and vital blue dye. Although the dye is easily acces-
sible and easy to inject in the operating room, drawbacks include
skin tattooing, unclear safety profi le in pregnancy, and the risk
of anaphylactic reaction. Although early studies showed higher
identification rates when blue dye was used with radioisotope, 2
more recent studies reflecting the general learning curve of this
procedure show no difference in success rates with the use of
one agent alone versus a combination when performed by expe-
rienced surgeons.3,4
Similarly, the optimal site of injection has not been deter-
mined. The original reports relied on peritumoral injections;
however, this can be difficult in nonpalpable tumors. In one
early study of five patients with muticentric breast cancers who
had blue dye injections in one tumor and radioisotope injection
of another, SLNs were identified which were both blue and “hot”
suggesting that the entire breast drains into the same SLNs,
rather than each specific area of the breast having different
drainage patterns. Th is allowed for the possibility of alternative
injection sites such as subdermal or subareolar. 5 The data sup-
porting subdermal injection includes one study of 200 patients
who had peritumoral blue dye injections who then were ran-
domized to receive either peritumoral or intradermal radioiso-
tope injection. Overall SLN identification rates were excellent in
both groups with concordance between blue and “hot” nodes in
both groups. The intradermal injection patients had a slightly
higher identification rate (100% vs. 92%) possibly related to the
more rapid lymphatic drainage.6 Similar studies have evaluated
subareolar injections, including a prospective, multicenter study
from France that randomized 449 patients to receive either peri-
tumoral injection of blue dye and radioisotope or subareolar
injection of the combination. The rate of SLN identification was
similar between the two groups, and blue/“hot” concordance
was 95.6% in the subareolar group versus 91.5% in the peritu-
moral cohort.7 Although subdermal and subareolar injection
sites are accepted as valid, extra-axillary drainage sites such as
internal mammary nodes are rarely seen when these routes are
employed which has led some surgeons to advocate peritumoral
injections.
The number of SLNs removed can vary—in one retrospec-
tive review of 777 patients, the median number of SLNs removed
was 2.9 (range 1–13 nodes). The authors found that >99% of the
positive SLNs were identified within the fi rst five SLNs removed.8
Importantly, studies show that the morbidity of SLN biopsy does
not increase with an increasing number of nodes removed.9
When an SLN cannot be identified, the recommendation has
been for complete ALND. Patients should be counseled preop-
eratively about the risk of nonidentification; so their desires as
to whether or not to proceed to full ALND can be considered in
this circumstance.
In conclusion, the best technique for SLN biopsy should
be based on the surgeon’s experience, the patient’s character-
istics, and institutional resources. Radioisotope or blue dye or
the combination can be injected in peritumoral, subdermal,
or subareolar locations. The surgeon should then explore the
axilla and remove any nodes that are blue, “hot”, or clinically
suspicious.
PMPH_CH74.indd 598
ACCURACY OF SLN BIOPSY
2. Is SLN biopsy as accurate as ALND for breast cancer?
Although the concept of a minimally invasive technique is attrac-
tive, the primary goal of clinicians caring for breast cancer patients
is optimization of diagnostic and therapeutic modalities. There-
fore, less invasive techniques such as SLN biopsy must be tested
rigorously against standard therapies to ensure equivalency for
both accuracy and outcomes. The SLN concept has undergone
such an evaluation and has been shown to be even more sensi-
tive than ALND in identifying lymph nodes harboring metastatic
disease, particularly small volume metastases, because evaluating
fewer lymph nodes allows for more rigorous pathologic evaluation
of each node.
Th is question was fi rst addressed in a single-institution
study published in by Giuliano et al. in 1995.10 In this study,
they compared 134 patients who underwent ALND versus 162
who underwent SLN biopsy followed by ALND. Nodal metasta-
sis was identified in 29.1% of the ALND group versus 42% in the
group undergoing SLN biopsy followed by ALND (p < .03). Of
the patients with metastasis, only 10% of the ALND group were
micrometastasis (tumor focus of ≤2 mm) compared with 16% in
the SLN biopsy group (p < .0005) suggesting that SLN biopsy may
actually be more accurate than ALND in staging the axilla. This
was validated in a broader population in 1998 with a multicenter
trial that included 11 sites.11 This study enrolled 443 patients who
underwent SLN biopsy followed by full ALND to assess the accu-
racy of the SLN in determining the presence of SLN metastasis.
They found SLN biopsy to have an accuracy rate of 97% and a spec-
ificity of 100%. A single-institution randomized study from Italy
confirmed these results in 516 patients who were also randomized
to SLN biopsy followed by ALND versus SLN biopsy with ALND
only if metastasis was found. They reported an accuracy rate of
96.9% for SLN biopsy, and importantly had no cases of axillary
recurrence in the SLN biopsy only group after a median follow-up
of 46 months.12 The results of these large, randomized trials led
to the 2005 American Society of Clinical Oncology Guidelines
recommending SLN biopsy for nodal evaluation in patients with
clinically node-negative, early-stage breast cancer.13
Building on these data, the National Surgical Adjuvant Breast
and Bowel Project (NSABP) B-32 trial was designed to determine
whether SLN biopsy achieves the same cancer outcomes as ALND
with decreased morbidity. This was a randomized, controlled,
phase 3 trial performed at 80 centers in the United States and
Canada with end points that included survival, regional control,
and morbidity. A total of 5611 women were randomized to either
SLN biopsy followed by ALND or SLN biopsy followed by ALND
only if the SLN(s) were positive. SLN biopsy was performed
with blue dye and radioisotope, and participating surgeons were
required to show adequate experience with the technique. With a
mean follow-up of 95 months, there was no difference seen in the
overall survival (OS), disease-free survival, or locoregional recur-
rence in the two groups, thus further validating this technique in
the management of breast cancer patients.14
In conclusion, SLN biopsy is at least as accurate, if not more
accurate, as complete ALND for diagnosing the presence of nodal
metastasis as long as it is performed by an experienced surgeon.
Additionally, using this method to evaluate for nodal metastasis,
thus eliminating the need for ALND in node-negative patients,
5/22/2012 5:52:01 PM
 Breast Cancer: Lymphatic Mapping and Sentinel Lymph Node Biopsy
has been shown to have equivalent survival and locoregional
recurrence rates as the previous standard of ALND with the sig-
nificant benefit of decreased morbidity.
SURGICAL MANAGEMENT OF
AN SLN METASTASIS
3. Do all patients need a completion ALND when an SLN metas-
tasis is identified?
Current recommendations from the American Society of Clini-
cal Oncology and the National Comprehensive Cancer Network
(NCCN) recommend performing a completion ALND in patients
that have evidence of metastases in their SLN. This practice is sup-
ported by data from a meta-analysis of over 8000 patients who
underwent SLN biopsy and completion ALND where 53% of the
patients with a positive SLN were found to have additional axil-
lary disease.15 As the number of women with small volume nodal
disease to include micrometastases has increased, the need to
routinely perform a completion ALND after a positive SLN has
been questioned. Recent publications analyzing National Cancer
Data Base (NCDB) and the Surveillance, Epidemiology, and End
Results (SEER) data have demonstrated a trend toward omitting
cALND in selected patients.16,17 The NCDB data from 1998 to 2005
showed that 21% of patients with a positive SLN did not undergo
ALND. Analysis of the SEER data demonstrated that 16% of
patients with a positive SLN did not undergo ALND. This trend
was seen predominantly in older women with low-grade, estrogen
receptor (ER) positive tumors. When only patients with a micro-
metastasis in their SLN were considered, the proportion undergo-
ing SLN biopsy alone increased from 21% to 38% during the study
period. Taken together, these data suggest that many clinicians do
not believe that completion ALND plays an important role in the
management of breast cancer patients with small volume metas-
tases in their SLN.
Recently published results from the American College of
Surgeons Oncology Group Z0011 trial support this trend of
omitting ALND in a select group of patients with a positive SLN.
The Z0011 trial enrolled patients with clinical T1 or T2 inva-
sive breast cancer with clinically negative lymph nodes treated
with breast conserving surgery who had one or two SLNs con-
taining metastases identified by hematoxylin and eosin stain-
ing. Patients were randomized to undergo ALND or no further
surgery; all patients received whole breast irradiation. The trial
opened in 1999 with a planned accrual of 1900 patients and
closed in 2004 after 891 patients enrolled due to slow accrual and
a lower than expected event rate. The trial’s primary end point
was OS and at a median follow-up of 6.3 years, 5-year OS was
91.8% with ALND and 92.5% with SLN biopsy alone; a 0.7%
absolute difference favoring the SLN biopsy alone group. Both
cohorts had substantially better OS than the 80% that had been
anticipated at protocol design.18 Study investigators also evalu-
ated locoregional recurrences. At the 6.3-year median follow-up,
local recurrences were reported in 3.6% of patients in the ALND
group versus 1.8% in the SLN biopsy alone group. Ipsilateral axil-
lary recurrences were identified in 0.5% of patients after ALND
and 0.9% of patients in the SLN biopsy alone arm.19
It is anticipated that the Z0011 data will be practice chang-
ing; however, there are several considerations with respect to data
PMPH_CH74.indd 599
■ 599
interpretation and implementation.20 The trial enrolled a select
group of patients with 70% having T1 tumors, 83% ER positive
tumors, and 35% having only micrometastases identified in their
SLN. Adjuvant systemic therapy to include chemotherapy, endo-
crine therapy, or both was administered to 96% of women in the
ALND group and 97% in the SLN biopsy group. In addition, it is
important to remember that whole breast irradiation with stan-
dard tangential fields was given to patients as a component of their
breast conserving therapy. Whole breast irradiation administers
95% of the prescribed dose to approximately 50% of the level 1 and
25% of the level 2 axilla.21 Despite these caveats, the trial did have
strict eligibility criteria which resulted in a homogeneous popula-
tion of patients allowing clinicians to translate the study findings
into clinical practice in a clearly defined population of patients
who will not derive benefit from undergoing ALND after identifi-
cation of a positive SLN.20
The Z0011 trial did not enroll patients undergoing mastec-
tomy, those treated with accelerated partial breast irradiation, or
those receiving neoadjuvant therapy; therefore, in those patients,
ALND remains the standard practice when the SLN shows evi-
dence of disease. For patients such as these and others who do not
fulfi ll eligibility criteria for the Z0011 trial, the use of predictive
models including nomograms to predict non-SLN status in the set-
ting of a positive SLN has become popular. The most widely used
nomogram is the one developed at the Memorial Sloan-Kettering
Cancer Center.22 This nomogram is based on eight clinicopatho-
logic variables including tumor size, histology, nuclear grade, the
presence of lymphovascular invasion, multifocality, ER status,
method of SLN metastasis detection, number of positive SLN(s),
and number of negative SLN(s). From these data, the nomogram
generates a numerical probability of finding additional disease in
non-SLNs. The appeal of nomograms is that they provide reliable
prognostic information that is individualized to a given patient.
There is no cut-off below which a completion ALND can be omit-
ted with absolute certainty that additional disease will not be
missed; however, the information obtained from nomograms can
be valuable in counseling a patient and in guiding the decision as
to whether an ALND will be performed.
SEQUENCING OF AXILLARY SURGERY
IN PATIENTS RECEIVING PREOPERATIVE
CHEMOTHERAPY
4. Should SLN biopsy be performed prior to receiving preope-
rative systemic therapy or after systemic therapy?
There is increasing use of preoperative chemotherapy for breast
cancer. Use of SLN biopsy after preoperative chemotherapy has
the potential to reduce the morbidity associated with breast can-
cer staging and decrease the need for ALNDs. Preoperative che-
motherapy is generally utilized in women whose breast cancers
are larger and more likely to have stage II and III diseases. Women
in this category would be expected to have axillary lymph node
metastases approximately 40% to 80% of the time. As discussed
above, the current NCCN Guidelines recommend that ALND be
performed in patients known to have metastatic axillary nodes.23
Preoperative chemotherapy has now been shown to eradi-
cate documented axillary nodal metastases in 25% to 70% of
patients.24,25 Because of this, some groups strongly advocate and
5/22/2012 5:52:01 PM
 600 ■ Surgery: Evidence-Based Practice
utilize SLN biopsy only after preoperative chemotherapy to assess
and surgically manage the axilla. On the other hand, some cli-
nicians have suggested that SLN biopsy be performed before
preoperative chemotherapy, and that patients in whom axillary
metastases are detected be treated with ALND after preopera-
tive chemotherapy. Clinicians who prefer to perform initial SLN
biopsy state that they would prefer to have information about
axillary metastases for prognostic purposes before preoperative
chemotherapy is begun. A potential problem with this approach
is that many patients are then committed to two surgical proce-
dures, the SLN biopsy before preoperative chemotherapy and then
an ALND following the chemotherapy if the SLN is found to have
metastases during the first procedure. Even if the SLN is negative
during the first procedure, the patient will still need to have a sec-
ond surgery for management of the breast primary after comple-
tion of chemotherapy.
A possible way of minimizing the need for multiple surgeries
is using a potential alternative to SLN biopsy before preoperative
chemotherapy. At clinical presentation, many centers are increas-
ingly utilizing nodal ultrasound staging and ultrasound-guided
fine needle aspiration (FNA) biopsy to detect and document axil-
lary nodal disease without the need for surgery.25 For patients
with FNA biopsy-proven axillary metastases, standard ALND
is performed after preoperative therapy and can provide a mea-
sure of the response of axillary metastases to chemotherapy. For
patients where the axillary ultrasound is normal, SLN biopsy can
be performed after preoperative chemotherapy and patients
can be spared an ALND if the SLN is found to be normal. Axil-
lary node dissection can be performed if disease is identified
in the SLN(s) after preoperative chemotherapy.26 Furthermore,
residual disease in the axillary nodes after preoperative chemo-
therapy has powerful independent prognostic value.25 Two main
questions to be answered are (1) whether and (2) how the patient’s
systemic therapy would change if information about metastatic
nodal disease were available before, rather than after, preopera-
tive chemotherapy. Currently, in most circumstances, decisions
about systemic therapy would be based on the primary tumor
characteristics and therefore would not be altered. Proceeding
with upfront SLN biopsy prior to neoadjuvant chemotherapy
may also be appropriate if nodal ultrasound is not available or if a
patient’s particular multidisciplinary treatment team is uncom-
fortable because of disagreement regarding the timing of the
procedure.
There have now been many investigations and three pub-
lished systematic reviews evaluating the accuracy and safety of
SLN biopsy in patients treated with preoperative therapy.10,27,28
In the largest reported series of patients receiving SLN biopsy
after preoperative chemotherapy, Hunt et al. 29 compared 575
patients who underwent SLN biopsy after chemotherapy with 3171
patients who underwent surgery first. Preoperative chemotherapy
patients were younger and had more clinical T2–T3 tumors at
diagnosis. SLN identification rates were 97.4% in the preoperative
group and 98.7% in the surgery first group. False-negative rates
were similar between groups. Analyzed by presenting T stage,
there were significantly fewer positive SLNs in the neoadjuvant
group. Adjusting for clinical stage revealed no differences in local–
regional recurrences, disease-free, or OS between groups. This
study concluded that SLN biopsy after chemotherapy is as accu-
rate for axillary staging as SLN surgery prior to chemotherapy.
PMPH_CH74.indd 600
SLN biopsy after chemotherapy results in fewer positive SLNs and
decreases unnecessary ALNDs.
Twenty-seven studies, with a total of more than 2100 patients,
have evaluated SLN after preoperative chemotherapy for breast
cancer.10,28 Systematic review demonstrates robust estimates of
successful identification rates and false-negative rates of SLN
biopsy after preoperative therapy for early-stage breast cancer
patients.10 Overall, an SLN can be identified approximately 90%
of the time with a false-negative rate of approximately 8%. These
results compare favorably with other large prospective clinical tri-
als which have demonstrated identification rates of approximately
97% and an overall false-negative rate of 9.5% for patients with
early-stage breast cancer receiving SLN biopsy in the absence of
preoperative chemotherapy.30
One subgroup of patients where there remains controversy on
the accuracy of SLN biopsy is in women with documented known
axillary nodal metastases at presentation.28,31,32 To address this
group of patients, the American College of Surgeons Oncology
Group is currently accruing 660 patients to a prospective phase
II trial evaluating the role of SLN biopsy and ALND after preop-
erative chemotherapy in women with documented known node-
positive breast cancer at initial diagnosis.
Overall, SLN biopsy after preoperative chemotherapy appears
to be a reliable tool for planning treatment and as an alternative
to axillary surgery before preoperative chemotherapy among
patients who present with a clinically negative axilla.
ROLE OF SLN BIOPSY IN PATIENTS WITH
DUCTAL CARCINOMA IN SITU (DCIS)
5. Should SLN biopsy be performed in patients with Ductal
Carcinoma In Situ (DCIS)?
By definition, DCIS of the breast is a noninvasive lesion that does
not have the ability to metastasize. For the most part, this disease is
treated to prevent the occurrence of invasive breast cancer. Given
this background, ALND or SLN biopsy should be considered
inappropriate in patients with DCIS. However, patients with DCIS
sometimes also have microinvasive or frankly invasive carcinoma
that can be missed with image-guided biopsy. In fact, patients
treated for DCIS sometimes, although very rarely, die of meta-
static breast cancer, most likely as a result of an otherwise missed
invasive component of disease. It would be difficult to justify SLN
biopsy in the majority of patients treated for DCIS with segmental
resection, as this tissue can be thoroughly evaluated for the pres-
ence of invasive disease and SLN biopsy can be performed as a
subsequent surgical procedure. However, for patients undergoing
mastectomy for the treatment of DCIS, the ability to perform SLN
biopsy is lost if the breast is removed and invasive carcinoma is
identified. In this situation, ALND is indicated to assess the criti-
cal staging information. In a large series from the University of
Texas MD Anderson Cancer Center, 399 patients with an initial
diagnosis of DCIS were identified to determine which factors were
associated with finding invasive carcinoma on final pathologic
evaluation.33 On multivariate analysis, significant independent
predictors of finding invasive carcinoma were age younger than
or equal to 55 years; diagnosis made with a core biopsy; mam-
mographic primary tumor size greater than 4 cm; and high-grade
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 Breast Cancer: Lymphatic Mapping and Sentinel Lymph Node Biopsy ■ 601

tumor status. Overall, 20% of the patients with an initial diag-
nosis of DCIS were found to have invasive carcinoma, and 35%
of these patients underwent an SLN biopsy. Patients in this series
were more often offered SLN biopsy if they had a mastectomy.
Ten percent of the patients were found to have a positive SLN and
the only independent predictor of finding axillary metastases in
patients initially believed to have only DCIS was the presence of
a palpable tumor at diagnosis. On the basis of this analysis, the
investigators from that study do not routinely perform SLN biopsy
on all patients with an initial diagnosis of DCIS. Instead, the risks
and benefits of SLN biopsy are discussed with patients sched-
uled to undergo mastectomy, younger patients, and patients with
large or high-grade DCIS. At the European Institute of Oncology
(Milan, Italy), only 1.4% of 854 unselected patients with pure DCIS
were found to have a positive SLN and no patients were found to
have additional positive nodes on ALND.34 Finally, a recent meta-
analysis of 22 published studies found that approximately 3.7% of
patients with a postoperative pathologic diagnosis of DCIS were
found to have SLN metastases.35
In 2009, the NIH Consensus Conference on DCIS made some
important points regarding SLN biopsy use and DCIS: the clinical
significance of positive SLN metastases in patients who have DCIS
is indeterminate, given that the majority of them are micrometas-
tases or isolated tumor cells; existing studies of SLN biopsy have
been reported in highly selected patient populations that may
not represent the general population of women who have DCIS;
studies of the impact of SLN biopsy for DCIS on subsequent treat-
ments have been limited to descriptions of single (not multicenter)
practices, and although SLN biopsy is less invasive than ALND,
it is associated with some risk of complications, including lym-
phedema and pain in some women.36
Taken together, the results of published uncontrolled studies
indicate that lymphatic mapping and SLN biopsy for DCIS should
not be routinely done in all patients. Patients with a diagnosis
of DCIS who are scheduled to undergo mastectomy, and other
patients considered at high risk for having invasive disease based
on suspicion of invasion on core biopsy, can be offered SLN biopsy
as part of their initial surgical management.
CONCLUSIONS
In conclusion, SLN biopsy has become a standard technique in the
management of patients with breast cancer. It offers accurate stag-
ing of the axilla with much less morbidity than previous standard
of ALND. It should be offered as a component of initial surgical
management to clinically node-negative breast cancer patients,
even those who receive neoadjuvant chemotherapy, and patients
with DCIS who are either undergoing mastectomy or have a high
risk of discovering invasive cancer on pathologic evaluation of
their surgical specimen. Although the exact technical aspects may
vary, experienced surgeons can safely perform the procedure with
reliable results. Although the standard approach has been to per-
form ALND on all patients with SLN metastasis, new data from
the ACOSOG Z0011 trial shows that ALND can safely be omitted
in carefully selected patients. Clinicians caring for breast cancer
patients should be familiar with the technique and understand its
benefits and limitations.

Clinical Question Summary

Question Answer Level of Grade of References
Evidence Recommendation
1 What is the best Blue dye, radioisotope, or a combination of the 2b B 2-7
technique for SLN two should be injected in either a peritumoral,
biopsy? intradermal, or subareolar location. In exploring
the axilla, the surgeon should remove any node
that is blue, “hot”, or suspicious. Although no
technique has been shown to be superior to
another, the success of SLN biopsy is reliant on
surgeon experience.
2 Is SLN biopsy Yes. In fact, it may be more accurate as it allows for 1a A 10-14
as accurate as more thorough evaluation of lymph nodes.
ALND?
3 Do all patients No. Omission of ALND in the setting of a positive 1b A 15-19
need a completion SLN is appropriate for early-stage patients (T1/
ALND if SLN T2, clinically node-negative) treated with breast
metastasis is conserving therapy to include whole breast
identified? irradiation who have one or two positive SLN(s)
identified by H&E. Other patients, to include
those undergoing mastectomy, those treated
with accelerated partial breast irradiation, or
those receiving neoadjuvant therapy should
undergo ALND as standard practice when the
SLN shows evidence of disease.

(Continued)

PMPH_CH74.indd 601 5/22/2012 5:52:01 PM

 602 ■ Surgery: Evidence-Based Practice
(Continued)
Question Answer
4 Should SLN biopsy SLN biopsy after preoperative chemotherapy
be performed appears to be a reliable tool for planning
prior to receiving treatment and as an alternative to axillary
preoperative surgery before preoperative chemotherapy.
systemic therapy Additionally, it may decrease unnecessary axillary
or after therapy? dissections in patients presenting with clinically
negative axilla.
5 Should patients Not routinely. Those who are scheduled to undergo
with DCIS have an mastectomy and other patients considered at
SLN biopsy?. high risk for having invasive disease based can be
offered SLN biopsy as part of their initial surgical
management.
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12. Veronesi U, Paganelli G, Viale G, et al. A randomized compari-
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13. Lyman G, Giuliano A, Somerfield M, et al. American Society
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14. Krag D, Anderson S, Julian T, et al. Sentinel-lymph-node resec-
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16. Bilimoria K, Bentrem D, Hansen N, et al. Comparison of sentinel
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dissection for node-positive breast cancer. J Clin Oncol. 2009;
27:2946-2953.
17. Yi M, Giordano S, Meric-Bernstam F, et al. Trends in and out-
comes from sentinel lymph node biopsy (SLNB) alone vs. SLNB
with axillary lymph node dissection for node-positive breast can-
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18. Giuliano A, Hunt K, Ballman K, et al. Axillary dissection vs no
axillary dissection in women with invasive breast cancer and
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2011;305:569-575.
19. Giuliano A, McCall L, Beitsch P, et al. Locoregional recurrence
after sentinel lymph node dissection with or without axillary
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American College of Surgeons Oncology Group Z0011 random-
ized trial. Ann Surg. 2010;252:426-432.
20. Caudle A, Hunt K, Kuerer H, et al. Multidisciplinary consid-
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24. Dominici L, Negron-Gonzalez V, Buzdar A, et al. Cytologically
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accurate after neoadjuvant chemotherapy for breast cancer. J Clin
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27. Xing Y, Foy M, Cox S, et al. Meta-analysis of sentinel lymph node
biopsy after preoperative chemotherapy in patients with breast
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28. van Duerzen C, Vriens B, Tjan-Heijnen V, et al. Accuracy of senti-
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29. Hunt K, Mittendorf E, Guerrero C, et al. Sentinel lymph node sur-
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need for axillary dissection in breast cancer patients. Ann Surg.
2009;4:558-566.
30. Krag D, Ashikaga T, Harlow S, et al. Surgeon training, protocol
compliance, and technical outcomes from breast cancer sentinel
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of sentinel lymph node biopsy after preoperative chemotherapy
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Cancer. 2007;109:1255-1263.
32. Classe J, Bordes V, Campion L, et al. Sentinel lymph node biopsy
after neoadjuvant chemotherapy for advanced breast cancer:
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a French prospective multicentric study. J Clin Oncol. 2009;
27:726-732.
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in patients with an initial diagnosis of ductal carcinoma in situ: A
guide to selective use of sentinel lymph node biopsy in management
of ductal carcinoma in situ. J Am Coll Surg. 2005;200:516-526.
34. Intra M, Rotmensz N, Veronesi P, et al. Sentinel node biopsy is not
a standard procedure in ductal carcinoma in situ of the breast: The
experience of the European institute of oncology on 854 patients
in 10 years. Ann Surg. 2008;247:315-319.
35. Ansari B, Ogsten S, Purdie C, et al. Meta-analysis of sentinel
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5/22/2012 5:52:02 PM
 CHAPTER 75
Systemic Treatment Strategies for
Early-Stage Breast Cancers
Jennifer K. Litton and Kelly K. Hunt
INTRODUCTION
There have now been significant data accumulated demonstrating
an improvement in breast cancer-specific survival rates when adju-
vant systemic therapies are employed following the local-regional
management of breast cancer patients. Chemotherapy, endocrine
therapy, and, more recently, the addition of biologic therapies have
all contributed to improved outcomes. The treatment of breast cancer
has evolved into a more integrated multidisciplinary program with
differences in the sequencing of local-regional and systemic thera-
pies determined by individual patient and tumor characteristics. The
estrogen and progesterone receptor status of the primary tumor have
been used to personalize breast cancer treatment for decades and
HER2 status has been shown to be an important prognostic marker
and predictive factor for HER2-directed therapies. In addition to
improvements in overall (OS) and disease-free survival (DFS) with
the use of systemic therapies, these agents can also result in downsiz-
ing of the primary tumor to allowing for breast-conserving therapy
and response to therapy can provide important biologic information.
Therefore, it is paramount that all of the disciplines involved in the
treatment of breast cancer patients understand the indications for
systemic therapy and the available therapeutic strategies.
In this review, we will summarize the current recommenda-
tions and ongoing controversies in the systemic treatment of breast
cancer. The indications for chemotherapy and hormonal therapy and
emerging biologic therapies are reviewed, as well as the option for
utilizing these agents in the neoadjuvant setting. Information that
is used to improve patient selection for systemic treatment will be
discussed in an effort to avoid toxicity in those patients who would
likely derive little or no benefit. The goal is to improve our ability
to provide more targeted therapies and more effective, personalized
local and systemic treatments to our breast cancer patients.
DECISION-MAKING IN THE USE OF
ADJUVANT SYSTEMIC THERAPY
1. What are the indications for adjuvant chemotherapy in breast
cancer and which chemotherapy regimens should be used?
604
PMPH_CH75.indd 604
The indications for recommending adjuvant chemotherapy are
based not only on the stage of disease at presentation, but also
increasingly on the underlying biology of the tumor. There are
a number of important clinical, pathologic, and biologic factors
that determine prognosis and indications for treatment. These
factors include age, medical comorbidities, tumor grade, involve-
ment of regional lymph nodes, and hormone receptor (HR) status
and HER2 status of the primary tumor.1,2 There have been several
tools developed to guide clinicians in the assessment of risk of
recurrence and potential benefit from therapeutic interventions
when discussing adjuvant therapies with their patients. These
include the Adjuvant! Online computer program, 3 Mammaprint®,4
and the 21-gene recurrence score assay (Oncotype DxTM).5 These
are all discussed in more detail below. In addition, there are
treatment guidelines, such as those developed by the National
Comprehensive Cancer Network (NCCN)1 that provides expert
opinion synthesizing the available evidence for treatment recom-
mendations largely based on the stage of disease at presentation.
These guidelines are generally updated annually and are acces-
sible via www.nccn.org.
Much of the evidence for adjuvant treatment decisions in
early-stage breast cancer comes from the Early Breast Cancer Tri-
alists Collaborative Group (EBCTCG).2 Th is group meets every
5 years and reviews the clinical trial data from studies around the
world that initiated accrual by 1995. The last published update
was in 2005 and the most recent data have been reviewed by
the EBCTCG panel and a forthcoming publication is anticipated
in the near future. A series of important questions have been
asked by clinical trialists, the fi rst of which was the value of single-
agent chemotherapy versus polychemotherapy in the adjuvant
setting. The ECBCTG has data from 4000 women who received
single-agent chemotherapy and 29,000 women who received
polychemotherapy as part of a clinical trial. Polychemotherapy
regimens included agents such as CMF (cyclophosphamide,
methotrexate, and 5-fluorouracil), FEC, (5-fluorouracil, epiru-
bicin, cyclophosphamide), FAC (5-fluorouracil, doxorubicin,
and cyclophosphamide), and AC (doxorubicin and cyclophos-
phamide). Some regimens also included taxanes such as docetaxel
5/22/2012 5:52:42 PM

(D) or paclitaxel (T) among many other agents. Although
single-agent chemotherapy did lower the risk of recurrence, the
use of polychemotherapy more substantially decreased recurrence
and breast cancer mortality hazard ratios (HRs) (0.77 and 0.83,
respectively). Polychemotherapy was found in subgroup analy-
ses to be almost three times more effective in younger women
(<50 years old) compared with older women (ages 50–69 years).
In addition, the benefit of polychemotherapy for reducing breast
cancer recurrence and mortality remained significant in the sub-
groups of both hormone receptor-positive and negative tumors
in younger women. In older women, this benefit of polychemo-
therapy did not maintain statistical significance in the setting
of tamoxifen usage in patients with hormone receptor-positive
breast cancer but did show a 5-year gain of 9.6% with respect
to disease recurrence (logrank = p < .00001) in older women
(ages 50–69 years) with hormone receptor-negative tumors. Th is
overview analysis focused largely on age and hormone recep-
tor status and did not take into account other factors such as
HER2 status, grade, lymphovascular invasion, or molecular
subtypes.
There are many systemic chemotherapy agents that have
shown activity in breast cancer and the NCCN guidelines1 list 14
different polychemotherapy regimens and at least 6 trastuzumab-
containing regimens (for HER2-positive disease) that are con-
sidered appropriate choices for therapy. The choice is often based
on institutional preference but may also be impacted by patient
factors. Most regimens contain an anthracycline as part of the
therapy (doxorubicin or epirubicin) based on historical data dem-
onstrating that there is reduction in the risk of recurrence with
anthracycline- containing regimens over nonanthracycline-based
therapies. A selection of these pivotal studies is described below;
however, an excellent history of all of the randomized chemo-
therapy trials is detailed on www.cancer.gov/clinicaltrials/results/
type/breast.
The INT-01026 trial evaluated CMF versus CAF with and
without tamoxifen for high-risk, node-negative breast cancer
patients. CAF did not improve DFS but did trend toward the
improved OS. The use of tamoxifen was beneficial only in those
women with hormone receptor-positive disease. NSABP-B157
compared six cycles of CMF with four cycles of AC and showed
no difference in DFS and OS. The EBCTCG2 also compared
anthracycline-containing regimens with nonanthracycline-
containing regimens and confi rmed a modest benefit for the
anthracycline-containing regimens of 3.4% for recurrence and
3.3% for mortality at 15 years. With the addition of taxanes to
systemic therapy regimens, additional gains in breast cancer
outcomes have been realized. CALGB 93448 evaluated AC ×
4 ± paclitaxel every 3 weeks in patients with node-positive dis-
ease and demonstrated significant improvements in both DFS
and OS. Similar results were demonstrated in NSABP B-289
with slightly higher doses of paclitaxel. More recently, investiga-
tors have evaluated the concept of replacing the anthracycline
with a taxane. The US Oncology Clinical Trials Group random-
ized 1016 women with stage I–II breast cancer to TC (docetaxel
and cyclophosphamide) × 4 versus AC × 4. The TC regimen
resulted in a 6% (p = .018) improvement in DFS and 4% (p = .045)
improvement in OS at 7 years.10 The schedule and dosing of both
docetaxel and paclitaxel were evaluated in ECOG 1199.11 Th is
study had four arms and compared paclitaxel 175 mg/m 2 every
3 weeks × 4 versus paclitaxel 80 mg/m 2 weekly × 12 weeks versus
PMPH_CH75.indd 605
Systemic Treatment Strategies for Early-Stage Breast Cancers ■ 605
docetaxel 100 mg/m 2 every 3 weeks × 4 versus docetaxel 35 mg/m 2
weekly × 12 weeks. The every 3-week docetaxel dosing and the
weekly paclitaxel dosing were similar in terms of improved
DFS and OS but with differing toxicity profi les. Docetaxel had
increased hematologic toxicities, whereas the weekly paclitaxel
was associated with an increased incidence of peripheral neu-
ropathy. There are multiple ongoing studies currently accruing
to further address the benefit of taxanes in high-risk node-
negative disease settings as well as taxane combinations without
anthracyclines versus anthracycline-containing regimens.
There continues to be significant debate as to which patient
populations may derive additional benefit from anthracycline-
based chemotherapy and which patients can avoid the potential
cardiotoxicity of this class of agents. Several expert opinions
have emerged regarding this debate; however, clinicians are
forced to address this issue on a daily basis.12,13 In addition to the
potential for cardiotoxicity, other significant long-term toxicity
concerns with the use of many of these regimens include treat-
ment-related leukemia, peripheral neuropathy, and infertility.
The risk of congestive heart failure from adjuvant anthracycline
regimens when cumulative doses of 240 mg/m 2 or less were used
ranges from 0.5% to 2.1% in 5 years.14 Estimates from the SEER
database have been reported as HR of 1.26; 96% confidence inter-
val [CI] 1.12–1.42) for women aged 66 to 70 years. Cardiac risk
factors such as hypertension, diabetes, and coronary artery dis-
ease are predictors of developing congestive heart failure.15 The
risk of treatment-related leukemia at 10 years after treatment is
estimated at 1.8% versus 1.2% in breast cancer patients who did
not receive chemotherapy.16 Infertility related to chemotherapy
is difficult to measure and amenorrhea is often used as a sur-
rogate marker. In general, the closer a woman is to her natural
age of menopause, the more likely she is to experience premature
ovarian failure from systemic chemotherapy.17 Therefore, women
who are candidates for adjuvant chemotherapy and/or tamox-
ifen who are of child-bearing potential and desirous of future
pregnancies should discuss their risks and options for fertility
preservation prior to initiating therapy.
Answer: The NCCN guidelines recommend consideration of
adjuvant chemotherapy for women with node-positive disease.
For women with HER2-negative tumors, and tumors that are
>1 cm and node-negative or 0.6 to 1 cm with unfavorable features
such as high grade and lymphovascular invasion, the NCCN
guidelines recommend consideration of further information that
may impact treatment decisions, such as the 21-gene recurrence
score assay (Oncotype DxTM). Patients who can avoid adjuvant
chemotherapy or be considered for adjuvant endocrine therapy
alone are those patients with hormone receptor-positive tumors
<0.6 cm.
USE OF TUMOR MARKERS IN ADJUVANT
THERAPY DECISIONS
2. What are the indications for adjuvant endocrine therapy in
breast cancer?
Women with hormone receptor-positive tumors (estrogen recep-
tor and/or progesterone receptor positive) should be considered
for adjuvant endocrine therapy. The EBCTCG overview analysis
showed a significant benefit for the use of adjuvant tamoxifen in
5/22/2012 5:52:42 PM
 606 ■ Surgery: Evidence-Based Practice
women with hormone receptor-positive tumors but no benefit
for women with hormone receptor-negative tumors. In terms of
the length of tamoxifen therapy, 5 years was superior compared
with 2 years. For patients with hormone receptor-positive disease,
5 years of tamoxifen therapy resulted in a recurrence ratio of 0.59
and breast cancer mortality ratio of 0.66 when compared with no
endocrine therapy. Albain et al.18 evaluated the timing of tamox-
ifen therapy, either concurrent with chemotherapy or after the
completion of chemotherapy (sequentially) in a phase III parallel
randomized trial. The use of sequential therapy trended toward
superiority with a DFS HR of 0.84 (95% CI 0.70–1.01, p = .61) and
OS HR of 0.90 (95% CI 0.73–1.10, p = .30). Importantly, tamox-
ifen has demonstrated efficacy in both pre- and postmenopausal
women with hormone receptor-positive tumors.
Aromatase inhibitors (AI) have been compared with tamox-
ifen in postmenopausal women with hormone receptor-positive
breast cancer and have been shown to be superior in terms of DFS
and toxicity profi les. The NCCN guidelines recommend consider-
ing that a woman is postmenopausal if she has had an oophorec-
tomy, she is ≥ 60 years old, or ≤ 60 years old with amenorrhea for
12 or more months without exposure to chemotherapy, tamox-
ifen, or ovarian suppression, and FSH and plasma estradiol levels
are in the postmenopausal range. If a patient is taking tamoxifen,
it is important not to rely on FSH alone, but also on plasma estra-
diol levels. As ovarian function can be quite pulsatile and women
may regain ovarian function after chemotherapy-induced amen-
orrhea after 1 year, following these levels in women exposed to
chemotherapy is paramount. Women who are premenopausal or
perimenopausal at the time of initiation of chemotherapy should
be started on tamoxifen even if they experience treatment-related
ovarian failure.19
The American Society of Clinical Oncology (ASCO)19 has
recently released published guidelines regarding endocrine ther-
apy. These guidelines have been completed after an exhaustive
literature search and evaluation of several randomized clinical tri-
als. These trials include the ATAC,20 BIG-1-98,21 and ABCSG-1222
studies. The ATAC and BIG 1-98 trials evaluated tamoxifen ver-
sus an AI. The ATAC trial showed an improved DFS HR of 0.85;
95% CI 0.76–0.94, p = .003 for anastrozole when compared with
tamoxifen after 100 months of follow-up.20 There was no benefit
identified to administering tamoxifen concurrently with an AI.
The BIG 1-98 trial again supported this finding. There have been
multiple trials addressing the question of sequencing of tamoxifen
with aromatase inhibitors (BIG 1-98, MA-17,23 and TEAM24 tri-
als). Each AI-based therapy was superior to tamoxifen alone but
there was no statistically significant difference in the timing or
sequencing if tamoxifen and an AI were used. Therefore, the cur-
rent ASCO guidelines support using an AI at some point during
the first 5 years of therapy, if the patient is postmenopausal. There
is currently no evidence to support using an AI for more than
5 years. A multicenter, randomized clinical trial to evaluate this
question is ongoing through the NSABP.
Tamoxifen requires CYP2D6 to metabolize the drug into
its active form. This knowledge has led to significant debate as
to the utility of CYP2D6 isoenzyme testing in patients planned
for tamoxifen therapy. Clinical observations have been made
that women taking SSRI drugs have decreased the efficacy of
tamoxifen because of the interference with this metabolic path-
way.25 However, there has yet to be convincing evidence that
changes in the CYP2D6 isoenzyme affects outcomes; therefore
PMPH_CH75.indd 606
ASCO guidelines state that there is insufficient evidence to rec-
ommend testing for CYP2D6 isoenzyme to determine if a patient
should or should not receive tamoxifen therapy.19
Answer: Tamoxifen should be given to women with hormone
receptor-positive tumors and who are pre- or perimenopausal.
Women who are postmenopausal should receive an AI alone or in
sequence with tamoxifen for at least 5 years of adjuvant endocrine
therapy.
INCORPORATION OF BIOLOGIC
THERAPIES INTO SYSTEMIC
THERAPY REGIMENS
3. What are the indications for adjuvant biologic therapies in
breast cancer?
The use of trastuzumab in the adjuvant setting has made a sig-
nificant impact on survival for patients with HER2-positive
breast cancer. After multiple studies demonstrated its efficacy in
the metastatic setting, trastuzumab was tested in several large
adjuvant trials, and these all demonstrated impressive antitumor
activity. These studies included the North Central Cancer Treat-
ment Group (NCCTG) Intergroup N9831 trial, the National Sur-
gical Adjuvant Breast and Bowel Project (NSABP) B-31 trial, the
Herceptin Adjuvant trial (HERA), BCIRG 006, and FinHER.26-30
The HERA trial28,31 evaluated more than 5000 women who
received adjuvant chemotherapy from a list of acceptable chemo-
therapy regimens who were then randomized to receive either 1 or
2 years of trastuzumab therapy versus observation and no further
therapy. Trastuzumab was delivered upon completion of chemo-
therapy and not given concurrently with chemotherapy. The HR
for recurrence after the completion of chemotherapy and 1 year of
trastuzumab was 0.64 (p < .001). The results of extension of tras-
tuzumab to 2 years have not yet been reported.
The NSABP (B-31) and the NCCTG (N9831) trials had simi-
lar designs and data were pooled together once the HERA trial
fi rst reported. The only difference between the studies was the
schedule of paclitaxel administration of weekly versus every 3
weeks dosing. In one arm of the N9831 trial, trastuzumab was
given during the taxane portion of the chemotherapy and in the
other arm trastuzumab was administered after completion of
chemotherapy. Significant differences were noted in DFS in the
patients who received trastuzumab versus those who did not
(85.3% vs. 67.1%, p ≤ .0001). There was also a significant differ-
ence in OS of 91.4% versus 86.6%, p = .015, favoring trastuzumab
therapy.
The BCIRG 006 compared AC × 4 followed by docetaxel × 4
(AC-T) alone or with trastuzumab (AC-TH) versus TCH (doc-
etaxel, carboplatinum, and trastuzumab). In the third planned
efficacy analysis,30 which was presented at the San Antonio Breast
Cancer Symposium in 2009, AC-TH was associated with a DFS
of 84%, TCH of 81%, and AC-T of 75% at 60 months. When com-
pared with AC-T, AC-TH had a HR of 0.64, p < .001 and TCH
had a HR of 0.75, p = .04. When compared with AC-T in terms of
OS, AC-TH had a HR of 0.63, p < .001 and TCH had a HR of 0.77,
p = .038. The FinHER study27 was a smaller trial that random-
ized 1010 women with unselected primary breast cancer to receive
three cycles of vinorelbine or docetaxel, followed by FEC. HER2
amplification was identified in 232 tumors and these women were
5/22/2012 5:52:42 PM

further randomized to receive 9 weeks of trastuzumab with either
the vinorelbine or docetaxel. Trastuzumab was administered only
during treatment with vinorelbine or docetaxel. The patients who
received trastuzumab had a better 3-year recurrence-free survival
(RFS) when compared with those who did not receive trastuzumab
(89% vs. 78%, p = .01).
With the success of trastuzumab therapy in the adjuvant
treatment of patients with HER2-positive breast cancer, several
groups have initiated studies evaluating different regimens in the
neoadjuvant setting. Regimens that have been demonstrated to
be effective in the adjuvant setting are often used in the neoad-
juvant setting and several have been listed as potential options
in the NCCN guidelines. Although concerns have been raised
when giving anthracyclines concurrent with trastuzumab in the
metastatic setting, Buzdar et al.32 have demonstrated impres-
sive pathologic response rates when combining trastuzumab
with weekly paclitaxel (80 mg/m2) followed by FEC (with epi-
rubicin given at a lower dose of 75 mg/m2). After assessment of
the first 42 patients randomized on this trial, the data and safety
monitoring committee recommended that the trial be stopped
early as the pathologic complete response (pCR) rate for patients
receiving chemotherapy plus trastuzumab was 66.7% versus
25% in patients treated with chemotherapy alone. Given these
high pCR rates, this regimen of concurrent chemotherapy with
trastuzumab is being studied in an ongoing multi-institutional,
randomized trial through the American College of Surgeons
Oncology Groups (ACOSOG).
Given the known aggressive biology of HER2-positive disease
and the efficacy and tolerability of trastuzumab, the NCCN guide-
lines recommend trastuzumab-based chemotherapy for all patients
with node-positive tumors and for those with node-negative
tumors >1 cm. Several groups have also studied the outcomes of
patients with HER2-positive tumors less than 1 cm. Gonzalez-
Angulo et al.33 have reported that patients with HER2-positive
tumors that do not receive trastuzumab or chemotherapy, the
5-year RFS rates are as low as 77.1%. Therefore, trastuzumab-based
chemotherapy regimens should be considered for patients with
tumors 0.6 to 1 cm in size. Further evidence is being collected for
tumors <0.6 cm before further modifications to the guidelines can
be recommended.
Multiple other biologic therapies have been studied in the
metastatic setting including bevacizumab, pertuzumab, and lapa-
tinib. There are now several ongoing studies evaluating these and
other biologic therapies in the adjuvant and neoadjuvant settings;
however, to date, there is no indication for use of these agents
outside of a clinical trial in the adjuvant or in the neoadjuvant
setting.
Answer: Trastuzumab therapy should be used in combination
with chemotherapy for all patients with HER2-positive tumors
that are node-positive or node-negative and ≥0.6 cm in size.
SEQUENCING OF SYTEMIC AND
LOCAL-REGIONAL THERAPIES
4. What is the role for neoadjuvant therapies in breast cancer?
Neoadjuvant (or preoperative) chemotherapy has traditionally
been utilized in cases of inoperable or locally advanced disease
PMPH_CH75.indd 607
Systemic Treatment Strategies for Early-Stage Breast Cancers ■ 607
to improve or facilitate local-regional treatment with surgery and
radiation. Substantial clinical response rates (complete and partial)
have been documented in patients with locally advanced disease
leading many to opt for this approach in patients with operable
breast cancer. The landmark National Surgical Adjuvant Breast and
Bowel Project (NSABP) B-18 trial clearly demonstrated increased
rates of breast conservation in women randomized to neoadjuvant
chemotherapy.34 Patients underwent surgery first or received four
cycles of doxorubicin plus cyclophosphamide (AC) every 3 weeks.
The use of neoadjuvant AC increased the proportion of patients
able to undergo lumpectomy by 12%. At a mean follow-up of 9.5
years, no significant differences in DFS and OS rates were noted
between the two groups (69% vs. 70%, p = .80; 55% vs. 53%, p = .50,
respectively). Similar results have been published from other ran-
domized studies, and a recent pooled meta-analysis revealed that
survival outcomes are equivalent between the surgery first and
neoadjuvant approaches.35 Therefore, neoadjuvant chemotherapy
is a safe alternative to the use of adjuvant chemotherapy, especially
in patients who prefer breast conservation therapy and may not be
candidates if surgery is the initial approach.
Another advantage of shift ing chemotherapy to the neoadju-
vant setting is the ability to assess clinical and pathologic response
rates of the primary tumor and any nodal metastases to systemic
treatment. Both clinical and pathologic response rates have been
proposed to be surrogate markers for the traditional endpoints of
DFS and OS typically measured in adjuvant trials. In the European
Organisation for Research and Treatment of Cancer (EORTC)
10902 trial, patients with operable breast cancer were randomized
to pre- or postoperative therapy with four cycles of 5-fluorouracil,
epirubicin, and cyclophosphamide (FEC) every 3 weeks.36 At 56
months of follow-up, no significant differences were seen in DFS
and OS. There were 13 patients in the preoperative therapy arm
who achieved a pCR, defined as the absence of invasive cancer in
the breast and axillary nodes. This was associated with a statisti-
cally improved OS compared with patients who did not achieve a
pCR, with a HR of 0.86 (95% CI 0.77–0.96; p = .008). The use of
pCR after neoadjuvant chemotherapy has been suggested as a sur-
rogate endpoint for DFS and OS. Evaluation of agents in the neo-
adjuvant setting using pCR as a measure of efficacy can provide a
more rapid evaluation of treatments for patients with early-stage
breast cancer. Symmans et al. developed a prognostic model that
quantifies residual disease in the breast and lymph nodes after
neoadjuvant chemotherapy to estimate distant relapse rates at
5 years.37 This residual cancer burden index is a tool that has been
validated and is considered a useful surrogate marker for long-
term survival endpoints.
As described above, the neoadjuvant approach can facilitate
testing of novel biologic agents alone and in combination with
systemic chemotherapy. In addition to targeted treatment trials
with specific biologic agents, investigators are currently using
gene-expression profiling to estimate the likelihood of achiev-
ing a pCR with specific regimens. There have now been several
reports of in vitro chemosensitivity gene- expression signatures,
which can predict response to neoadjuvant chemotherapy with
high degrees of sensitivity and specificity.38 A similar concept is
being tested with neoadjuvant endocrine therapy in patients with
hormone receptor-positive disease in the American College of
Surgeons Oncology Group Z1031 trial. Patients are randomized
to receive one of three AIs for 16 weeks prior to surgical resection.
Pre- and posttreatment samples are obtained and gene-expression
5/22/2012 5:52:43 PM
 608 ■ Surgery: Evidence-Based Practice
profi ling is being performed with the goal of developing profi les
that can predict resistance to endocrine therapies.
The neoadjuvant therapy approach has the potential to allow
individualization of cancer therapies through the use of gene-
expression profi ling of tumors and assessment of pathologic
response rates. Th is approach can expedite evaluation of novel
therapies with the surrogate endpoints for survival of pCR and
residual cancer burden, without the need for long-term follow-up
typically required in adjuvant treatment trials. Using clinical
response early in the course of neoadjuvant therapies may spare
some patients the toxicities of ineffective therapies because they
can be discontinued if there is no response or progression of dis-
ease. The major question that remains is what to recommend for
patients who continue to have significant residual disease despite
the use of neoadjuvant chemotherapy. This is a group of patients at
significantly increased risk for systemic disease recurrence.
The NSABP B-18 and EORTC trials showed that breast-
conserving surgery was safe following neoadjuvant chemother-
apy. There is no consensus on the volume of tissue that should be
resected after chemotherapy; however, placing radiopaque clips at
the primary tumor site prior to chemotherapy can facilitate the
appropriate targeting of any residual nidus of disease after systemic
treatment.39 Investigators from the MD Anderson Cancer Center
have reported 5-year actuarial ipsilateral breast tumor RFS and
local-regional RFS rates of 95% and 91%, respectively, in patients
treated with breast conservation after chemotherapy.40 Factors cor-
relating with ipsilateral breast tumor recurrence were clinical N2
or N3 disease, pathologic residual tumor size >2 cm, a multifocal
pattern of residual disease, and lymphovascular space invasion.
Axillary lymph node dissection (ALND) has been routinely
performed for the management of the axilla following neoadjuvant
chemotherapy. As sentinel lymph node (SLN) surgery has increas-
ingly gained acceptance and reduced the need for ALND in early-
stage node-negative patients, surgeons have begun to incorporate
this technique in the management of patients after chemotherapy.
This allows for one operative procedure at the completion of che-
motherapy with the advantage of pathologic response data from
the breast and nodes. A number of institutions have demonstrated
feasibility of SLN surgery after neoadjuvant chemotherapy, and a
meta-analysis reported an overall accuracy rate of 94%, sensitiv-
ity of 88%, negative predictive value of 90%, and SLN identifica-
tion rate of 90%. In addition to increasing the breast preservation
rates, the use of neoadjuvant chemotherapy appears to reduce the
need for completion ALND because fewer patients will have posi-
tive lymph nodes after chemotherapy.41
Answer: Neoadjuvant chemotherapy is an established app-
roach for patients who present with inoperable and locally breast
cancer. It has the potential to improve surgical options in some
patients and is an important tool for evaluating novel therapeutics
in select subsets. The neoadjuvant approach allows for the patho-
logic assessment of systemic therapies on tumor biology which
can also provide information on expected outcomes for individ-
ual patients.
5. What is the role of the Adjuvant! Online computer program
in systemic treatment planning?
Adjuvant! Online (www.adjuvantonline.com) is a validated com-
puter model designed to help physicians determine the 10-year
risk of recurrence and death due to breast cancer for an individual
PMPH_CH75.indd 608
patient. It also informs the clinician how specific interventions,
chemotherapy, hormone therapy, or no therapy are expected to
impact survival.3 These estimates of prognosis are largely based
on Surveillance, Epidemiology, and End-Results (SEER) registry
estimates. The primary factors used in this model include age,
comorbidity, estrogen receptor status, grade, tumor size, and
nodal status. HER2 status has not yet been added in the model
but is expected in future updated versions. The computer program
provides patient-friendly graphics to depict 10-year RFS and OS
estimates as well as estimates adjusted for chemotherapy or endo-
crine interventions.
The Adjuvant! Online program does have several limitations.
It is based on registry information and therefore relapse data and
cause of death may be inaccurate. It does not incorporate data for
HER2-positivity or for breast cancer in women younger than 35
years old. In some cases, especially when estimating recurrence
and breast cancer-related deaths in women with locally advanced
disease, the estimates of survival and recurrence despite extensive
systemic therapy may still be distressing to patients. However, the
overall concept of this design allows the physician and patient to
have a more interactive discussion regarding the risks and ben-
efits of therapies. Several additions to this website have included
diagrams and other patient education tools that may also enhance
this dialog.
Answer: The Adjuvant! Online computer program is an effec-
tive web-based tool to inform discussions between physicians and
patients regarding expected recurrence rates due to breast can-
cer and the potential for improvements in outcome with current
interventions.
6. What molecular tools are available to assess the risk of recur-
rence from breast cancer?
It is widely believed that the use of anatomic staging and assess-
ment of clinical and pathologic factors to guide adjuvant systemic
treatment decisions likely results in the undertreatment and over-
treatment of some patients. In an effort to develop a more indi-
vidualized approach for defining risk and determining therapy,
multigene tumor assays have been developed and tested for use in
breast cancer patients. The 21-gene recurrence score assay (Onco-
type Dx) has been validated to quantify the risk of recurrence (low,
intermediate, and high) in patients with estrogen receptor-positive,
node-negative breast cancer.42 It also predicts the potential for
chemotherapy benefit.43 In a recent analysis of the 21-gene recur-
rence score in clinical practice, the knowledge of the recurrence
score altered treatment recommendations by the oncologist
in 31.5% of cases and 27% of patients changed their decision to
undergo treatment.44 There was a significant reduction in anxiety
and decisional conflict by incorporating the 21-gene recurrence
score results into decisions regarding systemic treatment. Another
multigene assay for determining prognosis is the Mammaprint
assay. The Mammaprint assay analyzes data from 70 genes to
develop a risk profile and provides a readout of low risk or high risk.
This tool can be used for risk assessment in patients with estrogen
receptor-positive and estrogen receptor-negative tumors.
Answer: Multigene assays are available to assist clinicians in
assessing the risk of recurrence in early-stage breast cancer. These
molecular tools can help to individualize treatment decisions and
may increase confidence in clinical decision-making and reduce
anxiety among patients.
5/22/2012 5:52:43 PM
 Systemic Treatment Strategies for Early-Stage Breast Cancers ■ 609

Clinical Question Summary

Question Answer Levels of Grade of References
Evidence Recommendations
1 What are the The NCCN guidelines recommend consideration 1 A 1-17
indications of adjuvant chemotherapy for women with node
for adjuvant positive disease. For women with HER2-negative
chemotherapy in tumors, and tumors that are >1 cm and node
breast cancer and negative or 0.6 to 1 cm with unfavorable features
which chemotherapy such as high grade and lymphovascular invasion,
regimens should be the NCCN guidelines recommend consideration
used? of further information that may impact treatment
decisions, such as the 21 gene recurrence score
assay (Oncotype Dx™). Patients who can avoid
adjuvant chemotherapy or be considered for
adjuvant endocrine therapy alone are those patients
with hormone receptor-positive tumors <0.6 cm.
2 What are the Tamoxifen should be given to women with hormone 1 A 2, 18-25
indications for receptor-positive tumors and who are pre- or
adjuvant endocrine perimenopausal. Women who are postmenopausal
therapy in breast should receive an AI alone or in sequence
cancer? with tamoxifen for at least 5 years of adjuvant
endocrine therapy.
3 What are the Trastuzumab therapy should be used in combination 1 A 26-33
indications for with chemotherapy for all patients with HER2-
adjuvant biologic positive tumors that are node positive or node
therapies in breast negative and ≥0.6 cm in size.
cancer?
4 What is the role Neoadjuvant chemotherapy is an established 1 A 34-41
of neoadjuavnt approach for patients who present with inoperable
therapies in breast and locally breast cancer. It has the potential to
cancer? improve surgical options in some patients and is an
important tool for evaluating novel therapeutics
in select subsets. The neoadjuvant approach
allows for the pathologic assessment of systemic
therapies on tumor biology, which can also
provide information on expected outcomes for
individual patients.
5 What is the role of The Adjuvant! Online computer program is an 2 B 3
Adjuvant! Online effective web-based tool to inform discussions
computer program between physicians and patients regarding
is systemic therapy expected recurrence rates due to breast cancer
treatment planning? and the potential for improvements in outcome
with current interventions.
6 What molecular Multigene assays are available to assist clinicians 2 B 42-44
tools are available in assessing risk of recurrence in early stage
to assess the risk breast cancer. These molecular tools can help to
of recurrence from individualize treatment decisions and may increase
breast cancer? confidence in clinical decision making and reduce
anxiety among patients.

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the European Organization for Research and Treatment of Can-
cer trial 10902. J Clin Oncol. 2001;19:4224-4237.
37. Symmans WF, Peintinger F, Hatzis C, et al. Measurement of
residual breast cancer burden to predict survival after neoadju-
vant chemotherapy. J Clin Oncol. 2007;25:4414-4422.
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38. Hess KR, Anderson K, Symmans WF, et al. Pharmacogenomic
predictor of sensitivity to preoperative chemotherapy with pacli-
taxel and fluorouracil, doxorubicin, and cyclophosphamide in
breast cancer. J Clin Oncol. 2006;24:4236-4244.
39. Oh JL, Nguyen G, Whitman GJ, et al. Placement of radiopaque
clips for tumor localization in patients undergoing neoadju-
vant chemotherapy and breast conservation therapy. Cancer.
2007;110:2420-2427.
40. Chen AM, Meric-Bernstam F, Hunt KK, et al. Breast conserva-
tion after neoadjuvant chemotherapy: the M.D. Anderson cancer
center experience. J Clin Oncol. 2004;22:2303-2312.
41. Hunt KK, Yi M, Mittendorf EA, et al. Sentinel lymph node sur-
gery after neoadjuvant chemotherapy is accurate and reduces the
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43. Paik S, Tang G, Shak S, et al. Gene expression and ben-
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44. Lo S, Mumby PB, Norton J, et al. Prospective multicenter study
of the impact of the 21-gene recurrence score assay on medical
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 CHAPTER 76
In Situ Carcinoma of the Breast:
Ductal and Lobular Carcinoma
Jane E. Méndez
INTRODUCTION
Ductal carcinoma in situ (DCIS) is a noninvasive breast cancer
that encompasses a wide spectrum of diseases ranging from low-
grade lesions that are nonlife threatening to high-grade lesions
that may harbor foci of invasive breast cancer. DCIS is typically
classified according to architectural pattern, tumor grade, and the
presence or absence of comedo necrosis.1 The incidence of DCIS
has increased dramatically since the early 1970s largely attrib-
uted to the widespread use of mammography. Before mammog-
raphy was common, DCIS was rare representing less than 1% of
all breast cancer. Today, DCIS is common representing 27% of
newly diagnosed breast cancer cases and as many as 30% to 50%
of breast cancer cases diagnosed by mammography. In 2009, more
than 67,000 new instances of DCIS were diagnosed in the United
States alone, making noninvasive breast cancer the fourth most
commonly diagnosed malignancy in women.2
The first description of lobular carcinoma in situ (LCIS) was
by Foote and Stewart in 1941.3 There are no specific clinical abnor-
malities that a patient will present with, in particular no palpable
mass and usually no associated microcalcifications on mammog-
raphy. Therefore, the diagnosis of LCIS is often made as an inci-
dental, microscopic finding in breast biopsy performed for other
indications. For these reasons, many asymptomatic women go
undiagnosed, and the true incidence of LCIS in the general pop-
ulation remains unknown. The incidence of LCIS in otherwise
benign breast biopsy is between 0.5% and 3.8%.4,5
The term atypical lobular hyperplasia (ALH) was subsequently
introduced to describe morphologically similar but less well-
developed lesions. Lobular neoplasia (LN) was a term introduced by
Haagensen in 1978 to cover the full range of proliferation, includ-
ing both ALH and LCIS within the spectrum.6 (LAK) ALH and
LCIS have since become well-established histopathologic entities
in the classification of breast neoplasia, but it has become clear over
the past 60 years that they are not precursor lesions for invasive
carcinoma in the same way as high-grade DCIS of comedo type.7
A diagnosis of ALH/LCIS today is often seen as a “risk indi-
cator” for subsequent carcinoma rather than a true precursor.
612
PMPH_CH76.indd 612
Characteristically, LCIS is multifocal and bilateral in a large pro-
portion of cases. Over 50% of patients diagnosed with LN contain
multiple foci in the ipsilateral breast and about 30% of cases will
have further LCIS in the contralateral breast.8,9 The most impor-
tant, and the most difficult, differential diagnosis of LCIS is from
low-nuclear-grade, solid DCIS. Correct identification is essential
as there are different management implications. However, dis-
tinction of LCIS from low-grade solid DCIS can be very difficult
because morphologically they can be strikingly similar.10
1. What is the appropriate surgical management for DCIS?
DCIS is a heterogeneous disease associated with high rates of long-
term, disease-free survival (96–98%) when treated with available
therapies. Given the heterogeneity, there is considerable con-
troversy regarding how best to surgically manage patients with
DCIS.11 Current management options for DCIS include mastec-
tomy, breast-conserving surgery (BCS), or BCS followed by whole
breast radiation therapy (BCS + RT).
Only one trial has compared mastectomy with breast conser-
vation for patients with DCIS, and the data were only inciden-
tally accrued.12 The National Surgical Adjuvant Breast Project
(NSABP) performed protocol B-06, a prospective randomized
trial for patients with invasive breast cancer with three treatment
arms: total mastectomy, excision of the tumor plus radiation, or
excision alone. A subgroup of 78 patients were found to have pure
DCIS without evidence of invasion. After 83 months of follow-up,
the percent of patients with local recurrences were 0% for mastec-
tomy, 7% for excision plus radiation, and 43% for excision alone.
Despite the differences in rates of local recurrence, there was no
difference among the three groups in terms of breast cancer-
specific survival. (Level 2b evidence)
Clinical factors associated with increased risk of local recur-
rence following breast-conserving treatment for DCIS are symp-
tomatic presentation (palpable mass) and young age at diagnosis.
To further evaluate the impact of age at diagnosis on the clinical
and pathologic features of DCIS, the influence of age on outcome
after lumpectomy and RT, and the impact of age on outcome after
mastectomy, Vicini and Recht conducted a search of MEDLINE
5/22/2012 5:53:15 PM
 In Situ Carcinoma of the Breast: Ductal and Lobular Carcinoma
and CancerLit databases and reviewed the available studies.13 DCIS
in younger patients more frequently contained adverse prognos-
tic pathologic factors and extended over a greater distance in the
breast than in older patients. In series with adequate follow-up,
younger patients treated with lumpectomy and RT had a signifi-
cantly higher rate of local recurrence than older patients, espe-
cially for invasive local recurrences. Some studies have suggested
that careful attention to margin status and excising larger volumes
of tissue can reduce this difference substantially. No available data
showed that younger patients have better long-term cancer-free
survival rates if treated by mastectomy rather than by lumpec-
tomy and RT. On the basis of this review, Vicini et al. concluded
that successful treatment of younger patients with DCIS with
lumpectomy and RT requires careful attention to patient evalu-
ation, selection, and surgical technique. Age at diagnosis should
not be a contraindication to breast-conserving therapy.
There is no consensus on what constitutes an adequate sur-
gical margin in patients receiving BCS and postoperative RT for
DCIS. Inadequate margins may result in high local recurrence,
and excessively large resections may lead to poor cosmetic out-
come without oncologic benefit. Dunne et al.14 conducted a com-
prehensive search for published trials that examined outcomes
after adjuvant RT after BCS for DCIS was performed using MED-
LINE and cross-referencing available data. Reviews of each study
were conducted, and data were extracted. Primary outcome was
ipsilateral breast tumor recurrence (IBTR) related to surgical mar-
gins. A total of 4660 patients were identified from trials examin-
ing BCS and RT for DCIS. Patients with negative margins were
significantly less likely to experience recurrence than patients
with positive margins after RT (odds ratio [OR] = 0.36; 95% CI
0.27–0.47). A negative margin significantly reduced the risk of
IBTR when compared with a close (OR = 0.59; 95% CI 0.42–0.83)
or unknown margin (OR = 0.56; 95% CI 0.36–0.87). When spe-
cific margin thresholds were examined, a 2-mm margin was supe-
rior to a margin less than 2 mm (OR = 0.53; 95% CI 0.26–0.96);
however, we saw no significant difference in the rate of IBTR with
margins between 2 mm and more than 5 mm (OR = 1.51; 95% CI
0.51–5.0; p > .05).
The authors concluded that negative surgical margins should
be obtained after BCS for DCIS. A margin threshold of 2 mm
seems to be as good as a larger margin when BCS for DCIS is com-
bined with RT.
Answer: Negative surgical margin is a critical component
of breast-conserving surgery in patients with DCIS. (Grade B
recommendation)
2. What is the role of RT in the treatment of DCIS?
The main risk of inadequately removing all the DCIS is either a
recurrence of DCIS or the development of invasive breast cancer
at a later time with the risk that this can progress to metastatic
disease. Giving RT after BCS is thought to reduce the risk of devel-
oping recurrent disease (either DCIS or invasive breast cancer).
Strong Level 1 evidence from four randomized prospective trials
on the value of RT after BCS for DCIS.15 These trials—NSABP and
Bowel Project-B17 (NSABP-B17),16,17 European Organisation for
Research and Treatment of Cancer 10853 (EORTC 10853),18 the
United Kingdom, Australia, and New Zealand trial (UKAusNZ),19
and the Swedish (SweDCIS) trial20—have consistently demon-
strated a risk reduction of approximately 50% in IBTR among
women randomly assigned to the BCS plus RT arms.
PMPH_CH76.indd 613
■ 613
Goodwin et al.15 conducted a search of Cochrane Breast Can-
cer Group Specialised Register (January 2008), Cochrane Central
Register of Controlled Trials (CENTRAL) (The Cochrane Library
2008, Issue 1), MEDLINE (February 2008), and EMBASE (Feb-
ruary 2008) of the randomized clinical trials (RCTs) of breast-
conserving surgery with and without radiotherapy in women
at first diagnosis of pure DCIS (no invasive disease present). Four
RCTs involving 3925 women were identified and included in this
review. All were high quality with minimal risk of bias. Three tri-
als compared the addition of RT with BCS. One trial was a two-by-
two factorial design comparing the use of RT and tamoxifen, each
separately or together, in which participants were randomized in at
least one arm. Analysis confirmed a statistically significant benefit
from the addition of radiotherapy on all ipsilateral breast events
(hazards ratio (HR) 0.49; 95% CI 0.41–0.58, p < .00001), ipsilateral
invasive recurrence (HR 0.50; 95% CI 0.32–0.76, p = .001) and ipsi-
lateral DCIS recurrence (HR 0.61; 95% CI 0.39–0.95, p = .03). All
the analyzed subgroups benefited from addition of radiotherapy.
No significant long-term toxicity from radiotherapy was found.
From their review, Goodwin et al. concluded that their findings
confirmed the benefit of adding radiotherapy to breast-conserving
surgery for the treatment of all women diagnosed with DCIS.
Although the randomized trials have demonstrated an over-
all reduction in IBTR in all patients with DCIS treated with BCS +
RT, the absolute benefit of whole breast radiotherapy may be
smaller in subsets of patients based on their age, tumor size, histol-
ogy, grade, and margin status.21 To date, subset analyses have not
been able to identify any patient or tumor characteristic groups in
which radiation could be omitted for DCIS. In a series published
by Silverstein et al., patients with small lesions, with favorable his-
tologies, and of low to intermediate grade with widely negative
margins (>1 cm) treated by BCS alone reported an IBTR rate as
low as 6% at 5 years.22 There are, however, conflicting retrospec-
tive data demonstrating higher local relapse rates with the omis-
sion of RT in even these favorable patient groups.23
In an effort to address this issue, a trial initiated by the East-
ern Cooperative Oncology Group (ECOG) enrolled patients with
DCIS into ECOG 5194, a single-arm, multi-institutional, prospec-
tive study of observation after BCS, with the end points of ipsilat-
eral and contralateral breast relapse.24 Patient eligibility included
low- or intermediate-grade (LIG) DCIS lesions measuring from 0.3
to 2.5 cm in size with margins ≥3 mm, or high-grade (HG) DCIS
lesions measuring from 0.3 to 1.0 cm in size with margins ≥3 mm.
With a median follow-up of 6.2 years, they reported 5- and 7-year
IBTR rates of 6.1% and 10.5% in the LIG cohort and 15.3% and
18% in the HG cohort, respectively. The authors concluded that
the LIG cohort had an acceptable rate of IBTR, although they
acknowledged that further follow-up is warranted and that the
HG cohort had an unacceptably high relapse rate of 15.3% at
5 years, suggesting BCS alone may be inadequate treatment in this
subgroup of patients. (Level 1b evidence)
Motwani et al.21 set to evaluate the outcomes in a large cohort
of DCIS patients who met the eligibility criteria for ECOG 5194
(E5194), but were treated with BCS and adjuvant whole breast
radiotherapy, to compare the ipsilateral and contralateral breast
tumor recurrence in these patients treated with radiation with
those treated with observation alone in the ECOG study. A total of
263 patients with DCIS were treated between 1980 and 2009 who
met the enrollment criteria for E5194: (1) LIG with size >0.3 cm
but <2.5 cm and margins >3 mm (n = 196), or (2) HG, size <1 cm
5/22/2012 5:53:15 PM
 614 ■ Surgery: Evidence-Based Practice
and margins >3 mm (n = 67). All patients were treated with
lumpectomy and whole breast RT with a boost to a median total
tumor bed dose of 6400 cGy. With a follow-up time of 6.9 years,
the 5- and 7-year IBTR for the LIG cohort in this study were 1.5%
and 4.4% compared with 6.1% and 10.5% in E5194, respectively.
The 5- and 7-year IBTR for the HG cohort were 2.0% and 2.0% in
this study compared with 15.3% and 18% in E5194, respectively.
Motwani et al. concluded that adjuvant RT reduces the risk of an
IBTR by more than 70% for both LIG and HG DCIS compared
with the results seen in ECOG 5194. Taking into consideration
the significant local failure after 5 years of follow-up, the authors
recommend both LIG and HG DCIS patients be considered for
whole breast radiation until longer follow-up of ECOG 5194 is
reported and a low-risk group of DCIS patients can be identified.
(Level 2b evidence)
Recent studies also demonstrate favorable results in selected
patients with BCS followed by partial breast irradiation. Goyal
et al. studied the IBTR in DCIS patients treated in the American
Society of Breast Surgeons MammoSite Breast Brachytherapy Reg-
istry Trial who met the criteria for E5194 treated with local exci-
sion and adjuvant accelerated partial breast irradiation (APBI).25
A total of 194 patients with DCIS were treated between 2002 and
2004 in the Mammosite registry trial; of these, 70 patients met
the enrollment criteria for E5194: (1) LIG-pathologic size >0.3
but <2.5 cm and margins ≥3 mm (n = 41) or (2) HG-pathologic
size <1 cm and margins ≥3 mm (n = 29). All patients were treated
with lumpectomy followed by adjuvant APBI using MammoSite.
Median follow-up was 52.7 months (range 0–88.4). In the LIG
cohort, the 5-year IBTR was 0%, compared with 6.1% at 5 years
in E5194. In the HG cohort, the 5-year IBTR was 5.3%, compared
with 15.3% at 5 years in E5194. The overall 5-year IBTR was 2%,
and there were no cases of elsewhere or regional failures in the
entire cohort. The 5-year contralateral breast event rate was 0%
and 5.6% in LIG and HG patients, respectively (compared with
3.5% and 4.2%, respectively, in E5194). This study found that
patients who met the criteria of E5194 treated with APBI had
extremely low rates of recurrence. (Level 1b evidence)
Answer: Radiation is an important adjuvant treatment
after breast-conserving surgery in patients with DCIS. (Grade A
recommendation)
3. What is the role for axillary sentinel lymph node biopsy in
DCIS?
Only 1.5 % of patients with DCIS have axillary node metastases
identified by conventional pathologic assessment.26,27 By long-
standing consensus, there is no role for ALND in DCIS.28 In five
series of SLN biopsy for patients with DCIS, SLN metastases were
found in 3% to 12% of cases,29-33 but even for series of “pure DCIS”
SLN metastases were present in 3% to 5%.32,34
The current American Society of Clinical Oncology guide-
lines for SLNB in early-stage breast cancer recommend SLNB for
patients undergoing mastectomy for DCIS because of the technical
difficulty of performing SLNB after mastectomy, but the routine
use of SLNB in patients who undergo BCS is not recommended.
In circumstances of high-risk DCIS or large tumors, SLNB should
be considered on a case-by-case basis.35 The 2001 Sentinel Lymph
Node Biopsy Consensus Conference recommendations were sim-
ilar. However, the Consensus generated a clearer statement rec-
ommending the use of SNB in patients who have DCIS with the
PMPH_CH76.indd 614
presence of any type of invasive breast cancer but against its use in
patients with DCIS without any type of invasive breast cancer.36
Answer: The routine use of SLNB in all patients with pure
DCIS is not warranted. For patients with proven invasive or
microinvasive disease with DCIS, SLNB is supported. In those
who undergo mastectomy for DCIS, SLNB is recommended at
the time of mastectomy. A case-by-case decision should be made
for the use of SLNB in patients who have high-risk DCIS or large
tumors. (Grade B recommendation)
4. What is the appropriate surgical management for LCIS?
The surgical management of LCIS has to be addressed considering
two different scenarios: (1) when LCIS pathology is found on core
biopsy and (2) when LCIS is found incidentally in a lumpectomy
specimen or at the resection margin of a patient with known inva-
sive carcinoma.
The significance of LIN diagnosed at core needle biopsy (CNB)
is unclear. To determine the incidence of malignancy (invasive
carcinoma or DCIS) in patients diagnosed with LN (B3) on CNB
of breast lesions, Hussain et al.37 reviewed the published litera-
ture on Medline, Embase, OVID-database, and reference lists to
identify and review all English-language articles addressing the
management of LN diagnosed on CNB. Of 1229 LN diagnosed
on CNB, 789 (64%) underwent surgical excision; 211 (27%) of
excisions contained either DCIS or invasive disease; 280 of the
excision specimens were classified as ALH, 241 as LCIS, 22 as
pleomorphic LCIS (PLCIS), and 246 unspecified LN on the origi-
nal CNB. After surgical excision, 19% of the ALH cases, 32% of
the LCIS cases, and 41% of the PLCIS cases contained malig-
nancy; 29% of the unspecified LNs were upgraded to malignancy.
The higher incidence of malignancy within excision specimens
for LCIS and PLCIS compared with ALH was significant (p < .04
and .003, respectively). The authors concluded that there is a sig-
nificant underestimation of malignancy in patients diagnosed
with breast LN on CNB and recommended that all patients diag-
nosed with LN on CNB should be considered for surgical excision
biopsy. (Level 2b evidence)
In contrast, Bowman et al. performed a PubMed search to
identify all published addressing management of LN diagnosed at
CNB.38 The 19 studies that form the basis of this report included a
total of 504 subjects. Limitations of the reviewed studies included
their retrospective nature, small number of subjects, inconsistent
inclusion criteria, and selection bias regarding surgical excision.
Based on the reviewed literature, the authors concluded that it
was difficult to reach a firm evidence-based conclusion regarding
optimal management of LN diagnosed at CNB. At this time, the
available retrospective literature does not support a routine exci-
sion for all patients. (Level 2b evidence)
To address the second scenario, when LCIS is found inciden-
tally in the lumpectomy or at the resection margin of a patient
with known invasive carcinoma, Ciocca et al. studied 2894 patients
treated with BCT for DCIS, stage I or II breast cancer.39 Group A
had 290 patients with LCIS in the lumpectomy; 84 had LCIS at the
final margin. Group B included 2604 patients with no evidence
of LCIS. The histologic distribution of tumor types in group A
was lobular in 47.2%, ductal in 34.5%, DCIS in 11.4%, and other
invasive histologies in 6.9%, compared with 4.1%, 76.3%, 13.6%,
and 6.0% for group B, respectively (p < .0001). The crude rate of LR
was 4.5% in group A and 3.8% in group B (p = NS); 5- and 10-year
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 In Situ Carcinoma of the Breast: Ductal and Lobular Carcinoma ■ 615

actuarial LR rates for LCIS at the margin were 6% and 6%, 1% and
15% for LCIS present but not at the margin, and 2% and 6% for no
LCIS (p = NS), for groups A and B, respectively. LCIS, either in the
specimen or at the margin, was not significantly associated with
LR. Presence of LCIS, even at the margin, in BCT specimens does
not have an impact on LR. Re-excision is not indicated if LCIS is
present or close to margin surfaces. Hence, when LCIS is found
incidentally at the surgical margin, re-excision is not necessary.
(Level 2b evidence)
Answer: The necessity of routine surgical excision for LCIS
remains controversial due to conflicting opinions on the biologic
behavior of lobular lesions, diagnostic confusion regarding his-
topathology, and uncertainty of their association with high-risk
lesions. (Grade C recommendation)
5. What is the role for chemoprevention in the treatment of
LCIS?
Although it is clear that LCIS is not an obligate precursor to invasive
lobular carcinoma, many studies have shown that a proportion
of women with LCIS go on to develop invasive carcinoma, with a
risk of 6.9 times to about 12 times that of women without LCIS.6,40
The time taken to develop invasive cancer after diagnosis of LCIS
is unclear. In the NSABP Breast Cancer Prevention Trial (BCPT),
the reduction in risk of noninvasive breast cancer was 50%.41 The
BCPT randomized 13,000 healthy women at increased risk for
breast cancer to receive 20 mg of tamoxifen daily or a placebo for
a 5-year period.42 Through 7 years of follow-up, the cumulative
incidence of noninvasive breast cancer among the placebo group
was 15.8 per 1000 women versus 10.2 per 1000 women in the
tamoxifen group.43 The cumulative rate of invasive breast cancer
was reduced 43% in the tamoxifen group and the cumulative rate
of noninvasive carcinoma was reduced 37%. The BCPT revealed
that significant net benefit accrues for women with a diagnosis of
either LCIS or atypical hyperplasia who take tamoxifen. Among
women with a history of LCIS, the reduction in risk was 46%.
(Level 1b evidence)
Answer: Chemoprevention is recommended for patients at
high risk of breast cancer including patients with LCIS. (Grade A
recommendation)

Clinical Question Summary

Question
1 What is the appropriate surgical
management for DCIS?
2 What is the role of RT in the
treatment of DCIS?
3 What is the role for axillary
sentinel lymph node biopsy in
DCIS?
4 What is the appropriate surgical
management for LCIS?
5 What is the role for
chemoprevention in the
treatment of LCIS?
Answer Grade of References
Recommendation
Negative surgical margin is a critical component of B 12-14
breast conserving surgery in patients with DCIS.
Radiation is an important adjuvant treatment after A 15-20
breast-conserving surgery in patients with DCIS.
The routine use of SLNB in all patients with pure B 35-36
DCIS is not warranted. For patients with proven
invasive or microinvasive disease with DCIS, SLNB
is supported. In those who undergo mastectomy
for DCIS, SLNB is recommended at the time of
mastectomy. A case-by-case decision should be
made for the use of SLNB in patients who have
high-risk DCIS or large tumors.
The necessity of routine surgical excision for LCIS C 37-39
remains controversial due to conflicting opinions
on the biologic behavior of lobular lesions,
diagnostic confusion regarding histopathology,
and uncertainty of their association with high-risk
lesions.
Chemoprevention is recommended for patients at A 41-43
high risk of breast cancer including LCIS.

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excision alone for ductal carcinoma in situ of the breast. J Clin
Oncol. 2006;24:1031-1036.
24. Hughes LL, Wang M, Page DL, et al. Local excision alone without
irradiation for ductal carcinoma in situ of the breast: A trial of the
Eastern Oncology Group. J Clin Oncol. 2009;27(32):5319-5324.
25. Goyal S, Vicini F, Beitsch PD, et al. Ductal carcinoma in situ treated
with breast-conserving surgery and accelerated partial breast irra-
diation: Comparison of the Mammosite registry trial with inter-
group study E5194. Cancer. 2011;117:1149-1155.
PMPH_CH76.indd 616
26. Cody HS. Sentinel lymph node biopsy for DCIS: Are we approach-
ing consensus? Ann Surg Oncol. 2007;14(8): 2179-2181.
27. Leonard GD, Swain SM. Ductal carcinoma in situ, complexities
and challenges. JNCI Cancer Spectrum. 2004;96:906-920.
28. Schwartz GF, Solin LJ, Olivotto IA, et al. The consensus confer-
ence on the treatment of in situ ductal carcinoma of the breast,
April 22–25, 1999. Breast J. 2000;6:4-13.
29. Pendas S, Dauway E, Giuliano AE, et al. Sentinel node biopsy in
duct carcinoma in situ patients. Ann Surg Oncol. 2000;7:15-20.
30. Klauber-DeMore N, Tan LK, Liberman L, et al. Sentinel lymph
node biopsy: Is it indicated in patients with high-risk ductal
carcinoma-in-situ and ductal carcinoma-in-situ with microin-
vasion? Ann Surg Oncol. 2000;7:636-642.
31. Cox CE, Nguyen K, Gray RJ, et al. Importance of lymphatic map-
ping in ductal carcinoma in situ (DCIS): Why map DCIS? Am
Surg. 2001;67:513-519.
32. Intra M, Veronesi P, Mazzarol G, et al. Axillary sentinel lymph
node biopsy in patients with pure ductal carcinoma in situ of the
breast. Arch Surg. 2003;138:309-313.
33. Yen TW, Hunt KK, Ross MI, et al. Predictors of invasive breast can-
cer in patients with an initial diagnosis of ductal carcinoma in situ:
A guide to selective use of sentinel lymph node biopsy in manage-
ment of ductal carcinoma in situ. J Am Coll Surg. 2005;200:516-526.
34. Wilkie C, White L, Dupont E, et al. An update of sentinel lymph
node mapping in patients with ductal carcinoma in situ. J Am
Coll Surg. 2005;200:516-526.
35. Lyman GH, Giuliano AE, Somerfield MR, et al. American Soci-
ety of Clinical Oncology guideline recommendations for senti-
nel lymph node biopsy in early-stage breast cancer. J Clin Oncol.
2005;23(30):7703-7720.
36. Schwartz GF, Giuliano AE, Veronesi U, et al. Proceedings of the
consensus conference on the role of sentinel lymph node biopsy
in carcinoma of the breast, April 19–22, 2001, Philadelphia, Penn-
sylvania. Cancer. 2002;94(10):2532-2551.
37. Hussain M, Cunnick GH. Management of lobular carcinoma in-
situ and atypical lobular hyperplasia of the breast—A review. Eur
J Surg Oncol. 2011;37:279-289.
38. Bowman K, Munoz A, Mahvi DM, et al. Lobular neoplasia diag-
nosed at core biopsy does not mandate surgical excision. J Surg
Res. 2007:142(2);275-280.
39. Ciocca RM, Li T, Freedman GM, et al. Presence of lobular carcinoma
in situ does not increase local recurrence in patients treated with
breast-conserving therapy. Ann Surg Oncol. 2008;15(8):2263-2271.
40. Andersen JA. Lobular carcinoma in situ. A long term follow up
in 52 cases. Acta Pathol Microbiol Scand. 1974;82:519-533.
41. Vogel VG, Constatino JP, Wickerham DL, et al. Carcinoma in
situ outcomes in National Surgical Adjuvant Breast and Bowel
Project Breast Cancer Chemoprevention Trials. J Natl Cancer Inst
Monogr. 2010;2010(41):181-186.
42. Fisher B, Constantino J, Wickerman DL, et al. Tamoxifen for pre-
vention of breast cancer: Report of the National Surgical Adju-
vant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 1998;
90:1371-1378.
43. Fisher B, Constantino J, Wickerman DL, et al. Tamoxifen for the
prevention of breast cancer: Current status of the National Surgi-
cal Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer
Inst. 2005;97:1652-1662.
5/22/2012 5:53:15 PM

Male Breast Cancer
INTRODUCTION
The incidence of breast cancer in men in the United States has
more than doubled in the last 20 years from 900 cases in 1987 to
an estimated 1970 cases in 2010.1,2 Despite the dramatic increase in
this uncommon cancer, the mortality for men has declined from
33% to 20%. Breast cancer incidence has increased in women 18%
during the same interval and mortality for women has declined
from 25% to 19%. In 2010, male breast cancer will account for
0.25% of all cancers in men, 0.13% of cancer deaths in men, and
0.94% of all breast cancers. These observations are supported by
a recent analysis of SEER data comparing male and female breast
cancer incidence and mortality.3 They also observed that male
breast cancers present later in life, at median age of 67 compared
with 62 for women.
1. What are the Risk Factors for Male Breast Cancer?
Risk factors for male breast cancer can be divided into those that
are accepted, confirmed with good statistical information, and
those that are suspected risk factors for which the supporting data
are anecdotal, generally based on case studies. Confirmed risk
factors include Klinefelter’s syndrome, obesity, testicular disor-
ders, family history of breast cancer, and mutation in BRCA2. The
largest study of risk factors for male breast cancer comes from the
analysis of the Patient Treatment File of the U.S. Veterans Affairs
medical system.4 Cases of male breast cancer (652) were identified
by ICD-9 codes among 4,501,578 patients hospitalized between
1969 and 1996. Additional medical conditions identified by ICD-9
codes and their frequency among breast cancer patients were com-
pared with their frequency among patients without breast cancer.
Using this method, men with breast cancer had a significantly
higher likelihood of also being diagnosed with Klinefelter’s syn-
drome, gynecomastia, obesity, and orchitis/epidydimitis.
Klinefelter’s syndrome is due to an extra X chromosome pres-
ent in an otherwise XY male.5 Men with Klinefelter’s have low
levels of testosterone and a high ratio of estrogens to androgens.
The relative risk of breast cancer among Klinefelter’s patients in
617
PMPH_CH77.indd 617
CHAPTER 77
Jessica Keto and Paul Ian Tartter
the VA study was 17 after adjustment of other medical conditions.
This increases their lifetime risk of breast cancer to 1.5%, still far
below the risk of a low-risk woman.
Gynecomastia was associated with breast cancer in the VA
study independent of obesity. Most likely, gynecomastia is a reflec-
tion of an abnormal hormonal milieu resulting in a high estrogen
to androgen ratio causing breast development, simply increasing
the amount of tissue at risk for malignancy.
The association of obesity with breast cancer risk noted in the
VA study was previously reported in men6,7 and, in women, high
body weight is an accepted risk and prognostic factor for breast
cancer.8 Obesity was found to be a significant risk factor for male
breast cancer in a case–control study conducted in Canada of 119
male breast cancer cases age-matched to 1905 controls identified
between 1994 and 1998.6 The risk of breast cancer increased with
increasing weight and increasing body mass index, with men over
90 kg having double the risk of men weighing less than 73 kg. In
Scandinavia, a similar case–control study of 468 male breast can-
cers and 780 controls noted a similar increased risk for men with
BMI’s over 30.7 These findings have been attributed to increased
production of estrogen by adipose tissue. Serum estrogen in men
increases with age, whereas testosterone declines resulting in high
estrogen to testosterone ratios in obese men.
The same Scandinavian and Canadian case–control studies
referred to above noted that family history of breast cancer was
also a significant risk factor for the development of breast cancer
in men. Family history of breast cancer in a fi rst degree rela-
tive was associated with a 3.3 to 3.6 times higher risk of breast
cancer compared with men with no family history. Certainly,
some of these men with breast cancer were carriers of mutations
in BRCA1 or BRCA2.9 The majority of inherited breast can-
cers in men are related to the BRCA2 gene mutation, account-
ing for approximately 15% of male breast cancer.10 The lifetime
risk of breast cancer for a man carrying the BRCA2 mutation
is increased 80 to 100 times with 6.9% diagnosed by the age
of 80.4 The BRCA1 gene mutation is associated with a lifetime
risk of 1.8%, approximately 15 times the risk in men without a
mutation.11 Other cancers including prostate, pancreatic, colon,
5/22/2012 5:53:45 PM
 618 ■ Surgery: Evidence-Based Practice

stomach, and melanoma have been associated with BRCA muta- Breast MRI studies have been done in men with breast can-
tions. Due to the significant association for the BRCA gene cer, but it is not clear that this adds to the information obtained
mutations with MBC, the diagnosis of breast cancer in a male is by clinical examination, mammography, and ultrasound-guided
an indication for genetic testing. biopsy.23
Radiation exposure is not proven to affect the risk of breast If axillary nodes or other sites of distant disease are sus-
cancer in men. Tumor registries for the survivors of the atomic pected, these should be biopsied for confirmation before proceed-
bomb in Japan were established in 1958 including 32,411 male ing to surgery. If the cancer is early, less than 4 cm, not invading
survivors with known radiation exposure.12 They were compared the skin, not fi xed to underlying muscle, and without evidence
with 10,491 male residents of Hiroshima and Nagasaki who were of lymph node or distant metastases, there is no need for preop-
not in the cities at the time of the bombings. There were 1.8 cases erative imaging with whole body PET/CT. If any of the foregoing
of male breast cancer per 100,000 person years in the radiation signs of advanced disease are present, distant metastases should
exposed men compared with 0.5 per 100,000 person years among be ruled out.
those not exposed. The small number of patients developing breast
cancer12 precludes statistical significance. A study of men exposed 3. What Histopathological Types are seen in Male Breast
to diagnostic and therapeutic ionizing radiation also observed Cancer?
an increased risk of breast cancer which did not reach statistical
Virtually, all breast cancers in men arise from ductal cells and
significance.13
85% of cancers in men are infi ltrating ductal.24 All pathologic
Exogenous estrogen taken by male to female trans-sexuals or
subtypes of ductal cancers reported in women have been reported
to treat prostate cancer has also been associated with the develop-
in men. As men are not screened with mammography and the
ment of male breast cancer.
majority of in situ ductal cancers are detected with mammog-
Numerous other suspected but statistically unproven risk
raphy in women, in situ ductal cancer is much less frequently
factors for male breast cancer include germline mutations in the
seen in men. The incidence of invasive papillary carcinoma in
PTEN tumor suppressor gene found in Cowden’s syndrome,14 ger-
men is twice than that in women, although still only accounting
mline mutation in the Androgen Receptor gene thought to influ-
for 4% of male breast cancers. The absence of lobular cells in the
ence estrogen/androgen ratios,15 polymorphism in the CYP17 gene
male breast has been attributed to the absence of high estrogen
which codes for an enzyme of estrogen and androgen synthesis,16
levels needed for lobular differentiation. The few lobular cancers
and mutation of the gene for CHEK2, a kinase which mediates
reported in men have been associated with Klinefelter’s syn-
DNA repair.17
drome and other clinical situations associated with high estro-
gen/androgen ratios.
2. What is the most common presentation for Male Breast Breast cancers in men tend to be more poorly differentiated
Cancer? than cancers in age-matched women, 25,26 although the major-
ity of breast cancers in men are intermediate or low grade and
Male breast cancer most commonly presents as a mass under the
they are more frequently estrogen receptor and progesterone
nipple/areolar complex and occasionally in the upper outer quad-
receptor-positive. More than 80% are estrogen receptor-posi-
rant. Small numbers of male breast cancers also present in the
tive and more than 75% progesterone receptor-positive. In fact,
same miscellaneous ways that breast cancers present in women:
breast cancers in men resemble those found in postmenopausal
nipple discharge, skin or nipple ulceration, palpable axillary mass
women, not surprising because 97% of men with breast cancer
or with distant metastases.
are over 50.27
The diagnosis of male breast cancer is often suspected from
The rates of human epidermal growth factor receptor 2 (her2/
physical examination alone: a hard, irregular mass is appreciated
neu) overexpression in male breast cancer reported in the litera-
under the nipple. Mammography may be helpful to differentiate
ture ranges from 1.7% to 15%28,29 compared with approximately
benign from malignant disease, but recent series indicate that
25% of breast cancers in women. SEER database statistics sup-
most, if not all, breast cancers in men are suspected on clinical
port lower her2/neu in cancers in men compared with cancers in
examination alone and mammography may be unnecessary in
women, but this is not a universal finding.11
men with clinical gynecomastia.18,19 Screening mammography
Breast cancers in men are diagnosed at more advance stage
is not used in men because the yield would be exceedingly low.
than in women because men are not screened with mammog-
When malignancy is suspected, a mammogram should be done
raphy. As a consequence, ductal carcinoma in situ, a common
prior to core needle biopsy because hemorrhage from the core
finding on mammography in women, is unusual in men. In addi-
needle biopsy will affect the mammographic appearance of the
tion, invasive breast cancers in men are generally more advanced
lesion. The mammogram may be helpful to assess the extent of
because many invasive cancers in women are found on screening
disease. Tissue diagnosis is often possible with fine needle aspira-
mammography before a palpable mass can be appreciated. More
tion.20 When a definitive diagnosis cannot be made by fine needle
than 40% of breast cancers in men are over 2 cm compared with
aspiration, ultrasound-guided core needle biopsy is indicated.21,22
one-third of breast cancers in women and 39% have involved axil-
The ultrasound confirms that the tissue removed comes from the
lary nodes.3
mass and the core needle is used because the volume of tissue
obtained gives a more reliable diagnosis than fine needle biopsy.
4. What is the best approach to Local Control for Male Breast
In addition, estrogen receptors and her2/neu can be measured on
Cancer?
the core needle biopsy. If the presentation is with excoriation of
the skin or the nipple, the diagnosis can be made with a punch Mastectomy continues to be the standard surgical management of
biopsy. male breast cancer because the cancers are usually located under

PMPH_CH77.indd 618 5/22/2012 5:53:46 PM


the nipple and areola. In the absence of invasion of the pectoralis
muscle, modified radical mastectomy is preferred over radical
mastectomy. When breast cancer in men is not adherent or invad-
ing the nipple, breast conservation can be attempted. However,
adjuvant radiation therapy will be required to reduce the risk of
local recurrence to acceptable levels. Surgical treatment without
mastectomy is possible in many cases with excellent local con-
trol.30 Mastectomy should be accompanied by axillary lymph
node sampling using sentinel node biopsy or axillary node dissec-
tion. Sentinel node biopsy is now an accepted alternative to axil-
lary lymph node dissection in men with clinically node-negative
breast cancer.31,32
Radiation should be considered in patients with locally advan-
ced disease not amenable to surgical removal.
5. Is Adjuvant Therapy Indicated for Male Breast Cancer?
Adjuvant hormonal therapy with Tamoxifen has been exten-
sively used in estrogen receptor-positive male breast cancers
because of the proven benefits of Tamoxifen in randomized
trials among women with breast cancer. Several retrospective
studies, but not all, have found a benefit in men.31-34 Aromatase
inhibitors are also being given to men with advanced estrogen
receptor-positive breast cancer. Doyen et al. 35 administered aro-
matase inhibitors to 15 men with metastatic breast cancer with
complete response in two, partial response in four, stable dis-
ease in two, and progressive disease in seven. In men, circulat-
ing estrogens are derived both from peripheral aromatization
of testosterone and by direct synthesis in the testes. Aromatase
inhibitors do not affect estrogen production by the testes and
measurable levels of serum estrogen are present in men taking
aromatase inhibitors. In addition, as aromatase inhibitors in
healthy men cause increases in leutenizing hormone and follicle
stimulating hormone, the resultant increased synthesis of tes-
tosterone would partially over-ride the inhibition of aromatase.
Perhaps, combining an aromatase inhibitor with Tamoxifen or
with the rHLH would result in better outcomes.
Chemotherapy is used in men with estrogen receptor-negative
cancers, especially those with nodal involvement or distant dis-
ease, and with estrogen receptor-positive cancers that progress on
hormonal therapy. Less than one-quarter of patients receive che-
motherapy alone and less than one-third receive chemotherapy in
addition to hormonal therapy.34-36 This is because there are no stud-
ies of survival benefit for chemotherapy in men with breast cancer.
There are no randomized trials of chemotherapy in MBC. Walshe
et al.33 reported on the 20-year follow-up for 31 node-positive
patients given cyclophosphamide, methotrexate, and fluorouracil
after mastectomy at the National Cancer Institute. Tamoxifen was
given to only four patients despite a high rate of estrogen receptor
positivity (22/23 with known receptor status). Twenty-one of the 31
patients have died, one from a treatment-related complication.
As previously noted, HER2 overexpression occurs in up to
15% of MBC. As data from randomized controlled trials clearly
show an improved DFS in women with HER2-positive cancers
treated with trastuzumab independent of age, hormonal status,
nodal status, and tumor size, adjuvant trastuzumab therapy
should be considered in node-positive or high-risk node-negative
HER2-positive MBC.
Adjuvant radiation therapy should be considered in patients
undergoing breast conservation, for patients with large cancers,
PMPH_CH77.indd 619
Male Breast Cancer ■ 619
with invasion of the pectoralis muscle, and in patients with
multiple-positive nodes. These are the same determinants of radi-
ation therapy used in women and, in the absence of contradicting
data for men, these indications must be accepted. Men undergo-
ing mastectomy more frequently receive radiation than women
because the pectoralis muscle or the skin is more frequently
involved. Radiation is thought to reduce the local recurrence rate
as it does in women.30,37,38
6. What is the Prognosis for Male Breast Cancer?
Breast cancer-specific survival in men is influenced by the same
factors that affect survival in women: lymph node involvement
and tumor size. However, as men with breast cancer are diag-
nosed at more advanced age than women, and life expectancy
for men is in general is lower than for women, men with breast
cancer have a higher risk of noncancer death than women with
breast cancer.39-41 As a consequence, one of the most significant
prognostic factors for men is age: the risk of dying from breast
cancer is 15 times higher for men over 80 years than for men 65
to 69 years.40 This observation comes from the analysis of the 510
men in the SEER database. After age, stage is the next most signif-
icant variable affecting outcome, followed by comorbidities and
race. This analysis found no survival benefit for chemotherapy or
radiation therapy. This is well illustrated by a study by EL-Tamer
et al.39 who matched 53 male breast cancer cases by age, date of
diagnosis, stage, and pathology to female cases. Ten-year breast
cancer-specific survival for men was 90% compared with 70% for
women. Overall survivals at 10 years for men and women were
57% and 51%. These findings were replicated in a similar study by
Marchal et al.41These seeming contradictory results were due to a
fourfold higher rate of noncancer death among the men.
The only additional significant prognostic factors in men
besides age and stage are estrogen receptor status, and expres-
sion of her2/neu and p53. However, these observations come from
studies with small numbers of patients.
Men treated for breast cancer have higher risks of developing
a second breast malignancy.42-44 The largest available study assem-
bled data for 3409 men with breast cancer from 13 cancer registries
in different countries.44 Excess risk of a second breast cancer, and
cancers of the small bowel, rectum, pancreas, lymphatics, prostate,
and nonmelanoma skin were also noted. Analysis of SEER data43
and data from the California Cancer Registry42 noted increase risk
of melanoma and, in California, stomach cancer. Male breast can-
cer patients need genetic testing for BRCA 1 and 2 mutations, and
these patients need to be followed up closely because the risk of a
second breast cancer is increased at least 30 times.
The prognosis for men with breast cancer is highly influenced
by race.40 Using SEER data, Crew et al. found that Black men pre-
sented with significantly more advanced stage, with significantly
lower socioeconomic status, and were half as likely to receive che-
motherapy than White male patients. Breast cancer mortality was
three times higher among Black patients.
Breast cancers of men are frequently compared with cancers
of postmenopausal women.39-41,45 However, breast cancers in men
differ from those in women in many ways: risk factors, presenta-
tion, pathology, treatment, and outcome. Reproductive risk factors,
age at menarche, first birth, and menopause are absent in men.
More than half of breast cancers in women are detected on screen-
ing mammography when nonpalpable and often in situ, whereas
5/22/2012 5:53:46 PM
 620 ■ Surgery: Evidence-Based Practice

in men almost all cancers present as a palpable mass. We are not
advocating screening mammography in men, but the absence of
screening causes cancers to present when larger, more frequently
with nodal involvement, and seldom when in situ. Hormone
receptor positivity is much more frequent in men and they should
be receiving Tamoxifen. Lumpectomy is not commonly used in
men as it is in women and, consequently, fewer men with early
disease receive radiation. Despite optimistic reports by oncolo-
gists concerning adjuvant chemotherapy, there are no substantive
data to support this optimism. Prognosis for men is worse than
for women because they are diagnosed later in life and at more
advanced stage than women.

Clinical Question Summary

Question Answers Level of Grade of References
Evidence Recommendation
What are the risk factors? BRCA mutation 2a A 4, 9-11
Family History 6, 7
Testicular disorders 4
Klinefelter’s 4, 5
Obesity 4, 6, 7
Presentation? Hard Subareolar Mass 2a A
Diagnosis Made by? Needle biopsy 2a A 20-22
Pathology, ER, Her2/neu? Infiltrating Ductal 2a A 24
Estrogen-Positive 25, 26
Her2/neu-Negative 28, 29
Surgical Management? Mastectomy 2a
Node Sampling
Best Hormonal Therapy? Tamoxifen 2a A 31-34
Role of chemotherapy? Estrogen-Negative 5
Tamoxifen Failure
Role of Radiation? Breast Conservation 5 30, 37, 38
Advanced Local Stage

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36. Liukkonen S, Saarto T, Maenpaa H, Sjostrom-Mattson J. Male
breast cancer: A survey at the Helskinki University Central Hos-
pital during 1981-2006. Acta Oncol. 2010;49:322-327.
37. Chakravarthy A, Kim CR. Post-mastectomy radiation in male
breast cancer. Radiother Oncol. 2002;65:99-103.
38. Zabel A, Milker-Mabel S, Zuna I, Wannenmacher M, Debus
J. External beam radiotherapy in the treatment of male breast
carcinoma: Patterns of failure in a single institution experience.
Tumori. 2005;91:151-155.
39. El-Tamer MB, Komenaka IK, Troxel A, et al. Men with breast can-
cer have better disease-specific survival than women. Arch Surg.
2004;139:1079-1082.
40. Crew KD, Neugut AI, Wang X, et al. Racial disparities in the
treatment and survival of male breast cancer. J Clin Oncol.
2007;25:1089-1098.
41. Marchal F, Salou M, Marchal C, Lesur A, Desandes E. Men with
breast cancer ave same disease-specific and event-free survival as
women. Ann Surg Oncol. 2009;16:972-978.
42. Satram-Hoag S, Ziogas A, Anton-Culver H. Risk of second
primary cancer in men with breast cancer. Breast Cancer Res.
2007;9:R10.
43. Wemberg JA, Yap J, Murekeyisoni C, et al. Multiple primary
tumors in men with breast cancer diagnoses: A SEER database
review. J Surg Oncol. 2009:99:16-19.
44. Grenader T, Goldberg A, Shavit L. Second cancers in patients
with male breast cancer: A literature review. J Cancer Surviv.
2008;2:73-78.
45. Speirs V, Ball G; the Male Breast Cancer Consortium. Male ver-
sus female breast cancer: A comparative study of 523 matched
cases reveals differences behind similarity. Breast Cancer Res.
2010;12(Suppl 1):O1.
5/22/2012 5:53:46 PM
 CHAPTER 78
Breast Reconstruction
Following Mastectomy
David M. Adelman and Steven J. Kronowitz
INTRODUCTION
Breast reconstruction is a very important component of the multi-
disciplinary care of patients with breast cancer. Although in some
patients, especially those who will require postmastectomy radia-
tion therapy (PMRT), it may be preferable to delay breast recon-
struction, immediate breast reconstruction offers aesthetic and
technical benefits over delayed reconstruction.1,2 Immediate breast
reconstruction also provides psychologic benefits.3 Patients who
undergo immediate breast reconstruction do not have to experience
the psychologic trauma of not having a breast because they awake
from anesthesia with a breast mound. Despite these benefits, many
patients continue to present for delayed reconstruction, which is
often more complex than immediate breast reconstruction and
which may be associated with an increased risk of complications.
In patients undergoing breast reconstruction after total mas-
tectomy, choosing the best method of reconstruction is essential
to optimize the aesthetic outcome and minimize the potential for
postoperative complications. Patient desires are extremely impor-
tant in selecting the reconstructive technique. Unfortunately,
sometimes patient’s desires cannot be fulfi lled because of patient
anatomy or other clinical realities.
1. Does smoking add increased risk to outcome in breast recon-
struction following mastectomy?
The detrimental effects of smoking on the outcome of any recon-
structive surgery in which flaps are utilized are well documented.4-6
Smoking has been found to adversely affect outcomes in many
types of breast surgery, including breast reduction. In 2007, Bikh-
chandani et al. suggested that stoppage of smoking in the periop-
erative period should be adopted as an essential eligibility criterion
for breast reduction, given the significantly increased complica-
tion rate.7 In breast cancer patients undergoing reconstruction, the
complication rate is similarly increased compared with nonsmok-
ers. In implant-based reconstructions, smoking was found to be
an independent predictor of increased surgical site infection rates.8
In a separate study, smoking, obesity, hypertension, and age over
622
PMPH_CH78.indd 622
65 were the independent risk factors for perioperative complica-
tions following expander/implant breast reconstruction. Smoking,
obesity, and hypertension were similarly associated with recon-
structive failure.9 These complications are not only found in patients
undergoing implant-based reconstructions, however. In a study
of pedicled transverse rectus abdominis myocutaneous (TRAM)
flap reconstructions, both active and former smokers had a higher
incidence of multiple flap-related complications. Active smokers
had a statistically significant higher rate of TRAM infection com-
pared with nonsmokers. Former smokers were also found to have
a higher rate of TRAM-related delayed wound healing compared
with nonsmokers.10 With the advent of microsurgical breast recon-
struction, most studies found that smokers again had increased
rates of complications. Free TRAM flap breast reconstruction in
smokers was not associated with a significant increase in the rates
of vessel thrombosis, flap loss, or fat necrosis compared with rates
in nonsmokers. However, smokers were at significantly higher
risk for mastectomy skin flap necrosis, abdominal flap necrosis,
and hernia compared with nonsmokers. Patients with a smoking
history of greater than 10 pack years were at especially high risk
for perioperative complications, suggesting that this should be
considered a relative contraindication for free TRAM flap breast
reconstruction. Smoking-related complications were significantly
reduced when the reconstruction was delayed or when the patient
stopped smoking at least 4 weeks before surgery.11 Additional
data advocate that microsurgical complications are not directly
increased by smoking, but rather the donor site and overall healing
abilities are affected.12 Perforator free flaps are part of the continued
evolution of autologous breast reconstruction. In one large study,
active smoking (within 1 month of surgery) was considered a spe-
cific contraindication to perforator flap surgery.13 Current smokers
with a large flap weight were also shown to have decreased intraflap
blood flow and more severe flap complications.14
Answer: Most studies demonstrate that smoking increases
the rates of mastectomy flap necrosis, implant and autologous-
based infections, delayed wound healing, and generally worse
outcome, and patients should be counseled as such prior to any
postmastectomy breast reconstruction.
5/22/2012 5:54:18 PM
 Breast Reconstruction Following Mastectomy ■ 623

2. Do neoadjuvant or adjuvant therapies increase risk in breast a study by Knottenbelt et al.19 The majority of patients in this
reconstruction following mastectomy? study had stage I or II cancers, and was reconstructed with tis-
sue expanders and implants. A later study by McCarthy et al.
An increasing number of patients are receiving chemotherapy
agreed with these fi ndings.20 They found that prosthetic breast
or radiation therapy as adjuncts to surgical treatment for breast
reconstruction neither hinders detection of locoregional cancer
cancer. Various protocols exist that differ in both the types of
recurrence, nor does it often necessitate removal of the recon-
therapy, as well as the timing of the intervention. The goals
struction for management of the disease. Similar fi ndings exist
of these therapies may be to shrink primary tumor size, and/or
in a retrospective study of patients reconstructed with autolo-
to treat nodal or metastatic disease. Common concerns of recon-
gous tissue in the form of a TRAM flap.21 A literature review of
structive surgeons are related to these therapies. First, might
the impact of breast reconstruction on the incidence and detec-
performing breast reconstruction following mastectomy lead to
tion of locoregional recurrence and treatment options was also
delayed implementation of these adjuvant therapies? Two stud-
recently performed, 22 and highlights some of the aforementioned
ies found that immediate breast reconstruction did not appear
studies and fi ndings.
to lead to omission of adjuvant chemotherapy, but was associ-
Answer: Taken together, the data suggest that surveillance
ated with a statistically significant delay in initiating treatment.
for breast cancer recurrence may be performed sufficiently even
For most patients, however, it was unlikely that, or unclear if,
in reconstructed breasts, and should not delay reconstruction.
this delay had any clinical significance.15,16 Second, might use
of these therapies before (neoadjuvant) or after (adjuvant) sur-
gery lead to increased morbidity related to the reconstruction? 4. Is patient anatomy important in the selection of reconstruc-
Most surgeons will wait to perform mastectomy and reconstruc- tive technique?
tion until a patient has recovered from neoadjuvant treatments.
As with most reconstructive or aesthetic procedures, patient
Likewise, most patients will not be initiated on adjuvant thera-
anatomy plays a critical role in breast reconstruction follow-
pies until sufficient healing from reconstruction has occurred.
ing mastectomy. Anatomy may be divided into three categories:
One recent study looked at the prevalence of complications after
body habitus, breast size/shape, and donor site, each with its own
breast reconstruction following mastectomy in cohorts that did
importance. Patients may be too thin or too obese, but prefer-
and did not receive adjuvant chemotherapy. Although the high-
ably fall somewhere in between. Thin patients may be malnour-
est rate of surgical site infections was in the adjuvant chemother-
ished from chemotherapy. They may lack adequate donor sites
apy group, there were no differences between groups with respect
for autologous reconstruction, and/or may have thin mastectomy
to unplanned return to the operating room, expander loss, or
flaps through which implants are easily palpated and poorly pro-
donor-site complications. Neither the inclusion of chemotherapy
tected. On the contrary, obese patients tend to have high rates
nor the timing of its administration seemed to significantly affect
of perioperative complications. However, it is generally safe to
the complication rates after mastectomy and immediate breast
perform autologous reconstruction in obese patients, and they
reconstruction.17 A separate study asked if adjuvant chemother-
tend to have high rates of satisfaction.23,24 The largest implants
apy and radiation therapy had effect on immediate postmastec-
available are frequently too small for the body frame of an obese
tomy autologous breast reconstructions. Patient-specific factors,
patient, and therefore may not look appropriate. Ideally, a patient
including diabetes mellitus and smoking, were found to increase
should reach her goal weight and be stable at that weight prior to
the risk of post-irradiation parenchymal changes, and neoadju-
surgery if possible. However, given that these are cancer opera-
vant chemotherapy was associated with a greater than twofold
tions, rather than merely aesthetic operations, one often must
increase in skin complications. However, they concluded that
proceed under less than ideal circumstances. Patient education
overall, autologous breast reconstruction followed by irradiation
becomes critical in such situations so that expectations can be
can be successful, but patients with specific risks factors should
appropriately met.
be aware of increased complication rates.18
Preoperative and postoperative breast size plays an impor-
Answer: The data suggest that although these neoadjuvant
tant role. Tissue expansion may allow a small-breasted woman
and adjuvant therapies may contribute to increased morbidity, they
to achieve a larger cup size postoperatively. An autologous recon-
are generally not a contraindication to performing breast recon-
struction from the abdomen may provide enough tissue for a
struction following mastectomy.
unilateral breast reconstruction, but not for a bilateral reconstruc-
tion. Similarly, a breast lift (mastopexy), reduction, or implant
3. Does surveillance for locoregional recurrence necessitate
augmentation may be required to enable symmetry between a
delay of breast reconstruction following mastectomy?
native and reconstructed breast. It is important to have discus-
The primary aim of surgery in breast cancer is to achieve a local sions preoperatively regarding patient desires, and what can be
control of disease. Secondly, patient satisfaction and improve- accomplished with safety, efficacy, and the best possible aesthetic
ment in quality of life are of utmost importance. Although the outcomes.
positive effects of breast reconstruction following mastectomy Donor and recipient site anatomy also play critical roles in
on the psychologic well-being of women with breast cancer has breast reconstruction. Free (microvascular) flaps are not possible
been demonstrated, evidence-based data on its oncologic safety without adequate recipient vessels. The decision between harvest-
remain sparse. There is concern that the presence of an implant ing a superficial inferior epigastric artery (SIEA), TRAM, or deep
or autologous tissue may mask locoregional recurrence. How- inferior epigastric perforator (DIEP) flap requires a patient’s vas-
ever, this concern has not been borne out in the literature thus culature to be favorable toward one or all types of flap.25 Number,
far. For example, immediate breast reconstruction after mastec- caliber, and location of perforating vessels, as well as perfusion
tomy was determined to be an oncologically safe approach in through these vessels, must be evaluated in each patient.

PMPH_CH78.indd 623 5/22/2012 5:54:18 PM

 624 ■ Surgery: Evidence-Based Practice
Answer: Patient anatomy is critical in both selection of
tech nique and execution of breast reconstruction following
mastectomy.
5. Is there an age limit on breast reconstruction following
mastectomy?
Elective surgery in the elderly is not without its associated risks.
Although the benefits of breast reconstruction following mastec-
tomy have been fully validated, do these benefits become limited
with advanced age? One study suggested that all types of recon-
struction should be an option for women older than 60 years of age
and that age as an isolated factor should not deter physicians from
offering these women the option of breast reconstruction.26 This
may be true for implant-based reconstruction, but can the same
be said for a free microvascular autologous tissue flap reconstruc-
tion? In recent years, many studies have looked at this question
and all arrived at the same conclusions—that free-tissue transfer
in the elderly population has demonstrated similar success rates to
those of the general population. In other words, age alone should
not be considered a contraindication or an independent risk fac-
tor for free-tissue transfer.27,28 More recent studies have had simi-
lar findings.29,30 In the study by Selber et al., despite higher rates
of hypertension, higher American Society of Anesthesiologists
status, higher body mass index, and higher rates of blood transfu-
sion, the 65 years and older group had outcomes equal to those of
the general population.
Answer: Breast reconstruction following mastectomy, and in
particular free microvascular autologous tissue flap breast recon-
struction, in patients of advanced age is safe, and should be offered
when indicated.
6. Which patients should receive immediate breast recon-
struction as opposed to delayed reconstruction after radiation
therapy?
PMRT can improve survival and locoregional control in patients
with invasive breast cancer. The optimal timing and techniques
of breast reconstruction in patients requiring PMRT are con-
troversial. Kronowitz and Robb recently performed a review of
the literature and published their findings.31 The indications for
radiation vary, but in general are favored in patients with more
advanced disease (larger tumor size, increased number of posi-
tive nodes, extra-nodal disease, etc.).32-34 In multiple studies,
radiation has been shown to adversely affect the aesthetic out-
come and increase complication rates of both implant-based35-38
and autologous tissue reconstructions.39-42 A study by Cordeiro
et al.43 suggests that if a tissue expander is exchanged for a per-
manent implant prior to radiation therapy, the outcomes can be
more favorable. However, other studies demonstrate that the pres-
ence of a fully inflated implant, or an autologous tissue flap, may
even compromise the design and delivery of radiation treatment
fields.44-51 The suggestion is therefore made that in patients who
are likely, or at least at high risk, for requiring PMRT, reconstruc-
tion of any kind be delayed until therapy is completed. There is a
population of patients, however, for whom the need for radiation
at the time of surgery is unclear (mostly stage II and some stage I).
For these patients, a “delayed- immediate” type approach may be
of benefit.46,52
Answer: In patients known prior to mastectomy to require
radiation, delay breast reconstruction until after radiation; in
PMPH_CH78.indd 624
patients who are considered at an increased risk for requiring post-
mastectomy radiation perform a delayed-immediate approach.
7. Is a breast implant or an autologous tissue flap preferable for
reconstruction following mastectomy?
An old adage in reconstructive surgery says to “replace like with
like.” As the adult breast is mostly skin and fat, it is sensible to
replace it with skin and fat. Autologous tissue flap options, includ-
ing those from the lower abdomen (SIEA, TRAM, DIEP), would
adhere to this adage well. But there are advantages and disad-
vantages to such types of reconstruction. Benefits of autologous
reconstruction may include the placement of well-vascularized
tissue into a previously irradiated chest wall, which may alleviate
some of the negative effects of the radiation. Autologous tissue is
able to prevent and treat infection more so than implants, given
its ample blood supply. It can also provide a better match with the
native breast in a unilateral reconstruction. And, it can remain
viable for the life of the patient. The disadvantages of autologous
reconstruction include additional donor-site morbidity (such as
scars, abdominal hernia or bulge, delayed wound healing, infec-
tion), prolonged operating times, insufficient quantity or quality
of tissue, and the need to change the position of the patient during
the operation (e.g., latissimus dorsi or gluteal flaps).
By contrast, a breast implant can be the best reconstruc-
tive choice for many women. Surgery is confined to the breast,
requires minimal recovery, does not depend on the availability or
the quality of donor tissue, and implants are available in different
sizes and shapes. Sounds perfect, so why don’t all women choose
implants? Well, implants are foreign bodies, and incite a reaction
from the body to wall it off (i.e., a capsule). In many women, this
capsule is thin and soft, but in others it can be hard, painful, and
even distort the breast.53 This is particularly seen after radiation.35
Implants are also prone to infection, as they do not have a blood
supply capable of bringing immune agents to the affected region.
They may rupture, undergo positional changes, or otherwise
require replacement, even multiple times throughout the length
of a woman’s life.
Answer: Both implants and autologous tissues have their
advantages and disadvantages. The decision regarding each one’s
use is best made when all factors regarding patient anatomy, ther-
apies, and desires are taken into account.
8. Is a free microvascular TRAM flap better than a pedicle
TRAM flap?
The “reconstructive ladder” is used by plastic surgeons to define
reconstructions from the simple to complex.54 In this paradigm,
pedicle flaps are generally lower on the ladder than free micro-
vascular flaps, suggesting that pedicle flaps are somehow easier
or less complex. The reconstructive ladder also implies a certain
evolutionary quality, in that the higher up the ladder, the more
recent the innovation. This is certainly true with microsurgery, in
that it has only existed in any serious form since the 1970s.55 How-
ever, many pedicle flaps are far more difficult to plan and execute
than their free flap counterparts, and may be less ideal forms of
reconstruction. Currently, many reconstructive surgeons take the
“reconstructive elevator” to the top and perform free flap recon-
structions as a primary means.56
There are many advantages to a pedicle TRAM flap for breast
reconstruction. 57 These flaps follow a well-defined anatomy,
5/22/2012 5:54:18 PM
 Breast Reconstruction Following Mastectomy ■ 625

making them straightforward to harvest. Special microsurgical
expertise is not required, making this technique readily available
to most surgeons. Because recipient vessels do not need to be pre-
pared, their availability and quality does not factor into the suc-
cess of the reconstruction. The harvest and inset of a pedicle flap
can be fast, minimizing operative time and cost.
However, there are problems associated with some pedicle
TRAM flaps. By definition, they are based off the superior epi-
gastric blood supply, itself a continuation of the internal mam-
mary vessels. In many patients, this pedicle is less robust when
compared with the deep inferior epigastric system. When based
on the superior system, there may be a higher rate of fat necro-
sis, especially in larger flaps. With pedicle TRAM flaps, minimal
efforts traditionally have been made to spare muscle and fascia.
In bilateral pedicle TRAM flap reconstructions more than uni-
lateral reconstructions, there is a higher incidence of abdominal
wall weakness, bulge, and hernia.58-60 Although free TRAM and
DIEP flap operative times are considerably longer than with pedi-
cle TRAM flaps, many surgeons still prefer the free TRAM flap
because of the better blood supply and decreased abdominal wall
morbidity. Microsurgical experience plays a much larger role in
free TRAM survival and outcomes. Also, community hospitals
without specialized equipment and trained staff may not be pre-
pared to support microsurgical breast reconstruction.
Answer: The benefits of a free microvascular TRAM (and its
variations, such as the DIEP flap) probably outweigh those of the
pedicle TRAM flap. However, the pedicle TRAM flap still has its
role and can provide a long-lasting reconstruction with minimal
donor-site morbidity.
CONCLUSIONS
Breast reconstruction following mastectomy is not a “one size
fits all” endeavor. Multiple techniques may be appropriate for a
given patient, and achieving the best outcome requires thought-
ful planning and execution. Various factors including anatomy,
comorbidity, and associated therapies must be considered. As our
expectations for outcomes continue to evolve, so must our under-
standing of the factors surrounding breast reconstruction.

Clinical Question Summary

Question
1 Does smoking add
increased risk to outcome
in breast reconstruction
following mastectomy?
2 Do neoadjuvant or
adjuvant therapies
increase risk in breast
reconstruction following
mastectomy?
3 Does surveillance for
locoregional recurrence
necessitate delay of breast
reconstruction following
mastectomy?
4 Is patient anatomy
important in the selection
of reconstructive
technique?
5 Is there an age limit on
breast reconstruction
following mastectomy?
6 Which patients should
receive immediate breast
reconstruction as opposed
to delayed reconstruction
after radiation therapy?
Answer Level of Grade of References
Evidence Recommendation
Most studies demonstrate that smoking increases 3b B 4-14
rates of mastectomy flap necrosis, implant and
autologous-based infections, delayed wound
healing, and generally worse outcome, and
patients should be counseled as such prior to
any postmastectomy breast reconstruction.
The data suggest that although these neoadjuvant 2b B 15-18
and adjuvant therapies may contribute to
increased morbidity, they are generally not
a contraindication to performing breast
reconstruction following mastectomy.
Taken together, the data suggest that surveillance 3b C 19-22
for breast cancer recurrence may be
performed sufficiently even in reconstructed
breasts, and should not delay reconstruction.
Patient anatomy is critical in both selection 3b C 23-25
of technique and execution of breast
reconstruction following mastectomy.
Breast reconstruction following mastectomy, and 2b B 26-30
in particular free microvascular autologous
tissue flap breast reconstruction, in patients
of advanced age is safe, and should be offered
when indicated.
In patients known prior to mastectomy to 3b C 31-52
require radiation, delay breast reconstruction
until after radiation and in patients who are
considered at an increased risk for requiring
postmastectomy radiation perform a delayed-
immediate approach.

(Continued)

PMPH_CH78.indd 625 5/22/2012 5:54:18 PM

 626 ■ Surgery: Evidence-Based Practice

(Continued)
Question
7 Is a breast implant or
an autologous tissue
flap preferable for
reconstruction following
mastectomy?
8 Is a free microvascular
TRAM flap better than a
pedicle TRAM flap?
Answer Level of Grade of References
Evidence Recommendation
Both implants and autologous tissues have their 3b C 53
merits and demerits. The decision regarding
each one’s use is best made when all factors
regarding patient anatomy, therapies, and
desires are taken into account.
The benefits of a free microvascular TRAM (and 3b C 54-60
its variations, such as the DIEP flap) probably
outweigh those of the pedicle TRAM flap.
However, the pedicle TRAM still has its role
and can provide a long-lasting reconstruction
with minimal donor site morbidity.

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2009;124(2):395-408.
32. Harris JR, Halpin-Murphy P, McNeese M, Mendenhall NP,
Morrow M, Robert NJ. Consensus Statement on postmastec-
tomy radiation therapy. Int J Radiat Oncol Biol Phys. 1999;44(5):
989-990.
33. Recht A, Edge SB, Solin LJ, et al. Postmastectomy radiotherapy:
clinical practice guidelines of the American Society of Clinical
Oncology. J Clin Oncol. 2001;19(5):1539-1569.
34. Truong PT, Olivotto IA, Whelan TJ, Levine M; Steering Commit-
tee on Clinical Practice Guidelines for the Care and Treatment
of Breast Cancer. Clinical practice guidelines for the care and
treatment of breast cancer: 16. Locoregional post-mastectomy
radiotherapy. CMAJ. 2004;170(8):1263-1273.
35. Ascherman JA, Hanasono MM, Newman MI, Hughes DB.
Implant reconstruction in breast cancer patients treated with
radiation therapy. Plast Reconstr Surg. 2006;117(2):359-365.
36. Behranwala KA, Dua RS, Ross GM, Ward A, A’hern R, Gui GP.
The influence of radiotherapy on capsule formation and aesthetic
outcome after immediate breast reconstruction using biodimen-
sional anatomical expander implants. J Plast Reconstr Aesthet
Surg. 2006;59(10):1043-1051.
37. Benediktsson K, Perbeck L. Capsular contracture around saline-
fi lled and textured subcutaneously-placed implants in irradi-
ated and non-irradiated breast cancer patients: five years of
monitoring of a prospective trial. J Plast Reconstr Aesthet Surg.
2006;59(1):27-34.
38. Spear SL, Onyewu C. Staged breast reconstruction with saline-
fi lled implants in the irradiated breast: recent trends and
therapeutic implications. Plast Reconstr Surg. 2000;105(3):
930-942.
39. Rogers NE, Allen RJ. Radiation effects on breast reconstruction
with the deep inferior epigastric perforator flap. Plast Reconstr
Surg. 2002;109(6):1919-1924; discussion 1925-1926.
40. Spear SL, Ducic I, Low M, Cuoco F. The effect of radiation on
pedicled TRAM flap breast reconstruction: outcomes and impli-
cations. Plast Reconstr Surg. 2005;115(1):84-95.
41. Tran NV, Chang DW, Gupta A, Kroll SS, Robb GL. Comparison
of immediate and delayed free TRAM flap breast reconstruction
in patients receiving postmastectomy radiation therapy. Plast
Reconstr Surg. 2001;108(1):78-82.
42. Williams JK, Carlson GW, Bostwick J 3rd, Bried JT, Mackay G.
The effects of radiation treatment after TRAM flap breast recon-
struction. Plast Reconstr Surg. 1997;100(5):1153-1160.
PMPH_CH78.indd 627
Breast Reconstruction Following Mastectomy ■ 627
43. Cordeiro PG, Pusic AL, Disa JJ, McCormick B, VanZee K. Irradi-
ation after immediate tissue expander/implant breast reconstruc-
tion: outcomes, complications, aesthetic results, and satisfaction
among 156 patients. Plast Reconstr Surg. 2004;113(3):877-881.
44. Buchholz TA, Strom EA, Perkins GH, McNeese MD. Contro-
versies regarding the use of radiation after mastectomy in breast
cancer. Oncologist. 2002;7(6):539-546.
45. Kronowitz SJ. Immediate versus delayed reconstruction. Clin
Plast Surg. 2007;34(1):39-50; abstract vi.
46. Kronowitz SJ, Hunt KK, Kuerer HM, et al. Delayed-immediate
breast reconstruction. Plast Reconstr Surg. 2004;113(6):1617-1628.
47. Kronowitz SJ, Kuerer HM. Advances and surgical decision-
making for breast reconstruction. Cancer. 2006;107(5):893-907.
48. Kronowitz SJ, Robb GL. Breast reconstruction with postmas-
tectomy radiation therapy: current issues. Plast Reconstr Surg.
2004;114(4):950-960.
49. Motwani SB, Strom EA, Schechter NR, et al. The impact of
immediate breast reconstruction on the technical delivery of
postmastectomy radiotherapy. Int J Radiat Oncol Biol Phys. 2006;
66(1):76-82.
50. Schechter NR, Strom EA, Perkins GH, et al. Immediate breast
reconstruction can impact postmastectomy irradiation. Am J
Clin Oncol. 2005;28(5):485-494.
51. Woodward WA, Strom EA, Tucker SL, et al. Locoregional recur-
rence after doxorubicin-based chemotherapy and postmastec-
tomy: Implications for breast cancer patients with early-stage
disease and predictors for recurrence after postmastectomy
radiation. Int J Radiat Oncol Biol Phys. 2003;57(2):336-344.
52. Kronowitz SJ. Delayed-immediate breast reconstruction: techni-
cal and timing considerations. Plast Reconstr Surg. 2010;125(2):
463-474.
53. Embrey M, Adams EE, Cunningham B, Peters W, Young VL, Carlo
GL. A review of the literature on the etiology of capsular contrac-
ture and a pilot study to determine the outcome of capsular con-
tracture interventions. Aesthetic Plast Surg. 1999;23(3):197-206.
54. Janis JE, Kwon RK, Attinger CE. The new reconstructive lad-
der: modifications to the traditional model. Plast Reconstr Surg.
2011;127(Suppl 1):205S-212S.
55. Buncke HJ. Microsurgery—retrospective. Clin Plast Surg. 1986;
13(2):315-318.
56. Gottlieb LJ, Krieger LM. From the reconstructive ladder to
the reconstructive elevator. Plast Reconstr Surg. 1994;93(7):
1503-1504.
57. Larson DL, Yousif NJ, Sinha RK, Latoni J, Korkos TG. A compar-
ison of pedicled and free TRAM flaps for breast reconstruction
in a single institution. Plast Reconstr Surg. 1999;104(3):674-680.
58. Man LX, Selber JC, Serletti JM. Abdominal wall following free
TRAM or DIEP flap reconstruction: a meta-analysis and critical
review. Plast Reconstr Surg. 2009;124(3):752-764.
59. Selber JC, Fosnot J, Nelson J, et al. A prospective study compar-
ing the functional impact of SIEA, DIEP, and muscle-sparing free
TRAM flaps on the abdominal wall: Part II. Bilateral reconstruc-
tion. Plast Reconstr Surg. 2010;126(5):1438-1453.
60. Selber JC, Nelson J, Fosnot J, et al. A prospective study compar-
ing the functional impact of SIEA, DIEP, and muscle-sparing free
TRAM flaps on the abdominal wall: Part I. unilateral reconstruc-
tion. Plast Reconstr Surg. 2010;126(4):1142-1153.
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PMPH_CH78.indd 628 5/22/2012 5:54:18 PM
 PART XIII

CHEST WALL, MEDIASTINUM,

TRACHEA

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PMPH_CH79.indd 630 5/22/2012 5:54:50 PM
 CHAPTER 79

Lung Cancer Staging

Joe B. Putnam, Jr.

THE NEW (2010) AMERICAN JOINT
COMMITTEE ON CANCER LUNG
CANCER STAGING SYSTEM
Staging of lung cancer or any cancer attempts to quantitatively
describe the extent of the disease process so as to compare patient
selection, results of therapy, and survival outcomes. Staging pro-
vides clinicians a shorthand description of the tumor, lymph
node, and metastatic characteristics to (1) facilitate selection of
patients for specific therapy, (2) apply optimal therapy for individ-
ual patients, and (3) evaluate outcome based on the clinical stage
and the pathologic stage.
Clinical stage is the best determination of the extent of the
disease, based on all available information, prior to the initiation
of definitive therapy. Pathologic stage is the determination of the
physical extent of the disease based on the resected specimen,
including the hilar and mediastinal lymph nodes. The choice
of therapy depends on the patient’s clinical stage of the disease
and the unique anatomic, mechanical, and biological properties
of the specific lung cancer and the specific patient. Optimal clini-
cal staging is essential for selecting optimal therapy.
Current staging models use anatomic characteristics of
the tumor or lymph nodes (Table 79.1). These characteristics
include size, location, or presence of metastatic disease. Clinically
these characteristics, although crude, are used as a surrogate for
the biological behavior of the tumor. Treatment usually based on
anatomic characteristics will yield results that are highly vari-
able. Biological characteristics including genetic mutations may

Table 79.1 TNM Descriptors

T—Primary Tumor
TX Primary tumor cannot be assessed; or tumor proven by the presence of malignant cells in sputum or bronchial washings but
not visualized by imaging or bronchoscopy
T0 No evidence of primary tumor
Tis Carcinoma in situ
T1 Tumor 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of
invasion more proximal than the lobar bronchus (e.g., not in the main bronchus)
T1a Tumor 2 cm or less in greatest dimension
T1b Tumor more than 2 cm but not more than 3 cm in greatest dimension
T2 Tumor more than 3 cm but 7 cm or less, or tumor with any of the following features (note: T2 tumors with these features
are classified as T2a if 5 cm or less):
• Invades visceral pleura (PL1 or PL2)
• Involves main bronchus, 2 cm or more distal to the carina
• Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire
lung
T2a tumor is more than 3 cm but 5 cm or less in greatest dimension
T2b tumor is more than 5 cm but 7 cm or less in greatest dimension
(Continued)

631

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 632 ■ Surgery: Evidence-Based Practice

Table 79.1 (Continued)

T—Primary Tumor
T3 Tumor more than 7 cm; or tumor that directly invades any of the following: parietal pleura (PL3), chest wall (including
superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium; or tumor in the main
bronchus less than 2 cm distal to the carina1 but without involvement of the carina; or associated atelectasis or
obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe as the primary.
T4 Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve,
esophagus, vertebral body, carina; separate tumor nodule(s) in a different ipsilateral lobe to that of the primary.a
N—Regional Lymph Nodes
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement
by direct extension
N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)
M—Distant Metastasis
M0 No distant metastasis
M1 Distant metastasis
• M1a Separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or malignant pleural or pericardial
effusion
• M1b Distant metastasis (in extrathoracic organs)
a
From Goldstraw et al.7

provide a more sensitive measure of the tumor biology but is not
in common use at this time. For now, clinical stage should be as
accurate as possible to guide selection of therapy, and pathologic
stage, to guide adjuvant therapy and decisions based on the sur-
vival associated with specific-stage disease.
The American Joint Committee on Cancer (AJCC) 5th edition
(1997) lung cancer staging model1,2 consisted of 5319 patients, who
were mostly treated at the University of Texas M. D. Anderson
Cancer Center. In that iteration, stage I was subdivided into IA
(T1 N0 M0) and IB (T2 N0 M0). Stage II was divided into IIA (T1
N1 M0) and IIB (T2 N1 M0 and T3 N0 M0). Satellite nodules (ipsi-
lateral, same lobe) were characterized as T4 and separate nodules
(ipsilateral, different lobe) as M1.
The AJCC 6th edition (2002) lung cancer staging had no
changes recommended. There was a valid need to obtain larger
patient numbers from different data sets, to evaluate survival
based on various treatment strategies (alone or in combination),
and to develop proposals for future changes in the AJCC and the
Union for International Cancer Control (UICC) lung cancer stag-
ing model. The International Association for the Study of Lung
Cancer (IASLC) embarked on its lung cancer staging project to
include all treatment and diagnostic groups, and to collect data for
analysis and reform future revisions.3 The current AJCC 7th edi-
tion lung cancer staging model reflects the impact of the IASLC
lung cancer staging project.4,5
The IASLC collected over 100,000 non-small cell lung cancer
(NSCLC) cases treated between 1990 and 2000. Each patient had
a minimum of 5 years of follow-up and all treatment modalities
were included. Over 81,000 cases were submitted and eligible for
analysis. These included 67,725 patients with NSCLC and 13,290
patients with small cell carcinoma. Survival was calculated
by the Kaplan-Meier method. Prognostic groups were created
using Cox regression analysis and results were both internally
and externally validated. Stage groupings were revised to reflect
these analyses, and they were internally and externally validat-
ed.7 Selected changes in the AJCC 7th edition are shown in Table
79.2. TNM stage groupings are shown in Table 79.3.
AJCC 7TH EDITION NSCLC TUMOR (T)
Over 18,000 patients had a T1-T4 tumor with N0 lymph node dis-
section and an R0 resection.8 A running long-rank test was per-
formed to assess cut points by tumor size. T1 was divided into T1a
(≤2 cm) and T1b (>2–3 cm). T2 was divided into T2a (>3–5 cm)
and T2b (>5–7 cm). “T2c” would have been >7 cm; however,
patients with a tumor size >7 cm had a survival that was statisti-
cally similar to survival of T3 patients. Therefore, lung cancers
>7 cm were categorized as T3. Survival curves based on tumor size
had excellent separation between each T designator (Figure 79.1).
Other T2 descriptors such as visceral pleural invasion and
partial atelectasis (less than the entire lung) could not be evalu-
ated because of small number of patients and inconsistent data. In
the AJCC 7th edition, nodules in the same lobe were categorized
as T3; nodules in a different lobe were categorized as T4; a nod-
ule in a contralateral lobe was designated as M1a unless there was
compelling evidence to suggest a management strategy for syn-
chronous primary tumors.
T3 tumors may also be characterized as a tumor with inva-
sion into the pleura, pericardium, or diaphragm; an endobronchial

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 Lung Cancer Staging ■ 633

Table 79.2 Selected Changes in the AJCC 7th Edition NSCLC Tumor (T) and Metastasis (M) Characteristics
T/M Descriptor T/M N0 N1 N2 N3
T1 (≤2 cm) T1a IA IIA IIIA IIIB
T1 (>2–3 cm) T1b IA IIA IIIA IIIB
T2 (≤5 cm) T2a IB IIA IIIA IIIB
T2 (>5–7 cm) T2b IIA IIB IIIA IIIB
T2 (>7 cm) T3 IIB IIIA IIIA IIIB
T3 invasion IIB IIIA IIIA IIIB
T4 (same lobe nodules) IIIB IIIA IIIA IIIB
T4 (extension) T4 IIIA IIIA IIIB IIIB
M1 (ipsilateral lung) IIIA IIIA IIIB IIIB
T4 (pleural effusion) M1a IV IV IV IV
M1 (contralateral lung) IV IV IV IV
M1 (distant) M1b IV IV IV IV

Table 79.3 AJCC 7th Edition TNM Stage Groupings

Occult Ca TX N0 M0
Stage 0 Tis N0 M0
Stage IA T1a/b N0 M0
Stage IB T2a N0 M0
Stage IIA T2b N0 M0
T1a/b; T2a N1 M0
Stage IIB T2b N1 M0
T3 N0 M0
Stage IIIA Any T1; T2 N2 M0
T3 N1/N2 M0
T4 N0/N1 M0
Stage IIIB T4 M0
Any T N3 M0
Stage IV Any T Any N M1a/b

tumor less than 2 cm from the carina; or an obstructing tumor
causing atelectasis of the entire lung; and as mentioned before,
two nodules in the same lobe.
T4 tumors would involve the mediastinal structures such as
the heart, great vessels, esophagus, and trachea, as well as the ver-
tebral body or the carina. Two nodules, one each in two separate
ipsilateral lobes, would also be characterized as T4.
The characteristic of pleural metastases was changed from
T4 to M1. Patients previously categorized as a clinical T4 based
on a malignant pleural eff usion, malignant pericardial eff usions,
or pleural nodules, are now categorized as clinical M1 on the basis of
poor survival, which more closely resembles patients with meta-
static disease.
AJCC 7TH EDITION NSCLC LYMPH
NODES (N)
The nodal characteristic and designations did not change in the
AJCC 7th edition.9 Over 67,000 patients had T, N, and M charac-
teristics as well as histologic type and survival. A total of 38,265
patients had cN and 28,371 patients had pN staging informa-
tion. Clinical staging studies included tests such as diagnostic
imaging, computed tomography, and mediastinoscopy. Thora-
cotomy for staging was excluded. Positron emission tomography
(PET) was not widely used internationally in this cohort during
this time. A new international lymph node map was proposed
combining the integral aspects of the Japanese/Naruke and the

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 634 ■ Surgery: Evidence-Based Practice

A m e r i c a n J o i n t C o m m i t t e e o n C a n c e r

Lung Cancer Staging 7t h E D I T I O N

Regional Lymph Nodes (N)

NX Regional lymph nodes
cannot be assessed
N0 No regional lymph
node metastases
N1 Metastasis in ipsilateral
peribronchial and/or
ipsilateral hilar lymph nodes
and intrapulmonary nodes,
including involvement
by direct extension
N2 Metastasis in ipsilateral
mediastinal and/or
subcarinal lymph node(s)
N3 Metastasis in contralateral
mediastinal, contralateral
hilar, ipsilateral or
contralateral scalene, or
supraclavicular lymph node(s)

Printe d with per mission f rom the A JCC.

ILLUSTRATION
The IASLC lymph node map shown
with the proposed amalgamation

•
of lymph into zones.

Co p y r i g h t 2 0 0 9 A m e r i c a n J o i n t Co m m i t t e e o n C a n ce r
(© Memorial Sloan-Kettering
Cancer Center, 2009.)

Financial support for AJCC 7th Edition Staging Posters

provided by the American Cancer Society

2 of 2

Figure 79.1 American Joint Committee on Cancer 7th Edition Lung Cancer Staging Regional Lymph Node Map.

North American/Mountain lymph node maps.10 Of special note,
the authors proposed radiographic regions, particularly for inte-
gration with computed tomography, to guide the radiologic stag-
ing of patients with NSCLC.
AJCC 7TH EDITION NSCLC
METASTASES (M)
Metastases were divided into M1a and M1b. Patients with metas-
tasis to the contralateral lung only were designated as M1a;
metastases to regions outside the lung/pleura were designated as
M1b. A second nodule in the nonprimary ipsilateral lobe, previ-
ously designated as M1, was changed to T4 M0. In this situation,
the patient received the “benefit of the doubt” approach as this
might represent a second primary.
COMMENTS ON THE AJCC 7TH EDITION
NSCLC STAGING
The AJCC 7th edition is based on a large international series
including centers from Europe, Japan, and North America. The
surgical foundation continues; however, other treatment catego-
ries are included and will be further refi ned. The data collected
were both internally and externally validated with training and
validation sets. External validation was assessed against the
Surveillance, Epidemiology, and End Results (SEER) program
database. The data collected were retrospective, and an audit of
the data was not performed. However, information was provided
by credible centers that facilitated data collection and analysis
of a large patient population. Future directions will most cer-
tainly include prospective data collection11 and proteomic and
genomic characteristics. Additional revisions should include
more rare cancer types, pleural malignancies such as mesothe-
lioma, different treatment strategies, and even wider geographi-
cal representation.
In general, clinical stage or pathologic stage does not dic-
tate treatment; it guides treatment. This critical statement must
be considered in application of the AJCC 7th edition NSCLC
staging system to patients. Optimal therapy depends on opti-
mal staging and the clinicians’ best efforts to achieve optimal out-
comes. A visual schematic has been created for the lymph nodes
(Figure 79.1)12 and T characteristics.13
Lung cancer clinical stage is an integral part of all patient care
and clinical trials. Clinical stage and pathologic stage is collected as
part of the Society of Thoracic Surgeons National General Thoracic
Surgery Database. Lung cancer clinical stage has been proposed
and approved by the Steering Committee of the National Quality
Forum as a Physician Level Perioperative Quality Indicator.
The AJCC 8th edition is planned for 2018. The IASLC staging
project papers are available to the public at http://www.jto.org.

PMPH_CH79.indd 634 5/22/2012 5:54:50 PM


REFERENCES
1. Mountain CF, Dresler CM. Regional lymph node classification
for lung cancer staging. Chest. 1997;111(6):1718-1723.
2. Mountain CF. Revisions in the international system for staging
lung cancer. Chest. 1997;111(6):1710-1717.
3. Goldstraw P, Crowley JJ, IASLC International Staging Project. The
international association for the study of lung cancer international
staging project on lung cancer. J Thor Oncol. 2006;1:281-286.
4. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti AI.
AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2009.
5. Lung. In: Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL,
Trotti AI, eds. AJCC Cancer Staging Manual. 7th ed. Springer;
2009:253-270.
6. Groome PA, Bolejack V, Crowley JJ, et al. The IASLC lung can-
cer staging project: validation of the proposals for revision of
the T, N, and M descriptors and consequent stage groupings in
the forthcoming (seventh) edition of the TNM classification of
malignant tumours. J Thorac Oncol. 2007;2:694-705.
7. Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Can-
cer Staging Project: proposals for the revision of the TNM stage
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Lung Cancer Staging ■ 635
groupings in the forthcoming (seventh) edition of the TNM Classi-
fication of malignant tumours. J Thorac Oncol. 2007;2(8):706-714.
8. Rami-Porta R, Ball D, Crowley J, et al. The IASLC Lung Cancer
Staging Project: proposals for the revision of the T descriptors in
the forthcoming (seventh) edition of the TNM classification for
lung cancer. J Thorac Oncol. 2007;2(7):593-602.
9. Rusch VW, Crowley J, Giroux DJ, et al. The IASLC Lung Cancer
Staging Project: proposals for the revision of the N descriptors
in the forthcoming seventh edition of the TNM classification for
lung cancer. J Thorac Oncol. 2007;2(7):603-612.
10. Rusch VW, Asamura H, Watanabe H, et al. The IASLC lung
cancer staging project: a proposal for a new international lymph
node map in the forthcoming seventh edition of the TNM clas-
sification for lung cancer. J Thorac Oncol. 2009;4(5):568-577.
11. Giroux DJ, Rami-Porta R, Chansky K, et al. The IASLC Lung
Cancer Staging Project: data elements for the prospective proj-
ect. [Review] [25 refs]. J Thorac Oncol. 2009;4(6):679-683.
12. Lung Cancer Staging. AJCC 7th Edition. 2010. http://www.
cancerstaging.org/staging/posters/lung8.5x11.pdf.
13. Rice TW, Murthy SC, Mason DP, Blackstone EH. A cancer stag-
ing primer: lung. J Thorac Cardiovasc Surg. 2010;139(4):826-829.
5/22/2012 5:54:51 PM
 CHAPTER 80
Primary Chest Wall Tumors
Adam H. Lackey, Joseph B. Levin, and Harvey I. Pass
INTRODUCTION
Primary chest wall tumors are a heterogeneous group of neo-
plasms arising from the bone, cartilage, or soft tissue of the tho-
racic cage. The differential diagnosis of these tumors is broad,
because the group encompasses a wide range of malignant and
benign diseases. In contrast to secondary chest wall tumors, which
can include local invasion from lung, breast, pleura, or even dis-
tant metastases, primary tumors originate from tissues of the
chest wall exclusively.1 Owing to their rarity and heterogeneity,
primary tumors of the chest wall present challenges in both accu-
rate diagnosis and effective treatment methods.
The most common chest wall tumors are secondary, repre-
senting invasion from underlying adjacent malignancies or dis-
tant metastases. Primary tumors are rare, with an incidence of
1% to 2% of the population and accounting for only 0.04% of all
newly diagnosed cancers.2,3 Further, they represent only 5% of
all thoracic neoplasms and less than 2% of all primary tumors.4
Approximately 50% to 80% of chest wall tumors are malignant,
with about 55% originating from bone or cartilage and 45% from
soft tissue.2,5,6 Although primary chest wall tumors are diagnosed
in every age group, they are more common at the ends of the spec-
trum, in the elderly and children/adolescents. Patients develop-
ing malignant primary chest wall tumors tend to be older than
patients with benign neoplasms.2
In most cases involving neoplasms of the chest wall, surgery is
considered the gold standard. The first case of chest wall resection
to be published was in 1778, when Airman removed an osteosar-
coma lesion from the ribs. Later, in 1820, Cittadini also reported
a case of a bony chest wall tumor resection. The first large series
was published by Parham in 1899, which described a periopera-
tive mortality rate of 30% of malignant tumors involving the bony
chest wall.7 Since that time, advancements in anesthesia, surgical
techniques, and perioperative care have dramatically reduced the
morbidity and mortality rates associated with chest wall resec-
tion and reconstruction. Today, mortality rates for the procedure
range from 2% to 7%, and most chest wall tumors are treated with
636
PMPH_CH80.indd 636
wide resection and reconstruction.8-10 There are exceptions, and
multimodality treatments involving chemotherapy and radiation
therapy have shown to be more effective than surgery alone in cer-
tain malignant primary tumors.
CLINICAL PRESENTATION
Most patients with chest wall tumors present with a palpable,
enlarging mass. Pain is the most common symptom, but many
patients can also be asymptomatic. Chest wall tumors may also be
found incidentally on routine x-ray, although this occurs in less
than 20% of all cases.11 Pain resulting from a primary neoplasm can
be attributed to local invasion into adjacent structures, which most
commonly represents bony lesions invading the periosteum. Com-
pared to lesions arising from bone, patients with soft-tissue tumors
are generally pain-free. Nearly all malignant tumors will cause
pain, but studies show that almost two-thirds of benign lesions
will also become painful as a result of musculoskeletal damage due
to growth and compression.2,5 Weakness and paresthesias are also
common symptoms among patients with chest wall tumors, result-
ing from the mass’ involvement with neurological structures, such
as the brachial plexus and spinal cord. Systemic symptoms such
as fever, malaise, fatigue, and weight loss can also be present
in patients with certain types of tumors such as Ewing’s sarcoma.
Differential diagnosis can be difficult based on the clinical
presentation of a patient with a primary chest wall neoplasm.
Owing to their rarity, pain is often attributed to musculoskeletal
conditions such as arthritis or physical trauma. This can result
in a significant amount of time between the onset of symptoms
and diagnosis. When a palpable mass is present, clinicians often
associate pain with malignancy although, as mentioned previ-
ously, the symptom does not possess high diagnostic value as both
malignant and benign lesions may cause pain. Clinical presenta-
tion assessment alone is not a reliable tool in the diagnosis of pri-
mary chest wall tumors, as there are no true signs or symptoms
that will determine if a lesion is malignant or benign.
5/22/2012 5:55:29 PM

IMAGING
Following physical examination, the diagnostic workup of a patient
presenting with a chest wall tumor should proceed to imaging stud-
ies to identify characteristic radiological features of the lesion. Chest
radiography (x-ray) is often the first imaging technique to be used
to determine the size, location, and rate of growth of the mass. In
addition, characteristic features such as calcification, ossification,
and bone involvement can be obtained. When employing chest
x-ray as a diagnostic tool, it is important to use the appropriate tech-
nique so that the desired clinical information will be ascertained.
Low-kilovoltage x-ray for bone imaging will more accurately define
calcifications and soft-tissue planes when compared with high-
kilovoltage techniques and should be used when assessing bony
involvement and tumor matrix characteristics.12 Although x-ray
should not be used as the only diagnostic study when evaluating a
chest wall mass, it can provide essential clinical data and in some
cases is the source of incidental tumor discovery.
Computed tomography (CT) is essential in the radiologi-
cal evaluation of a patient with a chest wall tumor. The technique
possesses greater sensitivity than chest x-ray, and allows for more
detailed assessment of size, location, and morphology of the lesion.
Tumor involvement with local and adjacent structures such as
pleura, mediastinum, lymph nodes, and lungs can also be visual-
ized with high quality.12,13 When intravenous contrast is used in
conjunction with CT scan, tumor angiogenesis and vascularity
can be evaluated. Owing to their sensitivity and ability to capture a
diverse set of tumor characteristics, CT scans are also used exten-
sively to evaluate response to neoadjuvant therapy and during the
postoperative period to monitor tumor recurrence.
Magnetic resonance imaging (MRI) provides high-contrast
resolution, multiplanar imaging that is currently the preferred
imaging technique to assess tumors of the chest wall. This modal-
ity is ideal for distinguishing soft-tissue planes and can provide
detailed information on tumor relationship with the vascular sys-
tem, neural invasion including the spine and epidural space, and
extension to the thoracic inlet. To obtain optimal image quality,
MRI techniques such as cardiac gating and respiratory compensa-
tion can reduce artifacts on images of anterior chest wall masses.
In addition, surface coils are employed to obtain detailed imaging
of surface chest wall neoplasms; in cases in which lesions have
greater intrathoracic extension, torso coils may be used.12
In many cases, the findings of CT and MRI imaging can deter-
mine if a chest wall lesion is benign or malignant based on charac-
teristic radiographic features. The presence of a well-defined mass
lacking extension into adjacent structures, bone erosion rather than
destruction, and slow growth over a period of time are all indicative
of a benign lesion. Malignant processes, while in many cases pos-
sessing a nonspecific imaging profile, often present as large, poorly
marginated masses that infiltrate surrounding tissues. In addition,
these masses generally have low density necrotic areas and local bony
destruction.14 There are times when tumor characteristics, in both
benign and malignant lesions, can suggest a tissue of origin based
on imaging. Most chest wall masses, however, will require tissue
excision with histological analysis to confirm a diagnosis.
More recently, practitioners have turned to the use of positron
emission technology (PET) to improve the diagnostic capability of
CT scans. Although further studies are needed to evaluate the effi-
cacy of PET/CT in the diagnosis of chest wall lesions specifically,
there are data that illustrate superior abilities of PET and PET/CT
PMPH_CH80.indd 637
Primary Chest Wall Tumors ■ 637
in detecting, staging, restaging, and evaluating treatment response
in primary bone and soft-tissue sarcomas when compared with CT
alone.2,15-18 Other studies, however, recognize the limits of PET in
malignancy detection and staging, recommending that PET should
not replace CT/MRI for diagnosis or staging, but can help confirm
malignancy when the findings of conventional imaging methods
are equivocal.19
TECHNIQUES OF BIOPSY FOR
TISSUE DIAGNOSIS
In a patient presenting for evaluation for a chest wall mass, tis-
sue diagnosis is of paramount importance as this will allow fur-
ther decisions regarding imaging choices and further treatment.
The techniques of biopsy range from simple core needle biopsy or
fine needle aspiration done in the office under local sedation to
ultrasound-guided and CT-guided needle biopsies. The particular
technique used varies from patient to patient, and largely depends
on whether or not the mass is palpable and easily discernable from
underlying structures. In selected cases in which it is unclear if
the mass arises from the lung or intrathoracic structures versus
the actual chest wall, a video-assisted thoracic approach may be
more appropriate and may be done through one thoracoscopic
port.20 In all instances in which a thoracic mass is biopsied with
percutaneous techniques, the patient should be counseled that this
approach does raise the potential risk of recurrence along the nee-
dle track. Prior to any biopsy, the patient should be counseled about
the potential risk, and the approach should be oriented so that the
entire site can be removed en bloc at a later date if necessary.
Given the relative rarity of primary chest wall neoplasms,
immunohistochemical techniques may need to be employed to
determine the exact cell line from which the tumor arises. Although
almost all patients with primary chest wall neoplasms will have
surgical management of their disease, proper identification of the
tumor will allow tailoring of the surgical and chemotherapeutic
approach to the tumor, as well as allow identification of the patients
that are appropriate for neoadjuvant techniques.
TYPES OF PRIMARY CHEST WALL TUMORS
A variety of primary chest wall tumors, both malignant and benign,
can arise from various tissues of the thoracic cage. Table 80.1,
although not inclusive, lists some of the more common primary
chest wall lesions with respective appropriate treatments. Approxi-
mately 55% of primary chest wall tumors will arise from bone
or cartilage. The most common benign bony tumors are fibrous
dysplasia (30–50%), osteochondroma (30–50%), and chondroma
(10–25%).3 Of the malignant bony lesions, chondrosarcoma, Ewing’s
sarcoma, osteosarcoma, and solitary plasmacytoma are most fre-
quently observed. Primary tumors may also arise from soft tissue of
the thorax, accounting for approximately 45% of all primary chest
wall neoplasms. Common benign soft-tissue tumors are lipoma,
desmoid, giant cell tumors, and Schwannoma. Soft-tissue sarcomas
are the most frequent soft-tissue malignancies of the chest wall,
accounting for 45% of all primary malignant chest tumors.6 This
group includes malignant fibrous histiocytoma, synovial sarcomas,
rhabdomyosarcoma, and fibrosarcoma. Other sarcomas, such as
leiomyosarcoma and neuroblastomas, are uncommon in the chest.
5/22/2012 5:55:30 PM
 638 ■ Surgery: Evidence-Based Practice

Table 80.1 Types of Primary Chest Wall Tumors

Tumor (Benign) Cell Type Features Treatment
Fibrous dysplasia Osteoblast Usually monostotic Resection if painful
Osteochondroma Osteoblast Frequently ostochondral junction Wide resection if symptomatic
Chondroma Chondrocyte Well-defined osteolytic lesion Wide resection (cannot differentiate from
chondrosarcoma)
Langerhans cell Langerhans cell Systemic symptoms (fever, malaise) Excisional if single lesion, systemic treatment
histiocytosis if multiple
Osteoid osteoma Osteoblast Dull pain, more severe at night Radiofrequency ablation
Osteoblastoma Osteoblast Pain most common symptom, not Complete resection if locally aggressive
worse at night
Giant cell tumor Giant cell Stromal “Soap bubble” appearance on Excision vs. radiation, radiation may cause
cells chest-ray degeneration to malignant
Lipoma Lipomatous cells May be intra- and extra thoracic Resection if large or disfiguring
Lipoblastoma Embryonal fat cells Exclusively in infants and children Wide resection
Desmoid tumor Connective Tissue Can grow intrathoracic Surgical resection with negative margins
Schwannoma Schwann cells Extremely painful when biopsied Surgical resection when possible
Tumor (Malignant) Cell Type Features Treatment
Chondrosarcoma Chondrocytes Bone destruction, irregular Resection, adjuvant radiotherapy
contours, intratumoral
mineralization
Osteosarcoma Osteoblasts “Sunburst” pattern on chest x-ray Wide surgical resection, adjuvant
chemotherapy
Ewing’s sarcoma Round cell type “Onion peel” on chest x-ray Neoadjuvant chemotherapy, wide resection,
possible adjuvant radiation
Soft tissue sarcoma Mesoderm Painless mass Wide surgical resection, >5-cm margins
Solitary plasmacystoma Plasmacytes Lytic lesion with cortical thinning Radiation therapy is primary treatment
on chest x-ray

The location of a neoplasm can often aid in the diagnosis of
a tumor, as many primary chest wall tumors are common to a
particular structure. Rib lesions comprise 50% of bony malignant
tumors and a majority of benign bony tumors of the chest wall.3
They can be derived from bone, cartilage, bone marrow, vascu-
lar, or neural structures. The most common benign primary chest
wall tumors occurring in the rib are fibrous dysplasia (usually
limited to one rib) and chondroma. Chondrosarcoma and osteo-
sarcoma are the malignant rib lesions with the highest incidence;
however, Ewing’s sarcoma is the most common rib malignancy
among pediatric patients.3 Tumors located in the sternum are usu-
ally malignant, the most common types being osteosarcoma and
chondrosarcoma. Primary scapular tumors make up to 30% of all
malignant bony chest wall lesions and are a common site for the
rare, benign soft-tissue neoplasm elastofibroma dorsi.3 Bony lesions
can also occur in the clavicle, but this is relatively uncommon.
treatment may be withheld unless a patient experiences pain or
discomfort due to an enlarging mass, such is the case with fibrous
dysplasia, osteochondroma, and lipoma. In other tumor types,
combination chemoradiation therapy or ablation techniques have
proven to be more effective than surgery alone. When the primary
tumor is an Ewing’s sarcoma, or locally invasive breast or lung
cancer, neoadjuvant therapy may be indicated prior to definitive
resection, and the approach should be multidisciplinary.4 Soli-
tary plasmacytoma is treated solely with radiation. Of the benign
tumor types, osteoid osteoma is treated with radiofrequency
ablation and rarely requires surgical resection. Although the role
of chemotherapy and radiation has been established in certain
tumor types, further study is necessary to describe the benefits in
others such as soft-tissue sarcomas.1-3
CONSIDERATIONS PRIOR TO RESECTION

TREATMENT
Most benign and malignant chest wall tumors are treated with
surgical resection due to the propensity for local invasion, recur-
rence, or resistance to chemotherapy. In certain benign types,
Prior to undergoing resection for a chest wall mass, all patients
should undergo workup for metastatic disease if the initial mass
is malignant. Patients who have extrathoracic spread of malig-
nant neoplasms are not appropriate for resection for curative
intent, but resection may be indicated for palliation (i.e., in the

PMPH_CH80.indd 638 5/22/2012 5:55:30 PM


case of a painful or fungating lesion).21 In such cases, if the pri-
mary lesion is radiosensitive, consideration for radiation therapy
should be part of the treatment plan as this may provide local
control of symptoms without the morbidity of a chest wall resec-
tion. In prepubertal females, if the lesion is proven benign and
resection may impinge on the breast bud, consideration should
be given to deferring defi nitive treatment until after breast devel-
opment in order to preserve symmetry. Finally, as with any
large resectional therapy, careful attention should be paid to the
patient’s nutritional status in the pre-, peri-, and postoperative
period and aggressive efforts should be undertaken to correct
any nutritional deficit.
TECHNICAL CONSIDERATIONS
OF RESECTION
The margin of resection depends on the type of tumor encoun-
tered. For benign tumors, grossly negative margins are adequate,
unless the tissue type of the tumor is prone to recurrence. In those
cases, a 2-cm margin of histologically negative tissue should be
the goal. Th is is also an appropriate margin for metastatic tumors
and locally invasive breast and lung cancer, although a histologi-
cally R0 resection is more important for survival, and frozen sec-
tions should be obtained if there is any doubt to the completeness
of the resection.22 Desmoid tumors may be the exception to this
rule as their high rate of recurrence may mandate a more gener-
ous resectional margin.23 Primary malignant tumors of the chest
should be resected with generous margins, with the primary
concern being the prevention of locally recurrent disease. Patho-
logically clear margins continue to be the ultimate goal, and
some studies have shown that this is more important than the
number of ribs resected or empiric margins.23 Other studies have
shown a 5-year survival benefit to resection with 4-cm versus
2-cm margins; correspondingly, for primary malignant tumors
of the chest a 4-cm margin is preferred.24,25 The entirety of any
directly involved rib should be resected, along with partial resec-
tion of adjacent ribs to accomplish control with margins noted
above. Any structures attached directly to the tumor should be
excised.24 Any directly involved lung should be resected en bloc
as an R0 resection is the goal. However, the surgeon should be
aware that resection of lung has been shown to increase morbid-
ity and mortality, especially concordant chest wall resection and
pneumonectomy.26
Table 80.2 Local Musculocutaneous Flaps in the Thorax
Flap Vascular Supply
Latissiumus dorsi Thoracodorsal artery
Pectoralis major Thoracoacromial artery
Rectus abdominis Epigastric artery
Serratus anterior Serratus artery (Thoracodorsal)
External oblique Posterior intercostal arteries
Other
Pedicled omental flap Gastroepiploic arteries
Free flaps Varied
PMPH_CH80.indd 639
Primary Chest Wall Tumors ■ 639
WHEN TO RECONSTRUCT THE BONY
THORAX AFTER RESECTION
The decision to reconstruct the bony thorax is a point of contro-
versy and depends to some extent on the location of the resection
and patient preference. As a general rule, resections of two ribs or
less can be constructed with local techniques and tissue transpo-
sition. Many authors agree that segmental resection of three ribs
or less does not require reconstruction of the bony thorax and that
defects of less than 5 cm may be treated similarly, although such
resections may be reconstructed for cosmetic reasons, especially
when anterior. Resections of four or more ribs are generally rec-
ommended to be reconstructed, although there is some debate on
this subject. As a general rule, the more compromised the patient’s
underlying pulmonary function, the more aggressive an approach
should be taken to stabilize the thorax, as this will optimize post-
operative lung function and pulmonary reserve. Resections that
encompass the posterior aspect of the first four ribs do not need to
be reconstructed. Alternately, posterior resections that are more
inferior should be evaluated for the risk of entrapping the scapular
tip and reconstructed if this is a possibility.
METHODS OF CHEST WALL
RECONSTRUCTION
Muscle flaps are an attractive option for chest wall reconstruction
as they are derived from the patient’s own tissue, are well vascular-
ized, and can be used to fill space left from the resection. Depend-
ing on the particular flap used, skin and subcutaneous tissues can
be harvested with the flap, aiding in reconstruction (Table 80.2).
Appropriate drainage of the spaces created by muscle flap transfer
is paramount to avoid postoperative seroma and poor flap apposi-
tion to the graft site.
When rigid stabilization of the chest is required, several opt-
ions are available. Using methylmethacrylate sandwiched between
polyproylene mesh has been well described for reconstruction of
large chest wall defects, including situations in which part of the
entire sternum has been resected. This technique has the benefit
of being versatile and uses a replacement for the chest wall that
is initially malleable into almost any configuration in the oper-
ating room before the methylmethacrylate hardens into its final
shape. This technique requires either local tissue advancement
techniques to cover the prosthetic or coverage with local or free
Territory Covered
Entire ipsilateral chest wall
Anterior chest
Anterior and anteriolateral
Lateral
Lateral and inferior anterior
Limited by length only
Limited by arterial supply
5/22/2012 5:55:30 PM
 640 ■ Surgery: Evidence-Based Practice
flaps and a skin graft for final coverage. As this is a foreign body,
it should not be used in situations where there is active infection
or questions about the sterility of the operative field (i.e. resection
of an open, fungating chest lesion) exists. Postoperative studies of
functional outcomes and patient satisfaction have shown this to
be a very effective, durable repair for patients undergoing chest
wall resection and reconstruction.8
Placement of titanium struts to bridge the bony gap has also
been described. This technique offers excellent stability due to
the rigidity of the metal used. Mesh can be attached to the tita-
nium struts for improved cosmetic result and stability between
the struts. Because the titanium struts are not as occlusive as the
methylmethacrylate sandwich, fluid egress from the operative site
may be improved. This technique, much like the methylmethacry-
late method described above, represents placement of a foreign
substance into the body, and should be used with caution in situ-
ations where infection is suspected. Outcomes following titanium
strut reconstruction of the thorax appear to be similarly excellent
from a functional standpoint.27
In patients in whom concerns for infection exist, other tech-
niques must be used to avoid infection of the material used to
reconstruct the chest. A potential solution to this is now possible
with the advent of bioprosthetic materials that can be placed into
infected spaces with less concern of infection of the prosthetic.
The currently available bioprosthetics do not have the strength of
the rigid prosthesis discussed previously, but do have the benefit of
being somewhat more resistant to infection.27 In particular, using
these techniques may allow for staged repairs in which infected tis-
sue is removed and formal resection is undertaken at a later time.
In current incarnation, given the lack of rigidity of the available
bioprosthetics, the use of these materials for resection of large chest
wall defects has not been studied in large patient series.
A definitive list of all available materials that can be used to
reconstruct the bony thorax is large and evolving, limited only
by the imagination of the surgeons reconstructing the chest and
the biomedical companies developing the products. In any chest
reconstruction scenario, the two goals of restoration of function
in the setting of adequate cosmetic result are paramount, and the
techniques available for reconstruction are often used in a comple-
mentary fashion to achieve both of these goals for the patient. The
ideal materials and methods for chest wall reconstruction have not
been found, and as more experience is being obtained with this
clinical situation, the standards of care will continue to evolve.
MANAGEMENT OF THE POSTRESECTION
PLEURAL SPACE
Following resection of a chest wall neoplasm, consideration must
be given to management of the pleural space. Any residual blood
or fluid should be evacuated from the pleural space as the chest is
closed, and the lung should be fully expanded. This is a separate con-
sideration from the drainage systems employed to prevent seroma
formation under the flaps and grafts that are employed to close
the chest wall defect. In any case of chest wall resection in which
the pleural is violated, a closed suction drainage system should be
employed. In cases where lung has been resected or inadvertently
damaged during the resection, the closed drainage system allows
for management of any resultant air leaks. The particular drainage
system used can be at the discretion of the operating surgeon, but
PMPH_CH80.indd 640
should accomplish the dual goals of complete inflation of the lung
with full apposition of the parietal and visceral pleura, manage-
ment of any air leaks, and complete drainage of any postoperative
fluid draining into the pleural space. In the event that the lung is
not able to fill the entire thoracic cavity after resection, pedicled
muscle flap or omental transposition into the intrathoracic cavity
should be undertaken to obliterate any space expected to remain
after chest wall reconstruction. This will help prevent postopera-
tive accumulation of fluid into the space, assist in healing any air
leaks from the lung parenchyma, and avoid infection of the space.
PERI- AND POSTOPERATIVE CARE
The most common postoperative complications following chest
wall resection are pulmonary in nature, and significant effort
should be used to minimize this risk.9-10 An attempt should be
made to extubate the patient in the operating room or as soon
after the operation as possible. The concept of delayed extubation
for concerns of chest wall stability reflects a poor operative sta-
bilization, and it is highly unlikely that any additional stability
would be generated in the first few days postoperatively. Standard
approaches to improving pulmonary function postoperatively
should be undertaken aggressively, such as incentive spirometry,
early ambulation, and aggressive pain control. Thoracic epidural
catheters should be used judiciously to this end. Risk stratification
and appropriate treatment for perioperative β-blockade and deep
vein thrombosis (DVT) prophylaxis is appropriate in all patients.
COMPLICATIONS OF CHEST
WALL RESECTION
Chest wall resection for primary chest wall tumors yields good
oncologic results and adequate patient satisfaction in most patients.
The most common complication in the postoperative period is usu-
ally respiratory in nature in most patients. In a review of 197 patients
from the Mayo Clinic undergoing chest wall resection, postoperative
respiratory complications were noted in 24.4% of the patients, and
were the proximate cause of death in three patients.10 Similarly, in
a review of 200 patients over 25 years of chest wall resection,
Mansour et al. noted that 20% of patients developed a respiratory
complication (14% pneumonia, 6% acute respiratory distress syn-
drome [ARDS]).9 In this study, although the rate of pneumonia
was observed to be higher in the patients undergoing concomitant
lung and chest wall resection, mortality and intensive care unit
(ICU) length of stay did not differ between the two groups.
Prolonged air leak is uncommon outside the setting of con-
current lung and chest wall resection. Other complications par-
ticular to chest wall resection and reconstruction include seroma
due to the large potential spaces created during reconstruction,
flap or graft failure, and donor site complications such as hernias
for muscle flaps or large wounds in the setting of skin grafts.
FOLLOW-UP POSTRESECTION
All patients should be followed as dictated by their underlying
oncologic diagnosis. A postoperative visit should be scheduled on
discharge for evaluation of wound healing and seroma formation.
5/22/2012 5:55:30 PM

This is typically 10 to 14 days postdischarge, but may be sooner
for patients who have a wound issue or are discharged with active
wound care such as negative pressure wound therapy. A repeat CT
of the chest should be obtained in all patients once the inflamma-
tory response has subsided (typically 3–6 months) to define a new
baseline for chest anatomy.
In the initial postoperative period, recurrent masses at the
resection site will most likely be seromas or other fluid collections.
However, depending on the type of reconstruction used, a change
in chest contour may represent a failure of the rigid prosthesis.
If the diagnosis of seroma is not immediately and definitively
evident on clinical examination, a CT scan should be obtained
to further delineate the problem. After the initial postoperative
period has passed, changes in the chest wall contour may repre-
sent recurrence of the underlying malignancy and will require a
CT scan and biopsy if a solid mass is found. The role of PET scan
in this situation is unclear as the operative site will be PET avid as
long as there is ongoing tissue inflammation, which may be pro-
longed as the body incorporates prosthetic material.
Patients who have stable pulmonary function do not need any
specific follow-up of their chest wall reconstruction. Serial pul-
monary function tests are not indicated. In patients who present
with decreased pulmonary function, especially acutely, failure of
the rigid prosthesis or accumulation of fluid in the pleural space
should be suspected. While chest x-ray may be helpful, this situa-
tion will likely require CT scan to fully delineate the diagnosis.
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2. Shah AA, D’Amico TA. Primary chest wall tumors. J Am Coll Surg.
2010;210:360-366.
3. Smith SE, Keshavjee S. Primary chest wall tumors. Thorac Surg
Clin. 2010;20:495-507.
4. Incarbone M, Pastorino U. Surgical treatment of chest wall tumors.
World J Surg. 2001;25:218-230.
5. Hsu PK, Hsu HS, Lee HC, et al. Management of primary chest
wall tumors: 14 years’ clinical experience. J Chin Med Assoc. 2006;
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6. Burt M. Primary malignant tumors of the chest wall. The Memo-
rial Sloan-Kettering Cancer Center experience. Chest Surg Clin
N Am. 1994;4:137-154.
7. Parham FW. Thoracic resecion for tumors growing from the bony
wall of the chest. Trans South Surg Gynecol Assoc. 1898;11:223-363.
8. Weyant MJ, Bains MS, Venkatraman E, et al. Results of chest wall
resection and reconstruction with and without rigid prosthesis.
Ann Thorac Surg. 2006;81:279-285.
9. Mansour KA, Thourani VH, Losken A, et al. Chest wall resections
and reconstruction: a 25-year experience. Ann Thorac Surg. 2002;
73:1720-1725; discussion 5-6.
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10. Deschamps C, Tirnaksiz BM, Darbandi R, et al. Early and long-
term results of prosthetic chest wall reconstruction. J Thorac Cardi-
ovasc Surg. 1999;117:588-591; discussion 91-92.
11. Sabanathan S, Salama FD, Morgan WE, Harvey JA. Primary
chest wall tumors. Ann Thorac Surg. 1985;39:4-15.
12. Tateishi U, Gladish GW, Kusumoto M, et al. Chest wall tumors:
radiologic findings and pathologic correlation: part 1. Benign
tumors. Radiographics. 2003;23:1477-1490.
13. Tateishi U, Gladish GW, Kusumoto M, et al. Chest wall tumors:
radiologic findings and pathologic correlation: part 2. Malignant
tumors. Radiographics. 2003;23:1491-1508.
14. Schaefer PS, Burton BS. Radiographic evaluation of chest-wall
lesions. Surg Clin North Am. 1989;69:911-945.
15. Volker T, Denecke T, Steffen I, et al. Positron emission tomogra-
phy for staging of pediatric sarcoma patients: results of a prospec-
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16. Tateishi U, Hosono A, Makimoto A, et al. Comparative study of
FDG PET/CT and conventional imaging in the staging of rhab-
domyosarcoma. Ann Nucl Med. 2009;23:155-161.
17. Piperkova E, Mikhaeil M, Mousavi A, et al. Impact of PET and CT
in PET/CT studies for staging and evaluating treatment response in
bone and soft tissue sarcomas. Clin Nucl Med. 2009;34:146-150.
18. Petermann D, Allenbach G, Schmidt S, et al. Value of positron
emission tomography in full-thickness chest wall resections for
malignancies. Interact Cardiovasc Thorac Surg. 2009;9:406-410.
19. Schuetze SM. Utility of positron emission tomography in sarco-
mas. Curr Opin Oncol. 2006;18:369-373.
20. McDonald JM, Freeman RK. Thoracoscopic localization of non-
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21. Warzelhan J, Stoelben E, Imdahl A, Hasse J. Results in surgery
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5/22/2012 5:55:30 PM
 CHAPTER 81
Tracheostomy: Timing and
Techniques
Matthew O. Dolich
INTRODUCTION
Tracheostomy is one of the most commonly performed proce-
dures in the intensive care unit (ICU), and it is estimated that
as many as 10% of patients who require mechanical ventilation
for 3 or more days will undergo this procedure.1 Tracheostomy
provides a stable airway in patients who require prolonged
mechanical ventilation. It provides relatively easy access to the
lower airways for suctioning of tracheobronchial secretions,
and may help protect the oropharynx and larynx from dam-
age related to prolonged translaryngeal intubation via either the
orotracheal or nasotracheal routes. Reduced work of breathing,
enhanced patient comfort, lower sedation requirements, more
rapid weaning from mechanical ventilation, diminished risk
of ventilator-associated pneumonia, and shorter length of stay
in the hospital or ICU have all been proposed as benefits of
transitioning from translaryngeal intubation to tracheostomy.
Despite descriptions of tracheostomy performed thousands of
years ago—and common performance for almost a century—
considerable controversy persists regarding selection of appro-
priate candidates for the procedure, as well as timing and
techniques. Th is chapter will review the literature regarding
these issues and will provide recommendations based on the
available evidence.
1. What is the optimal timing of tracheostomy?
Considerable debate has persisted regarding the appropriate tim-
ing of tracheostomy in patients requiring mechanical ventila-
tion. Advocates of early tracheostomy cite improved patient
comfort, reduced complications from prolonged translaryngeal
intubation, better pulmonary toilet, and improved ability to
communicate. However, the procedure itself is not without risk,
and routine performance of early tracheostomy incurs the pos-
sibility of per forming unnecessary procedures in patients who
might have otherwise been extubatable if given more time for
recovery. In addition, early tracheostomy incurs extra cost, risk,
642
PMPH_CH81.indd 642
and pain in patients unlikely to survive more than a few days in
the ICU, and is therefore undesirable in that subpopulation of
patients requiring an artificial airway.
In a recent prospective, randomized, multicenter trial of 600
patients, Terragni and colleagues2 examined the effect of early
tracheostomy (after 6–8 days of translaryngeal intubation) ver-
sus late tracheostomy (after 13–15 days of translaryngeal intuba-
tion) in reducing the incidence of pneumonia. Although there
were statistically significant reductions in ICU days and days
on mechanical ventilation in the early tracheostomy group,
long-term outcomes did not differ and there was no differ-
ence in the rate of ventilator-associated pneumonia. Given that
39% of the patients in each group experienced a tracheostomy-
related adverse event, the authors concluded that tracheostomy
should not be performed prior to 13 to 15 days of translaryngeal
intubation.
Sugerman and colleagues, 3 in a prospective study of 127
patients randomized to either early tracheostomy (days 3–5) or pro-
longed translaryngeal intubation, found no difference in mortality
rate, ICU length of stay, or pneumonia. However, this study was
notable for its limitations, including physician bias and randomi-
zation issues.
In another randomized, prospective, multicenter trial, Blot
and colleagues4 compared outcomes in patients undergoing early
tracheostomy (within 4 days) or prolonged translaryngeal intuba-
tion. Interim analysis after enrollment of 123 patients revealed no
differences in 28-day or 60-day mortality, duration of mechanical
ventilation, incidence of pneumonia, or other infectious compli-
cations. Tracheostomy appeared to afford greater patient comfort,
though this was not objectively evaluated in the study.
Zagli and colleagues5 retrospectively analyzed their experi-
ence with 506 percutaneous tracheostomies performed at a single
institution. They found no difference in mortality, pneumonia
incidence, or hospital length of stay in patients undergoing early
(1.9 +/− 0.9 days) versus late (6.8 +/− 3.8 days) tracheostomy. How-
ever, duration of mechanical ventilation and ICU length of stay
were significantly shorter in the group of patients who underwent
5/22/2012 5:56:04 PM

early tracheostomy (13.3 vs. 16.7 days and 16.9 vs. 20.8 days, res-
pectively; P < .0001).
In the systematic review and meta-analysis of randomized
and quasi-randomized controlled studies, Griffiths 6 found that
early tracheostomy (defi ned as within the fi rst week of mechani-
cal ventilation) did not alter the risk of either mortality or pneu-
monia. However, early tracheostomy did significantly reduce
the duration of mechanical ventilation (−8.5 days, 95% confi-
dence interval −15.3 to −1.7) and ICU length of stay (−15.3 days,
−24.6 to −6.1). In another meta-analysis of trauma patients by
Dunham,7 the authors found that early tracheostomy had no
influence on mortality, pneumonia, or rates of laryngotracheal
injury.
Recommendation: Early tracheostomy does not appear to
influence mortality or incidence of pneumonia (Grade B). Con-
flicting evidence exists regarding any beneficial effect of early
tracheostomy on ICU length of stay and duration of mechani-
cal ventilation. Considerable variation exists in the defi nition of
“early” tracheostomy (1–7 days).
2. What patient populations benefit from tracheostomy?
Despite several intuitive physiologic benefits from tracheostomy,
active debate continues regarding patient selection for perfor-
mance of this procedure. Indeed, many of the recommendations
regarding tracheostomy are based on expert opinion or consensus
statements, rather than on credible evidence. The primary reason
for this relates to treatment selection bias confounding many of
the prospective studies of the relationship between tracheostomy
and outcome.
In an attempt to control for this type of physician bias, Clec’h
and colleagues8 utilized propensity scoring in a multicenter, pro-
spective, observational cohort study of 2186 unselected medi-
cal and surgical patients requiring mechanical ventilation for
more than 48 hours. Two different models of propensity scores
were created using multivariate logistic regression. One hundred
seventy-seven (8.1%) received a tracheostomy. In both propensity
score models, tracheostomy did not improve ICU survival, and
there was no difference in survival whether tracheostomy was
performed early (within 7 days) or late (after 7 days). In fact, tra-
cheostomy was associated with increased post-ICU mortality in
patients who were not decannulated on discharge from the ICU
(odds ratio 3.73– 4.63, P = .003–.008).
In a single-center, prospective, randomized study, Barquist9
studied adult trauma patients both with and without brain injury.
Patients requiring tracheostomy for facial trauma or neck inju-
ries were excluded, and patients were randomized to early (before
day 8) or late (after day 28) tracheostomy. The study was halted
after enrollment of 60 patients when interim analysis revealed no
differences in duration of ventilatory support, ICU length of stay,
pneumonia rate, or mortality.
Although many practitioners recommend tracheostomy for
patients with severe traumatic brain injuries (TBIs), surprisingly
little data exist to support this practice. Ahmed10 performed a ret-
rospective review of 55 patients with severe TBI who underwent
early (within 1 week) or late (after 1 week) tracheostomy. Early
tracheostomy was beneficial with regard to ICU length of stay
(19.0 +/− 7.7 days vs. 25.8 +/− 11.8 days, P = .008). However, no
differences were noted in hospital length of stay, pneumonia, or
mortality.
PMPH_CH81.indd 643
Tracheostomy: Timing and Techniques ■ 643
In a prospective, randomized study, Bouderka11 evaluated
trauma patients with isolated head injury and Glasgow Coma
Scale (GCS) score < 8. Patients were randomized on day 5 to
receive a tracheostomy within the next 24 hours, or prolonged
translaryngeal intubation. Although there was no difference in
mortality or rate of pneumonia, early tracheostomy was associated
with shorter duration of mechanical ventilation (14.5 +/− 7.3 days
vs. 17.5 +/− 10.6 days, P = .02). An additional benefit was noted
in the subgroup of patients who developed pneumonia, in that
the duration of mechanical ventilation was significantly shorter
after diagnosis of pneumonia (6.0 +/− 4.7 days vs. 11.7 +/− 6.7
days, P = .01).
Goettler et al.12 utilized multivariate logistic regression to
determine predictors for the need for tracheostomy in adult
trauma patients. They retrospectively reviewed 992 patients, 430
of who underwent tracheostomy. Injury severity score (ISS), age,
and pulmonary/neurologic risk factors were found to correlate
with the need for tracheostomy. Specifically, they found > 90%
risk of requiring tracheostomy in patients of any age with ISS
> 54, patients > 40 years old with ISS > 40, patients > 55 years old
with GCS = 3 after 24 hours, patients > 40 years old with paralysis
at any level, and patients > 55 years old with bilateral pulmonary
contusions.
Recommendation: In unselected patients, tracheostomy does
not appear to affect mortality (Grade C). Tracheostomy may offer
modest benefits in patients with brain injury in terms of duration
of mechanical ventilation and ICU length of stay (Grade C).
3. Is open or percutaneous tracheostomy preferable?
Tracheostomy was popularized by Jackson almost a century ago,
and for decades the procedure was typically performed in the
operating room. Though many tracheostomies are still performed
in this setting, improvements in ICU care and monitoring have
increasingly allowed performance at the bedside in the ICU.
Bedside tracheostomy avoids the time, cost, and risks associated
with transfer to the operating room. In 1985, Ciaglia13 described
bedside percutaneous dilatational tracheostomy as an alternative
to the traditional open technique. Although several variations
exist, the procedure is generally performed by insertion of a nee-
dle into the trachea, followed by a flexible guidewire. Dilatation
is achieved by passage of a series of plastic dilators of increasing
diameter, or by a single large conical dilator (Blue RhinoTM tech-
nique). After dilatation, a cuffed tracheostomy tube is inserted
over the guidewire using modified Seldinger technique. The pro-
cedure may be performed with or without bronchoscopic guid-
ance. Percutaneous bedside tracheostomy has enjoyed increasing
popularity due to its relatively short learning curve, low compli-
cation rate, and short procedure time.
In a recent retrospective review of 1000 bedside percutane-
ous tracheostomies, Kornblith and colleagues14 observed a very
low complication rate in both low-risk (1.2%) and high-risk (1.7%)
patients. There was only one procedure failure (0.1%) requiring
cricothyroidotomy, and there were no deaths related to perfor-
mance of tracheostomy. The authors concluded that based on
the safety of the procedure, bedside percutaneous tracheostomy
should be considered the gold standard.
Silvester and colleagues15 prospectively analyzed perioperative
and long-term complications in patients randomly assigned to per-
cutaneous or open surgical tracheostomy. The overall procedural
5/22/2012 5:56:04 PM
 644 ■ Surgery: Evidence-Based Practice
complication rate was low (3.5%), and there were no significant
differences in short- or long-term complications between the two
groups. The authors concluded that both procedures were safe and
equivalent.
In another prospective randomized study, Wu et al.16 found
no difference in complication rates between percutaneous and
open tracheostomy, but did observe significantly shorter proce-
dure times in the percutaneous group (22.0 +/− 12.1 minutes vs.
41.5 +/− 5.9 minutes, P < .001).
In a meta-analysis of open versus percutaneous tracheostomy,
Higgins and Punthakee17 reviewed 15 prospective randomized
controlled trials and found no significant difference in compli-
cation rates between open and percutaneous techniques. Case
length was shorter by almost 5 minutes (not including time for
transport) for percutaneous tracheostomy, and costs were lower
by US$456. In another systematic review and meta-analysis of
randomized controlled trials, Delaney et al.18 found a decreased
rate of wound infection favoring percutaneous tracheostomy
(OR = 0.28; 95% CI 0.16–0.49; P < .0005). Early and late complica-
tions were otherwise equivalent between the two groups.
Recommendation: Both open and percutaneous tracheo-
stomy may be performed safely with low complication rates, and
both short- and long-term complication rates are roughly equiva-
lent (Grade A). Percutaneous tracheostomy appears to have advan-
tages with regard to both cost and time efficiency.
4. Is bronchoscopic guidance necessary to perform percutane-
ous tracheostomy safely?
Percutaneous tracheostomy may be performed with bronchoscopic
visualization via the endotracheal tube, or may be performed
“blind” without fiberoptic visualization. Proposed advantages of
bronchoscopic guidance include avoidance of posterior tracheal
injury, avoidance of endotracheal tube puncture, minimizing risk
of premature extubation, and decreasing risk of paratracheal inser-
tion. However, bronchoscopy does add additional cost, and it may
result in hypercarbia in patients with smaller caliber endotracheal
tubes. In addition, operative times may be marginally increased,
and costly damage to the bronchoscope may be incurred by inad-
vertent needle puncture.
In a retrospective review of 183 patients, Tomsic et al.19 ana-
lyzed complications felt to have been correctable by utilization
of bronchoscopic guidance. These included needle puncture of
the endotracheal tube (2.2%), passage of the guidewire through
the Murphy eye of the endotracheal tube (1.6%), and injury of the
posterior trachea (1.1%). Although the overall complication rate
was low, the findings prompted the authors to adopt routine use
of bronchoscopic guidance for all percutaneous tracheostomies at
their institution.
In another retrospective study, Paran and colleagues20 rev-
iewed their experience with blind percutaneous tracheostomy
in 61 patients. Three procedures were aborted due to anatomical
problems, and one patient required operative revision secondary
to bleeding. There were no other procedure-related complications,
and the authors deemed blind insertion a safe practice.
Capnography has been evaluated as an alternative to bron-
choscopy for confirmation of endotracheal needle position prior
to guidewire insertion. In a small prospective study, Mallick
et al. 21 found no difference in operative times or complication
rates in patients undergoing tracheostomy with capnographic
PMPH_CH81.indd 644
confirmation of needle placement as compared with broncho-
scopic guidance. In two cases where bronchoscopic guidance was
utilized, the bronchoscope was damaged by needle puncture and
required repair.
Recommendation: On the basis of limited data, percutane-
ous tracheostomy may be safely performed without bronchoscopic
guidance (Grade C). When bronchoscopic guidance is utilized,
care should be taken to avoid needle puncture of the broncho-
scope and subsequent costly repairs.
5. Is routine chest x-ray necessary after performance of open or
percutaneous tracheostomy?
Because performance of a tracheostomy may be associated with
immediate complications such as bleeding, pneumothorax, hemo-
thorax, or tube malposition, many centers obtain routine chest
radiographs after conclusion of the procedure. However, major
postoperative complications are relatively rare, and are frequently
detectable on physical examination or bedside assessment of the
ventilator. Thus, the utility of routine postprocedure chest radiog-
raphy has been called into question.
Hoehne and colleagues22 retrospectively reviewed records
from 73 trauma patients who underwent percutaneous tracheo-
stomy for prolonged mechanical ventilatory support. All pat-
ients underwent routine postprocedure chest radiography. One
patient required conversion to an open procedure secondary to
bleeding, and no immediate complications were diagnosed by
chest x-ray.
In a similar retrospective study, Datta et al.23 examined records
of 60 patients who underwent percutaneous tracheostomy. Two
patients (3.3%) had complications diagnosed by postprocedure
chest x-ray. Both procedures were noted to be technically difficult.
The remainder of postprocedure chest x-rays showed no compli-
cations and did not influence patient management.
In a more recent prospective cohort study of 239 patients,
Haddad et al. 24 compared posttracheostomy chest radiographs
with preprocedure fi lms and recorded management modifica-
tions based on radiographic findings. Atelectasis was the only new
posttracheostomy radiographic finding, occurring in 24 (10%)
patients. Although the finding of atelectasis spurred changes in
management such as ventilator alteration and chest physiotherapy
in 4% of the total patient population, the authors concluded that
routine chest x-ray had low diagnostic yield and changed manage-
ment in a minority of patients.
In another prospective observational study, Kumar and col-
leagues25 evaluated the utility of chest x-ray after both routine and
technically difficult percutaneous tracheostomies performed in a
cohort of 384 patients. In the 93 patients who had a procedure
described as technically difficult, the rate of new findings on chest
x-ray was 7.5%. In the 252 patients who underwent uncomplicated
tracheostomy, the detection rate for new abnormalities was only
0.4%. From this data, the authors concluded that routine chest
radiography is justified after technically difficult or complicated
tracheostomy, but may be safely omitted after uncomplicated
procedures.
Recommendation: Routine postprocedure chest radiography
may be safely omitted in patients who undergo uncomplicated,
technically uneventful tracheostomy (Grade B). In cases where
technical difficulty is noted, postprocedure chest x-rays should be
obtained.
5/22/2012 5:56:04 PM
 Tracheostomy: Timing and Techniques ■ 645

6. What is the impact of tracheostomy on swallowing and and ventilation is unachievable by bag valve mask (BVM) tech-
aspiration? niques. In these circumstances, the cricothyroid membrane is
the access point of choice due to its relatively superficial ana-
The presence of an artificial airway, either translaryngeal or tran-
tomical position and technically easy surgical approach. After
stracheal, may have an effect on both deglutition and incidence of
establishment of an emergency airway via cricothyroidotomy,
aspiration. This relationship may be impacted by other variables,
the traditional approach has been conversion to a tracheostomy,
including the specific indication for prolonged mechanical venti-
particularly if the need for prolonged mechanical ventilation is
lation and duration of pulmonary failure.
anticipated. However, this is not universally accepted, and several
In a nonrandomized study, Sharma and colleagues26 prospec-
authors have challenged this approach.
tively assessed the incidence of swallowing dysfunction in trauma
In a small retrospective study, Wright and colleagues29 reviewed
and nontrauma patients with and without tracheostomy. Bedside
the records of 15 surviving trauma patients who had undergone
swallow studies and videofluoroscopy were used to assess degluti-
surgical cricothyroidotomy. Eight patients underwent subsequent
tion and incidence of aspiration. The overall aspiration rate was
conversion to tracheostomy, whereas seven underwent prolonged
38% (36% in patients with tracheostomy, and 40% in patients with-
ventilation via cricothyroidotomy until decannulation. Mean dura-
out tracheostomy). Dysphagia was common, but rates were similar
tion of ventilation via cricothyroidotomy was 14.1 days (range, 2–41
in patients with and without tracheostomy (71% vs. 77%, P > .05).
days). There was no difference in acute complications between the
In an attempt to clarify a causal relationship between tra-
two groups, but there was a trend toward increased infectious com-
cheostomy and aspiration, Leder and Ross27 prospectively evalu-
plications in the group that underwent conversion to tracheostomy.
ated pre- and postprocedure aspiration data in 20 adult patients
These findings suggest that routine conversion to tracheostomy
undergoing tracheostomy. Nineteen of 20 patients (95%) exhibited
may not be necessary in all patients who have undergone emergent
the same aspiration status before and after tracheostomy. All 12
cricothyroidotomy.
patients who aspirated prior to tracheostomy continued to aspi-
In another retrospective study, Hawkins et al.30 reviewed
rate afterwards, and 7 of 8 (88%) patients who did not aspirate
records of 26 patients who underwent cricothyroidotomy and sur-
before tracheostomy also did not aspirate afterwards (P > .05).
vived to hospital discharge. Seven patients underwent decannula-
In a more recent follow-up study of 25 consecutive patients,
tion of the cricothyroidotomy without further airway procedures,
the same authors confirmed similar results.28 Twenty-two (88%)
and 19 patients underwent conversion to tracheostomy. No patients
patients demonstrated the same aspiration status or resolved aspi-
experienced cricothyroidotomy-related morbidity, irrespective of
ration posttracheostomy. Three patients were felt to exhibit new
subsequent conversion to tracheostomy.
aspiration posttracheostomy secondary to worsening medical
Cricothyroidotomy has also been utilized in the elective man-
conditions, and four patients demonstrated resolution of aspira-
agement of critically ill patients requiring prolonged mechanical
tion after tracheostomy. On the basis of the results from these two
ventilation. Rehm et al.31 retrospectively compared 18 patients
studies, the authors concluded that the presence or absence of a
who underwent elective cricothyroidotomy in the ICU for pro-
tracheostomy is irrelevant to swallowing success or failure.
longed ventilatory support with a matched cohort of patients who
Recommendation: Patients requiring artificial airways are
underwent tracheostomy. One patient from the cricothyroidotomy
at high risk for both swallowing dysfunction and aspiration. The
group required silver nitrate treatment for excess granulation
presence of a tracheostomy does not appear to significantly influ-
tissue; no other complications were noted. Rates of minor voice
ence these risks (Grade C). Formal bedside swallowing evaluation
change deemed insignificant by patients were identical between
should be performed in patients who have undergone recent tra-
the two groups.
cheostomy, prior to institution of oral intake.
In a more recent review32 of complication rates after cricothy-
roidotomy in trauma patients, Talving and colleagues found little
7. Is conversion to tracheostomy necessary after emergent
data to support the contention that cricothyroidotomy was associ-
cricothyroidotomy?
ated with more frequent or severe complications, and concluded
In certain emergent circumstances, it may be necessary to access that routine conversion to tracheostomy was not supported by the
the airway via the cricothyroid membrane. Cricothyroidotomy available evidence.
may be performed in the setting of severe maxillofacial trauma, Recommendation: Patients who undergo emergent cricothy-
pharyngeal injury, or airway obstruction when intubation by either roidotomy may not require routine conversion to tracheostomy
the orotracheal or nasotracheal routes is difficult or impossible, (Grade C).

Clinical Question Summary

Question Answer Grade of References
Recommendation
1 What is the optimal timing of Unclear. Early tracheostomy does not appear to B 2-7
tracheostomy? influence rates of mortality or pneumonia.
2 What patient populations benefit Patients with brain injuries may experience C 8-12
from tracheostomy? modest benefits.

(Continued)

PMPH_CH81.indd 645 5/22/2012 5:56:04 PM

 646 ■ Surgery: Evidence-Based Practice
(Continued)
Question Answer
3 Is open or percutaneous Open and percutaneous approaches are safe and
tracheostomy preferable? equivalent in terms of complication rates.
4 Is bronchoscopic guidance necessary No
to perform percutaneous
tracheostomy safely?
5 Is routine chest x-ray necessary No
after performance of open or
percutaneous tracheostomy?
6 What is the impact of tracheostomy Minimal, though all patients with artificial airways
on swallowing and aspiration? are at high risk for swallowing dysfunction.
7 Is conversion to tracheostomy No
necessary after emergent
cricothyroidotomy?
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1. Durbin CG. Tracheostomy: why, when, and how? Resp Care.
2010;55(8):1056-1068.
2. Terragni PP, Antonelli M, Fumagalli R, et al. Early vs late trache-
otomy for prevention of pneumonia in mechanically ventilated
adult ICU patients: a randomized controlled trial. JAMA. 2010;
303(15):1483-1489.
3. Sugerman HJ, Wolf L, Pasquale MD, et al. Multicenter, random-
ized prospective trial of early tracheostomy. J Trauma. 1997;
43(5):741-747.
4. Blot F, Similowski T, Trouillet JL, et al. Early tracheotomy versus
prolonged endotracheal intubation in unselected severely ill ICU
patients. Intensive Care Med. 2008;34(10);1779-1787.
5. Zagli G, Linden M, Spina R, et al. Early tracheostomy in inten-
sive care unit: a retrospective study of 506 cases of video-guided
Ciaglia Blue Rhino tracheostomies. J Trauma. 2010;68(2):
367-372.
6. Griffiths J, Barber VS, Morgan L, et al. Systematic review and meta-
analysis of studies of timing of tracheostomy in adult patients
undergoing artificial ventilation. BMJ. 2005;330(7502):1243.
7. Dunham CM, Ransom KJ. Assessment of early tracheostomy
in trauma patients: a systematic review and meta-analysis. Am
Surg. 2006;72(3): 276-281.
8. Clec’h C, Alberti C, Vincent F. Tracheostomy does not improve
the outcome of patients requiring prolonged mechanical ventila-
tion: a propensity analysis. Crit Care Med. 2007;35(1):132-138.
9. Barquist EQ, Amortegui J, Hallal A, et al. Tracheostomy in ven-
tilator dependent trauma patients: a prospective, randomized,
intention-to-treat study. J Trauma. 2006;60(1):91-97.
10. Ahmed N, Kuo YH. Early versus late tracheostomy in pat-
ients with severe traumatic head injury. Surg Infect. 2007;8(3):
343-347.
11. Bouderka MA, Fakhir B, Bouaggad A, et al. Early tracheostomy
versus prolonged endotracheal intubation in severe head injury.
J Trauma. 2004;57(2):251-254.
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Grade of References
Recommendation
A 13-18
C 19-21
B 22-25
C 26-28
C 29-32
12. Goettler CE, Fugo JR, Bard MR, et al. Predicting the need for
early tracheostomy: a multifactorial analysis of 992 intubated
trauma patients. J Trauma. 2006;60(5):991-996.
13. Ciaglia P, Firsching R, Syniec C. Elective percutaneous dilata-
tional tracheostomy: a simple new bedside procedure; prelimi-
nary report. Chest. 1985;87(6):715-719.
14. Kornblith LZ, Cothren Burlew C, Moore EE, et al. One thousand
bedside percutaneous tracheostomies in the surgical intensive
care unit: time to change the gold standard. J Am Coll Surg. 2011;
212(2):163-170.
15. Silvester W, Goldsmith D, Uchino S, et al. Percutaneous versus
surgical tracheostomy: a randomized controlled study with long-
term followup. Crit Care Med. 2006;34(8):2145-2152.
16. Wu JJ, Huang MS, Tang GJ, et al. Percutaneous dilatational tra-
cheostomy versus open tracheostomy—a prospective, random-
ized, controlled trial. J Chin Med Assoc. 2003;66(8):467-473.
17. Higgins KM, Punthakee X. Meta-analysis comparison of open
versus percutaneous tracheostomy. Laryngoscope. 2007;117(3):
447-454.
18. Delaney A, Bagshaw SM, Nalos M. Percutaneous dilatational tra-
cheostomy versus surgical tracheostomy in critically ill patients: a
systematic review and meta-analysis. Crit Care. 2006;10(2):R55.
19. Tomsic JP, Connolly MC, Joe VC, et al. Evaluation of bron-
choscopic assisted percutaneous tracheostomy. Am Surg. 2006;
72(10):970-972.
20. Paran H, Butnaru G, Hass I, et al. Evaluation of a modified per-
cutaneous tracheostomy technique without bronchoscopic guid-
ance. Chest. 2004;126(3):868-871.
21. Mallick A, Venkatanath D, Elliot C, et al. A prospective randomized
controlled trial of capnography vs. bronchoscopy for Blue RhinoTM
percutaneous tracheostomy. Anaesthesia. 2003;58(9):864-868.
22. Hoehne F, Ozaeta M, Chung R. Routine chest x-ray after percuta-
neous tracheostomy is unnecessary. Am Surg. 2005;71(1):51-53.
23. Datta D, Onyirimba F, McNamee MJ. The utility of chest radio-
graphs following percutaneous dilatational tracheostomy. Chest.
2003;123(5):1603-1606.
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24. Haddad SH, Aldawood AS, Arabi YM. The diagnostic yield and
clinical impact of a chest x-ray after percutaneous dilatational
tracheostomy: a prospective cohort study. Anaesth Intensive
Care. 2007;35(3):393-397.
25. Kumar VM, Grant CA, Hughes MW, et al. Role of routine chest
radiography after percutaneous dilatational tracheostomy. Br J
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26. Sharma OP, Oswanski MF, Singer D, et al. Swallowing disor-
ders in trauma patients: impact of tracheostomy. Am Surg. 2007;
73(11):1173-1180.
27. Leder SB, Ross DA. Investigation of the causal relationship
between tracheotomy and aspiration in the acute care setting.
Laryngoscope. 2000;110(4):641-644.
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Tracheostomy: Timing and Techniques ■ 647
28. Leder SB, Ross DA. Confirmation of no causal relationship bet-
ween tracheotomy and aspiration status: a direct confirmation
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29. Wright MJ, Greenberg DE, Hunt JP, et al. Surgical cricothyroido-
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31. Rehm CG, Wanek SM, Gagnon EB, et al. Cricothyroidotomy for
elective airway management in critically ill trauma patients with
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5/22/2012 5:56:05 PM
 Commentary on
Tracheostomy: Timing and
Techniques
Matthew E. Lissauer and Thomas M. Scalea
In this well-constructed evidence-based review of the tracheos-
tomy literature, Dr Dolich tackles several questions vital to the
care of the mechanically ventilated patient. Unfortunately, the
data can be contradictory and the findings divergent. It is for this
reason that there are many varied opinions on the role, timing,
and method of tracheostomy. Dr Dolich summarizes the available
literature well, but there are still significant gaps in knowledge
that need to be overcome.
Much has been written on the subject of when a tracheostomy
should be performed, but few randomized studies have been per-
formed. The recent study by Terragni et al.1 is the largest random-
ized study to evaluate the timing of tracheostomy in the intensive
care unit (ICU). As pointed out in the review, there was no dif-
ference in ventilator-associated pneumonia or 28-day survival
with early tracheostomy. However, 31% of the early tracheostomy
group and 43% of the late group did not get a tracheostomy as
assigned. In a study by Blot et al.,2 16 of 61 patients assigned to the
prolonged intubation group received a delayed tracheostomy.
Determining the risk of prolonged ventilation early in the
clinical course of a patient in the ICU is difficult. Ventilator asyn-
chrony as measured by ineffective triggering predicts increased
duration of mechanical ventilation.3 In surgical patients, a lung
injury score of ≥1 may predict duration of ventilation >15 days.4
However, none of these indicators has the sensitivity or specific-
ity needed to be useful to predict the need for prolonged ventila-
tion. These results suggest that prior to studying the question of
when a tracheostomy is indicated, we need much better studies to
understand who requires prolonged mechanical ventilation and,
therefore, may benefit from early tracheostomy.
Trauma patients are the most studied group in terms of
identifying who should get a surgical airway, but the results are
still disappointing. Prolonged mechanical ventilation in patients
with cervical spine injury is common, particularly if the level is
high.5,6 Therefore, this is one subgroup of patients that may ben-
efit from tracheostomy. Brain injured patients may benefit from
an early surgical airway. That may be because some patients with
traumatic brain injury (TBI) do not need mechanical ventilation
but do require access to the trachea for suctioning secondary to
their depressed mental state. In the medical ICU, patients who
were deemed to require mechanical ventilation for more than
14 days also seemed to benefit from early tracheostomy.7 Once
648
PMPH_CH81.indd 648
again, 17% of those randomized to late tracheostomy avoided one,
again underscoring the difficulty in predicting who will need a
tracheostomy. More rigorous studies are needed to develop scores
predictive of prolonged ventilation in potential ICU survivors.
Ideally these would take into account both diagnosis and physiol-
ogy. Once developed, a multicenter randomized trial evaluating
early tracheostomy (or tracheostomy in general) using this score
as either entry criteria or an independent variable can be devel-
oped. In the meantime, given the current state of the literature,
the individual clinician must evaluate the known risks and ben-
efits of tracheostomy and decide if the procedure is beneficial for
their patient.
Once the decision to place a tracheostomy is made, the next
decision is method. The equivalence of percutaneous and open
tracheostomy in terms of outcomes and complications is nicely
described in the review. As it does not require the operating room
and has shorter operative time, percutaneous tracheostomy costs
less. With percutaneous tracheostomy now being more commonly
used, general surgery residents and trauma fellows perform fewer
open tracheostomies. They may become less competent in per-
forming open surgical airways in general. In the course of most
general surgeons’ career, there is a high likelihood they will need
to perform an emergent cricothyroidotomy. Although cadaver,
animal, and simulation labs allow for training in noncritical situ-
ations, there is still a difference between simulated procedures
and real life experience. The first open surgical airway performed
by a physician should not be an emergent airway. Open tracheos-
tomy allows a resident to gain experience with the feel of surgical
airways in a controlled situation with an attending physician to
teach them. Performing at least some open tracheostomies dur-
ing residency has the potential to improve education and possibly
save lives.
If the percutaneous route of tracheostomy is chosen, most
would favor bronchoscopic guidance as it helps confirm place-
ment and adds to surgeon comfort. Visualizing the airway and the
subsequent needle stick and guidewire placement alleviates much
concern. As with other questions in this review, the literature on
the subject is remarkably lacking. There are no randomized or con-
trolled trials. Only descriptive data exist. In a recent prospective
observational cohort, the risks related to blind placebo controlled
trial (PCT) remained slim but real.8 In this carefully selected
5/22/2012 5:56:05 PM

group of patients, there was a 10% risk of periprocedural com-
plications including bleeding, transient oxygen desaturation, and
perforation of the endotracheal tube cuff. These were mostly minor
and the rate was similar to the described rate of complications
using the bronchoscope.9 There is almost no work comparing both
strategies head to head in a controlled manner. Dr Dolich is cor-
rect in stating the blind procedure is safe, but if the main risk of
bronchoscopic guidance is damage to the scope, most of us would
gladly trade the cost of fi xing a scope for potentially avoiding a
major airway complication on a patient.
The remainder of the questions in the review focus on mana-
gement after the surgical airway has been obtained. Well exp-
lained is the Grade B recommendation that a chest x-ray is not
required after tracheostomy unless the procedure is technically
difficult. We would add that any clinical change in respiratory
status after tracheostomy requires x-ray evaluation as well, even
if the procedure was uncomplicated, though this would be good
clinical care even in the absence of airway manipulation. In
terms of dysphagia after artificial airway management, patients
who have not had a tracheostomy, but have been managed with
prolonged translaryngeal intubation should also have a bedside
swallow as dysfunction is common in patients intubated for
greater than 48 hours.10
Finally in regards to the question of an emergent cricothy-
roidotomy requiring conversion to formal tracheostomy, the lit-
erature suggests this is not necessary. Although we concur with
the literature and this review, the events surrounding an emer-
gent cricothyroidotomy are often chaotic. The cricothyroidotomy
is often performed with an endotracheal tube, not a tracheostomy
tube. A trip to the operating room if and when the patient has
stabilized, affords the opportunity to ensure the surgical airway is
secure with an appropriate tube and that hemostasis is complete,
though of course we have no data to back this recommendation.
In summary, the literature provides a reasonable guide to
clinical questions surrounding the surgical airway. These ques-
tions are adeptly answered by Dr Dolich. Unfortunately, the litera-
ture is incomplete and unsatisfactory for many of these questions,
PMPH_CH81.indd 649
Tracheostomy: Timing and Techniques ■ 649
especially need and timing of tracheostomy. As such, future work
should be directed toward better answering these questions.
REFERENCES
1. Terragni PP, Antonelli M, Fumagalli R, et al. Early vs. late trache-
otomy for prevention of pneumonia in mechanically ventilated
adult ICU patients: a randomized controlled trial. JAMA. 2010;
303(15):1483-1489.
2. Blot F, Similowski T, Trouillet JL, et al. Early tracheotomy versus
prolonged endotracheal intubation in unselected severely ill ICU
patients. Intensive Care Med. 2008;34(10);1779-1787.
3. de Wit M, Miller KB, Green Da, et al. Ineffective triggering pre-
dicts increased duration of mechanical ventilation. Crit Care Med.
2009;37(10):2740-2745.
4. Troche G, Moine P. Is the duration of mechanical ventilation
predictable? Chest 1997;112(3):745-751.
5. Romero J, Vari A, Gambarutta C, Oliveiro A. Tracheostomy timing
in traumatic spinal cord injury. Eur Spine J. 2009;18:1452-1457.
6. Como JJ, Sutton ER, McCunn M, et al. Characterizing the need
for mechanical ventilation following cervical spinal cord injury
with neurological deficit. J Trauma. 2005;59:912-916.
7. Rumbak MJ, Newton M, Truncale T, et al. A prospective, random-
ized, study comparing early percutaneous dilational tracheotomy
to prolonged translaryngeal intubation (delayed tracheotomy) in
critically ill medical patients. Crit Care Med. 2004;32:1689-1694.
8. Ahmed R, Rady RS, Siddique JIM, Iqbal M. Percutaneous tra-
cheostomy in critically ill patients: 24 months experience at a
tertiary care hospital in the United Arab Emirates. Ann Thoracic
Med. 2010;5(1):26-29.
9. Polderman KH, Spijkstra JJ, de Bree R, et al. Percutaneous dilata-
tional tracheostomy in the ICU: optimal organization, low com-
plication rates, and description of a new complication. Chest.
2003;123:1595-1602.
10. Leder SB, Cohn SM, Moller BA. Fiberoptic endoscopic documen-
tation of the high incidence of aspiration following extubation in
critically ill trauma patients. Dysphagia. 1998;13:208.
5/22/2012 5:56:05 PM
 CHAPTER 82
Pneumothorax and Hemothorax
Joseph J. DuBose
INTRODUCTION
Pneumothorax and hemothorax are commonly encountered
in both trauma and elective surgical practice. The identifica-
tion and treatment of these entities remain a demanding task
that requires both effective utilization of diagnostic tools and
timely employment of therapeutic interventions. Many issues
surrounding the optimization of outcomes following these fi nd-
ings, however, are either not well defi ned or remain controver-
sial. Do all pneumothoraces require treatment? Are antibiotics
necessary for thoracostomy tube placement? What is the optimal
management algorithm for thoracostomy tube use? When can
these tubes be discontinued, and how should they be removed?
What is the significance and optimal treatment of a retained
hemothorax? These questions continue to warrant debate and
investigation.
1. Does every pneumothorax require treatment?
Just as there are multiple potential causes of pneumothorax, the
clinical manifestations of this entity can vary significantly. At
present, it remains unclear what amount of air within the pleu-
ral space requires drainage. It is clearly important to provide for
prompt drainage of any pneumothorax contributing to tension
physiology. Although the definition of “symptomatic” in this set-
ting has not been particularly well defined, it is also prudent that
any pneumothorax causing significant pain or pulmonary com-
promise should also be evacuated. The optimal management of
small asymptomatic collections, however, remains controversial.
At present, no system for estimation of the size of pneu-
mothorax has been adequately validated. As such, even the defini-
tion of size of pneumothorax remains a matter of contention. The
best examinations of this topic are found in the evolving trauma
literature. In recent years “occult” pneumothorax, or those pleural
space air collections visible on computed tomography (CT) of the
chest, but not on plain radiography, have merited some atten-
tion. With the increased utilization of CT in imaging for trauma,
the occult pneumothorax may be an increasingly appreciated
650
PMPH_CH82.indd 650
phenomena. In a recent examination conducted by Ball et al.,
investigators found that this entity may be present in up to 15% of
trauma patients undergoing CT imaging of the chest. The major-
ity of these individuals prove asymptomatic and have no physi-
cal exam findings that would arouse suspicion for the presence
of pneumothorax, such as subcutaneous emphysema.1 Over the
past 5 years, it has subsequently become an accepted practice to
manage appropriately selected patients with occult pneumotho-
rax without drainage.
In a study of 338 trauma patients with paired plain fi lms of
the chest and a chest CT after trauma, Ball and colleagues found
that among 103 identified pneumothoraces, 55% (57 of 103) were
occult. In their series, no complications were observed when
observation of the pneumothorax was chosen as management.
In contrast, 23% of patients undergoing thoracostomy had tube-
related complications or required repositioning of their tube on
follow-up imaging. Interestingly, when this group of investiga-
tors compared patients with occult pneumothorax to those with
“overt” collections visible on plain radiography, they found that
the CT estimated size of the collections in both groups were simi-
lar, suggesting that a number of overt pneumothoraces would also
have been appropriate for observation without the potential risk
associated with thoracostomy tube placement.2
In the largest review on the topic, Yadav and colleagues
conducted an evidence-based review of 411 articles on occult
pneumothorax management. They identified three random-
ized trials for consideration, comprising 101 patients. This group
found that there was no difference between observation and tube
thoracostomy placement for patients with occult pneumothorax
with regards to progression of pneumothorax, risk of pneumo-
nia, hospital length of stay (LOS), intensive care unit (ICU) LOS,
empyema, or mortality. These findings suggest that observation
is an appropriate and safe management approach to patients with
occult pneumothorax.3
There remains, however, a concern for the potential increase
in size of an occult or small pneumothorax if observation is
selected in the setting of positive pressure mechanical ventila-
tion requirement. Although this topic has not been particularly
5/22/2012 5:56:37 PM

well examined, Ouelet et al.4 have reported their experience with
a small trial of 24 stable trauma patients with occult pneumotho-
rax who were randomized to observation or tube thoracostomy
drainage. These investigators found that, between these two man-
agement choices, there was no difference in the rates of respira-
tory distress, mortality, or median ICU or hospital LOS. The topic
requires additional study, however, and at present it remains pru-
dent to place a thoracostomy tube in the treatment of occult pneu-
mothorax when positive pressure ventilation is required, when
very close observation cannot be achieved, or when air transport
of the injured patient is required.
Answer: Although available literature suggests that occult
pneumothoraces can be safely observed without tube thoracos-
tomy or percutaneous drainage, it remains difficult to extrapolate
this experience to all small air collections in the pleural space. It
is likely that small, asymptomatic pneumothoraces may be safely
observed in appropriately selected patients and settings. The role
of follow-up imaging for patients under observation, however,
has not been adequately examined (Level 2 evidence, Grade C
recommendation).
2. Are antibiotics necessary for thoracostomy tube placement?
The use of antibiotic prophylaxis for tube thoracostomy has been
examined in several populations, including both trauma patients
and patients requiring elective general surgery. The larger body
of examination, however, exists in the trauma literature. Deme-
triades et al., in 1991, compared penetrating trauma patients who
received a single dose of ampicillin at the time of thoracostomy
tube placement to counterparts who had antibiotics continued
until thoracostomy removal. These investigators found that the
incidence of pneumonia and empyema were the same between
these groups, concluding that there was no benefit to prolonged
antibiotics after trauma thoracostomy placement.5 Subsequent
studies that followed examined the importance of periprocedural
antibiotics for posttraumatic thoracostomy tube placement. The
study of this topic has remained convoluted, however, due to the
wide range and types of antibiotics utilized, as well as differences
in dosing. In addition, the outcome measures from these small
studies proved inconsistent in comparison. Two separate meta-
analytic studies reported in 19926 and 1995,7 however, concluded
that prophylactic antibiotics made a significant impact on the
incidence of empyema when utilized for thoracostomy tube place-
ment after trauma.
The Eastern Association for the Surgery of Trauma contrib-
uted to available knowledge of antibiotic prophylaxis when they,
in 2000, published a comprehensive review of the literature and
their accompanying guidelines on the topic. Th is group8 could
find no Level 1 or Level 2 evidence on the topic, and were left to
conclude that a first generation cephalosporin should be utilized,
but no longer than 24 hours after thoracostomy placement. Based
on Level 3 evidence, these investigators noted that available data
suggested that there may be a reduction in the incidence of pneu-
monia, but not empyema in trauma patients receiving antibiotics
with tube thoracostomy placement. Their review was followed by
a prospective, randomized, double-blind trial reported by Max-
well and colleagues in 2004,9 who found that, among 224 patients
requiring thoracostomy tube placement, presumptive antibi-
otic use did not significantly effect the incidence of pneumonia
PMPH_CH82.indd 651
Pneumothorax and Hemothorax ■ 651
after trauma. The investigators in this examination were not,
however, able to reach conclusion on the effects of antibiotic use
on empyema, as the rate of this infectious manifestation in both
of the arms of their study was too small to facilitate adequate
examination.
The question of prophylactic antibiotic utilization in the gen-
eral thoracic surgery population has also been examined. Although
these studies are comparatively smaller in overall number, several
have been fairly well-designed prospective randomized trials. In a
study of 127 patients conducted by Aznar and colleagues in 1991,10
investigators randomized 127 patients undergoing thoracic sur-
gical procedures to receive either a single perioperative dose of
cefazolin or placebo. These researchers found that cefazolin sig-
nificantly reduced the subsequent incidence of wound infection
rate, but not that of empyema or pneumonia. Another examina-
tion by Olak et al. examined 228 consecutive patients admitted for
elective thoracotomy and lung resection, randomizing patients to
either a single perioperative dose of cefazolin or a six dose con-
tinuation regimen of the same antibiotic. This group found that
additional doses of cefazolin did not confer any clinically signifi-
cant benefit with regards to any infectious complication beyond
that obtained from a single prophylactic dose.11
The use of antibiotic prophylaxis for thoracostomy treatment
of spontaneous pneumothorax has also bee studied. In 2006,
Olgac and colleagues12 examined 119 of these patients who did not
receive antibiotics. Although the investigators reported that 25%
of patients developed some induration around the entry site of the
chest tube, none of these required further treatment. They also
noted that no bacterial cultures from suspected sites of infection
revealed significant growth.
Answer: Available data from small prospective randomized
trials suggest that a single perioperative dose of cefazolin confers
adequate protection for elective thoracic surgery patients with
thoracostomy tubes. The trauma literature on the topic remains
inadequate, but presently available data suggest that utiliza-
tion of a single generation cephalosporin for no more than 24
hours postprocedure may confer some protection against sub-
sequent pneumonia development (Level 3 evidence, Grade C
recommendation).
3. What is the optimal management of a thoracostomy tube?
Once a thoracostomy tube has been placed, for either trauma or
elective surgical indications, a management plan to facilitate the
subsequent safe removal of the tube must be implemented. To this
end, the variables that are commonly manipulated include the
duration of use for phases of suction and water seal cycles until the
requirement for the tube has resolved. Practice patterns remain
variable, with mixed literature on the role and duration of the suc-
tion phase following placement.
In a prospective randomized trial reported by Davis and col-
leagues in 199413 investigators conducted a prospective random-
ized trial of 80 patients requiring tube thoracostomy for various
indications. They found that patients continued on suction until
thoracostomy removal required a shorter duration of tube use
(72.2 vs. 92.5 hours, P = .013), and there were more patients
requiring prolonged removal times (defi ned as >36 hours) in
the water seal group (P = .009). A more recent prospective ran-
domized trial of 100 patients requiring tube thoracostomy after
5/22/2012 5:56:37 PM
 652 ■ Surgery: Evidence-Based Practice
penetrating thoracic trauma found that continuous low pres-
sure suction promoted shorter duration of tube requirement,
increased the number of patients achieving full lung expansion,
prevented the development of clotted hemothorax or empyema
requiring intervention, and resulted in shorter hospital stays.14
In contrast, a number of authors have suggested that early
water seal use after tube thoracostomy placement may be benefi-
cial. Martino et al.15 reported the results of a prospective random-
ized trial of 205 blunt and penetrating trauma patients in 1999.
Among patients who had thoracostomy output on suction at less
than 150 cc per 24 hours, the investigators randomized to either
immediate tube removal under suction or a 6-hour trial of water
seal followed by chest x-ray (CXR) prior to removal. These research-
ers found that there was no difference between the two groups with
regards to tube duration or hospital LOS. A subsequent prospec-
tive study reported in 200216 examined 68 patients undergoing
elective thoracic surgery procedures. All patients in this study
were subjected to a brief initial period of suction, followed by ran-
domization to continued suction at −20 cm of water or water seal.
The water seal group was found to have shorter durations of air
leak (mean 1.5 vs. 3.3 days, P = .05) and shorter durations of tube
requirement (mean 3.3 vs. 5.5 days, P = .06). Another smaller study
conducted by Reed et al.17 randomized 29 patients with iatrogenic
or spontaneous pneumothorax to either −20-cm water, −10-cm
water, or water seal after all were initially treated with 1 hour of
suction at −20 cm water. This group found that there was no differ-
ence between the three groups with regards to successful removal
rates at 48 hours or the need for pleurodesis. The investigators con-
cluded that early water seal is safe in the treatment of iatrogenic or
spontaneous pneumothorax.
Answer: The role of suction and water seal cycling following
thoracostomy tube placement requires additional examination.
Limited available evidence suggests that prolonged suction use
may decrease the number of clotted hemothoraces or empyema
requiring intervention after trauma. The preponderance of exist-
ing data suggests that early water seal is safe for use in patients
with pneumothorax and following elective procedures. Early
water seal may also decrease the duration of postoperative air leak
following elective thoracic surgical procedures (Level 1b evidence,
Grade B recommendation).
4. What is the appropriate approach to thoracostomy tube
removal?
Once the need for a thoracostomy tube has resolved, the tube
must be safely removed. The appropriate conduct of this seem-
ingly simple action has inspired considerable debate. In partic-
ular, questions remain about the optimal phase or respiration
during which to remove the tube, the relative safety of remov-
ing a thoracostomy tube in a patient requiring positive pressure
ventilation, and the role of follow-up imaging once the tube has
been removed.
Traditional teaching has provided rationales for thoracos-
tomy tube removal at either end-inspiration or end-expiration
during the respiratory cycle. In an effort to reconcile existing
opinions on the matter, Bell and colleagues at Yale18 conducted
a prospective randomized study of 102 trauma patients undergo-
ing thoracostomy tube removal. They found that, when random-
ized to either end of the respiratory cycle spectrum, there was no
PMPH_CH82.indd 652
subsequent difference in postremoval recurrent pneumothorax
or enlargement of small pneumothorax (8% vs. 6%, P = 1.0). In
addition, there was no difference between the two methods with
regard to the need for subsequent repeat thoracostomy. Their find-
ings suggest that the phase of the respiratory cycle during which
a thoracostomy tube is removed has no significant influence on
outcome.
The safety of removing a thoracostomy tube from a patient
requiring positive pressure ventilation has traditionally repre-
sented a concern for both trauma providers and practitioners of
elective surgery. Although prospective studies on the topic have
not yet been conducted, Tawil et al. did report the results of a size-
able retrospective review in 2010.19 In their examination of 234
thoracostomy removals, they compared the removal under posi-
tive pressure ventilation for 58% of patients to those of the 42%
of patients who underwent tube discontinuations while breathing
spontaneously unassisted. These researchers found that there was
no difference between the two groups with regard to pneumotho-
rax rates or need for tube reinsertion, regardless of ventilatory
support requirement.
Postthoracostomy tube removal imaging has traditionally
been a mainstay of practice at most centers. Most commonly, this
consists of plain radiography follow-up at a prescribed interval.
Two groups, however, have suggested that the routine utiliza-
tion of postremoval imaging may not be required for all patients.
In an initial report by Palesty et al.,20 investigators conducted a
5-year retrospective examination of 73 trauma patients undergo-
ing thoracostomy tube removal. The researchers found that only
eight patients had postprocedure imaging reports that differed
from those of pre-removal fi ndings. Only two patients in this
study required subsequent reinsertion of tube thoracostomy and,
in each of these instances, the reinsertion was conducted based
on clinical appearance of the patient, and not radiographic data
alone. A more recent retrospective review conducted by Good-
man and colleagues21 at the University of Cincinnati’s level I
trauma center found that patients undergoing tube removal with-
out subsequent radiographic imaging were less severely injured
and were less likely to have suffered penetrating thoracic injuries.
They found, however, that patients who did not undergo imaging
after thoracostomy removal had fewer CXRs overall and shorter
LOS after chest tube removal. These investigators estimated that
foregoing CXR in selected patients resulted in an annual decrease
in charges of $16,280 for their institution.
The role of postremoval radiographic follow-up has also been
examined among patients who require mechanical ventilation.
Pizano and colleagues22 examined 75 patients requiring ventila-
tion who underwent removal and subsequent CXR at approxi-
mately 1, 10, and 36 hours. They found that, although postremoval
pneumothorax was identified in 12% of patients, all of these were
identified on the initial fi lms obtained between 1 and 3 hours. The
investigators concluded that plain radiography within this time
frame effectively identified postremoval pneumothorax among
mechanically ventilated patients.
Answer: The phase of the respiratory cycle during which a
thoracostomy tube is removed has not been shown to have any
impact on subsequent outcome. Available data supports the posi-
tion that patients requiring positive pressure ventilation can
safely undergo thoracostomy tube removal. Limited retrospective
data suggest that appropriately selected patients may not require
5/22/2012 5:56:37 PM

routine imaging after thoracostomy tube removal. Further pros-
pective validation and randomized study is required before the
latter practice should be routinely advocated (Level 1b evidence,
Grade B recommendation).
5. What is the optimal management of retained hemothorax?
The diagnosis and optimal management of retained posttraumatic
hemothorax remains a problematic issue. It is generally accepted
that persistent blood within the thoracic cavity represents a con-
cerning finding; primarily due to concern for the subsequent devel-
opment of fibrothorax (“trapped lung”) and empyema. Although a
link between uncomplicated retained hemothorax and “trapped
lung” has been less well established,23 the presence of retained blood
within the chest has more clearly been identified as a risk factor for
the development for empyema.24-27 Although empyema remains
an infrequent complication of thoracic trauma,25,27 diagnosis and
management of this infectious process remains controversial,28-31
and the occurrence of empyema may be associated with significant
morbidity and mortality.32 For this reason, the establishment of the
ideal modality for the effective evacuation of retained hemothorax
has remained an area of active investigation.
The identification of individuals at greatest risk for subsequent
complications due to retained hemothorax is, however, problem-
atic. Although liquefied hemothorax can frequently be effectively
drained with the placement of an initial or secondary thoracos-
tomy tube, clotted and loculated collections may be more likely to
require more aggressive management for evacuation. The natural
history of retained hemothoraces, particularly smaller collections,
has also not been well defined.33,34 Although largely dependent on
the screening modality used, even the incidence of this entity has
not been well defined; although small studies have reported rates as
high as 10%.35 In addition, although CT appears a more sensitive and
specific modality by which to characterize and quantify retained
hemothorax,35 the effective use of radiographic assessment to stratify
risk and guide therapeutic decisions has remained elusive.29,33,34
Despite these controversies, several evacuation strategies for
retained hemothorax have been effectively used, including open
thoracotomy, thoracostomy, video-assisted thoracoscopy (VATS),
and the use of intrapleural fibrinolytics. Thoracotomy remains
the gold standard to which newer approaches are compared, but
this surgical approach can be associated with significant morbid-
ity. Less invasive modalities are more commonly employed in the
modern era. VATS has emerged as an increasingly used modality
in recent years, although the use of intrapleural fibrinolytics has
garnered some interest.
Increasing experience with thoracoscopy has increased the
enthusiasm for the use of this modality to evacuate retained
PMPH_CH82.indd 653
Pneumothorax and Hemothorax ■ 653
hemothoraces.35-47 Although early VATS appears to be beneficial,
the definition of “early” has varied among available retrospec-
tive series and there is a paucity of prospective studies available
in the literature.37,38,40,44-47 However, in one prospective, random-
ized report of VATS use within 72 hours of initial thoracostomy
tube placement, Meyer et al.37 found that VATS at this interval
was associated with shorter hospital stays and lower hospital costs
compared to individuals randomized to additional thoracostomy
tube placement.
The use of intrapleural fibrinolytics for the degradation
and subsequent drainage of retained hemothorax has also been
investigated. The safe use of this approach for the treatment of
organized hemothorax and infectious collections of the pleu-
ral space has already been reported by several groups.29,35,48-65
In a review of studies from the Cochrane Database of System-
atic Reviews reported in 2008, Cameron and Davies29 identified
seven randomized control trials examining the use of fibrinolyt-
ics for empyema and parapneumonic eff usions. These investi-
gators found that fibrinolytics utilized in these settings safely
resulted in a significant decrease in the risk of requiring sub-
sequent surgical drainage. Although these fi ndings appear to
demonstrate the utility of intrapleural fibrinolytic use, none of
these studies included posttraumatic retained hemothorax in
their examinations.
At present, no Level 1 evidence supporting the use of fibrin-
olytics for the treatment of posttraumatic retained hemothorax
exists. However, in one small, prospective observational study
reported by Kimbrell and colleagues, the use of fibrinolytics
resulted in successful resolution of residual hemothorax in 92%
of patients.59 Another limited retrospective examination con-
ducted by Oguzkaya et al.35 compared the use of VATS to intra-
pleural streptokinase for management of posttraumatic retained
hemothorax, finding that the use VATS resulted in shorter hospital
stay and a decreased need for subsequent thoracotomy. Given the
documented success of these adjuncts in the treatment of pleural
space infections, the utility of fibrinolytics for the treatment of
retained hemothorax warrants further examination.
Answer: Reflective of the complexities in diagnosis and risk
stratification for patients with the fi nding of retained hemotho-
rax, no single therapeutic approach has emerged as a superior
modality. At present, VATS appears to hold the most promise,
having been shown to decrease hospital stay and cost in one
small, randomized trial comparing the use of this approach to
additional tube thoracostomy placement. To date, however, no
prospective examination of less invasive techniques has shown
any treatment modality to prove superior in decreasing the
need for subsequent thoracotomy (Level 2b evidence, Grade C
recommendation).
5/22/2012 5:56:37 PM
 654 ■ Surgery: Evidence-Based Practice

Clinical Question Summary

Question Answer Level of Grade of References
Evidence Recommendation
1 Does every Occult pneumothoraces can be safely observed 2 C 2-4
pneumothorax without tube thoracostomy or percutaneous
require treatment? drainage.
2 Are antibiotics A single perioperative dose of cefazolin may 3 C 6-11
necessary for confer adequate protection for elective
thoracostomy thoracic surgery patients with thoracostomy
tube placement? tubes. Among trauma patients, the use of
a single generation cephalosporin for no
more than 24 hours postprocedure may
confer some protection against subsequent
pneumonia development.
3 What is the optimal Thoracostomy suction may reduce clotted 1b B 13, 14, 16, 17
management of a hemothoraces or empyema requiring
thoracostomy intervention after trauma. Early water seal is
tube? safe for use in patients with pneumothorax
and following elective procedures—and may
decrease the duration of postoperative air
leak.
4 What is the Thoracostomy tubes can safely be removed 1b B 18, 19
appropriate approach anywhere in the respiratory cycle.
to thoracostomy tube Patients requiring positive pressure ventilation can
removal? safely undergo thoracostomy tube removal.
5 What is the optimal Early VATS for retained hemothorax may 2b C 43, 44, 45
management of decrease hospital stay and cost.
retained hemothorax?

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tors, and outcomes for occult pneumothoraces in victims of major
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12. Olgac G, Aydogmus U, Mulazimoglu L, Kutlu CA. Antibiotics are
not needed during tube thoracostomy for spontaneous pneumo-
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13. Davis JW, Mackersie RC, Hoyt DB, Garcia J. Randomized study
of algorithms for discontinuing tube thoracostomy drainage.
J Am Coll Surg. 1994;179(5):553-557.
14. Muslim M, Bilal A, Salim M, Khan MA, Baseer A, Ahmed M.
Tube thoracostomy: Management and outcome in patients with
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20(4):108-111.
15. Martino K, Merrit S, Boyakye K, et al. Prospective random-
ized trial of thoracostomy removal algorithms. J Trauma. 1999;
46(3):369-371; discussion 372-373.
16. Marshall MB, Deeb ME, Bleier JI, et al. Suction vs water seal after
pulmonary resection: a randomized prospective study. Chest.
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17. Reed MF, Lyons JM, Luchette FA, Neu JA, Howington JA. Pre-
liminary report of a prospective, randomized trial of underwater

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seal for spontaneous and iatrogenic pneumothorax. J Am Coll
Surg. 2007;204(1):84-90.
18. Bell RL, Ovadia P, Abdullah F, Spector S, Rabinovici R. Chest
tube removal: end-inspiration or end-expiration? J Trauma. 2001;
50(4):674-677.
19. Tawil I, Gonda JM, King RD, Marinaro JL, Crandall CS. Impact
of positive pressure ventilation on thoracostomy tube removal. J
Trauma. 2010;68(4):818-821.
20. Palesty JA, McKelvey AA, Dudrick SJ. The efficacy of X-rays after
chest tube removal. Am J Surg. 2000;179(1):13-16.
21. Goodman MD, Huber NL, Johannigman JA, Pritts TA. Omis-
sion of routine chest x-ray after chest tube removal is safe in
selected trauma patients. Am J Surg. 2010;199(2):199-203.
22. Pizano LR, Houghton DE, Cohns SM, Frisch MS, Grogan RH.
When should a chest radiograph be obtained after chest tube
removal in mechanically ventilated patients? A prospective study.
J Trauma. 2002 Dec;53(6):1073-1077.
23. Doelken P, Sahn SA. Trapped lung. Semin Respir Crit Care Med.
2001;22(6):631-636.
24. Aguilar MM, Battistella FD, Owings JT, Su T. Posttraumatic
empyema: risk factor analysis. Arch Surg. 1997;132(6):647-650;
discussion 650-651.
25. Eren S, Esme H, Sehitogullari A, Durkan A. The risk factors and
management of posttraumatic empyema in trauma patients.
Injury. 2008;39(1):44-49.
26. Sriussadaporn S, Poomsuwan P. Post-traumatic empyema thora-
cis in blunt chest trauma. J Med Assoc Thai. 1995;78(8):393-398.
27. Mandal AK, Thadepalli H, Mandal AK, Chettipalli U. Posttrau-
matic empyema thoracis: a 24-year experience at a major trauma
center. J Trauma. 1997;43(5):764-771.
28. Wong KS, Lin TY, Huang YC, Chang LY, Lai SH. Scoring system
for empyema thoracis and help in management. Indian J Pediatr.
2005;72(12):1025-1028.
29. Cameron R, Davies HR. Intra-pleural fibrinolytic therapy ver-
sus conservative management in the treatment of adult parap-
neumonic eff usions and empyema. Cochrane Database Syst Rev.
2008;(2)(2):CD002312.
30. Bilgin M, Akcali Y, Oguzkaya F. Benefits of early aggressive man-
agement of empyema thoracis. ANZ J Surg. 2006;76(3):120-122.
31. Molnar TF. Current surgical treatment of thoracic empyema in
adults. Eur J Cardiothorac Surg. 2007;32(3):422-430.
32. Wehr CJ, Adkins RB, Jr. Empyema thoracis: a ten-year experi-
ence. South Med J. 1986;79(2):171-176.
33. Stafford RE, Linn J, Washington L. Incidence and management
of occult hemothoraces. Am J Surg. 2006;192(6):722-726.
34. Meyer DM. Hemothorax related to trauma. Thorac Surg Clin.
2007;17(1):47-55.
35. Oguzkaya F, Akcali Y, Bilgin M. Video thoracoscopy versus
intrapleural streptokinase for management of post traumatic
retained haemothorax: a retrospective study of 65 cases. Injury.
2005;36(4):526-529.
36. Velmahos GC, Demetriades D, Chan L, et al. Predicting the need
for thoracoscopic evacuation of residual traumatic hemothorax:
chest radiograph is insufficient. J Trauma. 1999;46(1):65-70.
37. Meyer DM, Jessen ME, Wait MA, Estrera AS. Early evacuation of
traumatic retained hemothoraces using thoracoscopy: a prospec-
tive, randomized trial. Ann Thorac Surg. 1997;64(5):1396-1400;
discussion 1400-1401.
38. Morales Uribe CH, Villegas Lanau MI, Petro Sanchez RD. Best
timing for thoracoscopic evacuation of retained post-traumatic
hemothorax. Surg Endosc. 2008;22(1):91-95.
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39. Cetindag IB, Neideen T, Hazelrigg SR. Video-assisted thoracic
surgical applications in thoracic trauma. Thorac Surg Clin. 2007;
17(1):73-79.
40. Casos SR, Richardson JD. Role of thoracoscopy in acute manage-
ment of chest injury. Curr Opin Crit Care. 2006;12(6):584-589.
41. Carrillo EH, Richardson JD. Thoracoscopy in the management
of hemothorax and retained blood after trauma. Curr Opin Pulm
Med. 1998;4(4):243-246.
42. Navsaria PH, Vogel RJ, Nicol AJ. Thoracoscopic evacuation of
retained posttraumatic hemothorax. Ann Thorac Surg. 2004;
78(1):282-285; discussion 285-286.
43. Tomaselli F, Maier A, Renner H, Smolle-Juttner FM. Thoraco-
scopical water jet lavage in coagulated hemothorax. Eur J Car-
diothorac Surg. 2003;23(3):424-425.
44. Velmahos GC, Demetriades D. Early thoracoscopy for the
evacuation of undrained haemothorax. Eur J Surg. 1999;165(10):
924-929.
45. Vassiliu P, Velmahos GC, Toutouzas KG. Timing, safety, and effi-
cacy of thoracoscopic evacuation of undrained post-traumatic
hemothorax. Am Surg. 2001;67(12):1165-1169.
46. Heniford BT, Carrillo EH, Spain DA, Sosa JL, Fulton RL, Rich-
ardson JD. The role of thoracoscopy in the management of
retained thoracic collections after trauma. Ann Thorac Surg. 1997;
63(4):940-943.
47. Brutsche MH, Tassi GF, Gyorik S, et al. Treatment of sonograph-
ically stratified multiloculated thoracic empyema by medical
thoracoscopy. Chest. 2005;128(5):3303-3309.
48. Khalil BA, Corbett PA, Jones MO, et al. Less is best? The impact
of urokinase as the first line management of empyema thoracis.
Pediatr Surg Int. 2007;23(2):129-133.
49. Agarwal R, Aggarwal AN, Gupta D. Intrapleural fibrinolysis in
clotted haemothorax. Singapore Med J. 2006;47(11):984-986.
50. Aye RW, Froese DP, Hill LD. Use of purified streptokinase in
empyema and hemothorax. Am J Surg. 1991;161(5):560-562.
51. Misthos P, Sepsas E, Konstantinou M, Athanassiadi K, Skottis I,
Lioulias A. Early use of intrapleural fibrinolytics in the manage-
ment of postpneumonic empyema. A prospective study. Eur J
Cardiothorac Surg. 2005;28(4):599-603.
52. Basile A, Boullosa-Seoane E, Dominguez Viguera L, et al. Intrapleu-
ral fibrinolysis in the management of empyemas and haemothora-
ces: our experience. Radiol Med (Torino). 2003;105(1-2):12-16.
53. Lim TK, Chin NK. Empirical treatment with fibrinolysis and
early surgery reduces the duration of hospitalization in pleural
sepsis. Eur Respir J. 1999;13(3):514-518.
54. Sahn SA. Use of fibrinolytic agents in the management of com-
plicated parapneumonic effusions and empyemas. Thorax. 1998;
53(Suppl 2):S65-72.
55. De Gregorio MA, Ruiz C, Alfonso ER, Fernandez JA, Medrano J,
Arino I. Transcatheter intracavitary fibrinolysis of loculated
pleural eff usions: experience in 102 patients. Cardiovasc Inter-
vent Radiol. 1999;22(2):114-118.
56. Davies RJ, Traill ZC, Gleeson FV. Randomised controlled trial of
intrapleural streptokinase in community acquired pleural infec-
tion. Thorax. 1997;52(5):416-421.
57. Davies CW, Lok S, Davies RJ. The systemic fibrinolytic activity
of intrapleural streptokinase. Am J Respir Crit Care Med. 1998;
157(1):328-330.
58. Jerjes-Sanchez C, Ramirez-Rivera A, Elizalde JJ, et al. Intrapleu-
ral fibrinolysis with streptokinase as an adjunctive treatment
in hemothorax and empyema: a multicenter trial. Chest. 1996;
109(6):1514-1519.
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 656 ■ Surgery: Evidence-Based Practice
59. Kimbrell BJ, Yamzon J, Petrone P, Asensio JA, Velmahos GC.
Intrapleural thrombolysis for the management of undrained
traumatic hemothorax: a prospective observational study.
J Trauma. 2007;62(5):1175-1178; discussion 1178-1179.
60. Bouros D, Schiza S, Patsourakis G, Chalkiadakis G, Panagou P,
Siafakas NM. Intrapleural streptokinase versus urokinase in the
treatment of complicated parapneumonic effusions: a prospective,
double-blind study. Am J Respir Crit Care Med. 1997;155(1):291-295.
61. Bouros D, Schiza S, Siafakas N. Fibrinolytics in the treatment of
parapneumonic eff usions. Monaldi Arch Chest Dis. 1999;54(3):
258-263.
62. Bouros D, Schiza S, Tzanakis N, Drositis J, Siafakas N. Intrapleu-
ral urokinase in the treatment of complicated parapneumonic
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pleural eff usions and empyema. Eur Respir J. 1996;9(8):1656-
1659.
63. Diacon AH, Theron J, Schuurmans MM, Van de Wal BW, Bol-
liger CT. Intrapleural streptokinase for empyema and com-
plicated parapneumonic eff usions. Am J Respir Crit Care Med.
2004;170(1):49-53.
64. Maskell NA, Davies CW, Nunn AJ, et al. U.K. controlled trial
of intrapleural streptokinase for pleural infection. N Engl J Med.
2005;352(9):865-874.
65. Tuncozgur B, Ustunsoy H, Sivrikoz MC, et al. Intrapleural
urokinase in the management of parapneumonic empyema:
a randomised controlled trial. Int J Clin Pract. 2001;55(10):
658-660.
5/22/2012 5:56:38 PM
 Commentary on
Pneumothorax and Hemothorax
J. D. Richardson
The chapter entitled “Pneumothorax and Hemothorax” by Dr
Joseph J. Dubose provides excellent insight into the level of evi-
dence supporting clinical decisions made in five fundamental
areas relevant to the management of pleural space problems; that
is, pneumothorax and hemothorax. The questions addressed
include (1) Does every pneumothorax require treatment? (2) Are
antibiotics necessary for thoracotomy tube placement? (3) What
is the optimal management of a thoracostomy tube? (4) What is
the appropriate approach to thoracostomy tube removal? and (5)
What is the optimal management of retained hemothorax?
Although these are all important questions, the level of evi-
dence supporting recommendations on each of these questions
is often inadequate to permit firm conclusions. Reports on these
questions are generally experiential and, with the possible excep-
tion of the antibiotic question (#2), have rarely been subjected to
randomized clinical trials. In addition, many of the adverse events
that could be attributed to a particular treatment method are
uncommon: thus, studies would have to be enormously powered,
with many subjects, to show a statistical difference. Having stated
this, the author does an excellent job in reviewing the available
literature supporting, refuting, or being an agnostic on these fun-
damental questions.
Regarding the necessity to treat every pneumothorax, the
reviewed literature suggests that observation is safe with most
small pneumothoraces. The author, however, offers a note of cau-
tion (properly in my opinion) about observing and not insert-
ing a tube in a patient with positive pressure ventilation (PPV).
The exacerbation of a small pneumothorax by PPV is not a myth;
I have observed it several times in my career including a near-
fatal event in an operating room for an orthopedic procedure.
However, statistically the occurrence is likely fairly small. Thus
the conundrum: most small studies will disclose no problems;
however, do we offer no treatment to prevent known chest tube
complications at the peril of an occasional (perhaps rare) life-
threatening event?
The second question about the use of antibiotics for chest
tube insertion has long been a subject of interest to me. I was a co-
author of the first randomized, double blind control trial on this
subject published in 1997.1 Although several recent reports imply
that no randomized trials have occurred, our study of 75 patients
with penetrating trauma (38 antibiotics and 37 placebos) demon-
strated positive effects in the antibiotic group. Perhaps the results
would differ in blunt trauma patients, but the EAST guidelines of
657
PMPH_CH82.indd 657
20022 recommending a 24-hour course of narrow-spectrum anti-
biotics aimed at Gram-positive organisms seems prudent. How-
ever, if empyema is the endpoint, the incidence will be low and the
value of prophylaxis will be very difficult to prove except by a very
large contemporaneous multi-institutional study.
The third question revolves around the use of water seal or suc-
tion prior to chest tube removal. Not surprisingly, data from trials
using both techniques provide contradictory results. All of the tri-
als use a variety of patients with different indications for tube place-
ment. I am convinced (but cannot prove) that suction is preferential
for patients with a recent air leak or for the potential of a visceral
pleura that is not firmly opposed to the parietal pleura of the chest
wall. One can determine this fairly well clinically, by simply observ-
ing the fluctuation in the fluid column of a chest tube with deep
inspiration. If there is little variance on deep inspiration, the patient
could go to water seal (or likely have the tube pulled), whereas a sig-
nificant fluctuation should cause continued suction to be employed.
Pulling a tube in such a scenario frequently leads to a pneumotho-
rax and the lung may not stay fully expanded on water seal. I have
observed this in over 35 years of chest tube management but it is
hardly the stuff on a randomized trial.
Does the cycle of respiration matter when a tube is pulled,
and is post-pull imaging necessary? Studies show no difference
in which ventilating cycle a tube is pulled and preference for one
method over another is likely mythical. The articles cited regard-
ing post-pull imaging display a problem with medical literature
that is often not recognized.3 A study with 73 trauma patients
treated over 5 years by chest tube would have little validity to me
(barely over one per month). In addition, an 11% rate of change
seems significant to me even though Goodman and colleagues
apparently did not.4 They noted a whooping annual savings of
$16,280 by foregoing a post-pull radiograph.1 I would submit that
one adverse outcome for lack of a follow-up film will likely negate
such miniscule saving.
Finally, the author reviews the question of the optimal man-
agement of retained hemothorax. Our group has published exten-
sively on the use of video-assisted thoracoscopy (VATS) for this
problem as we believe in its use.5-7 Having admitted our bias, we
would hasten to add we have an extremely busy unit where retained
collections are a potential problem; we have surgeons skilled in the
procedure, and we use it reasonably aggressively. The EAST recently
issued guidelines on VATS for retained hemothorax that noted
class II and III evidence supporting the use of VATS.8 However, I
5/22/2012 5:56:38 PM
 658 ■ Surgery: Evidence-Based Practice
concur with Dr Dubose’s summary statement that this is an area
that can be managed by multiple strategies and no “evidence” to the
superiority of one over another has been forthcoming to date.
REFERENCES
1. Grover FL, Richardson JD, Fewel JG, Arom KV, Trinkle JK, Webb
GE. Prophylactic antibiotics in the treatment of penetrating chest
wounds—a prospective double blind study. J Thorac Cardiovasc
Surg. 1977;74(4):528-536.
2. Luchette FA, Barrie PS, Oswanski ME, et al. Practice management
guidelines for prophylactic antibiotic use in tube thoracostomy
for traumatic hemopneumothorax: the EAST practice manage-
ment guidelines work group. Eastern Association for Trauma. J
Trauma. 2000;48(4):753-757.
PMPH_CH82.indd 658
3. Palesty JA, McKelvey AA, Dudrick SJ. The efficacy of X-rays after
chest tube removal. Am J Surg. 2000;179(1):13-16.
4. Goodman MD, Huber NL, Johannigman JA, Pritts TA. Omission
of routine chest x-ray after chest tube removal is safe in selected
trauma patients. Am J Surg. 2010;199(2):199-203.
5. Carrillo EH, Heniford BT, Richardson JD, et al. Video-assisted
thoracic surgery in trauma patients. J Am Coll Surg. 1997;184:
316-324.
6. Heniford BT, Carrillo EH, Richardson JD, et al. The role of thora-
coscopy in the management of retained thoracic collections after
trauma. Ann Thorac Surg. 1997;63:940-943.
7. Carrillo EH, Richardson JD. Thoracoscopy for the acutely injured
patient. Am J Surg. 2005;190:234-238.
8. Mowery NT, Gunter OL, Collier BR, et al. Practice management
guidelines for management of hemothorax and occult pneu-
mothorax. J Trauma. 2011;70:510-518.
5/22/2012 5:56:38 PM
 PART XIV

VASCULAR SYSTEM

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PMPH_CH83.indd 660 5/22/2012 5:57:08 PM

Abdominal Aortic Aneurysm
Abdominal aortic aneurysm (AAA) remains a common vascu-
lar surgical problem, with roughly 40,000 annual repairs in the
United States alone. It is also one of the most well-studied prob-
lems, both in terms of natural history and procedures for repair.
This chapter will summarize the evidence available regarding the
most relevant clinical issues related to AAAs.
1. What are the risk factors for AAA development?
In a Veterans Administration study, the relative risk of developing
an aneurysm greater than 4 cm in diameter was five-folds higher
in smokers as opposed to nonsmokers.1 Men were also 5.6 times
more likely than women to have an AAA. Caucasians had a two-
fold higher risk than non-Caucasians and persons with a positive
family history were also twice as likely to have an AAA versus
individuals with a negative family history. Diabetes is negatively
correlated with AAA development.2,3 AAA is mostly a diseased of
advanced age, with few cases reported in individuals under the
age of 50 years.
The mean growth rate for AAAs less than 5.5 cm ranges from
2.6 to 3.2 mm per year, being higher in larger aneurysms.3 AAA
expansion is most strongly associated with diameter at baseline.
Other risk factors include continued smoking.
There is Level I evidence that smoking, male sex, white race,
and positive family history increase the likelihood of a patient har-
boring an AAA.
2. Should screening for AAA be carried out?
There have been three randomized controlled trials addressing
this question. The first such study was carried out in Chichester
in the United Kingdom and enrolled 6058 individuals aged 65 to
80 years.1 AAAs greater than 3 cm were detected in 7.6%. AAA-
related death was reduced by 41% at 5 years, when compared to
men not offered screening. No such benefit was seen in women
in whom the prevalence of AAA was only 1.3%. The second trial
was carried out in Denmark and involved 12,658 men aged 65 to
73 years.2 AAA was diagnosed in 4% and in-hospital AAA-related
661
PMPH_CH83.indd 661
CHAPTER 83
Boulos Toursarkissian
death was reduced by 68%.2 The third trial was the Multicenter
Aneurysm Screening Study that randomized 33,839 men aged 65
to 74 years to screening and 33,961 to a control group. AAA-related
mortality was reduced in the screened patients after 4 years.3
There is Level I evidence that AAA screening is effective in
reducing AAA-related mortality. Screening, however, should be
directed at individuals who are at higher risk for the disease. The
US Preventive Services Task Force recommends screening men
aged 65 to 74 years who have ever smoked (Grade B recommenda-
tion). Women with a family history of AAA should also likely be
included (Grade B recommendation).
3. Are there any proven medical therapies for AAAs?
The UK Small Aneurysm Trial showed in a multivariate analysis
that ongoing smoking was linked to increased AAA expansion
rates4 (Level I evidence). Continued smoking has been associated
with more rapid aneurysm expansion.5 Patients diagnosed with
AAA should therefore be counseled to stop smoking (Grade A
recommendation).
β-Blockers have been shown not to be beneficial in terms of
reducing AAA growth rates in prospective randomized trials6,7
(Level I evidence). They are not therefore routinely recommended
unless indicated for other cardiovascular indications (Grade A
recommendation).
Some retrospective studies have suggested that statin use is
associated with slower AAA expansion rates8-10 (Level II evidence).
However, there are no prospective randomized trials proving that
point. Statin use should therefore be decided on its own cardio-
vascular merits for secondary atherosclerosis prevention and not
for AAA management per se (Grade B recommendation).
Three small randomized trials have shown that doxycycline
and roxithromycin reduce AAA expansion rates, likely through
inhibition of wall degrading matrix metalloproteinases.11-13 The
total number of patients in these studies was rather small (Level IB
evidence). It is therefore reasonable to consider the use of such
medications in patients who can otherwise tolerate them (Grade B
recommendation).
5/22/2012 5:57:08 PM
 662 ■ Surgery: Evidence-Based Practice
4. What is the risk of AAA rupture and when should repair be
recommended?
The Aneurysm Detection and Management trial (ADAM trial)
randomized veterans aged 50 to 79 years with AAA from 4.0 to
5.4 cm to either immediate open surgical in 569 patients repair
or to ultrasound surveillance in 567 patients, with repair if the
AAA reaches 5.5 cm or becomes symptomatic. With an opera-
tive mortality of 2.7%, there was no significant difference between
the two groups in the primary outcome of long-term mortality,
with a mean follow-up of 4.9 years. Sixty-two percent of patients
in the observation group ended up with repair by the end of the
observation period. Only 0.6% per year of the observation patients
suffered a ruptured AAA. The likelihood of needing repair in
the observation group varied with the initial size of the AAA at
enrollment, with 81% of those in the 5- to 5.4-cm group need-
ing repair by the end of the study. Ultrasound follow-up was done
every month in patients randomized to observation.
The UK small aneurysm trial randomized 1090 patients aged
60 to 76 years with AAA of 4.0 to 5.5 cm to either open surgical
repair or periodic ultrasound surveillance.14 For those observed,
repair was done if the AAA exceeded 5.5 cm on follow-up ultra-
sound, or grew by more than 1 cm in a year. Follow-up averaged
4.6 years. Ninety-three percent of patients adhered to the assigned
treatment. The 30-day operative mortality averaged 5.8%, and all
repairs were open. At 2, 4, and 6 years, there was no difference
in the main endpoint mortality between the two groups. Sixty
percent of the patients in the observation group ended up getting
the AAA repaired at a median of 2.9 months after enrollment. The
operative mortality in that group was 7%. The initial size of the
AAA did not correlate with the need for operative repair, a finding
different form the ADAM trial.
The UK trial also followed a cohort of patients with AAAs
who were not randomized for a variety of reasons including
patient refusal or unfitness. This cohort was followed prospective-
ly.15 Seventy-six percent of the ruptures occurred in AAA larger
than 5 cm. The risk of rupture was associated with female sex,
larger initial diameter, current smoking, and higher mean blood
pressure. These risk factors have been reported in other retrospec-
tive studies. A low forced expiratory volume has also been associ-
ated with risk of rupture.
There were no women in the ADAM trial and only 17% of
participants in the UK trial were female. Some retrospective stud-
ies have suggested that at a given size, women have higher risk of
rupture, and a higher mortality when rupture occurs. Therefore
the results of the above studies should be interpreted with caution
in women.
Since both the ADAM trial and the UK small aneurysm trial
were of open repair versus observation, another trial was con-
ducted of EVAR versus observation in patients with AAA sized
4 to 5 cm. The PIVOTAL (Positive Impact of Endovascular Options
for Treating Aneurysms Early) trial randomized 366 such patients
to early EVAR and 362 patients to periodic ultrasound surveil-
lance.16 After a mean of 12 months, there was no difference in
overall mortality between the two groups (4.1%) or AAA-related
mortality (0.6%).
Retrospective studies have shown that the risk of rupture
increases exponentially once the diameter exceeds 6 cm.
In summary, in men, it seems reasonable to delay surgi-
cal treatment until AAA diameter size reaches 5.5 cm (Level I
PMPH_CH83.indd 662
evidence, Grade A recommendation). Follow-up should be on a 6
months basis in patients being observed. In some cases, justifica-
tion can be made for intervening on smaller sizes (greater than
5 cm) (Grade B recommendation). Women may warrant inter-
vention at smaller sizes than men (Level II evidence, Grade B
recommendation).
CHOICE OF REPAIR: OPEN VERSUS
ENDOVASCULAR
The UK’s EVAR1 trial randomized 1252 patients aged 60 years or
older with 5.5 cm or greater AAA with anatomy suitable to either
open repair (OR) or endovascular repair (EVAR) to either treat-
ment, at 1of 34 hospitals.17,18 Ninety-four percent of the patients
completed their allocated treatment. The 30-days mortality was
lower in EVAR (1.8% vs. 4.3%). After 4 years, all cause mortality
was similar in the two groups, although AAA-related mortality
was less in the EVAR group (4% vs. 7%). However, late complica-
tions were more frequent in the EVAR group (41% vs. 9%), even
after exclusion of the benign type 2 endoleak, with increased need
for reinterventions. At 10 years of follow-up, there was still no dif-
ference in all cause related mortality and there was no longer any
difference in AAA-related mortality between the two groups. That
difference evened out at 6 years. There was a 30% reintervention
rate in the EVAR group due to an increase in graft complications
compared to the OR group. The obvious criticism leveled at the
study has been that many of the grafts used were first or second
generation devices more prone to late complications than later
devices.
The Dutch Randomised Aneurysm Management trial
(DREAM) randomized 351 patients with AAA greater than 5 cm
suitable for both techniques to either OR or EVAR.19,20 Operative
mortality was lower for EVAR (1.2%) as opposed to OR (4.6%), as
were early complications. However, at 6 years of follow-up, there
was again no difference in all cause related mortality. The survival
curves crossed at 2 years. At 6 years, there was a 30% reinterven-
tion rate in the EVAR group versus 18% in the OR group.
The OVER trial (open vs. endovascular repair) was conducted
by the US Department of Veterans affairs and randomized 881
patients from 42 VA Hospitals. Patients had to be candidates for
OR and EVA R.21 The 2-year outcomes have been reported. Once
again, 30-day mortality was lower for EVAR than OR (0.5% vs. 3%)
with less blood loss and shorter hospital stays. Overall, mortality
again was similar at 2 years (7% vs. 9.8%), with similar reinterven-
tion rates between the two groups. This latter result is different
than that reported by the UK and Dutch trials. It likely reflects the
inclusion of incisional hernias as a complication as well as a more
conservative approach toward type 2 endoleaks.
A French randomized prospective trial of open versus EVAR
for AAA dubbed ACE has been completed, but the results have
not been released as of the date of this writing. From these stud-
ies, it is clear that EVAR is associated with less operative blood
loss, lower 30-days mortality, but not any lesser long-term mor-
tality, and it is associated with a higher rate of late interventions
(Level I data). For patients with relatively limited long-term life
expectancy, EVAR will likely be the procedure of choice (Grade A
recommendation). For younger healthier patients the jury is still
out as to what the preferred treatment modality should be.
5/22/2012 5:57:08 PM

PATIENTS UNFIT FOR OR
The EVAR 2 trial Endovascular Aneurysm Repair evaluated the
results of EVAR in patients judged to be unfit for OR.22,23 From
1999 through 2004, 404 patients in the United Kingdom with
AAA > 5.5 cm considered unfit for open AAA repair were ran-
domized to either EVAR or observation. Aneurysm related mor-
tality was lower in the EVAR group, but this did not result in an
improvement or benefit in total mortality. Twenty-seven percent
of patients in the EVAR subgroup required reintervention in the
first 6 years. The trial has been criticized because of the long delays
in getting patients to the OR in the subgroup randomized to
EVAR, the relatively high 30-days mortality of 7.3%, as well as the
high degree of crossover into EVAR from the group randomized
initially to observation. It is, however, the only Level I evidence
available in this field.
The Eurostar registry, which collects data from 101 European
sites, published a report on 399 patients considered unfit for open
surgery for anatomic or physiologic reasons.24 The early and late
mortality rates were higher in this group compared to patients
considered fit (3-year survival of 68% vs. 83%). On the basis of a
mathematical model, the authors concluded that EVAR is of ben-
efit in prolonging life if the life expectancy is longer than 1 year.
Finally, a retrospective US study looking at EVAR in patients
considered at high risk for open surgery evaluated outcomes in
565 such patients.25 The 30-days mortality was 2.9%, the AAA-
related death rate at 4 years was 4.2%, and overall mortality at
4 years was 56%. The authors concluded that EVAR in such
patients affords protection against AAA-related mortality. Some
have suggested that the patients in this study may not have been
as unfit as those in the Eurostar registry.
From these studies, one may conclude that EVAR in patients
at high risk for open surgery does result in a decrease in AAA-
related mortality (Level I evidence). It may not improve overall
mortality over time and must therefore be offered only to non-
moribund patients (Grade A recommendation).
ENDOVASCULAR REPAIR:
CHOICE OF DEVICES
There are currently six devices for EVAR on the market in the
United States (AneuRx, Talent and Endurant from Medtronic,
Excluder from Gore, Zenith from Cook , and Endologix). Direct
randomized controlled trials comparing devices directly have not
been performed. All devices were FDA approved via clinical trials
comparing EVAR with the device under study versus open AAA
repair.
The Eurostar registry (European Collaborators on Stent
Graft Techniques for Aortic Aneurysm Repair) enrolled patients
from 1996 to 2005. It includes a majority of patients treated
with AneuRx, Talent, Excluder, and Zenith, but hardly any with
Endologix. Distal migration of the stent graft was most common
with AneuRx and Talent and least common with Zenith. Zenith
had the highest rate of limb occlusion. Excluder had the lowest
rate of AAA size shrinkage. Some of these findings such as migra-
tion differences have been reported in single center retrospective
studies, but such studies typically have had low number of patients
and are therefore subject to potential errors.26,27
PMPH_CH83.indd 663
Abdominal Aortic Aneurysm ■ 663
The Lifeline Registry is pooled data from industry spon-
sored trial comparisons of OR versus EVAR of AAA.28 It does not
include any Zenith cases. It is not useful in comparing individual
devices. Individual center series are usually limited by the num-
ber of cases.
A retrospective review of 565 elective EVAR cases from Bos-
ton showed that reintervention rates were comparable between
devices, with all devices performing worse if used outside the
described indications for use.29
It appears that devices with active fixation (hooks or barbs) and
devices with suprarenal fixation may have less migration than others
(Level II evidence). Limb occlusion rates may be different between
various devices as well, as well as rates of AAA sac shrinkage. One
should choose the device that fits best a given patient anatomy.
ENDOVASCULAR REPAIR:
MANAGEMENT OF ENDOLEAKS
A type 1 endoleak, which represents an attachment site failure, is
widely recognized to need treatment in order to prevent aneurysm
sac rupture. Type 1 endoleaks will happen 5% to 10% of the time
on follow-up, depending on the population study and how well the
device indications for use (IFU) are followed. Endovascular options
(cuff, angioplasty, bare stent) or open surgical conversion should be
entertained (Level IIA evidence, Grade A recommendation).
A type 2 endoleak indicates flow around the stent graft in the
aneurysm sac, usually from the lumbar or inferior mesenteric arter-
ies. A majority of these will resolve with observation, and a period
of observation can be recommended in the absence of aneurysm
enlargement. A recent review of such endoleaks from the United
Kingdom showed that only 24% were associated with AAA sac
size expansion. However, other reviews have suggested that up to
20% of ruptures after EVAR are due to type 2 endoleaks. There are
no prospective randomized trials in this regard, but mostly retro-
spective reviews and a few short-term prospective series. There is,
however, agreement that, in the case of AAA enlargement (more
than 5 mm in 6 months or more than 10 mm from pre-EVAR
size), intervention should be considered. The endoleak can often
be addressed by endovascular means (coil embolization, oblitera-
tion of the cavity); other options include surgical control of the
feeding vessels, or plain stent graft explantation and open conver-
sion (Level IIA evidence, Grade A recommendation).30-35
A recent review of 1768 EVAR cases from one institution
over an 8-year period showed that 19.2% of patients required
secondary interventions, with type 2 endoleaks accounting for
40% of those interventions.36 That institution, however, followed
an aggressive program of interventions for type 2 endoleaks pres-
ent at 6 months without decrease in AAA sac diameter. Mortality
data were provided but the long-term durability of the secondary
interventions was not clarified.
OR: TRANSABDOMINAL VERSUS
RETROPERITONEAL
Both the retroperitoneal (RP) and transabdominal or transperi-
toneal (TP) approaches to open AAA repair have had their propo-
nents over the years.
5/22/2012 5:57:08 PM
 664 ■ Surgery: Evidence-Based Practice
Sicard et al. randomized 145 patients between the two app-
roaches and found that the incidence of prolonged ileus and small
bowel obstruction was less in the RP group, whereas incisional pain
was more frequent. There was a trend toward shorter hospitalization
in the RP group. However, in that study, the percentage of patients
with COPD was significantly higher in the RP group.37
Cambria et al. randomized 113 patients between the RP
and TP approaches. They found no differences between the two
approaches in terms of operative or postoperative complications.
Nearly 80% of the patients had epidural anesthesia.38
A very small prospective randomized trial in 35 patients
showed improved intestinal function and shorter hospital stay
with the use of the RP approach.39
Most others studies in this subject have been retrospective
series by proponents of the retroperitoneal approach, suggest-
ing its superiority in terms of fluid requirements, resumption of
intestinal function, and length of intensive care unit (ICU) stay.
A recent retrospective review has suggested that the RP approach
may be beneficial for suprarenal clamping in the treatment of jux-
tarenal aneurysms.40-44
The best analysis of all this data is that both approaches are
clearly acceptable and likely equivalent today (Level II evidence,
Grade B recommendation). There are clear-cut indications for the
RP approach such as the presence of multiple prior laparotomies,
right-sided stomas, inflammatory aneurysms, horseshoe kidneys,
and massive morbid obesity. Control of the suprarenal aorta may
be relatively easier with that approach, whereas exposure of the
right renal artery may be quite difficult. A large right iliac aneu-
rysm may also be challenging to control with the RP approach.
PRESERVATION OF COLLATERAL FLOW
IN OR AND EVAR
A major complication of AAA repair by any modality is the
development of mesenteric ischemic complications, especially
ischemic colitis (IC). A ruptured aneurysm and prolonged
Summary Table
Clinical Issue
Risk factors for AAA are smoking, age, white race, and family history.
Screening is effective in reducing AAA-related mortality.
Smoking cessation should be recommended for patients with AAA.
AAA repair should be considered when the diameter exceeds 5 to 5.5 cm.
EVAR is associated with decreased early morbidity and mortality, but similar to open
repair on longer-term follow-up.
EVAR is preferable in patients with numerous comorbidities.
Stent grafts with active fixation mechanisms seem to be less prone to migration.
Type II endoleaks with increase in AAA size should be treated.
The transabdominal and the retroperitoneal approaches for open repair produce
equivalent results.
It is preferable to try to maintain flow to at least one hypogastric artery during EVAR.
EVAR for AAA should be considered whenever possible.
PMPH_CH83.indd 664
hypotension are two accepted risk factors for the development of
this complication.
A number of retrospective studies, single center and multi-
center, have examined the role of the inferior mesenteric artery
(IMA) and the internal iliac arteries (IIAs) in the development
of this complication in open aneurysm repair.45-47 The results are
conflicting, with some studies suggesting that failing to preserve
flow to a patent IMA may lead to IC, with others failing to find
a correlation. Some studies have also found a decreased inci-
dence of IC in cases where flow can be preserved to at least one
IIA, whereas others have not. Broad recommendations cannot be
made therefore, although it appears prudent to preserve flow to a
patent (but poorly backbleeding) IMA, or to at least one IIA (Level
II evidence, Grade B recommendation), especially in cases where
the normal collateral network may have been disrupted, such as
from prior colon operations.
Buttock claudication is fairly common after IIA emboliza-
tion prior to stent graft placement, occurring in nearly one-third
of cases. More severe complications such as buttock necrosis or
ischemic colitis are far less common. Different retrospective series
have reported conflicting results on the risk associated with bilat-
eral IIA embolization for stent graft placement.48-50 If possible, it
makes sense to try to preserve flow to at least one IIA (since the
IMA is routinely covered in EVAR). This could be accomplished
by open reimplantation of the IIA on the distal external iliac
artery (EIA) or by the use of branches of endografts now becom-
ing available (Level IIb evidence, Grade B recommendation).
5. Should EVAR be used for ruptured aneurysms?
There are no randomized controlled trials comparing OR and
EVAR for ruptured aneurysms. Many retrospective and cohort
studies suggest that in patients with ruptured aneurysms who are
EVAR candidates, the use of EVAR may be associated with a lower
mortality and morbidity (Level IIb evidence).51,52 The big issue to
consider is whether the facility is equipped with all that is needed
for EVAR repair. EVAR for ruptured AAA should be considered
when possible (Grade B recommendation).
Level of Grade of
Evidence Recommendation
I NA
I A
I A
I A
I NA
I A
II B
II A
II B
IIb B
IIb B
5/22/2012 5:57:08 PM

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10. Sukhija R, Aronow WS, Sandhu R, et al. Mortality and size of
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Cardiol. 2006;97:279-280.
11. Baxter BT, Pearce WH, Waltke EA, et al. Prolonged admin-
istration of doxycycline in patients with small asymptomatic
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multicenter study. J Vasc Surg. 2002;36:1-12.
12. Mosorin M, Juvonen J, Biancari F, et al. Use of doxycycline to
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13. Vammen S, Lindholt JS, Ostergaard L, et al: Randomized double-
blind controlled trial of roxithromycin for prevention of abdom-
inal aortic aneurysm expansion. Br J Surg 2001; 88:1066-1072.
14. Mortality results for randomised controlled trial of early elective
surgery or ultrasonographic surveillance for small abdominal
aortic aneurysms. The UK Small Aneurysm Trial Participants.
Lancet 1998;352:1649-1655.
15. Brown LC, Powell JT. Risk factors for aneurysm rupture in
patients kept under ultrasound surveillance. The UK Small
Aneurysm Trial. Ann Surg. 1999;230(3):289-296.
16. Ouriel K, Clair DG, Kent KG, Zarins CK. Endovascular repair
compared with surveillance for patients with small abdominal
aortic aneurysms. J Vasc Surg. 2010;51:1081-1087.
17. Endovascular aneurysm repair versus open repair in patients
with abdominal aortic aneurysm (EVAR trial 1): randomised
controlled trial. Lancet. 2005;365:2179-2186.
18. The United Kingdom EVAR trial investigators. Endovascular
versus open repair of Abdominal Aortic Aneurysm. N Engl J
Med. 2010;362:1863-1871.
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19. Prinssen M, Verhoeven EL, Buth J, et al. A randomized trial
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20. De Bruin JL for the DREAM study group. Long term outcome
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32. Brewster DC, Jones JE, Chung TK, et al. Long-term outcomes
after endovascular abdominal aortic aneurysm repair: the first
decade. Ann Surg. 2006;244:426-438.
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34. Conrad MF, Adams AB, Guest JM, et al. Secondary intervention
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35. Mehta M, Sternbach Y, Taggert JB, et al. Long term outcomes
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36. Jones JE, Atkins, MD, Brewster DC, et al. Persistent type 2
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37. Sicard GA, Reilly JM, Rubin BG, et al. Transabdominal versus
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38. Cambria RP, Brewster DC, Abbott WM, et al. Transperitoneal
versus retroperitoneal approach for aortic reconstruction: a ran-
domized prospective study. J Vasc Surg. 1990;11:314-353.
39. Arya N, Sharif MA, Lau, LL, et al. Retroperitoneal repair of
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40. Todd GJ, DeRose Jr JJ. Retroperitoneal approach for repair of
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41. Arko FR, Bohannon WT, Mettauer M, et al. Retroperitoneal
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42. Darling 3rd C, Shah DM, Chang BB, et al. Current status of the
use of retroperitoneal approach for reconstructions of the aorta
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43. Sieunarine K, Lawrence-Brown MM, Goodman MA. Comparison
of transperitoneal and retroperitoneal approaches for infrarenal
aortic surgery: early and late results. Cardiovasc Surg. 1997;5:71-76.
44. Wahlgren C, Piano G, Desai T, et al. Transperitoneal vs retroperi-
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2007;21(6):687-694.
45. Pittaluga P, Batt M, Hassen-Khodja R, et al. Revascularization
of internal iliac arteries during aortoiliac surgery: a multicenter
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46. Van Damme H, Creemers E, Limet R. Ischaemic colitis following
aortoiliac surgery. Acta Chir Belg. 2000;100:21-27.
47. Bast TJ, van der Biezen JJ, Scherpenisse J, et al. Ischaemic disease
of the colon and rectum after surgery for abdominal aortic aneu-
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Vasc Surg. 1990;4:253-257.
48. Rayt HS, Bown MJ, Lambert KV, et al. Buttock claudication and
erectile dysfunction after internal iliac artery embolization in
patients prior to endovascular aortic aneurysm repair. Cardio-
vasc Intervent Radiol. 2008;31:728-734.
49. Karch LA, Hodgson KJ, Mattos MA, et al. Adverse consequences
of internal iliac artery occlusion during endovascular repair of
abdominal aortic aneurysms. J Vasc Surg. 2000;32:676-683.
50. Mehta M, Veith FJ, Ohki T, et al. Unilateral and bilateral hypo-
gastric artery interruption during aortoiliac aneurysm repair
in 154 patients: a relatively innocuous procedure. J Vasc Surg.
2001;33:S27-S32.
51. Veith FJ, Lachat M, Mayer D, et al. Collected world and single cen-
ter experience with endovascular treatment of ruptured abdomi-
nal aortic aneurysms. Ann Surg. 2009;250:818-824.
52. Holst J, Resch T, Ivancev K, et al. Early and intermediate outcome
of emergency endovascular aneurysm repair of ruptured infrare-
nal aortic aneurysm: a single center experience of 90 consecutive
patients. Eur J Vasc Endovasc Surg. 2009;7:413-419.
5/22/2012 5:57:08 PM
 Commentary on
Abdominal Aortic Aneurysm
Gregorio Sicard
The chapter titled “Abdominal Aortic Aneurysm” by Dr Boulos
Toursarkissian provides an outstanding review of the risk factors,
diagnosis, and treatment of infrarenal abdominal aortic aneu-
rysms based on current levels of evidence. These selected reviews
of levels of evidence and recommendations will serve as practice
guidelines for healthcare providers who care for patients with this
condition.
Abdominal aortic aneurysm (AAA) is a common vascular
condition, the incidence of which increases as the population
ages. As a disease of the elderly, this condition has undergone
extensive scrutiny of its pathobiology, diagnosis, and best thera-
peutic options. As with any other complex disease, many ques-
tions remain unanswered by lack of sufficient strong evidence
and reflects the need for further work to strengthen or modify the
recommendations. This chapter by Dr Toursarkissian addresses
some of the main issues that are important for the diagnosis and
treatment of this condition, and the level of scientific evidence
currently available to support the practice recommendations.
In this chapter Dr Toursarkissian presents strong levels of evi-
dence that identifies those important risk factors such as smoking,
gender, and family history that have been clearly associated with
the development of AAA. Dr Toursarkissian addresses the fre-
quently controversial issue of which patients should be screened
and what the patient characteristics are that best defines the popu-
lation that may benefit from such screening to yield a high inci-
dence of early detection.
An important and related area of investigation addressed in
this chapter is whether pharmacologic treatment can influence
the progression or stabilization of the growth of an AAA. Con-
siderable progress has been made over the past 20 years defi n-
ing the pathologic processes responsible for the development
of AAA.
However, there is a general agreement among investiga-
tors that one of the most important factors in the formation and
continued growth of aneurysms is the destruction of the medial
lamellar structure by elastolytic tissue enzymes known as metal-
loproteinases (MMPs). Many studies using animal models have
confi rmed the positive effect of an MMP inhibitor such as doxy-
cycline in AAA growth. Dr Toursarkissian reviews some of the
recent studies that have attempted to pharmacologically affect
the growth rate of small aneurysms. A few interesting studies
667
PMPH_CH83.indd 667
have demonstrated reduction in rate of growth of AAA in short
courses of tetracycline both in intact aneurysms and in endograft-
treated patients. The lack of robust randomized control trials
has made it difficult to generate strong levels of evidence and
therapeutic recommendations at this point. Phase I trials have
established the safety profi le of this pharmacologic treatment in
a clinical setting. A novel medical therapy trial for small AAA
is currently being reviewed by the National Institute of Aging,
which anticipates to receive funding for the trial. The noninva-
sive treatment for abdominal aneurysm clinical trial (N-TA3CT)
is a randomized, double blind, and placebo controlled study that
is aimed at detecting a significant reduction in the growth rate
of an aneurysm of between 3.5 and 5.0 cm. Th is study is sched-
uled to enroll over 240 patients selected in 15 centers. The vas-
cular community eagerly awaits this trial as it may defi ne the
importance of early detection and the pharmacologic treatment
of small aortic aneurysms.
Since the first report in 1991 by Parodi and collaborators,
endovascular repair of abdominal aortic aneurysm (EVAR) has
achieved worldwide acceptance. The levels of evidence and rec-
ommendations of this innovative therapeutic approach is based
on well-constructed randomized trials performed in the United
States, United Kingdom, and Europe. All of these studies have
clearly and universally demonstrated the early benefits in mortal-
ity and morbidity of the endovascular approach over the standard
open surgical repair. Longer-term follow-up of both therapeutic
approaches also show similar outcomes. In his chapter, Dr Tour-
sarkissian nicely reviews the levels of evidence and grades of rec-
ommendation to the most common problems associated with this
new less-invasive therapeutic approach for treating AAA. Simi-
larly, because of the paucity of high levels of evidence for com-
parisons of EVAR for ruptured aneurysms, Dr Toursarkissian
identifies the need for further research in this group of patients
with symptomatic aneurysms.
In summary, this excellent chapter by Dr Toursarkissian
demonstrates the significant progress that has been achieved
in the diagnosis and treatment of this common condition. By
identifying the levels of evidence in selected areas, he has pro-
vided practice recommendations, and as a result of the analysis,
areas that need further research to advance the field have been
identified.
5/22/2012 5:57:08 PM
 668 ■ Surgery: Evidence-Based Practice
REFERENCES
1. Chaikof EL, Brewster DC, Dalman RL, et al. The care of pat-
ients with abdominal aortic aneurysm: the Society for Vascular
Surgery practice guidelines. J Vasc Surg. 2009; October
(Supplement).
2. Lindeman JHN, Abdul-Hussien H, van Bockel JH, Wolterbeek
R, Kleeman R. Clinical trial of doxycycline for matrix metallo-
proteinase-9 inhibition in patients with an abdominal aneurysm:
PMPH_CH83.indd 668
doxycycline selectively depletes aortic wall neutrophils and cyto-
toxic T cells. Circulation. 2009;119:2209-2216.
3. Masorin M, Juvonen J, Biancari F, et al. Use of doxycycline
to decrease the growth rate of abdominal aortic aneurysms: a
randomized, double-blind, placebo-controlled pilot study. J Vasc
Surg. 2001;34:606-610.
4. Hackman AE, Rubin BG, Sanchez LA, Geraghty PA, Thompson RW,
Curci JA. A randomized, placebo-controlled trial of doxycycline
after endoluminal aneurysm repair. J Vasc Surg. 2008;48:519-526.
5/22/2012 5:57:08 PM

INTRODUCTION
Aortic dissection is both a misunderstood and fearful entity. Often
referred to as a dissecting aneurysm, aortic dissection can occur
both in the setting of atherosclerotic degenerative aneurysm and
in normal sized aorta. More recent attempts have been made to
classify the anatomic and physiologic response of the acute aor-
tic syndrome. It is clear that the risk of aortic dissection goes
beyond the anatomic malady and is a systemic process. This likely
accounts for the relatively high mortality of even the most benign
presentations.
The nomenclature of aortic dissection is critical to under-
standing treatment recommendations. The most important dis-
tinction is related to the site of the initial entry tear as any
dissection proximal to the left subclavian artery is considered a
surgical emergency, whereas others may be considered for medi-
cal management. The simplest classification is the Stanford system
that uses the treatment recommendations and is Stanford type A
Dissection (type A dissection) for any dissection involving the
aortic arch proximally and type B Dissection (type B dissection)
for those at or distal to the left subclavian artery.1 Aortic dissec-
tion is defined temporally as well, owing to Dr Crawford’s descrip-
tion that 74% of all mortalities with a new dissection occur within
14 days.2 Hence, acute aortic dissections are of <14-days duration
and chronic aortic dissections are of >14-days duration.
Acute aortic dissection is the most common aortic emer-
gency, nearly doubling the incidence of ruptured aneurysm.3 Left
untreated, acute aortic dissection carries a mortality of 1% to 2%
per hour with a >90% mortality at 1 week.4 Acute type A dissec-
tion is the most lethal presentation. The mortality is mainly related
to dissection into the aortic root leading to valvular dysfunction,
coronary ischemia, tamponade, free rupture, or some combina-
tion of these events. Surgical replacement of the ascending aorta
with valve and coronary artery repair as indicated has been proven
as the definitive treatment of acute type A dissection with a surgi-
cal mortality as low as 9%.5 The decision making for acute type A
dissection is clear as the majority of untreated patients will die.
As such, the focus of this chapter will be on the decision making
669
PMPH_CH84.indd 669
CHAPTER 84
Aortic Dissection
Benjamin J. Pearce
behind the evaluation and treatment of acute type B dissection in
the evolving era of advanced imaging and endovascular therapy.
EPIDEMIOLOGY
1. Who gets aortic dissection and how do they present?
The largest contemporary attempt at evaluating aortic dissection is
the International Registry of Acute Aortic Dissection (IRAD) data-
base. This registry is composed of 21 international referral centers
for aortic pathology and published the initial analysis of the registry
in 2000.6 Multiple subsequent cohort analyses have been published
to evaluate nuances of aortic dissection and long-term survival, and
the most recent publication encompasses 1417 patients.7
The peak incidence of type B dissection is in the seventh
decade of life and the most common risk factor is hypertension,
which is present in 72% of patients prior to presentation of dissec-
tion.6 Males are predominately at risk, accounting for 70% of all
type B dissection. Personal history of atherosclerotic disease has
not been described as an absolute risk factor for dissection;8 how-
ever, in a large series of open repairs done to treat acute aortic dis-
section, atheroma or plaque was found in the suspected lead point
of the dissection in up to 83% of patients.9 Likewise, Marfan’s
disease is a well-described risk factor for all aortic pathology,10
yet only 4.9% of patients in the IRAD database had documented
Marfan’s disease.6 The incidence of aortic dissection in pregnancy
is quite small, but in pre-eclampsia it can be as high as 13%.11 The
overwhelming majority of these are type A dissections initiat-
ing at the sinotubular junction in the absence of atherosclerosis.
Another infrequent overall population is iatrogenic dissection
from another endovascular procedure. However, with the number
of endoluminal procedures for all arterial pathology increasing
yearly, a history of recent catheterization cannot be overlooked.
The most common presentation is acute onset of severe and
localized pain.8 However, the presence of chest, back, or abdominal
pain has been reported as low as 63%, 64%, and 43% respectively
in acute type B dissection8 versus pain as a presenting symptom in
85% of type A dissections.6 Therefore, not all patients with aortic
5/22/2012 5:57:42 PM
 670 ■ Surgery: Evidence-Based Practice
dissection will have pain, and clinical suspicion should remain
high in evaluation of the hypertensive patient with other vascular
deficits. Other manifestations of type B dissection include tran-
sient, or persistent, spinal cord ischemia in 2% to 10%,12 anuria,
mesenteric ischemia, lower extremity pulse deficit, and acute
congestive heart failure (CHF) from severe afterload increase in
patients with significant proximal true lumen collapse.6 In addi-
tion to important clinical signs leading to diagnosis, these fea-
tures are critical signs of malperfusion and will aid in directing
subsequent therapy. An often overlooked presenting feature of
acute dissection is syncope. As high as 20% of patients with type A
dissection can have syncope from involvement of the aortic valve
or cerebral perfusion. Yet even true type B dissection patients can
present with syncope from activation of aortic baroreceptors.8
Careful evaluation for presenting symptoms and physical exam
findings of malperfusion will lead to expeditious workup and ini-
tial therapy. The cost of misdiagnosis is high with 20% mortality in
acute type B dissection at day 2 if presenting with malperfusion.8
DIAGNOSIS
2. What modalities are appropriate for diagnosis and thera-
peutic planning?
Unfortunately, acute chest pain is one of the most frequent pre-
sentations in emergency visits. Contrast-based imaging is not
necessary in the majority of these cases, thus careful correlation
between history and physical findings as described above can
prompt efficient diagnostic evaluation.
Plain chest x-ray is often included in the initial workup for
chest pain. This is not adequate for confirmation of diagnosis;
however, close observation for potential aortic pathology on plain
radiograph can lead a clinician to an appropriate imaging study.
Widening of the mediastinum or left-sided pleural eff usion should
be assessed on chest x-ray.13 Historically, patients with a question
of dissection underwent conventional catheter-based aortogra-
phy.14 Intravascular ultrasound (IVUS) performed at the time of
angiography can yield useful information regarding the location
of the entry tear in relation to branch vessels, location of fenes-
trations, the nature of malperfusion to visceral and extremity
branches, and sizing for potential therapy. With the improvement
in computed tomography angiography (CTA) and magnetic reso-
nance angiography (MRA), conventional angiography has largely
been replaced for diagnostic purposes.
CTA is the overwhelming diagnostic study of choice with sensi-
tivity and specificity reported as high as 95%. One continuous scan
of the chest, abdomen, and pelvis can not only confirm the diagno-
sis, but can provide essential information for planning of potential
interventions. Evaluation of a helical scan of the aorta from the root
to the femoral bifurcation can determine the true lumen from the
false one by the continuity to the undissected arch segment. In addi-
tion, the false lumen is the larger of the two lumens in acute type B dis-
section in >90% of cases. These features allow the surgeon to evaluate
the perfusion of the visceral and extremity branches and determine
potential need for intervention.15 In addition, the nature of the flap
can yield important information regarding chronicity of the injury.
Acute dissection flaps are bowed in over 60% of patients due to pres-
sure differential between the two lumens. Conversely, the flap is flat
in chronic dissection as the pressures have equalized over time.15 As
patients can have delayed presentation, or occasionally incidental
findings of dissection, these features may aid in determining acuity.
PMPH_CH84.indd 670
Similar to CT scanning, MRA is an excellent noninvasive
test for evaluation of aortic dissection with sensitivity and speci-
ficity also approaching 100%.16,17 Similar to CTA, MRA can pro-
vide valuable detail regarding branch vessel involvement and
operative planning. In addition, there is hope that the emerging
technique of dynamic MR may provide important information
to predict success of medical versus surgical treatment owing to
improved evaluation of the nature of obstruction by the aortic
flap. Unfortunately, MR requires longer scan times and decreased
access to the patient during the scan, in addition to exclusion of
patients with implants.
All contrast-based imaging modalities (angiography, CTA,
MRA) increase the risk of nephropathy in patients already at
increased risk for renal failure due to malperfusion, chronic hyper-
tension, or acute shock. Thus, additional diagnostic modalities may
be considered before administration of contrast in patients with ele-
vated creatinine or documented anaphylactic reactions to contrast.
Echocardiography, either transthoracic (TTE) or transesophageal
(TEE), was the first diagnostic test in 33% of patients in the initial
IRAD database.6 Sensitivity and specificity of TEE in diagnosis of
acute dissection have been reported as >90%.18 Ultimately, an aver-
age of two diagnostic studies were utilized in confirming the diag-
nosis and formulating a treatment plan in the IRAD patients.6
MANAGEMENT
3. Which patients are appropriate for medical management
and which require operative intervention?
All patients diagnosed with acute type B dissection require imme-
diate initiation of anti-impulse therapy (unless presenting in
hypotensive shock) and movement to a critical care setting. Place-
ment of right arm arterial line, central venous access, and urinary
drainage catheterization is warranted. Patients should be main-
tained nil per os (NPO). The next critical decision is whether the
patients can be maintained successfully on medical therapy or
warrant surgical intervention.
Indications for immediate intervention include rupture, acute
aneurismal degeneration of the aorta (greater than 4-cm false
lumen or 5-cm total aortic diameter), and, most commonly, end
organ ischemia presenting as malperfusion syndrome. Malper-
fusion in the setting of acute aortic dissection is a complicated
mechanism dependent on the location of the entry tear, extent of
intimal flap, presence/absence/location of distal re-entry tears,
cardiac output, dissection of branch vessels, and thrombosis. The
two main types of obstruction are static and dynamic.
Static obstruction is relatively straightforward. As dissection
is carried to a visceral or extremity branch, the flap may propagate
into the branch itself. If no re-entry exists within the branch ves-
sel, the false lumen will often thrombose, leading to constriction
of flow into the branch and occlusion or severe hypoperfusion.
Conversely, the ostium of a branch vessel (commonly the left renal
artery) can be completely fed from the false lumen. In this sce-
nario, as long as flow is maintained within the false lumen, the
end organ remains perfused.19 However, if the false lumen is
thrombosed, or excluded by intervention, preservation of the end
organ perfusion will be dependent on reperfusion of the branch
via bypass or stenting across the intimal flap.
Dynamic obstruction is the most common cause of malperfu-
sion in acute type B dissection.20 Flow into the false lumen creates
a pressure differential between the two lumens. The most obvious
5/22/2012 5:57:42 PM

form of dynamic obstruction is when no re-entry tear exists in the
distal aorta. In this scenario, the false lumen pressure will greatly
exceed the true lumen and essentially compress the true lumen to
the extent that the entire aortic segment is hypoperfused. In this
setting, the afterload on the cardiac pump becomes so great that
it precipitates acute heart failure. Conversely, dissections often
have multiple sites of re-entry, or natural fenestration, between
the two lumens. During the cardiac cycle, the flow through the false
lumen can cause pulsation of the intimal flap to cover the ostium
of a branch vessel in systole; effectively creating hypoperfusion.
In an experimental model, it has been demonstrated that the
degree of dynamic obstruction is governed by cardiac output,
blood pressure, peripheral resistance, and location and size of the
entry and re-entry tears.21 An understanding of how these factors
combine to create malperfusion are essential for appropriate man-
agement of acute type B dissection.
Medical Therapy
In the uncomplicated, hypertensive patient, medical management
continues to be the mainstay of therapy for acute type B dissection.
In all patients with acute type B dissection, except those present-
ing with hypotensive shock, immediate control of heart rate, cardiac
output, and peripheral resistance can (1) prevent progression of the
entry tear; (2) prevent progression of the dissection flap; and (3) allow
for equalization of pressures between the true and false lumens.
No randomized trial has specifically compared pharmacologic
strategies for treatment of acute type B dissection. The goals of ther-
apy are to reduce systolic blood pressure to less than 120 mm Hg.
This is best achieved with a combination of pain control, inotropic/
chronotropic blockade, and afterload reduction. Often overlooked is
the importance of adequate analgesia. The contribution of acute pain
to the cascade of catecholamine release is significant, and appropri-
ate treatment with intravenous opiates is warranted. One of the most
feared complications of acute type B dissection is paraplegia from
spinal cord infarction either spontaneously or from treatment. As
such, the use of intrathecal analgesia is relatively contraindicated.
Initiation of therapy with β-blockade is the standard of care.22
The goal heart rate is <80 bpm. By initiating β-blockade early, reflex
tachycardia and catecholamine release are blunted with the initia-
tion of afterload reducing agents. Choice of a β-blocker, for example,
labetalol, with α and β adrenergic effects may achieve appropriate
cardiac and peripheral effects with a single agent. However, this may
precipitate pulmonary complications in at-risk patients and thus ini-
tiation of therapy with a short acting agent, for example, esmolol,
may be more prudent in selected cases.19 Initiation of sodium nitro-
prusside infusion after β-blockade has been an effective agent. How-
ever, recent data have shown similar efficacy of nicardipine infusion
in treatment of acute type B dissection without the risk of cyanide
toxicity.23 Conversion to oral β-blockade and oral afterload reducing
agents such as angiotensin converting enzyme inhibitors or minoxi-
dil are appropriate after patient is pain free for 48 hours.
Open Surgical Therapy
Historically, surgical therapy for complicated acute type B dissec-
tion required central aortic replacement with either obliteration
of false lumen flow via distal anastomosis, or open fenestration.
The largest early series of central aortic repair carried a mortal-
ity of 45% in 1986.9 And yet, in the most recent IRAD update on
surgically repaired type B dissection, the in-hospital mortality
PMPH_CH84.indd 671
Aortic Dissection ■ 671
remained at 30%.24 In addition, the indication of acute type B dis-
section carries the highest risk of spinal cord ischemia in series of
open thoracic aortic surgery.25,26 Central aortic repair has essen-
tially been reserved only for acute rupture or acute aneurysm for-
mation that cannot be excluded by endograft technology.
Endovascular Therapy
Endovascular therapy for acute type B dissection is aimed at both
treatment of malperfusion and stabilization of the aortic true
lumen. The most straightforward technique to achieve both goals
is thoracic endovascular aortic repair (TEVAR) with commercially
available covered stent grafts. Theoretically, TEVAR can exclude
the entry tear thus reducing pressure in the false lumen. Simul-
taneously, the stent supports the true lumen and flow is directed
preferentially into the true lumen to improve distal organ perfu-
sion. A few essential components unique to TEVAR warrant spe-
cial attention. Deployment of the stent graft within the true lumen
is perhaps the most important tenet in TEVAR for acute type B
dissection. Although this may seem intuitive, wire selection from
the femoral artery into the ascending aorta may pass from lumen
to lumen through multiple fenestrations. The adjunctive use
of IVUS can assure placement and prevent distal ischemia. Use of
right brachial access can also aid in appropriate wire access.
In addition, complete exclusion of the proximal entry tear is
necessary for both acute and long-term success. This requires cov-
erage of the left subclavian artery in up to 46% of cases in registry
data.27 Whenever coverage of the left subclavian artery is neces-
sary, careful evaluation of vertebral artery anatomy and presence
of internal mammary to coronary bypass is warranted. This also
is an independent risk factor for postoperative neurologic deficit.28
However, the incidence of permanent paraplegia is reported as low
as 0.8% with TEVAR for acute type B dissection29 and overall spi-
nal cord ischemia/stroke rate as low as 2.9%.30 As such, expectant
management of spinal cord complications with postoperative lum-
bar drainage and hypertensive management is well supported.31,32
Alternative, and/or adjunctive, endovascular techniques exist
to treat malperfusion. In addition to the malperfusion syndrome
of type B dissection, distal malperfusion persists in up to 25% of
patients after successful proximal correction of type A dissection.33
Endovascular correction of malperfusion can be achieved through
fenestration, aortic stenting, and branch artery stenting. However,
unlike TEVAR, endovascular management of malperfusion will not
have a long-term impact on the remodeling of the aorta or subse-
quent aneurysm formation. Endovascular management of malp-
erfusion requires wire access to each lumen and is often aided by
IVUS and brachial access. Power injection into the true lumen can
spuriously identify flow in the setting of dynamic obstruction and
should not be utilized for diagnostic purposes. To accurately assess
hypoperfusion, selection of the target vessel must be obtained and a
pressure gradient determined between the ascending aorta proximal
to the entry tear and the actual pressure within the branch vessel.34
Fenestration of the intimal flap immediately proximal to the
area of malperfusion can result in equalization of pressures and
restoration of flow in areas of dynamic obstruction. Confirma-
tion of wire access in both lumens and fenestration from the true
to false lumen with the use of various needles is the basic tech-
nique. Use of the Pioneer catheter (Medtronic Inc., Santa Rosa,
CA) allows for visualization of the flap and false lumen during
needle placement using IVUS. Once wire access is gained, the
fenestration is widened with a standard angioplasty balloon.
5/22/2012 5:57:42 PM
 672 ■ Surgery: Evidence-Based Practice
Conversely, an “endo-scissors” technique has been described in
which a sheath is advanced over both the true and false lumen
wires after fenestration.35
Stenting of branch arteries involved in static obstruction is
straightforward. If the dissection flap progresses into the branch,
true lumen access into the branch and use of standard stents
can support true lumen flow and restore perfusion. In cases of
dynamic obstruction, branch artery stenting usually requires
fenestration of the flap from the true to false lumen, expansion of
the fenestration with balloon angioplasty, and, ultimately, stent-
ing from the branch vessel across the flap into the true lumen.
Conversely, restoration of perfusion can be achieved with sup-
port of true lumen flow in the distal thoracic aorta using larger
stents36 and placement of appropriate branch stents distal to the
supported true lumen.
OUTCOME
4. What is the natural history of patients treated medically
versus surgically? Are there predictors of success with either
modality?
Acute aortic dissection continues to have significant morbidity
and mortality even in its most benign presentation. In the IRAD
database, 80% of type B dissection patients had no signs of malp-
erfusion and received medical therapy. And yet these patients still
had an in-hospital mortality of 10.7%6 and the long-term sequelae
of dissection in survivors is not benign. Onitsuka et al.37 demon-
strated a 13% rate of conversion to surgery in a group of 76 patients
randomized to medical therapy and 23% incidence of dissection-
related events including rupture and sudden death in the medical
cohort studied for 10 years. Others have reported a rupture risk of
18% during follow-up of medically treated type B dissection38 and
that 20% of all thoracoabdominal aneurysms have chronic dis-
section as the etiology.39 The overall 3-year mortality of patients
with type B dissection in the IRAD database who survived initial
hospitalization was 24.9%.40 In fact, in the interim analysis of the
IRAD data, the patients with the best 1- and 3-year survival are
those who survive open surgical intervention during their initial
presentation.7
Numerous factors have been evaluated for improved outcome
in patients with type B dissection. Successful surgical correction
in the acute phase likely leads to improved long-term survival via
obliteration of the false lumen while restoring normal perfusion
to the distal aortic segment and stabilizing aortic size. Akutsu
et al.41 demonstrated that in medically managed type B dissec-
tions followed over 10 years, patent false lumen was a significant
predictor of dissection-related death (HR = 5.6) and dissection-
related event (HR = 7.6). Mean aortic size and aortic growth rate
have been demonstrated as independent predictors of dissection-
related events during follow-up of medically treated patients.37
These observations support the potential benefit of excluding the
entry point of the aortic dissection with stent grafts. In a non-
randomized cohort, Dialetto42 demonstrated a thrombosed false
lumen rate of 75% in stent grafted patients versus 10.7% in medi-
cally treated patients. The same cohort showed aneurysmal degen-
eration in only 3.5% of the stent grafted patients versus 28.5% in
the medically treated group.
Stent graft technology is quickly replacing open graft replace-
ment as the treatment of choice for complicated type B dissection.
PMPH_CH84.indd 672
Ideally, TEVAR should offer patients improvement in hospital
mortality compared to traditional repair, while maintaining the
survival benefit demonstrated by surgical correction. Multiple
generations of thoracic endografts are now commercially avail-
able in various sizes, thus increasing the number of patients eligi-
ble for endovascular treatment of complicated type B dissections.
Technical success in device implantation covering the proximal
entry tear is between 86% and 95%.43-46
Perioperative 30-day mortality rates of TEVAR for compli-
cated type B dissection have been reported ranging from 3.2% to
13.3%.27,29-30,42-44 This mortality rate corresponds to reported mor-
tality of medically treated patients in historic controls and is bet-
ter than the expected open surgical mortality for these patients.
Effectively, endovascular techniques have shifted these patients
from the higher mortality associated with complicated dissec-
tion treated surgically to a lower mortality commensurate with
uncomplicated dissection.
Significant complications of permanent dialysis, spinal cord
ischemia, bowel ischemia, limb ischemia, and stroke can occur
in both medically and endovascularly treated patients. A meta-
analysis of stent grafts for type B dissection demonstrated a major
complication rate of 11.2% with neurologic deficits persisting in
only 2.9% of patients.30
In addition to acute improvement in outcomes, the goal of
endovascular therapy is to improve long-term remodeling of the
aorta and prevent late complications. Success in thrombosing
the segment of false lumen within the stented segment may not
change the overall risk. Nathanson et al.46 noted no reduction in
aortic size in TEVAR patients despite absence of endoleak in 71%
and bring into question the fate of the uncovered abdominal aorta as
demonstrated by a 56% rate of increase in abdominal false lumen
diameter. Likewise, Schoder et al.44 demonstrated that in TEVAR
treated patients, the false lumen thrombosed in the stented segment
in 90% of patients with significant diameter reduction in the aorta
at 2 years. However, in the segment of aorta adjacent to the stent, the
thrombosis rate dropped to 60% and in the distal aorta it was 22%.
In the distal segment a significant increase in aortic size was noted.
5. Has endovascular technology changed the treatment para-
digm for acute type B dissection?
To assess the potential for TEVAR to improve outcomes in patients
with type B dissection, a randomized trial comparing best medi-
cal therapy to elective TEVAR in uncomplicated type B dissection
was performed in Europe.47 The INvestigation of STEnt grafts in
patients with type B Aortic Dissection (INSTEAD) trial random-
ized patients 2 weeks after presentation to chronic medical therapy
versus TEVAR. This excluded patients who may have benefited from
TEVAR for acute malperfusion syndrome, but it was designed to
evaluate if freedom from chronic complications could be provided
by TEVAR. However, at 1 year, the all cause mortality was higher
in the TEVAR cohort than medical therapy (8.6% vs. 3%, p NS).48
This effect persisted at 2 years with survival in the medical cohort
of 96% and in the TEVAR cohort of 89% (p NS), although it is par-
tially attributed to the surgical mortality of 3%.49 Other complica-
tions included spinal cord ischemia in one medical patient and two
TEVAR, and one stroke in the TEVAR group. The trial did demon-
strate a significant rate of false lumen thrombosis and stabilization
of aortic size in 91% (P < .05) of TEVAR patients, whereas 16% of
medically treated patients required crossover into surgery due to
aneurysm expansion >6 cm during follow-up.49 Despite this effect,
5/22/2012 5:57:42 PM
 Aortic Dissection ■ 673

however, the all cause endpoints are not significantly different and
cannot justify the empiric use of TEVAR for uncomplicated dissec-
tion at this time. This is reflected in the 3-year follow-up analysis
of IRAD patients stratified by treatment. Survival in the medically
treated patients was 77% versus 76% in those treated with stent
graft.7 In essence, TEVAR can alter the risk of a complicated dis-
section into the same category as the uncomplicated dissection, but
current medical therapy has reached a threshold at which patients
with acute aortic pathology cannot be improved.
Likewise, alternative endovascular management of malper-
fusion has mixed results. In one of the largest series of balloon
fenestration, the technical success rate of resolving malperfusion
was 93%; yet the 30-day mortality was still 25%.50 In addition,
the aortic segments in patients treated with fenestration or tradi-
tional stents remain pressurized and have demonstrated expan-
sion in the postoperative period.51 In fact, these patients may be at
increased risk as fenestration should lead to persistent false lumen
flow and a decreased rate of thrombosis.
Chronic Dissection
The most common complication of survivors of acute dissection
is degeneration of dissected segment into aneurysm, occurring
in 20% to 40% of chronic type B dissections.52-53 More impor-
tantly, up to 60% of late mortality in patients with chronic type
B dissection is attributed to aortic-related death, either from
rupture, ischemia, or complications of subsequent repair of tho-
racoabdominal aneurysm.7 Among those suffering late mortal-
ity, independent risk factors for dissection-related death were
identified, these include female gender, atherosclerosis, aneu-
rysm at time of dissection, renal failure, and in-hospital shock.
CONCLUSION
Acute aortic dissection continues to be a significant source of diag-
nostic and therapeutic anxiety for patients and medical practitio-
ners. The spectrum of disease is severe with major morbidity and
mortality. Because of the acute nature of the disease process, very
little randomized data exist to guide optimal treatment practice.
However, a large amount of registry data have now been accumu-
lated to assess presentation, evaluation, and subsequent manage-
ment. Despite significant advances in endovascular technology,
the mainstay of treatment for uncomplicated dissection continues
to be medical therapy. Endovascular technique has improved the
outcome in patients requiring intervention.

Clinical Question Summary

Question Answer Levels of Grade of References
Evidence Recommendation
1 Who gets aortic Predominently males in seventh decade of life 1b A 6-12
dissection and how with history of hypertension. Acute pain and
do they present? hypertensive episode is the most common
presentation. Can also present with syncope,
pulse deficit, visceral ischemia, and paraplegia.
2 What modalities CTA and MRA are first-line studies. In patients 3b, 4 B 6, 15-18
are appropriate with acute renal failure or contrast allergy,
for diagnosis and TEE can confirm diagnosis before making
therapeutic planning? decision about adding contrast study.
3 Which patients are Unless presenting in shock, all patients warrant 2a, 3b, 4 B 6, 8, 22, 27,
appropriate for initiation of anti-impulse therapy with 29-30
medical management β-blockade and afterload reduction. Indication
and which for operative intervention are recurrent pain
require operative on appropriate anti-impulse therapy, acute
intervention? aneurismal expansion, rupture, end organ
malperfusion.
4 What is the natural The best outcome is in patients with successful 1b, 4 C 7, 37-41
history of patients surgical correction. Thrombosis of the
treated medically false lumen with either medical or surgical
versus surgically? Are management is the best long-term predictor
there predictors of of freedom from aortic-related morbidity/
success with either mortality.
modality?
5 Has endovascular Yes and no. Endovascular management has 1b, 2a, B 27, 29, 30,
technology changed essentially replaced open central aortic 2b, 4 42-44,
the treatment repair when surgery is indicated. This has 48-49
paradigm for acute dramatically improved the morbidity and
type B dissection? mortality of treatment for complicated
dissection. However, endovascular therapy
has not improved medical management in
uncomplicated patients.

PMPH_CH84.indd 673 5/22/2012 5:57:42 PM

 674 ■ Surgery: Evidence-Based Practice
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tic dissection: part II. Evaluation of treatment methods in phan-
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22. Nienaber CA, Eagle KA. Aortic dissection: new frontiers in diag-
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follow-up. Circulation. 2003;108(6):772-778.
23. Kim KH, Moon IS, Park JS, Koh YB, Ahn H. Nicardipine hydro-
chloride injectable phase IV open-label clinical trial: study on
the anti-hypertensive effect and safety of nicardipine for acute
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24. Trimarchi S, Nienaber CA, Rampoldi V, et al. for the IRAD Inves-
tigators. Role and results of surgery in acute type B aortic dis-
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Dissection (IRAD). Circulation. 2006;114(1 Suppl):I357-I364.
25. Estrera AL, Miller CC 3rd, Huynh TT, et al. Preoperative and
operative predictors of delayed neurologic deficit following repair
of thoracoabdominal aortic aneurysm. J Thorac Cardiovasc Surg.
2003;126(5):1288-1294.
26. Safi HJ, Miller CC 3rd, Reardon MJ, et al. Operation for acute and
chronic aortic dissection: recent outcome with regard to neurologic
deficit and early death. Ann Thorac Surg. 1998;66(2):402-411.
27. Pearce BJ, Passman MA, Patterson MA, et al. Early outcomes of
thoracic endovascular stent-graft repair for acute complicated
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Surg. 2008;22(6):742-749.
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rators on Stent/Graft Techniques for Aortic Aneurysm Repair
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29. Leurs LJ, Bell R, Degrieck Y, Thomas S, Hobo R, Lundbom J, for
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Endovascular treatment of thoracic aortic diseases: combined
experience from the EUROSTAR and United Kingdom Thoracic
Endograft registries. J Vasc Surg. 2004;40(4):670-679.
30. Eggebrecht H, Nienaber CA, Neuhäuser M, et al. Endovascular
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31. Tiesenhausen K, Amann W, Koch G, Hausegger KA, Oberwalder
P, Rigler B. Cerebrospinal fluid drainage to reverse paraplegia after
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2000;7(2):132-135.
32. Chiesa R, Melissano G, Marrocco-Trischitta MM, Civilini E,
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35. Beregi JP, Prat A, Gaxotte V, Delomez M, McFadden EP. Endo-
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36. Patel HJ, Williams DM, Meerkov M, Dasika NL, Upchurch GR
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thoracic aortic endovascular repair. J Thorac Cardiovasc Surg.
2009;138(2):300-308.
37. Onitsuka S, Akashi H, Tayama K, et al. Long-term outcome and
prognostic predictors of medically treated acute type B aortic
dissections. Ann Thorac Surg. 2004;78(4):1268-1273.
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38. Juvonen T, Ergin MA, Galla JD, et al. Risk factors for rupture
of chronic type B dissections. J Thorac Cardiovasc Surg. 1999;
117(4):776-786.
39. Black JH, Cambria RP. Aortic Dissection: perspectives for the
vascuar/endovascular surgeon. In: Rutherford’s Vascular Surgery.
6th ed., Chapter 104. Philadelphia, PA: Elsevier Saunders; 2005.
40. Tsai TT, Evangelista A, Nienaber CA, et al.for the International
Registry of Acute Aortic Dissection. Partial thrombosis of the
false lumen in patients with acute type B aortic dissection. N
Engl J Med. 2007;357(4):349-359.
41. Akutsu K, Nejima J, Kiuchi K, et al. Effects of the patent false
lumen on the long-term outcome of type B acute aortic dissec-
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42. Dialetto G, Covino FE, Scognamiglio G, et al. Treatment of type
B aortic dissection: endoluminal repair or conventional medical
therapy? Eur J Cardiothorac Surg. 2005;27(5):826-830.
43. Xu SD, Huang FJ, Yang JF, et al. Endovascular repair of acute type
B aortic dissection: early and mid-term results. J Vasc Surg. 2006;
43(6):1090-1095.
44. Schoder M, Czerny M, Cejna M, et al. Endovascular repair of acute
type B aortic dissection: long-term follow-up of true and false
lumen diameter changes. Ann Thorac Surg. 2007;83(3):1059-1066.
45. Palma JH, de Souza JA, Rodrigues Alves CM, Carvalho AC, Buffolo
E. Self-expandable aortic stent-grafts for treatment of descending
aortic dissections. Ann Thorac Surg. 2002;73(4):1138-1141; discus-
sion 1141-1142.
46. Nathanson DR, Rodriguez-Lopez JA, Ramaiah VG, et al. Endolu-
minal stent-graft stabilization for thoracic aortic dissection. J Endo-
vasc Ther. 2005;12(3):354-359.
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47. Nienaber CA, Zannetti S, Barbieri B, Kische S, Schareck W, Reh-
ders TC, for the INSTEAD study collaborators. INvestigation of
STEnt grafts in patients with type B Aortic Dissection: design of
the INSTEAD trial—a prospective, multicenter, European ran-
domized trial. Am Heart J. 2005;149(4):592-599.
48. Nienaber CA, Kische S, Akin I, et al. Strategies for subacute/
chronic type B aortic dissection: the Investigation Of Stent
Graft s in Patients with type B Aortic Dissection (INSTEAD)
trial 1-year outcome. J Thorac Cardiovasc Surg. 2010;140(6 Suppl):
S101-S108.
49. Nienaber CA, Rousseau H, Eggebrecht H, et al.for the INSTEAD
Trial. Randomized comparison of strategies for type B aortic
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50. Slonim SM, Miller DC, Mitchell RS, Semba CP, Razavi MK, Dake
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51. Beregi JP, Haulon S, Otal P, et al. for the Societé Fraçaise d’Ima-
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Dissection. Endovascular treatment of acute complications asso-
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5/22/2012 5:57:42 PM

In the chapter titled “Aortic Dissection,” Benjamin J. Pearce has
attempted to summarize the available data on acute and chronic
type A and type B dissection. A significant portion is dedicated to
the evolving stent graft technology to treat dissections. Although
no devices are specifically approved in the United States for dis-
sections, this is a rapidly evolving field with interest now extend-
ing into the development of percutaneous aortic valve with stent
grafts for the treatment of acute type A dissection. Although lit-
tle is dedicated to the treatment of chronic dissections, various
authors have described promising results with use of stents grafts
for patients with chronic dissections.
1. Who gets aortic dissection and how do they present? Aortic
dissection is most commonly seen in patients with uncontrolled
hypertension. It is important to note that most often patients
are thought to present with an acute myocardial infarction or
a pulmonary embolism. A CT or a MRA is obtained usually
after these have been ruled out. Early diagnosis and treatment
cannot be stressed enough, given the high mortality with each
passing hour.
2. What modalities are appropriate for diagnosis and therapeutic
planning? Importance of early contrast-enhanced CTA or MRA
are well described by the author. It is also important to get a
complete imaging of the chest/abdomen and pelvis, as various
visceral vessels can be involved and may need to be incorporated
into the treatment plan. Although indication for a CTA and
MRA often overlap, I have found CTA to be more user-friendly
with regard to evaluation of the branch vessels, and obtaining
the required measurements for stent graft placement. ECHO
is often limited to the unstable patient or an unreliable CTA
or MRA due to excessive patient movement. I have found the
intraoperative use of transesophageal ECHO to be a valuable
tool to exclude a type A conversion after stent graft placement.
3. Which patients are appropriate for medical management and
which patients require operative interventions? Typically all
patients with proximal dissections require operative interven-
tions. Dissections distal to the left subclavian artery are best
managed with anti-impulse therapy unless they have compli-
cations. Indications for nonmedical intervention in type B dis-
sections include rupture, rapid false lumen enlargement,
persistent back pain despite blood pressure control, and end-
organ hypoperfusion (visceral or limbs). I have also found
renal stenting to be useful in patients with difficult to control
676
PMPH_CH84.indd 676
Commentary on
Aortic Dissection
Karthikeshwar Kasirajan
hypertension if any one of the renals has a partial or complete
false lumen blood supply. This technique involves placement of
self-expanding nitinol stents extending from the true lumen to
the involved renal vessel. Endovascular therapy with stent grafts
has rapidly replaced open surgery in patients with complicated
type B dissections. However, current data and available devices
do not support their use in patients who can be managed with
anti-impulse therapy. Regarding fenestration, in my experience
this technique is rarely required to relieve end-organ ischemia
and should be avoided if possible. Extensive areas of fenestration
in the thoracic aorta and the visceral segment often result in
rapid false lumen enlargement during follow-up. In these pat-
ients with prior fenestration and false lumen aneurysm few
endovascular options are available, converting this to a complex
open procedure. In my practice, fenestration is limited to patients
presenting with acute paraplegia. Follow-up imaging on a yearly
basis is important as a significant number of the patients with
developed false lumen dilatation require delayed intervention
despite adequate blood pressure control.
4. Outcomes: Although no long-term data are available for stent
graft therapy for acute dissections, mid-term data are very
promising. I have noticed that a significant number of patients
treated in the first few months have the capacity for total aortic
remodeling, that is, the aorta reverts to the predissection state
once the entry tear has been covered. It is important to note
that long-segment (subclavian to celiac) coverage should be
avoided in acute dissections, as this substantially increases
the risk of paraplegia with no added benefit. I typically would
use a 15-cm thoracic stent graft in most patients with minimal
oversizing (size to the normal nondissected proximal aorta).
5. Chronic dissection: The authors have dedicated little to this less
understood entity. In spite of the resistance to the use of stent
grafts for dissections, I have found this to be very effective
in causing false lumen thrombosis across the stented segment of
the aorta, despite distal perfusion of the false lumen. Based on
my experience, I believe that chronic dissections, despite having
a false lumen aneurysm, do not behave in a similar fashion to
degenerative aneurysms. Elimination of the primary entry tear
by stent grafts results in false lumen remodeling in most patients,
suggestive of a different mechanism for aneurysm formation
other than pressure. Factors such as shear stress and flow velocity
tend to play a more important role in false lumen dilatation of
these patients.
5/22/2012 5:57:42 PM

Arterial Pseudoaneurysms and
Arteriovenous Fistulae
J. Leigh Eidson III and Marvin D. Atkins
INTRODUCTION
As the number of percutaneous arterial catheter-based treatments
has surged over the past two decades, complications of such inter-
ventions including arteriovenous fistulae (or arteriovenous fistulas
[AVFs]) and arterial pseudoaneurysms (PAs) have become com-
mon. Pseudoaneurysms, sometimes referred to as pulsatile hema-
tomas, differ from aneurysms in that the boundaries of the aneurysm
sac do not contain elements of the arterial wall but rather con-
sist of surrounding soft tissue, muscle, compressed thrombus, or
even dermis. Penetrating trauma, usually iatrogenic, frequently
initiates the PA. As arterial blood is exposed to the extralumenal
tissues, it dissects and forms a cavity that remains pressurized by
its continuity with the intravascular space. Unlike a hematoma,
continuous flow within a PA prevents clot formation and sealing
of the arteriotomy.
Femoral PAs typically present as a pulsatile mass and bruit
that forms at the arterial puncture site within 48 hours of an arte-
rial procedure. Pain and swelling is the most common presenta-
tion. Infrequently, patients may also experience femoral vein and
nerve compression—leading to deep vein thrombosis or neuropa-
thy. Occasionally a large PA will result in uncontrolled hemor-
rhage, hypotension, and even skin necrosis and free rupture.
An AVF is a communication between an artery and vein. An
AVF is similar to PA in that it is typically the result of vascular
trauma or percutaneous intervention, occurring in 0.001% to
2.8% of catheter-based treatments.1-5 Such communications result
in abnormal arterial to venous flow, which may be palpated as a
thrill or auscultated as a bruit. Although usually clinically insig-
nificant at the femoral vessels, AVF can rarely lead to high cardiac
output, resulting in heart failure.
According to a recent report from the American Heart Asso-
ciation, one in three Americans will die from cardiovascular dis-
ease and half of these specifically from coronary artery disease. In
the year 2007 alone, nearly 1,059,000 cardiac catheterizations with
622,000 interventions were performed in the United States.6 With
the incidence of iatrogenic PA reported from 0.1% to as high as 5.5%
following percutaneous arterial procedures, such complications
677
PMPH_CH85.indd 677
CHAPTER 85
undoubtedly result in considerable economic impact.1-2,7-10 Conse-
quently, numerous products and devices have been developed in
an attempt to reduce these complications while curtailing proce-
dure times.
The following questions were selected to provide practitioners
with clinically useful information collected from the most current
and validated scientific literature.
RISK FACTORS
1. What are the risk factors for the development of PAs and
AVFs?
At the origin of every PA and AVF is the initiating vascular injury.
Many variables exist that may predispose patients to complica-
tions of vascular access. In addition to recognizable factors such
as catheter size, other considerations include catheter removal and
hemostatic techniques, location of arteriotomy, gender, hyperten-
sion, anticoagulation, vascular calcification, and obesity. Fre-
quently, the location of the arteriotomy is either too high (distal
external iliac) or too low (bifurcation of the superficial femoral
and profunda femoris or the superficial femoral itself).
In a large prospective study of 11,992 consecutive patients
undergoing cardiac catheterization, Popovic et al.9 reported 76
(0.6%) PAs. Significant risk factors included catheter size (>6 fr;
P = 0.03), percutaneous intervention (OR, 1.99; P < .05), and left
femoral access site (OR, 4.65; P < .05) (Level 2a evidence). Ates
et al.7 in their series of 41,322 catheterizations causing 630 PAs
(1.5%) found hypertension, coronary artery disease, diabetes,
catheter size, body-mass index (OR, 2.21), procedure room vol-
ume, and catheter size (>7 fr; OR, 2.82) to all be statistically sig-
nificant risk factors (Level 2b evidence).
Ohlow and colleagues8 similarly report PA and AVF rates
of 1.2% and 0.6%, respectively, in their series of 18,165 patients
undergoing cardiac catheterization. In addition to hypertension,
they discovered a statistically significant increased risk for women
(OR, 1.65) and in patients treated with emergency procedures
(OR, 2.13) (Level 2a evidence).
5/22/2012 5:58:15 PM
 678 ■ Surgery: Evidence-Based Practice
Juergens et al.11 in their prospective, randomized controlled
trial found no difference in vascular complication rates between
6-fr and 7-fr catheters used to treat 414 patients (Level 1b evi-
dence). Another study found that ambulation at 4 hours, after
manual compression was used for hemostasis, does not increase
the risk of vascular complications12 (Level 3b evidence). Arterial
access over the femoral head is less likely to have associated com-
plications because greater seal is attained when the artery is com-
pressed against this structure13 (Level 2b evidence).
Perings and colleagues5 in analyzing 88 patients with AVFs
following 10,271 cardiac catheterizations found that female gen-
der, left groin access, hypertension, and systemic anticoagulation
all increased the risk of fistula formation. Other factors such as
sheath size, interventions, and body-mass index did not increase
the risk of AVF (Level 2b evidence).
Answer: Catheter size, percutaneous intervention, female
gender, left groin access, body-mass index, procedure room vol-
ume, diabetes mellitus, and hypertension are all risk factors for
developing femoral artery PA. Female gender, left groin access,
hypertension, and systemic anticoagulation increase one’s risk of
developing an AVF (Grade A statement).
DIAGNOSIS
2. What is the optimal imaging study to diagnose PAs and
AVFs?
Duplex ultrasound has superseded angiography as the diagnostic
study of choice for detecting femoral PAs and AVFs over the past
25 years. Duplex ultrasound is noninvasive, avoids radiation expo-
sure and intravascular contrast, and has become widely accessible
with many clinicians using them in their daily practices.
In the mid-1980s, Doppler ultrasound was first reported to
be 94% sensitive and 95% specific14 (Level 4 evidence). The flow
characteristics of the PAs, initially known as the “to-and-fro,”
distinguished them from hematomas.15 Ultimately, ultrasound
technology and experience improved that led to a widespread
acceptance despite the lack of data characterizing these intrinsic
qualities. Additional advantages in this setting include the quick
ability to detect local disease in the arterial system and deep
venous thrombus.
Computed tomography angiography (CTA), although it exposes
patients to radiation and IV contrast, can be a useful tool for detect-
ing PAs. It is a valuable study when there is a concern of proximal
arterial injury with associated retroperitoneal hemorrhage. CTA
can also differentiate vascular calcifications, thus characterizing
the severity of underlying peripheral atherosclerotic disease.
Magnetic resonance angiography (MRA) is an alternative
form of angiography that is less commonly used in this setting.
Although cumbersome and expensive, it may be clinically useful
in the setting of complex AVFs or PAs being evaluated for sur-
gical repair. There has been some recent concern regarding the
use of gadolinium contrast in patients with chronic renal disease
as they are at increased risk for developing nephrogenic systemic
fibrosis.16
Regardless of which imaging modality is used, the patient’s
history and physical examination remain essential to good prac-
tice. Documenting symptoms of peripheral vascular disease, dis-
tal pulse characteristics, and ankle-brachial indices both before
PMPH_CH85.indd 678
and after any invasive procedure will aid significantly in the rec-
ognition of complications.
Answer: Despite the lack of formal studies comparing duplex
ultrasound to angiography, clinicians were quick to adopt this
pragmatic tool given its inherent attributes. There remains a
secondary role for catheter-based, CTA and MRA (Grade C
statement).
TREATMENT
3. When do AVFs require surgical repair and when can they
be observed?
Iatrogenic AVFs are difficult to study because they are somewhat
rare and mostly asymptomatic. Small cohorts have reported a 66%
to 81% spontaneous closure rate for AVFs not selected for imme-
diate repair17,18 (Level 4 evidence). Kelm and colleagues reported
a rate of 0.86% for AVF formation for 10,271 consecutive femoral
catheterization patients that they evaluated with duplex ultra-
sound. Interestingly, more than one-third of these spontaneously
closed within 12 months, and all remained asymptomatic. In their
series, none of the AVFs resulted in cardiac dysfunction or limb
threat4 (Level 2b evidence).
Answer: Most small and asymptomatic AVFs can safely be
observed—awaiting spontaneous closure. If persistent, large, or
symptomatic, open surgical repair is recommended. Stent graft
repair of such lesions, although several case reports suggest this
is technically feasible, is not recommended in the femoral loca-
tion except in the most extenuating of circumstances (Grade C
recommendation).
4. What is the optimal treatment of femoral PAs: thrombin
injection, ultrasound compression, or surgical repair?
Traditionally, the standard treatment for arterial PAs was surgical
repair with direct closure of the arteriotomy. By the nature of their
underlying vascular disease, patients undergoing surgical repair
for PAs have complication and mortality rates reported as high as
21% and 3.3%, respectively19-20 (Level 2c evidence).
Compression of the PA, either by hand or with a mechanical
device, can disrupt the flow characteristics within the aneurysm
sac leading to thrombosis and cure. One early report demonstrated
that manual compression of up to 1 hour was successful in nearly
87% of 85 patients selected for this method (74% on first attempt).
Of the 96 patients enrolled, 10 were treated with primary surgical
repair, as were all study failures21 (Level 3b evidence).
Treatment with compression dressing alone is less useful and
has a reported 25.8% success rate, useful only for small PA with low
neck velocities.22 Furthermore, for small PA (<2 cm), there is some
evidence that with observation alone 56% to 87% could resolve
within a few weeks17-18 (Level 3b evidence).
As ultrasound devices became more widespread, clinicians
were quick to utilize them as a compression tool so that PA could
be observed during the process. Ultrasound-guided compression
(UGC) has reported success rates of 74% to 95%, with much varia-
tion in compression times and the number of attempts23-25 (Level
3b evidence). In one study, UGC was 95% successful in 57 patients;
however, only 83% of those were cured on first attempt. In that
study, heparinized patients were more likely to fail treatment.25
5/22/2012 5:58:16 PM

Paschalidis et al. in a prospective randomized study, selected 168
of 185 PAs for treatment by either manual compression or UGC
with 98% and 99% success rates, respectively. In their experience,
only a handful required more than one treatment session and suc-
cess was defined as clinical resolution26 (Level 2b evidence).
Compression techniques have lost favor because they are labor
intensive and uncomfortable for patients, often requiring multiple
attempts at time intervals as long as 41.5 minutes in one study.23
With compression, there is a small risk for developing arterial and
deep venous thrombosis.
Direct thrombin injection into the PA sac, typically guided by
ultrasound, results in rapid sac thrombosis with minimal patient
discomfort. This technique is usually accompanied by some degree
of compression, which promotes thrombus formation. Eleven case
series, reporting 757 cases of iatrogenic femoral PAs treated with
ultrasound-guided thrombin injection (UGTI) were reviewed. The
overall success rate of UGTI ranged from 90% to 100%. The rates
for a successful first injection, or primary treatment, varied from
71% to 100%, with the majority of authors indicating that additional
treatments were commonly required23-24,27-35 (Level 3a evidence).
Complications of UGTI were unusual. Five arterial embolic
complications were reported, but none caused significant mor-
bidity or limb loss. 28-29,33,36 There were 18 reports of PA recur-
rence following UGTI, underscoring the importance of follow-up
imaging for patients with this complication. Many recurrences
occurred early but some were detected as late as 4 weeks following
treatment.24,33,36
The dosage of thrombin injected varied greatly between stud-
ies. In the largest series reviewed, Krueger et al. reported that a
mean thrombin dose of 425 IU (1000 IU/mL concentration) was
used to attain a 93.8% primary, and 99.6 secondary success rates.
Large, multilobulated PAs were more likely to require a larger
injection and secondary treatments.33
Embolization by ultrasound-guided coil placement is an alter-
native to thrombin injection, though not well studied. In one small
series, Kobeiter et al. reported a 100% embolization rate insert-
ing an average 3.8 (size: 4–15 cm × 10 mm) stainless steel spring
coils containing synthetic fibers. Two of the 17 patients (11.7%) had
recurrences discovered at 1 and 4 weeks postprocedure37 (Level 4
evidence). In a recent case report, Bellmunt et al. described a
new technique of PA treatment using a single 20-cm Inconel coil
(IMWCE; Cook Medical Inc., Bloomington Ind), part of which was
left externally exposed and later removed.38
Answer: Manual or UGC is still a viable treatment for uncom-
plicated PAs and can be performed at bedside. Thrombin injection is
more rapid, causes less discomfort, and ought to be considered first-
line for large or complex PAs. Distal perfusion should be assessed
before and after any intervention so that limb-threatening compli-
cations can be rapidly detected. Direct surgical repair should only
be considered for patients who repeatedly fail less-invasive meth-
ods, have hemodynamic instability, or those at high risk for PA
rupture, or when embolic complications are encountered (Grade B
recommendation).
5. Is there are role for endovascular therapy in the manage-
ment of femoral PAs and AVFs?
At this time, there are only case reports and small case series
describing the successful placement of covered stent grafts in the
femoral artery to exclude AVF and PA.39,40
PMPH_CH85.indd 679
Arterial Pseudoaneurysms and Arteriovenous Fistulae ■ 679
Waigand and colleagues reported treating 47 of 53 patients
(30 PAs, 21 AVFs, 2 combined lesions) with either covered stents
(32) or endovascular embolization (14) and one by a combined
procedure. Six failures were treated surgically. Ultimately, the
authors report four late stent occlusions (12.5%) with a follow-
up of 301 (± 280 days)40 (Level 4 evidence).
In their small series, Onal et al. reported successfully treating
9/10 AVFs involving the profunda femoris artery using covered
stent grafts. Mean follow-up was 18.5 months, at which time Dop-
pler ultrasound demonstrated 100% stent graft patency.41 Thal-
hammer et al. repaired 16 PAs, 9 AVFs, and 1 combined lesion
using 26 covered stent grafts. In addition to three immediate fail-
ures, four occluded stents (17%) were detected at 1 year42 (Level 4
evidence).
Answer: The use of covered stent grafts as primary repair for
femoral PAs and AVFs is not recommended as a routine first-line
treatment. Stent occlusion and fracture remain a concern and long-
term patency has not been reported (Grade C recommendation).
PREVENTION
6. What is the role of vascular closure devices in the manage-
ment of arterial access catheterization sites?
Attaining natural hemostasis by direct pressure over arteriotomy
site is labor intensive and can be unpredictable in the setting
of antiplatelet and anticoagulation therapy. Numerous devices
and products, known as vascular closure devices (VCDs), have
been brought to market over the past two decades with intent to
facilitate arteriotomy seal while reducing the risk of access site
complications. VCDs work through a variety of methods includ-
ing mechanized external compression, deposition of hemostatic
material near arteriotomy, the use hemostatic dressings, and
reapproximation of the arteriotomy. With the global market
of such devices expected to exceed $1 billion by 2013, further
refi nement and ongoing development is expected.43 Table 85.1
lists several common devices, their manufacturers, and specific
functions.
With a huge commercial interest in VCDs, the evidence sup-
porting their use is somewhat mixed. Lack of standardization of
manual compression controls and lack of intent-to-treat method-
ology obscures results. As technology and devices rapidly evolve,
there remains lag between reported results and the “generation” of
device currently in use.
Mechanical compression devices are the simplest VCDs.
Clamp-style or inflatable (pressure regulated) appliances are
usually anchored to the bed or counter-supported by the patient’s
body, replacing manual digital compression. In a recent prospec-
tive study involving 908 patients, the risk of PA formation with
mechanical compression (3.3%) was found to be statistically
equivalent to manual compression with two different hemostatic
dressings (calcium ion 4.3%, thrombin 3.3%).44 Although quite
popular given their ease of use, compressive devices limit early
ambulation and can result in substantial discomfort.
Implanted substances, such as collagen, polyethylene glycol,
and thrombin, are thought to aid in hemostasis directly at the
arteriotomy site. Two of the earliest devices that utilized this con-
cept, Duett and VasoSeal, are no longer available secondary to
concerns about increased complication rates. The meta-analysis
5/22/2012 5:58:16 PM
 680 ■ Surgery: Evidence-Based Practice
Table 85.1 Vascular Closure Devices
Device Manufacturer
AngioSeal St. Jude Medical, St. Paul, MN
VasoSeal* Maquet, Montvale, NJ
Duett* Vascular Solutions, Minneapolis, MN
Mynx AccessClosure, Mountain View, CA
D-Stat Dry Vascular Solutions, Minneapolis, MN
Syvek Marine Polymer Technologies, Danvers, MA
Prostar Abbott Vascular, Redwood City, CA
Perclose Abbott Vascular, Redwood City, CA
Starclose Abbott Vascular, Redwood City, CA
Catalyst III Cardiva Medical, Mountainview, CA
FemoStop St. Jude Medical, St. Paul, MN
Safeguard Maquet, Mahwah, NJ
CompressAR Advanced Vascular Dynamics, Portland, OR
Clamp Ease ClampEase, Portland, OR
*Device is no longer produced.
by Koreny et al. that investigated 30 prospective randomized trials
(N = 4000) primarily investigated Angioseal, Vasoseal, and Per-
close. In their analysis, they found that the use of VCDs short-
ened procedure times by a mean of 17 minutes and resulted in
no significant difference in the number of PA or AVF compared
to manual compression. However, the subanalysis of the only two
trials to utilize an intention-to-treat methodology and blinded-
outcomes had a significant increase in the relative risk of PA for-
mation (RR 5.4, P = .02)45 (Level 1a evidence).
Nikolsky et al., in another meta-analysis, analyzed data from
30 prospective and retrospective studies, representing 37,066
patients treated with AngioSeal, VasoSeal, and Perclose. Again,
no significant differences in risk were detected for all device
groups except for VasoSeal, which was found to have a significant
association with vascular complications (OR 2.27, 95% CI = 1.35–
3.8). Several of the reports in this analysis were published early
in the endovascular experience, using first-generation products46
(Level 2a evidence).
A more recent meta-analysis by Biancari et al. studied 7528
patients from 31 prospective, randomized studies—many of which,
the authors comment, excluded high-risk patients. Comparable to
earlier meta-analyses, there was no statistically significant differ-
ence in occurrence of PA. They did report a significant risk of groin
infection with VCD use (RR 2.48, P = .02) as well as a trend toward
increased risk of limb ischemic complications (RR 3.28, P = .07),
though the VasoSeal data contributed positively toward both of
these complications47 (Level 1a evidence).
The StarClose device is less studied as it is newer to the
marketplace. To date, major complication rates of 0.4% to 3.4%
have been reported. It is currently approved for closure of 5- to
6-fr catheter sites and has the advantage of providing a suitable site
for future arterial access. Device deployment success is reported
between 87% and 95.7%.48-50
Answer: VCDs reduce procedure times by supplanting
manual compression; however, there is no evidence that they
PMPH_CH85.indd 680
Function
Implanted collagen plug
Implanted collagen plug
Implanted thrombin and collagen
Implanted polyethylene glycol
Topical thrombin dressing
Topical poly-N-acetyl glucosamine
Direct suture closure
Direct suture closure
Direct clip closure
Removable internal clip with protamine-coated wire
External compression
External compression
External compression
External compression
decrease vascular access complications. Further studies are
needed to characterize the advantages of newer products and to
clearly establish whether or not they are cost-effective (Grade A
recommendation).
SPECIAL CIRCUMSTANCES
7. How does one manage the infected femoral PA?
Almost always related to intravenous drug abuse, infected femo-
ral PAs traditionally require operative debridement with arterial
ligation and aneurysmectomy. When ligation results in limb-
threatening ischemia, surgeons should attempt to revascularize
the extremity.
Johnson and colleagues reported that 32% of 28 patients
with ligation of the common femoral artery or femoral bifurca-
tion had limb-threatening ischemia. Six of these required arterial
bypass. Distal stump arterial pressure may be useful for deter-
mining adequacy of collateral circulation. Extra-anatomic bypass
through the obturator foramen using Dacron or polytetrafluoro-
ethylene (PTFE) should be considered in these circumstances,
though with a high risk of graft infection or thrombosis51-53 (Level
4 evidence).
Alternatively, CryoVein (CryoLife, Kennesaw, GA) human
allografts have been used in the reconstruction of infected arte-
rial graft s and might be considered in this setting54 (Level 5
evidence).
Endovascular repair using a stent graft has been reported, but
should only be considered as a temporizing measure in moribund
patients who cannot undergo immediate ligation or reconstruc-
tion55 (Level 5 evidence).
Answer: Uncommon, infected femoral PAs should be excised
with or without extra-anatomic bypass. Endovascular stenting is
not recommended (Grade D recommendation).
5/22/2012 5:58:16 PM
 Arterial Pseudoaneurysms and Arteriovenous Fistulae ■ 681

Clinical Question Summary

Question
1 What are the risk factors
for the development of
PAs and AVFs?
2 What is the optimal
imaging study to diagnose
PA and AVF?
3 When do AVF require
surgical repair and when
can they be observed?
4 What is the optimal
treatment for femoral PA?
5 Is there a role for
endovascular therapy
in the management of
femoral PA and AVF?
6 What is the role of vascular
closure devices in the
management of arterial
access catheterization
sites?
7 How does one manage the
infected femoral PA?
PA = pseudoaneurysm, AVF = arteriovenous fistula, HTN = hypertension.
Answer Level of Grade of References
Evidence Recommendation
PA risk: catheter size, PCI, female 1b A 5, 7-13
gender, left groin access, HTN,
obesity, diabetes
AVF risk: anticoagulation, female
gender, left groin access, HTN
Duplex ultrasound, angiography 4 C 14-15
If asymptomatic and small, AVF can be 2b C 17-18
observed
Thrombin injection is faster and 3a B 19-38
moderately more effective than
compression
Endovascular repair is not 4 C 39-42
recommended
Closure devices decrease procedure 1a A 44-50
times but they do not reduce access
site complications, their cost-
effectiveness is unknown
Femoral artery ligation with 4 D 51-55
aneurysmectomy, reconstruction in
selected patients

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15. Abu-Yousef MM, Wiese JA, Shamma AR. The “to-and-fro” sign:
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30. Sultan S, Nicholls S, Madhavan P, Colgan MP, Moore D, Shanik
G. Ultrasound guided human thrombin injection. A new modal-
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32. Olsen DM, Rodriguez JA, Vranic M, Ramaiah V, Ravi R, Diethrich
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34. Etemad-Rezai R, Peck DJ. Ultrasound-guided thrombin injection
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36. Madaric J, Mistrik A, Vulev I, et al. The recurrence of iatrogenic
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37. Kobeiter H, Lapeyre M, Becquemin J, Mathieu D, Melliere D, Des-
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39. Kendrick AS, Sprouse LR. Repair of a combined femoral pseudo-
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41. Onal B, Kosar S, Gumus T, Ilgit ET, Akpek S. Post catheteriza-
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42. Thalhammer C, Kirchherr AS, Uhlich F, Waigand J, Gross CM.
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45. Koreny M, Riedmuller E, Nikfardjam M, Siostrzonek P, Mullner
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5/22/2012 5:58:16 PM
 CHAPTER 86
Carotid Occlusive and
Aneurysmal Disease
Matthew J. Sideman and Lori L. Pounds
INTRODUCTION
Stroke is the third leading killer in the United States. Strokes cost
over $29 billion annually in disability and lost productivity. Eighty-
five percent of strokes are ischemic and 15% are hemorrhagic.
Ischemic strokes are caused by carotid artery stenosis, cardiac
thromboembolism, hypertension, and diabetes but the majority
of ischemic strokes are due to carotid artery occlusive disease. The
pathophysiology of ischemic strokes from carotid artery occlusive
disease is distal emboli. The emboli can be atheroemboli, platelet
aggregates, or thrombus. Symptoms of carotid occlusive disease
include amaurosis fugax, transient ischemic attacks (TIA), and
strokes. Amaurosis fugax is a transient monocular blindness that
is often described as a “shade coming down over eye” that then
resolves. TIAs are motor or sensory deficits, aphasia, or dysarthria
that lasts less than 24 hours by definition. A stroke is any neuro-
logic deficit that lasts for greater than 24 hours.
Risk factors for carotid occlusive disease include smoking,
hypertension, hyperlipidemia, age, gender, genetic predisposition,
and diabetes. There are usually no specific physical findings for
carotid occlusive disease although a carotid bruit may be heard.
Bruits must be differentiated from transmitted cardiac murmurs.
A complete neurologic examination should be part of the physical
examination to detect any deficits. If a carotid bruit is present, it
is only 50% predictive of a surgically significant stenosis. In addi-
tion, critical stenoses can have such low flow that the bruits often
disappear.
STROKE RISKS
1. What is the stroke risk for symptomatic carotid stenosis?
Differences in opinion about the optimal treatment of carotid
occlusive disease led to the North American Symptomatic Carotid
Endarterectomy Trial (NASCET).1
It was a prospective, randomized trial conducted at 50 cen-
ters across the United States and Canada that planned to enroll
684
PMPH_CH86.indd 684
3000 symptomatic patients. They were randomized into a medi-
cal arm (aspirin) and a surgical arm (carotid endarterectomy)
with plans to follow them for a minimum of 5 years. Patients
were subdivided into 30% to 69% stenosis and 70% to 99% steno-
sis. A total of 659 patients were enrolled between January 1, 1988
and February 21, 1991. The trial was stopped early by the over-
sight committee due to a clear benefit to the patients randomized
into the surgery arm.
The results of the NASCET trial are as follows. There was a
26% risk of stroke or death over a 2-year period for patients ran-
domized into the medical arm. The risk of stroke was 9% over
the same 2-year period for patients in the surgical arm. This
translated into a 17% absolute risk reduction and a 65% relative
risk reduction for endarterectomy. Post hoc analysis showed that
the surgical benefit remains down to 50% stenosis, but there was
no benefit for less than 50% stenosis.2 The benefit from carotid
endarterectomy (CEA) was also shown to be greatest with the
most severe symptoms.2 In other words, the benefit of CEA is
greatest in a patient whose symptom was a previous stroke than a
patient whose symptom was TIA that was greater than a patient
whose symptom was amaurosis fugax. Benefits of endarterectomy
were also found to be greater for men than women, although this
may be a result of the greater number of men compared to women
who were enrolled in the study.2
The European Carotid Surgery Trial (ECST)3 was similarly
designed to answer the question of optimal treatment for symp-
tomatic carotid occlusive disease. It enrolled 3024 patients between
1981 and 1994 who had experienced symptoms within the previ-
ous 6 months. There were unequal groups with 1811 patients allo-
cated to the surgical arm and 1213 patients in the control group.
Analysis of the data showed a 26.5% risk of major stroke or death
in the control group versus a 14.9% risk in the surgical group at
3 years for an absolute benefit from surgery of 11.6%. The inves-
tigators recommended surgery for symptomatic lesions greater
than about 80%.
Several differences should be highlighted between NASCET
and ECST. The largest difference was the method for determin-
ing the percentage of stenosis. NASCET used the normal distal
5/22/2012 5:58:48 PM

internal carotid artery diameter as the denominator when calcu-
lating percent stenosis. ECST used the estimated diameter of the
internal carotid at the level of the disease. This difference resulted in
approximately 350 patients being included in the severe steno-
sis group that would have been classified as less than 70% in the
NASCET study. There was also a longer lead in period for symp-
toms in ECST compared to NASCET (6 months vs. 120 days) and
more patients in the surgical arm compared to the medical arm
raising questions of study design. Despite these differences, ECST,
like NASCET, showed benefit for surgical intervention compared
to medical management for severe symptomatic carotid occlusive
disease.
Answer: The risk of stroke or death for a symptomatic carotid
lesion of 70% stenosis or greater is 26% over a 2-year period
with medical management alone compared to 9% for surgical
management.
2. What is the stroke risk for asymptomatic carotid stenosis?
Just as NASCET was designed to answer the question of the
optimal treatment for symptomatic carotid artery occlusive
disease, and the enrolling and completing its data acquisition,
the Asymptomatic Carotid Artery Study (ACAS)4 was designed
to answer the question “What about asymptomatic stenosis?”.
It was a prospective, randomized trial conducted at 39 centers
across the United States and Canada that planned to enroll 1500
patients to daily aspirin or carotid endarterectomy. The initial
endpoint of the study was TIA but was later amended to include
stroke and death. Between December 1987 and December 1993,
1662 patients were enrolled. The inclusion criteria were asymp-
tomatic carotid lesions greater than or equal to 60% stenosis. The
study was completed in 1994 after the planned enrollment had
been reached. The results of ACAS showed an 11% risk of stroke
or death over the 5-year study period for the patients randomized
into the medical arm of the study. The risk of stroke or death in
the same 5-year period was 5% for patients randomized into the
surgical arm. Th is equates to a 5.9% absolute reduction, and a
53% aggregate risk reduction.
There were other lessons learned from ACAS as well. There
was a 1.2% stroke rate from the diagnostic arteriogram performed
as part of the study. The perioperative stroke rate in the trial was
1.5%. There is a transient increase in the risk of stroke by operat-
ing on an asymptomatic patient. For a patient to enjoy the preven-
tative benefit from surgery, they need to live 3 years afterwards.
Another asymptomatic carotid trial was undertaken in
Europe. The Asymptomatic Carotid Surgery Trial (ACST)5
enrolled 3120 asymptomatic patients between 1993 and 2003.
They were randomized into an immediate carotid endarterectomy
arm and an indefinite deferral arm and followed for up to 5 years.
The 30-day risk of stroke or death in the after CEA was 3.1%. The
5-year stroke risks were 6.4% for the immediate CEA group and
11.8% for the deferred group. The investigators recommended
immediate CEA for asymptomatic patients younger than 75 years
with 70% stenosis by ultrasound. The findings in this study sup-
port those of ACAS.
The significance of symptoms from a carotid lesion was
clearly illustrated by the results of NASCET and ACAS. Both
studies looked at patients with 70% carotid stenosis; however, the
stroke risks were significantly different between the two studies.
The stroke risk in NASCET is 26% over a 2-year period compared
with an 11% risk over 5 years in ACAS. Annualized, the risk of
PMPH_CH86.indd 685
Carotid Occlusive and Aneurysmal Disease ■ 685
stroke is 13% versus 2.2% for symptomatic versus asymptomatic
patients. This clearly demonstrates that the symptomatic plaques
are more unstable and much more dangerous or “virulent.” These
facts all need to be taken into consideration when recommend-
ing medical management or intervention for patients with carotid
occlusive disease.
Answer: The risk of stroke for an asymptomatic 70% stenosis
of the carotid artery is 11% over a 5-year period for medical man-
agement compared with a 5% risk in the same 5-year period for
patients undergoing surgical management.
DIAGNOSIS
3. What is the optimal diagnostic test for carotid occlusive
disease?
There are four modalities available for imaging the extracranial
carotid arteries. They are duplex ultrasonography, computed
tomographic angiography (CTA), magnetic resonance angiogra-
phy (MRA), and conventional digital angiography. Each modal-
ity is associated with its own advantages and limitations. The
gold standard continues to be conventional digital angiography;
however, this is the most invasive method and carries the largest
risk of complications including the risk of stroke as was shown
in ACAS.4 Despite these risks, conventional digital angiography
is performed when there is discordance between less invasive
modalities or as part of the treatment of the patient when endo-
vascular intervention is planned.
CTA provides direct imaging of the extracranial carotid
arteries and can measure the severity of stenosis.6 Calcification,
metallic artifacts, and patient compliance can all limit the quality
of the imaging and thus the accuracy of the exam. In addition, the
need for intravenous contrast will limit its applicability to patient
with borderline renal function. Magnetic resonance imaging
similarly images the carotid arteries and can estimate the severity
of stenosis.6 MRA does not expose patients to radiation like CTA
and conventional digital angiography. Calcium is not a limitation
either but patient size and compliance are. MRA tends to overes-
timate the degree of stenosis and it has difficulty discriminating
between near occlusions and complete occlusions. Again, patients
with borderline renal function are not candidates due to the risk
of nephrogenic systemic fibrosis from the gadolinium contrast
agents.7
Duplex ultrasonography is inexpensive, noninvasive, and
reproducible. It uses measurement of blood flow velocities to cal-
culate categories of stenosis. Its accuracy was developed through
extensive comparison research looking at duplex exams, angio-
graphic findings, and operative specimens.8,9 Based on this, duplex
criteria were established. The most commonly used criteria are
those reported by Strandness.10 In this scheme, carotid arteries are
classified as either normal, 1% to 15% stenosis, 16% to 49% steno-
sis, 50% to 79% stenosis, 80% to 99% stenosis, or occluded. The
major determining factors are the peak systolic velocity (PSV) in
the internal carotid artery and the end diastolic velocity (EDV). A
PSV > 125 cm/s qualifies for a 50% to 79% stenosis, and an EDV >
140 cm/s qualifies for a stenosis of 80% to 99%. While proven and
reliable, the Strandness criteria do not fit well with the indications
for intervention as outlined in the NASCET and ACAS trials. To
address these concerns, other authors have looked for more spe-
cific criteria to define a 70% stenosis more in line with the trials.11
5/22/2012 5:58:49 PM
 686 ■ Surgery: Evidence-Based Practice
Internal validation of any vascular lab is crucial to verify accuracy
of its own test results and criteria.
Answer: Duplex ultrasonography is the optimal test for diag-
nosis carotid occlusive disease based on its cost-effectiveness, and
it is the least invasive modality; however, there is no strong evi-
dence to support one modality over another and the best resources
available in a given setting should be used.
TREATMENT
4. What are the indications for intervention of the carotid
artery?
The fi rst decision point on whether or not to intervene on a
patient with carotid occlusive disease centers around the presence
or absence of symptoms. There is a significant difference in the
stroke risks between these two groups as outlined above. Utilizing
the results from NASCET and ECST, symptomatic patients with
50% or greater carotid stenosis should undergo treatment. There
is no benefit for symptomatic patients with less than 50% stenosis.
According to ACAS and ACST, asymptomatic patients with 60%
or greater stenosis benefit from surgical intervention, although the
benefit was small for lesser stenosis and may no longer exist with
today’s maximal medical management compared to the medical
management given in those trials. More recently, multispecialty
consensus guidelines have been published by the American Heart
Association.12 This group examined all available evidence and
recommended the following indications with regards to carotid
endarterectomy:
• Patients at average or low surgical risk who experience
nondisabling ischemic stroke or transient cerebral ischemic
symptoms, including hemispheric events or amaurosis fugax,
within 6 months (symptomatic patients) should undergo
CEA if the diameter of the lumen of the ipsilateral internal
carotid artery is reduced more than 70% as documented by
noninvasive imaging (Level of evidence: 1) or more than 50%
as documented by catheter angiography (Level of evidence: 2)
and the anticipated rate of perioperative stroke or mortality is
less than 6%.12
• It is reasonable to perform CEA in asymptomatic patients who
have more than 70% stenosis of the internal carotid artery if the
risk of perioperative stroke, myocardial infarction (MI), and
death is low (Level of evidence: 1).12
• Prophylactic carotid artery stenting (CAS) might be considered
in highly selected patients with asymptomatic carotid stenosis
(minimum 60% by angiography, 70% by validated Doppler
ultrasound), but its effectiveness compared with medical
therapy alone in this situation is not well established (Level of
evidence: 2).12
Answer: Symptomatic patients with >50% carotid stenosis and
asymptomatic patients with greater than 60% stenosis.
5. What is the best medical treatment for carotid occlusive
disease?
The medical management for carotid occlusive disease has
advanced since the days of NASCET and ACAS. At the time of those
trials, medical management consisted of varying doses of daily
aspirin. Since that time, recognition of carotid artery occlusive
PMPH_CH86.indd 686
disease as a part of atherosclerosis overall has led to more aggres-
sive risk factor modification and medical management. Hyper-
tensive patients should be treated to maintain their blood pressure
below 140/90 mm Hg.13 Patients who smoke cigarettes should be
advised to quit.14 Patients with hyperlipidemia should be treated
with statins to lower their low-density lipoprotein (LDL) choles-
terol to below 100 mg/dL at a minimum.15 Some authors suggest
lowering the LDL to below 70 mg/dL.16 Diabetics should have their
blood sugars controlled with a goal of a glycosylated hemoglobin
A1c level less than 7.0%.17
There have been multiple studies looking into the type of anti-
platelet agents used to treat carotid artery occlusive disease with
varied results. Aspirin, 75 to 325 mg daily, is recommended for the
treatment of carotid occlusive disease and to prevent myocardial
infarctions.15 In patients who have suffered symptoms from their
carotid disease, aspirin or clopidogrel (75 mg daily)18 or a combi-
nation of aspirin and dipyridamole (25 and 200 mg twice daily)19
is recommended. The use of aspirin and clopidogrel as dual agents
is not recommended20 nor is the use of warfarin.21 Of course, if the
patient has atrial fibrillation or a mechanical heart valve neces-
sitating treatment with warfarin, this medical need outweighs the
recommendations for carotid artery occlusive disease.
Answer: Carotid artery occlusive disease should be treated
medically with antiplatelet therapy consisting of either aspirin
(75–325 mg daily), clopidogrel (75 mg daily), or a combination of
aspirin and dipyridamole (25 and 200 mg twice daily). Aggres-
sive risk factor modification should also be employed including
the use of statins, blood pressure control, smoking cessation, and
diabetic control.
6. What are the best surgical techniques for carotid endar-
terectomy?
The first report of a successful carotid operation for a symptomatic
patient was by Eastcott22 in 1954. They performed an end to end
anastomosis of the common carotid artery to the distal internal
carotid artery in a patient who was having TIAs. The first carotid
endarterectomy was likely performed by Dr DeBakey23 in 1953.
Since its introduction, the surgical technique has been modi-
fied and refined. Its utilization has also changed over time with
decreasing volume during the 1980s followed by an increase after
publication of the randomized trials in the 1990s. Despite its long
history of success, there are multiple variables in how a carotid
endarterectomy is performed.
One of the first variations in technique begins with the anes-
thetic choice. The majority of surgeons perform CEA under gen-
eral anesthesia but some choose local anesthesia and/or a cervical
block. The benefits of general anesthesia are decreased cerebral
metabolism, a controlled airway, and a quiet operating theater. The
drawback is the inability to directly monitor the neurologic func-
tion of the patient. Those that prefer regional anesthesia propose
that it is the safest modality for monitoring intraoperative neuro-
logic status of the patient; however, one recent, large randomized
trial showed no difference in outcomes between the two groups.24
The best anesthetic option is therefore the one with which the
operating surgeon and anesthesiologist are most adept.
The surgical incision can be performed in a longitudinal
direction parallel to the sternocleidomastoid muscle or trans-
versely in the mid-portion of the neck. The longitudinal incision
provides superior exposure but can lead to excessive scarring
and contractures. The horizontal incision may limit exposure to
5/22/2012 5:58:49 PM

the distal internal carotid artery and/or the proximal common
carotid artery. It does provide for improved wound healing and
a more cosmetic scar. There is little evidence to support one inci-
sion over the other25 and the best option is likely again surgeon
familiarity and preference.
The standard surgical technique involves exposure and con-
trol of the common carotid, internal carotid, and external carotid
arteries followed by clamping and longitudinal arteriotomy. At
this point a vascular shunt can be used to maintain antegrade
blood flow around the operative site, or the surgery can be done
without a shunt, relying on collateral blood flow from the other
carotid and vertebrals. Routine shunters argue that is the safest
way to maintain blood flow and prevent ischemic events. Selective
shunters use either back pressure in the internal carotid artery
(stump pressure) and/or neurologic monitoring to decide when
to use a shunt.26 Neurologic monitoring is done with continuous
intraoperative electroencephalogram (EEG) with or without the
addition of somatosensory evoked potentials. The arguments for
selective shunting are that only 10% to 15% of patients will require
a shunt, it avoids potential embolization or intimal injury during
the placement of a shunt, and that it makes the operation techni-
cally easier if the shunt is not used. Despite strong beliefs of supe-
riority held by surgeons supportive of both methods, there is little
evidence to support either approach.27-29 Like the choice of anes-
thesia and incision, the choice of routine versus selective shunting
is best left to surgeon familiarity and comfort.
There is good evidence to support three techniques for the
performance of carotid endarterectomy. Kresowik et al.,30 demon-
strated in their review of surgical outcomes for CEA in 10 states
that preoperative use of antiplatelet agents, intraoperative use of
heparin, and patch angioplasty closure were associated with lower
stroke and death rates. Furthermore, they showed that quality
improvement initiatives and adoption of preoperative antiplatelet
agents and routine patch angioplasty resulted in improved results
for CEA in all states studied.31
Answer: The preoperative use of antiplatelet agents and
routine patch angioplasty closure for CEA are associated with
improved stroke and death rates. Choice of anesthetic, incision,
and routine versus selective use of shunts do not have sufficient
evidence to be supported one way or another. These options are
best left to the comfort of the operating surgeon.
7. When should you do carotid stenting versus carotid endarte-
rectomy?
Carotid artery angioplasty and stenting is the newest treatment
modality for carotid occlusive disease. There has been much
debate and research over the past 10 years comparing CAS
with CEA. Most of the data has been industry driven and regis-
try data lending very little evidence on which to base treatment
decisions.32-36 The earliest trial comparing the two modalities was
the Carotid and Vertebral Artery Transluminal Angioplasty Study
(CAVATAS).37 It was a multicenter trial in Europe, Australia, and
Canada that randomized 504 patients from March 1, 1992 to July
31, 1997 into either angioplasty/stent or CEA arms. The inclusion
criteria were rather lax and described as a stenosis that a physi-
cian thought needed treatment. The results were a 10.0% stroke
and/or death rate for the angioplasty/stent arm and a 9.9% stroke/
death rate for CEA. They concluded that there were similar major
risks and effectiveness with decreased complications compared to
surgery. There were multiple critiques of CAVATAS, mainly the
PMPH_CH86.indd 687
Carotid Occlusive and Aneurysmal Disease ■ 687
exceedingly high stroke and death rate in the surgical arm of the
trial but carotid stenting was gaining ground.
The breakthrough study for CAS was Stenting and Angioplasty
with Protection in Patients at High Risk for Endarterectomy study
(SAPPHIRE).38 SAPPHIRE randomized “high-risk” patients into
surgical or stent arms. Medical and/or anatomic criteria were used
to define high risk. The medical criteria included congestive heart
failure (CHF), recent MI, unstable angina, coronary revascular-
ization, chronic obstructive pulmonary disease (COPD), chronic
renal insufficiency (CRI), or age greater than 80 years. Anatomic
criteria included prior radical neck dissection, neck radiation
therapy, recurrent stenosis, high carotid lesions, or lesions below
the clavicle. A total of 307 high-risk patients were randomized to
stent or surgery at 29 institutions. Patients turned down for surgery
were entered into the stent registry. One stent and distal embolic
protection device combination was used for the study. The tra-
ditional study endpoints of stroke and death were expanded to
include cardiac events. The 30-day results showed a 5.8% death/
stroke/MI rate in the stent arm and a 12.6% death/stroke/MI rate
in the CEA arm (P = .05). When subdivided into medical and ana-
tomic comorbidities, the results were 2.8% versus 15.5% (CAS vs.
CEA) (P = .02) for the medical high-risk patients and 5.5% ver-
sus 10.0% (CAS vs. CEA) (P = .47) for the anatomic high-risk
patients. The investigators concluded that CAS was not inferior to
endarterectomy in high-risk patients. The results can be criticized
by the expanded endpoints, the definitions of high risk, and the
large number of registry data; however, the stroke rate in surgical
arm cannot be denied. Based on SAPPHIRE data, the Food and
Drug Administration and the Centers for Medicare and Medicaid
Services (CMS) approved CAS for high-risk patients.
SAPPHIRE was followed by larger randomized controlled trials
without registry data. They include two studies performed in Europe
and one in the United States. The European trials were Endarterec-
tomy versus Stenting in Patients with Symptomatic Severe Carotid
Stenosis (EVA 3S)39 and Stent-Supported Percutaneous Angioplasty
of the Carotid Artery versus Endarterectomy (SPACE).40 EVA 3S was
a multicenter, randomized, noninferiority trial looking at symptom-
atic carotid lesions of at least 60% stenosis. Multidisciplinary teams
including a neurologist, a vascular surgeon (who had performed
at least 25 CEAs), and an interventionalist (who had performed at
least 12 CASs) were used to treat the patients. They enrolled 527
patients between November 2000 and September 2005. The study
was stopped early by the safety committee. The results showed a
30-day stroke/death rate of 3.9% versus 9.6% (CEA vs. CAS) and
a 6-month stroke/death rate of 6.1% versus 11.7% (CEA vs. CAS).
They concluded that CEA was superior. SPACE was a multinational,
multicenter, randomized trial looking at symptomatic carotid lesions
of at least 60% stenosis. Multidisciplinary teams including a neurol-
ogist, a vascular surgeon (who had performed at least 25 CEAs), and
an interventionalist (who had performed at least 25 CASs) were used
to treat the patients. SPACE enrolled 1183 patients between March
2001 and February 2006. The study was stopped due to futility and
lack of funds. The results showed a 30-day stroke/death of 5.64% ver-
sus 6.95% (CEA vs. CAS).
The long-awaited results of the American study were pub-
lished in the Carotid Revascularization Endarterectomy versus
Stent Trial (CREST).41 CREST randomized 2502 symptomatic and
asymptomatic patients to CAS or CEA over a 10-year period. Pri-
mary endpoints were 30-day stroke, death, or MI and ipsilateral
stroke within 4 years postprocedure. The results of overall 30-day
5/22/2012 5:58:49 PM
 688 ■ Surgery: Evidence-Based Practice

endpoints were not significantly different between the two groups
with 5.2% for CAS and 4.5% for CEA. The 30-day stroke/death rate
was 4.1% versus 2.3% (CAS vs. CEA) and the 30-day MI rate was
1.1% versus 2.3% (CAS vs. CEA). There were no statistical differ-
ences between symptomatic and asymptomatic patients. The inves-
tigators concluded that CAS and CEA were equivalent treatments.
The International Carotid Stenting Study (ICSS) is another ongoing
randomized trial in Europe looking into the relative risks of CAS
versus CEA. The enrollment criteria are symptomatic patients with
>50% stenosis. An interim report of 1713 symptomatic patients
randomized to CAS or CEA was published in the Lancet.42
The results showed a 30-day stroke, death, and MI rate of
8.5% for CAS and 5.2% for CEA. They concluded that long-term
follow-up was needed to determine the appropriate role for CAS
but that CEA remained the treatment of choice.
In summary, there have been many studies over the past
decade dedicated to comparing CAS and CEA. Some have favored
CAS whereas others have favored CEA. Critiques of all of the
studies abound. Taken as a whole, the body of evidence seems to
support the current recommendations of CMS. That is to say that
CEA is the treatment of choice for carotid occlusive disease and
CAS is indicated for high-risk, symptomatic patients.
Answer: CAS is indicated for the treatment of high-risk
patients with symptomatic carotid occlusive disease.
CAROTID ANEURYSMAL DISEASE
Aneurysms of the extracranial carotid artery are exceedingly
rare. Intracranial carotid artery aneurysms are more common
but fall under the scope of the neurosurgeon and the neuroint-
erventional radiologist. Extracranial carotid aneurysms include
both true aneurysms and false aneurysms (pseudoaneurysms).
Etiologies include atherosclerosis, fibromuscular dysplasia,
trauma (penetrating and nonpenetrating), dissection, postsur-
gical, and infection. Syphilis was once the most common cause
of carotid aneurysms but is seldom seen today. It is generally
felt that extracranial carotid aneurysms should be treated when
found to prevent the occurrence of neurologic events from embo-
lism. Surgical treatment involves resection of the aneurysm and
bypass to restore cerebral blood flow.43 Th is approach is good for
aneurysms of the common carotid artery or the carotid bifur-
cation but may be impossible for lesions extending to the skull
base. Endovascular treatment with covered stents 44 or emboliza-
tion45 is likely the preferred method for distal lesions where vas-
cular control would be problematic or in reoperative fields where
dissection would carry unacceptable risks. Given the rarity of
extracranial aneurysms, there is very little literature to delin-
eate the natural history of the disease or the best management
strategies.

Clinical Question Summary

Question Answer Grade of References
Recommendation
1 What is the stroke Medical management 26% over 2 years A 1-3
risk for symptomatic Surgical management 9% over 2 years A
carotid stenosis?
2 What is the stroke Medical management 11% over 5 years A 4-5
risk for asymptomatic Surgical management 5.1% over 5 years A
carotid stenosis?
3 What is the optimal Duplex ultrasonography C 6
diagnostic test for
carotid stenosis?
4 What are the Symptomatic >70% A 1-5
indications for Symptomatic >50% B
intervention of the Asymptomatic >70% A
carotid artery? Asymptomatic ≥60% B
5 What is the best Antiplatelet therapy: aspirin (75 to 325 mg daily), A 12-21
medical treatment clopidogrel (75 mg daily) or combination aspirin and
for carotid occlusive dipyridamole (25 and 200 mg twice daily)
disease? Statin use
Risk factor modification
6 What are the best Preoperative use of antiplatelet agents and routine patch B 30-31
surgical techniques angioplasty closure for CEA
for carotid
endarterectomy?
7 When should you CAS is indicated for the treatment of high-risk patients B 38
do carotid stenting with symptomatic carotid occlusive disease
versus carotid
endarterectomy?

PMPH_CH86.indd 688 5/22/2012 5:58:49 PM


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44. Yi AC, Palmer E, Luh GY, Jacobson JP, Smith DC. Endovascular
treatment of carotid and vertebral pseudoaneurysms with cov-
ered stents. AJNR Am J Neuroradiol. 2008;29(5):983-987.
45. Cox MW, Whittaker DR, Martinez C, Fox CJ, Feuerstein IM,
Gillespie DL. Traumatic pseudoaneurysms of the head and
neck: early endovascular intervention. J Vasc Surg. 2007;46(6):
1227-1233.
5/22/2012 5:58:49 PM

Aortoiliac Occlusive Disease
Jeffrey S. Horn and William D. Jordan, Jr.
INTRODUCTION
Aortoiliac occlusive disease (AOID) is a common entity in modern
vascular surgery practice as an obstructive disease of the terminal
aorta and iliac arteries. Patients present over many age groups
with the concentration in the 50 to 60 year olds. The patients
report varying levels of symptomatology from claudication to
critical limb ischemia depending on concomitant infrainguinal
disease. Successful treatments include both open and endovascu-
lar reconstruction. Best medical therapy may reduce overall risk
from systemic disease or halt the progression of the process, but
medical therapy does not reverse the presence of atherosclerosis
in this region. Controversy continues to exist over the best course
of management for patients with this disease.
HISTORY
Pathology of the aortoiliac segment was fi rst addressed in the
medical community in the early 1900s. Leriche made a series of
observations on young patients with a specific constellation of
symptoms, namely claudication and absence of femoral pulses
on exposure.1 Subsequently, impotence and leg atrophy were
also noted in many of these patients. He reported his fi ndings
on a cohort of 20 patients in 1948 and went so far as to recom-
mend arteriography and arterial resection for likely obliterative
disease of the aorta. Cid Dos Santos in 1946 developed tech-
niques of thromboendarterectomy by accidentally entering the
wrong dissection plane while attempting femoral embolecto-
my.2 Once the plaque was excised he was met with brisk flow,
and later coined the term “disobliteration.” His pioneering tech-
niques were then applied to the aortoiliac segment by Wylie in
the early 1950s.3 Direct replacement of the aortoiliac segment
was devised after the development of prosthetic vascular grafts
in the 1950s. Further refinements in technique over the ensu-
ing decades have made direct reconstruction with aortofemo-
ral grafts, the standard to which newer therapies are compared.
The first successful percutaneous treatment of pathology in this
691
PMPH_CH87.indd 691
CHAPTER 87
segment was reported in 1979.4 Early results with angioplasty
were disappointing due to poor recanalization rate, high failure
rate, and higher than expected complication rates. The introduc-
tion of stents and better delivery platforms as well as increased
operator skill has made endovascular therapy the chosen treat-
ment for a great majority of patients with AOID. Indeed, the
number of direct reconstructions has decreased in recent years as
endovascular means are increasingly used to treat even the most
complex forms of disease.5
EPIDEMIOLOGY
Peripheral arterial disease (PAD) is defined by an ankle-brachial
index (ABI) of ≤0.9. In epidemiologic samples, PAD affects over
8 million men and women over age 40.6 This disease worsens with
age, with a 12% to 20% incidence in those over 65.7 The ratio of
symptomatic to asymptomatic disease is independent of age and
on the order of 5% to 33%.8 PAD is caused by advancing athero-
sclerosis which has numerous risk factors including smoking,
hypertension, diabetes mellitus, dyslipidemia, age, race, gender,
and chronic renal disease.
There are several patterns of distribution of atherosclerosis
in patients with PAD. The most common description, based on
arteriographic study separates the periphery into (1) aortoiliac,
(2) femoropopliteal, and (3) tibioperoneal disease. Aortoiliac
“inflow” disease can be subdivided into (1) isolated aortoiliac
disease, (2) abdominal inflow disease extending into external
iliacs, and (3) multilevel disease with extensive atherosclero-
sis of infrainguinal vessels.9 Those with type I AOID tend to be
younger with fewer risk factors and present with claudication.
Severe symptoms are usually absent owing to the brisk collater-
alization around this segment. Symptoms on presentation may
include hip and buttock claudication, impotence in men, and
diminished femoral pulses (classically, the Leriche syndrome).
Women make up a good part of this group, especially those with
extensive smoking history and those with a small, hypoplastic
aorta. Isolated AOID is seen in 5% to 10% of patients undergoing
5/22/2012 5:59:24 PM
 692 ■ Surgery: Evidence-Based Practice
intervention, whereas multilevel disease is present in 20% to 50%.
Patients suffering from multilevel disease tend to be older and
present with critical limb ischemia. Hansen studied the arterio-
grams of patients younger and older than 50 to see if there were
differences in distribution of atherosclerosis. Of the 59 patients
younger than 50, 42% had disease of the aortoiliac segment, and
there was isolated disease in 54%. In contrary, 140 patients older
than 50 had similar percentage aortoiliac disease but was isolated
in only 16%.10
The natural history of those with PAD indicates increased
risk of cardiac events, stroke, and death. Cardiovascular causes
account for almost 70% of mortality in this population. Several
investigations indicate that degree of ABI reduction corresponds
to risk for cardiovascular death. Patients with symptomatic PAD
have shortened life spans compared to age-matched controls.
DIAGNOSIS
Symptomatic patients with AOID may complain of either hip
and buttock or sometimes calf claudication depending on the
distribution of atherosclerosis as discussed. Examination may
reveal absent or diminished femoral pulses, as well as bruits or
thrills over the groins. These fi ndings may be present only after
brisk exercise on a treadmill. History of impotence should also
be ascertained, as up to 30% of males with AOID may have this
symptom on questioning. History and physical exam should be
followed by noninvasive studies. ABI may be mildly reduced
and pressure waveform reduction at the thigh level may indicate
stenosis or occlusion on that site. Exercise testing may unmask
disease in a patient with otherwise normal ABI measurements.
Duplex ultrasound can be used to determine levels of disease
and velocity across stenoses, but is rarely used alone in pre-
operative preparation. Computed tomography and magnetic
resonance give the most detailed noninvasive information.
Advances in technology such as multislice scanners and devel-
opment of iso-osmotic contrast agents make these tests highly
accurate with minimal but not negligible risk to the patient.
Runoff studies can give high resolution to the tibial vessels for
operative planning. Arteriography remains the gold standard
for diagnosis and preoperative planning in AOID. Although
invasive, it shows volume flow in real time. Pressure measure-
ments can also be taken across lesions to determine their physi-
ologic significance.
1. Which lesions in aortoiliac occlusive disease are favorable
for endovascular repair?
Since the first iliac angioplasty and subsequent development of
stents, there have been many progressive reports regarding suc-
cessful treatment of various lesions. Originally published in 2000,
the TASC (Trans-Atlantic Inter-Society Consensus Document on
Management of Peripheral Arterial Disease) document has been
updated in 2007.8 This guide gives recommendations on treatment
of various risk factors of PAD as well as treatment algorithms for
the lower extremities. Aortoiliac disease is broken down into four
subgroups based on severity of disease. These groupings are based
on successful treatments with either modality. Endovascular suc-
cess is defined as technical ability to cross and treat the offending
PMPH_CH87.indd 692
lesion, as well as long-term patency after intervention. TASC A
encompasses short focal stenoses of the common or external iliac
artery. Total occlusions, longer stenoses, tandem, and bilateral
stenoses progress through TASC B and C to TASC D, the most
severe pattern of disease, which is best treated by open reconstru-
ction. Although TASC-II recommendation 36 states that the
treatment of choice for A is endovascular therapy and for D is
open therapy,8 treatments for B and C are less clear and depend
on comorbidities, informed patient decision making, and opera-
tor skill.
Timaran studied this less clearly defined group of TASC B
and C and compared open against endovascular revascularization
for each.11 One hundred eighty-eight patients were treated: 136
endovascularly with 178 angioplasty and stent procedures, and
52 patients undergoing 60 direct surgical reconstructions. Patient
comorbidities were well matched, but more were treated for clau-
dication in the open surgery group. The percutaneous group was
more likely to be TASC B and have stenoses, whereas the open
group more commonly had occlusions and fit into TASC C. There
was no difference in runoff to the lower extremity. Primary pat-
ency at 1, 3, and 5 years was 89%, 86%, and 86%, respectively, after
surgical bypass compared with 85%, 72%, and 64%, respectively,
after angioplasty and stenting. Patency was not affected by TASC
classification in this study. Survival was not significantly different
between the groups.
As technology and experience improve, more research is
looking at safety and efficacy of endovascular treatment of TASC
C and D lesions. Leville in 2005 published results from a series
of percutaneous treatment of varying degrees of unilateral or
bilateral iliac occlusion.12 Eighty-nine patients underwent 92
procedures for symptomatic lesions. Technical success was 94%
and 86% for TASC C and D patients, respectively. Primary pat-
ency ranged from 73% to 80% and did not differ significantly
between TASC groups. Secondary patency rates where 93% and
83%. Claudicants had better secondary patency than did those
with critical limb ischemia. Th is study showed good patency and
limb salvage with similar to open repair but with lower compli-
cation rate.
Hans compared results of 32 aortofemoral bypass (ABF)
patients to 40 aortoiliac stenting (AIS) patients.13 There was no
difference between TASC groups or indications for procedure for
open or percutaneous methods. Stented patients were older in this
cohort. Primary patency was 93% for ABF and 69% in AIS. Com-
plications occurred in 10% of AIS, including dissections, throm-
bosis, and access-related problems. Secondary patency was 100%
in ABF and 89% in AIS, suggesting that open repair had better
patency and clinical results.
These studies indicate that all TASC lesions can be approached
percutaneously with moderate success. One may be trading the
difficulty of open aortic reconstruction (hospital stay, pulmonary
and cardiac complications) with reduced durability of the inter-
vention. So, the clinician should consider both the comorbidities
of the patient and the anatomic distribution of disease when plan-
ning open versus endovascular repair.
There are no large prospective randomized trials comparing
the various modalities. Most series are retrospective reviews of
nonrandomized cohorts or case series (Level II evidence, Grade B
recommendation).
5/22/2012 5:59:24 PM

2. Is primary stenting better than selective stenting?
Aortoiliac angioplasty and stenting has proven itself for TASC A
and most TASC B lesions, with increasing use in more advanced
lesions. Prior investigations have tried to identify which combina-
tions of angioplasty and stenting give the best results, whether it
is angioplasty alone with selective stenting or primary stent place-
ment. Selective stent placement is used after angioplasty if there is
a residual angiographic lesion ≥30% or a persistent mean pressure
gradient of ≥5 mm Hg.
The Dutch Iliac Stent Trial (DIST) in 2006 attempted to
answer this question in a prospective randomized trial.14 Two
hundred seventy-nine patients were randomized to either pri-
mary stent (143) or PTA and selective stent (136). Of the selective
group, 43% ultimately required stents. Mortality, hemodynamic
success, patency, and reintervention rates were similar between
groups. Symptomatic success, defined by quality of life tools, was
improved for the selective group at 5 years, and approached that
of age-matched controls. Equivalence of treatments and perhaps
improved quality of life in selective stenting led them to recom-
mend selective stenting as the procedure of choice for iliac steno-
sis and occlusion. The implications of their findings were reduced
costs with selective stenting, and introduction of less foreign
material into the body.
Kudo reviewed his institution’s 11-year experience with
151 limbs in 104 patients treated with angioplasty and selective
stenting.15 Demographics were similar, with a trend toward more
male smokers in the PTA-only group. The distribution of TASC
A through D was 26%, 47%, 24%, and 3%. The stent group had
more patients being treated in higher TASC categories. Primary,
assisted, and secondary patencies were not significantly different
between the two groups. Technical success was high (99%) and
complication rates were low (0.7%). Distal SFA stenosis and Type
C and D TASC lesions were associated with PTA failure. Although
equivalence of treatment arms was reported, overall patency was
low at 59% and 49% at 3 and 5 years, respectively.
De Roeck in 2006 published results of a cohort undergoing
primary stenting in complex aortoiliac lesions.16 Thirty-eight
patients were analyzed, twelve TASC B, ten TASC C and sixteen
TASC D. Reported initial success was 97% and clinical improve-
ment was noted in 96% of patients. Primary patency was 94%,
89%, and 77% at 1, 3, and 5 years. Secondary patency was 100%,
94%, and 94% at the same interval. Complication rate was 5.4%.
As in the Dutch Iliac Stent Trial, AbuRahma compared selec-
tive with primary stenting in a cohort of 110 consecutive patients
with 149 lesions.17 Unlike the DIST, this study included TASC C
and D lesions. Technical success was 100%. Clinical success was
defined by symptom resolution, increased ABI, and low residual
stenosis. This was achieved in 97% of the primary group and 83%
of the selective group, which was clinically significant. When
evaluated by TASC grouping, type A and B lesion outcomes were
similar regardless of treatment. TASC C and D lesions, however,
fared much better with primary stenting, with 84% clinical suc-
cess compared to 46% in the selective group, again statistically
significant. This trend held true for patency data as well. Patency
for C and D lesions at 1, 2, and 3 years was 96%, 90%, and 72%
whereas selective stenting had 46%, 46%, and 28% at similar inter-
vals. Overall complication rate in this sample was 2.6%.
PMPH_CH87.indd 693
Aortoiliac Occlusive Disease ■ 693
Whereas TASC II does not give specific recommendations
on which technique to use, the above reports may indicate better
results with primary stenting in longer, more advanced aortoiliac
lesions, leaving selective stenting for shorter focal stenoses (Level I b
evidence, Grade B recommendation).
3. Does open reconstruction trump endovascular repair?
The decision to intervene for AOID is similar to other vascu-
lar interventions: lifestyle limiting claudication, rest pain, and
gangrene. For asymptomatic patients, lifestyle modification and
medical management should be initial treatment. Once interven-
tion is deemed necessary to improve pain or heal tissue, one must
decide on how to treat the lesion based on anatomic distribu-
tion and patient-specific risk factors. Anatomic factors include
lesion location, severity, distal extent, stenosis or occlusion, and
calcium burden. Patient factors include age, medical comorbidi-
ties, preference to one type of operation, and allergies (contrast).
Open reconstruction, the gold standard, is durable and success-
ful if the above technical factors are followed. However, not all
are candidates for major open reconstruction, especially the
elderly, medically infirmed patient in need of inflow to the lower
extremity.
Although not randomized, several studies have compared
direct reconstruction to endovascular repair. Burke in 2009 per-
formed a retrospective review comparing 118 aortobifemoral
bypasses to 174 aortoiliac angioplasty and stent procedures.18
Operations that included both open femoral endarterectomy and
proximal endovascular treatment were excluded from the study.
The endovascular group was older, suffered more from CHF and
COPD and was more likely to claudicate. The ABF group was more
likely to have undergone prior intervention and more commonly
presented with critical limb ischemia. TASC D classification was
more common in the ABF group. Outcomes with regard to mortal-
ity, myocardial infarction, or stroke were no different between the
groups. The ABF group had more complications postoperatively
and had longer stays in hospital and the ICU. After controlling for
several variables, the change in postprocedural ABI was higher in
the ABF group. Freedom from amputation or reintervention was
no different, however, between the two cohorts at mean follow-up
of 32 months. The two cohorts were not exactly similar with
respect to TASC distribution, but the single center study indicated
no difference in the study endpoints of freedom from amputation
or reintervention.
A similar study was published by Kashyap in 2008.19 Their
study included 86 patients with ABF or ileofemoral bypass (IFB),
and 83 patients with percutaneous angioplasty and stenting
(PTAS). Demographics were similar except that ABF patients
were younger with higher cholesterol and more frequent tobacco
abuse. General anesthesia was more common in ABF. A signifi-
cant difference in primary patency at 3 years was reported at 93%
for ABF and 74% for PTAS (P = .002). Assisted patency, second-
ary patency, limb salvage, and survival were similar between the
groups. On univariate analysis diabetes, age less than 60, and
requirement of distal bypass were found to adversely affect pat-
ency. Although no patency data were presented in the fi rst study,
they both indicate that excellent results can be achieved with
both methods. In the second study although initial patency was
5/22/2012 5:59:24 PM
 694 ■ Surgery: Evidence-Based Practice
not as good, assisted patency matched open repair and patients
were better matched as far as TASC classification is concerned.
In light of these studies, patients should be made aware of all
options for revascularization with attendant risks: ICU stay,
hospital stay, transfusion requirements, durability, and need for
future treatments to maintain patency of the intervention. With
a skilled surgeon at hand, they can then assist in the process
of informed decision making to agree on the most appropriate
method of revascularization.
4. What technical factors result in successful direct reconstruc-
tion of AOID?
Aortofemoral graft ing has become the “gold standard” of aor-
toiliac reconstruction, but many technical controversies emerged
during its development.20 Although certain generalizations can
be made, operations should be tailored to the patient and clinical
scenario as appropriate.
Approach
Transperitoneal exposure of the abdominal aorta is the preferred
route for direct reconstruction. This incision is rapid and provides
ample access to pathology in question. A retroperitoneal incision
may be used for alternative access and has been reported to reduce
postoperative ileus and pulmonary complications. Retroperitoneal
incisions are also advantageous in that they can avoid a “hostile”
abdomen from prior aortic surgery or intestinal catastrophes. Left
renal and visceral arterial approaches are also facilitated by this
technique, making it the incision of choice for combined revascu-
larizations to those beds. The right renal, iliac, and femoral sys-
tems are sometimes difficult to access during this approach.
Several reports have compared the two operative exposures
with attention toward pulmonary and gastrointestinal (GI) mor-
bidity. Some studies included both aneurysmal and occlusive
disease together. One prospective randomized trial by Cambria
evaluated outcomes after transperitoneal or retroperitoneal expo-
sures in 113 patients.21 Baseline characteristics between the groups
were similar. The study found no difference between cohorts for
operative times, transfusion requirements, respiratory morbidity,
recovery of GI function, narcotic requirements, or hospital stay.
Other case series demonstrated significantly more ileus and lon-
ger hospital stay. No series demonstrated increased mortality with
one method. In another randomized study of 145 patients under-
going aortic reconstruction for aneurysmal or occlusive disease of
the aorta, Sicard discovered higher incidence of ileus, small bowel
obstruction, and longer hospital stay in the transperitoneal expo-
sure cohort.22 The surgeon can thus choose either approach (Level Ib
evidence, Grade B recommendation).
Proximal Anastomoses
End to end and end to side are the two possible configurations
for the proximal anastomosis. Both are considered acceptable
and effective, and each has its place in certain types of occlusive
distributions in the aortoiliac segment. End-to-end configura-
tion should be sought when there is complete degeneration of the
aorta or there is occlusion of the infrarenal segment. Benefits of
the end-to-end anastomoses include straight in-line flow without
hemodynamic alterations, as well as lack of competing flow into
PMPH_CH87.indd 694
the native distal aortic segment. With heavy calcification of the
aorta, end-to-side connections may be much more difficult than
being able to endarterectomize a circumferential cuff of distal
aorta prior to suturing end to end. Other considerations include
maintaining patency of inferior mesenteric artery (IMA) and
accessory renal vessels, best suited by end-to-side technique. For
patients with occluded external iliac arteries, end-to-end configu-
rations may devoid the pelvis of antegrade blood flow if additional
hypogastric grafting is not sought and lead to disabling hip and
buttock claudication or impotence.
Amelli in 1991 prospectively studied 120 patients with aor-
tofemoral bypass, 42.5% with end-to-end and 57.5% with end-to-
side anastomoses.23 Cumulative survival and patency were similar
in both groups, whereas the end-to-end group experienced more
operative death. The end-to-end cohort was older, suffered more
from coronary disease, and contained a higher proportion of
aneurismal aortic disease. Dunn in 1982 compared proximal
technique in 192 patients undergoing aortofemoral bypass, 101
end to end and 91 end to side.24 The cohorts achieved similar
5-year patency, 87% in end to end and 85% in end to side. There
were two aortoduodenal fistulas in their study, both in the end-to-
side group although not reaching statistical significance. Grafts
secured by end-to-end proximal anastomosis fit better anatomi-
cally in the native aorta bed, allowing for adequate coverage by
retroperitoneal tissue. End-to-side configurations are more diffi-
cult to cover, possibly exposing them to duodenal adherence and
fistulization.
Interestingly, in computed tomography follow-up of end-to-
side anastomoses, Mikati revealed distal aortic occlusion in 48 of
52 patients (92%).25 These investigations were done 5 to 10 years
after bypass, potentially allowing time for collateralization prior
to thrombosis. These findings were confirmed in nine patients
studied by O’Connor, of which six had distal aortic occlusion
within 8 months.26 No patients in either series developed symp-
toms of pelvic ischemia, regardless of aortic patency.
Although no recent data exist on this topic, most proximal
anastomoses are constructed according to surgeon preference
and training, taking into account aortic calcium burden, pelvic
blood flow, ease of retroperitoneal coverage, and inferior mesen-
teric and accessory branch blood flow (Level II evidence; Grade B
recommendation).
Distal Anastomosis
Because atherosclerosis is a progressive disease, distal anastomo-
ses should be brought to the femoral system in the majority of
cases. Obese or diabetic patients with unsanitary groins would
be an obvious exception, where all graft material should be kept
in the abdomen. Baird demonstrated increase in graft failure
when not bringing the graft to the femoral arteries.27 The femoral
exposure is straightforward and allows direct examination of the
outflow vessels. When groin infection is a concern, autogenous
reconstruction with deep femoral veins can be done to minimize
risk of infection.
Outflow Vasculature
For a vascular bypass to be successful, there must be adequate out-
flow. Profundaplasty, including removal of an obstructing plaque
at the profunda origin has been shown to be a vital component
5/22/2012 5:59:24 PM

of reconstruction in patients with disease at the anastamotic site.
Reconstruction of the profunda can be performed with endart-
erectomy, autogenous patch angioplasty, or extension of the graft
limb onto the profunda itself. Malone identified profunda disease
as the sole source for aortofemoral graft limb occlusion to 71 of
522 femoral arteries in his series.28 Occlusions were treated with
angioplasty of diseased profunda arteries, with 100% patency. In
this series, autogenous angioplasty was 2.5 times more likely to be
successful than on-lay Dacron patch (Level IIb evidence).
5. What adjunctive medication and follow-up protocol support
successful AOID interventions?
Successful arterial bypass requires meticulous anastomoses to
prevent short-term graft failures. Long-term, adjunctive anti-
thrombotic agents likely assist with patency. Prior studies have
shown that failure rates of lower extremity bypasses can be as high
as 45% without these medications. Tangelder in 1999 performed a
meta-analysis of randomized control trials of aspirin and warfa-
rin in lower extremity bypass grafts.29 The relative risk for occlu-
sion with aspirin was 0.78. This was reduced to 0.38 if aspirin was
combined with oral anticoagulation. No reductions in the com-
bined endpoints of myocardial infarction, stroke, or death were
seen in this meta-analysis.
Two Cochrane reviews evaluating antiplatelet in periph-
eral intervention have been performed. In 2008, Brown showed
improved patency with antiplatelet medications of both venous
and artificial grafts compared to placebo.30 Those with prosthetic
grafts were more likely to benefit than those with vein grafts.
Again, the outcomes related to cardiac morbidity and mortality
were not different between antiplatelet and placebo. In 2011 Dörf-
fler-Melly noted that addition of aspirin and dipyridamol reduced
recurrent obstruction by 60% after percutaneous angioplasty.31
Clinical Question Summary
Question Answer
1 Which lesions in AOID All lesions can be approached and treated
are favorable for with moderate success.
endovascular repair?
2 Is primary stenting Selective stenting should be used in TASC
better than selective A and B short focal lesions, whereas
stenting? primary stenting should be used on
TASC C and D lesions.
3 Does open Patency is better with open
reconstruction trump reconstruction, while postoperative
endovascular repair? complications may be higher.
4 What technical factors Via transperitoneal or retroperitoneal
result in successful approach, bypass should be taken to
direct reconstruction the femoral arteries with end-to-end
of AOID? or end-to side proximal anastomoses,
depending on clinical situation.
Profunda femoris disease should be
addressed during femoral anastomosis.
5 What adjuncts Antiplatelet agents should be used after
and follow-up are open or percutaneous revascularization.
recommended after Follow-up every 6 to 12 months with
intervention? history, physical, and noninvasive lab.
PMPH_CH87.indd 695
Aortoiliac Occlusive Disease ■ 695
As a result of these findings and level of evidence, recommen-
dation 41 of the TASC-II document suggests adding antiplatelet
therapy to all those undergoing open or endovascular revascular-
ization procedures for both atherosclerotic and nonatherosclerotic
disease, that is, trauma.8 Antiplatelet agents should be continued
indefinitely unless contraindicated by bleeding risk (Level I evi-
dence; Grade A recommendation).
Clinical follow-up of any intervention should be multifac-
eted and incorporate interval history, physical exam findings,
and warranted imaging or noninvasive studies. New claudication
after intervention should raise suspicion of graft or stent problems
or development of distal disease. Graft surveillance can be per-
formed in a dedicated vascular laboratory with duplex examina-
tion to examine stent or ABF limb velocities. Early elevations in
velocities can indicate anastomotic problems with the interven-
tion and need for revision. With elevated velocities at anastomotic
sites, patients should be placed in a more frequent surveillance
protocol if reintervention is not pursued. Patients with AOID
intervention should be evaluated every 6 months with history,
physical, and duplex of the graft or stent. Although there are
several nonrandomized studies evaluating the efficacy of duplex
exam after infrainguinal bypass, data are lacking for similar stud-
ies on aortoiliac intervention. Rigorous evaluation of interventions
may identify the failing graft needing intervention prior to throm-
bosis. These exams may indicate pending aortofemoral limb
thrombosis, in-stent restenosis, new dissection from prior angio-
plasty, or anastomotic intimal hyperplasia at graft connections.
The vascular noninvasive lab can also detect new lesions in the
femoropopliteal or tibioperoneal region that may restrict outflow
of a prior functioning inflow procedure. All these are reasons to
enroll patients in an intense follow-up protocol and prevent future
limb problems.
Level of Grade of References
Evidence Recommendation
II B 11-13
Ib B 14-17
II B 18, 19
II B 21-28
I A 29-31
D
5/22/2012 5:59:24 PM
 696 ■ Surgery: Evidence-Based Practice
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 Commentary on
Aortoiliac Occlusive Disease
Alan B. Lumsden
Perhaps no area of vascular intervention has undergone such
radical changes in approach than aortoiliac occlusive disease.
Frequency of aortobifemoral bypass has dwindled to almost non-
sustainable training levels in most programs, while endovascular
enthusiasts tout that no lesion in this segment should be excluded
from catheter-based intervention! Drs Horn and Jordan have pro-
vided an excellent and traditional review of therapy for aortoiliac
occlusive disease. In this commentary I will be deliberately pro-
vocative and hope to stimulate the reader into considering more
forward thinking and “nontraditional” interventions.
Let us first consider that all procedures consist of a delivery
system and a therapeutic component to the operation. The latter
consists of inflating the balloon, deploying the stent, or sewing in
the bifurcated graft. Although the aortoiliac segment may be the
only area in which real debate could exist, few would argue that
the successful placement of the Dacron conduit reigns supreme.
But the delivery system for placement of an aortoiliac Dacron
graft leaves a lot to be desired, and that is an understatement.
Who in the right mind would not give up some patency for the
more acceptable catheter-based delivery of balloons, stent, and
stent grafts? However, the implication is that we surgeons have
sacrificed durability for delivery and we have been more than
complicit in enhancing public acceptance of this approach. Had
we placed as much emphasis on maintaining the core therapeutic
part of our operation while changing the delivery system to make
it more acceptable, we could have experienced the best of both
worlds. Hence the ongoing, although limited flirtation with robot-
ics. Several groups both in the United States, Canada, and Europe
continue to flirt with robotic aortofemoral bypass grafting and the
more challenging repair of aneurysms. Criticisms abound: takes too
long, technically too difficult, too many ports, not enough vascu-
lar surgeons with laparoscopic skills, and not enough right instru-
ments. Perhaps too many of the surgeons have moved too far away
from traditional surgery to even objectively consider laparoscopic
or robotic bypass grafting. Let us not forget the rapid development
of highly sophisticated hybrid rooms, where blending endovascular
techniques and open skills are the order of the day. I watch our car-
diac surgeons perform left internal mammary artery (LIMA) to left
anterior descending artery (LAD) bypass through a thoracotomy
on a beating heart or sew a vein graft on to the aorta through the
same incision using anastamotic staplers, while cardiologists pro-
vide catheter interventions for difficult to access lesions. Where are
the anastamotic staplers in our world? Such devices could transform
697
PMPH_CH87.indd 697
our ability to perform minimally invasive bypass. Similarly direct
aortic access through a mini-sternotomy can be used for a tanscath-
eter aortic valve implant (TAVI) placement. So the vascular surgical
community that has led so much of the minimally invasive vascular
community must continue to re-evaluate our delivery systems and
preserve durability of our interventions. Optimal therapy for aor-
toiliac occlusive disease has yet to be defined and we should keep an
open mind; all options should be on the table and vascular surgeons
alone could objectively evaluate hybrid approaches.
In talking about hybrid procedures, I wanted to address an
area that has been a particular concern of vascular surgeons,
namely the interface between a heavily diseased common femoral/
distal external iliac and an iliac system relined with stent grafts
or bare metal stents. Here is the typical scenario: surgeon opts to
cut down on the common femoral artery, perform an endarterec-
tomy, and use catheter-based techniques to open the ipsilateral
iliac system. The sequence is usually the following: expose the
common femoral artery, direct puncture with needle as far dis-
tally as possible within the common femoral, pass wire, and work
through sheath. Once the iliac system has been opened, endolumi-
nal control is obtained with a balloon. This is easy for a stent graft;
a balloon placed close to the distal end will provide good control,
not so with a bare metal stent, where collaterals are often preserved
and the balloon can be ruptured on the stent edges. Control of
all the common femoral branches is necessary. The artery is then
opened and if possible the distal end of the stent/stent graft directly
visualized. This will allow the interface between the endoluminal
and open reconstruction to be inspected directly. The endarterec-
tomy is then performed, and the plaque sharply transected at the
stent edge, ensuring no residual plaque protruding into the lumen.
Often, however, this is an area that is difficult to visualize when
the stent ends higher in the external iliac artery. A patch should be
initiated as close to the end of the stent as possible, necessitating
the endoluminal control to move a little higher. If the endoluminal
open interface is not directly visualized, then a completion retro-
grade arteriogram should be performed and the stent extended
across any residual plaque if required.
Regarding the totally occluded aorta, an open end-to-end
aortobifemoral bypass is often required in our opinion. This
procedure, which preserves renal flow by preventing throm-
bus extension, has excellent durability and is tolerated by many
because the aorta is already occluded. An axillobifemoral graft is
a poor second choice, although there remains a role in patients
5/22/2012 5:59:24 PM
 698 ■ Surgery: Evidence-Based Practice
with prohibitive cardiac or pulmonary comorbidities. Likewise,
although rarely necessary, thoracofemoral bypass graft ing from
the distal descending thoracic aorta is an operation vascular
surgeons should continue to maintain in their armamentarium,
and perhaps this is an application for an endoscopic proximal
anastomosis.
Finally, as the romance with stent grafting continues, we
can expect even more aggressive endoluminal interventions. The
PMPH_CH87.indd 698
technical challenges that we continue to face are controlled navi-
gation through an occluded segment with deliberate and precise
re-entry into perfused segments. Solutions for these technical chal-
lenges are all currently being evaluated. So I am certainly not pro-
posing to throw away the hard-earned catheter, wire, and imaging
skills. What I am proposing is that we surgeons continue to inno-
vate toward optimal delivery and optimal durability, and that we
continue to evaluate and refine all the skills at our disposal.
5/22/2012 5:59:25 PM
 CHAPTER 88

Femoropopliteal and
Tibioperoneal Occlusive
and Aneurysmal Disease
Luke X. Zhan and Joseph L. Mills

CLASSIFICATION OF INFRAINGUINAL systolic pressure <50 mm Hg or toe systolic pressure <30 mm Hg

ARTERIAL DISEASE AND INDICATION FOR (or absent pedal pulses in diabetic patients).2
REVASCULARIZATION INTERVENTION PAD is clinically staged b