Sabiston Textbook of Surgery: The Biological Basis of Modern Surgical Practice [21 ed.] 9780323640626, 9780323640633, 9780323640657, 9780323640664, 9780323640640, 0323640621, 2020936664

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SABISTON

21ST

EDITION

TEXTBOOK of

SURGERY The BIOLOGICAL BASIS of MODERN SURGICAL PRACTICE

COURTNEY M. TOWNSEND, JR., MD

B. MARK EVERS, MD

Professor Robertson-Poth Distinguished Chair in General Surgery Department of Surgery The University of Texas Medical Branch Galveston, Texas

Professor and Vice-Chair for Research Department of Surgery Director, Lucille P. Markey Cancer Center Markey Cancer Foundation Endowed Chair Physician-in-Chief, Oncology Service Line UK Healthcare University of Kentucky Lexington, Kentucky

R. DANIEL BEAUCHAMP, MD J.C. Foshee Distinguished Professor of Surgery Professor of Cell and Developmental Biology Deputy Director, Vanderbilt-Ingram Cancer Center Vice President Cancer Center Network Affairs Vanderbilt University Medical Center Nashville, Tennessee

KENNETH L. MATTOX, MD Distinguished Service Professor Michael E. DeBakey Department of Surgery Baylor College of Medicine Chief of Staff and Surgeon-in-Chief Ben Taub General Hospital Houston, Texas

Elsevier 3251 Riverport Lane St. Louis, Missouri 63043

SABISTON: TEXTBOOK OF SURGERY: THE BIOLOGICAL BASIS OF  Standard Edition: 978-0-323-64062-6 MODERN SURGICAL PRACTICE, TWENTY FIRST EDITION International Edition: 978-0-323-64063-3 Copyright © 2022, Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Control Number: 2020936664

Content Strategist: Jessica L. McCool Senior Content Development Specialist: Joanie Milnes Content Development Manager: Kathryn DeFrancesco Publishing Services Manager: Shereen Jameel Senior Project Manager: Umarani Natarajan Design Direction: Margaret Reid Printed in Canada Last digit is the print number: 9 8 7 6 5 4 3 2 1

To our patients, who grant us the privilege of practicing our craft; to our students, residents, and colleagues, from whom we learn; and to our wives—Mary, Shannon, Karen, and June—without whose support this would not have been possible.

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CONTRIBUTORS Corinne M. Aberle, MD Assistant Professor Division of Cardiothoracic Surgery University of Miami Miami, Florida United States

Kristen A. Aliano, MD Plastic Surgeon Private Practice McGuiness Dermatology and Aesthetics Dallas-Fort Worth, Texas United States

Naim Abu-Freha, MD, MHA Department of Gastroenterology and Hepatology Soroka University Medical Center Faculty of Health Sciences Ben-Gurion University of the Negev Director, Department of Gastroenterology Assuta Medical Center—Beer Sheva Beer Sheva, Israel

Ronald D. Alvarez, MD, MBA Professor and Chair Obstetrics and Gynecology Vanderbilt University Medical Center Nashville, Tennessee United States

Andrew B. Adams, MD, PhD Associate Professor Surgery Emory University School of Medicine Atlanta, Georgia United States Reid B. Adams, MD Chair, Department of Surgery Claude A. Jessup Professor of Surgery University of Virginia Charlottesville, Virginia United States Nikhil Agrawal, MD Resident Surgery Baylor College of Medicine Houston, Texas United States Vanita Ahuja, MPH, MBA, MD Associate Professor of Surgery Yale University School of Medicine New Haven, Connecticut United States Chief, General Surgery VA Connecticut HealthCare System West Haven, Connecticut United States Sophoclis Alexopoulos, MD Associate Professor Section of Surgical Sciences Chief, Division of Liver Transplantation and Hepatobiliary Surgery Vanderbilt University Medical Center Nashville, Tennessee United States

Vamsi Aribindi, MD Surgical Resident Department of Surgery Baylor College of Medicine Houston, Texas United States Amanda K. Arrington, MD Associate Professor Department of Surgery University of Arizona Tucson, Arizona United States Omar Atassi, MD Assistant Professor of Orthopedic Trauma Ben Taub General Hospital Department of Orthopedic Surgery Baylor College of Medicine Houston, Texas United States I. Raul Badell, MD Assistant Professor Surgery Emory University School of Medicine Atlanta, Georgia United States Faisel G. Bakaeen, MD Professor Thoracic and Cardiovascular Surgery Cleveland Clinic Cleveland, Ohio United States Juan Camilo Barreto, MD Assistant Professor of Surgery Division of Surgical Oncology University of Arkansas for Medical Sciences Little Rock, Arkansas United States

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CONTRIBUTORS

R. Daniel Beauchamp, MD, FACS J.C. Foshee Distinguished Professor of Surgery Professor of Cell and Developmental Biology Deputy Director, Vanderbilt-Ingram Cancer Center Vice President Cancer Center Network Affairs Vanderbilt University Medical Center Nashville, Tennessee United States

Benjamin S. Brooke, MD, PhD Associate Professor of Surgery & Population Health Sciences Chief, Division of Vascular Surgery Section Chief, Health Services Research Department of Surgery University of Utah Salt Lake City, Utah United States

Yolanda Becker, MD, FACS, FAST Professor of Surgery Director of Kidney and Pancreas Transplant University of Chicago Chicago, Illinois United States

Carlos V.R. Brown, MD, FACS Chief, Division of Acute Care Surgery Department of Surgery Dell Medical School, University of Texas at Austin Austin, Texas United States

Elizabeth E. Blears, MS General Surgery Resident Allegheny Health Network Pittsburgh, Pennsylvania United States

Alfredo Maximiliano Carbonell, DO Vice Chairman of Academic Affairs Department of Surgery Prisma Health -Upstate Professor of Surgery University of South Carolina School of Medicine - Greenville Greenville, South Carolina United States

Iuliana Bobanga, MD Case Western Reserve University School of Medicine Clinical Assistant Professor Department of Surgery University Hospitals Cleveland Medical Center Cleveland, Ohio United States Morgan Bonds, MD Fellow General, Vascular, and Thoracic Surgery Virginia Mason Medical Center Seattle, Washington United States Mimi R. Borrelli, MBBS, MSc Research Fellow Surgery Stanford University Palo Alto, California United States Resident Department of Plastic Surgery Brown University Providence, Rhode Island United States Stefanos Boukovalas, MD Microvascular Reconstructive Fellow Department of Plastic Surgery The University of Texas MD Anderson Cancer Center Houston, Texas United States

Samuel P. Carmichael II, MD MS Assistant Professor of Surgery Department of Surgery Wake Forest University School of Medicine Wake Forest Baptist Health Winston-Salem, North Carolina United States Joshua S. Carson, MD Assistant Professor of Surgery Department of Surgery University of Florida College of Medicine Gainseville, Florida United States Howard C. Champion, MD, FACS Professor of Surgery F. Edward Hébert School of Medicine Uniformed Service University of the Health Sciences Bethesda, Maryland United States Kevin J. Chiang, BA, MD Acute Care Surgery Fellow Division of Trauma, Emergency Surgery, and Surgical Critical Care Massachusetts General Hospital Harvard Medical School Cambridge, Massachusetts United States

CONTRIBUTORS Dai H. Chung, MD, FACS Professor and Strauss Chair in Pediatric Surgery UT Southwestern Medical Center Dallas, Texas United States Michael Coburn, MD Professor and Chairman Scott Department of Urology Baylor College of Medicine Houston, Texas United States Eric L. Cole, MD Assistant Professor Division of Plastic Surgery The University of Texas Medical Branch Galveston, Texas United States Carlo M. Contreras, MD Associate Professor Surgery The Ohio State University Columbus, Ohio United States Robert N. Cooney, MD, FACS, FCCM Professor and Chairman Surgery SUNY Upstate Medical University Syracuse, New York United States Jack Dawson, MD Associate Professor of Orthopedic Trauma Chief of Orthopedic Surgery Ben Taub General Hospital Department of Orthopedic Surgery Baylor College of Medicine Houston, Texas United States Abe DeAnda Jr., MD Professor and Chief Division of Cardiovascular and Thoracic Surgery University of Texas Medical Branch Galveston, Texas United States Bradley M. Dennis, MD, FACS Associate Professor of Surgery Division of Trauma and Surgical Critical Care Vanderbilt University Medical Center Nashville, Tennessee United States

Rajeev Dhupar, MD, MBA, FACS Chief of Thoracic Surgery Surgical Services Division VA Pittsburgh Healthcare System Assistant Professor Cardiothoracic Surgery University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania United States Jose J. Diaz, MD, CNS, FACS, FCCM Professor of Surgery Vice Chair Quality & Safety Chief, Division of Acute Care Surgery Program Director Acute Care Surgery Fellowship Program in Trauma R. Adams Cowley Shock Trauma Center University of Maryland School of Medicine Baltimore, Maryland United States Sharmila Dissanaike, MD, FACS, FCCM Peter C. Canizaro Chair and Professor Department of Surgery Texas Tech University Health Sciences Center Lubbock, Texas United States Roger R. Dmochowski, MD, MMHC Professor Department of Urologic Surgery Vice Chair for Faculty Affairs and Professionalism Section of Surgical Sciences Associate Surgeon-in-Chief Vanderbilt University Medical Center Nashville, Tennessee United States Vikas Dudeja, MBBS, FACS Selwyn M. Vickers Endowed Scholar Director and Associate Professor Division of Surgical Oncology University of Alabama Department of Surgery Birmingham, Alabama United States Quan-Yang Duh, MD Professor, Chief Section of Endocrine Surgery Surgery University of California, San Francisco Attending Surgeon Surgery Veterans Affairs Medical Center San Francisco, California United States

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CONTRIBUTORS

James S. Economou, MD, PhD Beaumont Distinguished Professor of Surgery Distinguished Professor of Microbiology, Immunology, and Molecular Genetics Distinguished Professor of Molecule and Medical Pharmacology University of California-Los Angeles David Geffen School of Medicine Los Angeles, California United States

Samuel R.G. Finlayson, MD, MPH, MBA, FACS Professor of Surgery Claudius Y. Gates, MD, and Catherine B. Gates Presidential Endowed Chair in Surgery Department of Surgery University of Utah School of Medicine Salt Lake City, Utah United States

Michael E. Egger, MD, MPH Assistant Professor Hiram C. Polk Jr, MD, Department of Surgery University of Louisville James Graham Brown Cancer Center Louisville, Kentucky United States

Celeste C. Finnerty, PhD Professor Surgery The University of Texas Medical Branch Galveston, Texas United States

C. Tyler Ellis, MD, MSCR Instructor of Surgery Surgery University of Louisville Louisville, Kentucky United States B. Mark Evers, MD, FACS Professor and Vice-Chair for Research Department of Surgery Director, Lucille P. Markey Cancer Center Markey Cancer Foundation Endowed Chair Physician-in-Chief, Oncology Service Line UK Healthcare University of Kentucky Lexington, Kentucky United States Diana L. Farmer, MD, FACS, FRCS Chair and Professor Surgery University of California, Davis Sacramento, California United States Jeffrey S. Farroni, PhD, JD Associate Professor Institute for the Medical Humanities The University of Texas Medical Branch Galveston, Texas United States Anthony Ferrantella, MD General Surgery Resident Department of Surgery University of Miami Miller School of Medicine Miami, Florida United States Ryan Fields, MD Chief, Surgical Oncology; Professor of Surgery Surgery Barnes-Jewish Hospital & The Alvin J. Siteman Comprehensive Cancer Center at Washington University School of Medicine St. Louis, Missouri United States

Nicholas A. Fiore II, Private Practice Fiore Hand and Wrist Houston, Texas United States Thomas Fishbein, MD Executive Director MedStar Georgetown Transplant Institute MedStar Georgetown University Hospital Professor of Surgery Georgetown University School of Medicine Washington, DC United States Yuman Fong, MD Sangiacomo Chair and Chairman Department of Surgery City of Hope Medical Center Duarte, California United States Chuck D. Fraser Jr., MD, FACS Professor of Surgery and Perioperative Care Department of Surgery and Perioperative Care The University of Texas at Austin - Dell Medical School Section Chief for Pediatric and Congenital Cardiothoracic Surgery Texas Center for Pediatric and Congenital Heart Disease Austin, Texas United States Gerald M. Fried, MD, CM, FRCSC, FACS Edward W. Archibald Professor and Chairman Department of Surgery McGill University Surgeon-in-Chief, McGill University Health Centre Montreal, Quebec Canada Susan Galandiuk, MD Professor of Surgery, Program Director, Section of Colon & Rectal Surgery Hiram C. Polk Jr, MD, Department of Surgery University of Louisville Director Price Institute of Surgical Research University of Louisville Louisville, Kentucky United States

CONTRIBUTORS Tong Gan, MD, MS Resident Physician Surgery University of Kentucky Lexington, Kentucky United States S. Peter Goedegebuure, PhD Associate Professor Surgery Washington University School of Medicine Saint Louis, Missouri United States Oliver L. Gunter, MD, FACS Associate Professor Director of Emergency General Surgery Division of Trauma & Surgical Critical Care Vanderbilt University Medical Center Nashville, Tennessee United States Jennifer M. Gurney, MD, FACS Chief Defense Committee on Trauma Joint Trauma System Falls Church, Virginia Surgeon United States Army Institute of Surgical Research San Antonio, Texas United States

David N. Herndon, MD Retired Kelleys Island, Ohio United States Marty J. Heslin, MD, MSHA Professor and Vice Chair Surgery The University of Alabama at Birmingham Birmingham, Alabama United States Shinjiro Hirose, MD Professor of Pediatric Surgery University of California, Davis Sacramento, California United States Trung Ho, MD Staff Physician Surgery Baylor College of Medicine Houston, Texas United States Richard Hodin, MD Professor of Surgery Chief of Academic Affairs Massachusetts General Hospital Harvard Medical School Boston, Massachusetts United States

Jennifer L. Halpern, MD Assistant Professor Department of Orthopedics Vanderbilt University Medical Center Nashville, Tennessee United States

Wayne L. Hofstetter, MD Professor of Surgery and Deputy Chair Thoracic and Cardiovascular Surgery The University of Texas MD Anderson Cancer Center Houston, Texas United States

Jason Hawksworth, MD Transplant Surgeon Hepatopancreatobiliary and Transplant Surgeon Assistant Professor of Surgery MedStar Georgetown Transplant Institute MedStar Georgetown University Hospital Washington, DC United States

Ginger E. Holt, MD Professor and Vice Chair of Education Orthopaedic Surgery and Rehabilitation Adult Reconstruction Surgery and Musculoskeletal Oncology Director, Musculoskeletal Oncology Program Director, Orthopaedic Residency Program, Musculoskeletal Oncology Fellowship Division of Pediatric Orthopaedics Vanderbilt University Medical Center Nashville, Tennessee United States

Mary Hawn, MD, MPH Professor and Chair Surgery Stanford University Stanford, California United States Antonio Hernandez, MSc, MD Associate Professor Anesthesiology Vanderbilt University Medical Center Nashville, Tennessee United States

Michael S. Hu, MD, MPH, MS Post-Doctoral Fellow Surgery Stanford University Stanford, California United States Resident Physician Plastic Surgery University of Pittsburgh Medical Center Pittsburgh, Pennsylvania United States

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CONTRIBUTORS

Yinnin Hu, MD Fellow, Complex General Surgical Oncology, Department of Surgery Memorial Sloan-Kettering Cancer Center New York, New York United States Kelly K. Hunt, MD, FACS Professor and Chair Breast Surgical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas United States Neil Hyman, MD Chief, Section of Colon and Rectal Surgery, Codirector Digestive Disease Center Department of Surgery University of Chicago Medicine Chicago, Illinois United States Uzi Izhar, MD Professor of Cardiothoracic Surgery Head - General Thoracic Surgery Unit Cardiothoracic Surgery Hadassah University Medical Center Jerusalem, Israel Eric H. Jensen, MD, FACS Professor and Chief of Surgical Oncology Department of Surgery University of Minnesota Medical Center Minneapolis, Minnesota United States Gregory J. Jurkovich, MD Professor and Vice-Chairman Department of Surgery University of California, Davis Sacramento, California United States Shana S. Kalaria, MD, MBA Resident Physician Division of Plastic Surgery University of Texas Medical Branch Galveston, Texas United States Seth J. Karp, MD Chairman Section of Surgical Sciences Surgeon-in-Chief Director Vanderbilt Transplant Center Vanderbilt University Medical Center Nashville, Tennessee United States

Samuel J. Kesseli, MD Resident Physician General Surgery Duke University Medical Center Durham, North Carolina United States Leena Khaitan, MD, MPH Professor of Surgery Department of Surgery Director, Metabolic and Bariatric Surgery Center Director, Esophageal and Swallowing Center Digestive Health Institute University Hospitals, Cleveland Medical Center Cleveland, Ohio United States Kimberly H. Khoo, BS Medical Student School of Medicine The University of Texas Medical Branch Galveston, Texas United States Jae Y. Kim, MD Chief, Division of Thoracic Surgery Surgery City of Hope Cancer Center Duarte, California United States V. Suzanne Klimberg, MD, PhD, MSHCT, FACS Courtney M. Townsend, Jr., MD Distinguished Chair in General Surgery Department of Surgery The University of Texas Medical Branch Galveston, Texas Adjunct Professor The University of Texas MD Anderson Cancer Center Houston, Texas United States Patrick H. Knight, MD Resident Department of Surgery Western Michigan University Homer Stryker MD School of Medicine Kalamazoo, Michigan United States Katherine E. Kramme, DO Resident Department of Surgery Western Michigan University Homer Stryker MD School of Medicine Kalamazoo, Michigan United States

CONTRIBUTORS Bradley A. Krasnick, MD Resident Surgery Washington University School of Medicine St. Louis, Missouri United States

Amin Madani, MD, PhD, FRCSC, DABS Resident Department of Surgery University Health Network Toronto General Hospital Toronto, Ontario Canada

Amanda M. Laird, MD Chief, Section of Endocrine Surgery Surgical Oncology Rutgers Cancer Institute of New Jersey Associate Professor of Surgery Surgery Rutgers Robert Wood Johnson Medical School New Brunswick, New Jersey United States

David A. Mahvi, MD Surgical Resident Surgery Brigham and Women’s Hospital Boston, Massachusetts United States

Alessandra Landmann, MD Pediatric Surgery Fellow Surgery University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma United States Christian P. Larsen, MD, DPhil Professor of Surgery Mason Professor of Transplantation Emory University School of Medicine Atlanta, Georgia United States Lillian Liao, MD, MPH Associate Professor of Surgery Pediatric Trauma Medical Director UT Health San Antonio San Antonio, Texas United States Steven K. Libutti, MD Director Rutgers Cancer Institute of New Jersey New Brunswick, New Jersey United States

David M. Mahvi, MD Professor of Surgery Surgery Medical University of South Carolina Charleston, South Carolina United States William Marston, MD Professor Division of Vascular Surgery University of North Carolina School of Medicine Chapel Hill, North Carolina United States Matthew J. Martin, MD, FACS, FASMBS Director of Trauma Research Scripps Mercy Hospital San Diego, California United States R. Shayn Martin, MD, MBA, FACS Associate Professor of Surgery Department of Surgery Wake Forest University School of Medicine Executive Director, Critical Care Services Wake Forest Baptist Health Winston-Salem, North Carolina United States

Masha Livhits, MD Assistant Professor of Surgery Surgery University of California-Los Angeles David Geffen School of Medicine Los Angeles, California United States

Christopher R. McHenry, MD, FACS Professor of Surgery Case Western Reserve University School of Medicine Vice Chair Department of Surgery MetroHealth Medical Center Cleveland, Ohio United States

Michael T. Longaker, MD, MBA Deane P. and Louise Mitchell Professor Surgery Stanford University Stanford, California United States

Kelly M. McMasters, MD, PhD Chairman Surgery University of Louisville Louisville, Kentucky United States

H. Peter Lorenz, MD Pediatric Plastic Surgery Service Chief and Professor Plastic and Reconstructive Surgery Stanford University School of Medicine Palo Alto, California United States

Saral Mehra, MD, MBA, FACS Associate Professor Surgery Yale University School of Medicine New Haven, Connecticut United States

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CONTRIBUTORS

Matthew Mell, MD, MS Professor and Chief, Division of Vascular Surgery Surgery University of California, Davis Sacramento, California United States J. Wayne Meredith, MD, FACS Richard T. Myers Professor and Chair Department of Surgery Wake Forest University School of Medicine Chief of Clinical Chairs Chief of Surgery Wake Forest Baptist Health Winston-Salem, North Carolina United States Richard S. Miller, MD, FACS Professor of Surgery, Chief, Division of Trauma and Surgical Critical Care Carol Ann Galvin Directorship in Trauma and Surgical Care Surgery, Section of Surgical Sciences Vanderbilt University Medical Center Nashville, Tennessee United States Joseph L. Mills Sr., MD Reid Professor and Chief of Vascular Surgery and Endovascular Therapy Michael E. DeBakey Department of Surgery Baylor College of Medicine Houston, Texas United States Emilio Morpurgo, MD, FASCRS Chairman Department of Surgery Regional Center for Videolaparoscopic Robotic Surgery Hospital Camposampiero Chief ad interim Department of Surgery Hospital Sant Antonio Padova, Italy Nathan T. Mowery, MD, FACS Associate Professor of Surgery Department of Surgery Wake Forest University School of Medicine Wake Forest Baptist Health Winston-Salem, North Carolina United States

Elaine E. Nelson, MD Medical Director of the Emergency Department Regional Medical Center of San Jose San Jose, California United States David Netscher, MD Professor Division of Plastic Surgery, Department of Orthopedic Surgery Baylor College of Medicine Houston, Texas United States Uri Netz, MD Vice Chairman Department of Surgery A Soroka University Medical Center Faculty of Health Sciences Ben-Gurion University of the Negev Beer Sheva, Israel William B. Norbury, MD, FRCS (Plast) Assistant Professor Division of Plastic Surgery The University of Texas Medical Branch Staff Surgeon Critical Care and Burns Reconstruction Shriners Hospital for Children Galveston, Texas United States Robert L. Norris, MD Emeritus Professor of Emergency Medicine Stanford University Medical Center Stanford, California United States Brant K. Oelschlager, MD Professor and Chief; Byers Endowed Professor of Esophageal Research Division of General Surgery University of Washington Medical Center Seattle, Washington United States Shuab Omer, MD Associate Professor Advanced Cardiopulmonary Therapies and Transplantation University of Texas Health Science Center Houston Houston, Texas United States

Carmen L. Mueller, BSc(H), MD, MEd, FRCSC, FACS Associate Professor Department of Surgery McGill University Montreal, Quebec Canada

Edwin OnKendi, MBChB, FACS Assistant Professor Department of Surgery Texas Tech University Health Sciences Center Lubbock, Texas United States

Aussama K. Nassar, MD, MSc, FACS, FRCSC Clinical Assistant Professor Surgery Stanford University Stanford, California United States

Pablo L. Padilla, MD Plastic Surgery Resident Division of Plastic and Reconstructive Surgery The University of Texas Medical Branch Galveston, Texas United States

CONTRIBUTORS Zachary S. Pallister, MD Assistant Professor of Surgery Michael E. DeBakey Department of Surgery Baylor College of Medicine Houston, Texas United States

Benjamin K. Poulose, MD, MPH Robert M. Zollinger Lecrone-Baxter Chair Chief, Division of General and Gastrointestinal Surgery Center for Abdominal Core Health The Ohio State University Wexner Medical Center Columbus, Ohio United States

Julie E. Park, MD, FACS Stephen R. Lewis Professor and Program Director Division of Plastic Surgery Department of Surgery The University of Texas Medical Branch Galveston, Texas United States

Lauren S. Prescott, MD, MPH Assistant Professor Obstetrics and Gynecology, Division of Gynecologic Oncology Vanderbilt University Medical Center Nashille, Tennessee United States

Luigi Pascarella, MD, FACS Associate Professor of Surgery University of North Carolina School of Medicine Chapel Hill, North Carolina United States

Anna M. Privratsky, DO Assistant Professor of Surgery Division of Trauma, Critical Care, and Acute Care Surgery University of Arkansas for Medical Sciences Little Rock, Arkansas United States

Samip Patel, MD, FACS Associate Professor Otolaryngology/Head and Neck Surgery University of North Carolina School of Medicine Chapel Hill, North Carolina United States Joel T. Patterson, MD, FACS Associate Professor Department of Neurosurgery The University of Texas Medical Branch Galveston, Texas United States Linda G. Phillips, MD Truman G. Blocker Distinguished Professor and Chief Division of Plastic Surgery Surgery University of Texas Medical Branch Galveston, Texas United States Iraklis I. Pipinos, MD, PhD Professor Surgery University of Nebraska Medical Center Chief Vascular Surgery VA Nebraska and Western Iowa Medical Center Omaha, Nebraska United States Russell Postier, MD Dean Emeritus College of Medicine University of Oklahoma Oklahoma City, Oklahoma United States

Napat Pruekprasert, MD Resident General Surgery SUNY Upstate Medical University Syracuse, New York United States Pejman Radkani, MD, MSPH Assistant Professor of Surgery, Hepatopancreatobiliary, and Liver ­Transplant Surgeon Transplant Institute Medstar Georgetown University Hospital Assistant Professor of Surgery Surgery Georgetown University School of Medicine Washington, DC United States Ravi Rajaram, MD, MSc Assistant Professor of Surgery Thoracic and Cardiovascular Surgery The University of Texas MD Anderson Cancer Center Houston, Texas United States Taylor S. Riall, MD, PhD Professor Department of Surgery University of Arizona Tucson, Arizona United States William O. Richards, MD Professor and Chair Department of Surgery University of South Alabama College of Medicine Mobile, Alabama United States

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Bryan Richmond, MD, MBA The Bert Bradford Chairman and Professor of Surgery and Section Chief-General Surgery Department of Surgery West Virginia University/Charleston Division Charleston, West Virginia United States J. Bart Rose, MD, MAS, FACS Director of Pancreatobiliary Disease Center Assistant Professor Division of Surgical Oncology University of Alabama Department of Surgery Birmingham, Alabama United States Michael J. Rosen, MD Professor of Surgery Lerner College of Medicine Cleveland Clinic Foundation Cleveland, Ohio United States Todd K. Rosengart, MD Professor and Chairman Michael E. DeBakey Department of Surgery Baylor College of Medicine Professor Texas Heart Institute Houston, Texas United States Ronnie A. Rosenthal, MS, MD Professor of Surgery and Geriatrics Yale University School of Medicine New Haven, Connecticut United States Chief Surgical Service VA Connecticut Health Care System West Haven, Connecticut United States Evan Ross, MD Postdoctoral Fellow Department of Surgery The University of Texas Medical Branch Galveston, Texas United States Rachel M. Russo, MD, MS Assistant Professor Department of Surgery University of California, Davis Sacramento, California United States Major United States Air Force Medical Corps Travis Air Force Base, California United States

Ira Rutkow, MD, DrPH Independent Scholar New York United States Christopher Ryan, MD Resident General Surgery Baylor College of Medicine Houston, Texas United States Payam Saadai, MD, FACS, FAAP Assistant Professor Pediatric Surgery University of California, Davis Assistant Professor Pediatric Surgery Shriners Hospitals Northern California Sacramento, California United States Noelle N. Saillant, MD, FACS Instructor of Surgery Division of Trauma, Emergency Surgery, and Surgical Critical Care Massachusetts General Hospital Harvard Medical School Boston, Massachusetts United States Warren Sandberg, MD, PhD Professor and Chair Department of Anesthesiology Chief of Staff for Perioperative and Critical Care Services Vanderbilt University Medical Center Nashville, Tennessee United States Ariel P. Santos, MD, MPH, FRCSC, FACS, FCCM Associate Professor and Director of Telemedicine Department of Surgery Texas Tech University Health Sciences Center Lubbock, Texas United States Robert G. Sawyer, MD, FACS, FCCM Professor and Chair of Surgery Surgery Western Michigan University Homer Stryker MD School of Medicine Kalamazoo, Michigan Adjunct Professor of Surgery Surgery University of Virginia Charlottesville, Virginia Adjunct Professor of Engineering and Applied Sciences Engineering and Applied Sciences Western Michigan University Kalamazoo, Michigan United States

CONTRIBUTORS John P. Saydi, MD Surgical Resident Michael E. DeBakey Department of Surgery Baylor College of Medicine Houston, Texas United States

Thomas G. Smith III, MD Associate Professor Department of Urology, Division of Surgery The University of Texas MD Anderson Cancer Center Houston, Texas United States

Martin Allan Schreiber, MD Professor of Surgery and Chief, Division of Trauma, Critical Care & Acute Care Surgery Oregon Health & Science University Portland, Oregon United States

Christian Sommerhalder, MD, MMS Surgical Resident Surgery The University of Texas Medical Branch Galveston, Texas United States

Herbert S. Schwartz, MD Professor of Orthopaedic Surgery and Rehabilitation Professor of Pathology, Microbiology, and Immunology Vanderbilt University Medical Center Nashville, Tennessee United States

Julie Ann Sosa, MD, MA Leon Goldman MD Distinguished Professor of Surgery and Chair Department of Surgery Professor Department of Medicine University of California San Francisco Affiliated faculty Philip R. Lee Institute for Health Policy Studies University of California-San Francisco San Francisco, California United States

Boris Sepesi, MD Associate Professor Thoracic and Cardiovascular Surgery The University of Texas MD Anderson Cancer Center Houston, Texas United States Edward R. Sherwood, MD, PhD Professor and Vice Chair for Research Department of Anesthesiology Vanderbilt University Medical Center Nashville, Tennessee United States Mihir Sheth, MD Orthopedic Surgery Resident Department of Orthopedic Surgery Baylor College of Medicine Houston, Texas United States Michael J. Sise, MD, FACS Clinical Professor of Surgery University of California-San Diego School of Medicine Senior Vascular and Trauma Surgeon Scripps Mercy Hospital San Diego, California United States Michael C. Smith, MD Assistant Professor Surgery Vanderbilt University Medical Center Nashville, Tennessee United States Sawyer Gordon Smith, MD Surgery Resident Department of Surgery Oregon Health & Science University Portland, Oregon United States

Jonathan D. Spicer, MD, PhD Assistant Professor of Surgery Department of Surgery McGill University Montreal, Canada Ronald M. Stewart, MD Professor and Chair of Surgery Dr. Witten B. Russ Endowed Chair in Surgery Department of Surgery University of Texas Health Science Center at San Antonio San Antonio, Texas United States Debra L. Sudan, MD Professor of Surgery Chief, Division of Abdominal Transplant Surgery Duke University Medical Center Durham, North Carolina United States David J. Sugarbaker Chief of Division of Thoracic Surgery Baylor College of Medicine Houston, Texas United States Insoo Suh, MD Associate Professor Section of Endocrine Surgery Department of Surgery University of California, San Francisco Staff Surgeon, Endocrine and General Surgery San Francisco Veterans Affairs Health Care System San Francisco, California United States

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Daniel Sun, MD Orthopedic Surgery Resident Department of Orthopedic Surgery Baylor College of Medicine Houston, Texas United States

Konstantin Umanskiy, MD Associate Professor of Surgery Department of Surgery University of Chicago Medicine Chicago, Illinois United States

Jennifer M. Taylor, MD, MPH Assistant Professor Scott Department of Urology Baylor College of Medicine Houston, Texas United States

Selwyn M. Vickers, MD, FACS James C. Lee, Jr. Endowed Chair and Professor Senior Vice President and Dean School of Medicine University of Alabama Birmingham Birmingham, Alabama United States

Jonathan R. Thompson, MD, RPVI Assistant Professor of Surgery Surgery University of Nebraska Medical Center Omaha, Nebraska United States S. Rob Todd, MD, FACS, FCCM Senior Vice President Chief, Acute Care Surgery Grady Health System Atlanta, Georgia United States James S. Tomlinson, MD, PhD Professor of Surgery University of California-Los Angeles David Geffen School of Medicine Los Angeles, California United States Alfonso Torquati, MD, MSCI Helen Sheddd Keith Professor and Chairman Department of Surgery Rush University Chicago, Illinois United States Sara Maria Tosato, MD General Surgeon Department of Surgery Regional Center for Videolaparoscopic Robotic Surgery Hostpital of Camposampiero, Padova, Italy Richard H. Turnage, MD Professor of Surgery Department of Surgery University of Arkansas for Medical Sciences Little Rock, Arkansas Executive Associate Dean for Clinical Affairs College of Medicine University of Arkansas for Medical Sciences Medical Center Little Rock, Arkansas United States Douglas S. Tyler, MD, MSHCT, FACS John Woods Harris Distinguished Chair in Surgery, Professor and Chairman Department of Surgery The University of Texas Medical Branch Galveston, Texas United States

Ori Wald, MD, PhD Attending Thoracic Surgeon Cardiothoracic Surgery Hadassah Hebrew University Hospital Jerusalem, Israel Andrew Well, MD, MPH, MSHCT Health Transformation Fellow Congenital Heart Surgery Texas Center for Pediatric and Congenital Heart Disease at Dell Medical School University of Texas Austin, Texas United States William J. Winslade, PhD, JD, PhD James Wade Rockwell Professor of Philosophy in Medicine Institute for the Medical Humanities and Department of Preventive Medicine and Community Health The University of Texas Medical Branch Galveston, Texas United States Steven E. Wolf, MD Joseph D. and Lee Hage Jamail Chari in Surgery Professor and Vice-Chair for Finance Division Chief - Trauma, Burns, and Acute Care Surgery Surgery The University of Texas Medical Branch Chief of Staff Shriners Hospital for Children - Texas Galveston, Texas United States Yanghee Woo, MD, FACS Associate Professor Director of Gastrointestinal Minimally Invasive Therapies Vice Chair of International Affairs City of Hope National Medical Center Duarte, California United States Jennifer Worsham, MD Assistant Professor Surgery - Vascular Surgery The University of Texas Medical Branch Galveston, Texas United States

CONTRIBUTORS James C. Yang, MD Senior Investigator Surgery Branch National Cancer Institute Bethesda, Maryland United States Wendell G. Yarbrough, MD, MMHC, FACS Thomas J. Dark Distinguished Chair Otolaryngology/Head and Neck Surgery University of North Carolina School of Medicine Chapel Hill, North Carolina United States Robert B. Yates, MD Clinical Assistant Professor Center for Esophageal and Gastric Surgery University of Washington Medical Center Montlake, Washington United States Michael W. Yeh, MD Professor, Chief Section of Endocrine Surgery University of California-Los Angeles David Geffen School of Medicine Los Angeles, California United States Natesh Yepuri, MBBS Resident Anesthesiology The Guthrie Clinic Sayve, Pennsylvania United States

Amanda C. Yunker, DO, MSCR Associate Professor Obstetrics and Gynecology Vanderbilt University Medical Center Nashville, Tennessee United States Adam Zanation, MD, FACS Harold C. Pillsbury Distinguished Professor Executive Vice Chair Otolaryngology/Head and Neck Surgery University of North Carolina School of Medicine Chapel Hill, North Carolina United States Ramón Zapata Sirvent, MD, FACS Associate Professor Department of Surgery, Division of Plastic Surgery The University of Texas Medical Branch Galveston, Texas United States Victor M. Zaydfudim, MD, MPH Associate Professor of Surgery Section of Hepatobiliary and Pancreatic Surgery, Division of Surgical Oncology University of Virginia Charlottesville, Virginia United States

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P r e fa c e Surgery continues to evolve as new technology, techniques, and knowledge are incorporated into the care of surgical patients. The 21st edition of the Sabiston Textbook of Surgery reflects these exciting changes and new knowledge. We have incorporated two new chapters (Robotic Surgery and Fetal Surgery) and more than 119 new authors to ensure that the most current information is presented. This new edition has been revised and the current chapters have been enhanced to reflect these changes.

The primary goal of this new edition is to remain the most thorough, useful, readable, and understandable textbook presenting the principles and techniques of surgery. It is designed to be equally useful to students, trainees, and experts in the field. We are committed to maintaining this tradition of excellence begun in 1936. Surgery, after all, remains a discipline in which the knowledge and skill of a surgeon combine for the welfare of our patients. Courtney M. Townsend, JR., MD

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Foreword This is the 21st edition of Sabiston’s Textbook of Surgery. It continues the strong tradition of being the definitive text for our discipline. Each chapter provides evidence-based references, and each has special references that will be of particular interest to the reader. The majority of authors are new and are recognized experts or “rising stars” in their respective fields. Each chapter provides the most up-to-date information on surgical innovations and techniques, as well as the latest in multidisciplinary treatments. This edition begins with an historical overview as well as a newly designed chapter on ethics and professionalism. The book then continues with knowledge needed to care for the surgical patient. The chapters on inflammatory response to surgical illness, shock, metabolism, and wound healing provide practical suggestions for the management of otherwise complex conditions in the surgical patient. There is a completely new chapter on assessment of surgical outcomes and an overview of health services research. This edition emphasizes the practical support of an actively practicing surgeon, as seen in emergency care of musculoskeletal injuries and the surgeon’s role in mass casualty incidents. Similarly, there is a new chapter on robotic surgery, which balances the need for innovation and technical advancement with an obligation for additional training and increased cost. Many chapters provide detailed descriptions of the most innovative surgical approaches, such as the chapter on breast reconstruction detailing not only reconstructive techniques following mastectomy, but oncoplastic reconstructive interventions as well. There are superb chapters dealing with various disciplines within surgery, such as the pathophysiology and underlying biologic principals of transplantation and tumor immunology and immunotherapy. Each anatomic area is presented by a disease expert. For example, the chapter on melanoma not only provides the most recent recommendations for surgical intervention, but also

details the multidisciplinary approaches of novel immunotherapies and targeted therapies. The chapter on the liver is particularly comprehensive, detailing new nonoperative interventions, advances in the medical management of hepatitis and fatty liver, and new minimally invasive surgical techniques. Each chapter is concise, focused, and provides the reader with the evidence-based information to provide contemporary surgical management for any clinical problem. This new edition is available in both print and electronic format. Enhanced content, consisting of interactive images with magnification, and specific details, is available through Expert Consult (https://expertconsult.inkling.com/). There is also annotated self-testing material available through this feature. Frederick Christopher first published this Textbook of Surgery in 1936. Dr. Townsend and his coeditors have once again done a masterful job in balancing the comprehensiveness of this text with a prioritization for information most needed by the practicing surgeon as well as the surgeon-in-training. The emphasis is on understanding the biologic basis of disease and presenting the most precise, state-of-the-art approach to treatment. This edition sets the standard for what a comprehensive textbook of surgery should be. It is a mandatory, efficient reference for any surgeon intent on expanding their knowledge. Timothy J. Eberlein, MD, FACS, FRCSEd (Hon), FRCS, Glasg (Hon) Bixby Professor and Chair, Department of Surgery Spencer T. and Ann W. Olin Distinguished Professor Director, Alvin J. Siteman Cancer Center Senior Associate Dean for Cancer Programs Washington University School of Medicine in St. Louis

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A C K N OW L E D G M E N T S We would like to recognize the invaluable contributions of Karen Martin, Steve Schuenke, Eileen Figueroa, David Chavarria, and administrator Barbara Petit. Their dedicated professionalism, tenacious efforts, and cheerful cooperation are without parallel. They accomplished whatever was necessary, often on short or instantaneous deadlines, and were vital for the successful completion of the endeavor. Our authors, respected authorities in their fields and busy physicians and surgeons, all did an outstanding job in sharing their wealth of knowledge.

We would also like to acknowledge the professionalism of our colleagues at Elsevier: Jessica McCool, Content Strategist; Joanie Milnes, Senior Content Development Specialist; Kathryn DeFrancisco, Content Development Manager; Shereen Jameel, Publishing Services Manager; Umarani Natarajan, Senior Project Manager and Margaret Reid, Senior Book Designer.

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CONTENTS SECTION I SURGICAL BASIC PRINCIPLES, 1 1. The Rise of Modern Surgery: An Overview, 2 Ira Rutkow

2. Ethics and Professionalism in Surgery, 20 Jeffrey S. Farroni and William J. Winslade

3. The Inflammatory Response, 26

Katherine E. Kramme, Patrick H. Knight and Robert G. Sawyer

4. Shock, Electrolytes, and Fluid, 44

Sawyer Gordon Smith and Martin Allan Schreiber

5. Metabolism in Surgical Patients, 95

Elizabeth E. Blears, Joshua S. Carson, Celeste C. Finnerty, Evan Ross, Christian Sommerhalder and David N. Herndon

6. Wound Healing, 119

Stefanos Boukovalas, Kristen A. Aliano, Linda G. Phillips and William B. Norbury

18. The Difficult Abdominal Wall, 429

Michael C. Smith, Oliver L. Gunter and Richard S. Miller

19. Emergency Care of Musculoskeletal Injuries, 440 Jack Dawson, Omar Atassi, Daniel Sun and Mihir Sheth

20. Burns, 484

Steven E. Wolf

21. Bites and Stings, 506

Lillian Liao, Robert L. Norris, Elaine E. Nelson and Ronald M. Stewart

22. Surgical Critical Care, 521

John P. Saydi, Vamsi Aribindi and S. Rob Todd

23. Bedside Surgical Procedures, 546

Bradley M. Dennis, Oliver L. Gunter and Jose J. Diaz

24. The Surgeon’s Role in Mass Casualty Incidents, 555 Jennifer M. Gurney and Matthew J. Martin

7. Regenerative Medicine, 150

Mimi R. Borrelli, Michael S. Hu, Michael T. Longaker and H. Peter Lorenz

8. Critical Assessment of Surgical Outcomes and Health Services Research, 159 Benjamin S. Brooke and Samuel R.G. Finlayson

9. Safety in the Surgical Environment, 170

Warren Sandberg, Roger R. Dmochowski and R. Daniel Beauchamp

SECTION IV TRANSPLANTATION AND IMMUNOLOGY, 571 25. Transplantation Immunobiology and Immunosuppression, 572

I. Raul Badell, Andrew B. Adams and Christian P. Larsen

26. Liver Transplantation, 614

Seth J. Karp and Sophoclis Alexopoulos

SECTION II PERIOPERATIVE MANAGEMENT, 186 10. Principles of Preoperative and Operative Surgery, 187 Victor M. Zaydfudim, Yinnin Hu and Reid B. Adams

27. Kidney and Pancreas Transplantation, 627 Yolanda Becker

28. Small Bowel Transplantation, 644 Samuel J. Kesseli and Debra L. Sudan

11. Surgical Infections and Antibiotic Use, 223

Ariel P. Santos, Edwin OnKendi and Sharmila Dissanaike

12. Surgical Complications, 238

Natesh Yepuri, Napat Pruekprasert and Robert N. Cooney

13. Surgery in the Geriatric Patient, 284 Vanita Ahuja and Ronnie A. Rosenthal

14. A  nesthesiology Principles, Pain Management, and Conscious Sedation, 315 Antonio Hernandez and Edward R. Sherwood

15. E merging Technology in Surgery: Informatics, Electronics, 349 Amin Madani, Carmen L. Mueller and Gerald M. Fried

16. Robotic Surgery, 362

Yanghee Woo and Yuman Fong

SECTION III TRAUMA AND CRITICAL CARE, 385 17. Management of Acute Trauma, 386

Samuel P. Carmichael II, Nathan T. Mowery, R. Shayn Martin and J. Wayne Meredith

SECTION V SURGICAL ONCOLOGY, 655 29. Tumor Biology and Tumor Markers, 656

Bradley A. Krasnick, S. Peter Goedegebuure and Ryan Fields

30. Tumor Immunology and Immunotherapy, 687

James S. Economou, James C. Yang and James S. Tomlinson

31. Melanoma and Cutaneous Malignancies, 705

Kelly M. McMasters, Douglas S. Tyler and Michael E. Egger

32. Soft Tissue Sarcoma, 734

Carlo M. Contreras and Marty J. Heslin

33. Bone Tumors, 754

Herbert S. Schwartz, Ginger E. Holt and Jennifer L. Halpern

SECTION VI HEAD AND NECK, 770 34. Head and Neck, 771

Wendell G. Yarbrough, Adam Zanation, Samip Patel and Saral Mehra

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SECTION VII BREAST, 808 35. Diseases of the Breast, 809

V. Suzanne Klimberg and Kelly K. Hunt

36. Breast Reconstruction, 856

Stefanos Boukovalas, Shana S. Kalaria and Julie E. Park

55. Biliary System, 1489

Pejman Radkani, Jason Hawksworth and Thomas Fishbein

56. Exocrine Pancreas, 1528

Vikas Dudeja, J. Bart Rose, Eric H. Jensen and Selwyn M. Vickers

57. The Spleen, 1566

Aussama K. Nassar and Mary Hawn

SECTION VIII ENDOCRINE, 872 37. Thyroid, 873

Insoo Suh and Julie Ann Sosa

38. The Parathyroid Glands, 921

Iuliana Bobanga and Christopher R. McHenry

39. Endocrine Pancreas, 941

Amanda K. Arrington and Taylor S. Riall

40. The Adrenal Glands, 964

Michael W. Yeh, Masha Livhits and Quan-Yang Duh

41. The Multiple Endocrine Neoplasia Syndromes, 998

SECTION XI CHEST, 1583 58. Lung, Chest Wall, Pleura and Mediastinum, 1584 Ori Wald, Uzi Izhar and David J. Sugarbaker

59. Congenital Heart Disease, 1641 Andrew Well and Chuck D. Fraser Jr.

60. Acquired Heart Disease: Coronary Insufficiency, 1679 Shuab Omer and Faisel G. Bakaeen

61. Acquired Heart Disease: Valvular, 1711

Todd K. Rosengart, Corinne M. Aberle and Christopher Ryan

Amanda M. Laird and Steven K. Libutti

SECTION IX ESOPHAGUS, 1013 42. Esophagus, 1014

Ravi Rajaram, Jonathan D. Spicer, Rajeev Dhupar, Jae Y. Kim, Boris Sepesi and Wayne L. Hofstetter

43. Gastroesophageal Reflux Disease and Hiatal Hernia, 1056 Robert B. Yates and Brant K. Oelschlager

SECTION XII VASCULAR, 1743 62. T he Aorta, 1744

Abe DeAnda Jr., Jennifer Worsham and Matthew Mell

63. P  eripheral Arterial Disease, 1767

Joseph L. Mills Sr. and Zachary S. Pallister

64. V  ascular Trauma, 1792

Michael J. Sise, Carlos V.R. Brown and Howard C. Champion

65. V  enous Disease, 1812

SECTION X ABDOMEN, 1079 44. Abdominal Wall, Umbilicus, Peritoneum, Mesenteries, Omentum and Retroperitoneum, 1080

Luigi Pascarella and William Marston

66. T he Lymphatics, 1834

Jonathan R. Thompson and Iraklis I. Pipinos

Anna M. Privratsky, Juan Camilo Barreto and Richard H. Turnage

45. Hernias, 1105

Benjamin K. Poulose, Alfredo Maximiliano Carbonell and Michael J. Rosen

46. Acute Abdomen, 1134

Alessandra Landmann, Morgan Bonds and Russell Postier

47. Acute Gastrointestinal Hemorrhage, 1150

Kevin J. Chiang, Noelle N. Saillant and Richard Hodin

48. Morbid Obesity, 1167

William O. Richards, Leena Khaitan and Alfonso Torquati

49. Stomach, 1196

David A. Mahvi and David M. Mahvi

50. Small Intestine, 1240

Tong Gan and B. Mark Evers

51. The Appendix, 1301 Bryan Richmond

52. Colon and Rectum, 1320

Susan Galandiuk, Uri Netz, Emilio Morpurgo, Sara Maria Tosato, Naim Abu-Freha and C. Tyler Ellis

53. Anus, 1401

Neil Hyman and Konstantin Umanskiy

54. The Liver, 1425

Vikas Dudeja, Anthony Ferrantella and Yuman Fong

SECTION XIII SPECIALTIES IN GENERAL SURGERY, 1843 67. Pediatric Surgery, 1844 Dai H. Chung

68. Neurosurgery, 1883 Joel T. Patterson

69. Plastic Surgery, 1916

Pablo L. Padilla, Kimberly H. Khoo, Trung Ho, Eric L. Cole, Ramón Zapata Sirvent and Linda G. Phillips

70. Hand Surgery, 1945

David Netscher, Nikhil Agrawal and Nicholas A. Fiore II

71. Gynecologic Surgery, 1999

Lauren S. Prescott, Amanda C. Yunker and Ronald Alvarez

72. Surgery in the Pregnant Patient, 2026

Rachel M. Russo, Gregory J. Jurkovich and Diana L. Farmer

73. Fetal Surgery, 2050

Payam Saadai, Shinjiro Hirose and Diana L. Farmer

74. Urologic Surgery, 2061

Jennifer M. Taylor, Thomas G. Smith III and Michael Coburn

Index, 2101

VIDEO CONTENTS SECTION I  SURGICAL BASIC PRINCIPLES

SECTION IX  ESOPHAGUS

5. Metabolism In Surgical Patients

43. Gastroesophageal Reflux Disease and Hiatal Hernia

Video 5-1:  Indirect Calorimetry Video 5-2: Body Composition and DEXA Video 5-3: Treadmill Elizabeth E. Blears Joshua S. Carson Celeste C. Finnerty Evan Ross Christian Sommerhalder David N. Herndon

SECTION II  PERIOPERATIVE MANAGEMENT 15. Emerging Technology in Surgery: Informatics, Electronics Video 15-1: Robot-Assisted Resection Amin Madani Carmen L. Mueller Gerald M. Fried

SECTION III  TRAUMA AND CRITICAL CARE 18. The Difficult Abdominal Wall

Video 18-1: Novel Management of an Enteroatmospheric Fistula Using a “Floating Stoma” Michael C. Smith Oliver L. Gunter Richard S. Miller

Video 43-1: Parathyroid Autotransplantation Video 43-2: Laparoscopic Adrenalectomy for Pheochromocytoma in Patients With Men 2A Robert B. Yates Brant K. Oelschlager

SECTION X  ABDOMEN 48. Morbid Obesity

Video 48-1: Laparoscopic Roux-en-Y-Gastric Bypass Surgery Technique Video 48-2: Laparoscopic Adjustable Gastric-Band Surgical Technique William O. Richards Leena Khaitan Alfonso Torquati

51. The Appendix

Video 51-1: Laparoscopic Appendectomy Video 51-2: Laparoscopic Appendectomy in Pregnant Patients Video 51-3: SILS Appendectomy Across a Spectrum of Disease Severity Bryan Richmond

52. Colon and Rectum

Video 52-1: The technique of transanal minimally invasive surgery (TAMIS) Video 52-2: The technique of transanal total mesorectal excision (TaTME) Susan Galandiuk

SECTION IV  TRANSPLANTATION AND IMMUNOLOGY 25. Transplantation Immunology and Immunosuppression Video 25-1: Results of the World’s First Successful Hand Transplant I. Raul Badell Andrew B. Adams Christian P. Larsen

56. Exocrine Pancreas

Video 56-1: Laparoscopic cyst gastrostomy Video 56-2: Laparoscopic Vessel-Preserving, Spleen-Preserving, Distal Pancreatectomy Video 56-3: Laparoscopic spleen-preserving distal pancreatectomy Vikas Dudeja J. Bart Rose Eric H. Jensen Selwyn M. Vickers

SECTION VI  HEAD AND NECK 34. Head and Neck

Video 34-1: Tracheo-esophageal speech after laryngectomy Video 34-2: Hands free tracheo-esophageal speech after laryngectomy Video 34-3: Parotidectomy Video 34-4: Salivary endoscopy (sialoendoscopy) Wendell G. Yarbrough Adam Zanation Samip Patel Saral Mehra

SECTION XI CHEST 58. Lung, Chest Wall, Pleura, and Mediastinum Video 58-1: Pleural Effusion Video 58-2: Pleural Sliding Video 58-3: Pneumothorax Ori Wald Uzi Izhar David J. Sugarbaker

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VIDEO CONTENTS

SECTION XII VASCULAR 62. The Aorta

Video 62-1: Aortic Replacement Abe DeAnda Jr. Jennifer Worsham Matthew Mell

65. Venous Disease

Video 65-1: TriVex 1 Video 65-2: TriVex 2 Luigi Pascarella William Marston

SECTION XIII  SPECIALTIES IN GENERAL SURGERY 70. Hand Surgery

Video 70-1: Extensor Compartments Video 70-2: Dorsal Hood Video 70-3: Flexor Tendons and Pulley System David Netscher Nikhil Agrawal Nicholas A. Fiore II

71. G  ynecologic Surgery

Video 71-1: Total Laparoscopic Hysterectomy With Right Salpingo-oophrectomy Video 71-2: Laparoscopic Right Salpingo-oophrectomy Video 71-3: Laparoscopic Unilateral Salpingo-oopherrectomy Lauren S. Prescott Amanda C. Yunker Ronald D. Alvarez

https://t.me/mebooksfree S E C T I O N

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Surgical Basis Principles

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CHAPTER

The Rise of Modern Surgery: An Overview Ira Rutkow “If there were no past, science would be a myth; the human mind a desert. Evil would preponderate over good, and darkness would overspread the face of the moral and scientific world.” Samuel D. Gross (Louisville Review 1:26–27, 1856)

OUTLINE The Beginnings Knowledge of Anatomy Control of Bleeding Control of Pain Control of Infection Other Advances That Furthered the Rise of Modern Surgery X-rays Blood Transfusion Frozen Section

THE BEGINNINGS From earliest recorded history through late in the 19th century, the manner of surgery changed little. During those thousands of years, surgical operations were always frightening, often fatal, and frequently infected. In this prescientific, preanesthetic, and preantiseptic time, procedures were performed only for the direst of necessities and were unlike anything seen today; fully conscious patients were held or tied down to prevent their fleeing the surgeon’s unsparing knife. When the surgeon, or at least those persons who used the sobriquet “surgeon,” performed an operation, it was inevitably for an ailment that could be visualized (i.e., on the skin and just below the surface, on the extremities, or in the mouth). Through the 14th century, most surgical therapy was delivered by minimally educated barber-surgeons and other itinerant adherents of the surgical cause. These faithful but obscure followers of the craft of surgery, although ostracized by aristocratic, universityeducated physicians who eschewed the notion of working with one’s hands, ensured the ultimate survival of what was then a vocation passed on from father to son. The roving “surgeons” mainly lanced abscesses; fixed simple fractures; dressed wounds; extracted teeth; and, on rare occasions, amputated a digit, limb, or breast. Around the 15th century, the highborn physicians began to show an interest in the art of surgery. As surgical techniques evolved, knife bearers, whether privileged physicians or wandering vagabonds, ligated arteries for readily accessible aneurysms, excised large visible tumors, performed trephinations, devised ingenious methods to reduce incarcerated and strangulated hernias, and created rudimentary colostomies and ileostomies by simply incising the skin over an expanding intraabdominal mass that represented the end stage of an intestinal blockage. The more entrepreneurial

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Ascent of Scientific Surgery Standardized Postgraduate Surgical Education and Training Programs Experimental Surgical Research Laboratories Specialty Journals, Textbooks, Monographs, and Treatises Professional Societies and Licensing Organizations The Modern Era Diversity The Future

scalpel wielders widened the scope of their activities by focusing on the care of anal fistulas, bladder stones, and cataracts. Notwithstanding the growing boldness and ingenuity of “surgeons,” surgical operations on the cavities of the body (i.e., abdomen, cranium, joints, and thorax) were generally unknown and, if attempted, fraught with danger. Despite the terrifying nature of surgical intervention, operative surgery in the prescientific era was regarded as an important therapy within the whole of Medicine. (In this chapter, “Medicine” signifies the totality of the profession, and “medicine” indicates internal medicine as differentiated from surgery, obstetrics, pediatrics, and other specialties.) This seeming paradox, in view of the limited technical appeal of surgery, is explained by the fact that surgical procedures were performed for disorders observable on the surface of the body: There was an “objective” anatomic diagnosis. The men who performed surgical operations saw what needed to be fixed (e.g., inflamed boils, broken bones, bulging tumors, grievous wounds, necrotic digits and limbs, rotten teeth) and treated the problem in as rational a manner as the times permitted. For individuals who practiced medicine, care was rendered in a more “subjective” manner involving diseases whose etiologies were neither seen nor understood. It is difficult to treat the symptoms of illnesses such as arthritis, asthma, diabetes, and heart failure when there is no scientific understanding as to what constitutes their pathologic and physiologic underpinnings. It was not until the 19th century and advances in pathologic anatomy and experimental physiology that practitioners of medicine were able to embrace a therapeutic viewpoint more closely, approximating that of surgeons. There was no longer a question of treating signs and symptoms in

CHAPTER 1  The Rise of Modern Surgery: An Overview a blind manner. Similar to surgeons who operated on maladies that could be physically described, physicians now cared for patients using clinical details based on “objective” pathophysiologic findings. Surgeons never needed a diagnostic and pathologic/physiologic revolution in the style of the physician. Despite the imperfection of their knowledge, prescientific surgeons with their unwavering amputation/extirpation approach to treatment sometimes did cure with technical confidence. Notwithstanding their dexterity, it required the spread of the revolution in Medicine during the 1880s and 1890s and the implementation of aseptic techniques along with other soon-to-come discoveries, including the x-ray, blood transfusion, and frozen section, to allow surgeons to emerge as specialists. It would take several more decades, well into the 20th century, for administrative and organizational events to occur before surgery could be considered a bona fide profession. The explanation for the slow rise of surgery was the protracted elaboration of four key elements (knowledge of anatomy, control of bleeding, control of pain, and control of infection) that were more critical than technical skills when it came to the performance of a surgical procedure. These prerequisites had to be understood and accepted before a surgical operation could be considered a viable therapeutic option. The first two elements started to be addressed in the 16th century, and, although surgery greatly benefited from the breakthroughs, its reach was not extended beyond the exterior of the body, and pain and infection continued to be issues for the patient and the surgical operation. Over the ensuing 300 years, there was little further improvement until the discovery of anesthesia in the 1840s and recognition of surgical antisepsis during the 1870s and 1880s. The subsequent blossoming of scientific surgery brought about managerial and socioeconomic initiatives (standardized postgraduate surgical education and training programs; experimental surgical research laboratories; specialty journals, textbooks, monographs, and treatises; and professional societies and licensing organizations) that fostered the concept of professionalism. By the 1950s, the result was a unified profession that was practical and scholarly in nature. Some of the details of the rise of modern surgery follow—specifically how the four key elements that allowed a surgical operation to be viewed as a practical therapeutic choice came to be acknowledged. 

KNOWLEDGE OF ANATOMY Although knowledge of anatomy is the primary requirement of surgery, it was not until the mid-1500s and the height of the European Renaissance that the first great contribution to an understanding of the structure of the human body occurred. This came about when Popes Sixtus IV (1414–1484) and Clement VII (1478–1534) reversed the church’s long-standing ban of human dissection and sanctioned the study of anatomy from the cadaver. Andreas Vesalius (1514–1564) (Fig. 1.1) stepped to the forefront of anatomic studies along with his celebrated treatise, De Humani Corporis Fabrica Libri Septem (1543). The Fabrica broke with the past and provided more detailed descriptions of the human body than any of its predecessors. It corrected errors in anatomy that were propagated thousands of years earlier by Greek and Roman authorities, especially Claudius Galen (129–199 ad), whose misleading and later church-supported views were based on animal rather than human dissection. Just as groundbreaking as his anatomic observations was Vesalius’ blunt assertion that dissection

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FIG. 1.1  Andreas Vesalius (1514–1564).

had to be completed hands-on by physicians themselves. This was a direct repudiation of the long-standing tradition that dissection was a loathsome task to be performed only by individuals in the lower class while the patrician physician sat on high reading out loud from a centuries-old anatomic text. Vesalius was born in Brussels to a family with extensive ties to the court of the Holy Roman Emperors. He received his medical education in France at universities in Montpellier and Paris and for a short time taught anatomy near his home in Louvain. Following several months’ service as a surgeon in the army of Charles V (1500–1558), the 23-year-old Vesalius accepted an appointment as professor of anatomy at the University of Padua in Italy. He remained there until 1544, when he resigned his post to become court physician to Charles V and later to Charles’ son, Philip II (1527–1598). Vesalius was eventually transferred to Madrid, but for various reasons, including supposed trouble with authorities of the Spanish Inquisition, he planned a return to his academic pursuits. However, first, in 1563, Vesalius set sail for a year-long pilgrimage to the Holy Land. On his return voyage, Vesalius’ ship was wrecked, and he and others were stranded on the small Peloponnesian island of Zakynthos. Vesalius died there as a result of exposure, starvation, and the effects of a severe illness, probably typhoid. The 7 years that Vesalius spent in Padua left an indelible mark on the evolution of Medicine and especially surgery. His wellpublicized human dissections drew large crowds, and Vesalius was in constant demand to provide anatomic demonstrations in other Italian cities, all of which culminated in the publication of the

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SECTION I  Surgical Basic Principles

Fabrica. Similar to most revolutionary works, the book attracted critics and sympathizers, and the youthful Vesalius was subjected to vitriolic attacks by some of the most renowned anatomists of that era. To his many detractors, the impassioned Vesalius often responded with intemperate counterattacks that did little to further his cause. In one fit of anger, Vesalius burned a trove of his own manuscripts and drawings. The popularity of Vesalius’ Fabrica rested on its outstanding illustrations. For the first time, detailed drawings of the human body were closely integrated with an accurate written text. Artists, believed to be from the school of Titian (1477–1576) in Venice, produced pictures that were scientifically accurate and creatively beautiful. The woodcuts, with their majestic skeletons and flayed muscled men set against backgrounds of rural and urban landscapes, became the standard for anatomic texts for several centuries. The work of Vesalius paved the way for wide-ranging research into human anatomy, highlighted by a fuller understanding of the circulation of blood. In 1628, William Harvey (1578–1657) showed that the heart acts as a pump and forces blood along the arteries and back via veins, forming a closed loop. Although not a surgeon, Harvey’s research had enormous implications for the evolution of surgery, particularly its relationship with anatomy and the conduct of surgical operations. As a result, in the 17th century, links between anatomy and surgery intensified as skilled surgeon-anatomists arose. During the 18th century and first half of the 19th century, surgeon-anatomists made some of their most remarkable observations. Each country had its renowned individuals: In The Netherlands were Govard Bidloo (1649–1713), Bernhard Siegfried Albinus (1697–1770), and Pieter Camper (1722–1789); Albrecht von Haller (1708–1777), August Richter (1742–1812), and Johann Friedrich Meckel (1781–1833) worked in Germany; Antonio Scarpa (1752–1832) worked in Italy; and in France, Pierre-Joseph Desault (1744–1795), Jules Cloquet (1790–1883), and Alfred Armand Louis Marie Velpeau (1795–1867) were the most wellknown. Above all, however, were the efforts of numerous British surgeon-anatomists who established a well-deserved tradition of excellence in research and teaching. William Cowper (1666–1709) was one of the earliest and best known of the English surgeon-anatomists, and his student, William Cheselden (1688–1752), established the first formal course of instruction in surgical anatomy in London in 1711. In 1713, Anatomy of the Human Body by Cheselden was published and became so popular that it went through at least 13 editions. Alexander Monro (primus) (1697–1767) was Cheselden’s mentee and later established a center of surgical-anatomic teaching in Edinburgh, which was eventually led by his son Alexander (secundus) (1737–1817) and grandson Alexander (tertius) (1773–1859). In London, John Hunter (1728–1793) (Fig. 1.2), who is considered among the greatest surgeons of all time, gained fame as a comparative anatomist-surgeon, while his brother, William Hunter (1718–1783), was a successful obstetrician who authored the acclaimed atlas, Anatomy of the Human Gravid Uterus (1774). Another brother duo, John Bell (1763–1820) and Charles Bell (1774–1842), worked in Edinburgh and London, where their exquisite anatomic engravings exerted a lasting influence. By the middle of the 19th century, surgical anatomy as a scientific discipline was well established. However, as surgery evolved into a more demanding profession, the anatomic atlases and illustrated surgical textbooks were less likely to be written by the surgeonanatomist and instead were written by the full-time anatomist. 

FIG. 1.2  John Hunter (1728–1793).

FIG. 1.3  Ambroise Paré (1510–1590).

CONTROL OF BLEEDING Although Vesalius brought about a greater understanding of human anatomy, one of his contemporaries, Ambroise Paré (1510– 1590) (Fig. 1.3), proposed a method to control hemorrhage during a surgical operation. Similar to Vesalius, Paré is important to the history of surgery because he also represents a severing of the final link between the surgical thoughts and techniques of the ancients and the push toward a more modern era. The two men were acquaintances, both having been summoned to treat Henry II (1519–1559), who sustained what proved to be a fatal lance blow to his head during a jousting match. Paré was born in France and, at an early age, apprenticed to a series of itinerant barber-surgeons. He completed his indentured

CHAPTER 1  The Rise of Modern Surgery: An Overview education in Paris, where he served as a surgeon’s assistant/wound dresser in the famed Hôtel Dieu. From 1536 until just before his death, Paré worked as an army surgeon (he accompanied French armies on their military expeditions) while also maintaining a civilian practice in Paris. Paré’s reputation was so great that four French kings, Henry II, Francis II (1544–1560), Charles IX (1550–1574), and Henry III (1551–1589) selected him as their surgeon-in-chief. Despite being a barber-surgeon, Paré was eventually made a member of the Paris-based College of St. Côme, a self-important fraternity of university-educated physician/surgeon. On the strength of Paré’s personality and enormity of his clinical triumphs, a rapprochement between the two groups ensued, which set a course for the rise of surgery in France. In Paré’s time, applications of a cautery or boiling oil or both were the most commonly employed methods to treat a wound and control hemorrhage. Their use reflected belief in a medical adage dating back to the age of Hippocrates: Those diseases that medicines do not cure, iron cures; those that iron cannot cure, fire cures; and those that fire cannot cure are considered incurable. Paré changed such thinking when, on a battlefield near Turin, his supply of boiling oil ran out. Not knowing what to do, Paré blended a concoction of egg yolk, rose oil (a combination of ground-up rose petals and olive oil), and turpentine and treated the remaining injured. Over the next several days, he observed that the wounds of the soldiers dressed with the new mixture were neither as inflamed nor as tender as the wounds treated with hot oil. Paré abandoned the use of boiling oil not long afterward. Paré sought other approaches to treat wounds and staunch hemorrhage. His decisive answer was the ligature, and its introduction proved a turning point in the evolution of surgery. The early history of ligation of blood vessels is shrouded in uncertainty, and whether it was the Chinese and Egyptians or the Greeks and Romans who first suggested the practice is a matter of historical conjecture. One thing is certain: The technique was long forgotten, and Paré considered his method of ligation during an amputation to be original and nothing short of divine inspiration. He even designed a predecessor to the modern hemostat, a pinching instrument called the bec de corbin, or “crow’s beak,” to control bleeding while the vessel was handled. As with many groundbreaking ideas, Paré’s suggestions regarding ligatures were not readily accepted. The reasons given for the slow embrace range from a lack of skilled assistants to help expose blood vessels to the large number of instruments needed to achieve hemostasis—in preindustrial times, surgical tools were hand-made and expensive to produce. The result was that ligatures were not commonly used to control bleeding, especially during an amputation, until other devices were available to provide temporary hemostasis. This did not occur until the early 18th century when Jean-Louis Petit (1674–1750) invented the screw compressor tourniquet. Petit’s device placed direct pressure over the main artery of the extremity to be amputated and provided the shortterm control of bleeding necessary to allow the accurate placement of ligatures. Throughout the remainder of the 18th and 19th centuries, the use of new types of sutures and tourniquets increased in tandem as surgeons attempted to ligate practically every blood vessel in the body. Nonetheless, despite the abundance of elegant instruments and novel suture materials (ranging from buckskin to horsehair), the satisfactory control of bleeding, especially in delicate surgical operations, remained problematic. Starting in the 1880s, surgeons began to experiment with electrified devices that could cauterize. These first-generation electrocauteries were ungainly machines, but they did quicken the

5

conduct of a surgical operation. In 1926, Harvey Cushing (1869– 1939), professor of surgery at Harvard, experimented with a less cumbersome surgical device that contained two separate electric circuits, one to incise tissue without bleeding and the other simply to coagulate. The apparatus was designed by a physicist, William Bovie (1881–1958), and the two men collaborated to develop interchangeable metal tips, steel points, and wire loops that could be attached to a sterilizable pistol-like grip used to direct the electric current. As the electrical and engineering snags were sorted out, the Bovie electroscalpel became an instrument of trailblazing promise; almost a century later, it remains a fundamental tool in the surgeon’s armamentarium. 

CONTROL OF PAIN In the prescientific era, the inability of surgeons to perform painfree operations was among the most terrifying dilemmas of Medicine. To avoid the horror of the surgeon’s merciless knife, patients often refused to undergo a needed surgical operation or repeatedly delayed the event. That is why a scalpel wielder was more concerned about the speed with which he could complete a procedure than the effectiveness of the dissection. Narcotic and soporific agents, such as hashish, mandrake, and opium, had been used for thousands of years, but all were for naught. Nothing provided any semblance of freedom from the misery of a surgical operation. This was among the reasons why the systematic surgical exploration of the abdomen, cranium, joints, and thorax had to wait. As anatomic knowledge and surgical techniques improved, the search for safe methods to render a patient insensitive to pain became more pressing. By the mid-1830s, nitrous oxide had been discovered, and so-called laughing gas frolics were coming into vogue as young people amused themselves with the pleasant side effects of this compound. After several sniffs, individuals lost their sense of equilibrium, carried on without inhibition, and felt little discomfort as they clumsily knocked into nearby objects. Some physicians and dentists realized that the pain-relieving qualities of nitrous oxide might be applicable to surgical operations and tooth extractions. A decade later, Horace Wells (1815–1848), a dentist from Connecticut, had fully grasped the concept of using nitrous oxide for inhalational anesthesia. In early 1845, he traveled to Boston to share his findings with a dental colleague, William T.G. Morton (1819–1868), in the hopes that Morton’s familiarity with the city’s medical elite would lead to a public demonstration of painless tooth-pulling. Morton introduced Wells to John Collins Warren (1778–1856), professor of surgery at Harvard, who invited the latter to show his discovery before a class of medical students, one of whom volunteered to have his tooth extracted. Wells administered the gas and grasped the tooth. Suddenly, the supposedly anesthetized student screamed in pain. An uproar ensued as catcalls and laughter broke out. A disgraced Wells fled the room followed by several bystanders who hollered at him that the entire spectacle was a “humbug affair.” For Wells, it was too much to bear. He returned to Hartford and sold his house and dental practice. However, Morton understood the practical potential of Wells’ idea and took up the cause of pain-free surgery. Uncertain about the reliability of nitrous oxide, Morton began to test a compound that one of his medical colleagues, Charles T. Jackson (1805–1880), suggested would work better as an inhalational anesthetic—sulfuric ether. Armed with this advice, Morton studied the properties of the substance while

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SECTION I  Surgical Basic Principles

perfecting his inhalational techniques. In fall 1846, Morton was ready to demonstrate the results of his experiments to the world and implored Warren to provide him a public venue. On October 16, with the seats of the operating amphitheater of Massachusetts General Hospital filled to capacity, a tense Morton, having anesthetized a 20-year-old man, turned to Warren and told him that all was ready. The crowd was silent and set their gaze on the surgeon’s every move. Warren grabbed a scalpel, made a 3-inch incision, and excised a small vascular tumor on the patient’s neck. For 25 minutes, the spectators watched in stunned disbelief as the surgeon performed a painless surgical operation. Whether the men in the room realized that they had just witnessed one of the most important events in Medical history is unknown. An impressed Warren, however, slowly uttered the five most famous words in American surgery: “Gentlemen, this is no humbug.” No one knew what to do or say. Warren turned to his patient and repeatedly asked him whether he felt anything. The answer was a definitive no—no pain, no discomfort, nothing at all. Few medical discoveries have been so readily accepted as inhalational anesthesia. News of the momentous event spread swiftly as a new era in the history of surgery began. Within months, sulfuric ether and another inhalational agent, chloroform, were used in hospitals worldwide. The acceptance of inhalational anesthesia fostered research on other techniques to achieve pain-free surgery. In 1885, William Halsted (1852–1922) (Fig. 1.4), professor of surgery at the Johns Hopkins Hospital in Baltimore, announced that he had used cocaine and infiltration anesthesia (nerve-blocking) with great success in more than 1000 surgical cases. At the same time, James Corning (1855–1923) of New York carried out the earliest experiments on spinal anesthesia, which were soon expanded on by August Bier (1861–1939) of Germany. By the late 1920s, spinal anesthesia and epidural anesthesia were widely used in the United States and Europe. The next great advance in pain-free surgery

occurred in 1934, when the introduction of an intravenous anesthetic agent (sodium thiopental [Sodium Pentothal]) proved tolerable to patients, avoiding the sensitivity of the tracheobronchial tree to anesthetic vapors. 

FIG. 1.4  William Halsted (1852–1922).

FIG. 1.5  Joseph Lister (1827–1912).

CONTROL OF INFECTION Anesthesia helped make the potential for surgical cures more seductive. Haste was no longer of prime concern. However, no matter how much the discovery of anesthesia contributed to the relief of pain during surgical operations, the evolution of surgery could not proceed until the problem of postoperative infection was resolved. If ways to deaden pain had never been conceived, a surgical procedure could still be performed, although with much difficulty. Such was not the case with infection. Absent antisepsis and asepsis, surgical procedures were more likely to end in death rather than just pain. In the rise of modern surgery, several individuals and their contributions stand out as paramount. Joseph Lister (1827–1912) (Fig. 1.5), an English surgeon, belongs on this select list for his efforts to control surgical infection through antisepsis. Lister’s research was based on the findings of the French chemist Louis Pasteur (1822–1895), who studied the process of fermentation and showed that it was caused by the growth of living microorganisms. In the mid-1860s, Lister hypothesized that these invisible “germs,” or, as they became known, bacteria, were the cause of wound healing difficulties in surgical patients. He proposed that it was feasible to prevent suppuration by applying an antibacterial solution to a wound and covering the site in a dressing saturated with the same germicidal liquid. Lister was born into a well-to-do Quaker family from London. In 1848, he received his medical degree from University College. Lister was appointed a fellow of the Royal College of Surgeons 4 years later. He shortly moved to Edinburgh, where he became an assistant to James Syme (1799–1870). Their mentor/mentee

CHAPTER 1  The Rise of Modern Surgery: An Overview relationship was strengthened when Lister married Syme’s daughter Agnes (1835–1896). At the urging of his father-in-law, Lister applied for the position of professor of surgery in Glasgow. The 9 years that he spent there were the most important period in Lister’s career as a surgeon-scientist. In spring 1865, a colleague told Lister about Pasteur’s research on fermentation and putrefaction. Lister was one of the few surgeons of his day who, because of his familiarity with the microscope (his father designed the achromatic lens and was one of the founders of modern microscopy), had the ability to understand Pasteur’s findings about microorganisms on a first-hand basis. Armed with this knowledge, Lister showed that an injury was already full of bacteria by the time the patient arrived at the hospital. Lister recognized that the elimination of bacteria by excessive heat could not be applied to a patient. Instead, he turned to chemical antisepsis and, after experimenting with zinc chloride and sulfites, settled on carbolic acid (phenol). By 1866, Lister was instilling pure carbolic acid into wounds and onto dressings and spraying it into the atmosphere around the operative field and table. The following year, he authored a series of papers on his experience in which he explained that pus in a wound (these were the days of “laudable pus,” when it was mistakenly believed the more suppuration the better) was not a normal part of the healing process. Lister went on to make numerous modifications in his technique of dressings, manner of applying them, and choice of antiseptic solutions—carbolic acid was eventually abandoned in favor of other germicidal substances. He did not emphasize hand scrubbing but merely dipped his fingers into a solution of phenol and corrosive sublimate. Lister was incorrectly convinced that scrubbing created crevices in the palms of the hands where bacteria would proliferate. A second major advance by Lister was the development of sterile absorbable sutures. Lister believed that much of the suppuration found in wounds was created by contaminated ligatures. To prevent the problem, Lister devised an absorbable suture impregnated with phenol. Because it was not a permanent ligature, he was able to cut it short, closing the wound tightly and eliminating the necessity of bringing the ends of the suture out through the incision, a surgical practice that had persisted since the days of Paré. For many reasons, the acceptance of Lister’s ideas about infection and antisepsis was an uneven and slow process. First, the various procedural changes that Lister made during the evolution of his method created confusion. Second, listerism, as a technical exercise, was complicated and time-consuming. Third, early attempts by other surgeons to use antisepsis were abject failures. Finally, and most importantly, acceptance of listerism depended on an understanding of the germ theory, a hypothesis that many practical-minded scalpel wielders were loathed to recognize. As a professional group, German-speaking surgeons were the earliest to grasp the importance of bacteriology and Lister’s ideas. In 1875, Richard von Volkmann (1830–1889) and Johann Nussbaum (1829–1890) commented favorably on their treatment of compound fractures with antiseptic methods. In France, Just Lucas-Championière (1843–1913) was not far behind. The following year, Lister traveled to the United States, where he spoke at the International Medical Congress held in Philadelphia and gave additional lectures in Boston and New York. Lister’s presentations were memorable, sometimes lasting more than three hours, but American surgeons remained unconvinced about his message. American surgeons did not begin to embrace the principles of antisepsis until the mid-1880s. The same was also true in Lister’s home country, where he initially encountered strong opposition led by the renowned gynecologist Lawson Tait (1845–1899).

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Over the years, Lister’s principles of antisepsis gave way to principles of asepsis, or the complete elimination of bacteria. The concept of asepsis was forcefully advanced by Ernst von Bergmann (1836–1907), professor of surgery in Berlin, who recommended steam sterilization (1886) as the ideal method to eradicate germs. By the mid-1890s, less clumsy antiseptic and aseptic techniques had found their way into most American and European surgical amphitheaters. Any lingering doubts about the validity of Lister’s concepts of wound infection were eliminated on the battlefields of World War I. Aseptic technique was virtually impossible to attain on the battlefield, but the invaluable principle of wound treatment by means of surgical debridement and mechanical irrigation with an antiseptic solution was developed by Alexis Carrel (1873– 1944) (Fig. 1.6), the Nobel prize-winning French-American surgeon, and Henry Dakin (1880–1952), an English chemist. Once antiseptic and aseptic techniques had been accepted as routine elements of surgical practice, it was inevitable that other antibacterial rituals would take hold, in particular, the use of caps, hats, masks, drapes, gowns, and rubber gloves. Until the 1870s, surgeons did not use gloves because the concept of bacteria on the hands was not recognized. In addition, no truly functional glove had ever been designed. This situation changed in 1878, when an employee of the India-Rubber Works in Surrey, England, received British and U.S. patents for the manufacture of a surgical glove that had a “delicacy of touch.” The identity of the first surgeon who required that flexible rubber gloves be consistently worn for every surgical operation is uncertain. Halsted is regarded as the individual who popularized their use, although the idea of rubber gloves was not fully accepted until the 1920s. In 1897, Jan Mikulicz-Radecki (1850–1905), a Polish-Austrian surgeon, devised a single-layer gauze mask to be worn during a surgical operation. An assistant modified the mask by placing two layers of cotton-muslin onto a large wire frame to keep the gauze away from the surgeon’s lips and nose. This modification was crucial because a German microbiologist showed that bacteria-laden droplets from the mouth and nose enhanced the likelihood of wound infection. Silence in the operating room became a cardinal feature of surgery in the early 20th century. At approximately

FIG.1.6  Alexis Carrel (1873–1944).

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SECTION I  Surgical Basic Principles

the same time, when it was also determined that masks provided less protection if an individual was bearded, the days of surgeons sporting bushy beards and droopy mustaches went by the wayside. 

OTHER ADVANCES THAT FURTHERED THE RISE OF MODERN SURGERY X-Rays Most prominent among other advances that furthered the rise of modern surgery was the discovery by Wilhelm Roentgen (1845– 1923) of x-rays. He was professor of physics at Würzburg University in Germany, and in late December 1895, he presented to that city’s medical society a paper on electromagnetic radiation. Roentgen was investigating the photoluminescence from metallic salts that had been exposed to light when he noticed a greenish glow coming from a screen painted with a phosphorescent substance located on a shelf over 9 feet away. He came to realize there were invisible rays (he termed them x-rays) capable of passing through objects made of wood, metal, and other materials. Significantly, these rays also penetrated the soft tissues of the body in such a way that more dense bones were revealed on a specially treated photographic plate. Similar to the discovery of inhalational anesthesia, the importance of x-rays was realized immediately. By March 1896, the first contributions regarding the use of roentgenography in the practice of Medicine in the United States were reported. In short order, numerous applications were developed as surgeons rapidly applied the new finding to the diagnosis and location of dislocations and fractures, the removal of foreign bodies, and the treatment of malignant tumors. 

Blood Transfusion Throughout the late 19th century, there were scattered reports of blood transfusions, including one by Halsted on his sister for postpartum hemorrhage with blood drawn from his own veins. However, it was not until 1901, when Karl Landsteiner (1868– 1943), an Austrian physician, discovered the major human blood groups, that blood transfusion became a less risky practice. George Crile (1864–1943), a noted surgeon from Cleveland, performed the first surgical operation during which a blood transfusion was used, and the patient survived 5 years later. The development of a method to make blood noncoagulable was the final step needed to ensure that transfusions were readily available. This method was developed in the years leading up to World War I when Richard Lewisohn (1875–1962) of New York and others showed that by adding sodium citrate and glucose as an anticoagulant and refrigerating the blood, it could be stored for several days. Once this was known, blood banking became feasible as demonstrated by Geoffrey Keynes (1887–1982), a noted British surgeon (and younger brother of the famed economist John Maynard Keynes), who built a portable cold-storage unit that enabled transfusions to be carried out on the battlefield. In 1937, Bernard Fantus (1874–1940), director of the pharmacology and therapeutics department at Cook County Hospital in Chicago, took the concept of storing blood one step further when he established the first hospital-based “blood bank” in the United States. Despite the success in storing and crossmatching blood, immune-related reactions persisted. In this regard, another important breakthrough came in 1939, when Landsteiner identified the Rh factor (so named because of its presence in the rhesus monkey). At the same time, Charles Drew (1904–1950) (Fig. 1.7),

FIG. 1.7  Charles Drew (1904–1950).

a surgeon working at Columbia University, showed how blood could be separated into two main components, red blood cells and plasma, and that the plasma could be frozen for long-term storage. His discovery led to the creation of large-scale blood banking, especially for use by the military during World War II. The storing of blood underwent further refinement in the early 1950s when breakable glass bottles were replaced with durable plastic bags. 

Frozen Section The introduction of anesthesia and asepsis allowed surgeons to perform more technically demanding surgical operations. It also meant that surgeons had to refine their diagnostic capabilities. Among the key additions to their problem-solving skills was the technique of frozen section, an innovation that came to be regarded as one of the benchmarks of scientific surgery. In the late 19th century and early years of the 20th century, “surgical pathology” consisted of little more than a surgeon’s knowledge of gross pathology and his ability to recognize lesions on the surface of the body. Similar to the notion of the surgeon-anatomist, the surgeonpathologist, exemplified by James Paget (1814–1899) of London and the renowned Theodor Billroth (1829–1894) (Fig. 1.8) of Vienna, authored the major textbooks and guided the field. In 1895, Nicholas Senn (1844–1908), professor of pathology and surgery at Rush Medical College in Chicago, recommended that a “freezing microtome” be used as an aid in diagnosis during a surgical operation. However, the early microtomes were crude devices, and freezing led to unacceptable distortions in cellular morphology. This situation was remedied as more sophisticated methods for hardening tissue evolved, particularly systems devised by Thomas Cullen (1868–1953), a gynecologist at the Johns Hopkins Hospital, and Leonard Wilson (1866–1943), chief of pathology at the Mayo Clinic. During the late 1920s and early 1930s, a time when pathology was receiving recognition as a specialty within Medicine and the influence of the surgeon-pathologist was

CHAPTER 1  The Rise of Modern Surgery: An Overview

FIG. 1.8  Theodor Billroth (1829–1894).

on the decline, the backing by Joseph Bloodgood (1867–1935), a distinguished surgeon from Baltimore and one of Halsted’s earliest trainees, led to the routine use of frozen section during a surgical operation. 

ASCENT OF SCIENTIFIC SURGERY By the first decades of the 20th century, the interactions of politics, science, socioeconomics, and technical advances set the stage for what would become a spectacular showcasing of the progress of surgery. Surgeons wore antiseptic-appearing white caps, gowns, and masks. Patients donned white robes, operating tables were draped in white cloth, and instruments were bathed in white metal basins that contained new and improved antiseptic solutions. All was clean and tidy, with the conduct of the surgical operation no longer a haphazard affair. So great were the innovations that the foundation of basic surgical procedures, including procedures involving the abdomen, cranium, joints, and thorax, was completed by the end of World War I (1918). This transformation was successful not only because surgeons had fundamentally changed, but also because Medicine and its relationship to science had been irrevocably altered. Sectarianism and quackery, the consequences of earlier medical dogmatism, were no longer tenable within the confines of scientific inquiry. Nonetheless, surgeons retained a lingering sense of professional and social discomfort and continued to be pejoratively described by some physicians as nonthinkers who worked in an inferior manual craft. The result was that scalpel bearers had no choice but to allay the fear and misunderstanding of the surgical unknown of their colleagues and the public by promoting surgical procedures as an acceptable part of the new armamentarium of Medicine. This was not an easy task, particularly because the negative consequences of surgical operations, such as discomfort

9

and complications, were often of more concern to patients than the positive knowledge that devastating disease processes could be thwarted. It was evident that theoretical concepts, research models, and clinical applications were necessary to demonstrate the scientific basis of surgery. The effort to devise new surgical operations came to rely on experimental surgery and the establishment of surgical research laboratories. In addition, an unimpeachable scientific basis for surgical recommendations, consisting of empirical data collected and analyzed according to nationally and internationally accepted standards and set apart from individual assumptions, had to be developed. Surgeons also needed to demonstrate managerial and organizational unity, while conforming to contemporary cultural and professional norms. These many challenges involved new administrative initiatives, including the establishment of self-regulatory and licensing bodies. Surgeons showed the seriousness of their intent to be viewed as specialists within the mainstream of Medicine by establishing standardized postgraduate surgical education and training programs and professional societies. In addition, a new type of dedicated surgical literature appeared: specialty journals to disseminate news of surgical research and technical innovations promptly. The result of these measures was that the most consequential achievement of surgeons during the mid-20th century was ensuring the social acceptability of surgery as a legitimate scientific endeavor and the surgical operation as a bona fide therapeutic necessity. The history of the socioeconomic transformation and professionalization of modern surgery varied from country to country. In Germany, the process of economic and political unification under Prussian dominance presented new and unlimited opportunities for physicians and surgeons, particularly when government officials decreed that more than a simple medical degree was necessary for the right to practice. A remarkable scholastic achievement occurred in the form of the richly endowed state-sponsored university where celebrated professors of surgery administered an impressive array of surgical training programs (other medical disciplines enjoyed the same opportunities). The national achievements of German-speaking surgeons soon became international, and from the 1870s through World War I, German universities were the center of world-recognized surgical excellence. The demise of the status of Austria-Hungary and Germany as the global leader in surgery occurred with the end of the World War I. The conflict destroyed much of Europe—if not its physical features, then a large measure of its passion for intellectual and scientific pursuits. The result was that a vacuum existed internationally in surgical education, research, and therapeutics. It was only natural that surgeons from the United States, the industrialized nation least affected psychologically and physically by the outcome of the war, would fill this void. So began the ascent of American surgery to its current position of worldwide leadership. Some details about the transformation and professionalization of modern American surgery follow.

Standardized Postgraduate Surgical Education and Training Programs For the American surgeon of the late 19th century, any attempt at formal learning was a matter of personal will with limited practical opportunities. There were a few so-called teaching hospitals but no full-time academic surgeons. To study surgery in these institutions consisted of assisting surgeons in their daily rounds and observing the performance of surgical operations; there was minimal hands-on operative experience. Little, if any, integration

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of the basic sciences with surgical diagnosis and treatment took place. In the end, most American surgeons were self-taught and, consequently, not eager to hand down hard-earned and valuable skills to younger men who were certain to become competitors. Conversely, the German system of surgical education and training brought the basic sciences together with practical clinical teaching coordinated by full-time academicians. There was a competitiveness among the young surgeons-in-training that began in medical school with only the smartest and strongest willed being rewarded. At the completion of an internship, which usually included a stint in a basic science laboratory, the young physician would, if fortunate, be asked to become an assistant to a professor of surgery. At this point, the surgeon-to-be was thrust into the thick of an intense contest to become the first assistant (called the chief resident today). There was no regular advancement from the bottom to the top of the staff, and only a small number ever became the first assistant. The first assistant would hold his position until called to a university’s chair of surgery or until he tired of waiting and went into practice. From this labyrinth of education and training programs, great surgeons produced more great surgeons, and these men and their schools of surgery offered Halsted the inspiration and philosophies he needed to establish an American system of education and training in surgery. Halsted was born into a well-to-do New York family and received the finest educational opportunities possible. He had private elementary school tutors, attended boarding school at Phillips Andover Academy, and graduated from Yale in 1874. Halsted received his medical degree three years later from the College of Physicians and Surgeons in New York (now Columbia University) and went on to serve an 18-month internship at Bellevue Hospital. With the accomplishments of the German-speaking medical world attracting tens of thousands of American physicians to study abroad, Halsted joined the pilgrimage and spent 1878 through 1880 at universities in Berlin, Hamburg, Kiel, Leipzig, Vienna, and Würzburg. He could not help but notice the stark difference between the German and American manner of surgical education and training. The surgical residency system that Halsted implemented at the Johns Hopkins Hospital in 1889 was a consolidation of the German approach. In his program, the first of its kind in the United States, Halsted insisted on a more clearly defined pattern of organization and division of duties. The residents had a larger volume of operative material at their disposal, a more intimate contact with practical clinical problems, and a graduated concentration of clinical authority and responsibility in themselves rather than the professor. Halsted’s aim was to train outstanding surgical teachers, not merely competent operating surgeons. He showed his residents that research based on anatomic, pathologic, and physiologic principles, along with animal experimentation, made it possible to develop sophisticated operative procedures. Halsted proved to an often leery profession and public that an unambiguous sequence of discovery to implementation could be observed between the experimental research laboratory and the clinical operating room. In so doing, he developed a system of surgery so characteristic that it was termed a “school of surgery.” More to the point, Halsted’s principles of surgery became a widely acknowledged and accepted scientific imprimatur. More than any other surgeon, it was the aloof and taciturn Halsted who moved surgery from the melodramatics and grime of the 19th century surgical theater to the silence and cleanliness of the 20th century operating room.

Halsted is regarded as “Adam” in American surgery, but he trained only 17 chief residents. The reason for this was that among the defining features of Halsted’s program was an indefinite time of tenure for his first assistant. Halsted insisted that just one individual should survive the steep slope of the residency pyramid and only every few years. Of these men, several became professors of surgery at other institutions where they began residency programs of their own, including Harvey Cushing at Harvard, Stephen Watts (1877–1953) at Virginia, George Heuer (1882–1950) and Mont Reid (1889–1943) at Cincinnati, and Roy McClure (1882– 1951) at Henry Ford Hospital in Detroit. By the 1920s, there were a dozen or so Halsted-style surgical residencies in the United States. However, the strict pyramidal aspect of the Halsted plan was so self-limiting (i.e., one first assistant/chief resident with an indefinite length of appointment) that in an era when thousands of physicians clamored to be recognized as specialists in surgery, his restrictive style of surgical residency was not widely embraced. For that reason, his day-to-day impact on the number of trained surgeons was less significant than might be thought. There is no denying that Halsted’s triad of educational principles— knowledge of the basic sciences, experimental research, and graduated patient responsibility—became a preeminent and permanent feature of surgical training programs in the United States. However, by the end of World War II, most surgical residencies were organized around the less severe rectangular structure of advancement employed by Edward Churchill (1895–1972) at the Massachusetts General Hospital beginning in the 1930s. This style of surgical education and training was a response to newly established national standards set forth by the American Medical Association (AMA) and the American Board of Surgery. In 1920, for the first time, the AMA Council on Medical Education published a list of 469 general hospitals with 3000 “approved” internships. The annual updating of this directory became one of the most important and well-publicized activities of the AMA and provided health care planners with their earliest detailed national database. The AMA expanded its involvement in postgraduate education and training 7 years later when it issued a registry of 1700 approved residencies in various medical and surgical specialties, including anesthesia, dermatology, gynecology and obstetrics, medicine, neuropsychiatry, ophthalmology, orthopedics, otolaryngology, pathology, pediatrics, radiology, surgery, tuberculosis, and urology. By this last action, the AMA publicly declared support for the concept of specialization, a key policy decision that profoundly affected the professional future of physicians in the United States and the delivery of health care. 

Experimental Surgical Research Laboratories Halsted believed that experimental research provided residents with opportunities to evaluate surgical problems in an analytic fashion, an educational goal that could not be achieved solely by treating patients. In 1895, he organized an operative course on animals to teach medical students how to handle surgical wounds and use antiseptic and aseptic techniques. The classes were popular, and, several years later, Halsted asked Cushing, who had recently completed his residency at Hopkins and then spent time in Europe sharpening his experimental research skills with the future Nobel laureates Theodor Kocher (1841–1917) (Fig. 1.9) and Charles Sherrington (1857–1952), to assume responsibility for managing the operative surgery course as well as his experimental laboratory. Cushing, the most renowned of Halsted’s assistants, was a graduate of Yale College and Harvard Medical School. He would go

CHAPTER 1  The Rise of Modern Surgery: An Overview

11

FIG. 1.9  Theodor Kocher (1841–1917).

on to become professor of surgery at Harvard and first surgeon-inchief of the newly built Peter Bent Brigham Hospital. Cushing’s clinical accomplishments are legendary and include describing basophil adenomas of the pituitary gland, discovering the rise in systemic blood pressure that resulted from an increase in intracranial pressure, and devising ether charts for the surgical operating room. Just as impressive are Cushing’s many achievements outside the world of medical science, the foremost being a Pulitzer Prize in Biography or Autobiography in 1926 for his two-volume work Life of Sir William Osler. Cushing found the operative surgery classroom space to be limited, and he persuaded university trustees to authorize funds to construct the first animal laboratory for surgical research in the United States, the Hunterian Laboratory of Experimental Medicine, named after the famed Hunter. Halsted demanded the same excellence of performance in his laboratory as in the hospital’s operating room, and Cushing assured his mentor that this request would be respected. Similar to Halsted, Cushing was an exacting and demanding taskmaster, and he made certain that the Hunterian, which included indoor and outdoor cages for animals, cordoned-off areas for research projects, and a large central room with multiple operating tables, maintained a rigorous scholarly environment where students learned to think like surgical investigators while acquiring the basics of surgical technique. As for the residents in Halsted’s program, time in the Hunterian became an integral part of their surgical education and training. Other American surgeons at the turn of the century demonstrated an interest in experimental surgical research (Senn’s book, Experimental Surgery, the first American book on the subject, was published in 1889, and Crile’s renowned treatise, An Experimental Research into Surgical Shock, was published in 1899), but their scientific investigations were not conducted in as formal a setting as the Hunterian. Cushing went on to use the Hunterian for his own neurosurgical research and later took the concept of a surgical research laboratory to Boston where, several surgical generations later, Joseph Murray (1919–2012), working alongside the Brigham’s

FIG. 1.10  Francis D. Moore (1913–2001).

Moseley Professor of Surgery, Francis D. Moore (1913–2001) (Fig. 1.10), won the 1990 Nobel Prize in Physiology or Medicine for his work on organ and cell transplantation in the treatment of human disease, specifically kidney transplant. One other American surgeon has been named a Nobel laureate. Charles Huggins (1901–1997) (Fig. 1.11) was born in Canada but graduated from Harvard Medical School and received his surgical training at the University of Michigan. While working at the surgical research laboratory of the University of Chicago, Huggins found that antiandrogenic treatment, consisting of orchiectomy or the administration of estrogens, could produce long-term regression in patients with advanced prostatic cancer. These observations formed the basis for the treatment of malignant tumors by hormonal manipulation and led to his receiving the Nobel Prize in Physiology or Medicine in 1966. Regarding the long-term influence of the Hunterian, it served as a model that was widely embraced by many university hospital officials and surgical residency directors. Thus began a tradition of experimental research that remains a feature of modern American surgical education and training programs, the results of which continue to be seen and heard at the American College of Surgeons Owen H. Wangensteen Forum on Fundamental Surgical Problems, held during the annual Clinical Congress. Owen H. Wangensteen (1898–1981) (Fig. 1.12) was the long-time professor of surgery at the University of Minnesota where he brought his department to prominence as a center for innovative experimental and clinical surgical research. 

Specialty Journals, Textbooks, Monographs, and Treatises Progress in science brought about an authoritative and rapidly growing body of medical and surgical knowledge. The timely

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SECTION I  Surgical Basic Principles

FIG. 1.11  Charles Huggins (1901–1997).

FIG. 1.12  Owen H. Wangensteen (1898–1981).

dissemination of this information into the clinical practice of surgery became dependent on weekly and monthly medical journals. Physicians in the United States proved adept at promoting this new style of journalism, and by the late 1870s, more health-related periodicals were published in the United States than in almost all of Europe. However, most medical magazines were doomed to early failure because of limited budgets and a small number of readers. Despite incorporating the words “Surgery,” “Surgical,” or “Surgical Sciences” in their masthead, none of these journals treated surgery as a specialty. There were simply not enough physicians who wanted to or could afford to practice surgery around the clock. Physicians were unable to operate with any reasonable anticipation of success, until the mid to late 1880s, and the acceptance of the germ theory and Lister’s concepts of antisepsis.

Once this occurred, the push toward specialization gathered speed as numbers of surgical operations increased along with a cadre of full-time surgeons. For surgeons in the United States, the publication of the Annals of Surgery in 1885 marked the beginning of a new era, one guided in many ways by the content of the specialty journal. The Annals became intimately involved with the advancement of the surgical sciences, and its pages record the story of surgery in the United States more accurately than any other written source. The magazine remains the oldest continuously published periodical in English devoted exclusively to surgery. Other surgical specialty journals soon appeared, and they, along with the published proceedings and transactions of emerging surgical specialty societies, proved crucial in establishing scientific and ethical guidelines for the profession. As important as periodicals were to the spread of surgical knowledge, American surgeons also communicated their knowhow in textbooks, monographs, and treatises. Similar to the rise of the specialty journal, these massive, occasionally multivolume works first appeared in the 1880s. When David Hayes Agnew (1818–1892), professor of surgery at the University of Pennsylvania, wrote his three-volume, 3000-page Principles and Practice of Surgery, he was telling the international surgical world that American surgeons had something to say and were willing to stand behind their words. At almost the same time, John Ashhurst (1839–1900), soon-to-be successor to Agnew at the University of Pennsylvania, was organizing his six-volume International Encyclopedia of Surgery (1881–1886), which introduced the concept of a multiauthored surgical textbook. The Encyclopedia was an instant publishing success and marked the first time that American and European surgeons worked together as contributors to a surgical text. Ashhurst’s effort was shortly joined by Keen’s An American Text-Book of Surgery (1892), which was the first surgical treatise written by various authorities all of whom were American. These tomes are the forebears of the present book. In 1936, Frederick Christopher (1889–1967), an associate professor of surgery at Northwestern University and chief surgeon to the Evanston Hospital in Evanston, IL, organized a Textbook of Surgery. The Textbook, which Christopher described as a “cross-sectional presentation of the best in American surgery,” quickly became one of the most popular of the surgical primers in the United States. He remained in charge for four more editions and, in 1956, was succeeded by Loyal Davis (1896–1982) (Fig. 1.13), professor of surgery at Northwestern University. Davis, who also held a Ph.D. in the neurologic sciences and had studied with Cushing in Boston, was an indefatigable surgical researcher and prolific author. Not only did he edit the sixth, seventh, eighth, and ninth editions of what became known as Christopher’s Textbook of Surgery, but from 1938 to 1981, Davis also was editor-in-chief of the renowned journal, Surgery, Gynecology and Obstetrics. (In the last years of his life, Davis gained further recognition as the father-in-law of President Ronald Reagan.) In 1972, David Sabiston (1924–2009) (Fig. 1.14), professor of surgery at Duke, assumed editorial control of the renamed Davis-Christopher Textbook of Surgery. Sabiston was an innovative vascular and cardiac surgeon who held numerous leadership roles throughout his career, including President of the American College of Surgeons, the American Surgical Association, the Southern Surgical Association, and the American Association for Thoracic Surgery. Not only did Sabiston guide editions 10 through 15 of the Davis-Christopher Textbook, but he also served as editor-in-chief of the Annals of Surgery for 25 years. Starting in 2000 with the 16th edition, Courtney M. Townsend, Jr. (1943-),

CHAPTER 1  The Rise of Modern Surgery: An Overview

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FIG. 1.13  Loyal Davis (1896–1982).

FIG. 1.14  David Sabiston (1924–2009).

professor of surgery at the University of Texas Medical Branch in Galveston, took over editorial responsibility for the retitled Sabiston Textbook of Surgery: The Biological Basis of Modern Surgical Practice. He has remained in charge through the current 21st edition, and the now legendary work, which Christopher first organized more than 8 decades ago, holds the record for having been updated more times and being the longest lived of any American surgical textbook. 

College of Surgeons three years later was meant to impress on general practitioners the limits of their surgical abilities and to show the public that a well-organized group of specialist surgeons could provide dependable and safe operations. The founding of the American College of Surgeons fundamentally altered the course of surgery in the United States. Patterned after the Royal Colleges of Surgeons of England, Ireland, and Scotland, the American College of Surgeons established professional, ethical, and moral guidelines for every physician who practiced surgery and conferred the designation Fellow of the American College of Surgeons (FACS) on its members. For the first time, there was a national organization that united surgeons by exclusive membership in common educational, socioeconomic, and political causes. Although the American Surgical Association had been founded more than three decades earlier, it was composed of a small group of elite senior surgeons and was not meant to serve as a national lobbying front. There were also regional surgical societies, including the Southern Surgical Association (1887) and the Western Surgical Association (1891), but they had less restrictive membership guidelines than the American College of Surgeons, and their geographic differences never brought about national unity. Because the integrity of the medical profession is largely assured by the control it exercises over the competency of its members, the question of physician licensing and limits of specialization, whether mandated by the government or by voluntary self-regulation, became one of crucial importance. State governments had begun to establish stricter licensing standards, but their statutes did not adequately delineate generalist from specialist. This lack of rules and regulations for specialty practice was a serious concern. Leaders in Medicine realized that if the discipline did not move to regulate specialists, either federal or state agencies would be forced to fill this role, a situation that few physicians wanted. There was also lay pressure. Patients, increasingly dependent on physicians for scientific-based medical and surgical care, could not determine who was qualified to do

Professional Societies and Licensing Organizations By the 1920s, surgery was at a point in American society where it was becoming “professionalized.” The ascent of scientific surgery had led to technical expertise that gave rise to specialization. However, competence in the surgical operating room alone was not sufficient to distinguish surgery as a profession. Any discipline that looks to be regarded as a profession must assert exclusive control over the expertise of its members and convince the public that these skills are unique and dependable (i.e., act as a monopoly). For the community at large, the notion of trustworthiness is regarded as a fundamental criterion of professional status. To gain and maintain that trust, the professional group has to have complete jurisdiction over its admission policies and be able to discipline and force the resignation of any associate who does not meet rules of acceptable behavior. In their quest for professionalization and specialization, American surgeons created self-regulating professional societies and licensing organizations during the first half of the 20th century. Around 1910, conflicts between general practitioners and specialists in surgery reached a fever pitch. As surgical operations became more technically sophisticated, inadequately trained or incompetent physicians cum surgeons were viewed as endangering patients’ lives as well as the reputation of surgery as a whole. That year, Abraham Flexner (1866–1959) issued his now famous report that reformed medical education in the United States. Much as Flexner’s manifesto left an indelible mark on more progressive and trustworthy medical schooling, the establishment of the American

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SECTION I  Surgical Basic Principles

what—state licensure only established a minimum standard, and membership in loosely managed professional societies revealed little about competency. By the end of World War I, most surgical (and medical) specialties had established nationally recognized fraternal organizations, such as the American College of Surgeons. In the case of the American College of Surgeons, although its founders hoped to distinguish full-time surgeons from general practitioners, the organization initially set membership guidelines low in its haste to expand enrollment—10 years after its creation, there were more than 7000 Fellows. The American College of Surgeons emphasized an applicant’s ability to perform a surgical operation and was less concerned about the depth of overall medical knowledge that sustained an individual’s surgical judgment. Furthermore, membership did not depend on examinations or personal interviews. Despite these flaws, the American College of Surgeons did begin to clarify the concept of a surgical specialist to the public. The sheer presence of the American College of Surgeons implied that full-time surgeons outperformed general practitioners and their part-time approach to surgery, while reinforcing the professional authority and clinical expertise of the surgical specialist. Even with the presence of organizations such as the American College of Surgeons, without a powerful centralized body to coordinate activities, attempts to regulate the push toward specialization in Medicine progressed in a confused and desultory manner. In response to this haphazard approach as well as mounting external pressures and internal power struggles, specialties began to form their own organizations to determine who was a bona fide specialist. These self-governed and self-regulated groups became known as “boards,” and they went about evaluating candidates with written and oral examinations as well as face-to-face interviews. The first board was created in 1917 for ophthalmology and was followed by boards for otolaryngology (1924), obstetrics and gynecology (1930), pediatrics (1933), psychiatry and neurology (1934), radiology (1934), and pathology (1936). Certification by a board indicated a practitioner’s level of expertise; thus the limits of specialization set by the board delineated the clinical boundaries of the specialty. For example, in 1936, practitioners of medicine organized a board to cover the whole of internal medicine. In doing so, the specialty exerted firm control over its budding subspecialties, including cardiology, endocrinology, gastroenterology, hematology, and infectious disease. Surgery took a more difficult and divisive path. Before surgeons were able to establish a board for the overall practice of surgery, surgical subspecialists had organized separate boards in otolaryngology, colon and rectal (1935), ophthalmology, orthopedics (1935), and urology (1935). The presence of these surgical subspecialty boards left an open and troubling question: What was to become of the general surgeon? In the mid-1930s, a faction of younger general surgeons, led by Evarts Graham (1883–1957), decided to set themselves apart from what they considered the less than exacting admission standards of the American College of Surgeons. Graham was professor of surgery at Washington University in St. Louis and the famed discoverer of cholecystography. He demonstrated the link between cigarettes and cancer and performed the first successful one-stage pneumonectomy (as fate would have it, the chain-smoking Graham died of lung cancer). Graham would go on to dominate the politics of American surgery from the 1930s through the 1950s. For now, Graham and his supporters told the leaders of the American College of Surgeons about their plans to organize a certifying board for general surgeons. Representatives of the American

College of Surgeons reluctantly agreed to cooperate, and the American Board of Surgery was organized in 1937. Despite optimism that the American Board of Surgery could formulate a certification procedure for the whole of surgery, its actual effect was limited. Graham attempted to restrain the surgical subspecialties by brokering a relationship between the American Board of Surgery and the subspecialty boards. It was a futile effort. The surgical subspecialty boards pointed to the educational and financial rewards that their own certification represented as reason enough to remain apart from general surgeons. The American Board of Surgery never gained control of the surgical subspecialties and was unable to establish a governing position within the whole of surgery. To this day, little economic or political commonality exists between general surgery and the various subspecialties. The consequence is a surgical lobby that functions in a divided and inefficient manner. Although the beginning of board certification was a muddled and contentious process, the establishment of the various boards did bring about important organizational changes to Medicine in the United States. The professional status and clinical authority that board certification afforded helped distinguish branches and sub-branches of Medicine and facilitated the rapid growth of specialization. By 1950, almost 40% of physicians in the United States identified themselves as full-time specialists, and of this group, greater than 50% were board certified. It was not long before hospitals began to require board certification as a qualification for staff membership and admitting privileges. 

THE MODERN ERA The three decades of economic expansion after World War II had a dramatic impact on the scale of surgery, particularly in the United States. Seemingly overnight, Medicine became big business with health care rapidly transformed into society’s largest growth industry. Spacious hospital complexes were built that epitomized not only the scientific advancement of the healing arts but also demonstrated the strength of America’s postwar boom. Society gave surgical science unprecedented recognition as a prized national asset, noted by the vast expansion of the profession and the extensive distribution of surgeons throughout the United States. Large urban and community hospitals established surgical education and training programs and found it relatively easy to attract residents. Not only would surgeons command the highest salaries, but also Americans were enamored with the drama of the operating room. Television series, movies, novels, and the more than occasional live performance of a heart operation on television beckoned the lay individual. It was an exciting time for American surgeons, with important advances made in the operating room and the basic science laboratory. This progress followed several celebrated general surgical firsts from the 1930s and 1940s, including work on surgical shock by Alfred Blalock (1899–1964) (Fig. 1.15), the introduction of pancreaticoduodenectomy for cancer of the pancreas by Allen Oldfather Whipple (1881–1963), and decompression of mechanical bowel obstruction by a suction apparatus by Owen Wangensteen. Among the difficulties in identifying the contributions to surgery after World War II is a surfeit of famous names—so much so that it becomes a difficult and invidious task to attempt any rational selection of representative personalities along with their significant writings. This dilemma was remedied in the early 1970s, when the American College of Surgeons and the American Surgical Association jointly sponsored Study on Surgical Services for the United

CHAPTER 1  The Rise of Modern Surgery: An Overview

FIG. 1.15  Alfred Blalock (1899–1964).

States (SOSSUS). It was a unique and vast undertaking by the surgical profession to examine itself and its role in the future of health care in the United States. Within the study’s three-volume report (1975) is an account from the surgical research subcommittee that named the most important surgical advances in the 1945 to 1970 era. In this effort, a group of American surgeons from all specialties and academic and private practice attempted to appraise the relative importance of advances in their area of expertise. General surgeons considered kidney transplantation, the replacement of arteries by grafts, intravenous hyperalimentation, hemodialysis, vagotomy and antrectomy for peptic ulcer disease, closed chest resuscitation for cardiac arrest, the effect of hormones on cancer, and topical chemotherapy of burns to be of first-order importance. Of second-order importance were chemotherapy for cancer, identification and treatment of Zollinger-Ellison syndrome, the technique of portacaval shunt, research into the metabolic response to trauma, and endocrine surgery. Colectomy for ulcerative colitis, endarterectomy, the Fogarty balloon catheter, continuous suction drainage of wounds, and development of indwelling intravenous catheters were of third-order importance. Among the other surgical specialties, research contributions deemed of first-order importance were as follows: Pediatric surgeons chose combined therapy for Wilms tumor; neurosurgeons chose shunts for hydrocephalus, stereotactic surgery and microneurosurgery, and the use of corticosteroids and osmotic diuretics for cerebral edema; orthopedists chose total hip replacement; urologists chose ileal conduits and the use of hormones to treat prostate cancer; otorhinolaryngologists selected surgery for conductive deafness; ophthalmologists selected photocoagulation and

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retinal surgery; and anesthesiologists selected the development of nonflammable anesthetics, skeletal muscle relaxants, and the use of arterial blood gas and pH measurements. Additional innovations of second-order and third-order value consisted of the following: Pediatric surgeons chose understanding the pathogenesis and treatment of Hirschsprung disease, the development of abdominal wall prostheses for omphalocele and gastroschisis, and surgery for imperforate anus; plastic surgeons chose silicone and Silastic implants, surgery of cleft lip and palate, and surgery of craniofacial anomalies; neurosurgeons chose percutaneous cordotomy and dorsal column stimulation for treatment of chronic pain and surgery for aneurysms of the brain; orthopedic surgeons chose Harrington rod instrumentation, compression plating, pelvic osteotomy for congenital dislocation of the hip, and synovectomy for rheumatoid arthritis; urologists selected the treatment of vesicoureteral reflux, diagnosis and treatment of renovascular hypertension, and surgery for urinary incontinence; otorhinolaryngologists selected translabyrinthine removal of acoustic neuroma, conservation surgery for laryngeal cancer, nasal septoplasty, and myringotomy and ventilation tube for serous otitis media; ophthalmologists selected fluorescein fundus angiography, intraocular microsurgery, binocular indirect ophthalmoscopy, cryoextraction of lens, corneal transplantation, and the development of contact lenses; and anesthesiologists chose progress in obstetric anesthesia and an understanding of the metabolism of volatile anesthetics. All these advances were important to the rise of surgery, but the clinical developments that most captivated the public imagination and showcased the brilliance of post–World War II surgery were the growth of cardiac surgery and organ transplantation. Together, these two fields stand as signposts along the new surgical highway. Fascination with the heart goes far beyond that of clinical medicine. From the historical perspective of art, customs, literature, philosophy, religion, and science, the heart has represented the seat of the soul and the wellspring of life itself. Such reverence also meant that this noble organ was long considered a surgical untouchable. Although suturing of a stab wound to the pericardium in 1893 by Daniel Hale Williams (1856–1931) and successful treatment of an injury that penetrated a cardiac chamber in 1902 by Luther Hill (1862–1946) were significant triumphs, the development of safe cardiothoracic surgery that could be counted on as something other than an occasional event did not occur until the 1940s. During World War II, Dwight Harken (1910–1993) gained extensive battlefield experience in removing bullets and shrapnel in or near the heart and great vessels. Building on his wartime experience, Harken and other pioneering surgeons, including Charles Bailey (1910–1993), expanded intracardiac surgery by developing operations for the relief of mitral valve stenosis. In 1951, Charles Hufnagel (1916–1989), working at Georgetown University Medical Center, designed and inserted the first workable prosthetic heart valve in a man. The following year, Donald Murray (1894–1976) completed the first successful aortic valve homograft. At approximately the same time, Alfred Blalock, professor of surgery at Johns Hopkins, working with Helen Taussig (1898– 1986), a pediatrician, and Vivien Thomas (1910–1985), director of the hospital’s surgical research laboratories, developed an operation for the relief of congenital defects of the pulmonary artery. The Blalock-Taussig-Thomas subclavian artery–pulmonary artery shunt for increasing blood flow to the lungs of a “blue baby” proved to be an important event in the rise of modern surgery. Not only was it a pioneering technical accomplishment, but it

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SECTION I  Surgical Basic Principles

FIG. 1.17  Michael DeBakey (1908–2008).

FIG. 1.16  John H. Gibbon, Jr. (1903–1973).

also managed to give many very ill children a relatively normal existence. The salutary effect of such a surgical feat, particularly its public relations value, on the growth of American surgery cannot be overstated. Despite mounting successes, surgeons who operated on the heart had to contend not only with the quagmire of blood flowing through the area of dissection but also with the unrelenting to-and-fro motion of a beating heart. Technically complex cardiac repair procedures could not be developed further until these problems were solved. John H. Gibbon, Jr. (1903–1973) (Fig. 1.16), addressed this problem by devising a machine that would take on the work of the heart and lungs while the patient was under anesthesia, in essence pumping oxygen-rich blood through the circulatory system while bypassing the heart so that the organ could be more easily operated on. The first successful open-heart operation in 1953, conducted with the use of a heart-lung machine, was a momentous surgical contribution. The surgical treatment of coronary artery disease gained momentum during the 1960s, and by 1980, more cardiac operations were completed annually for coronary artery insufficiency than for all other types of cardiac disease. Although the performance of a coronary artery bypass procedure at the Cleveland Clinic in 1967 by René Favaloro (1923–2000) is commonly regarded as the first successful surgical approach to coronary artery disease, Michael DeBakey (1908–2008) (Fig. 1.17) had completed a similar procedure three years earlier but did not report the case until 1973. DeBakey is probably the best-known American surgeon of the modern era. He was a renowned cardiac and vascular surgeon, clinical researcher, medical educator, and international medical statesman as well as the long-time Chancellor of Baylor College of Medicine. He pioneered the use of Dacron grafts to replace

or repair blood vessels, invented the roller pump, developed ventricular assist devices, and created an early version of what became the Mobile Army Surgical Hospital (MASH) unit. DeBakey was an influential advisor to the federal government about health care policy and served as chairman of the President’s Commission on Heart Disease, Cancer, and Stroke during the Lyndon Johnson administration. As reported in SOSSUS, when cardiothoracic surgeons were queried about first-order advances in their specialty for the 1945 to 1970 time period, they selected cardiopulmonary bypass, open and closed correction of congenital cardiovascular disease, the development of prosthetic heart valves, and the use of cardiac pacemakers. Of second-order significance was coronary bypass for coronary artery disease. What about the replacement of damaged or diseased organs? Even in the mid-20th century, the thought of successfully transplanting worn-out or unhealthy body parts verged on scientific fantasy. At the beginning of the 20th century, Alexis Carrel had developed revolutionary new suturing techniques to anastomose the smallest blood vessels. Using his surgical élan on experimental animals, Carrel began to transplant kidneys, hearts, and spleens. His research was a technical success, but some unknown biologic process always led to rejection of the transplanted organ and death of the animal. By the middle of the 20th century, medical researchers began to clarify the presence of underlying defensive immune reactions and the necessity of creating immunosuppression as a method to allow the host to accept the foreign transplant. In the 1950s, using high-powered immunosuppressant drugs and other modern modalities, David Hume (1917–1973), John Merrill (1917–1986), Francis Moore, and Joseph Murray blazed the way with kidney transplants. In 1963, the first human liver transplant occurred; four years later, Christiaan Barnard (1922–2001) successfully completed a human heart transplant. 

DIVERSITY The evolution of surgery has been influenced by ethnic, gender, racial, and religious bias. Every segment of society is affected by such discrimination, particularly African Americans, women, and certain immigrant groups, who were victims of injustices that forced them into struggles to attain competency in surgery. In the 1930s, Arthur Dean Bevan (1861–1943), professor of surgery at Rush Medical College and an important voice in American surgery,

CHAPTER 1  The Rise of Modern Surgery: An Overview urged that restrictive measures be taken against individuals with Jewish-sounding surnames to decrease their presence in Medicine. It would be historically wrong to deny the long-whispered belief held by the Jewish medical community that anti-Semitism was particularly rife in general surgery before the 1950s compared with the other surgical specialties. In 1868, a department of surgery was established at Howard University. However, the first three chairmen all were white Anglo-Saxon Protestants. Not until 1928, when Austin Curtis (1868–1939) was appointed professor of surgery, did the department have its first African American head. Similar to all black physicians of his era, Curtis was forced to train at a so-called Negro hospital, Provident Hospital in Chicago, where he came under the tutelage of Daniel Hale Williams, the most influential and highly regarded of that era’s African American surgeons. With little likelihood of obtaining membership in the AMA or its related societies, African American physicians joined together in 1895 to form the National Medical Association. Black surgeons identified an even more specific need when the Surgical Section of the National Medical Association was created in 1906. From its start, the Surgical Section held “hands-on” surgical clinics, which represented the earliest example of organized, so-called “show me” surgical education in the United States. When Williams was named a Fellow of the American College of Surgeons in 1913, the news spread rapidly throughout the African American surgical community. Still, applications of African American surgeons for the American College of Surgeons were often acted on slowly, which suggests that denials based on race were clandestinely conducted throughout much of the United States. In the mid-1940s, Charles Drew, chairman of the Department of Surgery at Howard University School of Medicine, acknowledged that he refused to accept membership in the American College of Surgeons because this supposedly representative surgical society had, in his opinion, not yet begun to accept routinely capable and well-qualified African American surgeons. Strides toward more racial equality within the profession have been taken since that time, as noted in the career of Claude H. Organ, Jr. (1926–2005) (Fig. 1.18), a distinguished editor, educator, and historian. Among his books, the two-volume A Century of Black Surgeons: The U.S.A. Experience and the authoritative Noteworthy Publications by African-American Surgeons underscored the numerous contributions made by African American surgeons to the U.S. health care system. In addition, as the long-standing editor-inchief of the Archives of Surgery as well as serving as president of the American College of Surgeons and chairman of the American Board of Surgery, Organ wielded enormous influence over the direction of American surgery. One of the many overlooked areas of surgical history concerns the involvement of women. Until more recent times, options for women to obtain advanced surgical training were severely restricted. The major reason was that through the mid-20th century, only a handful of women had performed enough operative surgery to become skilled mentors. Without role models and with limited access to hospital positions, the ability of the few practicing female physicians to specialize in surgery seemed an impossibility. Consequently, women surgeons were forced to use different career strategies than men and to have more divergent goals of personal success to achieve professional satisfaction. Through it all and with the aid of several enlightened male surgeons, most notably William Williams Keen of Philadelphia and William Byford (1817–1890) of Chicago, a small cadre of female surgeons did exist in turn-of-the-century America, including

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FIG. 1.18  Claude H. Organ, Jr. (1926–2005).

Mary Dixon Jones (1828–1908), Emmeline Horton Cleveland (1829–1878), Mary Harris Thompson (1829–1895), Anna Elizabeth Broomall (1847–1931), and Marie Mergler (1851–1901). The move toward full gender equality is seen in the role that Olga Jonasson (1934–2006) (Fig. 1.19), a pioneer in clinical transplantation, played in encouraging women to enter the modern, maledominated world of surgery. In 1987, when she was named chair of the Department of Surgery at Ohio State University College of Medicine, Jonasson became the first woman in the United States to head an academic surgery department at a coeducational medical school. 

THE FUTURE History is easiest to write and understand when the principal story has already finished. However, surgery continues to evolve. As a result, drawing neat and tidy conclusions about the future of the profession is a difficult task fraught with ill-conceived conclusions and incomplete answers. Nonetheless, several millennia of history provide plentiful insights on where surgery has been and where it might be going. Throughout its rise, the practice of surgery has been largely defined by its tools and the manual aspects of the craft. The last decades of the 20th century and beginning years of the 21st century saw unprecedented progress in the development of new instrumentation and imaging techniques. Advancement will assuredly continue; if the study of surgical history offers any lesson, it is that progress can always be expected, at least relative to technology. There will be more sophisticated surgical operations with better results. Automation will robotize the surgeon’s hand for certain procedures. Still, the surgical sciences will always retain their historical roots as, fundamentally, a manually based art and craft. Despite the many advances, these refinements have not come without noticeable social, economic, and political costs. These dilemmas frequently overshadow clinical triumphs, and this suggests that going forward, the most difficult challenges of surgeons may

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SECTION I  Surgical Basic Principles Studying the fascinating history of our profession, with its many magnificent personalities and outstanding scientific achievements, may not help us predict the future of surgery. Recall Theodor Billroth’s remark at the end of the 19th century, “A surgeon who tries to suture a heart wound deserves to lose the esteem of his colleagues.” The surgical crystal ball is a cloudy one at best. However, to understand our past does shed some light on current and future clinical practices. Still, if history teaches us anything, it is that surgery will advance and grow inexorably. If surgeons in the future wish to be regarded as more than mere technicians, members of the profession need to appreciate the value of its past glories better. Study our history. Understand our past. Do not allow the rich heritage of surgery to be forgotten.

SELECTED REFERENCES Bishop WJ. The Early History of Surgery. London: Robert Hale; 1960. Bishop, a distinguished medical bibliophile, describes surgery from the Middle Ages through the 18th century.

FIG. 1.19  Olga Jonasson (1934–2006).

not be in the clinical realm but, instead, in better understanding the sociologic forces that affect the practice of surgery. The most recent years can be seen as the beginnings of a schizophrenic existence for surgeons in that newly devised complex and lifesaving operations are met with innumerable accolades, whereas criticism of the economics of surgery portrays the surgeon as a financially driven selfish individual. Although they are philosophically inconsistent, the very dramatic and theatrical features of surgery, which make surgeons heroes from one perspective and symbols of mendacity and greed from the opposite point of view, are the very reasons why society demands so much of surgeons. There is the precise and definitive nature of surgical intervention, the expectation of success that surrounds every operation, the short time frame in which outcomes are realized, the high income levels of most surgeons, and the insatiable inquisitiveness of lay individuals about every aspect of consensually cutting into another human’s flesh. These phenomena, ever more sensitized in this age of mass media and instantaneous communication, make surgeons seem more accountable than their medical colleagues and, simultaneously, symbolic of the best and worst in Medicine. In ways that were previously unimaginable, this vast economic, political, and social transformation of surgery controls the fate of the individual surgeon to a much greater extent than surgeons as a collective force can manage through their own profession. National political aims have become overwhelming factors in securing and shepherding the future growth of surgery. Modern surgery is an arena of tradeoffs, a balance between costs, organization, technical advances, and expectations. Patients will be forced to confront the reality that no matter how advanced surgery becomes, it cannot solve all the health-related problems in life. Society will need to come to terms with where the ethical lines should be drawn on everything from face transplants to robotized surgery to gene therapy for surgical diseases. The ultimate question remains: How can the advance of science, technology, and ethics be brought together in the gray area between private and public good?

Cartwright FF. The Development of Modern Surgery From 1830. London: Arthur Barker; 1967. An anesthetist at King’s College Hospital in London, Cartwright’s book is rich in detail and interpretation.

Earle AS. Surgery in America: From the Colonial Era to the Twentieth Century. New York, NY: Praeger; 1983. A fascinating compilation of journal articles by well-known surgeons that trace the development of surgery in America.

Ellis H. A History of Surgery. London: Greenwich Medical; 2001. Ellis is one of modern day’s most prominent surgeon/historians. Renowned for his elegant prose, this book educates and entertains the reader.

Hollingham R. Blood and Guts, a History of Surgery. New York, NY: Thomas Dunne; 2008.

.

Hollingham is a science journalist who weaves a compelling narrative of the key moments in surgical history.

Hurwitz A, Degenshein GA. Milestones in Modern Surgery. New York, NY: Hoeber-Harper; 1958. The numerous chapters contain a short biography and a reprinted or translated excerpt of each surgeon’s most important clinical contribution.

Lawrence C, ed. Medical Theory, Surgical Practice: Studies in the History of Surgery. London: Routledge; 1992. This short book looks critically at orthodox surgical history and discusses how the act of surgery became increasingly possible from the mid-17th century onward.

Leonardo RA. History of Surgery. New York, NY: Froben; 1943.

CHAPTER 1  The Rise of Modern Surgery: An Overview Leonardo RA. Lives of Master Surgeons. New York, NY: Froben; 1948. Leonardo RA. Lives of Master Surgeons; supplement 1. New York, NY: Froben; 1949. These texts by the eminent Rochester, New York, surgeon and historian provide an in-depth description of the whole of surgery, from ancient times to the mid-20th century. Especially valuable are the countless biographies of famous and near-famous scalpel bearers.

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Rutkow IM. Seeking The Cure: A History of Medicine in America. New York, NY: Scribner; 2010. Using biographic compilations, colored illustrations, and detailed narratives, these books explore the evolution of surgery, internationally and in the United States.

Schlich T, ed. The Palgrave Handbook of the History of Surgery. London, GB: Palgrave; 2018.

Meade RH. An Introduction to the History of General Surgery. Philadelphia, PA: WB Saunders; 1968.

An important and scholarly work that covers the cultural, social, and technical history of surgery with special attention to the established historiography.

Meade, an indefatigable researcher of historical ­ topics, proacticed surgery in Grand Rapids, Michigan. With an ­ extensive bibliography, this book is among the most ­ ­ambitious of such systematic works.

Thorwald J. The Century of The Surgeon. New York, NY: Pantheon; 1956. Thorwald J. The Triumph of Surgery. New York, NY: Pantheon; 1960.

Nuland SB. Doctors, The Biography of Medicine. New York, NY: Knopf; 1988.

In a most dramatic literary fashion, Thorwald uses a fictional eyewitness narrator to create continuity in the story of the development of surgery during its most important decades of growth, the late 19th and early 20th centuries.

Nuland, a general surgeon, was the author of “How We Die: Reflections on Life’s Final Chapter,” winner of the 1994 National Book Award for Nonfiction. “Doctors” is the fascinating story of the development of modern medicine but with a slant towards the surgical side.

Van de Laar A. Under The Knife: A History of Surgery In 28 Remarkable Operations. New York, NY: St.: Martin’s Press; 2018.

Porter R. The Greatest Benefit to Mankind, A Medical History of Humanity. New York, NY: WW Norton; 1997.

Van de Laar, a surgeon, provides a deft and incisive look into the history of his profession.

A wonderful literary tour de force by one of the most erudite and entertaining of modern medical historians. Although more a history of the whole of medicine than of surgery, this text has become an instantaneous classic and should be required reading for all physicians and surgeons.

Wangensteen OH, Wangensteen SD. The Rise of Surgery, From Empiric Craft to Scientific Discipline. Minneapolis, MN: University of Minnesota Press; 1978.

Ravitch MM. A Century of Surgery: 1880–1980, the History of the American Surgical Association. Philadelphia, PA: JB Lippincott; 1981. Ravitch’s text provides a year-by-year account of the meetings of the American Surgical Association, once the most influential of America’s surgical organizations.

Richardson R. The Story of Surgery: An Historical Commentary. Shrewsbury. London, GB: Quiller Press; 2004. An absorbing account of surgical triumphs written by a physician turned medical historian.

Rutkow IM. The History of Surgery in The United States, 1775– 1900. San Francisco, CA: Norman Publishing; 1988. 1992. Rutkow IM. Surgery, An Illustrated History. St. Louis, MO: Mosby–Year Book; 1993. Rutkow IM. American Surgery, An Illustrated History. Philadelphia, PA: Lippincott-Raven; 1998. Rutkow IM. Bleeding Blue and Gray: Civil War Surgery and The Evolution of American Medicine. New York, NY: Random House; 2005.

Not a systematic history but an assessment of various operative techniques and technical achievements that contributed to or retarded the evolution of surgery. Wangensteen was a noted professor of experimental and clinical surgery at the University of Minnesota; his wife was an esteemed medical historian.

Young A. Scalpel, Men Who Made Surgery. New York, NY: Random House; 1956. This easy-to-read book tells surgery’s story through the lives of the men who brought about advances in surgical knowledge, specifically, the control of hemorrhage, the control of pain, the control of infection, and the control of shock.

Zimmerman LM, Veith I. Great Ideas in the History of Surgery. Baltimore, MD: Williams & Wilkins; 1961. A unique book that provides well-written biographic narratives to accompany numerous readings and translations from the works of almost fifty renowned surgeons of varying eras.

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CHAPTER

Ethics and Professionalism in Surgery Jeffrey S. Farroni, William J. Winslade

OUTLINE Ethical Frameworks A General Approach for Ethical Issue Resolution Physician–Patient Relationship “The intimacy between patient and surgeon is short-lived, but closer than between a son and his own father.” Aleksandr Solzhenitsyn, Cancer Ward

The privilege of opening the body of another to manipulate, remove, repair, or implant is a profound endeavor for both the surgeon and patient. The medical team viscerally bears witness to parts of the body the patient never sees. The surgeon’s practice, a culmination of extensive technical training, skill, and technology, renders the patient better off for the experience of being pierced, cut, and violated. High expectations and responsibilities are imposed upon the surgeon due, in part, to the rich history and current elevation in social standing of medical practice. Physician and author Brian Goldman analogizes these expectations to baseball. While referring to a legendary hitter as one with a batting average of 0.400, he poses the question: “What do you think a batting average for a cardiac surgeon or a nurse practitioner or an orthopedic surgeon, an OBGYN, or a paramedic is supposed to be?”1 The purpose of his inquiry is to highlight the high expectations of perfection; of batting 1.000. Patients do not want to be the exception, the mistake, or the error. These pressures are not new, in fact, accountability in medical practice has existed since the dawn of recorded history. The ∼4,200 year-old Persian Code of Hammurabi includes schedules of income-based payment and penalties for unsuccessful treatments.2 Documents from the Ottoman Empire in the sixteenth and seventeenth centuries indicate expectations for treatment, fees, and provision of postoperative care.3,4 Threads that connect ancient wisdom and modern practice include trust, vulnerability, and responsibility. Values such as elevating the patient’s benefit above one’s own interest, fidelity to one’s profession, and commitment to training echo through time, from the Hippocratic Oath to codification into professional standards such as the American College of Surgeons’ Code of Professional Conduct. In the latter, more contemporary notions of disclosure and informed consent arise.5 Entering the surgical profession means that one becomes part of its history, participates in its value-laden decisions that profoundly impacts people’s lives, and contributes to its future innovation. Medicine is as much a moral endeavor as it is a technical one and, as such, we need to reflect upon ways to analyze ethical dilemmas during the course of practice.

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Surgical Training and Innovation Conclusion

ETHICAL FRAMEWORKS The focus on ethical issues and moral ambiguity in healthcare is due to the increase in technology, our ability to keep bodies alive, and the need to have a reflective and systematic way for us to navigate these dilemmas. One of the most popular conceptions of clinical ethics is that practice should be guided by principles (i.e., autonomy, beneficence/nonmaleficence, and justice).6 These terms have become familiar to many clinicians and provide a foundational framework to consider when contemplating appropriate medical care. An example of honoring a patient’s autonomy is through the informed consent process by which the team bears the responsibility to provide sufficient information on treatment (or research) options so that the patient himself/herself can decide what is best for him/ her based upon his/her values, preferences, and goals. Autonomy, or right to self-determination, is often recognized as a dominant principle in Western culture. However, we must appreciate that we live in an increasingly mobile and diverse global community. Sensitivity to cultural practices and traditions may require us to not necessarily place the individual at the center of concern. While striving for proficiency in cultural competence is a worthwhile endeavor, we cannot not forget to engage with the individual.7 Having direct conversations and inviting the patient to indicate how best they wish to be informed is a good way to ensure their autonomy is respected. Beneficence and nonmaleficence are often contemplated together in the form of balancing the provision of benefit with mitigating risks/harms to the patient. The Hippocratic notion of primum non nocere is often invoked as a maxim to convey our commitment to the care and healing of the patient. Clinical risk:benefit analyses should be contextualized to the patient’s goals of care (e.g., the therapeutic options that may offer the “best” clinical outcomes may not be what the patient prefers based upon other considerations). The final principle is justice, or fairness. We typically think of justice in terms of equitable access to care, even distribution of health benefits and outcomes across society, and nondiscriminatory treatment.8 At a patient level, an appeal to justice would have the individual practitioner not succumb to the judgments of social worth, to consciously or unconsciously impose stigma based upon race, gender, socioeconomic, mental health status, addiction, country of origin, etc. Taken together, the principles of autonomy, beneficence, nonmaleficence, and justice are the foundational elements by which we view ethical issues.

CHAPTER 2  Ethics and Professionalism in Surgery TABLE 2.1  Examples of moral frameworks. MORAL FRAMEWORK

GUIDING PRINCIPLES

Consequentialism Utilitarian Common good

Results of Action Maximize the good with the least harm Maximize the good of the whole; mindful of the vulnerable

Nonconsequentialism Duty-based

Intentions of the Agents Moral obligations are binding irrespective of consequences; the categorical imperative The best action is the one that protects the rights of those affected by the action Social contract, equity

Rights Fairness Agent-Centered Virtue Feminist

Overall Status of the Individual Good ethical decision-making is based upon good character Particularly focused on gender-related oppression and the perspectives of the vulnerable and marginalized; ethics of care

However, principlism is only one framework within which we can analyze ethical questions in medicine. There are a number of moral traditions one may employ to broaden and enrich reflection on an ethical dilemma. Changing one’s perspective can provide different insights into the resolution of a quandary whether it be from the character of each agent (virtue), the act or duty (deontology), or the results (consequentialism) (see Table 2.1). Each framework will have its utility and caveats, but deeper reflection may provide a more robust understanding of the issue at hand. Some have argued ethical inquiry should be “a synthesis of theory and experience, reason and emotion, and philosophy and rhetoric.”9 What we may strive for is “getting beyond an overreliance upon a single approach…to remind us that ethical problems do not simply have a logic—they have a history; they have narrative meaning; and they occur within a social and cultural context.”10 With respect to qualities of character, renowned physician bioethicist, Edmond Pellegrino, indicated that essential virtues of medical practice include fidelity to trust, suppression of self-interest, intellectual honesty, compassion, courage, and prudence.11 The recognition of qualities that are inherent to the practice of medicine underscores the privileged space by which the physician is allowed to enter and the responsibility bestowed upon them.12 Another mechanism for ethical inquiry is casuistry or case-based analysis. In this method, one would attempt to derive principles from previously resolved cases and apply them to the issues or conflicts at hand.13,14 Problems may arise when attempting to abstract grand notions from a single or handful of instances; however, an advantage of a casuistic approach is that it is steeped in clinical reality, which may offer concrete, pragmatic solutions to ethical dilemmas.14 Whichever moral framework resonates with the physician, it can be helpful to have a general approach to ethical dilemmas which encourages practical thinking and reflection. 

A GENERAL APPROACH FOR ETHICAL ISSUE RESOLUTION 1. R  ecognizing a Need for Ethical Inquiry We are constantly making judgments, often unconsciously, ranging from the mundane, for example, deciding what to eat for

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lunch, to the life-changing, for example, what treatment modality am I going to recommend to my patient? The foundation of our practice is built upon judgement through training, knowledge, and experience as well as our own agency, values, and principles. Most of the time we do not even think about the ethical milieu that underpins our actions; for example, the patient comes to you with a problem, you offer a solution, the patient agrees, and hopefully all goes well. However, there are times when real conflicts arise and it may be unclear as to the preferred course of action, where technical training or experience fails to provide a concrete solution to an issue. Examples include when to consider the transition from curative intervention to palliative, encountering a colleague whose ability/judgment appears compromised, or a patient, who by your estimation, is making decisions that seem irrational or imprudent. These are all situations in which uncertainty can impose significant moral distress. It may seem an obvious point, but the initial step in analyzing an ethical dilemma is the recognition that there exists value conflict or moral ambiguity either in the patient’s care, within/ between the care team(s), or in the organization/operation of the health care facility. The next step is to then take action in gathering the necessary information to resolve the issue. 2. Collecting Significant Facts and Understanding the Perspectives of Relevant Stakeholders One useful, and most commonly used, tool to collect relevant information to analyze an ethical dilemma is the four topics method, which captures information within the domains of medical indications, patient preferences, quality-of-life factors, and contextual features (Table 2.2).15 Sometimes we may focus on the clinical disposition of the patient when there are other externalities that may be impacting the patient’s decision-making process. What we may identify as the clear medical recommendation may not be greeted with enthusiasm by the patient due to other circumstances. A conversation with the patient that delves into illuminating their values, preferences, motivations, etc. may reveal key insights that will aid in facilitating a solution to the dilemma. The four topics method includes prompts to consider within each domain that may evoke pertinent information. It is important to speak with all relevant parties involved in the dilemma, including other team members, other services, and significant family and loved ones, if appropriate. Reflecting upon a diversity of perspectives and opinions is a thorough approach to complex, value-laden issues. 3. Identify the Ethical Issues/Values at Conflict After pertinent information has been gathered, the next step is to identify which principles or values may be in conflict. The four topics method mentioned above maps each category of information to the ethical principles. Itemizing conflicting principles or competing obligations/duties will help formulate a spectrum of ethically appropriate options. Those options can then be prioritized into those that are ethically obligatory, ethically permissible, and ethically prohibitive. For example, abandoning the patient would clearly be ethically prohibitive, and ensuring the patient’s voice is heard or not denying basic care and hygiene would be things that are ethically obligatory. Often, the challenge is selecting options that are ethically permissible as there may be disagreement as to which option(s) is(are) the “right” one(s) with which to move forward. 4. Discuss Options and Develop a Plan Emerging from the previous step with a selected set of options, stakeholders are reengaged when the plan to move forward is realized. Generally, it would be advisable for the team to be on the

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SECTION I  Surgical Basic Principles

TABLE 2.2  The four topics commonly used to analyze ethical dilemmas in health care. TOPIC

ETHICAL PRINCIPLE(S)

CONSIDERATIONS

Medical Indications

Beneficence Nonmaleficence

• What is the patient’s medical problem? Is the problem acute? Chronic? Critical? Reversible? Emergent? Terminal? • What are the goals of treatment? • In what circumstances are medical treatments not indicated? • What are the probabilities of success of various treatment options? • In sum, how can this patient be benefited by medical and nursing care, and how can harm be avoided?

Patient Preferences

Respect for Autonomy

 as the patient been informed of benefits and risks of diagnostic and treatment • H recommendations, understood this information, and given consent? • Is the patient mentally capable and legally competent, and is there evidence of incapacity? • If mentally capable, what preferences about treatment is the patient stating? • If incapacitated, has the patient expressed prior preferences? • Who is the appropriate surrogate to make decisions for the incapacitated patient? What standards should govern the surrogate’s decisions? • Is the patient unwilling or unable to cooperate with medical treatment? If so, why?

Quality of Life

Beneficence Nonmaleficence Respect for Autonomy

•  What are the prospects, with or without treatment, for a return to normal life, and what physical, mental, and social deficits might the patient experience even if treatment succeeds? • On what grounds can anyone judge that some quality of life would be undesirable for a patient who cannot make or express such a judgment? • Are there biases that might prejudice the provider’s evaluation of the patient’s quality of life? • What ethical issues arise concerning improving or enhancing a patient’s quality of life? • Do quality-of-life assessments raise any questions regarding changes in treatment plans, such as forgoing life-sustaining treatment? • Are there plans to provide pain relief and provide comfort after a decision has been made to forgo life-sustaining treatment? • Is medically assisted dying ethically or legally permitted? • What is the legal and ethical status of suicide?

Contextual Features

Justice (Fairness)

• Are there professional, interprofessional, or business interests that might create conflicts of interest in the clinical treatment of patients? •  Are there parties other than clinicians and patients, such as family members, who have an interest in clinical decisions? • What are the limits imposed on patient confidentiality by the legitimate interests of third parties? • Are there financial factors that create conflicts of interest in clinical decisions? • Are there problems of allocation of scarce health resources that might affect clinical decisions? • Are there religious issues that might affect clinical decisions? • What are the legal issues that might affect clinical decisions? • Are there considerations of clinical research and education that might affect clinical decisions? • Are there issues of public health and safety that affect clinical decisions? • Does institutional affiliation create conflicts of interest that might influence clinical decisions?

From Jonsen AR, Siegler M, Winslade WJ. Clinical ethics: a practical approach to ethical decisions in clinical medicine. 8th ed. New York: McGrawHill Education; 2015.

same page with regard to a treatment plan (if that is the issue) prior to sitting down with the patient and/or family. Having a unified presentation typically provides for a more productive meeting than if the team(s) are debating issues in front of the family. 5. Implement Decisions and Reflect Upon Outcomes The final step is to realize the plan of action. An important consideration here is to have the tolerance for uncertainty. “The best laid schemes of mice and men, go often askew…”16 Words from an old Scottish poem ring true here as even despite careful reflection, consideration, and planning, things may not proceed as envisioned. Taking the time to contemplate how events could have been better planned, thinking about alternative scenarios, or contingency planning may better prepare for future care needs of the patients and/or refine one’s thinking should a similar case present itself in the future. See Box 2.1 for a scenario that highlights this process.17 

PHYSICIAN–PATIENT RELATIONSHIP The vulnerability of illness and injury, the potential impact of interventions, and the inherent power disparity of the physician– patient relationship imposes mindfulness of one’s moral agency in the practice of medicine. Patient care is as much a moral enterprise as it is a technical one. The relationship between a physician and the patient has changed over the course of the last 50 years since the dawn of the patient’s rights movement. Our jurisprudence has recognized a right to refuse treatment18 as well as to allow others to consent or refuse treatment on behalf of an incapacitated patient.19 As the pendulum has swung away from paternalistic medicine toward respecting the right of patients to do with their bodies as they see fit, a model of shared decision-making has emerged. This model incorporates the delivery of relevant medical information;

CHAPTER 2  Ethics and Professionalism in Surgery

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BOX 2.1  Ethics scenario—palliative surgery. Ms. Smith is a 78-year-old woman with advanced breast cancer who presents with a fungating malodorous lesion. The cancer is treatment-refractory and her current goals of care, in coordination with the palliative care team, include a focus on quality of life and comfort. She was referred to surgery for lesion resection. She is currently not receiving therapeutic interventions and has an Out-of-Hospital Do Not Resuscitate (DNR) order. Ms. Smith informs the team that someone told her the DNR order must be rescinded or she cannot have the procedure. Ms. Smith is unsure if she is willing to agree. Case Analysis: 1. Recognition The decision to offer Ms. Smith a surgical intervention may be complicated by reluctance to perform the procedure if she is imposing unreasonable restraints on its proper outcomes. 2. Facts Using the four topics method, we would consider whether or not the intervention is appropriate from a medical perspective. Clearly, Ms. Smith’s preference is to undergo the procedure to improve the quality of her life. Perhaps she wishes to comfortably interact with her family during her remaining time or maybe she is embarrassed by the smell and feels family will not attend to her. Contextual features could include liability exposure if the team agrees to not resuscitate her and she dies during the procedure. Important perspectives to understand are those of Ms. Smith, the palliative team, the surgical team, and her family (if she consents). 3. Issue Conflict There is an obvious risk:benefit (nonmaleficence:beneficence) conflict in that the procedure may not be safe to perform or the team may feel unduly constrained by Ms. Smith’s DNR order. Ms. Smith’s autonomy interest is at stake in that she is willing to accept potential risks for the prospect of reducing her illness burden and, hopefully, enjoy a better quality of life. A team’s denial of this intervention is denying her that prospect.

4. Discuss/Plan The possible options include: do not offer surgery unless Ms. Smith agrees to full resuscitation; offer surgery with the explicit agreement and Ms. Smith’s consent that no attempts at resuscitation will be made during the procedure; reach an agreement with Ms. Smith that limited attempts at resuscitation can be made, if appropriate. The first option seeks to maximize outcomes by offering the most flexibility to the team but may impose interventions that are contrary to Ms. Smith’s goals of care. What if she would not want prolonged intubation because that would negate her desire to spend what time she has interacting with family? Then again, not having the procedure may also compromise her goals. The second option may best honor her preferences, but the team may be unwilling to agree to such a plan, particularly if a transient, relatively easily correctable condition manifests. A risk of requiring resuscitation is always present under anesthesia, and it may be reasonable for the team to not offer the intervention rather than allowing a patient to die on the table, even if the patient agreed to such risk. The third option offers a compromise in having a more nuanced conversation with Ms. Smith. Instead of an all-or-nothing approach, the team may offer limited interventions during the perioperative period that are defined by her goals and expectations.* After discussions with all relevant stakeholders, it was decided that Ms. Smith would rescind her DNR order allowing limited interventions during the time of the procedure and recovery. The order would then be reinstated. 5. Act/Reflect How did the case turn out? What could have been done differently, if anything?  For Further Consideration: • What if Ms. Smith is adamantly opposed to rescinding the DNR during the procedure? • Is there a policy solution for this dilemma and, if so, what would that policy be? • Would the intervention be appropriate if Ms. Smith did not have capacity and the family is asking for the surgery on her behalf? What if the family wants Ms. Smith to have surgery because it will make it easier for them to care for her?

*Sumrall WD, Mahanna E, Sabharwal V, et al. Do not resuscitate, anesthesia, and perioperative care: a not so clear order. Ochsner J. 2016;16:176–179.

an explanation of treatment options (including no treatment); an exploration of the patient’s values, preferences, and goals; and, finally, the decision-making process.20 With shared decisionmaking, the physician is not imposing treatment upon the patient nor is the patient demanding interventions; rather, it is patientdriven care facilitated through mutual understanding (Box 2.2). A question may arise as to whether or not ethics in surgery offers unique issues for consideration. One perspective answers this question affirmatively based upon the “moral domain of the surgeon–patient relationship” and categorizes five distinctive features of surgical practice: rescue, proximity, ordeal, aftermath, and presence.21 These five domains exemplify a surgeon’s power and the intimacy by which he/she participates in the destruction and rebuilding of a person. The patient is aware of, and the surgeon is accountable to, the immediate aftermath of the procedure. As such, ethical issues and moral ambiguity are worthwhile topics for reflection and consideration. 

SURGICAL TRAINING AND INNOVATION Surgical training is rooted in antiquity, adopting an apprenticeship model of experiential learning. There have been concerns that this training modality may be compromised with residency hour

restrictions and increased demands on operating room throughput and outcomes.22 An ethical tension may arise when patient expectations demand the “best” care or the most competent and skilled surgeon with the fact that no one begins practice as “the best.” There always exists the first cut, the first mistake, and the first complication. The same is true for innovative practice and advancing the profession; we have an essential need to refine and improve techniques and approaches. However, surgical intervention does not necessarily lend itself to randomized controlled trials as, say, a pharmaceutical agent. Surgical innovation relies upon not only technology, but also new techniques, approaches, and strategies. One ethical justification for surgical innovation involves the prudent balancing of laboratory background (animal experience), field strength, and institutional stability.23 For example, while technology involved in routine neurosurgical practice would not be possible without innovation, development of new techniques does not always follow a systematic framework.24 One approach is innovation, development, exploration, assessment, and long-term study.25,26 Innovation may also be facilitated through varying degrees of oversight based upon the purpose, risk, ethical issues, and safety.27 An ethical approach to surgery including the imperative to

24

SECTION I  Surgical Basic Principles

BOX 2.2  Ethics scenario—level of appropriate treatment. Mr. Johnson, 27 years -old, was involved in a highspeed motorcycle accident while not wearing a helmet. He suffered numerous broken bones and severe head trauma. He is on ventilator support, and there is no evidence of awareness of self or environment. He shows no evidence of sustained, reproducible, purposeful, or voluntary behavioral responses to visual, auditory, tactile, or noxious stimuli. His acetabulum has been shattered and, from a medical perspective, in need of repair. At the bedside, both his wife and brother indicate that Mr. Johnson would not want to live like this, that the surgery should not be done, and they would like the team to “pull the plug.” Mr. Johnson’s parents vigorously disagree, informing the team that he had a passion for life, he has a 5-year-old daughter to live for, and they cannot “give up” on him. The parents feel he would want everything done to preserve his life, including the surgery. Case Analysis: 1. Recognition There is much uncertainty if Mr. Johnson should undergo surgery. 2. Facts The clinical picture may not be clear as there may be reasonable differences in practice as to whether or not surgery is appropriate for Mr. Johnson. Typically, this type of injury would need to be repaired as soon as possible but his prognosis and prospect for recovery is uncertain. Perhaps a formal consult with Neurology would be helpful. Since we cannot ask Mr. Johnson’s preferences, it is important to speak with all relevant stakeholders. Here, it will be Mr. Johnson’s spouse, parents and brother. All of them know Mr. Johnson through very different perspectives. We presume they all have his best interests in mind, and they each articulate different aspects of his personality that may all be true. The challenge from the team will be to discern how much each member of his family are projecting their own preferences into the conversation. We must try to understand what Mr. Johnson would find to be either an acceptable or unacceptable quality of life. 2,3 3. Issue Conflict The primary conflict here is discerning Mr. Johnson’s treatment preferences, i.e., honoring his right to self-determination, with what others may feel are his best medical interests, i.e., balancing beneficence versus nonmaleficence. This conflict is embodied by two central issues: a) Who gets to serve as health care agent for Mr. Johnson? Without a directive, most States define a prioritized list of people who may serve as surrogate decision-maker. The policy behind these laws is that the

people who are closest to the patient, know them best and are in a position to help guide the team in making treatment decisions. For example, in most jurisdictions, the spouse would be the decision-maker. b) Should he have the surgery? Shared decision-making does not mean total acquiescence to the spouse. As noted in the chapter, we would discuss treatment options within the context of the patient’s preferences, values, and beliefs to reach a mutual understanding in the goals of care and the treatment plan. Everyone in the family is in a position to illuminate the team in this regard despite acknowledging that the spouse holds decision-making authority. 4. Discuss/Plan Possible options include proceeding with the surgery despite the surrogate indicating otherwise, deferring the surgical option while gathering more facts or refusing to consider surgery, which will satisfy the spouse and brother but marginalize the parents input. The first option would be difficult to justify on the basis of the facts. The second option offers a measured approach with a couple of advantages, namely, it may provide more information that may clarify the course of action (e.g., screen for death by neurological criteria) and it affords more time to engage the family. It may be asking too much during the immediacy of this tragedy for the family to entertain endof-life decisions. The tincture of time may be necessary to facilitate goals of care with active listening, empathy, and trust building. For this reason, the third option may not be ideal either. The outright rejection may be misinterpreted as abandonment. 5. Act/Reflect How did the case turn out? What could have been done differently?  For Further Consideration: • Would this case have been easier if Mr. Johnson had a directive to physicians? What if Mr. Johnson’s surrogate decision-maker was requesting interventions that his directives clearly indicated he did not want? • How important is the concept of dignity in cases like this, if at all? • Would your perspective on this case change if the parents were malpractice attorneys? • Would it be acceptable to attempt surgical intervention, in part, because it offers a good training opportunity?

From Schneiderman LJ, Jecker NS, Jonsen AR. Medical futility: its meaning and ethical implications. Ann Intern Med. 1990;112:949–954; and Jox RJ, Schaider A, Marckmann G, et al. Medical futility at the end of life: the perspectives of intensive care and palliative care clinicians. J Med Ethics. 2012;38:540–545.

improve practice yet progress for its own sake is an insufficient rationale. It must be conducted in a way that protects patients, offers the prospect of benefit, and is conducted with the proper checks and balances. 

CONCLUSION It has been two decades since the Institute of Medicine (now the National Academy of Medicine) released their report identifying causes of patient deaths related to medical error and proposed solutions to creating safer health care systems.28 The increasing emphasis on patient safety and satisfaction in the service of not just better outcomes, but also increasingly slim profit margins, has culminated in higher demands on the health care team. Increasing focus on revenue value units, quality metrics, and resource allocation have driven a corporatization of medical care

that has arguably dehumanized medical practice to an extent. Consequences of this expanded professional distance includes a rise in provider stress, burnout, substance abuse, suicide, and compassion fatigue. Amongst all these performance and institutional pressures, the surgeon is left to care for his/her patient, as mentioned previously, without failure. Fallibility almost seems to be something that is impermissible to discuss openly. Additionally, surgery is a discipline that can carry negative stereotypes with the public that are not representative of its increasing diversity and inclusivity.29 Again, we return to the idea that the challenges facing physicians today have reverberated through history and are not insurmountable. What it may mean is that becoming a “complete surgeon” will be through not only technical mastery but also by the embodiment of the “great doctor” who is an effective communicator, worthy of a patient’s trust.30

CHAPTER 2  Ethics and Professionalism in Surgery

SELECTED REFERENCES Bosk CL. Forgive and Remember: Managing Medical Failure. 2nd ed. Chicago, IL: University of Chicago Press; 2003. A sociologist’s classic examination on the training and professionalization of surgeons.

Cassel EJ. The nature of suffering and the goals of medicine. N Engl J Med. 1982;306:639–645. A seminal article on the definition of suffering, its distinction from pain, and how we can broaden how we view our patients and increase our capacity for empathy.

Farmer P. Pathologies of Power: Health, Human Rights, and the New War on the Poor. Berkeley: University of California Press; 2004. A physician/medical anthropologist’s personal perspective on global health, human rights, and social justice.

Ferreres AR, Angelos P, Singer EA. Ethical Issues in Surgical Care. Chicago, IL: American College of Surgeons; 2017. An excellent resource for further information on the topics discussed in this chapter.

Jonsen AR, Siegler M, Winslade WJ. Clinical Ethics: A Practical Approach to Ethical Decisions in Clinical Medicine. 8th ed. New York, NY: McGraw-Hill Education; 2015. This book sets the standard for how to approach ethical dilemmas and their resolution.

Kalanithi P. When Breath Becomes Air. New York, NY: Random House; 2016. A neurosurgical resident’s posthumously published account of his illness journey with metastatic lung cancer.

Selzer R. Letters to a Young Doctor. New York, NY: Simon & Schuster; 1982. Insightful musings from an accomplished surgeon–writer.

Solzhenitsyn A. Cancer Ward. New York, NY: Farrar, Straus and Giroux; 1968. Literature Nobel laureate’s depiction of a provincial Soviet hospital. Although a complex sociopolitical polemic, the novel offers stirring perspectives of patient care through the lenses of surgeons, radiologists, nurses, and patients.

REFERENCES 1. Goldman B. Doctors make mistakes, can we talk about that? TED (TEDxToronto2010) website. https://www.ted.com/tal ks/brian_goldman_doctors_make_mistakes_can_we_talk_ab out_that. Accessed February 6, 2019. 2. Holmes B. The most ancient medical practice laws. The code of Hammurabi, 2200 B. C. JAMA. 1905;XLIV:293–294.

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3. Ajlouni KM. History of informed medical consent. Lancet. 1995;346:980. 4. Selek S. A written consent five centuries ago. J Med Ethics. 2010;36:639. 5.  American College of Surgeons. Statements on Principles. American College of Surgeons; 2016:19–34. 6. Beauchamp TL, Childress JF. Principles of Biomedical Ethics. 7th ed. New York, NY: Oxford University Press; 2013. 7. Epner DE, Baile WF. Patient-centered care: the key to cultural competence. Ann Oncol. 2012;23(suppl 3):33–42. 8. Rawls J. A Theory of Justice. Cambridge, MA: Belknap Press; 1971. 9. Carter MA. A synthetic approach to bioethical inquiry. Theor Med Bioeth. 2000;21:217–234. 10. Brody H. Literature and bioethics: different approaches? Lit Med. 1991;10:98–110. 11. Pellegrino ED. The internal morality of clinical medicine: a paradigm for the ethics of the helping and healing professions. J Med Philos. 2001;26:559–579. 12. MacIntyre AC. After Virtue : A Study in Moral Theory. 3rd ed. Notre Dame: University of Notre Dame Press; 2007. 13. Jonsen AR, Toulmin S. The Abuse of Casuistry : A History of Moral Reasoning. Berkeley: University of California Press; 1988. 14. Arras JD. Getting down to cases: the revival of casuistry in bioethics. J Med Philos. 1991;16:29–51. 15. Jonsen AR, Siegler M, Winslade WJ. Clinical Ethics : A Practical Approach to Ethical Decisions in Clinical Medicine. 8th ed. New York: McGraw-Hill Education; 2015. 16. Burns R. Poems, Chiefly in the Scottish Dialect. 1st ed. Edinburgh: William Creech of Edinburgh 1787. 17. Deleted in review. 18. In the matter of Karen Quinlan. Atl Report. 1976;355:647–672. 19. Director Cruzan v. Missouri Department of Health: US: U.S. Supreme Court. U.S. Reports. 1990;497:261–357. 20. Beers E, Lee Nilsen M, Johnson JT. The role of patients: shared decision-making. Otolaryngol Clin North Am. 2017;50:689–708. 21. Little M. Invited commentary: is there a distinctively surgical ethics? Surgery. 2001;129:668–671. 22. Holt G, Nunn T, Gregori A. Ethical dilemmas in orthopaedic surgical training. J Bone Joint Surg Am. 2008;90:2798–2803. 23. Moore FD. Ethical problems special to surgery: surgical teaching, surgical innovation, and the surgeon in managed care. Arch Surg. 2000;135:14–16. 24. Muskens IS, Diederen SJH, Senders JT, et al. Innovation in neurosurgery: less than IDEAL? A systematic review. Acta Neurochir (Wien). 2017;159:1957–1966. 25. McCulloch P, Cook JA, Altman DG, et al. IDEAL framework for surgical innovation 1: the idea and development stages. BMJ. 2013;346:f3012. 26. McCulloch P, Altman DG, Campbell WB, et al. No surgical innovation without evaluation: the IDEAL recommendations. Lancet. 374:1105–1112. 27. Gupta S, Muskens IS, Fandino LB, et al. Oversight in surgical innovation: a response to ethical challenges. World J Surg. 2018;42:2773–2780. 28. Kohn LT, Corrigan JM, Donaldson MS. To Err is Human: Building a Safer Health System. Washington, DC: National Academy Press; 2000. 29. Logghe HJ, Rouse T, Beekley A, et al. The Evolving Surgeon Image. AMA J Ethics. 2018;20:492–500. 30. Angelos P. Surgical ethics and the future of surgical practice. Surgery. 2018;163:1–5.

3

CHAPTER

The Inflammatory Response Katherine E. Kramme, Patrick H. Knight, Robert G. Sawyer

OUTLINE Components of the Inflammatory Response Cells of the Immune System Innate Immunity Complement System Adaptive Immunity The Nervous System and Immunity Inflammation and the Critically Ill Historical Perspective

The inflammatory response occurs following invasion by foreign microbes with direct tissue injury or in response to systemic stress such as hypothermia or hypotension. Multiple cellular pathways function simultaneously in an attempt to limit further injury and spur healing. While localized inflammatory response can be beneficial, major bodily insult can result in a dysregulated, inappropriate inflammatory response. The outcome can be catastrophic. It has become evident that the body’s response to injury is often as important a determinant in patient outcomes as the initial injury itself. Surgeons exist in a world of acute and chronic inflammatory response. The mechanisms regulating initiation, mitigation, and potentiation of the inflammatory response are critical to understanding the many phenotypes of a patient with a local reaction to surgery, systemic inflammatory response syndrome (SIRS), multisystem organ failure, and chronic critical illness.

COMPONENTS OF THE INFLAMMATORY RESPONSE The immune system is comprised of multiple cellular lineages, hormones, and signaling molecules functioning simultaneously. The balance between pro- and antiinflammatory pathways is essential for healing.

Cells of the Immune System Neutrophils The neutrophil, a type of polymorphonuclear (PMN) leukocyte, is a potent mediator of acute inflammation and often the first cell type recruited in response to injury and infection. As a circulating PMN leukocyte, neutrophils have a short half-life of approximately 8 hours; the longevity of the neutrophil is increased in response to inflammatory signals, although the exact duration is a topic

26

Systemic Inflammatory Response Syndrome Compensatory Antiinflammatory Response Genomics and Understanding Inflammation Diagnosis and Immunotherapy in Sepsis Multiple Organ Failure Persistent Inflammation, Immunosuppression, and Catabolism Syndrome

of debate. Neutrophils are continuously produced in the bone marrow in response to granulocyte colony-stimulating factor (GCSF), and their production is regulated by interleukin (IL)-17 from T-cells and IL-23 from macrophages. The neutrophil undergoes a process of tethering, rolling, adhesion, crawling, and transmigration to move from the bloodstream to the tissue (Fig. 3.1). Neutrophils contain three types of proinflammatory granules – azurophilic (primary) granules, specific (secondary) granules, and gelatinase (tertiary) granules. Proteolytic contents of these granules can be released extracellularly or into the intracellular phagosome to aid elimination of invading microbes. Neutrophils also release fiber meshwork to which histones, proteins, and enzymes adhere; this is the neutrophil extracellular trap (NET). Extracellular pathogens are trapped within the NET to prevent spread of the pathogen and aid phagocytosis.1 Although classically considered a key mediator of the initial inflammatory response, the functions of the neutrophil have been shown to extend beyond the acute inflammatory period. The neutrophil granules contain a number of proteases that are essential for tissue remodeling and wound healing. They directly stimulate angiogenesis via release of vascular endothelial growth factors (VEGFs). In addition, neutrophils display plasticity, and, although typically proinflammatory, antiinflammatory subsets of neutrophils have been identified in certain pathologic states.1  Macrophages Named for its ability to consume and degrade extracellular debris, the macrophage is a key player in innate immunity. Monocytes, the precursor to the macrophage, differentiate into macrophages in response to infection and tissue injury. Not displayed on immature monocytes, the macrophage expresses a large array of pattern

CHAPTER 3  The Inflammatory Response

27

Neutrophil Integrin

Selectin receptor

Endothelial cell

Tethering

Rolling and integrin activation

Firm adhesion Transmigration

E-selectin

n Selectin expression ICAM Inflammatory stimulus

Extracellular matrix

FIG. 3.1  Neutrophil recruitment and migration from the blood to the peripheral tissue. Once activated by an inflammatory signal, endothelial cells upregulate expression of adhesion molecules or selectins. Neutrophils bind selectins and roll along the endothelial cell. Integrins on the neutrophil surface interact tightly with intracellular adhesion molecules (ICAM) on the endothelial cell. Expression of molecules such as cadherin and platelet endothelial cell adhesion molecule (PECAM) facilitate transmigration into the periphery. (Adapted from Ouellete Y. Pediatric Critical Care. Philadelphia, PA: Elsevier, Inc; 2017.)

recognition receptors (PRRs) – receptors that recognize a variety of intracellular and extracellular danger signals. In response to PRR stimulation, macrophages neutralize, invading pathogens via phagocytosis and lysosomal degradation; they additionally secrete proinflammatory mediators, including IL-1β and tumor necrosis factor-α (TNF-α) that recruit other immune cells to the damaged tissue. Macrophages also process antigenic substances and present them on their surface to help stimulate the differentiation of helper T cells; thus, macrophages are professional antigen-presenting cells (APCs).2 Similar to neutrophils, once thought to be a single cell type, the macrophage demonstrates plasticity and phenotypic variance depending upon its environment. M1 macrophages express proinflammatory cytokines and proteolytic substances; they are predominant in viral and bacterial infection. M1 macrophages stimulate proinflammatory helper T cells. While M1 macrophage products facilitate a beneficial inflammatory response against invading microbes, they can result in a dangerous inflammatory state for the human host. High concentrations of M1-type cytokines correlate with mortality in sepsis models. M2 macrophages are essential for tissue remodeling and wound healing; they express a variety of antiinflammatory markers, including IL-10.2 Macrophages are abundant throughout the body. Their functions vary depending on the tissue in which they reside. For example, Kupffer cells of the liver and microglia of the central nervous system are macrophages.  Dendritic Cells Dendritic cells bridge the innate and adaptive immune response as the major professional APC. Upon encountering foreign material, the dendritic cell will engulf and degrade pathogen-derived proteins. These antigenic proteins are loaded onto a major histocompatibility (MHC) complex class I or class II molecule. The antigenMHC complex is transported to the surface of the dendritic cell,

and the dendritic cell travels from the tissue to the lymphoid organs, primarily the lymph nodes, and the spleen. Within the lymphoid organs, it stimulates naïve, resting T cells to differentiate into either cytotoxic T cells or helper T cells.3 Extracellular proteins are processed within the dendritic cell lysosome, and they are presented in conjunction with the MHC class II molecule to activate CD4+ helper T cells. In contrast, intracellular proteins are processed within the cytosol by the proteasome, and they are presented via the MHC class I molecule to CD8+ cytotoxic T cells. Certain subsets of dendritic cells, however, process extracellular proteins through a process called cross-presentation and allow for presentation of these molecules via MHC class I. Through the process of MHC-antigen presentation, the adaptive immune response begins.4 Dendritic cells additionally stimulate T cell activity via surface ligands, such as CD80 and CD86, and via production of proinflammatory cytokines, such as IL-12. As a result of its many costimulatory mechanisms, dendritic cells are highly efficient at provoking the adaptive immune response. While macrophages and B cells are also considered APCs, they do not function at this level of efficiency for adaptive immune stimulation.3 Dendritic cells also process self-antigens and nonpathogenic antigens. Presentation of this antigen type to a naïve T cell induces the regulatory T cell – an immunosuppressive type cell essential for tolerance and immune homeostasis. Disorders of this pathway result in autoimmunity to self-antigens and allergy response against nonpathogenic environmental material. The fact that dendritic cells use similar machinery both to induce an active immune response to foreign pathogens and to induce a tolerant response toward self-antigens is an interesting paradox and an area of interest in cancer immunobiology. Tumor cells can be considered master evaders of the immune system. One of their many and only partially understood mechanisms of immune evasion is via inhibition of dendritic cell function.3 

28

SECTION I  Surgical Basic Principles

T Cell T and B lymphocytes are the primary effector cells of the adaptive immune system; T cells are the primary effector cell of the cellular immune response, while B cells primarily mediate the humoral immune response. T and B cells are unique in their ability to recognize specific antigens and rapidly respond through clonal expansion. T and B cells are essential for the development of immune memory. T cell activation is a complex, multifaceted process. It can be simplified to three key steps. While keeping in mind that activation of the immune system is not a linear process (multiple events involving multiple cell types take place simultaneously) there are many branch points within the pathway that influence the ultimate outcome. Once transported to the lymphoid organs, mature dendritic cells present antigen-MHC complexes to naïve T cells. Antigens derived from cytosolic proteins are presented via the MHC class I molecule; the antigen-MHC class I complex activates CD8+ cytotoxic T cells. Antigens derived from extracellular proteins are presented via the MHC class II molecule; the antigen-MHC class II complex activates CD4+ helper T cells. Whereas MHC class I molecules can be found on all nucleated cells, MHC class II is confined to APCs. Although consistent with classic teaching, emerging research indicates that the formation of antigen-MHC complexes is not so straight forward. Recent studies have shown that activation of certain PRRs can alter whether a protein is loaded onto an MHC class I or MHC class II receptor following uptake. For example, toll-like receptor 4 (TLR4) is a PRR most famous for its role in recognizing lipopolysaccharide, a key component of the cell wall of extracellular gram-negative bacteria. Activation of TLR4 at the cell surface transiently results in an increase in cross-presentation and thus an increase in loading of antigenic peptides onto MHC class I molecules with activation of CD8+ cytotoxic T cells. However, once engulfed within the endosome, TLR4 switches to promote loading of antigenic peptides onto MHC class II molecules; this ultimately promotes a CD4+ helper T cell predominant immune response.4 As self-antigens and benign environmental antigens are able to be loaded on to MHC molecules, presentation of the antigenMHC complex alone is not sufficient to activate the adaptive immune pathway. Costimulatory molecules are additionally necessary for full T cell activation, most notably, CD80 and CD86, located on the activated dendritic cell and its interaction with CD28 upon T cells (Fig. 3.2). Stimulation of CD28 pathways results in a lower threshold for T cell activation and production of IL-2.4 Cytokines are also essential for full T cell activation, and the innate cytokine milieu varies based upon the type of PRR that has been stimulated. IL-12, IL-6, and TNF-α potentiate acute inflammation and influence T cell differentiation. IL-1 is essential for upregulating the acute-phase response. Interferon (IFN) type 1 drives an antiviral predominant response and drives activation of CD8+ cytotoxic T cells. In the context of CD4+ helper T cells, IL-12 promotes differentiation of helper T cell type 1 (Th1) cells. IL-4 promotes differentiation to Th2 cells. IL-6 and transforming growth factor-β (TGF-β) promote differentiation of Th17 cells. TGF-β can also promote differentiation to regulatory-type T cells in the absence of infection. In summary, T cell activation is achieved by three key steps: presentation of an antigen-MHC complex to a naïve T cell by a mature dendritic cell, costimulation of the T cell by surface molecules located on

the dendritic cell, and the presence of cytokines produced by cells of the innate immune system.4 Each activated T cell produces a unique profile of cytokines to elicit a variety of downstream effects. Of the CD4+ helper T cell lineage, the best-characterized cells are Th1, Th2, and Th17 cells. In regard to infection, Th1 cells primarily fight intracellular pathogens and do so via upregulation of IFN-γ and propagation of the inflammatory response. Th2 cells function to clear extracellular pathogens and mediate the allergic response through production of IL-4, IL-5, and IL-13. A growing body of research indicates that a healthy immune response is heavily influenced by the proportional response of Th1 and Th2 cells.5 Th17 cells differentiate in response to extracellular pathogens and fungi; they are frequently implicated in autoimmune disorders, and Th17 cells can acquire the characteristic of Th1 cells in chronic inflammatory states. Th17 cells drive production of IL-17. Regulatory T cells, another class of CD4+ helper T cells, are essential for the development of memory and tolerance to self-antigens; they produce potent antiinflammatory cytokines such as IL-10 and TGF-β. CD8+ cytotoxic T cells target cells that have been infected with a virus for destruction, and they produce the potent proinflammatory cytokine IFN-γ.5 In general, studies have shown that the adaptive T cell– dependent inflammatory response is dampened following general anesthesia, surgical stress, blood transfusion, hypothermia, hyperglycemia, and postoperative pain; this occurs with a simultaneous increase in adrenocorticotropic hormone (ACTH) and glucocorticoids. As T cells play a role in the destruction of circulating tumor cells and the prevention of micrometastasis, this observation has particular importance within the realm of surgical oncology. A recent study compared the postoperative T cell profile of patients undergoing surgery for invasive breast cancer and for benign fibroadenomas. Postoperatively, no change in the T cell profile was exhibited in patients within the fibroadenoma group, whereas patients within the invasive breast cancer group exhibited an increase in regulatory T cells. The regulatory T cells increase at 72 hours postoperatively correlated with a larger tumor size, human epidermal growth factor receptor-2 (HER2) positivity, and decrease in the length of disease-free survival. A lower burden of Th1 cells was correlated with a greater tumor burden and HER2 positivity. This suggests that postoperative immunosuppression may leave patients vulnerable to metastases and invites opportunity for research into immunomodulation in the postoperative immunosuppressed state.6  B Cell B cells, the primary effector cell of the humoral immune response, produce antibodies or immunoglobulins (Ig) and function as professional APCs. B cells initially develop in the bone marrow, where their cellular maturation can be correlated to the structural rearrangement of the immunoglobulin gene segments. B cells undergo a process termed V(D)J recombination in which a number of genetic recombinant events among gene segments V, D, and J of the immunoglobulin light and heavy chains ultimately allow for the production of different immunoglobulins; immunoglobulins have the capacity to recognize more than 5×1013 different antibodies. During the process of V(D)J recombination, the B cell progresses through the pro-B and pre-B cell phases. Following V(D)J recombination, surface-bound IgM marks the entrance of the B cell into the immature B cell state; it is at this point in its life

CHAPTER 3  The Inflammatory Response Expression

DCs; macrophages, B cells

Name

DCs; macrophages, B cells, other cells

29

DCs; macrophages, B cells; endothelial, epithelial, and tumor cells (PD-L1 only)

B7-1 (CD80)

B7-2 (CD86)

ICOS-L (CD275)

PD-L1 (B7-H1, CD274)

PD-L2 (B7-DC, CD273)

C

C

C

C

C

C

C

C

C

C

V

V

V

V

V

Ligands on APCs and other cells

N

Receptors on T cells

N

N

V

V

N

V

N

V

N

N

N

N

N

N

V

N

V

V

C C

C C

C C

C

Name

CD28

CTLA-4

ICOS

PD-1

Expression on T cells

Naive T cells

Regulatory T cells; activated T cells

Activated T cells; T follicular helper (Tfh) cells

Activated T cells

Activation of naive T cells; induction of immune responses

Inhibition of T cell activation

Generation of Tfh cells

Inhibition of T cell activation (mainly of effector T cells)

Major function

FIG. 3.2  Costimulatory molecules of the B7 family, including CD80/CD86, are expressed on antigen-presenting cells (APCs). CD28 receptors are expressed primarily on naïve T cells. The ligand-receptor binding produces a different effect depending upon the type of T cells being stimulated. (Adapted from Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular Immunology. Philadelphia, PA: Elsevier, Inc; 2018.)

cycle that it leaves the bone marrow and migrates to the spleen. Within the spleen, immature B cells will become naïve follicular or marginal zone B cells.7 Marginal zone B cells function in the spleen as the first line of defense against blood borne invaders. Independent of T cells, these B cells can rapidly produce soluble IgM during the early stages of infection. Naïve follicular B cells can be found within the lymph nodes or as circulating B cells. Their activation is T cell–dependent. Activation of follicular B cells results in a process termed class switching in which B cells transition from the production of IgM antibodies to the production of other classes of immunoglobulin, primarily IgG, IgA, and IgE, during times of infection. During the transition from IgM to other types of

immunoglobulins, further genetic rearrangements occur that result in immunoglobulins with a higher affinity for the antigen recognized by the B cell. Memory B cells are B cells that are maintained following an immune response. These memory cells retain the capacity to produce high-affinity immunoglobulins toward a certain antigen and, should that antigen ever be introduced again, these B cells can rapidly mount a robust immunologic response.7 

Innate Immunity Innate immunity represents the first line of cellular defense, as well as a key activator of the adaptive immune system. The innate components include physical barriers, such as epithelial

30

SECTION I  Surgical Basic Principles Pathogens

PAMPS

NLR agonists and inflammasome activators DAMPS

TLR

NLR TLR

Endogenous TLR agonists Injury and tissue damage TLR Alarmins (IL-1α, etc)

Inflammatory response

FIG. 3.3  Pathogen-associated molecular patterns (PAMPs) present on foreign invaders and danger-associated molecular patterns (DAMPs) prompted by cellular damage trigger multiple cellular signaling pathways via toll-like receptors (TLRs) and nucleotide-binding and oligomerization domain–like receptors (NLRs). The result is the production of pro- and antiinflammatory cytokines and the propagation of the inflammatory response. IL, Interleukin.

cells and mucus; specific immune cells including neutrophils, dendritic cells, macrophages, and natural killer cells; cytokine proteins that regulate an array of immunologic activity; and proteins of the complement system. While classic teaching posits that the responses of the innate immune system are largely nonspecific, recent evidence suggests a role for memory development within the innate immune system to allow for defense against reinfection in a T and B cell–independent manner, as well as specificity of response based on the type of PRR that is initially stimulated.8 The immunologic self/nonself theory – a theory that hinges on immune system activation by foreign stimuli – has largely been supplanted by Matzinger’s danger hypothesis. The self/ nonself theory fails to explain why the body does not mount an immunologic response to many nonself stimuli, such as the developing fetus or the mutating cancer cell. The danger hypothesis proposes that immune system activation and propagation is more dependent on cellular damage signals than on the presence of foreign substance.9 Cellular damage is communicated by danger signals known as danger-associated molecular patterns (DAMPs), also termed alarmins (Fig. 3.3). Danger signals specific to foreign pathogens are termed pathogenassociated molecular patterns (PAMPs). The initial danger hypothesis suggests that cellular necrosis and decompartmentalization occur during times of severe cellular stress, leading to a passive release of alarmins. These alarmins are typically confined to the intracellular space and, furthermore, are not typically released during programmed cellular death, or apoptosis. Newer theories suggest that severely stressed cells that are not undergoing necrosis are also capable of releasing alarmins in a more active manner by upregulation and overexpression.10 For example, IL-1α, a well-studied alarmin, can sense chromatin damage and actively report this finding to neighboring tissue via increased IL-1α secretion. In this instance, IL-1α can report genotoxic stress taking place in a cell that has not yet lost plasma membrane integrity.11

Toll-Like Receptors DAMPs are recognized by cellular receptors, broadly termed PRR, that are found on the cell surface or intracellularly. PRRs are evolutionarily conserved receptors that respond to specific PAMPs. These PAMPs are essential for survival from invading microbes and are not easily altered; microbes are typically unable to alter PAMPs in an attempt to evade the immune system. The bestcharacterized class of PRR involved in the inflammatory response is the toll-like receptor (TLR) family. The Toll signaling pathway was initially characterized in Drosophila melanogaster. The Toll protein had a known nuclear factor-κB (NF-κB)–dependent role in activation of B cells in response to lipopolysaccharide, a component of the gram-negative cell wall and a classic PAMP. IL-1, an important mediator of fever, T-cell activation, and the acute phase response had also previously demonstrated NF-κB–dependent signaling. The discovery that the IL-1 receptor (IL-1R) shared a homologous motif with the Drosophila protein, Toll, marked a key advancement in the understanding of intracellular signaling pathways of the innate immune system.12 The TLR is a transmembrane protein with an extracellular ligandbinding domain and an intracellular signaling domain. TLRs are expressed on the cell surface or within the endosome. Binding of a DAMP prompts dimerization of the TLR and subsequent intracellular activation of multiple signaling pathways. Ten human TLRs have been identified, each recognizing various PAMPs and triggering a variety of downstream cellular responses. TLR4 plays a key role in recognition of bacterial LPS, while TLR1, TLR2, and TLR6 recognize other common bacterial lipoproteins. TLR4 additionally plays a role in recognition of high-mobility group box protein 1 (HMGB1) and heat shock protein 70, two common alarmins, as well as mediation of sterile inflammation in the setting of ischemia-reperfusion injury. TLR3 recognizes double-stranded ribonucleic acid (RNA), and TLR7 and TLR8 recognize single-stranded RNA specific to viral invaders.12 TLRs function through NF-κB and mitogen-activated protein kinase intracellular pathways to upregulate a number of proinflammatory cytokines, including IL-1 and TNF-α. This allows for

CHAPTER 3  The Inflammatory Response activation of neighboring innate immune cells, and for activation of cell lines involved in adaptive immunity, including helper T cells, cytotoxic T cells, regulatory T cells, and B cells.12  Inflammasome Another well-characterized family of PRR is the nucleotide-binding and oligomerization domain (NOD)–like receptor (NLR) family. NLRs are assembled in the cytoplasm to form a key intracellular structure known as the inflammasome – an essential intracellular PRR. NLRs complex with apoptosis-associated speck-like protein containing a caspase recruitment domain to form the inflammasome. The inflammasome plays an essential role in regulating sterile inflammation via recognition of endogenous alarmins, as well as activating the innate immune response via recognition of foreign PAMPs.13 The best studied NLR is NLRP3. Once an NLRP3 inflammasome has been primed, it activates protease caspase 1. Caspase 1 is essential in the cleaving and subsequent secretion of proinflammatory cytokines IL-1β and IL-18 by macrophages in addition to the proinflammatory alarmin HMGB1. Endogenous factors capable of priming the NLRP3 inflammasome include hypoxia, complement, reactive oxygen species, oxidized low-density lipoproteins, amyloids, and misfolded proteins. The inflammasome plays a key role in the sterile inflammatory process that accompanies metabolic diseases, atherosclerosis, and neuroinflammatory disorders. Emerging evidence suggests that the NLRP3 inflammasome also plays a role in cardiomyopathy associated with sepsis.14  High-Mobility Group Box Protein 1 HMGB1 is an endogenous DAMP that mediates a plethora of downstream effects within the inflammatory cascade. It is highly conserved across multiple species, and it can be found in all human cell lines. The function of the molecule varies based on its location, the receptor it binds, and its reduction-oxidation state. Although initially identified as a deoxyribonucleic acid–binding protein in 1973, in 1999 it was found to additionally be an extracellular secretory product of macrophages in response to LPS and a key mediator of lethal endotoxemia.15 Within the nucleus, HMGB1 plays a role in regulation of gene transcription. In response to cellular injury or PAMPs such as LPS, HMGB1 is shuttled into the cytoplasm. HMGB1 makes its way to the extracellular space via both active and passive pathways. In cells undergoing necrotic death, the release of nonacetylated HMGB1 is nearly instantaneous. In stressed cells, pyropoptosis – or programmed, proinflammatory cellular death – facilitates release of hyperacetylated HMGB1 into the extracellular environment in a slower fashion. Pyropoptosis requires a functioning inflammasome and activated caspase 1. Extracellular HMGB1 stimulates release of proinflammatory cytokines TNF-α, IL-1, IL-6, and IL-18, and macrophage inflammatory protein 1 (MIP-1). It also serves as a chemoattractant for macrophages and neutrophils. In mouse models, neutralization via administration of antiHMGB1 antibodies has been shown to significantly reduce the lethality associated with endotoxemia.15 HMGB1 is a rapidly growing target of molecular and clinical research, both as a predictor of morbidity and mortality, and an immunologic therapeutic target. It has clinical implications in many acute conditions, including sepsis and hemorrhagic shock, as well as conditions of chronic inflammation, such as atherosclerosis and inflammatory bowel disease, and displays a key role in both pathogen-associated immune response and sterile immunity.15 

31

Cytokines Cytokines are small proteins that direct the inflammatory response through a variety of local and systemic effects. Individual cytokines typically achieve either proinflammatory or antiinflammatory downstream effects via induction of intracellular signaling pathways that influence gene expression. They can participate in autocrine, paracrine, or endocrine signaling.16 Historically, in regard to sepsis, it was thought that deaths occurring in early sepsis were primarily due to an overwhelming proinflammatory response rather than the infection itself. Late deaths were attributed to a diminished immune response secondary to the upregulation of antiinflammatory mediators that allowed the infection to overwhelm the host.17 Many studies have since shown that the acute inflammatory response is a complex balance between proinflammatory and antiinflammatory mediators coexisting and working in tandem. The following is a selection of important cytokines and their functions. An expanded list of cytokines, including their cellular origin and biologic effect, can be found in Tables 3.1 and 3.2. Key cytokines involved in the acute proinflammatory response include TNF-α, IL-1, IL-6, IL-8, IL-12, and IFN-γ.16,18,19 TNF-α and IL-1β are considered hyperacute mediators of the acute inflammatory response, exhibiting effects within 1 to 2 hours of injury, whereas IL-6 and IL-8 function in a subacute fashion with a peak at 1 to 4 hours postinjury and a more sustained plasma concentration as compared to the hyperacute mediators.18 Of the mediators of the antiinflammatory response, perhaps the best studied are TGF-β, IL-4, and IL-10.19 Within the first few hours of the acute inflammatory response, cytokines mediate recruitment of PMN leukocytes and stimulate the production of reactive oxygen species. Proinflammatory cytokines are intricately involved in the procoagulant state seen in trauma and infection. TNF-α is a 17-kDa protein secreted by both innate and adaptive immune cells, as well as nonimmune cells, such as fibroblasts. Along with IL-1, it is released rapidly in response to foreign invaders and tissue injury; in fact, TNF-α begins to elevate within 30 minutes of an inciting event.19 The half-life of TNF-α is a brief 14 to 18 minutes, and peak levels are reached within 1 to 2 hours of host tissue injury.18 TNF-α and IL-1 are two of the most extensively studied cytokines, as they play a role in nearly all inflammatory responses from sepsis and trauma to autoimmune disease and Alzheimer disease. TNF-α prompts cell signaling by binding to TNF receptor 1 (TNFR1) or TNFR2 – two transmembrane receptors found on a large variety of cells. The soluble TNF-α receptor (sTNFR) modulates the function of circulating TNF-α.19 IL-1 is released primarily from macrophages, although cells of the adaptive immune system and nonimmune cells secrete IL-1. IL-1 signals via two transmembrane receptors, IL-1 receptor type 1 (IL-1R1) and IL-1R2. Soluble IL-1R2 and IL-1R antagonist (IL1-Ra) modulate IL-1.19 Along with TNF-α, IL-1 is a hyperacute proinflammatory cytokine with a half-life of approximately 10 minutes. As the half-life and peak concentration of TNF-α and IL-1 are so brief, neither has proven to be a valuable prognosticator for injury severity or to predict development of organ dysfunction.18 TNF-α and IL-1 have many overlapping functions and act synergistically. Both mediate the fever response and are thus pyrogens. In addition to being secreted by macrophages, TNF-α and IL-1 act on macrophages in an autocrine and paracrine fashion to promote increased macrophage production, activity, and survival. In response to stimulation by TNF-α and IL-1, macrophages secrete other proinflammatory cytokines (including IL-6, IL-8, and macrophage migration inhibitory factor), lipid mediators, and

32

SECTION I  Surgical Basic Principles

TABLE 3.1  Cellular sources and important biologic effects of selected cytokines CYTOKINE

ABBREVIATION

MAIN SOURCES

IMPORTANT BIOLOGIC EFFECTS

Tumor necrosis factor Lymphotoxin-α Interferon-α Interferon-β Interferon-γ

TNF LT-α IFN-α IFN-β IFN-γ

Mφ, others Th1 cells, NK cells Leukocytes Fibroblasts Th1 cells

Interleukin-1α Interleukin-1β Interleukin-2

IL-1α IL-1β IL-2

Keratinocytes, others Mφ, NK cells, DC Th1 cells

Interleukin-3

IL-3

T cells, NK cells

Interleukin-4

IL-4

Th2 cells

Interleukin-5 Interleukin-6

IL-5 IL-6

Interleukin-8 Interleukin-9 Interleukin-10 Interleukin-11 Interleukin-12

IL-8 IL-9 IL-10 IL-11 IL-12

T cells, mast cells, Mφ Mφ, Th2 cells, EC, enterocytes Mφ, EC, enterocytes Th2 cells Th2 cells, Mφ DC, bone marrow Mφ, DC

Interleukin-13 Interleukin-17A Interleukin-18 Interleukin-21

IL-13 IL-17A IL-18 IL-21

Th2 cells, others Th17 cells Mφ, others Th2 cells, Th17 cells

Interleukin-23 Interleukin-27 Monocyte chemotactic protein-1 Granulocytemacrophage colonystimulating factor Granulocyte colonystimulating factor Erythropoietin Transforming growth factor-β

IL-23 IL-27 MCP-1

Mφ, DC Mφ, DC EC, others

See Table 3.2 Same as TNF Increases expression of cell surface class I MHC molecules; inhibits viral replication Same as IFN-α Activates Mφ; promotes differentiation of CD4+ T cells into Th1 cells; inhibits differentiation of CD4+ T cells into Th2 cells See Table 3.2 See Table 3.2 In combination with other stimuli, promotes proliferation of T cells; promotes proliferation of activated B cells; stimulates secretion of cytokines by T cells; increases cytotoxicity of NK cells Stimulates pluripotent bone marrow stem cells to increase production of leukocytes, erythrocytes, and platelets Promotes growth and differentiation of B cells; promotes differentiation of CD4+ T cells into Th2 cells; inhibits secretion of proinflammatory cytokines by Mφ Induces production of eosinophils from myeloid precursor cells Induces fever; promotes B cell maturation and differentiation; stimulates hypothalamicpituitary-adrenal axis; induces hepatic synthesis of acute-phase proteins Stimulates chemotaxis by PMN neutrophils; stimulates oxidative burst by PMN neutrophils Promotes proliferation of activated T cells; promotes immunoglobulin secretion by B cells Inhibits secretion of proinflammatory cytokines by Mφ Increases production of platelets; inhibits proliferation of fibroblasts Promotes differentiation of CD4+ T cells into Th1 cells; enhances IFN-γ secretion by Th1 cells Inhibits secretion of proinflammatory cytokines by Mφ Stimulates production of proinflammatory cytokines by Mφ and many other cell types Costimulation with IL-12 of IFN-γ secretion by Th1 cells and NK cells Modulation of B cell survival; inhibition of IgE synthesis; inhibition of proinflammatory cytokine production by Mφ In conjunction with TGF-β, promotes differentiation of naïve T cells into Th17 cells Suppresses effector functions of lymphocytes and Mφ Stimulates chemotaxis by monocytes; stimulates oxidative burst by Mφ

GM-CSF

T cells, Mφ, EC, others

Enhances production of granulocytes and monocytes by bone marrow; primes Mφ to produce proinflammatory mediators after activation by another stimulus

G-CSF

Mφ, fibroblasts

Enhances production of granulocytes by bone marrow

EPO TGF-β

Kidney cells T cells, Mφ, platelets, others

Enhances production of erythrocytes by bone marrow Stimulates chemotaxis by monocytes and induces synthesis of extracellular proteins by fibroblasts; promotes differentiation of naïve T cells into Treg cells; with IL-6 or IL-23, promotes differentiation of naïve T cells into Th17 cells; inhibits immunoglobulin secretion by B cells; downregulates activation of NK cells

DC, Dendritic cells; EC, endothelial cells; IgE, immunoglobulin E; Mφ, cells of the monocyte-macrophage lineage; MHC, major histocompatibility complex; NK, natural killer; PMN, polymorphonuclear neutrophils; Th1, Th2, Th17, subsets of differentiated CD4+ helper T cells; Treg, T-regulatory.

reactive oxygen species and thus propagate the inflammatory cascade. TNF-α upregulates the expression of adhesion molecules in endothelial cells, increases production of multiple chemokines, and promotes increased adhesive integrin molecule expression on neutrophils, thereby facilitating immune cell transmigration into the tissue. Together, IL-1 and TNF-α, along with the complement system, are the primary culprits implicated in the procoagulant state seen with acute inflammation, in part by inducing expression of procoagulant on endothelial cells. IL-1, TNF-α, and the various cytokines they induce also activate the hypothalamic-pituitary-adrenal (HPA) axis and increase cortisol production. On

its own, TNF-α infusion into experimental animals produces an inflammatory state that is nearly indistinguishable from septic shock; a similar state is provoked by isolated infusion of IL-1.19 Interleukin-6. IL-6 is a 21-kDa protein that is considered a secondary cytokine – that is, it is induced by the primary cytokines IL-1 and TNF-α, as well an array of other stimuli, including bacterial endotoxin LPS. IL-6 is secreted from multiple cell types, primarily macrophages, dendritic cells, lymphocytes, endothelial cells, fibroblasts, and smooth muscle cells. It is a pyrogen similar to IL-1 and TNF-α. In fact, the key function of IL-6 is to mediate the acute phase response, a stage of the inflammatory cascade characterized by

CHAPTER 3  The Inflammatory Response TABLE 3.2  Partial list of physiologic effects

induced by infusing interleukin-1 or tumor necrosis factor into human subjects

EFFECT

IL-1

TNF

Fever Headache Anorexia Increased plasma adrenocorticotropic hormone level Hypercortisolemia Increased plasma nitrite-nitrate levels Systemic arterial hypotension Neutrophilia Transient neutropenia Increased plasma acutephase protein levels Hypoferremia Hypozincemia Increased plasma level of IL-1Ra Increased plasma level of TNFR1 and TNFR2 Increased plasma level of IL-6 Increased plasma level of IL-8 Activation of coagulation cascades Increased platelet count Pulmonary edema Hepatocellular injury

+ + + +

+ + + +

+ +

+ +

+

+

+ + +

+ + +

+ − +

+ + +

+

+

+

+

+

+

−

+

+ − −

− + +

IL-1, Interleukin-1; IL-1Ra, interleukin-1 receptor antagonist; IL-6, interleukin-6; IL-8, interleukin-8; TNF, tumor necrosis factor; TNFR1, tumor necrosis factor type 1 receptor; TNFR2, tumor necrosis factor type 2 receptor.

fever, leukocytosis, and an increase in serum concentration of acute phase reactants.19 Acute phase reactants such as C-reactive protein (CRP), complement proteins, fibrinogen, and ferritin are produced by the liver.18,19 In trauma, CRP elevations begin around 8 hours postinjury and peak within 48 hours; as opposed to TNF-α and IL1, IL-6 is a subacute mediator of the proinflammatory response.18 In trauma patients with SIRS, sepsis, or multiorgan dysfunction syndrome (MODS), IL-6 is currently considered the most accurate prognosticator of outcome with increased and sustained levels of IL-6 directly correlating with a poorer prognosis.18,19 IL-6 is also implicated in the procoagulant state of the acute inflammatory response. IL-6 not only influences the innate immune response, but it also it has direct influence on the adaptive immune response by facilitating the activation and the differentiation of T and B cells and the production of new T and B cells from myeloid precursors. Evidence suggests that the myocardial dysfunction that accompanies septic shock is strongly mediated by IL-6.19 Interestingly, IL-6 also has antiinflammatory effects. Although its release is stimulated by IL-1 and TNF-α, IL-6 inhibits the release of subsequent TNF-α and IL-1 and upregulates the secretion of the modulatory IL-1Ra. Other antiinflammatory cytokines

33

such as IL-10 and TGB-β are also produced in response to IL-6 stimulation.19 Prostaglandin E2, a potent endogenous immunosuppressant, is released from macrophages following IL-6 signaling. IL-6 and its downstream antiinflammatory products have been heavily implicated in the development of the compensatory antiinflammatory response syndrome (CARS) – an immunosuppressed state that occurs in parallel with SIRS.18  Interleukin-4. The antiinflammatory cytokine IL-4 is secreted by innate immune cells common to the inflammatory response directed against extracellular pathogens, including mast cells, basophils, and eosinophils, as well as the adaptive immunity Th2 cell. It can act in both autocrine and paracrine pathways to increase release of IL-4, TGF-β, and IL-10. The most well characterized role of IL-4 is the promotion of Th2 cell differentiation and simultaneous inhibition of Th1 cell differentiation. Thus, IL-4 promotes the humoral, B-cell mediated immune response and antagonizes the cell mediated cytotoxic immune response.19 Following central nervous system injury, a population of IL-4–producing T cells appears. The presence of these IL-4–producing T cells appears to have a highly neuroprotective role and induces recovery in injured neurons. In mice models, IL-4–deficient mice with induced central nervous system injury exhibit a decreased functional recovery.20  Interleukin-10. IL-10 is a 35-kDa protein produced by cells of the innate and adaptive immune systems, including monocytes, macrophages, natural killer cells, and lymphocytes. IL-10 downregulates the expression of proinflammatory TNF-α, IL-1, IL-6, and IFN-γ while simultaneously upregulating the expression of proinflammatory cytokine modulators IL-1Ra and sTNFR to neutralize circulating TNF-α and IL-1. IL-10 impair phagocytosis among cells of the innate immune system and prevents efficient antigen presentation among APCs. In mouse models, infusion of recombinant IL-10 has shown protective effects in LPS endotoxemia, and immunoneutralization of IL-10 in these same models exhibits reversal of the protective effect. Interestingly, however, in models of polymicrobial sepsis induced by cecal ligation and puncture, this protective effect of IL-10 was not seen; in fact, inhibition of IL-10 12 hours after cecal ligation and puncture markedly increased survival. Taken together, this indicates that IL-10 can have both protective and injurious effects within the septic inflammatory response. It has been proposed that IL-10 plays a role in the transition from early reversible sepsis to late irreversible sepsis.19  Transforming growth factor-β. TGF-β is a 25-kDa dimeric cytokine with an array of functions that overall exert an antiinflammatory effect. It has three isoforms – TGF-β1, -β2, and -β3 – that exhibit overlapping functions. TGF-β1 is found within the bone, cartilage, and skin; TGF-β2 is expressed in neurons and astroglial cells; and TGF-β3 is localized to the palate and lung tissue. TGF-β regulates the epithelial-to-mesenchymal transition (EMT), a process essential for embryonic development, tissue remodeling, and wound repair. TGF-β upregulates VEGF on endothelial cells and is intricately involved in angiogenesis. Notably, TGF-β is involved in the development of all T cell types within the thymus, and it inhibits the survival of autoreactive T cells in the periphery.21 TGFβ inhibits various T cells functions, including IL-2 secretion and T cell proliferation; the presence of TGF-β promotes development of immunosuppressive regulatory T cells. Proinflammatory mediators from monocytes and macrophages including IL-1, TNF-α, and HMGB1 are suppressed by TGF-β, whereas immunosuppressive sTNFR and IL-1Ra are upregulated by TGF-β.19 TGF-β has an interesting paradoxical effect on malignant cells. In early malignancy, TGF-β functions as a tumor suppressor. In

34

SECTION I  Surgical Basic Principles

Classical

Lectin

Alternative

C1q binding to antigenantibody complexes

MBL binding to mannose

C3 LPS

C1inactive

C1s

C1inh

C4

Factor H

MBLactive

MBLinactive

Membrane C3b

C4b + C4a Factor I

C2

C4 binding protein

C3b + C3a

Factor B

C3bB

C4b2

Factor D

C3bB + Ba

C4b2a

Properdin (P)

C3 convertases C3

C3bBbP

C3a + C3b C5 convertases

(C4b2a3b and C3b2Bb)

C5

C5b + C5a

C6, C7, C8

Factor S C5b-C8

C9

CD59 C5b-C9

FIG. 3.4  Activation of the complement cascade via the classical, lectin, or alternative pathway. The common end result is formation of the membrane attack complex, or C5b-C9 complex. Inhibitors of the complement pathway include C1 inhibitor (C1inh), factor I, factor H, C4-binding protein, factor S, and CD59, among others not pictured.

healthy cells, TGF-β arrests the cell in the G1 phase of mitosis and thus limits cell division. This process also takes place in malignant cells early on. However, as malignancy progresses and the malignant cells acquire various mutations and adaptations, malignant cells can turn TGF-β to their advantage and use it to promote tumor cell proliferation, invasion, and metastasis. Through EMT, angiogenesis, and downregulation of the proinflammatory response, malignant cells can use TGF-β to proliferate, metastasize, and evade phagocytic and chemotoxic cells of the immune response.21 

Complement System Although classically recognized under the umbrella of the innate immune system, the complement system has now been distinguished as a major mediator of the inflammatory response with influence throughout both the innate and the adaptive immune system. As a common theme within the immune system, complement proteins assemble and activate in response to a number of DAMPs. There are three activation pathways for the complement pathway – termed the classical pathway, the lectin pathway, and the alternative pathway – that ultimately result in destruction of a targeted cell (Fig. 3.4).

In the classical pathway, an antigen-antibody complex (mediated by either IgM or IgG) binds with complement component 1q (C1q). C1q can also be bound by CRP or serum amyloid P within the classical activation pathway. From this point, the lectin pathway proceeds identically to the classical pathway, however, the lectin pathway initially activates C1q via mannan-binding lectin, ficolins, and collectins. C1q complexes with several other C1 proteins to form the C1q complex; the C1q complex further cleaves complement proteins C4 and C2, resulting in the C3 convertase (C4b2b complex). C3 convertase splits C3 into C3a and C3b. C3b complexes with C4b2b to form the C5 convertase and allows production of C5a and C5b. The primary function of C5b is to initiate the formation of the membrane-attack complex (MAC). The alternative pathway relies on a baseline spontaneous hydrolysis of C3 proteins. The resultant C3b can covalently bond with several components of the bacterial cell wall. Upon binding, factor B is recruited; the result is a C3bBb complex that also functions as a C3 convertase. From this point, the alternative pathway can proceed in a similar manner to the classical and lectin pathways.22

CHAPTER 3  The Inflammatory Response Over 30 mediators of the complement pathway have been identified, each with its own function. The end goal of the complement pathway, regardless of route of activation, is formation of the MAC. The MAC exists in two forms. It inserts into the membrane of targeted cells – including bacteria, cells invaded by a pathogen, or stressed cells expressing damage signals – where it promotes leakage of intracellular contents, cell lysis, and destruction. In its soluble form, the MAC, or sC5b-9, is a potent proinflammatory mediator.22 In addition to direct cell death, many components of the complement system also function as chemoattractants for other cells of the immune system. Complement proteins are recognized by professional APCs and promote phagocytosis. They also mediate T cell activity and lower the activation threshold of B cells. Host cells contain complement regulating proteins that function to prevent aberrant activation of the complement system against self. However, massive cellular damage and release of DAMPs, such as occurs with sepsis or trauma, can overwhelm the regulatory functions of the complement system and result in overactivation. This is one of the many mediators in systemic inflammation and thrombosis seen in traumatic injury. First in its class, the therapeutic agent eculizumab is an anti-C5 antibody that is approved by the U.S. Food and Drug Administration (FDA) in the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome (aHUS). Eculizumab has off-label uses in many processes, ranging from nephropathies to transplant medicine. A large number of clinical trials are underway to assess its efficacy in various disease states; notably, sepsis is a focus of several of these trials. Multiple other immunobiologic medications targeting the complement system are in development. An understanding of the pathophysiology of the complement system is key to expanding knowledge in this field.22 

Adaptive Immunity Historically, the terms innate and adaptive immunity were used to broadly categorize the immune response into nonspecific and specific phases of cellular response. The innate immune system, by its classic definition, is comprised of cells and cellular mediators that are conserved evolutionarily and are present within the host prior to introduction of a pathogen or tissue injury. In classic theory, the innate immune system responds essentially the same to repeated instances of tissue damage or infection. This classic definition falls short; more recent evidence suggests many innate immune cell types have some capacity for memory development. For example, epigenetic changes, primarily via methylation and acetylation, within macrophages and natural killer cells following exposure to various danger molecules induce a functional cellular reprogramming. Upon secondary stimulation, these cells can reactivate and function more efficiently and in a manner that is independent of either B or T cell stimulation.23 The line between innate and adaptive immunity has become less distinct.8,23,24 Adaptive immunity, in contrast, is historically characterized by the development of an efficient, targeted immune response to an invading pathogen and the subsequent development of memory cells. If the inciting antigen is reintroduced in a second encounter, memory cells mediate a vigorous, specific immune response to clear the invader. Although the classic separation of innate and adaptive immunity on the basis of specificity may no longer be entirely accurate, the adaptive immune system retains one critical, unique function – that is, the ability to undergo clonal expansion and the clonal expression of highly diversified antigen receptors, including T cell receptors (TCRs) and immunoglobulins.24

35

Adaptive immunity is further categorized into the humoral immune response and the cell-mediated immune response. The cellmediated immune response is driven by activated T lymphocytes; the effects of T cells are largely driven by cytokines. The humoral immune response is directed by activated B cells; immunoglobulins and cytokines carry out the end effects of the humoral immune system. Cellular immunity is dependent on activated T cells. When the TCR recognizes its corresponding antigen-MHC complex, the T cell undergoes maturation and differentiation as previously discussed. Essential in this process is IL-2 – a potent T cell growth factor. IL-2 is produced by CD4+ helper T cells in both autocrine and paracrine fashion and results in accelerated T lymphocyte differentiation and clonal expansion. IL-2 also promotes survival of regulatory T cells. In a secondary response to a repeat provocation of the immune system, IL-2 can be produced by CD8+ cytotoxic T cells directly. This drives rapid CD8+ cytotoxic T cell expansion and activation, rather than CD8+ cells depending on CD4+ cells for stimulation by IL-2.25 The humoral immune response is driven by activated B lymphocytes. In contrast to T cells, which require the MHC molecule to be present in order to recognize an antigen, B cells are able to recognize lone soluble and membrane-bound antigens via the B cell receptor (BCR). Once an antigen is recognized by the BCR, the B cell requires costimulatory signals for full activation. The costimulatory signals are provided by CD4+ helper T cells. The result is B cell maturation, class switching to IgG, IgA, and IgE production, and B cell clonal expansion. B cells can also recognize antigens and subsequently mature in a process that is facilitated by complement proteins and is independent of T cells.25 

The Nervous System and Immunity It has become increasingly clear that inflammation is a not a linear process mediated only by cells and proteins strictly associated with the immune system. Extensive crosstalk between the nervous system and the immune system is demonstrated in both chronic and acute inflammatory processes. Multiple neural circuits have been characterized in both the proinflammatory and antiinflammatory response. Multiple PRRs have been shown to be expressed directly on neurons, including TLRs (notably this includes TLR4), TNFR1, and IL-1R. Likewise, peripheral immune cells including macrophages, dendritic cells, and T cells express receptors for common neurotransmitters such as acetylcholine. Peripheral immune cells additionally produce and secrete acetylcholine, catecholamines, and other common neurotransmitters. The nervous system functions to suppress the inflammatory response by two key pathways: (1) the inflammatory reflex arc and cholinergic antiinflammatory pathway and (2) the HPA axis and glucocorticoid secretion.26–28 The Inflammatory Reflex Arc A neural reflex arc is characterized by peripheral afferent sensory input that is transmitted to the central nervous system and processed; the resultant action is carried by efferent motor neurons to the periphery. Thus, at least two synaptic connections are involved in every reflex arc. The vagus nerve mediates multiple reflex arcs across the cardiovascular, gastrointestinal, and endocrine systems. As the primary parasympathetic nerve, it is no surprise that it also plays a role in mediating the immune response. It is composed of 80% sensory fibers. Afferent sensory vagus neurons transmit peripheral signals to brainstem nuclei; efferent motor vagus neurons project to the periphery and signal primarily via

36

SECTION I  Surgical Basic Principles

acetylcholinesterase both at pre- and postganglionic neurons. Vagal neural arcs are integrated in the brain within the dorsal vagal complex, which is comprised of the nucleus tractus solitarius, dorsal motor nucleus of the vagus, and the area postrema.26 In addition to vagally mediated reflex arcs, the inflammatory signals carried via the afferent vagal fibers also play a role in mediating the fever response and regulating the HPA axis and subsequent glucocorticoid secretion.27 Neural regulation of the innate immune system. Sensory neurons in the periphery express several types of PRRs, including multiple subsets of TLRs and receptors for IL-1 and TNF-α, that can directly communicate the presence of inflammation to the nervous system.27 Vagal paraganglia also contain chemosensory cells that serve as mediators between the cells of the immune system and the neurons.26 The vagus participates in the cholinergic antiinflammatory pathway. Peripheral vagal nerve stimulation by proinflammatory mediators results in an increase in efferent vagal nerve signals that lead to a downregulation of TNF-α and other proinflammatory cytokines. This pathway has been demonstrated in the liver, heart, pancreas, and gastrointestinal tract to suppresses excess inflammation.26 Many efferent motor vagal nerve fibers travel to the spleen via the splenic nerve. The catecholaminergic nerve endings of the splenic nerve are in close association with splenic lymphocytes, particularly T cells, that express choline acetyltransferase (ChAT), the enzyme that catalyzes synthesis of acetylcholine. Acetylcholine produced by ChAT-expressing T lymphocytes acts upon the α7 nicotinic receptor expressed on macrophages; the result is an inhibition of NF-κB signaling pathways and an upregulation of Janus Kinase 2-Signal Transducer and Activator of Transcription Protein 3 (JAK2-STAT3) signaling pathways. This impairs the function of the inflammasome and overall decreases transcription of proinflammatory cytokines.26 In the rodent model, approximately 90% of TNF released systemically in the early stages of LPS-mediated endotoxemia originates from the spleen; in fact, splenectomy in this model is protective against lethality in endotoxemia. Efferent vagal signaling through the splenic nerve dramatically decreases systemic levels of TNF and is protective in the septic response. Thus, the spleen is a key site of vagally-mediated mitigation of the proinflammatory state within the inflammatory reflex.27  Neural regulation of the adaptive immune system. The inflammatory reflex arc has been linked to antibody production in B cells following exposure to blood borne antigens. In response to Streptococcus pneumoniae infection, vagus nerve signaling has been shown to promote retention of B cells within the marginal zone of the spleen. B cells retained within the marginal zone fail to migrate to the red pulp – the typical site of antibody production within the spleen.26,27 Daily treatment of the α7 nicotinic receptor with an agonist results in a 50% reduction of antibody production within the spleen during times of infection.27 Thus, by modulating cell trafficking, lymphoid architecture, and antibody production, the neural inflammatory reflex arc downregulates the humoral immune response to infection.  The Neuroendocrine System and Inflammation The HPA axis is activated in response to a large variety of stress signals and is responsible for the increase in glucocorticoids associated with injury and inflammation, as well as multiple other hormones that elevate with the inflammatory response. The protective role of glucocorticoids, primarily cortisol, in the stress response is well established. Proinflammatory cytokines TNF-α, IL1, and IL-6 exert effects at all three levels of the HPA axis – at the

paraventricular nucleus within the hypothalamus, they upregulate corticotropic release hormone (CRH); at the anterior pituitary, they upregulate ACTH; and at the adrenal gland, they directly stimulate release of cortisol.28 Direct input from afferent vagal fibers also signals the hypothalamus and prompts CRH release.27 Cortisol negatively feedbacks on the hypothalamus and pituitary to decrease release of CRH and ACTH, respectively. Additionally, cortisol exerts negative feedback on immune cells, resulting in a decrease in the production of proinflammatory TNF-α, IL-1, and IL-6.28 As a lipophilic molecule, cortisol is able to cross the cell membrane. Glucocorticoids exert their effects by binding the glucocorticoid receptor (GR) – a receptor found in nearly all cell types. The ubiquity of the GR allows glucocorticoids to influence nearly every cell type in the body, and it explains the incredible array of functions that are modulated by glucocorticoids. Upon binding cortisol, the GR is freed from its complex with heat shock proteins, and the new glucocorticoid–GR complex enters the nucleus and promotes or suppresses transcription of many target genes. The production of IL-1, TNF-α, and IL-6 notably decreases following glucocorticoid administration as does the production of key chemokines, adhesion molecules, inflammatory enzymes, and proinflammatory receptors. The GR also directly interacts with the NF-κB transcription factor to inhibit its function and thus limits the proinflammatory signaling pathway of the TLR system. These effects of glucocorticoids are, overall, antiinflammatory and are seen throughout the innate and adaptive immune systems.29 At the cellular level, glucocorticoids promote apoptosis of basophils, eosinophils, and neutrophils. They additionally promote apoptosis among Th1 and Th2 lymphocytes. Chronic exposure to glucocorticoids promotes a transition in the cytokine profile of the macrophage from proinflammatory to antiinflammatory and increases phagocytotic activity of the macrophage.29 As is a common theme throughout the immune system, once thought to be purely an antiinflammatory mediator, glucocorticoids also display some proinflammatory effects. Whether glucocorticoids exhibit a pro- or antiinflammatory effect is dependent upon the basal state of the immune system and the type of exposure to glucocorticoids. For example, chronic exposure to glucocorticoids certainly exemplifies an antiinflammatory response; however, acute exposure to high levels of glucocorticoids (as can be seen with infection, ischemia, and trauma) temporarily enhances the peripheral immune system. Studies suggest glucocorticoids play a role in transient expression of several genes of the innate immune response, including TLRs. Cytokines produced in response to stimulation of these TLRs by DAMPs are responsible for mediating the increase in proinflammatory IL-1, IL-6, and IL-8. Paradoxically, it is within these same cells that glucocorticoids downregulate the expression of proinflammatory cytokines. Genome microarray studies have suggested that dexamethasone and TNF-α may have a synergistic function; cells cotreated with dexamethasone and TNF-α exhibited a more robust secretion of the proinflammatory, acute phase protein SerpinA3. Expression of NLRP3, a key component of the proinflammatory inflammasome, in macrophages is also upregulated in response to glucocorticoids.29 The initial actions of glucocorticoid within the innate immune system suggest that it is an essential mediator for the acute inflammatory response. Mice that have undergone bilateral adrenalectomy are more susceptible to LPS endotoxemia, and humans with pathologic deficiencies of glucocorticoids are known for their tendency to develop recurrent infections.29 The extensive pro- and

CHAPTER 3  The Inflammatory Response antiinflammatory effects of glucocorticoids, several of which appear to be mediated simultaneously, are prime examples of the complexity and nonlinearity of the immune system. An overwhelming inflammatory response can impair the HPA axis. A state of true or relative hypocortisolism can result from increased levels of cortisol-binding globulin, alterations in function of the enzymes involved in glucocorticoid metabolism, or impairment of the cytosolic GR through mechanisms such as decreased binding affinity, receptor expression downregulation, or decreased translocation to the nucleus. In addition, glucocorticoid signaling at the level of CRH and ACTH can also occur. Taken together, there are a variety of ways that a state of hypocortisolism can result during the inflammatory response.28 In 2008, the Society for Critical Care Medicine introduced a term to describe the impaired function of the HPA axis seen with critical illness – critical illness–related corticosteroid insufficiency (CIRCI). It is characterized by a dysregulated systemic inflammatory state in the face of inadequate glucocorticoids and their antiinflammatory effects. The effects of CIRCI are seen throughout the neurologic, gastrointestinal, pulmonary, and cardiovascular systems and include signs and symptoms such as delirium, refractory hypotension, elevated cardiac index, intolerance of enteral nutrition, electrolyte imbalances, and persistent hypoxia. Updated guidelines for the management of CIRCI were published by the Society of Critical Care Medicine (SCCM) in conjunction with the European Society of Intensive Care Medicine (ESICM) in 2017; these guidelines highlight the patient-centered outcomes that have been published regarding CIRCI and provide recommendations for management of a clinical condition that appears to be much more prevalent than previously recognized.30 

INFLAMMATION AND THE CRITICALLY ILL Historical Perspective Historically, sepsis was characterized as the inflammatory response that resulted from a local infection transitioning to a systemic insult. It was manifested by systemic symptoms such as fever, tachycardia, and tachypnea. In the 1970s and 1980s, multiple clinical studies and case reports observed that the symptoms of sepsis could be present in patients without an infectious source. Major physiologic insults such as trauma, burns, and surgery were noted to evoke a clinical picture that suspiciously mimicked sepsis and often responded to similar therapies as sepsis – hence the term “sepsis syndrome” emerged. Multiple theories to explain this sepsis syndrome were put forth, including severe direct cellular injury and necrosis, bacterial translocation in the gut, cytokine storming, and ischemia-reperfusion injury. As understanding progressed, the term “sepsis syndrome” was gradually replaced by the SIRS.31 In 1992, Bone and colleagues defined SIRS as at least two of the following four criteria: temperature >38.0° Celsius (C) or 90 beats/minute; respiratory rate >20 breaths/min; and white blood count (WBC) >12,000 cells/mm,3 10% immature (band) forms.32,33 Today, clinicians accept that SIRS is intricately involved in the inflammatory response of patients with infectious and noninfectious insult. As a deeper understanding of SIRS developed, it became clear that systemic response to infection and trauma was not only driven by proinflammatory mediators, but that antiinflammatory mediators additionally complicated the picture. In the 1990s, the term CARS was introduced to describe the immunosuppressed state that accompanies the critically ill patient. SIRS was implicated in

37

the overwhelming proinflammatory response propagated by the innate immune system while CARS was primarily associated with the adaptive immune system and an attempt to return to immune homeostasis. The SIRS/CARS paradigm proposed that the early deaths following a large systemic insult (be it infectious or noninfectious) were the result of a vigorous SIRS response and that late deaths could be attributed to the immunosuppressed state driven by CARS. The paradigm has shifted over the last fifteen years, however, and it is now understood that a systemic insult appears to simultaneously trigger SIRS and CARS.33 The concept of an intensive care unit (ICU) dedicated to caring for the most critically ill of patients was first introduced in the 1970s. This, along with advancing clinical knowledge, facilitated an increase in survival of patients with single organ failure. Through the 1980s, as single organ failure survival improved, a new subset of organ failure patients emerged – the multiple organ failure (MOF) patients. Carrying a mortality of 40% to 80%, MOF rapidly became a topic of academic and clinical interest.33,34 Epidemiological studies suggest that MOF is a bimodal phenomenon with early and late mortality. Early mortality in MOF can occur following a single severe insult or a series of amplifying insults, termed the one-hit and two-hit models, respectively. Late mortality in MOF was attributed to secondary nosocomial infections (Fig. 3.5). Based on the previous understanding of the SIRS/CARS paradigm, early mortality in MOF was attributed to the overwhelming SIRS response, and late mortality in MOF was attributed to the immunosuppression of CARS, leaving patients vulnerable to develop secondary nosocomial infections.33 The changing SIRS/CARS paradigm complicates this initial theory. As clinical knowledge continues to move forward, early MOF deaths have declined due in large part to a better understanding of the pathophysiology of MOF, improved treatment strategies for shock and organ damage, and the increasing implementation of evidence-based, consensus protocols within the ICU, such as the Surviving Sepsis Campaign, ARDSnet, and ABCDEF Bundle for pain and delirium. Increasing compliance with these protocolized strategies correlates with a decrease in mortality.35 As overall deaths from MOF decline, more patients are moving into a state of chronic critical illness. Patients who do not succumb to early MOF enter one of two pathways: one of rapid restoration of immunologic homeostasis or one of continued immune dysregulation and the transition from acute critical illness to chronic critical illness. While the pathophysiology of this latter state is not completely understood, attempts to understand this increasing phenomenon have resulted in a new clinical entity: the persistent inflammation, immunosuppression, and catabolism syndrome (PICS).34 

Systemic Inflammatory Response Syndrome SIRS is primarily governed by the innate immune system. Tissue injury and cellular necrosis, ischemia-reperfusion injury, and invasive pathogens signal host danger locally via interaction with PRRs. These inciting signals trigger an array of systemic events including thrombosis, loss of cellular polarity, leakage of intracellular content, and leakage of fluid from the capillary system. Vasodilatation occurs secondary to mediators such as histamine and bradykinin; this, along with the upregulation of chemokines, allows extravasation of immune cells, notably phagocytic immune cells, into the periphery. Edema ensues. As described previously, an array of cytokines and other inflammatory proteins flood the area to direct cell signaling. This influx of cytokines and the ongoing inflammatory stimulus prompts the production of more

38

SECTION I  Surgical Basic Principles

Antiinflammation

First event: Injury Tissue disruption Shock

Proinflammation

Early MOF

SIRS Innate immune system Adaptive immune system SARS

Early recovery

Late recovery or death or PICS

Late MOF Second event (e.g., infection)

FIG. 3.5  The proposed framework of early and late mortality in multisystem organ failure, including the simultaneous functioning of the systemic inflammatory and systemic antiinflammatory response syndromes (SIRS and SARS, respectively). (Adapted from Sauaia A, Moore FA, Moore EE. Postinjury inflammation and organ dysfunction. Critical Care Clinics. 2017;33(1):167-91.)

cytokines through a series of positive feedback loops – this is the cytokine storm.16 When a critical threshold of inflammatory signaling is reached, microthrombi begin to form in the vessels about the inflamed area in an attempt to limit bacteria and injurious proinflammatory cytokines from accessing the systemic circulation.31 When local inflammatory responses fail to control a local insult or the inciting event is substantial enough to provoke an initial systemic response, the systemic effects of the inflammatory cascade become rapidly apparent. It is important to consider that, in addition to the magnitude of the inciting event, baseline patient factors such as chronic corticosteroid use, malnutrition, and age play a key role in determining the adequacy of the initial inflammatory response. Many of the local inflammatory actions that are viewed as beneficial, such thrombosis, vasodilation, and release of cytotoxic substances, have a detrimental effect when applied systemically.31 These events manifest as a decrease in systemic vascular resistance and an increase in venous capacitance. The cardiac index increases in response to a reduced afterload. Leakage from the vasculature leads to pulmonary edema. Cytotoxic mediators directly injure peripheral and central neurons and predispose toward ICU myopathy syndromes and delirium. The host is thus left vulnerable to subsequent development of multisystem organ dysfunction. Many therapies that target the cytokines and inflammatory mediators of the innate immune response have been proposed, including anti-TNF antibody, recombinant IL-1Ra, and recombinant activated protein C. Unfortunately, these have not shown a significant impact on decreasing mortality associated with sepsis and SIRS.31,36 

Compensatory Antiinflammatory Response The CARS was initially named as such under the assumption that it followed the SIRS response in a stepwise, compensatory fashion. This has proven to be a misnomer; it is now widely accepted that SIRS and CARS mediate simultaneous, opposing, inflammatory responses. If SIRS represents the overwhelming activation of the innate immune system, CARS can be succinctly described as

suppression of the adaptive immune system. CARS functions to limit the adaptive immune system and to prompt a return to a state of immunologic homeostasis, as well hasten the healing process. When the local proinflammatory response is overwhelmed, the SIRS response is seen. The same can be said for CARS – when the local antiinflammatory response is overwhelmed, the antiinflammatory effects begin to be seen systemically, leaving the host vulnerable to immunoparalysis, impaired healing, nosocomial infection, and potential for multisystem organ dysfunction.36,37 CARS has been tied to an increase in antiinflammatory IL-10 and IL-6 and a downregulation of the human leukocyte antigenDR (HLA-DR); HLA-DR is one of several molecules that can make up the MHC class II surface complex and is critical in presentation of antigens to the lymphocytes of the adaptive immune system. Without proper expression of HLA-DR on monocytes, CD4+ helper T cells are unable to properly differentiate into an effector cell in response to antigen stimulation, and a state of immunosuppression ensues.38,39 Lymphocytes, particularly T lymphocytes, undergo apoptosis, and a state of lymphopenia develops. Regulatory T cells appear and mediate the suppression of both APCs and effector T cells. Between the appearance of regulatory T cells and the decrease in activated CD4+ helper T cells, CD8+ cytotoxic T cell function fails. In both CD4+ and CD8+ populations, memory T cells fail to develop. As a result of the poor induction of the memory class cells and antiinflammatory genomic changes, immunoparalysis can extend beyond the acute inflammatory period and leave the host vulnerable to development of subsequent infection.40 

Genomics and Understanding Inflammation The previous SIRS/CARS paradigm – that the acute inflammatory response is initially governed by a proinflammatory response and then an antiinflammatory response subsequently follows over a period of days – is a tempting one. It takes the complex immune system, in addition to the neurohormonal system, and compartmentalizes it in a way that is academically easier to digest. However, multiple studies have debunked this previous line of thought. It has become evident that the systemic proinflammatory and the

CHAPTER 3  The Inflammatory Response systemic antiinflammatory response to infectious and noninfectious inciting events occur simultaneously. The first-SIRS-then-CARS paradigm was challenged in 2011 by Xiao and colleagues as part of the Glue Grant consortium, which endeavored to study the human response to injury at the genomic level.41 The group performed genome-wide expression analysis of whole blood leukocytes in patients with severe burn injury or severe blunt trauma and a small number of healthy patients following the administration of a low dose of bacterial endotoxin. The results were impressive. In patients with severe blunt trauma, 80% of the leukocyte genome exhibited changes in gene expression within the first 28 days following injury; this extreme reorganization and reprioritization of the leukocyte transcriptome in response to severe blunt trauma was termed the genomic storm. The expression of some leukocyte genes increased, including those genes involved in the innate response such as the TLRs, NOD receptors, and haptoglobin. The expression of leukocyte genes that decreased included genes for antigen presentation and T cell activation. Results were extraordinarily similar among burn patients, and remarkably similar among the healthy subjects receiving bacterial endotoxin. Interestingly, common clinical parameters that typically correlate with a poor outcome, such as volume of blood transfused, base deficit, and injury severity scores, had a very limited effect on gene expression.35,41 Importantly, Xiao and colleagues also demonstrated that levels of altered gene expression remain elevated in the postinjury period.41 At 28 days in the severe blunt trauma patients and at 90 days in the severe burn patients, messenger RNA of the leukocyte genes had not returned to baseline levels.41 They demonstrated that the posttraumatic outcomes are largely dependent on quantitative and not qualitative gene expression. In patients with an uncomplicated recovery, levels of gene expression had returned to or were in the process of returning to baseline by 7 to 14 days postinjury. This was seen for both upregulated and downregulated genes. In patients who experienced a more complicated hospital course, changes in gene expression largely did not return to baseline by 28 days; it was additionally noted in this subset that the early changes in gene expression were of a greater magnitude.41 Given the numerous changes in gene expression that occur with systemic inflammation, it can be logically assumed that genetic variants may alter the severity of an individual’s response to systemic inflammation and may subsequently alter clinical outcome. Certain single nucleotide polymorphisms (SNP) within the NF-κB signaling pathway have been tied to an increased risk of sepsis and multisystem organ failure following severe trauma.42 Persistent downregulation of HLA-DR, associated with the MHC-II receptor, has been shown to increase the risk of development of infected pancreatic necrosis following an episode of severe acute pancreatitis.38 The expanding field of genomics offers new insights into the pathophysiology of systemic inflammation and those patients most at risk for a complicated clinical course, as well as opens many doors for the development of clinical prognosticators and targeted therapeutics. 

Diagnosis and Immunotherapy in Sepsis Decades of research have attempted to develop an immunomodulatory therapy that alters the outcomes of sepsis. Unfortunately, immunomodulatory therapies for sepsis and systemic inflammation have shown variable, often unreproducible results. Targeted antibodies or recombinant formulations have been tested for IL-1, TNF-α, IL-10, activated protein C, bradykinin, antithrombin III, and TLR4, among many others, without encouraging results.37

39

Considering the results of the Glue Grant consortium, which strongly suggest that the changes in the leukocyte transcriptome begin almost immediately postinjury and that multiple pro- and antiinflammatory genomic changes occur simultaneously, if an intervention is intended to alter the trajectory of the innate or the adaptive immune response, it is conceivable that a benefit will be seen only if the intervention can be implemented almost immediately postinjury or post infection. One target that shows promise is IFN-γ. As described, HLADR downregulation accompanies the acute inflammatory response and has been implicated in CARS as one of the contributors to impaired T cell function. The loss of HLA-DR in the acute postoperative period has been linked to increased postoperative infection. Recent data suggest that soluble mediators that remain present in the serum 24 hours postoperatively are responsible for this downregulation of HLA-DR rather than direct tissue injury or anesthesia. Treatment in vitro with IFN-γ, however, improved antigen presentation among monocytes postoperatively.43 Other work has suggested that granulocyte-macrophage colony-stimulating factor (GM-CSF) may also improve expression of HLA-DR among critically ill patients.44 As immune-targeted therapeutic approaches for SIRS and sepsis remain limited, the importance of prevention and early recognition cannot be understated. Emphasis has been placed on the missed diagnosis of sepsis, as no standard test exists to determine whether a patient with systemic inflammation also has an underlying infection; the consequences of a missed diagnosis of sepsis include an increase in mortality, improper usage of antibiotics, and an increase in healthcare spending. A relatively new approach to this problem is the use of gene expression microarrays to better delineate patients with systemic inflammation. At the time of this review, three diagnostic gene expression microarrays – Sepsis MetaScore, FAIM3:PLAC8 ratio, and the Septicyte Lab – have been introduced with the aim to distinguish septic patients from patients with noninfectious inflammation. While all three scores require further testing and validation before widespread application, early data are promising for the performance of these microprofiling tests in distinguishing infectious from noninfectious systemic inflammation.45 

Multiple Organ Failure Sustained activation of SIRS and CARS results in systemic injury that can progress to a point of MOF. Innate immune effector cells extravasate from the vasculature systemically into the tissues; however, without adequate local levels of chemoattractant signals, these cells fail to migrate further than the tissue surrounding the microvasculature.31 While postinjury patients who do not develop MOF and those who do both exhibit an initial neutrophilia (within 3 hours postinjury), those patients who develop MOF exhibit a profound neutropenia within 6 to 12 hours postinjury; this suggests sequestration of neutrophils in the peripheral tissues. As activated immune cells, though, they continue to degranulate and release cytotoxic mediators. These cytotoxic substances directly injure the surrounding parenchyma. They additionally damage the microvasculature and severely limit the transport of nutrients into the tissue.31 Complement activation not only contributes to the hypercoagulable state, but also to the production of the lytic MAC, multiple inflammatory cytokines, and harmful reactive oxygen species.37 Prolonged exposure to inflammatory cytokines and prolonged alterations in leukocyte gene expression prompt the production of the powerfully immunosuppressive myeloid-derived

40

SECTION I  Surgical Basic Principles

suppressor cell (MDSC). MDSCs, unlike typical myeloid-derived cells, do not differentiate into immune cells with effector function. The result is immature immune cells that are unable to propagate inflammatory pathways implicated in the resolution of inflammation.36 Risk factors for the development of MOF include abdominal compartment syndrome, early requirement for blood product transfusion, and infection, among many others. Although resuscitation with blood products versus excessive crystalloid has been shown to lower the incidence of MOF, early transfusion requirement remains one of the strongest MOF risk factors. Blood products contain numerous immunoactive substances, including proinflammatory lipids and cytokines within the red blood cells that remain despite leukodepletion of blood products.36 Other risk factors include advanced age, increased body mass index (BMI), male sex, injury severity score, and base deficit on admission. Interestingly, while male sex confers a greater risk of developing MOF, female sex confers a greater risk of death.46 Additionally, orthopedic literature has indicated that damage control with external fixation is associated with a more controlled postoperative inflammatory response than in patients who undergo primary intramedullary nailing, despite more severe injuries in the damage control group.36 At this point, it is worth noting that the nomenclature surrounding multiple organ dysfunction and failure (as well as the nomenclature surrounding SIRS, CARS, and sepsis) is vast. Multiple definitions of MOF have been proposed, and multiple scoring systems exist in the literature. The most widely accepted scoring systems are the Denver Postinjury Multiple Organ Failure Score, the Sequential Organ Failure Assessment (SOFA), and the Marshall Multiple Organ Dysfunction Score (MODS). A recent study published in the Journal of Trauma and Acute Care Surgery advocates the use of the Denver scoring system based on its simplicity and ability to identify high-risk patients and its strongest association with early trauma mortality. The Denver scoring system uses laboratory values representing the respiratory, renal, hepatic, and cardiac systems to assign a score in patients with an injury severity score >15 who have survived more than 48 hours from injury to predict various outcomes.47 Another recently published study suggests that, in patients with traumatic hemorrhagic shock, a better prognostic indicator may be measurement of microcirculatory perfusion as an endpoint in resuscitation. This underscores the critical role of the hypercoagulable state in the pathophysiology of MOF.48 With improvements in understanding of disease and early implementation of protocolized ICU bundles, outcomes in MOF mortality have improved over time. For the patients who survive MOF, they enter into one of two clinical phenotypes. In the first phenotype, immunologic homeostasis is restored within 14 days of the clinical insult. In the second phenotype, immunologic dysfunction and organ dysfunction persist; these patients enter a state of chronic critical illness. This chronic critical illness is underpinned by persistent inflammation, immunosuppression, and catabolism.34 

Persistent Inflammation, Immunosuppression, and Catabolism Syndrome The physiologic effect on patients with chronic critical illness requiring prolonged intensive care has been a notable area of interest and study over the last 20 years. Within this group, a subset of patients exists that maintains a state of lingering, simultaneous immunosuppression, and inflammation associated with a

persistent acute phase response that drives a baseline catabolic state. The mechanism of this – (PICS) – is based on a pathophysiologic maintenance of low-grade inflammation with increased serum levels of IL-6 and neutrophils in conjunction with immunosuppression through lymphocyte depletion and dysfunction. Multiple organ injury and failure further reinforced the baseline immune dysfunction in a cycle that can prove extraordinarily hard to break.34 Although typically relatively quiescent, one of the functions of the innate immune system is activation and differentiation of hematopoietic stem cells. With activation of hematopoietic stem cells through multiple redundant pathways utilizing growth factors and cytokines as ligands, including IL-1, IL-6, and IL-17, the body attempts to replenish cells of the innate immune system. Severe cellular stress creates a state of “emergency myelopoiesis” at the expense of lymphopoiesis and erythropoiesis. It is through this process that MDSCs are formed. Although their function is incompletely understood, these cells prevent the toxic effects of persistent T cell proliferation and cytokine production. However, their action in chronic critical illness allows for continued immunosuppression, and the expansion of MDSCs after sepsis correlates with poor clinical outcomes.34 The chronicity of these pathways in critical illness is based upon the continual presence of DAMPs and PAMPs. PAMPs and DAMPs act on a number of receptors, such as TLRs, NLRs, retinoic acid-inducible gene-like receptors, and scavenger receptors with the resultant activation of the proinflammatory pathways and cytokine release. Neutrophilia occurs, although these immature myeloid cells lack full functionality for antigen presentation, expression of adhesion molecules, and formation of NETs. Simultaneously, the antiinflammatory IL-10 and TGFβ appear, MDSCs begin to form, and T lymphocytes fail to properly develop, leading to an immunosuppressed state. This immunosuppressed state is characterized by an overall lymphopenia, the appearance of regulatory T cells, Th2 polarization, and impaired functioning of dendritic cells. In addition to this myelodysplastic effect, lymphopenia is also induced by apoptosis of effector T and B lymphocytes (Fig. 3.6). Additionally, the ongoing physiologic stress perpetuates a state of catabolism, manifested by derangements in carbohydrate, lipid, and protein metabolism.34 Also problematic in chronic critical illness is the kidney. There is a strong correlation between acute kidney injury and the development of sepsis, and acute kidney injury progressing to chronic kidney disease has proven to be a risk factor for development of chronic critical illness. The epithelial cells that line the renal tubules are exquisitely sensitive to oxidative stress; necrosis of these cells provides a wide array of DAMPs to perpetuate the inflammatory process. An upregulation of TLRs occurs in the kidneys in response to stress, too. The overall result is direct toxicity to the kidney and release of DAMPs, a decrease in glomerular filtration, and an upregulation of one of the key receptor types responsible for the perpetuation of the innate immune response.49 Within skeletal muscle, sepsis and severe cellular stress induce dysfunction in the mitochondria, decrease in protein synthesis, and breakdown of myofibrillar proteins. The breakdown of skeletal muscle mitochondria releases proinflammatory substances and, given the size of the skeletal muscle system, provides an ample source of DAMPs. Clinically, this manifests as severe muscle wasting and cachexia; in a matter of weeks, patients can lose up to 30% of their lean muscle mass.49

CHAPTER 3  The Inflammatory Response

41

Death

miRNA, erythropoietin Dysfunctional myelopoiesis Acute insult Burn Pancreatitis Sepsis Trauma

HSCs

MDSCs

Chronic condition Aging Cancer Kidney disease

Anti-PDL1, erythropoietin, Flt3L, nicotinamide riboside

PICS

Continuous low-grade inflammation Exercise, propanolol, nutrition, antiinflammatory medication, anabolics

CCI

FIG. 3.6  Myelodysplasia and continuous inflammatory stimulus results in a vicious cycle associated with persistent inflammation, immunosuppression, and catabolism syndrome (PICS). Certain chronic conditions or aging increases the risk of PICS. CCI, Chronic critical illness; Flt3L, XXX. HSCs, hematopoietic stem cells; MDSCs, myeloid-derived suppressor cells; miRNA, microRNA; PDL1, XXX. (Adapted from Efron PA, Mohr AM, Bihorac A, et al. Persistent inflammation, immunosuppression, and catabolism and the development of chronic critical illness after surgery. Surgery. 2018;164(2):178-84.)

Specific therapies for sepsis and inflammation remain relatively elusive. Current recommendations continue to underscore the importance of optimal ICU care, including early recognition of sepsis; utilization of validated, protocolized bundles (such as those to treat pain and delirium); and early, aggressive patient mobilization. Several immunotherapies that have shown promise in the treatment of oncologic disease are under investigation for their potential role in treating sepsis, as these patients share certain characteristics of their immunosuppressed states.34 Adequate nutrition administration is emphasized, although septic patients demonstrate a dysfunctional utilization and metabolism of nutrients even in the presence of normal levels of key nutrients. The recommended daily protein supplementation for critically ill patients has recently been increased to >1.5 g/kg/day, with some top researchers continuing to recommend supplementation with 2.0 g/kg/day for the most critically ill patients.50 Although not yet studied in the chronically critically ill patient, administration of propranolol and oxandrolone, with the intent to decrease catabolic requirements, has shown good outcomes in the pediatric burn population, and the same principles may apply to critically ill adults.34,50 The end result of these processes is a chronic dysregulated inflammatory state that leaves the host vulnerable to opportunistic infection; this can have a particularly devastating effect in the critical care setting with multi–drug-resistant pathogens. With the onset of such infections, additional critical care measures are required and further PAMPs and DAMPs are provided for proliferation of this vicious cycle. For those patients who survive their ICU stay, chronic critical illness confers an increased risk of death following hospital discharge. Discharge to a skilled nursing facility remains one of the strongest predictors of mortality in this patient group. With such a profound effect on the patient, poor clinical outcomes in terms of mortality and functional status following discharge from the ICU are unfortunately commonplace.34,49 As the elderly population continues to grow, the incidence of chronic critical illness and PICS will likely increase as well.50

SELECTED REFERENCES Cruz-Topete D, Cidlowski JA. One hormone, two actions: anti- and pro-inflammatory effects of glucocorticoids. Neuroimmunomodulation. 2015;22(1-2):20–32. Historically thought to be primarily antiinflammatory, the proinflammatory role of glucocorticoids has proven to be important in a functional immune response. With the glucocorticoid receptor residing within nearly every cell in the human body, the proinflammatory and antiinflammatory effects and clinical implications of glucocorticoids are vast.

Efron PA, Mohr AM, Bihorac A, et  al. Persistent inflammation, immunosuppression, and catabolism and the development of chronic critical illness after surgery. Surgery. 2018;164(2):178–184.



As clinical care improves, in-hospital mortality of critically ill has declined. As more critically ill patients are surviving the early stages of multiple organ dysfunction, a new phenotype of multiple organ dysfunction and chronic critical illness has appeared: the persistent inflammation, immunosuppression, and catabolism syndrome. In this review, the pathophysiology and long-term clinical implications of this entity is reviewed.

Jain A, Pasare C. Innate control of adaptive immunity: beyond the three-signal paradigm. J Immunol. 2017;198(10):3791–3800. T cell activation within the adaptive immune system requires multiple signaling events from cells within the innate immune system. The complex process of T cell receptor engagement, presentation of costimulatory molecules, and essential priming cytokines is reviewed.

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Matzinger P. The danger model: a renewed sense of self. Science. 2002;296(5566):301–305. Matzinger’s danger hypothesis postulated that the immune response is more concerned with the presence of danger signals that are intrinsic to the host and to foreign invaders, as opposed to self versus nonself antigens. This represented a pivotal shift in understanding how the immune response begins.

Olofsson PS, Rosas-Ballina M, Levine YA, et  al. Rethinking inflammation: neural circuits in the regulation of immunity. Immunol Rev. 2012;248(1):188–204. Recent advances in molecular genetics have improved the understanding of the complex interplay of the nervous system and the immune system. Many of the same signals that activate the immune response also stimulate afferent sensory fibers of the vagus nerve; information is integrated centrally and relayed via efferent fibers that return to the periphery to complete the inflammatory reflex arc. A review of the physiology and potential therapeutic interventions is presented.

Rider P, Voronov E, Dinarello CA, et al. Alarmins: feel the stress. J Immunol. 2017;198(4):1395–1402. Danger-associated molecular patterns (DAMPs) propagate the noninfectious inflammatory response. Release of DAMPs has long been thought to be a passive process that occurs secondary to cell necrosis and release of intracellular products. Here, the authors demonstrate that DAMP release can be an active process that can occur without loss of subcellular compartmentalization.

Xiao W, Mindrinos MN, Seok J, et al. A genomic storm in critically injured humans. J Exp Med. 2011;208(13):2581–2590. The human response to injury was historically thought to occur in a stepwise fashion: the initial proinflammatory response and the subsequent antiinflammatory response. In this study, the authors propose a new paradigm of simultaneous activation of the pro- and antiinflammatory components of the immune system based on genomic wide expression from leukocytes. They show that 80% of the leukocyte transcriptome expression is altered in the event of injury, a true genomic storm.

REFERENCES 1. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013;13(3):159–175. 2. Franken L, Schiwon M, Kurts C. Macrophages: sentinels and regulators of the immune system. Cell Microbiol. 2016;18(4):475–487. 3. Mellman I. Dendritic cells: master regulators of the immune response. Cancer Immunol Res. 2013;1(3):145–149. 4. Jain A, Pasare C. Innate control of adaptive immunity: beyond the three-signal paradigm. J Immunol. 2017;198(10):3791–3800. 5. Geginat J, Paroni M, Facciotti F, et  al. The CD4-centered universe of human T cell subsets. Semin Immunol. 2013;25(4):252–262.

6. Fu G, Miao L, Wang M, et al. The postoperative immunosuppressive phenotypes of peripheral T helper cells are associated with poor prognosis of breast cancer patients. Immunol Invest. 2017;46(7):647–662. 7. Pieper K, Grimbacher B, Eibel H. B-cell biology and development. J Allergy Clin Immunol. 2013;131(4):959–971. 8. Romo MR, Perez-Martinez D, Ferrer CC. Innate immunity in vertebrates: an overview. Immunology. 2016;148(2):125–139. 9. Matzinger P. The danger model: a renewed sense of self. Science. 2002;296(5566):301–305. 10. Rider P, Voronov E, Dinarello CA, et  al. Alarmins: feel the Stress. J Immunol. 2017;198(4):1395–1402. 11. Cohen I, Rider P, Vornov E, et al. IL-1alpha is a DNA damage sensor linking genotoxic stress signaling to sterile inflammation and innate immunity. Sci Rep. 2015;5:14756. 12. Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity. 2011;34(5):637–650. 13. Patel MN, Carroll RG, Galvan-Pena S, et al. Inflammasome priming in sterile inflammatory disease. Trends Mol Med. 2017;23(2):165–180. 14. Kalbitz M, Fattahi F, Grailer JJ, et al. Complement-induced activation of the cardiac NLRP3 inflammasome in sepsis. FASEB J. 2016;30(12):3997–4006. 15. Yang H, Wang H, Chavan SS, et al. High mobility group box protein 1 (HMGB1): the prototypical endogenous danger molecule. Mol Med. 2015;21(suppl 1):S6–S12. 16. Chousterman BG, Swirski FK, Weber GF. Cytokine storm and sepsis disease pathogenesis. Semin Immunopathol. 2017;39(5):517–528. 17. King EG, Bauza GJ, Mella JR, et al. Pathophysiologic mechanisms in septic shock. Lab Invest. 2014;94(1):4–12. 18. Guisasola MC, Alonso B, Bravo B, et al. An overview of cytokines and heat shock response in polytraumatized patients. Cell Stress Chaperones. 2018;23(4):483–489. 19. Schulte W, Bernhagen J, Bucala R. Cytokines in sepsis: potent immunoregulators and potential therapeutic targets-an updated view. Mediators of Inflammation. 2013;2013:165974. 20. Walsh JT, Hendrix S, Boato F, et  al. MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4. J Clin Invest. 2015;125(2):699–714. 21. Haque S, Morris JC. Transforming growth factor-β: a therapeutic target for cancer. Hum Vaccin Immunother. 2017;13(8):1741–1750. 22. Ricklin D, Barratt-Due A, Mollnes TE. Complement in clinical medicine: clinical trials, case reports and therapy monitoring. Mol Immunol. 2017;89:10–21. 23. Netea MG, Latz E, Mills KH, et al. Innate immune memory: a paradigm shift in understanding host defense. Nat Immunol. 2015;16(7):675–679. 24. Boehm T, Swann JB. Origin and evolution of adaptive immunity. Annu Rev Anim Biosci. 2014;2:259–283. 25. den Haan JM, Arens R, van Zelm MC. The activation of the adaptive immune system: cross-talk between antigen-presenting cells, T cells and B cells. Immunol Lett. 2014;162(2 Pt B):103–112. 26. Pavlov VA, Tracey KJ. Neural regulation of immunity: molecular mechanisms and clinical translation. Nat Neurosci. 2017;20(2):156–166. 27. Olofsson PS, Rosas-Ballina M, Levine YA, et al. Rethinking inflammation: neural circuits in the regulation of immunity. Immunol Rev. 2012;248(1):188–204.

CHAPTER 3  The Inflammatory Response 28. Silverman MN, Sternberg EM. Glucocorticoid regulation of inflammation and its functional correlates: from HPA axis to glucocorticoid receptor dysfunction. Ann N Y Acad Sci. 2012;1261:55–63. 29. Cruz-Topete D, Cidlowski JA. One hormone, two actions: anti- and pro-inflammatory effects of glucocorticoids. Neuroimmunomodulation. 2015;22(1-2):20–32. 30. Annane D, Pastores SM, Rochwerg B, et  al. Guidelines for the Diagnosis and Management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in critically ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Crit Care Med. 2017;45(12):2078–2088. 31. Fry DE. Sepsis, systemic inflammatory response, and multiple organ dysfunction: the mystery continues. Am Surg. 2012;78(1):1–8. 32. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101(6):1644–1655. 33. Rosenthal MD, Moore FA. Persistent inflammatory, immunosuppressed, catabolic syndrome (PICS): a new phenotype of multiple organ failure. J Adv Nutr Hum Metab. 2015;1(1):e784. 34. Efron PA, Mohr AM, Bihorac A, et al. Persistent inflammation, immunosuppression, and catabolism and the development of chronic critical illness after surgery. Surgery. 2018;164(2):178–184. 35. Tompkins RG. Genomics of injury: the glue grant experience. J Trauma Acute Care Surg. 2015;78(4):671–686. 36. Binkowska AM, Michalak G, Slotwinski R. Current views on the mechanisms of immune responses to trauma and infection. Cent Eur J Immunol. 2015;40(2):206–216. 37. Sauaia A, Moore FA, Moore EE. Postinjury inflammation and organ dysfunction. Crit Care Clin. 2017;33(1):167–191. 38. Sharma D, Jakkampudi A, Reddy R, et al. Association of systemic inflammatory and anti-inflammatory responses with adverse outcomes in acute pancreatitis: preliminary results of an ongoing study. Dig Dis Sci. 2017;62(12):3468–3478.

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39. Doughty L. Adaptive immune function in critical illness. Curr Opin Pediatr. 2016;28(3):274–280. 40. Jensen IJ, Sjaastad FV, Griffith TS, et al. Sepsis-induced T cell immunoparalysis: the ins and outs of impaired T cell immunity. J Immunol. 2018;200(5):1543–1553. 41. Xiao W, Mindrinos MN, Seok J, et al. A genomic storm in critically injured humans. J Exp Med. 2011;208(13):2581–2590. 42. Pan W, Zhang AQ, Gu W, et  al. Identification of haplotype tag single nucleotide polymorphisms within the nuclear factor-κB family genes and their clinical relevance in patients with major trauma. Crit Care. 2015;19(1):95. 43. Longbottom ER, Torrance HD, Owen HC, et al. Features of postoperative immune suppression are reversible with interferon gamma and independent of interleukin-6 pathways. Ann Surg. 2016;264(2):370–377. 44. Shankar Hari M, Summers C. Major surgery and the immune system: from pathophysiology to treatment. Curr Opin Crit Care. 2018;24(6):588–593. 45. Sweeney TE, Khatri P. Benchmarking sepsis gene expression diagnostics using public data. Crit Care Med. 2017;45(1):1–10. 46. Sauaia A, Moore EE, Johnson JL, et  al. Temporal trends of postinjury multiple-organ failure: still resource intensive, morbid, and lethal. J Trauma Acute Care Surg. 2014;76(3):582– 592; discussion 592–583. 47. Hutchings L, Watkinson P, Young JD, et al. Defining multiple organ failure after major trauma: a comparison of the denver, sequential organ failure assessment, and marshall scoring systems. J Trauma Acute Care Surg. 2017;82(3):534–541. 48. Hutchings SD, Naumann DN, Hopkins P, et  al. Microcirculatory impairment is associated with multiple organ dysfunction following traumatic hemorrhagic shock: the MICROSHOCK study. Crit Care Med. 2018;46(9):e889–e896. 49. Hawkins RB, Raymond SL, Stortz JA, et al. Chronic critical illness and the persistent inflammation, immunosuppression, and catabolism syndrome. Front Immunol. 2018;9:1511. 50. Rosenthal MD, Kamel AY, Rosenthal CM, et  al. Chronic critical illness: application of what we know. Nutr Clin Pract. 2018;33(1):39–45.

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CHAPTER

Shock, Electrolytes, and Fluid Sawyer Gordon Smith, Martin Allan Schreiber

OUTLINE History Resuscitation Shock Fluids Blood Transfusions Physiology of Shock Bleeding Shock Index Lactate and Base Deficit Compensatory Mechanisms Lethal Triad Oxygen Delivery Optimization (Supernormalization) Global Perfusion Versus Regional Perfusion Septic Shock Problems With Resuscitation Bleeding Trauma Immunology and Inflammation Evolution of Modern Resuscitation Detrimental Impact of Fluids Damage Control Resuscitation Whole Blood Resuscitation Resuscitation With 1:1:1 Massive Transfusion Protocol

Current Status of Fluid Types Crystalloids Hypertonic Saline Colloids Future Resuscitation Research Blood Substitutes Perfluorocarbons Novel Fluids Dried Plasma Pharmacologic Agents Suspended Animation Perioperative Fluid Management Body Water Maintenance Fluids Adrenal Gland Antidiuretic Hormone and Water Electrolytes Sodium Potassium Calcium Magnesium

Surgeons are the masters of fluids because they need to be. They care for patients who cannot eat or drink for various reasons; for example, they have hemorrhaged, undergone surgery, or lost fluids from tubes, drains, or wounds. Surgeons are obligated to know how to care for these patients, who put their lives in their hands. This topic might appear simple only for those who do not understand the complexities of the human body and its ability to regulate and compensate fluids. In reality, the task of managing patients’ blood volume is one of the most challenging burdens surgeons face, often requiring complete control of the intake and output of fluids and electrolytes and often in the presence of blood loss. Surgeons do not yet completely understand the physiology of shock and resuscitation, and their knowledge is superficial. Given the nature of the profession, they have studied those topics and dealt with patients who bleed and exsanguinate. Historically, wartime experience has always helped them move ahead in their knowledge of the management of fluids and how to better resuscitate. The recent wars in Iraq and Afghanistan are no exception as we have learned much from these wars. Constant attention to and titration of fluid loss therapy is required because the human body is dynamic. The key to treatment

is to realize what an individual patient’s initial condition is and to understand that their fluid status is constantly changing. Bleeding, sepsis, neuroendocrine disturbances, and dysfunctional regulatory systems can all affect patients who are undergoing the dynamic changes of illness and healing. The correct management of blood volume is highly time-dependent. If it is managed well, surgeons are afforded the chance to manage other aspects of surgery, such as nutrition, administration of antibiotics, drainage of abscesses, relief of obstruction and of incarceration, treatment of ischemia, and resection of tumors. Knowing the difference between dehydration, anemia, hemorrhage, and overresuscitation is vital. The human body is predominantly water, which resides in the intravascular, intracellular, and interstitial (or third) space. Water movement between these spaces is dependent on many variables. This chapter focuses on the management of the intravascular space because it is the only space surgeons have direct access to, and managing the intravascular space is the only way to impact the other two fluid compartments. This chapter also examines historical aspects of shock, fluids, and electrolytes—not just to note interesting facts or to pay tribute to deserving physicians, but also to try to understand how

44

CHAPTER 4  Shock, Electrolytes, and Fluid knowledge evolved over time. Doing so is vital to understanding past changes in management as well as to accept future changes. We are often awed at the discoveries of the past yet also astounded by how wrong we often were and why. Certainly, in turn, future surgeons will look back at our current body of knowledge and be amazed at how little we knew and how frequently we were wrong. A consequence of not studying the past is to repeat its errors. After the historical highlights, this chapter discusses various fluids that are now used along with potential fluids under development. Finally, caring for perioperative patients is explored from a daily needs perspective.

HISTORY History is disliked by those who are in a hurry to just learn the bottom line. Learning from the past, however, is essential to know which treatments have worked and which have not. Dogma must always be challenged and questioned. Were the current treatments based on science? Studying the history of shock is important for at least three reasons. First, physicians and physiologists have been fascinated with blood loss out of necessity. Second, we need to assess what experiments have or have not been done. Third, we need to know more, because our current understanding of shock is elementary.

Resuscitation One of the earliest authenticated resuscitations in the medical literature is the “miraculous deliverance of Anne Green,” who was executed by hanging on December 14, 1650.1 Green was executed in the customary way by “being turned off a ladder to hang by the neck.” She hanged for half an hour, during which time some of her friends pulled “with all their weight upon her legs, sometimes lifting her up, and then pulling her down again with a sudden jerk, thereby the sooner to dispatch her out of her pain” (Fig. 4.1). When everyone thought she was dead, the body was taken down, put in a coffin, and taken to the private house of Dr. William Petty, who, by the King’s orders, was allowed to perform autopsies on the bodies of all persons who had been executed.

FIG. 4.1  Miraculous deliverance of Anne Green, who was executed in 1650. (From Hughes JT. Miraculous deliverance of Anne Green: an Oxford case of resuscitation in the seventeenth century. Br Med J (Clin Res Ed). 1982;285:1792–1793; by kind permission of the Bodleian Library, Oxford.)

45

When the coffin was opened, Green was observed to take a breath, and a rattle was heard in her throat. Petty and his colleague, Thomas Willis, abandoned all thoughts of dissection and proceeded to revive their patient. They held her up in the coffin and then, by wrenching her teeth apart, poured hot cordial into her mouth, which caused her to cough. They rubbed and chafed her fingers, hands, arms, and feet; after a quarter of an hour of such effort, they put more cordial into her mouth. Then, after tickling her throat with a feather, she opened her eyes momentarily. At that stage, they opened a vein and bled her of 5 ounces of blood. They continued administering the cordial and rubbing her arms and legs. Next, they applied compressing bandages to her arms and legs. Heating plasters were put to her chest, and another plaster was inserted as an enema “to give heat and warmth to her bowels.” They then placed Green in a warm bed with another woman to lie with her to keep her warm. After 12 hours, Green began to speak; 24 hours after her revival, she was answering questions freely. At 2 days, her memory was normal, apart from her recollection of her execution and the resuscitation. 

Shock Hemorrhagic shock has been extensively studied and written about for many centuries. Injuries, whether intentional or not, have occurred so frequently that much of the understanding of shock has been learned by surgeons taking care of the injured. What is shock? The current widely accepted definition is inadequate perfusion of tissue. However, many subtleties lie behind this statement. Nutrients for cells are required, but which nutrients are not currently well defined. Undoubtedly, the most critical nutrient is oxygen, but concentrating on just oxygenation alone probably represents very elemental thinking. Blood is highly complex and carries countless nutrients, buffers, cells, antibodies, hormones, chemicals, electrolytes, and antitoxins. Even if we think in an elemental fashion and try to optimize the perfusion of tissue, the delivery side of the equation is affected by blood volume, anemia, and cardiac output (CO). Moreover, the use of nutrients is affected by infection and drugs. The vascular tone plays a role as well; for example, in neurogenic shock, the sympathetic tone is lost, and in sepsis, systemic vascular resistance decreases because of a broken homeostatic process or possibly because of evolutionary factors. The term shock appears to have been first employed in 1743 in a translation of the French treatise of Henri Francois Le Dran regarding battlefield wounds. He used the term to designate the act of impact or collision, rather than the resulting functional and physiologic damage. However, the term can be found in the book Gunshot Wounds of the Extremities, published in 1815 by Guthrie, who used it to describe physiologic instability. Humoral theories persisted until the late nineteenth century, but in 1830, Herman provided one of the first clear descriptions of intravenous (IV) fluid therapy. In response to a cholera epidemic, he attempted to rehydrate patients by injecting 6 ounces of water into the vein. In 1831, O’Shaughnessy also treated cholera patients by administering large volumes of salt solutions intravenously and published his results in Lancet.2 Those were the first documented attempts to replace and to maintain the extracellular internal environment or the intravascular volume. Note, however, that the treatment of cholera and dehydration is not the ideal treatment of hemorrhagic shock. In 1872, Gross defined shock as “a manifestation of the rude unhinging of the machinery of life.” His definition, given its accuracy and descriptiveness, has been repeatedly quoted in the literature.

46

SECTION I  Surgical Basic Principles

Theories on the cause of shock persisted through the late nineteenth century; although it was unexplainable, it was often observed. George Washington Crile concluded that the lowering of the central venous pressure in the shock state in animal experiments was due to a failure of the autonomic nervous system.3 Surgeons witnessed a marked change in ideas about shock between 1888 and 1918. In the late 1880s, there were no all-encompassing theories, but most surgeons accepted the generalization that shock resulted from a malfunctioning of some part of the nervous system. Such a malfunctioning has now been shown to not be the main reason— but surgeons are still perplexed by the mechanisms of hemorrhagic shock, especially regarding the complete breakdown of the circulatory system that occurs in the later stages of shock. In 1899, using contemporary advances with sphygmomanometers, Crile proposed that a profound decline in blood pressure (BP) could account for all symptoms of shock. He also helped alter the way physicians diagnosed shock and followed its course. Before Crile, most surgeons relied on respiration, pulse, or a declining mental status when evaluating the condition of patients. After Crile’s first books were published, many surgeons began measuring BP. In addition to changing how surgeons thought about shock, Crile was a part of the therapeutic revolution. His theories remained generally accepted for nearly two decades, predominantly in surgical circles. Crile’s work persuaded Harvey Cushing to measure BP in all operations, which in part led to the general acceptance of BP measurement in clinical medicine. Crile also concluded that shock was not a process of dying but rather a marshaling of the body’s defenses in patients struggling to live. He later deduced that the reduced volume of circulating blood, rather than the diminished BP, was the most critical factor in shock. Crile’s theories evolved as he continued his experimentations; in 1913, he proposed the kinetic system theory. He was interested in thyroid hormone and its response to wounds but realized that epinephrine was a key component of the response to shock. He relied on experiments by Walter B. Cannon, who found that epinephrine was released in response to pain or emotion, shifting blood from the intestines to the brain and extremities. Epinephrine release also stimulated the liver to convert glycogen to sugar for release into the circulation. Cannon argued that all the actions of epinephrine aided the animal in its effort to defend itself.4 Crile incorporated Cannon’s study into his theory. He proposed that impulses from the brain after injury stimulated glands to secrete their hormones, which, in turn, effected sweeping changes throughout the body. Crile’s kinetic system included a complex interrelationship among the brain, heart, lungs, blood vessels, muscles, thyroid gland, and liver. He also noted that if the body received too much stress, the adrenal glands would run out of epinephrine, the liver of glycogen, the thyroid of its hormone, and the brain itself of energy, accounting for autonomic changes. Once the kinetic system ran out of energy, BP would fall, and the organism would go into shock. Henderson recognized the importance of decreased venous return and its effect on cardiac output and arterial pressure. His work was aided by advances in techniques that allowed careful recording of the volume curves of the ventricles. Fat embolism also led to a shock-like state, but its possible contribution was questioned because study results were difficult to reproduce. The vasomotor center and its contributions in shock were heavily studied in the early 1900s. In 1914, Mann noted that unilaterally innervated vessels of the tongues of dogs, ears of rabbits, and paws of kittens appeared constricted during shock compared with contralaterally denervated vessels.

Battlefield experiences continued to intensify research on shock. During the World War I era, Cannon used clinical data from the war as well as data from animal experiments to examine the shock state carefully. He theorized that toxins and acidosis contributed to the previously described lowering of vascular tone. He and others then focused on acidosis and the role of alkali in preventing and prolonging shock. The adrenal gland and the effect of cortical extracts on adrenalectomized animals were of fascination during this period. Then, in the 1930s, a unique set of experiments by Blalock5 determined that almost all acute injuries are associated with changes in fluid and electrolyte metabolism. Such changes were primarily the result of reductions in the effective circulating blood volume. Blalock showed that those reductions after injury could be the result of several mechanisms (Box 4.1). He clearly showed that fluid loss in injured tissues was loss of extracellular fluid (ECF) that was unavailable to the intravascular space for maintaining circulation. The original concept of a “third space,” in which fluid is sequestered and therefore unavailable to the intravascular space, evolved from Blalock’s studies. Carl John Wiggers first described the concept of “irreversible shock.”6 His 1950 textbook, Physiology of Shock, represented the attitudes toward shock at that time. In an exceptionally brilliant summation, Wiggers assembled the various signs and symptoms of shock from various authors in that textbook (Fig. 4.2), along with his own findings. His experiments used what is now known as the Wiggers prep. In his most common experiments, he used previously splenectomized dogs and cannulated the arterial system. He took advantage of an evolving technology that allowed him to measure the pressure within the arterial system, and he studied the effects of lowering BP through blood withdrawal. After removing the dogs’ blood to an arbitrary set point (typically, 40 mm Hg), he noted that their BP soon spontaneously rose as fluid was spontaneously recruited into the intravascular space. To keep the dogs’ BP at 40 mm Hg, Wiggers had to continually withdraw additional blood. During this compensated phase of shock, the dogs could use their reserves to survive. Water was recruited from the intracellular compartment as well as from the extracellular space. The body tried to maintain the vascular flow necessary to survive. However, after a certain period, he found that to keep the dogs’ BP at the arbitrary set point of 40 mm Hg, he had to reinfuse shed blood; he termed this phase uncompensated, or irreversible, shock. Eventually, after a period of irreversible shock, the dogs died.

BOX 4.1  Causes of shock according to

Blalock in 1930.

• Hematogenic (oligemia) • Neurogenic (caused primarily by nervous influences) • Vasogenic (initially decreased vascular resistance and increased vascular capacity, as in sepsis) • Cardiogenic (failure of the heart as a pump as in cardiac tamponade or myocardial infarction) • Large volume loss (extracellular fluid, as occurs in patients with diarrhea, vomiting, and fistula drainage) Data from Blalock A. Principles of surgical care: Shock and other problems. St. Louis, MO: CV Mosby; 1940.

CHAPTER 4  Shock, Electrolytes, and Fluid The ideal model is uncontrolled hemorrhage, but its main problem is that the volume of hemorrhage is uncontrolled by the nature of the experiment. Variability is the highest in this model even though it is the most realistic. Computer-assisted pressure models that mimic the pressures during uncontrolled shock can be used to reduce the artificiality of the pressure-controlled model. Smith and colleagues7 developed a hybrid model of controlled, uncontrolled hemorrhage whereby a standardized grade V liver laceration is made in swine. The swine bleed to either a specified pressure or fixed volume, and bleeding is controlled with packing. This removes the variability classically associated with uncontrolled hemorrhage.7 

Fluids How did the commonly used IV fluids, such as normal saline, enter medical practice? It is often taken for granted, given the vast body of knowledge in medicine, that they were adopted through a rigorous scientific process, but that was not the case.

Normal saline has a long track record and is extremely useful, but we now know that it also can be harmful. Hartog Jakob Hamburger, in his in vitro studies of red cell lysis in 1882, incorrectly suggested that 0.9% saline was the concentration of salt in human blood. He chose 0.9% saline because it has the same freezing point as human serum. This fluid is often referred to as physiologic or normal saline, but it is neither physiologic nor normal. In 1831, O’Shaughnessy described his experience in the treatment of cholera: Universal stagnation of the venous system, and rapid cessation of the arterialization of the blood, are the earliest, as well as the most characteristic effects. Hence the skin becomes blue—hence animal heat is no longer generated—hence the secretions are suspended; the arteries contain black blood, no carbonic acid is evolved from the lungs, and the returned air of expiration is cold as when it enters these organs.8

SYMPTOM COMPLEX OF SHOCK General appearance and reactions Mental state Apathy Delayed responses Depressed cerebration Weak voice Listless or restlessness Countenance Drawn–anxious Lusterless eyes Sunken eyeballs Ptosis of upper lids (slight) Upward rotation of eyeballs (slight) Neuromuscular state Hypotonia Muscular weakness Tremors and twitchings Involuntary muscular movements Difficulty in swallowing Neuromuscular tests Depressed tendon reflexes Depressed sensibilities Depressed visual and auditory reflexes General but variable symptoms Thirst Vomiting Diarrhea Oliguria Visible or occult blood in vomitus and stools

47

Skin and mucous membranes

Circulation and blood

Skin Pale, livid, ashen gray Slightly cyanotic Moist, clammy Mottling of dependent parts Loose, dry, inelastic, cold

Superficial veins Collapsed and invisible Failure to fill on compression or massage Inconspicuous jugular pulsations

Mucous membranes Pale, livid, slightly cyanotic

Heart Apex sounds feeble Rate usually rapid

Conjunctiva Glazed, lusterless

Radial pulse Usually rapid Small volume “feeble,” “thready”

Tongue Dry, pale, parched, shriveled Respiration and metabolism Respiration Variable but not dyspneic Usually increased rate Variable depth Occasional deep sighs Sometimes irregular or phasic Temperature Subnormal, normal, supernormal Basal metabolic rate reduced (?)

Brachial blood pressures Lowered Pulse pressure small Retinal vessels Narrowed Blood volume Reduced Blood chemistry Hemoconcentration or hemodilution Venous O2 decreased A-V O2 difference increased Arterial CO2 reduced Alkali reserve reduced

FIG. 4.2  Wiggers’ description of symptom complex of shock. (From Wiggers CJ. The present status of shock problem. Physiol Rev. 1942;22:74–123.)

48

SECTION I  Surgical Basic Principles

O’Shaughnessy wrote those words at the age of 22, having just graduated from Edinburgh Medical School. He tested his new method of infusing IV fluids on a dog and observed no ill effects. Eventually, he reported that the aim of his method was to restore blood to its natural specific gravity and to restore its deficient saline matters. His experience with human cholera patients taught him that the practice of bloodletting, then highly common, was good for “diminishing the venous congestion” and that nitrous oxide (laughing gas) was not useful for oxygenation. In 1832, Robert Lewins reported that he witnessed Thomas Latta injecting extraordinary quantities of saline into veins, with the immediate effects of “restoring the natural current in the veins and arteries, of improving the color of the blood, and [of ] recovering the functions of the lungs.” Lewins described Latta’s saline solution as consisting of “two drachms of muriate, and two scruples of carbonate, of soda, to sixty ounces of water.” Later, however, Latta’s solution was found to equate to having 134 mmol per liter of Na+, 118 mmol per liter of Cl−, and 16 mmol per liter of bicarbonate (HCO3−). During the next 50 years, many reports cited various recipes used to treat cholera, but none resembled 0.9% saline. In 1883, Sydney Ringer reported on the influence exerted by the constituents of the blood on the contractions of the ventricle (Fig. 4.3). Studying an isolated heart model from frogs, he used 0.75% saline and a blood mixture made from dried bullocks’ blood.9 In his attempts to identify which aspect of blood caused better results, he found that a “small quantity of white of egg completely obviates the changes occurring with saline solution.” He concluded that the benefit of “white of egg” was because of the albumin or the potassium chloride. To show what worked and what did not, he described endless experiments with alterations of multiple variables. However, Ringer later published another article stating that his previously reported findings could not be repeated; through careful study, he realized that the water used in his first article was

actually not distilled water, as reported, but rather tap water from the New River Water Company. It turned out that his laboratory technician, who was paid to distill the water, took shortcuts and used tap water instead. Ringer analyzed the water and found that it contained many trace minerals (Fig. 4.4). Through careful and diligent experimentation, he found that calcium bicarbonate or calcium chloride—in doses even smaller than in blood—restored good contractions of the frog ventricles. The third component that he found essential to good contractions was sodium bicarbonate. Thus, the three ingredients that he found essential were potassium, calcium, and bicarbonate. Ringer solution soon became ubiquitous in physiologic laboratory experiments. In the early twentieth century, fluid therapy by injection under the skin (hypodermoclysis) and infusion into the rectum (proctoclysis) became routine. Hartwell and Hoguet reported its use in intestinal obstruction in dogs, laying the foundation for saline therapy in human patients with intestinal obstruction. As IV crystalloid solutions were developed, Ringer solution was modified, most notably by pediatrician Alexis Hartmann. In 1932, wanting to develop an alkalinizing solution to administer to his acidotic patients, Hartmann modified Ringer solution by adding sodium lactate. The result was lactated Ringer (LR) or Hartmann solution. He used sodium lactate (instead of sodium bicarbonate); the conversion of lactate into sodium bicarbonate was sufficiently slow to lessen the danger posed by sodium bicarbonate, which could rapidly shift patients from compensated acidosis to uncompensated alkalosis. In 1924, Rudolph Matas, regarded as the originator of modern fluid treatment, introduced the concept of the continued IV drip but also warned of potential dangers of saline infusions. He stated, “Normal saline has continued to gain popularity but the problems with metabolic derangements have been repeatedly shown but seem to have fallen on deaf ears.” In healthy volunteers, modern-day experiments have shown that normal saline can cause abdominal discomfort and pain, nausea, drowsiness, and decreased mental capacity to perform complex tasks. The point is that normal saline and LR solution have been formulated for conditions other than the replacement of blood, and the reasons for the formulation are archaic. Such solutions have been useful for dehydration; when they are used in relatively small volumes (1–3 L/day), they are well tolerated and relatively harmless; they provide water, and the human body can tolerate the amounts of electrolytes they contain. Over the years, LR solution has attained widespread use for treatment of hemorrhagic shock. However, normal saline and LR solution are mostly permeable through

They consist of: Calcium

38.3

per million.

4.5

”

23.3

”

7.1

”

Combined carbonic acid

78.2

”

Sulfuric acid

55.8

”

Chlorine

15

”

Magnesium Sodium Potassium

Silicates Free carbonic acid

7.1

”

54.2

”

FIG. 4.3  Sydney Ringer, credited for the development of lactated Ringer

FIG. 4.4  Sidney Ringer’s report of contents in water from the New

solution. (From Baskett TF. Sydney Ringer and lactated Ringer’s solution. Resuscitation. 2003;58:5–7.)

River Water Company. (From Baskett TF. Sydney Ringer and lactated Ringer’s solution. Resuscitation. 2003;58:5–7.)

49

CHAPTER 4  Shock, Electrolytes, and Fluid the vascular membrane, but they are poorly retained in the vascular space. After a few hours, only about 175 to 200 mL of a 1-L infusion remains in the intravascular space. In countries other than the United States, LR solution is often referred to as Hartmann solution, and normal saline is referred to as physiologic (sometimes even spelled fisiologic) solution. With the advances in science in the last 50 years, it is difficult to understand why advances in resuscitation fluids have not been made. 

Blood Transfusions Concerned about the blood that injured patients lost, Crile began to experiment with blood transfusions. As he stated, “After many accidents, profuse hemorrhage often led to shock before the patient reached the hospital. Saline solutions, adrenalin, and precise surgical technique could substitute only up to a point for the lost blood.” At the turn of the nineteenth century, transfusions were seldom used. Their use waxed and waned in popularity because of transfusion reactions and difficulties in preventing clotting in donated blood. Through his experiments in dogs, Crile showed that blood was interchangeable: he transfused blood without blood group matching. Alexis Carrel was able to sew blood vessels together with his triangulation technique, using it to connect blood vessels from one person to another for the purpose of transfusions. However, Crile found Carrel’s technique too slow and cumbersome in humans, so he developed a short cannula to facilitate transfusions. By the time World War II occurred, shock was recognized as the single most common cause of treatable morbidity and mortality. At the time of the Japanese attack on Pearl Harbor on December 7, 1941, no blood banks or effectual blood transfusion facilities were available. Most military locations had no stocks of dried pooled plasma. Although the wounded of that era were evacuated quickly to a hospital, the mortality rate was still high. IV fluids of any kind were essentially unavailable, except for a few liters of saline manufactured by means of a still in the operating room. IV fluid was usually administered by an old Salvesen flask and a reused rubber tube. Often, a severe febrile reaction resulted from the use of that tubing. The first written documentation of resuscitation in World War II patients was 1 year after Pearl Harbor, in December 1942, in notes from the 77th Evacuation Hospital in North Africa. E. D. Churchill stated, “The wounded in action had for the most part either succumbed or recovered from any existing shock before we saw them. However, later cases came to us in shock, and some of the early cases were found to be in need of whole blood transfusion. There was plenty of reconstituted blood plasma available. However, some cases were in dire need of whole blood. We had no transfusion sets, although such are available in the United States: no sodium citrate; no sterile distilled water; and no blood donors.” The initial decision to rely on plasma rather than on blood appears to have been based in part on the view held in the Office of the Surgeon General of the Army and in part on the opinion of the civilian investigators of the National Research Council. Those civilian investigators thought that, in shock, the blood was thick and the hematocrit level was high. On April 8, 1943, the Surgeon General stated that no blood would be sent to the combat zone. Seven months later, he again refused to send blood overseas because of the following: (1) his observation of overseas theaters had convinced him that plasma was adequate for resuscitation of wounded men; (2) from a logistics standpoint, it was impractical to make locally collected blood available farther forward than general hospitals in the combat zone; and (3) shipping space was too sparse. Vasoconstricting drugs such as epinephrine were

condemned because they were thought to decrease blood flow and tissue perfusion as they dammed the blood in the arterial portion of the circulatory system. During World War II, out of necessity, efforts to make blood transfusions available heightened and led to the institution of blood banking for transfusions. Better understanding of hypovolemia and inadequate circulation led to the use of plasma as a favored resuscitative solution, in addition to whole blood replacement. Thus, the treatment of traumatic shock greatly improved. The administration of whole blood was thought to be extremely effective, so it was widely used. Mixing whole blood with sodium citrate in a 6:1 ratio to bind the calcium in the blood, which prevented clotting, worked well. However, no matter what solution was used—blood, colloids, or crystalloids—the blood volume seemed to increase by only a fraction of what was lost. In the Korean War era, it was recognized that more blood had to be infused for the blood volume lost to be adequately regained. The reason for the need for more blood was unclear, but it was thought to be due to hemolysis, pooling of blood in certain capillary beds, and loss of fluid into tissues. Considerable attention was given to elevating the feet of patients in shock. 

PHYSIOLOGY OF SHOCK Bleeding Research and experience have both taught us much about the physiologic responses to bleeding. The advanced trauma life support (ATLS) course defines four classes of shock (Table 4.1). In general, that categorization has helped point out the physiologic responses to hemorrhagic shock, emphasizing the identification of blood loss and guiding treatment. Conceptually, shock occurs at three anatomical areas of the cardiovascular system (Fig. 4.5). The first level occurs at the heart where cardiogenic abnormalities can be either extrinsic (tension pneumothorax, hemothorax, or cardiac tamponade) or intrinsic (myocardial infarction causing pump failure, cardiac contusion or laceration, or cardiac failure). The second level occurs at the large or medium vessel level in which hemorrhage and loss of blood volume leads to shock. The last level occurs with the small vessels in which either neurologic dysfunction or sepsis leads to vasodilatation and maldistribution of the blood volume leading to shock. The four classes of shock according to the ATLS course are problematic as they were not rigorously tested or proven and were TABLE 4.1  ATLS classes of hemorrhagic

shock.

Blood loss (%) Central nervous system Pulse (beats/ min) Blood pressure Pulse pressure Respiratory rate Urine (mL/hr) Fluid

CLASS I

CLASS II

0–15 Slightly anxious 100 >120

>40 Confused or lethargic >140

Normal Normal 14–20/min >30 Crystalloid

Normal Decreased 20–30/min 20–30 Crystalloid

Decreased Decreased >35/min Negligible Crystalloid + blood

ATLS, Advanced trauma life support.

CLASS III

Decreased Decreased 30–40/min 5–15 Crystalloid + blood

CLASS IV

50

SECTION I  Surgical Basic Principles

admittedly arbitrarily generated. Patients often do not exhibit all of the physiologic changes described by this table, particularly those at age extremes. Due to higher water composition of their bodies, children are able to compensate with large volumes of blood loss, often exhibiting only tachycardia until they reach a tipping point where they are no longer able to compensate, at which point they have a rapid clinical decline. Elderly patients show almost an opposite physiology, as they are less equipped to compensate for blood loss and will show signs of a higher level of shock at a lower volume of blood loss. This is due to a reduced ability of cardiac compensation and fluid reserve recruitment. The problem with the signs and symptoms classically taught in ATLS classes is that, in reality, the manifestations of shock can be confusing and difficult to assess, particularly in trauma patients. For example, changes in mental status can be caused by blood loss, traumatic brain injury (TBI), pain, or illicit drugs. The same dilemma applies for respiratory rate and skin changes. Are alterations in a patient’s respiratory rate or skin color caused by pneumothorax, rib fracture pain, or inhalation injury? Although there are various methods that have been developed for monitoring patients in shock, BP continues to be the most clinically useful measure. When caring for a patient in shock, goals of resuscitation need to be established, remembering that baseline BP and blood volume are extremely variable and often unknown while initiating treatment. Although there is no single universally applicable endpoint of resuscitation, a combination of normalization of serum lactate, base deficit, pH, and hemorrhage control, if

applicable, are markers that can be considered along with the rest of the patient’s overall clinical status.10 Clinical symptoms are relatively few in patients who are in class I shock with the exception of anxiety. Is the anxiety after injury from blood loss, pain, trauma, or drugs? A heart rate higher than 100 beats/min has been used as a physical sign of bleeding, but evidence of its significance is minimal. Brasel and collegues11 have shown that heart rate was neither sensitive nor specific in determining the need for emergent intervention, the need for packed red blood cell (PRBC) transfusions in the first 2 hours after an injury, or the severity of the injury. Heart rate was not altered by the presence of hypotension (systolic BP 5 mg prednisone (or dose equivalent), consensus guidelines recommend glucocorticoid replacement dependent on the extent of the planned operation (Box 10.7).  Neoplastic Endocrinopathies A number of solid organ neoplasms secrete endogenous hormones. Functional pancreatic neoplasms can secrete excess BOX 10.7  Perioperative supplemental

glucocorticoid regimens.

No HPAA Suppression 15% in 3 months) or BMI 10). = Total score

Score ≥3: the patient is nutritionally at-risk and a nutritional care plan is initiated. Score 40 or 40 who have a risk factor for heart failure or poor exercise tolerance. The STOP-BANG questionnaire is a sensitive screening test for OSA.26 Routine implementation of this eight-question survey in the obese population can help direct formal polysomnography testing and anticipate difficult airway problems. 

PREOPERATIVE CONSIDERATIONS AND CARE PROTOCOLS Evaluation of the patient in the preoperative setting on the day of surgery provides the surgeon a final opportunity to assess readiness for the operation. Interval changes in clinical condition since the preceding consultation visit should be queried. A reevaluation of preexisting medications, including the timing of the most recent doses, is performed. Appropriate management of baseline anticoagulant and antiplatelet agents, including timing of the last dose, is confirmed. Informed consent is verified again with the patient to ensure that there is an accurate and appropriate understanding of the procedure’s objectives and risks. Orders relevant to the immediate perioperative setting are reviewed with the surgery and anesthesiology teams. Important to every operation is a review of the indications for antibiotic prophylaxis and venous thromboembolism prophylaxis. Perioperative care protocols, such as ERAS protocols and similarly designed pathways, facilitate the standardization of patient care including preoperative expectations, intraoperative management, and postoperative recovery.

Patient Recovery Pathways A number of patient recovery pathways have been designed and implemented to standardize perioperative care. The ERAS protocols are the best studied and supported by recent literature.

207

Initially introduced in the late 1990s and early 2000s, these pathways were initially implemented in colorectal surgery. Strengths include (1) standardization of care; (2) preoperative patient education, management of expectations, and assessing the need for prehabilitation; (3) intraoperative anesthetic strategies aimed at opioid avoidance and maintenance of intravascular euvolemia; and (4) a postoperative care pathway with standardized early mobilization, multimodality pain management and opioid minimization, avoidance of volume overload, and early resumption of diet.39 There has been a proliferation of ERAS-type protocols across abdominal general surgery, thoracic surgery, gynecologic surgery, orthopedics, and other surgical subspecialties. The protocols themselves are very granular, typically enumerating the specific timing of preoperative, intraoperative, and postoperative medications and patient expectations. Patient buy-in and acceptance by multidisciplinary staff including surgeon, anesthesiologist, and nursing staff are vital for success of these patient care pathways. While pathway implementation frequently demonstrates early improvements in postoperative metrics (such as infections, pain scores, length of stay, and others), demonstration of long-term sustained effects have been elusive in some studies. Standardized reporting of compliance and outcomes of such postoperative care protocols has been recommended to understand which elements and/or pathways are best supported by data. 

Antibiotic Prophylaxis Surgical site infections (SSIs) are among the most common causes of nosocomial infection and are associated with increased mortality and postoperative length of stay. SSIs are classified as superficial (involving only the skin or subcutaneous tissue), deep incisional (involving fascia or muscle), and organ space infections. Risk factors for SSIs are numerous, including age, obesity, smoking, malnourishment, diabetes, immunosuppression, radiation, and others. While many risk factors are not modifiable in the immediate perioperative setting, two of the simplest actionable measures that reduce the risk of SSIs are the appropriate selection of perioperative antibiotics and the administration of these antibiotics within 1 hour of incision. The Centers for Disease Control and Prevention (CDC) categorizes wounds into four classes: clean, clean-contaminated, contaminated, and dirty-infected (Table 10.11). While useful from the standpoint of academic inquiry, recent research has reported limited utility of wound classification, as well as frequent misclassification of surgical incisions as a risk factor for postoperative complications,40 Antimicrobial prophylaxis may be justified regardless of wound classification for patients at particularly high

TABLE 10.11  Wound classification. WOUND CLASSIFICATION

DEFINITION

Clean

An uninfected operative wound in which no inflammation is encountered and the respiratory, alimentary, genital, or uninfected urinary tracts are not entered. Operative wounds in which the respiratory, alimentary, genital, or urinary tracts are entered under controlled conditions and without unusual contamination. Specifically, operations involving the biliary tract, appendix, vagina, and oropharynx, provided no evidence of infection or major break in technique is encountered. Open, fresh, accidental wounds. In addition, operations with major breaks in sterile technique or gross spillage from the gastrointestinal tract and incisions in which acute, nonpurulent inflammation is encountered, including necrotic tissue without evidence of purulent drainage. Old traumatic wounds with retained devitalized tissue and those that involve existing clinical infection or perforated viscera. Organisms causing postoperative infection were present in the operative field before the operation.

Clean-Contaminated

Contaminated

Dirty-Infected Adapted from www.cdc.gov.

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SECTION II  Perioperative Management

risk for SSI due to underlying medical conditions. Nevertheless, unless an indwelling prosthesis is anticipated, antibiotic prophylaxis generally is not required for clean wounds. The Clinical Practice Guidelines for Antimicrobial Prophylaxis in Surgery, a collaborative rubric developed in 2013, provides surgery-specific recommendations for antibiotic prophylaxis (Table 10.12).41 Selection of appropriate prophylaxis is guided by a few core principles. First, an antimicrobial agent is chosen to target common surgical site pathogens. Clean procedures encounter primarily skin flora, predominantly Staphylococcus aureus and coagulase-negative staphylococcus. Coverage for gram-negative rods and enterococci should be added for clean-contaminated cases involving abdominal viscera, the biliary tract, and the heart. Commonly used FDA-approved agents include cefazolin, cefoxitin, cefotetan, and vancomycin. For most operations, cefazolin is an appropriate choice given its low cost, antimicrobial spectrum, and duration of activity. For patients colonized with methicillinresistant Staphylococcus aureus, vancomycin may be an appropriate alternative. The second consideration in antimicrobial prophylaxis is timing of the first dose. Historic data from the early 1990s suggested that the lowest rate of surgical wound infection was associated with antibiotic administration within 2 hours prior to incision, compared to earlier or postoperative administration. However, the more recent Trial to Reduce Antimicrobial Prophylaxis Errors, a prospective, multicenter trial comparing antimicrobial timing before a variety of operations, reported the lowest infection risk when antibiotics were administered within 30 minutes of incision or between 31 and 60 minutes before incision.42 As such, current data support administration of the first dose of prophylactic antibiotics within 60 minutes before surgical incision. For antibiotics that require longer infusion times (vancomycin, fluoroquinolones), administration may begin within 120 minutes before incision. Redosing of antibiotics should be performed to maintain therapeutic serum levels, generally after every two half-lives or if there is blood loss greater than 1500 mL (Table 10.13). Duration of antimicrobial administration should be limited to the minimal effective length appropriate for each procedure. Most clean and clean-contaminated operations do not require postoperative antimicrobial administration; when indicated, postoperative antimicrobials should be limited to less than 24 hours. The evidence for short-duration or single-dose prophylaxis in cardiothoracic surgery has been inconsistent, and optimal antimicrobial duration following these operations remains contentious. While the Society of Thoracic Surgeons recognizes risks for resistance and superinfection with Clostridium difficile with prolonged antibiotic administration, there is evidence that antibiotic duration up to 48 hours reduces the risk of a sternal wound infection. Thus, the Surgical Infection Society and the Society of Thoracic Surgeons both recommend consideration of antimicrobial prophylaxis for up to 48 hours after cardiothoracic surgery. 

Review of Medications Management of home medications on the day of surgery should be tailored to the patient and the operation. The objective is to minimize disruption of baseline homeostasis while limiting risks of surgical bleeding and drug-drug interactions with anesthetic medications. A preoperative review of medications is mandatory, with attention to cardiac, psychiatric, neurologic, and diabetic medications, as well as to anticoagulants and antiplatelet agents. In general, cardiac drugs and inhalers should be continued on the morning of surgery. In the postoperative setting, parenteral

substitutes should be administered as indicated to minimize therapeutic lapse and avoid withdrawal symptoms such as rebound hypertension. Drugs that impact perioperative bleeding risk should be discontinued preoperatively based on the drug’s half-life. Institutional guidelines regarding timing for withholding antiplatelets and anticoagulants prior to local analgesic procedures such as epidural placement or spinal/regional blockade should be reviewed with the patient during the preoperative clinic visit. Herbal supplements, vitamins, oral contraceptives, and hormonal therapies are often underreported. Estrogen and tamoxifen should be held for 4 weeks preoperatively due to thromboembolic risk. Many herbal medicines can impact perioperative physiology and should be stopped days to weeks prior to surgery (Table 10.14). 

Preoperative Fasting Bronchopulmonary aspiration can be a life-threatening complication in the perioperative setting. Limiting preoperative oral intake is intended to reduce gastric volume during induction with the objective of minimizing aspiration risk. There is growing evidence, however, that the traditional protocol of fasting prior to surgery is not required for aspiration risk reduction. The ASA provided updated practice guidelines for preoperative fasting in 2017. Broadly, clear liquids—with or without carbohydrate supplementation— are permissible up to 2 hours before elective procedures requiring general anesthesia or procedural sedation. Breast milk may be ingested up to 4 hours before elective procedures. To date, evidence for a specific duration of solid food fasting is lacking. Current guidelines indicate that a light meal may be permissible for up to 6 hours before elective procedures; however, this interval may be lengthened for heavier meals and for patients at higher risk for aspiration (Table 10.15). The ASA does not recommend routine administration of gastrointestinal stimulants, antacids, antiemetics, or anticholinergics for the purpose of reducing aspiration risk or shortening the recommended preoperative fasting period. 

OPERATING ROOM Adequate preparation of the operating room—to ensure the availability and functionality of systems-based resources (e.g., videoendoscopic accessibility, anesthesia team, and blood products) and surgical equipment (e.g., instrument sets, stapler, and/or energy devices)—is as critical to a successful operation as appropriate patient selection and preoperative evaluation. Systems-based resources include operating room particulars such as temperature control, presurgical cleaning, and availability of anesthesia, pathology, and consultative services. Appropriate preoperative communication with the anesthesia team is imperative, especially when specific perioperative challenges are anticipated. Examples include patients with high-risk cardiac disease, those with significant underlying liver and/or kidney disease, or patients scheduled for high-risk operations where appropriate intraoperative hemodynamic and volume management is imperative. Recent implementation of patient recovery pathways has standardized many aspects of anesthetic care; however, active communication between the surgery and anesthesiology teams remains important to assure the most appropriate intraoperative management. Additional system-based resources include medications and products necessary in the immediate perioperative period such as analgesics, fluids, blood products, antibiotics, anticoagulants, and vasoactive drugs. Also important is the presence of appropriate surgical assistance and back-up. Despite

TABLE 10.12  Recommendations for surgical antimicrobial prophylaxis.

TYPE OF PROCEDURE

RECOMMENDED AGENTSa,b

ALTERNATIVE AGENTS IN PATIENTS WITH β-LACTAM ALLERGY

Cardiac coronary artery bypass Cardiac device insertion procedures (e.g., pacemaker implantation) Ventricular assist devices Thoracic noncardiac procedures, including lobectomy, pneumonectomy, lung resection, and thoracotomy Video-assisted thoracoscopic surgery Gastroduodenale procedures involving entry into lumen of gastrointestinal tract (bariatric, pancreaticoduodenectomyf) Procedures without entry into gastrointestinal tract (antireflux, highly selective vagotomy) for high-risk patients Biliary tract open procedure

Cefazolin, cefuroxime Cefazolin, cefuroxime

Clindamycin,d vancomycind Clindamycin, vancomycin

A A

Cefazolin, cefuroxime Cefazolin, ampicillin-sulbactam

Clindamycin, vancomycin Clindamycin,d vancomycind

C A

Cefazolin, ampicillin-sulbactam Cefazolin

Clindamycin,d vancomycind Clindamycin or vancomycin + aminoglycosideg or aztreonam or fluoroquinoloneh–j Clindamycin or vancomycin + aminoglycosideg or aztreonam or fluoroquinoloneh–j Clindamycin or vancomycin + aminoglycosideg or aztreonam or fluoroquinolone,h–j metronidazole + aminoglycosideg or fluoroquinoloneh–j

C A

  Laparoscopic procedure   Elective, low riskl   Elective, high riskl

Appendectomy for uncomplicated appendicitis

Small intestine  Nonobstructed  Obstructed Hernia repair (hernioplasty and herniorrhaphy) Colorectalm

Head and neck clean Clean with placement of prosthesis (excludes tympanostomy tubes) Clean-contaminated cancer surgery Other clean-contaminated procedures with the exception of tonsillectomy and functional endoscopic sinus procedures Neurosurgery elective craniotomy and cerebrospinal fluid–shunting procedures Implantation of intrathecal pumps Cesarean delivery Hysterectomy (vaginal or abdominal)

Ophthalmic

Cefazolin

Cefazolin, cefoxitin, cefotetan, ceftriaxone,k ampicillin-sulbactamh

None Cefazolin, cefoxitin, cefotetan, ceftriaxone,k ampicillin-sulbactamh

Cefoxitin, cefotetan, cefazolin + metronidazole

STRENGTH OF EVIDENCEc

A

A

None A Clindamycin or vancomycin + A aminoglycosideg or aztreonam or fluoroquinolone,h–j metronidazole + aminoglycosideg or fluoroquinoloneh–j Clindamycin + aminoglycosideg or aztreonam A or fluoroquinolone,h–j metronidazole + aminoglycosideg or fluoroquinoloneh–j

Clindamycin + aminoglycosideg or aztreonam or fluoroquinoloneh–j Cefazolin + metronidazole, cefoxitin, Metronidazole + aminoglycosideg or cefotetan fluoroquinoloneh–j Cefazolin Clindamycin, vancomycin Cefazolin + metronidazole, cefoxitin, Clindamycin + aminoglycosideg or aztreonam h cefotetan, ampicillin-sulbactam, or fluoroquinolone,h–j metronidazole + ceftriaxone + metronidazole,n ertapenem aminoglycosideg or fluoroquinoloneh–j None None Cefazolin, cefuroxime Clindamycind Cefazolin

C C A A

B C

Cefazolin + metronidazole, cefuroxime + metronidazole, ampicillin-sulbactam Cefazolin + metronidazole, cefuroxime + metronidazole, ampicillin-sulbactam

Clindamycind

A

Clindamycind

B

Cefazolin

Clindamycin,d vancomycind

A

Clindamycin,d vancomycind Clindamycin + aminoglycosideg Clindamycin or vancomycin + aminoglycosideg or aztreonam or fluoroquinolone,h–j metronidazole + aminoglycosideg or fluoroquinoloneh–j Topical neomycin-polymyxin B-gramicidin or None fourth-generation topical fluoroquinolones (gatifloxacin or moxifloxacin) given as 1 drop every 5–15 minutes for 5 doses.o Addition of cefazolin 100 mg by subconjunctival injection or intracameral cefazolin 1–2.5 mg or cefuroxime 1 mg at the end of procedure is optional. Cefazolin Cefazolin Cefazolin, cefotetan, cefoxitin, ampicillinsulbactamh

C A A

B

Continued

TABLE 10.12  Recommendations for surgical antimicrobial prophylaxis.—cont’d

TYPE OF PROCEDURE Orthopedic clean operations involving hand, knee, or foot and not involving implantation of foreign materials Spinal procedures with and without instrumentation Hip fracture repair Implantation of internal fixation devices (e.g., nails, screws, plates, wires) Total joint replacement Urologic lower tract instrumentation with risk factors for infection (includes transrectal prostate biopsy) Clean without entry into urinary tract

Involving implanted prosthesis

Clean with entry into urinary tract

RECOMMENDED AGENTSa,b None

ALTERNATIVE AGENTS IN PATIENTS WITH β-LACTAM ALLERGY None

STRENGTH OF EVIDENCEc C

Cefazolin Cefazolin Cefazolin

Clindamycin,d vancomycind Clindamycin,d vancomycind Clindamycin,d vancomycind

A A C

Cefazolin Fluoroquinolone,h-j trimethoprimsulfamethoxazole, cefazolin

Clindamycin,d vancomycind Aminoglycosideg with or without clindamycin

A A

Cefazolin (addition of a single dose of an aminoglycoside may be recommended for placement of prosthetic material [e.g., penile prosthesis]) Cefazolin ± aminoglycoside, cefazolin ± aztreonam, ampicillin-sulbactam

Clindamycin,d vancomycind

A

Cefazolin (addition of a single dose of an aminoglycoside may be recommended for placement of prosthetic material [e.g., penile prosthesis]) Cefazolin + metronidazole, cefoxitin

Clindamycin ± aminoglycoside or A aztreonam, vancomycin ± aminoglycoside or aztreonam A Fluoroquinolone,h–j aminoglycosideg ± clindamycin

Vascularp Heart, lung, heart-lung transplantationq; heart transplantationr Lung and heart-lung transplantationr,s

Cefazolin Cefazolin

Fluoroquinolone,h–j aminoglycosideg + metronidazole or clindamycin Clindamycin,d vancomycind Clindamycin,d vancomycind

Cefazolin

Clindamycin,d vancomycind

Liver transplantationq,t

Piperacillin-tazobactam, cefotaxime + ampicillin

Pancreas and pancreas-kidney transplantationr

Cefazolin, fluconazole (for patients at high risk of fungal infection [e.g., patients with enteric drainage of the pancreas]) Cefazolin

Clindamycin or vancomycin + aminoglycosideg or aztreonam or fluoroquinoloneh–j Clindamycin or vancomycin + aminoglycosideg or aztreonam or fluoroquinoloneh–j Clindamycin or vancomycin + aminoglycosideg or aztreonam or fluoroquinoloneh–j Clindamycin,d vancomycind

Clean-contaminated

Plastic surgery clean with risk factors or cleancontaminated

Cefazolin, ampicillin-sulbactam

A A A (based on cardiac procedures) A (based on cardiac procedures) B

A

A

C

From Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70:195–283. aThe antimicrobial agent should be started within 60 minutes before surgical incision (120 minutes for vancomycin or fluoroquinolones). Although single-dose prophylaxis is usually sufficient, the duration of prophylaxis for all procedures should be 70 years, conversion from laparoscopic to open cholecystectomy, American Society of Anesthesiologists classification of ≥3, episode of colic within 30 days before the procedure, reintervention in 1 L/h should be prewarmed. 

Preoperative Skin Preparation SSIs comprise more than 20% of all hospital-acquired infections and are associated with increased length of stay, mortality, and cost. Commensal skin bacteria (Staphylococci, Pseudomonas, etc.) are responsible for the majority of superficial SSIs. Preoperative antiseptic skin preparation reduces the number of transient and commensal microorganisms. The CDC guidelines recommend the following techniques for application: (1) wide area to include

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Patient Safety

Surgical Safety Checklist Before induction of anaesthesia (with at least nurse and anaesthetist) Has the patient confirmed his/her identity, site, procedure, and consent? Yes Is the site marked? Yes Not applicable Is the anaesthesia machine and medication check complete? Yes Is the pulse oximeter on the patient and functioning? Yes Does the patient have a: Known allergy? No Yes Difficult airway or aspiration risk? No Yes, and equipment/assistance available Risk of >500 mL blood loss (7 mL/kg in children)? No Yes, and two IVs/central access and fluids planned

Before skin incision

Before patient leaves operating room

(with nurse, anaesthetist, and surgeon) Confirm all team members have introduced themselves by name and role.

(with nurse, anaesthetist, and surgeon) Nurse Verbally Confirms: The name of the procedure Completion of instrument, sponge, and needle counts Specimen labelling (read specimen labels aloud, including patient name) Whether there are any equipment problems to be addressed

Confirm the patient’s name, procedure, and where the incision will be made. Has antibiotic prophylaxis been given within the last 60 minutes? Yes Not applicable Anticipated Critical Events

To Surgeon, Anaesthetist, and Nurse:

To Surgeon: What are the critical or nonroutine steps?

What are the key concerns for recovery and management of this patient?

How long will the case take? What is the anticipated blood loss? To Anaesthetist: Are there any patient-specific concerns? To Nursing Team: Has sterility (including indicator results) been confirmed? Are there equipment issues or any concerns? Is essential imaging displayed? Yes Not applicable

FIG. 10.6  Surgical safety checklist published by the World Health Organization. (From https://www.who.int/p atientsafety/safesurgery/checklist/en/.) IV, Intravenous;

any potential incision sites, (2) concentric circle motion, (3) use of a dedicated application instrument, and (4) adequate time to allow the solution to dry. Hair removal prior to incision can improve exposure and allow skin marking. However, hair should only be removed with a clipper, as shaving is associated with increased SSI risk. The benefits of skin preparation depend upon the antiseptic solution used. Common solutions include povidone-iodine scrub and paint (Betadine), chlorhexidine-alcohol scrub (ChloraPrep), and iodine povacrylex with isopropyl alcohol (DuraPrep). Alcohol-containing solutions should be avoided for mucosal surfaces. The optimal choice of antiseptic for intact skin remains controversial. Most randomized trials in the past comparing antiseptic solutions are underpowered. A Cochrane review in 2015 indicated that alcohol-containing products have the greatest probability of being effective but noted the overall low quality of evidence.43 A multi-institutional randomized comparison of chlorhexidinealcohol versus povidone-iodine scrub and paint for clean-contaminated surgeries found a lower rate of SSI in the chlorhexidine-alcohol group (9.5% versus 16.1%).44 Recently, a single-institution randomized trial of colorectal operations failed to conclude noninferiority of DuraPrep compared to ChloraPrep, with SSI rates of 18.7% vs. 15.9%, respectively. Therefore, based on these data, a skin preparation that contains an alcohol-based agent as part of the preparation appears optimal. 

Hemostasis Meticulous dissection and intimate knowledge of surgical anatomy are mandatory for minimization of intraoperative blood loss. Surgical bleeding obscures the operative field, prolongs operating

time, increases hemodynamic stress, induces coagulopathy, and makes postoperative resuscitation more challenging. For certain cancers, perioperative blood transfusion has been consistently associated with an increased risk of recurrence and a decrease in survival. While capillaries and small veins can be controlled and divided with monopolar electrocautery alone, vessels >1 mm in diameter—including all named vessels—are best controlled with ties, clips, staples, bipolar electrocautery, or ultrasonic devices. To prevent dislodgement of ties or clips, larger vessels may be controlled by suture ligation. Traditionally, vascular structures are ligated with permanent suture material, although use of absorbable suture has not been associated with increased risk of bleeding or reoperation. With the rapid expansion of minimally invasive operations and the associated explosion in manufactured surgical devices, numerous alternatives to the traditional hand-tied ligation have been marketed and popularized. In addition to minimally invasive (robotic or laparoscopic) surgical ties, endoloops are most similar to the hand-tie, with similar vessel burst pressures comparable to hand-ties. On the other end of the spectrum, stapling devices armed with vascular staple loads tolerate lower—but still supraphysiologic—burst pressures (Fig. 10.7). 

Wound Closure In general, incisions for clean and clean-contaminated operations can be closed primarily. Primary fascial closure can utilize permanent or dissolvable suture using running or interrupted techniques. Permanent suture is best suited for malnourished, debilitated patients and for scenarios in which early outpatient follow-up is anticipated. Dissolvable suture, particularly when

CHAPTER 10  Principles of Preoperative and Operative Surgery Burst pressure vs. method

Pressure (mm Hg)

5000 4000 3000 2000 1000 0 EL

EB HS EC LS JR ES Flex GIA LC Method

FIG. 10.7  Burst pressure of porcine carotid artery by sealing method. EB, ethibond hand-tie; EC, endoclip; EL, endoloop; ES, enseal; Flex, endopath stapler; GIA, endo GIA stapler; HS, harmonic scalpel; JR, JustRight; LC, proximate linear cutter; LS, ligaSure. (Adapted from Tharakan SJ, Hiller D, Shapiro RM, et al. Vessel sealing comparison: OLD school is still hip. Surg Endosc. 2016;30:4653–4658.)

used in the subcuticular layer, can often create a cosmetically appealing closure that does not require suture removal. When an incision is anticipated to be under significant tension, vertical mattress sutures distribute tension over two levels of depth at every longitudinal point and approximate the dermal layers effectively. Running suture techniques—especially when used across multiple layers—are more effective at controlling ascites, while interrupted suture allows intermittent wound packing for incisions at high risk for superficial SSI. Delayed primary closure may be suitable for carefully-selected patients following contaminated operations. Delayed closure is commonly attempted between 2 and 5 days following the index operation. While there is some evidence that delayed primary closure is associated with a reduction in SSI compared to primary closure, there is substantial heterogeneity across existing trials. Heavily contaminated dirty surgical wounds should be left open, allowing for healing by secondary intent with serial packing. Management of open wounds, in particular during the outpatient recovery period, can often be facilitated by applying a negative pressure vacuum device. Temporary closure of abdominal incisions is useful when a short-interval second-look laparotomy is anticipated, when there is threat of compartment syndrome, and when monitoring of intraabdominal contents is prudent. In almost all cases, temporary closure involves a nonadherent material used as a bridge across an open fascial incision. Traditionally, this was commonly achieved using fenestrated plastic in the form of an IV bag, surgical towel, or cassette covering, covered by foam or surgical towels. An airtight seal is achieved by placing a vacuum drain over the device and covering the bridge with Ioban. The vacuum mechanism reduces intraabdominal fluid accumulation. It also provides a means of monitoring for bleeding, visceral compromise, or infection and has a retention effect that counteracts natural abdominal wall retraction. However, care should be taken to monitor fluid and electrolyte balance in these patients, as massive fluid shifts can occur rapidly. More recently, dedicated vacuum-assisted closure devices

215

such as the V.A.C. Abdominal Dressing System and the ABThera System have gained popularity due to ease of application. Delayed primary fascial closure should be achieved when possible within 7 to 10 days.45 If this is not possible, serial closure should be initiated using devices such as a Wittman patch, which may be serially tightened every 24 to 48 hours. Once the fascia is less than a few centimeters apart, definitive fascial closure can be attempted. The downside to this technique is that application of a Wittman patch requires suturing the patch to native fascia, which can compromise fascial integrity. For malnourished patients and those who cannot tolerate the abdominal pressure associated with serial closure, an absorbable mesh bridge can allow visceral coverage during the acute phase of illness. However, loss of domain and a large complex hernia will result. More recently, bioprosthetic dermal matrices have gained favor as an alternative material for fascial bridging. Derived from cadaveric dermis (porcine, human, or bovine), acellular dermal matrix is devoid of all cellular components while retaining the extracellular matrix and basement membrane. This structure promotes fibroblast incorporation and collagen deposition and remodeling. Early revascularization results in greater resistance to infection than permanent mesh, while collagen deposition and retained extracellular matrix lend acellular dermal matrix a more durable tensile strength and flexibility than absorbable mesh. However, there is a paucity of large published series capturing experience with acellular dermal matrix, and recurrent hernia and abdominal laxity may develop with longer follow-up. Use of barrier agents for adhesion prevention has gained popularity over recent years, particularly for patients for whom multiple operations are anticipated. Agents include oxidized regenerated cellulose, polytetrafluoroethylene, and hyaluronic acidcarboxymethylcellulose. These materials are applied to the raw surfaces of abdominal viscera and degenerate into gelatin shortly after surgery. A metaanalysis within the gynecologic literature noted low-quality evidence of efficacy for all three materials over no treatment; however, the relative efficacy between agents remains unclear.46 

Surgical Adhesives Tissue adhesives for skin closure were first introduced in the early 1960s. Over the last 25 years, improved tensile strength was brought about by plastic and stabilizer composites. The most common adhesives are Dermabond (octylcyanoacrylate) and Histoacryl (butylcyanoacrylate). Inherent benefits of tissue adhesives include water impermeability, low infection rate, and improved cosmesis. Adhesives can be used without skin sutures for small incisions and is commonly adopted in this manner in the emergency room setting. For larger incisions, tissue adhesives are more commonly used to provide a watertight barrier following subcuticular or dermal closure with absorbable suture. A recent metaanalysis found no significant difference between tissue adhesives and sutures in terms of dehiscence, infection, and surgeon-rated cosmesis. Fibrin sealant confers both adhesive and hemostatic functions. Blood bank–derived fibrin sealant functions by combining thrombin and fibrinogen to replicate the final step in the clotting cascade. Because the agent contains all necessary components for this reaction, it forms a clot regardless of a patient’s intrinsic pathway status. Some data have suggested that the addition of fibrin sealant can serve as a hemostatic adjunct to manual compression in controlling anastomotic hemorrhage following insertion of polytetrafluoroethylene vascular grafts. Although fibrin sealant also has been approved as an adjunct for gastrointestinal

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anastomoses, application for this purpose has not gained widespread popularity. Fibrin agents have been adopted for a variety of other clinical applications. For perianal fistulae, fibrin glue avoids an adverse impact on continence; however, it exhibits inferior durability compared to conventional surgical treatment. Fibrin glue has been used to treat bronchopleural fistulae, either as a direct injection of fibrinogen followed by topical thrombin or as a diluted pleurodesis agent. As is true for many manufactured and marketed products, primary study data need to be reviewed critically to estimate potential benefit and to balance this benefit against potential harm, noninferiority of alternatives, and associated cost. 

SURGICAL DEVICES, ENERGY SOURCES, AND STAPLERS Technologic advances in energy devices and tissue stapling have revolutionized the way surgeons approach dissection, division, hemostasis, and reconstruction. Energy devices as a whole direct focused energy to the target tissue with the purpose of dissection and division, coagulation, or ablation and cytotoxicity. Stapling devices are traditionally used for alimentary tract division and anastomosis but can also be used for vascular and tissue transection. This section focuses on some of the common energy and stapling devices encountered in the operating room.

Electrosurgery and Electrocautery While use of electricity to induce thermal cauterization and tissue division has been reported since the mid-1800s, modern electrosurgery as we know it was introduced between 1914 and 1927 by William T Bovie. Diathermy, first described by Karl Franz in 1909, uses high-frequency electric currents to generate heat and penetrate tissues. Bovie developed a commercially available alternating current cautery device between 1914 and 1927, and Harvey Cushing popularized it with a 1928 report of 500 neurosurgical procedures. Monopolar Electrosurgery In strict terms, electrocautery implies thermal conduction via a probe heated by a direct electrical current. In modern surgery, this technology most commonly is seen with portable, pen-type cautery devices that function like a soldering iron. Electrosurgery, on the other hand, indicates conduction of an alternating radiofrequency current through a circuit that is completed by the patient’s tissue. However, these two terms are often used interchangeably. Classically, monopolar electrosurgery is performed using a current generator, a handheld electrode that delivers current to the patient, and a second large electrode (the “pad”) that returns current to complete the circuit. The application electrode has a small area of contact, resulting in focused thermal conversion, while the returning electrode has a large surface area to dissipate energy. With a continuous waveform (“cut” mode), the monopolar device cuts through tissue with little thermal spread and minimal coagulation. With an intermittent waveform (“coagulation” mode), current is delivered over less than 10% of the time that the device is activated and is interspersed with short periods of inactivity. The result is lower thermal energy and greater thermal spread, resulting in tissue dehydration and vessel thrombosis. Many surgeons adopt a blended waveform setting (“blend” mode), which replaces the pure cutting function with small periods of current inactivity to achieve a partial coagulative effect.  Bipolar Electrosurgery Bipolar devices place the delivering and returning electrodes in close proximity in a single device. In this way, the tissue in between

the two electrodes completes the electric circuit. A grounding pad is unnecessary, and thermal spread beyond the tissue between the two electrodes is minimal. By compressing vascularized tissue using bipolar forceps, blood is excluded from the circuit, improving heat delivery to the compressed tissue. Bipolar devices are most useful when precise coagulation is necessary in close proximity to vital structures. Because current is only delivered across tissue between the two hand-held electrodes, bipolar devices are safe to use when a patient has an implanted electronic device that may otherwise be impacted by the delivery of monopolar current.  LigaSure and Enseal Adaptations of bipolar electrosurgery are bipolar fusion devices such as LigaSure and Enseal. Similar to conventional bipolar electrosurgery, these tissue dissection and division devices transmit current between two adjacent electrodes, causing tissue coagulation. By applying uniform compression of the target tissue and monitoring tissue impedance between the jaws of the instrument, these devices adjust energy delivery during the activation process to minimize thermal spread and seal larger vessels (up to 7 mm). Denaturation followed by cross-linking of collagen and elastin results in a natural tissue sealant. A blade within the instrument then divides the sealed tissue.  Saline-Cooled Radiofrequency Dissectors A commonly encountered problem when using radiofrequency electrosurgery within highly vascularized parenchyma is the formation of dense eschar that limits coagulation and may result in delayed hemorrhage. Eschar formation occurs when temperature at the contact surface of the target tissue exceeds what is necessary for protein denaturation and vessel sealing. Saline-cooled radiofrequency dissectors (i.e., TissueLink, Aquamantys) overcome this issue by directing a steady irrigation stream of saline to the tissue contact point, thereby maintaining surface temperature 5.5; pregnancy-specific exclusions—complicated pregnancy, fetus >21 weeks, gestation; and other high-risk patient comorbidities—muscular dystrophy, highly contagious airborne infections (e.g., tuberculosis), high-risk for hemorrhage, and others. Patients with chronic reflux, difficult airway, or poorly controlled diabetes are at heightened risk of anesthesia-related complications and should be considered for outpatient surgery only at centers with capabilities for postoperative admission. Patients considered for outpatient surgery should have adequate supportive resources following discharge. Following sedation, a patient should not be responsible for transportation home and should have an adult to take them home and be available overnight to provide help if needed. Ideally, emergency care facilities should be readily accessible near the patient’s residence should unforeseen complications arise. Absence of these outpatient resources should prompt consideration of elective postoperative hospitalization for observation.

SELECTED REFERENCES Bilimoria KY, Liu Y, Paruch JL, et al. Development and evaluation of the universal ACS NSQIP surgical risk calculator: a decision aid and informed consent tool for patients and surgeons. J Am Coll Surg. 2013;217:833–842; e831–833. Study summarizing development and implementation of the American College of Surgeons National Surgical Quality Improvement Surgical Risk Calculator. The risk calculator is available online to estimate patient-specific postoperative risk of selected morbidities and mortality.

Chow WB, Rosenthal RA, Merkow RP, et  al. Optimal preoperative assessment of the geriatric surgical patient: a best practices guideline from the American College of Surgeons National Surgical Quality Improvement Program and the American Geriatrics Society. J Am Coll Surg. 2012;215:453–466. Summary of the best practice management guidelines for geriatric surgical patient developed in collaboration between the American Geriatrics Society and the American College of Surgeons National Surgical Quality Improvement Program.

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Canet J, Gallart L, Gomar C, et  al. Prediction of postoperative pulmonary complications in a population-based surgical cohort. Anesthesiology. 2010;113:1338–1350. A large prospective study summarizing risk factors associated with postoperative pulmonary complication.

Devereaux PJ, Mrkobrada M, Sessler DI, et  al. Aspirin in patients undergoing noncardiac surgery. N Engl J Med. 2014;370:1494–1503. A randomized control trial demonstrating no significant protective effect of aspirin on 30-day mortality or nonfatal myocardial infarction in perioperative noncardiac surgery patients.

Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med. 2015;373:823–833. A randomized control trial establishing safety of foregoing bridging anticoagulation for patients with atrial fibrillation requiring temporary interruption of chronic anticoagulation for elective invasive procedure or operation.

Douketis JD, Spyropoulos AC, Spencer FA, et  al. Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141:e326S–e350S. Summary of the best practice management guidelines for management of antithrombotic medications in prevention of venous thromboembolism.

Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/ AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2014;64:e77–e137. Summary of the best practice management guidelines for preoperative cardiovascular evaluation and management developed in collaboration between the American College of Cardiology and The American Heart AssociationTask Force.

Holst LB, Haase N, Wetterslev J, et al. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med. 2014;371:1381–1391. A randomized control trial demonstrating safety of lower packed red blood cell transfusion threshold (7 g/dL) among critically ill patients with septic shock.

Lee TH, Marcantonio ER, Mangione CM, et  al. Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation. 1999;100:1043–1049. Study summarizing development and validation of the Revised Cardiac Risk Index, which has served as a backbone for study and risk stratification of patients considered for elective operation.

Steinberg JP, Braun BI, Hellinger WC, et al. Timing of antimicrobial prophylaxis and the risk of surgical site infections: results from the Trial to Reduce Antimicrobial Prophylaxis Errors. Ann Surg. 2009;250:10–16. Study summarizing association between timing of administration of antimicrobial prophylaxis and postoperative surgical site infection.

REFERENCES 1. Hyder JA, Reznor G, Wakeam E, et al. Risk prediction accuracy differs for emergency versus elective cases in the ACSNSQIP. Ann Surg. 2016;264:959–965. 2. Kluger Y, Ben-Ishay O, Sartelli M, et  al. World society of emergency surgery study group initiative on Timing of Acute Care Surgery classification (TACS). World J Emerg Surg. 2013;8:17. 3. Hopkins TJ, Raghunathan K, Barbeito A, et al. Associations between ASA physical status and postoperative mortality at 48 h: a contemporary dataset analysis compared to a historical cohort. Perioper Med (Lond). 2016;5:29. 4. Glance LG, Lustik SJ, Hannan EL, et  al. The Surgical Mortality Probability Model: derivation and validation of a simple risk prediction rule for noncardiac surgery. Ann Surg. 2012;255:696–702. 5. Bilimoria KY, Liu Y, Paruch JL, et al. Development and evaluation of the universal ACS NSQIP surgical risk calculator: a decision aid and informed consent tool for patients and surgeons. J Am Coll Surg. 2013;217:833–842; e831–833. 6. Liu Y, Cohen ME, Hall BL, et al. Evaluation and enhancement of calibration in the American College of Surgeons NSQIP Surgical Risk Calculator. J Am Coll Surg. 2016;223:231–239. 7. Bagnall NM, Pucher PH, Johnston MJ, et al. Informing the process of consent for surgery: identification of key constructs and quality factors. J Surg Res. 2017;209:86–92. 8. Kinnersley P, Phillips K, Savage K, et al. Interventions to promote informed consent for patients undergoing surgical and other invasive healthcare procedures. Cochrane Database Syst Rev. 2013:CD009445. 9. Chow WB, Rosenthal RA, Merkow RP, et al. Optimal preoperative assessment of the geriatric surgical patient: a best practices guideline from the American College of Surgeons National Surgical Quality Improvement Program and the American Geriatrics Society. J Am Coll Surg. 2012;215:453–466. 10. Partridge JS, Harari D, Martin FC, et al. The impact of preoperative comprehensive geriatric assessment on postoperative outcomes in older patients undergoing scheduled surgery: a systematic review. Anaesthesia. 2014;69(suppl 1):8–16. 11. Borson S, Scanlan J, Brush M, et al. The mini-cog: a cognitive “vital signs” measure for dementia screening in multi-lingual elderly. Int J Geriatr Psychiatry. 2000;15:1021–1027. 12. Postoperative delirium in older adults: best practice statement from the American Geriatrics Society. J Am Coll Surg. 2015;220:136–148 e131. 13. American Geriatrics Society 2015 Updated beers criteria for potentially inappropriate medication use in older Adults. J Am Geriatr Soc. 2015;63:2227–2246. 14. Knittel JG, Wildes TS. Preoperative assessment of geriatric patients. Anesthesiol Clin. 2016;34:171–183. 15. Larsen KD, Rubinfeld IS. Changing risk of perioperative myocardial infarction. Perm J. 2012;16:4–9.

CHAPTER 10  Principles of Preoperative and Operative Surgery 16. Podsiadlo D, Richardson S. The timed “up & go”: a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc. 1991;39:142–148. 17. Huisman MG, van Leeuwen BL, Ugolini G, et al. “Timed up & go”: a screening tool for predicting 30-day morbidity in onco-geriatric surgical patients? A multicenter cohort study. PLoS One. 2014;9:e86863. 18. Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery): developed in collaboration with the American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, and Society for Vascular Surgery. Circulation. 2007;116:1971–1996. 19. Lee TH, Marcantonio ER, Mangione CM, et al. Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation. 1999;100:1043–1049. 20. Fleisher LA, Fleischmann KE, Auerbach AD, et  al. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/ American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2014;64:e77–137. 21. Ainsworth BE, Haskell WL, Herrmann SD, et  al. 2011 Compendium of Physical Activities: a second update of codes and MET values. Med Sci Sports Exerc. 2011;43:1575–1581. 22. Wijeysundera DN, Duncan D, Nkonde-Price C, et  al. Perioperative beta blockade in noncardiac surgery: a systematic review for the 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130:2246–2264. 23. Smetana GW, Lawrence VA, Cornell JE. Preoperative pulmonary risk stratification for noncardiothoracic surgery: systematic review for the American College of Physicians. Ann Intern Med. 2006;144:581–595. 24. Canet J, Gallart L, Gomar C, et al. Prediction of postoperative pulmonary complications in a population-based surgical cohort. Anesthesiology. 2010;113:1338–1350. 25. Gupta H, Gupta PK, Schuller D, et al. Development and validation of a risk calculator for predicting postoperative pneumonia. Mayo Clin Proc. 2013;88:1241–1249. 26. Chung F, Abdullah HR, Liao P. STOP-Bang Questionnaire: a practical approach to screen for obstructive sleep apnea. Chest. 2016;149:631–638. 27. de Goede B, Klitsie PJ, Lange JF, et al. Morbidity and mortality related to non-hepatic surgery in patients with liver cirrhosis: a systematic review. Best Pract Res Clin Gastroenterol. 2012;26:47–59. 28. Neeff H, Mariaskin D, Spangenberg HC, et al. Perioperative mortality after non-hepatic general surgery in patients with liver cirrhosis: an analysis of 138 operations in the 2000s using Child and MELD scores. J Gastrointest Surg. 2011;15:1–11.

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29. Teh SH, Nagorney DM, Stevens SR, et al. Risk factors for mortality after surgery in patients with cirrhosis. Gastroenterology. 2007;132:1261–1269. 30. Balzan S, Belghiti J, Farges O, et al. The “50-50 criteria” on postoperative day 5: an accurate predictor of liver failure and death after hepatectomy. Ann Surg. 2005;242:824–828; discussion 828–829. 31. Holst LB, Haase N, Wetterslev J, et al. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med. 2014;371:1381–1391. 32. Mazer CD, Whitlock RP, Fergusson DA, et al. Restrictive or liberal red-cell transfusion for cardiac surgery. N Engl J Med. 2017;377:2133–2144. 33. Devereaux PJ, Mrkobrada M, Sessler DI, et  al. Aspirin in patients undergoing noncardiac surgery. N Engl J Med. 2014;370:1494–1503. 34. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e326S–e350S. 35. Douketis JD, Spyropoulos AC, Kaatz S, et  al. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med. 2015;373:823–833. 36. Sun Kara T, Ofori E, Zarubin V, et  al. Perioperative management of direct oral anticoagulants (DOACs): a systemic review. Health Serv Insights. 2016;9:25–36. 37. Salpeter SR, Greyber E, Pasternak GA, et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2010:CD002967. 38. McClave SA, Kozar R, Martindale RG, et al. Summary points and consensus recommendations from the North American Surgical Nutrition Summit. JPEN J Parenter Enteral Nutr. 2013;37:99S–105S. 39. Merchea A, Larson DW. Enhanced recovery after surgery and future directions. Surg Clin North Am. 2018;98:1287–1292. 40. Levy SM, Lally KP, Blakely ML, et al. Surgical wound misclassification: a multicenter evaluation. J Am Coll Surg. 2015;220:323–329. 41. Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Surg Infect (Larchmt). 2013;14:73–156. 42. Steinberg JP, Braun BI, Hellinger WC, et al. Timing of antimicrobial prophylaxis and the risk of surgical site infections: results from the Trial to Reduce Antimicrobial Prophylaxis Errors. Ann Surg. 2009;250:10–16. 43. Dumville JC, McFarlane E, Edwards P, et  al. Preoperative skin antiseptics for preventing surgical wound infections after clean surgery. Cochrane Database Syst Rev. 2015:CD003949. 44. Darouiche RO, Wall Jr MJ, Itani KM, et al. Chlorhexidinealcohol versus povidone-iodine for surgical-site antisepsis. N Engl J Med. 2010;362:18–26. 45. Diaz Jr JJ, Dutton WD, Ott MM, et al. Eastern Association for the Surgery of Trauma: a review of the management of the open abdomen, part 2: “Management of the open abdomen”. J Trauma. 2011;71:502–512. 46. Ahmad G, O’Flynn H, Hindocha A, et al. Barrier agents for adhesion prevention after gynaecological surgery. Cochrane Database Syst Rev. 2015:CD000475. 47. Sankaranarayanan G, Resapu RR, Jones DB, et al. Common uses and cited complications of energy in surgery. Surg Endosc. 2013;27:3056–3072.

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48. Nunez TC, Young PP, Holcomb JB, et al. Creation, implementation, and maturation of a massive transfusion protocol for the exsanguinating trauma patient. J Trauma. 2010;68:1498–1505. 49. Hollenbeck BK, Dunn RL, Suskind AM, et al. Ambulatory surgery centers and their intended effects on outpatient surgery. Health Serv Res. 2015;50:1491–1507.

50. Fleisher LA, Pasternak LR, Herbert R, et  al. Inpatient hospital admission and death after outpatient surgery in elderly patients: importance of patient and system characteristics and location of care. Arch Surg. 2004;139:67–72.

CHAPTER

11

Surgical Infections and Antibiotic Use Ariel P. Santos, Edwin Onkendi, Sharmila Dissanaike

OUTLINE Surgical Site Infections Classification of Surgical Site Infection Risk Factors for Surgical Site Infection Surgical Site Infection Prevention Treatment of Surgical Site Infection Necrotizing Soft Tissue Infections Diagnosis Imaging Local Exploration Treatment of Necrotizing Soft Tissue Infections Specific Infections Intraabdominal Abscess Intrathoracic Abscess

Clostridium Difficile Infection Clostridium septicum and Colorectal Malignancy Health Care–Associated Infections Catheter-Associated Bloodstream Infections Catheter-Associated Urinary Tract Infections Ventilator-Associated Pneumonia Antibiotic Resistance Appropriate Antibiotic Use Clinically Important Pathogens Carbapenem-Resistant Enterobacteriaceae Vancomycin-Resistant Enterococcus Fungal Infections in Surgical Patients

Surgical infections encompass a wide-ranging group of diseases, which account for a large burden of mortality and morbidity worldwide. Surgical infections include de novo infectious diseases that require surgery or procedural interventions for cure; common examples include abscesses, intraabdominal infections such as cholangitis and appendicitis, and necrotizing soft tissue infections (NSTIs), all of which are dealt with in detail in this chapter. Another major type of surgical infection is surgical site infections (SSIs)—infections occurring at the site within 30 days of a surgical procedure. SSIs account for 20% of health care–acquired infections and result in significant morbidity and hospital costs. Surgical infections may lead to sepsis, a life-threatening organ dysfunction due to a dysregulated host response to infection.1 Sepsis is the leading cause of in-hospital mortality in the United States.2 Sepsis is estimated to affect 30 million people worldwide each year, although this is likely an underestimate given the paucity of data from low- and middle-income countries.3 Early and effective source control is important for the successful treatment of sepsis. This requires that the physician recognize when the source of infection is amenable to a surgical cure and effects this without delay in conjunction with other treatments such as fluid resuscitation and antibiotics. The Surviving Sepsis Campaign (SSC) provides expert consensus on guidelines for the treatment of sepsis, which should be familiar to all surgeons treating patients with infection.4

associated with increased length of stay and a twofold to eleven fold increase in the risk of mortality.5 In the United States, there are more than 40 million surgical operations performed and 2% to 5% are complicated by SSIs. There is an estimated annual incidence ranging from 160,000 to 300,000, with an annual cost of SSIs in the United States estimated at $3.5 billion to $10 billion.6 The increased cost is due to prolonged hospitalization, increase in emergency room visits, readmission, antibiotic costs, and additional procedural costs. About 60% of SSIs are preventable with evidence-based guidelines6; as a result, SSI is one of the quality metrics frequently used to assess quality of surgical care, which is then linked to performance ranking, reimbursement, and patient satisfaction.

SURGICAL SITE INFECTIONS

The CDC classifies wound into four groups: clean, clean-contaminated, contaminated, and dirty-infected (Table 11.2), with progressively increasing risk of SSIs. In addition, patient, environmental, and treatment factors can increase the risk of subsequent

SSIs are the most common and costly of all hospital-acquired infections, accounting for 20% of all hospital infections. It is

Classification of Surgical Site Infection The most commonly used definition of SSI is that of the Centers for Disease Control and Prevention (CDC). The SSI must occur within 30 days after the operative procedure if no implant is left in place, or within 1 year if implant is in place, and the infection appears to be related to the operative procedure.7 SSIs are classified based on the depth and tissue layers involved as superficial incisional, deep incisional, and organ/space (Table 11.1). Standardization of reporting plays an important role in ensuring accurate data collection for research, quality improvement, and public reporting. 

Risk Factors for Surgical Site Infection

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TABLE 11.1  CDC/NHSN classification of surgical site infection. CLASSIFICATION

DEFINITION

Superficial incisional SSI (SIS)

Infection occurs within 30 days after the operative procedure and involves only skin and subcutaneous tissue of the incision and had at least one of the following: a. Purulent drainage from the superficial incision. b. Organisms isolated from an aseptically obtained culture of fluid or tissue from the superficial incision. c. At least one of the following signs or symptoms of infection: pain or tenderness, localized swelling, redness, or heat, and superficial incision is deliberately opened by surgeon and is culture positive or not cultured. A culture-negative finding does not meet this criterion. d. Diagnosis of superficial incisional SSI by the surgeon or attending physician. Infection occurs within 30 days after the operative procedure if no implant is left in place or within 1 year if implant is in place and the infection appears to be related to the operative procedure and involves deep soft tissues (e.g., fascial and muscle layers) of the incision and patient has at least one of the following: a. Purulent drainage from the deep incision but not from organ/space component of the surgical site. b. Deep incision spontaneously dehisces or is deliberately opened by a surgeon and is culture-positive or not cultured when the patient has at least one of the following signs or symptoms: fever (>38°C) or localized pain or tenderness. A culture-negative finding does not meet this criterion. c. An abscess or other evidence of infection involving the deep incision is found on direct examination, during reoperation, or by histopathologic or radiologic examination. d. Diagnosis of a deep incisional SSI by a surgeon or attending physician.Wound that has both superficial and deep incisional infection is classified as DIS. Infection occurs within 30 days after the operative procedure if no implant is left in place or within 1 year if implant is in place and the infection appears to be related to the operative procedure and infection involves any part of the body, excluding the skin incision, fascia, or muscle layers, that is opened or manipulated during the operative procedure and patient has at least one of the following: a. Purulent drainage from a drain that is placed through a stab wound into the organ/space. b. Organisms isolated from an aseptically obtained culture of fluid or tissue in the organ/space. c. An abscess or other evidence of infection involving the organ/space that is found on direct examination, during reoperation, or by histopathologic or radiologic examination. d. Diagnosis of an organ/space SSI by a surgeon or attending physician.

Deep incisional SSI (DIS)

Organ/space SSI

CDC, Centers for Disease Control and Prevention; NHSN, National Healthcare Safety Network; SSI, surgical site infection.

development of SSIs (Box 11.1). Of particular interest are risk factors amenable to preoperative optimization such as smoking cessation, protein-calorie malnutrition, and obesity. In general, laparoscopic surgical approaches carry a lower risk of SSIs compared with open techniques for the same procedure. 

Surgical Site Infection Prevention Numerous interventions have been proposed to reduce the risk of SSI. In 2002, the CDC and Center for Medicare and Medicaid Services initiated the Surgical Infection Prevention Project to reduce SSIs, and in 2006, this became the expanded Surgical Care Improvement Program. The U.S. Congress authored the Deficit Reduction Act of 2005, which mandates hospital reporting process and outcome and quality improvement measures to be made available to the public and Center for Medicare and Medicaid Services. The act also allows payment adjustment downward for health care–associated infections that could have been prevented through application of evidence-based strategies.8 These interventions can be broadly divided into three stages: preoperative, intraoperative, and postoperative strategies. The CDC provided a new and updated evidence-based recommendation for the prevention of SSIs.8 Preventive measures for SSI include a full-body bath or shower with soap (antimicrobial or nonantimicrobial) or an antiseptic agent the night before or the morning of the operation, appropriate antimicrobial prophylaxis before incision, and skin preparation with an alcohol-based agent unless contraindicated. In clean and clean-contaminated procedures, additional prophylactic antimicrobial agents should not be

administered even in the presence of a drain nor should topical antimicrobials be applied to the surgical incision. Maintenance of normothermia, glycemic control with targets less than 200 mg/ dL, and the provision of supplemental oxygen are other adjunct measures proposed to reduce SSI in the perioperative bundle. In addition to the 2017 CDC guideline for the prevention of SSI, a randomized study showed that prophylactic use of negative pressure dressings for closed laparotomy wounds significantly reduces the incidence of SSI at 30 days postoperatively, concomitantly decreasing length of stay (6.1 vs. 14.7 days; P = 0.01).9 

Treatment of Surgical Site Infection There are five steps in the treatment of SSI (Box 11.2). Once SSI is diagnosed, it is paramount to obtain a high-quality specimen for Gram stain and culture to identify the causative pathogens. With the increasing prevalence of multidrug resistant organisms associated with wound infection, identification of the causative pathogen and its antimicrobial susceptibility helps guide appropriate antibiotic therapy as well as facilitate rapid de-escalation, which is important in preventing unnecessary antibiotic use that facilitates further development of resistant organisms. Source control in superficial and deep SSI usually requires opening of the incision site and irrigation, drainage, and debridement of devitalized or infected tissue as needed. Organ space infections often can be controlled by image-guided drainage using computed tomography (CT) scan or ultrasound (US) if localized and well contained. However, where there are multiple sites or widespread infection–interloop abscesses between loops of small

CHAPTER 11  Surgical Infections and Antibiotic Use TABLE 11.2  CDC surgical wound

classification.

II—Cleancontaminated

III—Contaminated

IV—Dirty-infected

BOX 11.1  Risk factors for the development

of surgical site infection.

CLASSIFICATION DESCRIPTION I—Clean

225

An uninfected operative wound in which no inflammation is encountered and the respiratory, alimentary, genital, or uninfected urinary tract is not entered. In addition, clean wounds are primarily closed and, if necessary, drained with closed drainage. Operative incisional wounds that follow no penetrating (blunt) trauma should be included in this category if they meet the criteria. An operative wound in which the respiratory, alimentary, genital, or urinary tracts are entered under controlled conditions and without unusual contamination. Specifically, operations involving the biliary tract, appendix, vagina, and oropharynx are included in this category, provided no evidence of infection or major break in technique is encountered. Open, fresh, accidental wounds. In addition, operations with major breaks in sterile technique (e.g., open cardiac massage) or gross spillage from the gastrointestinal tract and incisions in which acute, no purulent inflammation is encountered are included in this category. Old traumatic wounds with retained devitalized tissue and those that involve existing clinical infection or perforated viscera. This definition suggests that the organisms causing postoperative infection were present in the operative field before the operation.

CDC, Centers for Disease Control and Prevention.

intestine, for example, surgical drainage is necessary and can be performed either by laparoscopic or open approach. 

NECROTIZING SOFT TISSUE INFECTIONS NSTIs are rapidly progressing skin and soft tissue infections associated with necrosis of the dermis, subcutaneous tissue, superficial fascia, deep fascia, or muscle. This definition includes a variety of conditions, such as Fournier gangrene affecting the perineum and genitalia, Meleney streptococcal gangrene, and clostridial myonecrosis. While a wide range of organisms might be responsible and different body regions and tissues are affected, these infections are grouped together due to the common characteristics of rapid progression, irreversible tissue necrosis, high rates of sepsis, and mortality rates between 10% and 25%. Patients with NSTIs are often referred to regional burn centers because of the need for intensive care, multiple operations, and resource-intensive complex reconstruction of large tissue and skin defects. Although uncommon compared with other skin infections such as cellulitis or abscesses, the incidence of NSTI appears to be increasing in the United States. This is often attributed to the increased prevalence of obesity, type 2 diabetes mellitus, and people living with chronic immunosuppression, all of which may predispose an individual to NSTI.2,5 While these conditions do increase risk, NSTIs may also be diagnosed in previously healthy young adults and even children, although this is rare. NSTIs are rarely “idiopathic”; a minor wound or injury almost always precedes the devastating infection, often by several weeks. NSTI caused by

Patient Factors Alcoholism Ascites Age Chronic inflammation Diabetes History of skin or soft tissue infection Hyperbilirubinemia >1 mg/dL Hypercholesterolemia Hypoalbuminemia Hypoxemia Immunosuppression Malignancies Malnutrition Obesity Peripheral vascular disease Postoperative anemia Preexisting infection Recent radiotherapy Smoking Steroid therapy  Environmental Factors Contamination Inadequate antisepsis Inadequate disinfection Inadequate ventilation Increased operating room traffic  Treatment Factors Blood transfusion Contamination: poor scrubbing technique, breach in asepsis, poor gloving, etc. Drains Emergency surgery High wound classification Hypothermia Hypoxemia Inadequate or inappropriate antibiotic prophylaxis Poor glycemic control Prolonged operation

BOX 11.2  Treatment strategies for surgical

site infection.

1. Pathogen identification. 2. Source control by opening the incision in superficial or deep surgical site infections (SSIs) or by image-guided percutaneous drainage, laparoscopic, or open drainage if indicated in organ space SSIs. 3. Immediate empiric antibiotic coverage. 4. Timely antibiotic de-escalation. 5. Local wound care.

streptococci and clostridia often have a fulminant course with rapid onset of symptoms and worsening over days or even hours and may be rapidly progressing to death if untreated. In contrast, infections caused by mixed flora, staphylococcus, and gram-negative organisms often have an indolent course over days to weeks, which may mislead clinicians into not considering the diagnosis of NSTI.

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TABLE 11.3  Laboratory risk indicator for

necrotizing fasciitis (LRINEC) scoring system. VARIABLE

UNITS

SCORE

C-reactive protein White blood cell count (per mm) Hemoglobin

≥150 mg/L 15–25 >25 11.0–13.5 g/dL 141 pmol/L) >180 mg/dL (or >10 mmol/L)

4 points 1 point 2 points 1 point 2 points 1 point 2 points 2 points 1 point

Serum sodium Serum creatinine Serum glucose RISK CATEGORY Low Intermediate High

LRINEC SCORE, points PROBABILITY OF NSTIS, (%) ≤5 75

LRINEC, Laboratory risk indicator for necrotizing fasciitis; NSTIs, necrotizing soft tissue infections.

Since the progression of NSTI is often fulminant, patient prognosis depends on early recognition and administration of appropriate treatment as soon as possible.

Diagnosis A major obstacle to the effective treatment of NSTIs and one reason for the high mortality of these conditions is delay in diagnosis. Since these infections affect subcutaneous tissues, muscle, and fascia, visible skin changes on the surface are often underwhelming, misleading clinicians as to the true extent of ongoing necrosis below. The most common clinical features of NSTIs present in 90% of cases are erythema, warmth, and pain—unfortunately, common symptoms and signs that are also present in mild infections such as cellulitis and in almost every case of inflammation from any cause. Crepitus, skin necrosis, and bullae are much more specific to NSTI but unfortunately are present less than 40% of the time, rendering them markedly less useful in diagnosis.10 Signs of skin and tissue necrosis are pathognomonic and should provoke urgent resuscitation and surgery; however, the lack of obvious necrosis and a superficial appearance similar to cellulitis should not deter the surgeon from further investigation, including local wound exploration, if necessary, based on the patient’s systemic signs and symptoms. Signs and symptoms of systemic illness (i.e., sepsis) are much more likely to be a feature of NSTI than simple skin infections and should prompt serious consideration of the diagnosis. While fever may be present in nearly every infection, hypotension should not be and should serve as a warning sign if present. Similarly, organ failure such as renal failure or hypoxia should not be present with cellulitis or an uncomplicated abscess; these findings on clinical and laboratory examination, in conjunction with pain in a focal body region, should be considered highly suspicious for ­NSTIs and treated accordingly. The laboratory risk indicator for necrotizing fasciitis scoring system was developed based on laboratory values commonly deranged in NSTIs (Table 11.3); it has been shown to be useful in differentiating NSTI from other infections, although correlation of laboratory risk indicator for necrotizing fasciitis score with outcome in NSTI is less robust, and recent metaanalyses have disputed its value.11 Nonetheless, whether utilizing a formal scoring system or not, any sign of systemic derangement such as unexpected hyperglycemia, acute renal failure,

or hyponatremia will place the burden firmly on the surgical team to disprove the diagnosis of NSTI, requiring further evaluation such as imaging studies or direct surgical exploration. 

Imaging Given the difficulty of diagnosing NSTIs based on physical examination alone, there has been much interest in the use of imaging modalities to differentiate NSTI from other infections. US, magnetic resonance imaging, and CT scans have all been evaluated for their efficacy in NSTI diagnosis; based on ease of access and interpretability of results, CT is the most commonly favored modality for adjuvant imaging. Features suggestive of NSTI on CT include gas in the soft tissues (the easiest finding for nonradiologists to diagnose and the most specific), multiple fluid collections, absence or heterogeneity of tissue enhancement by intravenous (IV) contrast, and significant inflammatory changes under the fascia. Using these criteria, the sensitivity of CT in identifying NSTI was 100%, the specificity 98%, the positive predictive value 76%, and the negative predictive value 100% in one series of 184 patients.12 

Local Exploration Given the difficulty in diagnosis and the increase in mortality associated with delays in definitive treatment, surgical exploration of the questionable area is a very reasonable next step when the diagnosis remains in doubt. This requires a full-thickness elliptical excision of all tissues down through fascia and including muscle to rule out necrotizing fasciitis or myositis in addition to subcutaneous infection. A 2-cm elliptical excision on an extremity will usually suffice and can be performed under local anesthesia at the bedside. In areas of adiposity such as the pannus or groin, this will be easier performed in the operating room. The surgeon should visually inspect for tissue necrosis, dishwater fluid or purulence, greyish discoloration of tissues, or failure of the muscle to react to electrocautery. The tissue at the edges of the incision should be firm and resist pressure—the “push” test. If the surgeon is able to dissect more than a centimeter subcutaneously with blunt finger pressure alone, this is considered a positive finding and wide debridement in the operating room is indicated. Any fluid encountered should be collected and sent for immediate Gram stain and culture in addition to at least 1 cm3 of skin and subcutaneous tissue and samples from fascia and muscle. 

Treatment of Necrotizing Soft Tissue Infections Surgery Surgical debridement is the mainstay of NSTI treatment. All affected tissue should be sharply excised with at least 1 cm rim of normal tissue (Fig. 11.1). The “push” test described previously will allow the surgeon to quickly delineate the extent of resection necessary. Bleeding is not an indication of tissue viability, since the presence of active infection will often cause these areas to be hyperemic; significant blood loss is often encountered so the surgical team should be prepared for this eventuality. The use of tourniquets in extremity dissection and attention to hemostasis are necessary to prevent sudden major blood loss from destabilizing an already unstable patient. All questionable tissue should be resected at the initial operation; the need for multiple operations and the spread of infection both increase the risk of mortality.13 While skin-sparing procedures have been shown in limited series to improve eventual reconstructive options for both cosmesis and function, it is essential that the skin not be directly involved in these cases and that wide undermining be able to be performed to remove all necrotic tissue, which remains the mainstay of NSTI treatment. 

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removing the need for scheduled second-look operations. Removing the need for dressing changes also reduces the pain experienced by the patient, and this approach is surprisingly well tolerated by patients and families alike, after the indications are explained. In body areas such as the groin or under intertriginous folds where it is not possible to leave the tissue exposed to air, we use conventional wet-to-dry gauze dressings changed once or twice a day. Once the infection is resolved, the wound is placed in a negative pressure vacuum dressing and reconstructive procedures, usually a skin graft, is planned in 2 to 4 weeks. This allows time for the patient to engage in rehabilitation with physical therapy and optimal nutrition in order to optimize the chances of a good longterm outcome. The inclusion of tissue substitutes such as acellular dermal matrix and regeneration templates in reconstruction may improve cosmetic and functional outcomes, although this increases cost significantly.  FIG. 11.1  Surgical debridement of necrotizing soft tissue infection.

Antibiotics Broad-spectrum antibiotics should be initiated as soon as the diagnosis is suspected; once the patient is clinically improving and culture results are available, these may be de-escalated to one or two agents. In general, it is advisable to give one broad-spectrum agent effective against most gram-positive and gram-negative organisms and ensure Methicillin-resistant S. aureus coverage and good anaerobic coverage, tailored to local antibiogram. The impact of anaerobes in NSTI outcomes has been underrecognized due to the difficulty of growing anaerobes in conventional culture media; however, recent studies using 16S ribonucleic acid (RNA) sequencing have demonstrated that anaerobes are likely a significant contributor to mortality in NSTIs.14 Finally, there is evidence that clindamycin has toxin-neutralization properties, especially in streptococcal and clostridial infections; for this reason, we routinely add clindamycin to the initial regimen.  Resuscitation Patients demonstrating sepsis and septic shock should be managed in an intensive care unit (ICU), using the standard guidelines for sepsis. These include early, goal-directed resuscitation with isotonic fluids, vasopressor support as needed with norepinephrine and vasopressin, and control of hyperglycemia. The use of adjuncts such as IV immunoglobulin and hyperbaric oxygen has been described; however, there is insufficient evidence to recommend routine use. While there is no specific evidence for the use of antioxidants or steroids in NSTIs, recent studies suggest that IV thiamine, vitamin C, and hydrocortisone in combination might improve outcomes in sepsis.15 Further investigation is warranted as to the utility of this approach in NSTIs.  Wound Care and Reconstruction The large soft tissue defects that result from appropriate debridement of NSTI will require extensive reconstructive procedures once the patient has recovered from the acute episode. We routinely leave the debrided area completely open to air, sometimes under heat lamps, for the first 48 hours after surgery; a spritz of antibiotic irrigation is used to keep the muscle from drying out excessively, and lubricant is used to cover tendons and other vulnerable areas.16 This approach allows for continuous evaluation of the wound in the ICU, facilitating the earlier recognition of spreading infection and

SPECIFIC INFECTIONS Intraabdominal Abscess Intraabdominal infections encompass a wide range of infections that have been classified previously in a variety of ways, including classification based on the nature of the infection (uncomplicated and complicated), the setting of infection (community acquired vs. hospital acquired), and severity of the infection as well as risk of significant morbidity, mortality, and failure of treatment (low, moderate, and high risk). This chapter focuses on one of these infections (i.e., intra-abdominal abscess) in the surgical patient. Definition, Etiology, and Classification of Intraabdominal Abscess Intraabdominal abscess refers to a localized walled-off collection of infected fluid within the confines of the abdomen (peritoneal cavity, retroperitoneum, and pelvic cavity) that occurs as a result of the protective containment of the host’s intraabdominal defense mechanisms. Failure of the host intraabdominal defense mechanisms to wall off and localize the infection leads to an uncontained infection with acute diffuse peritonitis and systemic infection associated with a high morbidity and mortality. An abscess can develop at a later stage of what was previously uncontained intraabdominal “free-floating infection.” With the intraabdominal host defense mechanisms against infection in effect, there is, then, the development of a capsular wall around the inflammatory fluid or infected fluid for containment, resulting in a walled-off abscess. A previously uninfected fluid collection that becomes walled off may later become secondarily infected from systemic bacteremia or from external translocation via a drain or instrumentation, for example, secondary infection of a post pancreatitis pseudocyst (Fig. 11.2). On the other hand, intra-abdominal fluid may already be infected at the onset and then become walled off (e.g. purulent fluid from ruptured acute appendicitis or leaked hollow viscus contaminated fluid like in a colonic anastomotic leak) (Table 11.4). Intraabdominal abscesses can, therefore, be classified into the following categories based on location, etiology, and severity (Box 11.3).  Diagnostic Evaluation Patients with intraabdominal abscess usually present with acute abdominal pain associated with signs and symptoms of infection/inflammation (fever, rigors, tachycardia, tachypnea, and

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SECTION II  Perioperative Management

A

B

C FIG. 11.2  (A) Retroperitoneal abscess that developed in a previously walled-off infected pancreatic necrosis cavity that had been operatively debrided by robotic pancreatic necrosectomy. (B) Percutaneous large bore drainage of the retroperitoneal abscess. (C) Complete resolution of the retroperitoneal abscess 6 weeks after percutaneous drainage.

leukocytosis) as well as gastrointestinal symptoms (nausea, anorexia, emesis, ileus, obstipation, and diarrhea). Initial work-up should include a detailed history and physical examination as well as laboratory tests. These will be suggestive of an underlying infection possibly with abscess in most patients. If the patient’s history and physical examination are not available or reliable (e.g., due to patient’s altered mental status, intubated patient, or immunocompromised patient), an intraabdominal infection including abscess should be suspected if the patient has features of infection of unknown origin including persistent fever. Imaging work-up is typically necessary to localize an intraabdominal abscess and determine its characteristics including size, relationship to nearby structures, and presence or absence of multiloculations. CT scan of the abdomen and pelvis with IV contrast is the imaging modality of choice and is the gold standard in high resource countries to assess all these features as well as determine the likely source of the abscess. Whenever possible, CT scan of the abdomen and pelvis should be obtained with IV contrast for better characterization and differentiation of the abscess from surrounding structures. Enteral and per rectal water-soluble contrast may be necessary in patients with suspected gastrointestinal leak.

In areas where there is limited access to CT, US may be helpful in diagnosis. US has become widely available worldwide, with affordable, smaller, portable US machines in widespread use. US in the diagnosis of intraabdominal abscess is especially useful for solid organ abscesses and abscesses not obscured by loops of bowel. It is limited by high user–dependency, limited detail of associated surrounding pathology, and lack of utility for abscesses surrounded by bowel.  Management of Intraabdominal Abscess Initial resuscitation and management. The treatment approach to intraabdominal abscess should include prompt diagnosis, adequate and early fluid resuscitation, early initiation of IV antibiotic therapy, and early and complete source control by drainage of the abscess and reassessment for clinical improvement/deterioration with as-needed adjustment of therapy.17 Intraabdominal abscess and associated sepsis and septic shock should be managed as medical emergencies in accordance with the SSC guidelines. Treatment should focus on immediate initial resuscitation followed by frequent hemodynamic reassessments and additional fluid administration as needed. Initial fluid resuscitation and

CHAPTER 11  Surgical Infections and Antibiotic Use TABLE 11.4  Types of intraabdominal

abscess.

Secondary intraabdominal abscess (previously sterile walled-off intraabdominal fluid collection becomes secondarily infected, transforming into abscess)

BOX 11.3  Intraabdominal abscesses

classifications.

TYPE OF INTRAABDOMINAL ABSCESS ETIOLOGY/EXAMPLES Primary intraabdominal abscess (established infections that rupture into peritoneal cavity and become walled-off into abscesses) Delayed primary intraabdominal abscess (microbial-laden hollow viscus fluid leaking into abdomen and transforming into walled-off abscess with time)

229

Ruptured acute appendicitis abscess, acute diverticulitis with abscess

Gastrointestinal perforation or postoperative anastomotic leak leading to abscess formation later, subhepatic abscess developing later from infected fluid around after cholecystectomy for acute cholecystitis Postpancreatitis sterile pseudocyst with secondarily infection from systemic bacteremia or microbial translocation into it via external drain; loculated sterile ascitic/intraabdominal fluid secondarily infection for external instrumentation or systemic infection.

reassessments should precede diagnostic work-up. Patients with intraabdominal abscess are often volume depleted due to intravascular fluid losses (from tachypnea, fever, vomiting, and diarrhea) and decreased fluid intake (due to nausea, anorexia, emesis, and ileus). If volume depletion is severe, associated acute renal failure may be present. As a result, IV fluid repletion is a necessary part of initial treatment. Even in patients without overt signs of volume depletion, fluid administration may be beneficial as suggested by historical data. Patients with severe volume depletion associated with septic shock and organ failure should be managed with more aggressive fluid resuscitation according to the SSC guidelines. Key treatment measures according to the “Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016” include early clinical endpoint-directed fluid therapy (30 mL/kg of crystalloid fluid within the first 3 to 6 hours to restore mean arterial pressure to >65 mm Hg with hemodynamic reassessments and additional fluid therapy guided by serum lactate levels as a marker of tissue perfusion; use of vasopressors in septic shock to maintain mean arterial pressure of 65 mm Hg if not fluid responsive; inotropic support for low cardiac output despite fluid and vasopressor therapy; packed red blood cell transfusion if hemoglobin 2× upper limit normal, aspartate aminotransferase/alanine aminotransferase >3× upper limit normal; history of stroke: sudden focal neurologic deficit from bleeding lasting >24 hours and diagnosed by neurologist; history of bleeding: bleeding that requires hospitalization or causing >2 g/L drop in hematocrit or blood transfusion; labile INRs: therapeutic range 38°C) and localized pain or tenderness, unless incision is culture-­ negative. 3. An abscess or other evidence of infection involving the deep incision found on direct examination, during reoperation, or by histopathologic or radiographic examination. 4. Diagnosis of deep incisional SSI made by a surgeon or attending physician.  Organ/Space Surgical Site Infection Infection occurs within 30 days after the operation if no implant is left in place or within 1 year if implant is in place and the infection appears to be related to the operation and infection involves part of the anatomy (e.g., organs and spaces) other than the incision, which was opened or manipulated during an operation and at least one of the following. 1. Purulent drainage from a drain that is placed through a stab wound into the organ/space. 2. Organisms isolated from an aseptically obtained culture of fluid or tissue in the organ/space. 3. An abscess or other evidence of infection involving the organ/space that is sound on direct examination, during reoperation, or by histopathologic or radiologic examination. 4. Diagnosis of organ/space SSI made by a surgeon or attending physician. From Horan TC, Gaynes RP, Martone WJ, et al. CDC definitions of nosocomial surgical site infections, 1992: a modification of CDC definitions of surgical wound infections. Am J Infect Control. 1992;20:271–274.

Table 12.3  Risk and protective factors of

surgical site infections.

Patient Factors Advanced age Increased BMI High ASA score High NNIS score Diabetic mellitus Smoking Dependence or frailty Malnutrition Severe wound class Ascites Coexisting remote infection Staphylococcal colonization Skin disease at surgical site Anemia Increased number of comorbidities

Duration of surgery Implantation of prostheses Reoperation Longer hospital stay before surgery Corticosteroid medication Inadequate sterilization, skin antisepsis Emergency procedure Hypothermia Intraoperative blood transfusion Perioperative shaving Failure to obliterate dead space PROTECTIVE FACTORS Laparoscopic procedures Antibiotic prophylaxis

Adapted from Korol E, Johnston K, Waser N, et al. A systematic review of risk factors associated with surgical site infections among surgical patients. PLoS One. 2013;8:e83743; Global Guidelines for the Prevention of Surgical Site Infection. Geneva: World Health Organization; 2018. https://www.who.int/infectionprevention/publications/ssi-prevention-guidelines/en/; and BerriosTorres SI, Umscheid CA, Bratzler DW, et al. Centers for Disease Control and Prevention guideline for the prevention of surgical site infection, 2017. JAMA Surg. 2017;152:784–791. ASA, American Association of Anesthesiologists; BMI, body mass index; NNIS, National Nosocomial Infections Surveillance.

Table 12.4  Classification of surgical

wounds.

Category

Criteria

Clean

No hollow viscus entered Primary wound closure No inflammation No breaks in aseptic technique Elective procedure Hollow viscus entered but controlled No inflammation Primary wound closure Minor break in aseptic technique Mechanical drain used Bowel preparation preoperatively Uncontrolled spillage from viscus Inflammation apparent Open, traumatic wound Major break in aseptic technique Untreated, uncontrolled spillage from viscus Pus in operative wound Open suppurative wound Severe inflammation

Cleancontaminated

SSI, Surgical site infection.

Contaminated

colonic surgery (Table 12.5). Overall, S. aureus is the most common SSI pathogen. Other common pathogens include coagulase negative Staphylococcus, Enterococcus spp., Escherichia coli, ­Enterobacter spp., and Pseudomonas aeruginosa. Methicillin-resistant S. aureus (MRSA) is a serious SSI pathogen because it is more virulent, difficult to treat, and associated with longer hospital stay, higher hospital costs, and increased mortality. MRSA infections are increased in patients with nasal

Factors Related to Surgery and Management

Dirty

Infection Rate (%) 1–3

5–8

20–25

30–40

Chapter 12  Surgical Complications colonization of MRSA, prior MRSA infection, recent hospitalization, and recent antibiotic use. The majority of SSIs occur within 30 days of surgery and up to 1 year after implantation of a surgical prosthesis. Superficial SSIs present with localized redness, swelling, tenderness, warmth, presence of purulent discharge, or failure of wound healing. Deep SSIs may present with systemic signs and symptoms of infection, including fever, wound dehiscence, and purulent discharge from deep tissues. Organ or deep space infection can present as purulent discharge from surgical drains or with systemic signs of sepsis, including fever, tachycardia, tachypnea, and leukocytosis with associated signs of organ failure (decreased partial arterial oxygen pressure [PaO2]/fraction of inspired oxygen [FiO2] ratio, thrombocytopenia, hyperbilirubinemia, hypotension, delirium, or acute kidney injury [AKI]). Prevention and Management Patients scheduled for surgery should be managed to minimize the risk of SSI. Before performing surgery, any coexisting infection Table 12.5  Common pathogens related

to surgical procedures.

Type of Surgery

Likely Pathogens

Placement of all grafts, prostheses, or implants Cardiac

Staphylococcus aureus, coagulasenegative staphylococci S. aureus, coagulase-negative staphylococci S. aureus, coagulase-negative staphylococci S. aureus, coagulase-negative staphylococci S. aureus, coagulase-negative staphylococci, streptococci, gram-negative bacilli

Neurosurgery Breast

Ophthalmic (limited data, however, commonly used in procedures such as anterior segment resection, vitrectomy, and scleral buckles) Orthopedic (total joint replacement, S. aureus, coagulase-negative closed fractured/use of nails, bone staphylococci, gram-negative plates, other internal fixation device, bacilli functional repair without implant/ device trauma) Noncardiac thoracic (lobectomy, S. aureus, coagulase-negative pneumonectomy, wedge resection, staphylococci, Streptococcus other noncardiac mediastinal pneumoniae, gram-negative bacilli procedures), closed tube thoracotomy Vascular S. aureus, coagulase-negative staphylococci Appendectomy Gram-negative bacilli, anaerobes Biliary tract Gram-negative bacilli, anaerobes Colorectal Gram-negative bacilli, anaerobes Gastroduodenal Gram-negative bacilli, streptococci, oropharyngeal anaerobes (e.g., peptostreptococci) S. aureus, streptococci, Head and neck (majorly procedures oropharyngeal anaerobes (e.g., with incision through oropharyngeal mucosa) peptostreptococci) Obstetric and gynecologic Gram-negative bacilli, enterococci, group B streptococci, anaerobes Urologic Gram-negative bacilli From Sganga G, Tascini C, Sozio E, et al. Focus on the prophylaxis, epidemiology and therapy of methicillin-resistant Staphylococcus aureus surgical site infections and a position paper on associated risk factors: the perspective of an Italian group of surgeons. World J Emerg Surg. 2016;11:26.

243

(skin, urine, and lung) should be treated and resolved. Patients who smoke cigarettes should stop for 1 to 2 months before elective surgery if possible and diabetic patients should have their blood sugar well controlled. Other conditions that may need to be “optimized” include nutritional status, anemia, and obesity. Decolonizing staphylococcal carriers with 2% mupirocin nasal ointment can reduce the risk of postoperative S. aureus infection in cardiac and orthopedic surgery. However, there is limited consensus regarding who to screen or for which operations screening should be considered. Preoperative antibiotics should be administered within 60 minutes of the skin incision to reach therapeutic concentration in serum and tissue during the surgical procedure. Vancomycin and fluoroquinolones may need to be started earlier due to their prolonged infusion times and half-lives. Redosing of antibiotics may be required if the duration of surgery exceeds 2 half-lives of the drugs or with massive blood loss. Caution should be used in patients with poor drug clearance (e.g., renal insufficiency or hepatic dysfunction) and the choice of drug should correlate with the common organisms found at the surgical site. In general, prophylactic antibiotics should not be continued after surgery and the duration of antimicrobial prophylaxis should not exceed 24 hours. Table 12.6 summarizes prophylactic antibiotic choice, dosing, and redosing, and Table 12.7 reviews the recommended antibiotic prophylaxis by surgical procedure. For skin preparation, patients should shower with soap the night before surgery. If hair needs to be removed from the surgical site, a clipper should be used. Skin should be prepared with alcohol-based antiseptic solution (e.g., chlorhexidine) before incision. Perioperative glycemic control has been shown to reduce SSIs with a glucose threshold of 110 beats/min, and leukocytosis >12,000/μL, or when cellulitis (erythema extends >5 cm from wound edge) is present. Patients with risk factors for MRSA infection should be treated with appropriate antibiotics (e.g., vancomycin, daptomycin, linezolid, or ceftaroline). Empiric antibiotics for operations involving axillae, groin, perineum, genital tract, and gastrointestinal (GI) tract should cover gram-negative and anaerobic bacteria. Moreover, patients requiring antibiotics should have drainage or discharge from the wound or site of infection sent for culture to identify the pathogen and its

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antibiotic resistance profile. The wound should be wet dressed with normal saline damped sterile gauze at least daily. Antibiotics should be optimized according to the culture results when available. 

Thermal Regulation Hypothermia

Causes Maintenance of normothermia is important physiologically as even modest deviations in core body temperature contribute to metabolic alterations, resulting in cellular and tissue dysfunction. Hypothermia is a common complication in surgical patients and is defined as core body temperature below 35oC. It can be classified by severity into three categories: mild (32oC–35°C), moderate (28°C–32°C), and severe (120 kg 1.5 g 1g 2g 2g 2g 400 mg 900 mg 1g 400 mg 5 mg/kg* 500 mg 500 mg 400 mg 3.375 g 15 mg/kg 1g 1g

Redosing (Hours After Preoperative Dose) 2 2 4 4 4 3 2 6 NA NA 6 NA NA NA NA NA NA 2 NA NA NA

Adapted from Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70:195–283. NA, Not applicable. No redosing needed for typical case duration. For unusually long operations, redosing should be considered. *Gentamicin is calculated based on actual body weight, if the actual body weight is >20% above ideal body weight (IBW), the dosing weight (DW) can be calculated from DW = IBW + 0.4(Actual body weight - IBW)

mechanisms, both of which may be impaired in the perioperative period. Risk factors for heat loss and perioperative hypothermia include elderly patients, burn injuries, open surgical procedures, cool operating rooms, prolonged surgeries (>4 hours), infusion of room-temperature fluids, cutaneous vasodilatation from anesthetic agents, and increased evaporative losses from serosal surfaces. Hypothermia can develop during any stage of surgery: preoperatively, intraoperatively, or postoperatively. Preoperatively, the use of muscle relaxants impairs shivering. Intraoperatively, heat loss occurs from large, exposed operative area, anesthetic effects on heat production, cool room temperatures, vasoconstriction, and shivering. Hypothermia after surgery contributes to organ injury through various mechanisms: ventilation-perfusion (V/Q) mismatch; shift of oxyhemoglobin-dissociation curve to the left causes tissue hypoxia, decreases myocardial contractility and peripheral vasoconstriction, increased blood viscosity; reduced platelet function; and decreased activation of the coagulation cascade. Hypothermia is common after traumatic injury due to shock, alcohol intoxication, environmental exposure, fluid resuscitation, and loss of shivering. Hypothermia is also associated with increased risk of SSI.  Presentation Intraoperative hypothermia causes significant postoperative discomfort and shivering. Hypothermia significantly impairs cardiovascular function, blood clotting, and wound healing and increases the risk of infection. When the core temperature falls below 32°C, significant reductions in blood pressure and cardiac output occur. Cardiovascular manifestations of hypothermia include cardiac depression, myocardial ischemia, dysrhythmias, peripheral vasoconstriction, impaired tissue oxygen delivery, blunted response to catecholamines, and hypotension. The characteristic electrocardiogram finding of J point elevation, and Osborn wave (notch and deflection at the QST-ST junction), are considered pathognomonic of hypothermia. Adverse myocardial outcomes have been reported in hypothermic patients with preexisting cardiovascular disease (when compared with postoperative normothermic patients). Peripheral vasoconstriction due to shock is the most important impediment to wound oxygenation. Mild core hypothermia results in immune dysfunction by impeding granulocyte chemotaxis and phagocytosis, macrophage function, and antibody production. These changes in immune function, in combination with decreased tissue oxygen tension, abnormal collagen deposition, and poor wound healing, increase susceptibility to infection. Hypothermia also induces coagulopathy by attenuating hemostatic enzyme function and platelet sequestration, resulting in an increased risk of bleeding. With mild and moderate hypothermia, renal perfusion and glomerular filtration are decreased, resulting in “cold-induced diuresis.” Decreased hepatic and renal blood flows, in turn, reduce drug metabolism and excretion, with resultant decreases in plasma clearance and potential prolongations in drug effects, which can lead to delays in emergence from anesthesia and prolonged postoperative anesthesia care unit stays. Also, fluid resuscitation with Ringer’s lactate in a patient with existing metabolic acidosis further worsens cardiac function. Severe hypothermia impairs cough reflex and increases the risk of a comatose surgical patient to postoperative pneumonia.  Treatment Patients at risk for hypothermia should be monitored frequently and every attempt should be made to maintain normal central core temperature. Pulmonary artery, tympanic membrane,

Chapter 12  Surgical Complications urinary bladder, esophagus, trachea, nasopharynx, or rectum have been established as reliable sites for estimation of core temperatures. Continuous temperature monitoring and maintaining normothermia are essential during surgery as anesthesia, cool operating room environment, and significant evaporative cooling occurs during skin preparation making most surgical patients susceptible to hypothermia. Increasing the ambient room temperature, administering warmed IV fluids, covering patients with blankets, and using forced-air warming devices are commonly used techniques to prevent intraoperative hypothermia. Invasive core rewarming techniques can also be used during surgery, including intraperitoneal irrigation with warmed saline and intubation and ventilation with warmed humidified air or gases.6 Circulating water warmers produce faster rewarming than heat exchanging systems. Inadvertent core hypothermia is commonly seen in the immediate postoperative period. Maintenance of normal body temperature decreases blood loss, fluid requirement, length of intensive care unit (ICU) stay, organ failure, and mortality. Maintenance of intravascular volume and electrolytes is important, particularly in head injuries where mannitol can augment the effects of cold diuresis. However, in the case of major abdominal,

cardiothoracic surgery, surgery involving intentional hypothermia (cardiac bypass), or prolonged surgery (>4 hours), forced-air warming, warm IV fluids, and ambient temperature alone are inadequate for maintaining normothermia. When rapid warming is needed, continuous arteriovenous rewarming is more effective. In patients with asystole, defibrillation and drugs have unpredictable efficacy, and cardiopulmonary bypass is essential for rewarming and maintaining perfusion. 

Malignant Hyperthermia Malignant hyperthermia is a life-threatening condition that develops in approximately 1:10,000 to 1:250,000 anesthetic cases, with a higher incidence in younger patients.7 It is an autosomal dominant pharmacogenetic disorder that presents as hypermetabolic response to inhalation anesthetic agents like halothane, isoflurane, sevoflurane, desflurane, or depolarizing muscle relaxants succinylcholine or suxamethonium. During muscle contraction, the neuronal signal action potential is transferred to muscle cells, resulting in the release of intracellular calcium from sarcoplasmic reticulum via ryanodine receptors to initiate muscle contraction. The energy used in this process also generates heat and oxygen is consumed with carbon

Table 12.7  Recommended antibiotic prophylaxis by surgical procedure. Type of Procedure

Recommended Agents

Gastroduodenal

Cefazolin

245

Alternatives For Patients with β-Lactam Allergy

Clindamycin or vancomycin + aminoglycoside or aztreonam or fluoroquinolone Biliary tract Cefazolin, cefoxitin, cefotetan, ceftriaxone, –Clindamycin or vancomycin + aminoglycoside or aztreonam or ampicillin-sulbactam fluoroquinolone –Metronidazole + aminoglycoside or fluoroquinolone Appendectomy for uncomplicated Cefoxitin, cefotetan, cefazolin + metronidazole –Clindamycin + aminoglycoside or aztreonam or fluoroquinolone appendicitis –Metronidazole + aminoglycoside or fluoroquinolone Nonobstructed small bowel Cefazolin Clindamycin + aminoglycoside or aztreonam or fluoroquinolone Obstructed small bowel Cefazolin + metronidazole, cefoxitin, cefotetan Metronidazole + aminoglycoside or fluoroquinolone Hernia repair Cefazolin Clindamycin, vancomycin Colorectal –Cefazolin + metronidazole, cefoxitin, –Clindamycin + aminoglycoside or aztreonam or fluoroquinolone cefotetan, ampicillin-sul bactam, –Metronidazole + aminoglycoside or fluoroquinolone ceftriaxone + metronidazole, ertapenem Head and neck –None –None –Clean wound –Cefazolin, cefuroxime –Clindamycin –Clean wound with placement of prosthesis –Cefazolin + metronidazole, cefuroxime + –Clindamycin –Clean-contaminated wound metronidazole –Aminoglycoside with or without clindamycin –Fluoroquinolone, trimethoprimUrologic surgery –Clindamycin, vancomycin sulfamethoxazole, cefazolin –Lower urinary tract instrumentation –Clindamycin ± aminoglycoside or aztreonam, vancomycin ± –Cefazolin (addition of aminoglycoside for –Clean wound without entry into urinary aminoglycoside or aztreonam placement of prosthetic material) tract –Fluoroquinolone, aminoglycoside with or without clindamycin –Cefazolin ± aminoglycoside, cefazolin ± –Involving prosthetic implantation –Fluoroquinolone, aminoglycoside + metronidazole or clindamycin aztreonam, ampicillin-sulbactam –Clean wound with entry into urinary tract –Cefazolin (addition of aminoglycoside for –Clean-contaminated wound placement of prosthetic material) –Cefazolin + metronidazole, cefoxitin Vascular Cefazolin Clindamycin, vancomycin Transplant surgery –Piperacillin-tazobactam, cefotaxime + –Clindamycin or vancomycin + aminoglycoside or aztreoman or fluoroquinolone –Liver ampicillin –Pancreas and pancreas-kidney –Cefazolin, fluconazole (for high risk of fungal –Clidamycin or vancomycin + aminoglycoside or aztreonam or fluoroquinolone infection) Plastic surgery Cefazolin, ampicillin-sul bactam Clindamycin, vancomycin From Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70:195–283.

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dioxide (CO2) release. Calcium is transported back to storage and muscles are then relaxed. In genetically susceptible patients, most commonly ryanodine receptor mutations, certain triggers can stimulate continuous release of calcium, leading to persistent high levels of intracellular calcium causing constant muscle contraction or rigidity, generation of heat, increased oxygen consumption, and (CO2) release, which lead to respiratory and metabolic acidosis and eventually, if left untreated, rhabdomyolysis. Early presentations of malignant hyperthermia include an increase in end-tidal (CO2) or tachypnea if the patient is not intubated and ventilated, hypoxia, tachycardia, masseter muscle spasm, or trismus. Later presentations of malignant hyperthermia include muscle rigidity, cardiac arrhythmias, respiratory and metabolic acidosis, rhabdomyolysis, and hyperthermia, as the name suggests. Complications from rhabdomyolysis include disseminated intravascular coagulation, AKI, hyperkalemia, and possible cardiac arrest. Since malignant hyperthermia is an autosomal dominant disorder, patients with a family history of malignant hyperthermia should be carefully evaluated and consider testing before surgery. They should be carefully monitored during anesthesia and triggerfree anesthetic agents should be used. Once malignant hyperthermia develops, the initial management is to discontinue the inciting anesthetic agent and halt the operation if possible. Dantrolene is the medication of choice to treat malignant hyperthermia, and an initial dose of 2.5 mg/kg IV should be given and can be repeated according to the response: end-tidal CO2, tachycardia, muscle rigidity, and acidosis. Oxygen supplementation should be given with hyperventilation. Blood should be tested for electrolyte and blood gas to assess for acidosis and hyperkalemia, creatine phosphokinase, and renal function and then treated accordingly. The electrocardiogram should be continuously monitored for arrhythmias. Core body temperature should be measured and monitored. Active cooling with ice packs and 4°C normal saline IV should be initiated if the body temperature is more than 39°C but should be stopped when the body temperature decreases to 38.5°C to avoid overcooling and hypothermia. Renal function should be assessed and urine output should be closely monitored. IV hydration should be given with diuresis when rhabdomyolysis is present; hemodialysis may be needed in some cases. Clotting studies and platelet count should be checked for the possibility of disseminated intravascular coagulation. When stable (i.e., end-tidal CO2 and temperature are decreased, tachycardia or other arrhythmia is improved, and muscle rigidity is resolved), patients should be monitored in the intensive setting for at least 24 hours with dantrolene maintenance. Muscle weakness is a side effect from dantrolene so breathing and oxygenation should be monitored and aspiration should be prevented. Other side effects of dantrolene are hepatitis, phlebitis, and drowsiness. First-degree relatives should be advised of the potential risks and provided with genetic counseling. 

Postoperative Fever Causes Fever refers to an increase in the body’s normal core temperature. Postoperative fevers can be broadly divided into infectious and noninfectious (systemic inflammatory response syndrome [SIRS]) causes (Table 12.8). Fevers are most often transient increases in temperature caused by the systemic inflammatory stimuli as a normal response to injury. However, fever can also be an early sign of potentially life-threatening infection. Pyrogenic cytokines are produced in response to infection and trauma (including surgery) and

play an important role in regulating host inflammation and fever. Duration and extent of tissue trauma during surgery cause a release of interleukin-1 (IL-1), a primary activator of the febrile response; IL-1 levels correlate with an increase in core temperature. Also, the timing of fever onset provides an important diagnostic clue; early postoperative fever is characterized by the release of cytokines during surgery. Immediate postoperative fever occurring within the first 48 hours after surgery is most likely due to an inflammatory response to surgery. The proinflammatory mediators (tumor necrosis factor-α [TNF-α], IL-6, and interferon γ), released in response to inflammation, cause a cascade of systemic effects that induce a febrile inflammatory response, also known as SIRS.8 SIRS is diagnosed when there is presence of two or more of the following criteria: temperature >36°C, heart rate (HR) >90 beats/min, respiratory rate >20/min or PaCO2 12,000/mm3, or 10% band forms. A fever that develops 72 hours or more after surgery is more likely to be due to infection. Hence, it can sometimes be clinically challenging to delineate the precise etiology of these fevers since they can result from infectious and/or noninfectious causes. In the postoperative period, the most common infectious causes are wound infections, urinary tract infections (UTIs), and pneumonia. Prolonged IV access, bladder catheterization, or endotracheal intubation presents ongoing risks of infection that result from disruption of normal host defense mechanisms. Postoperative UTI is more common in patients with preexisting prostrate hypertrophy. Urinary tract instrumentation and indwelling urinary catheters damage the epithelial lining, eliciting an inflammatory response that facilitates bacterial adherence and the risk of UTI increases with duration of bladder catheterization. Catheter-related bloodstream infection (CRBSI) is the most common cause of nosocomial bacteremia and septicemia. As such, early diagnosis and treatment are vital to reduce the morbidity and mortality involved. The incidence of CRBSI varies

Table 12.8  Causes of postoperative fever. Infectious

Noninfectious

Abscess  Acalculous cholecystitis  Bacteremia  Decubitus ulcers  Device-related infections  Empyema  Endocarditis  Fungal sepsis  Hepatitis  Meningitis  Osteomyelitis  Pseudomembranous colitis  Parotitis  Perineal infections  Peritonitis  Pharyngitis  Pneumonia  Retained foreign body  Sinusitis  Soft tissue infection  Tracheobronchitis  Urinary tract infection

Acute hepatic necrosis  Adrenal insufficiency  Allergic reaction  Atelectasis  Dehydration  Drug reaction  Head injury  Hepatoma  Hyperthyroidism  Lymphoma  Myocardial infarction Pancreatitis  Pheochromocytoma  Pulmonary embolus  Retroperitoneal hematoma  Solid organ hematoma  Subarachnoid hemorrhage  Systemic inflammatory response syndrome Thrombophlebitis  Transfusion reaction  Withdrawal syndromes  Wound infection 

Chapter 12  Surgical Complications considerably by type of catheter, frequency of catheter manipulation, underlying patient-related factors, and local risk factors such as poor personal hygiene, occlusive transparent dressing, and moisture around the exit site9; administration of parenteral nutrition through intravascular catheters choice to treat malignant hyperth risk. The mode of contamination for CRBSI varies with the duration of catheterization (short vs. long). Short-term CRBSIs (10 days) that results in sepsis with multiorgan failure. The organisms most commonly involved in CRBSI are Staphylococci (both S. aureus and the coagulase-­negative staphylococci), enterococci, aerobic gram-negative ­bacilli, and fungal species (e.g., Candida albicans). The diagnosis of CRBSI requires at least one positive blood culture o­ btained from a peripheral vein, clinical manifestations of infection (e.g., fever, chills, and/or h ­ ypotension), and no apparent source for the blood stream infection (BSI) except the catheter. Antibiotic therapy is often initiated empirically; Vancomycin is recommended for empirical therapy for MRSA. Factors responsible for recurrent bacteremia despite parenteral therapy include antibiotic administration through retained catheter and biofilm formation. Severe sepsis and metastatic infectious complications (e.g., infective endocarditis) prolong the course of CRBSI. Catheters should be removed from patients with CRBSI associated with any local or systemic inflammation or immunocompromised condition. 

Respiratory Complications General Considerations Surgical interventions (especially thoracic and abdominal) and anesthesia impact pulmonary physiology by decreasing functional residual capacity (FRC). In most patients, this is well tolerated, but patients with underlying pulmonary disease (e.g., chronic obstructive pulmonary disease, emphysema, cigarette smokers, etc.) may be prone to develop pulmonary complications. Identifying “high-risk” patients before surgery can be helpful and preoperative pulmonary function testing, tobacco cessation, or sleep studies may help the surgical team reduce the risk of complications by optimizing the patient’s condition before surgery (e.g., preoperative bilevel positive airway pressure ventilation, bronchodilator therapy, etc.). More recently, standard patient care protocols (e.g., iCough) have been developed to decrease the risk of pulmonary complications, which include incentive spirometry, coughing and deep breathing, oral care (brushing teeth and using mouthwash), elevating the head of bed, and getting out of bed three times a day. Multimodal pain control and judicious use of regional analgesia (e.g., thoracic epidurals) may also help to prevent pulmonary complications in surgical patients. 

Atelectasis Atelectasis due to partial or complete collapse of alveoli is the most common respiratory complication in the postoperative patient. Predisposing factors for atelectasis include general anesthesia and upper abdominal or thoracic surgery with stimulation of GI viscera, which can alter diaphragmatic function for several days. The mechanisms include decreased lung compliance (due to reduced FRC), along with accumulated endobronchial secretions, resulting in V/Q mismatch and shunt, which directly correlates with the degree of atelectasis. Anesthesia, cigarettes, morbid obesity, and preexisting pulmonary disease also impair mucociliary clearance and decrease

247

the patient’s ability to cough and clear secretions, contributing to an increased risk of atelectasis. Atelectasis is the most common cause of postoperative fever in the early postoperative period. It may also present with tachypnea, decreased oxygen saturation ± accessory muscle use. On physical examination, breath sounds may be absent or reduced, or “bronchial” in nature. The chest radiograph may reveal loss of the left hemidiaphragm, air bronchograms, or decreased lung volume with tracheal deviation toward the collapsed side in severe cases. Atelectasis can be reversed in the first 24 to 48 hours with early mobilization, deep breathing (five sequential breaths held for 5–6 seconds), incentive spirometry, coughing, chest physiotherapy, bronchodilator therapy, hydration, and tracheal suction­ onsteroidal ing. Multimodal pain control using acetaminophen, n ­antiinflammatory agents, and opioids as needed or regional blocks represent the most commonly effective approach for optimal perioperative pain control. 

Pneumonia Nosocomial pneumonia is the second leading cause of nosocomial infection and is more common in surgical patients. The diagnosis of postoperative pneumonia requires the absence of infiltrates prior to admission or before surgery and can be classified as either hospital-acquired pneumonia (developing 48 hours after admission) or ventilator-associated pneumonia (VAP) (pneumonia developing 48–72 hours after endotracheal intubation). Aspiration of oropharyngeal secretions, diminished humoral defense mechanisms, injury to the surface epithelium by instrumentation (endotracheal or nasogastric [NG] tube), azotemia, critical illness, duration of surgery/ventilation, advanced age, preexisting pulmonary conditions (e.g., chronic obstructive pulmonary disease), cigarette smoking within a year prior to surgery, altered sensorium, malnutrition, and prior antibiotic therapy may facilitate colonization. Stress ulcer prophylaxis (histamine 2 [H2] blockers, antacids) and enteral feeding can increase gastric pH, gastric colonization, and aspiration (gastropulmonary route), which plays an important role in the pathogenesis of VAP.10 Postoperative pneumonias are commonly caused by gram-negative, aerobic bacteria, S. aureus in neurosurgical patients or fungal organisms in immunocompromised patients. VAP is polymicrobial in nearly half of cases, and the most common organisms include enteric gram-negative bacilli (Pseudomonas aeruginosa, Actinobacter species, Enterobacter species, Klebsiella species, Serratia marcescens, Escherichia coli, Proteus species, and Legionella species) or grampositive organisms (S. aureus). In surgery, trauma, and critically ill patients, the use of prophylactic antibiotics can alter the microbial flora. In early-onset VAP (4 days postintubation) is frequently due to drug-resistant bacteria. Also, risk of VAP is greatest during the first 5 days of mechanical ventilation (3%, with a mean of 3.3 days); thereafter, between 5 and 10 days, the risk declines to 2% per day, further declining to 1% per day after 10 days. Refractory VAP is defined as VAP with failure to improve after 72 hours. Postoperative pneumonia is associated with a high mortality (50%). Diagnosis A high index of suspicion is required for the diagnosis of postoperative pneumonia, especially in mechanically ventilated patients. Patients with postoperative pneumonia usually present with fever, leukocytosis, and a new pulmonary infiltrate. In intubated patients, VAP should be suspected when two or more of the

248

Section II  Perioperative Management

following clinical features are present (purulent respiratory secretions, temp >38oC or 4 mm) primary melanomas have an increased risk for distant metastatic disease, prior thinking held that the status of the SLN did not add much additional prognostic information. However, a number of studies have shown that thick melanoma patients with tumor-negative SLN have a better prognosis than those with tumor-positive SLN. Because there is a continuum of risk that does not abruptly end at 4-mm thickness, SLN biopsy for thick melanomas provides important risk stratification in these patients, especially for the consideration of adjuvant therapy. SLN biopsy can also be considered for patients with nonnodal regional disease (i.e., in-transit disease) with clinically negative nodes, because the number of positive nodes is prognostically important in this group.  Technical Details. The technical details of a proper SLN biopsy are worthy of attention. All patients should undergo preoperative lymphoscintigraphy, typically performed on the same day

716

SECTION V  Surgical Oncology RT Anterior axilla LT

LN site

RT Anterior axilla

A

LN site

B

FIG. 31.11  Preoperative lymphoscintigraphy can aid in identification of sentinel lymph nodes. (A) Melanoma of the back with drainage to the axilla. (B) Periumbilical melanoma with drainage to the left inguinal lymph nodes. LN, Lymph node; LT, left; RT, right.

as the operation to perform SLN biopsy and WLE (Fig. 31.11). Technetium-99 sulfur colloid (0.5 mCi) should be injected into the dermis, raising a wheal in four aliquots around the melanoma or biopsy site. It is important to inject the tracer into the normal skin approximately 0.5 cm away from the melanoma or scar from the biopsy and not into the melanoma itself or biopsy scar. A common mistake is to inject the radioactive tracer too deeply into the subcutaneous tissue, which will result in failure to detect a sentinel node. If no sentinel nodes are identified after the initial injection, repeat injection should be performed with the proper technique by an experienced clinician. In almost all cases, this will result in identification of sentinel nodes. Imaging is performed with a gamma camera, with dynamic and static images that allow identification of lymphatic channels and sentinel nodes. Although patterns of lymphatic drainage can be predictable at times, lymphoscintigraphy often identifies lymph nodes in locations that are not anticipated. This is especially true for melanomas in ambiguous lymphatic drainage areas, such as the trunk, head, or neck, where anatomic predictions of nodal spread are unreliable. In such cases, lymphoscintigraphy may identify sentinel nodes in more than one nodal basin. Furthermore, it is not uncommon to identify sentinel nodes outside the traditional cervical, axillary, and inguinal nodal basins. So-called interval, intercalated, or in-transit nodes may be found in subcutaneous locations or between muscle groups. For distal upper or lower extremity melanomas, it is important to assess the presence of epitrochlear or popliteal sentinel nodes, respectively. These interval nodes have the same risk of harboring melanoma cells as sentinel nodes in traditional nodal basins; therefore, it is recommended that they be removed at the time of sentinel node biopsy. In addition, 85% of the time, the interval lymph node is the only positive node, even for those patients with other SLNs identified in traditional basins. Therefore, all sentinel nodes identified by preoperative lymphoscintigraphy should be removed (Fig. 31.12). At operation, which is generally performed under general anesthesia, a vital blue dye (e.g., isosulfan blue) is injected into the dermis around the melanoma site in a manner similar to that for injection of the radioactive tracer (Fig. 31.13). This combined lymphatic mapping technique allows for the identification of the sentinel nodes in 99% of patients. Because the blue dye will not

Popliteal SLN

FIG. 31.12  Popliteal sentinel lymph node (SLN) on lymphoscintigraphy.

FIG. 31.13  Intradermal injection of isosulfan blue dye for intraoperative lymphatic mapping and sentinel lymph node biopsy.

CHAPTER 31  Melanoma and Cutaneous Malignancies persist in the sentinel nodes for prolonged periods, it is injected just before the operation; 1 to 5 mL is used, depending on the size of the melanoma. Because blue dye will persist in the skin for many months after injection; it is best to inject it within the margins of the planned WLE. A handheld gamma probe is used to identify the location of the sentinel node(s), and dissection is performed to identify blue lymphatic channels entering into any blue lymph nodes (Fig. 31.14). A sentinel node is defined as any lymph node that is the most radioactive node in the nodal basin, any node that is blue, any node that has a radioactive count of 10% or higher of the most radioactive node in that basin, or any node that is palpably abnormal and suspicious for tumor. All such nodes require resection. By following these guidelines, the risk of a false-negative SLN biopsy is minimized. Although multiple radioactive lymph nodes may be evident within a nodal basin on lymphoscintigraphy, many of these represent mildly radioactive second-echelon nodes and not true sentinel nodes. There is often a poor correlation between the number of nodes visualized on the lymphoscintigram and the number of SLNs identified. In general, the average number of sentinel nodes identified is two per nodal basin. Sentinel nodes should be sent for permanent section histopathology with immunohistochemical stains for melanoma markers (e.g., S-100, HMB-45, and Melan-1). Immediate frozen section histology should be avoided because even expert pathologists have difficulty diagnosing micrometastatic melanoma in the SLN on frozen sections. SLN biopsy is more challenging in the head and neck than for other regions because of the rich lymphatic drainage network in this location. Correspondingly, the false-negative rate for SLN biopsy is generally higher for melanomas in these locations. Cross-sectional imaging, such as with a single-photon emission CT, can allow the surgeon to identify the exact anatomic location of the SLNs more accurately than with the planar lymphoscintograms. Precise knowledge of the anatomy in this region is essential to avoid inadvertent neurologic injury. Parotid SLNs can be identified and removed, usually without the need for superficial parotidectomy. However, if there is any concern for facial nerve injury, superficial parotidectomy may be a safer option. A common site for cervical SLN is directly adjacent to the spinal accessory nerve, which should be visualized and preserved.  Multicenter Selective Lymphadenectomy Trial. The only randomized control trial to compare outcomes between SLN biopsy and nodal observation is the first Multicenter Selective Lymphadenectomy Trial (MSLT-I).14 The trial randomized 1347 patients with intermediate-thickness melanoma (1.2–3.5 mm thick) and 314 patients with thick melanoma (>3.5 mm thick) to either SLN biopsy or observation. Patients with disease identified by SLN biopsy underwent immediate completion lymphadenectomy. The frequency of nodal metastasis across all groups was 20.8% and was similar within each treatment arm. No difference in 10-year melanoma-specific survival was found between SLN biopsy and observation group in either the intermediate thickness (81.4% vs. 78.3%; P = 0.18) or thick melanoma groups (58.9% vs. 64.4%; P = 0.56). However, improved 10-year disease-free was observed with SLN biopsy in both intermediate and thick melanomas. The status of the sentinel node was the strongest predictor of recurrence or death from melanoma: in patients with intermediate thickness melanoma, 10-year survival was 85.1% with a negative SLN biopsy, compared to 62.1% for positive nodes (HR, 3.09; P < 0.001). Interestingly,

717

FIG. 31.14  Blue lymphatic channels leading to a blue sentinel lymph node.

on subgroup analysis limited only to patients with nodal metastasis (disease identified either on SLN biopsy or that developed while under observation), improved melanoma-specific survival, disease-free survival, and distant disease-free survival was observed in the SLN biopsy arm among patients with intermediate thickness lesions. Lymph Node Dissection

Historical. Lymph node dissection, historically, was an important component of the surgical treatment of melanoma, but with the development of the SLN biopsy technique and an improved understanding of the biology of melanoma, it has become less important. Prior to the use of SLN biopsy, an elective lymph node dissection of the draining regional nodal basin was often performed for high-risk melanomas in order to identify early, clinically occult lymph node metastases and provide accurate staging. The SLN technique accomplishes the same objectives with decreased morbidity; therefore, elective lymph node dissection is of historical interest only. Lymph node dissection does still play an important role in the treatment of melanoma; therefore, the surgeon treating melanoma should be familiar with the technical details of the operation and its indications.  Completion Lymphadenectomy. Completion lymphadenectomy or CLND is used to remove the remaining lymph nodes in a regional nodal basin that is found to have metastatic melanoma by SLN biopsy. A wide range of prognosis exists in stage III, SLNpositive melanoma. CLND allows one to identify nonsentinel node metastases. This is an important prognostic factor, as multiple studies have demonstrated that metastases to the nonsentinel nodes represent an additional echelon of metastatic disease with more aggressive biology and worse prognosis compared to disease limited to the SLNs. CLND may have a potential therapeutic benefit by removing additional lymph nodes with micrometastatic disease, improving disease-free survival as seen in MSLT-I. CLND

718

SECTION V  Surgical Oncology

FIG. 31.15  Subcapsular micrometastatic melanoma deposits within the lymph node.

does, however, greatly increase the short- and long-term morbidity to the patients. Complications include wound complications, paresthesias, and permanent lymphedema. Only 15% to 20% of patients with SLN-positive micrometastatic lymph node disease have additional micrometastatic nonsentinel nodes after CLND; thus, 5 out of 6 patients undergoing CLND for SLN-positive disease derive no therapeutic benefit from the procedure and experience all the morbidity associated with the CLND. Efforts to predict nonsentinel node metastases have focused on clinical and pathologic factors that identify high- and lowrisk patients in whom a CLND could either be selectively omitted (in patients at low risk for non-SLN disease) or in whom a CLND would be particularly beneficial. Multiple different scoring systems evaluating the burden of micrometastatic disease within the lymph node have been developed, with criteria including location of tumor deposits, tumor cross-sectional area, tumor diameter (either summed across all foci or only within the largest focus), or depth of invasion into the lymph node (Fig. 31.15). In general, the maximum diameter of the largest tumor deposit is the most prognostically significant tumor burden measure that can predict survival and non-SLN metastases.15,16 Ongoing research that harmonizes these clinical and pathologic factors with novel genetic markers of increased risk, either in the primary tumor or SLN biopsy, will allow development of comprehensive risk models that can give a patient-specific assessment of the risk of non-SLN metastases. The ability to predict nonSLN metastases may be used in the future to select patients for adjuvant therapy, rather than a CLND, based on two landmark studies discussed below.  Multicenter Selective Lymphadenectomy Trial II and German Dermatologic Cooperative Group Trial (DeCOGSLT). Two studies were conducted to answer the question concerning whether CLND after a tumor-positive SLN biopsy improved survival compared to observation alone. The rationale for the observation approach is that, as discussed above, upward of 85% of patients do not have any additional micrometastatic disease after a positive SLN biopsy; therefore, no survival benefit is achieved from routine CLND. The DeCOG-SLT study was a multicenter, randomized clinical trial conducted in Germany, the results of which were published in 2016.17 In the study, 483 patients with a positive SLN

biopsy were randomized to either a CLND of the positive lymph node basin or observation. The trial was closed early due to difficulties in accrual and low event rates; the planned enrollment was 550. With a median follow-up of 35 months, there were no differences in the primary endpoint or distant metastasis-free survival between the two groups (77% vs. 75%). There were no differences in recurrence-free or overall survival. Subgroup analysis of the primary endpoint based on micrometastatic tumor burden (≤1 mm or >1 mm) showed no differences in distant metastasisfree survival. The study has been criticized as being underpowered and failing to meet accrual, but it is an important study that establishes the safety of an observation strategy with SLN-positive melanoma. The MSLT-II was a larger, multicenter randomized clinical trial that confirmed the findings of the DeCOG study. In MSLT-II, 1939 patients with a tumor-positive SLN biopsy were randomized to a CLND or observation, which consisted of ultrasound-based surveillance of the involved nodal basin.18 There was no difference in the primary endpoint, melanoma-specific survival, between the two groups. The 3-year melanoma-specific survival rate was 86% in both groups, while the 3-year disease-free survival rate was numerically (but not statistically) greater in the CLND group compared to the observation group (68% vs. 63%; P = 0.05). There was an increase in the cumulative incidence of non-SLN metastases in the observation group versus the CLND group (26% vs. 20% at 5 years; P = 0.005). Taken together, the findings of DeCOG-SLT and MSLT-II have been practice-changing. Only in very selective circumstances, in which there is a high degree of concern for non-SLN metastases and failure of regional nodal control, or inability to follow the observation surveillance strategy, is CLND considered after a positive SLN. Although not universally accepted at all centers, the DeCOG and MSLT-II studies firmly establish that it is safe and reasonable to avoid CLND for the vast majority of patients with positive SLN. The issues of this approach and the selection of patients for adjuvant therapy will be discussed below.  Therapeutic Lymph Node Dissection. A therapeutic lymph node dissection, which is a lymphadenectomy of a regional nodal basin with clinically apparent nodal metastases, remains an important part of the armamentarium of the surgeon treating melanoma. It is an excellent procedure for achieving locoregional disease control, and given the findings of MSLT-II and DeCOGSLT, it will likely be the most common reason for performing a lymphadenectomy in the future. Suspected nodal metastases based on palpable lymph nodes or radiographic abnormalities should be confirmed by fine needle aspiration. On occasion, benign lymphadenopathy may be found, but in a patient with cutaneous melanoma, palpable lymph nodes should be concerning for metastatic disease until proven otherwise. Palliative resection of bulky, painful regional lymphadenopathy can be considered, recognizing that there will be a high risk of regional and distant metastatic recurrence in the absence of effective adjuvant therapy (Fig. 31.16). A therapeutic lymph node dissection should remove all the fibrofatty and lymphatic tissue in the involved regional nodal basin according to standard anatomic boundaries. For the axilla, a thorough level I, II, and III axillary dissection is performed. This includes complete removal of all fibrofatty tissue around the axillary vein, thoracodorsal and medial pectoral neurovascular bundles, and long thoracic nerve. The pectoralis minor muscle may need to be divided near its insertion on the coracoid process in order to clear bulky level II and III nodes. On rare occasions, the pectoralis

CHAPTER 31  Melanoma and Cutaneous Malignancies

A

719

B

FIG. 31.16  (A) Advanced axillary lymph node metastases. (B) Levels I, II, and III axillary lymph node dissection.

major muscle may need to be divided as well. The axillary vein may be ligated and divided if it becomes involved with tumor, often with less consequence in terms of edema than one might anticipate. Inguinal lymph node dissection includes the superficial inguinal (femoral) lymph nodes, and may also include dissection of deep or pelvic (internal iliac, external iliac, and obturator) nodes. There is no consensus as to when pelvic nodal dissection should be performed for patients with macroscopic disease confined to the superficial inguinal nodal basin. For patients with palpable nodal disease or with imaging suggestive of involved pelvic lymph nodes, the deep nodes should be dissected in most cases. Metastasis to Cloquet node, which links the femoral and iliac nodal chains underneath the inguinal ligament, has traditionally been a common indication for pelvic nodal dissection. Similarly, gross involvement of multiple femoral nodes is another traditional indication for pelvic dissection. For cervical lymphadenectomy, a functional neck dissection with sparing of the internal jugular vein and spinal accessory nerve is usually sufficient. The need for superficial parotidectomy may be guided by the lymphoscintigraphy and SLN results. Epitrochlear or popliteal lymphadenectomy is frequently unnecessary but requires careful attention to the particular anatomy in these regions (Fig. 31.17).  Adjuvant Therapy As with most solid organ malignancies, the dismal prognosis historically associated with advanced melanoma was the result of lack of effective systemic therapies. Melanoma biology has historically trumped the locoregional disease control strategies of the surgeon. With the exception of some increase in the sophistication of our understanding of the evaluation and management of the regional lymph nodes, vis-á-vis SLN biopsy and indication for completion lymphadenectomy, the operative treatment of melanoma has not changed much in the last few decades. The same cannot be said for systemic treatment options. It is an exciting time to be treating melanoma, as advances in targeted therapy and immunotherapy have been occurring at breakneck speed. We now have multiple adjuvant therapy options that are safe and effective, which offer melanoma patients the hope for durable disease remission after operative therapy (Table 31.3).

A

B FIG. 31.17  Popliteal lymph node dissection with (A) exposed popliteal artery and vein and (B) closure.

Historical. Prior to 2015, the only adjuvant systemic therapy approved for melanoma by the U.S. Food and Drug Administration (FDA) was high-dose interferon alfa-2b. This drug was quite

720

SECTION V  Surgical Oncology

TABLE 31.3  Summary of adjuvant therapy trials for BRAF-MEK inhibition and immunotherapy

in cutaneous melanoma. TRIAL NAME EORTC 18071 (Eggermont et al)21

COMBI-AD (Long et al)19

CheckMate 238 (Weber et al)22

EORTC 1325 (Eggermont, et al)23

STUDY POPULATION

INTERVENTION TREATMENT

CONTROL TREATMENT

IIIA (with >1 mm micrometastasis), IIIB, IIIC (with no in-transit metastases) IIIA (with >1 mm micrometastasis), IIIB, IIIC BRAF V600 mutation Completely resected IIIB, IIIC, or IV

Ipilimumab 10 mg/kg every 3 weeks × 4, then every 3 months × 3 years Daily dabrafenib/ trametinib x 12 months

Placebo

Nivolumab every 2 weeks × 12 months

IIIA (with >1 mm micrometastasis), IIIB, IIIC (with no in-transit metastases)

Pembrolizumab every 3 weeks x 12 months

Ipilimumab 10 mg/kg every 3 weeks × 4, then every 12 weeks × 12 months Placebo

Placebo

PRIMARY OUTCOME

NOTES

Improved recurrence-free survival (HR, 0.76; 95% CI, 0.64–0.89)

Improved overall survival at 5 years (65.4% vs. 54.4%; HR, 0.72; 95% CI, 0.58–0.88) Improved relapse-free Improved 3-year overall survival (3 year RFS 58% survival (86% vs. 77%; vs. 39%; HR, 0.47; 95% CI, HR, 0.57; 95%, CI 0.39–0.58) 0.42–0.79) Improved 12-month recurrence- Better safety profile with free survival with nivolumab nivolumab (grade 3 or 4 (70.5% vs. 60.8%; HR, 0.65; adverse events, 14.4% 97.5% CI, 0.51–0.83) vs. 45.9%) Improved recurrence-free Improved RFS in both survival (HR, 0.57; 98.4% CI, PD-L1-positive and PD0.43–0.74) L1-negative tumors

CI, Confidence interval; HR, hazard ratio; PD-L1, programmed death ligand 1; RFS, recurrence-free survival.

toxic, with a prolonged treatment course and numerous serious adverse events. Therapy was typically delivered for 1 month via intravenous therapy, followed by 11 months of thrice-weekly subcutaneous injections. Common side effects included influenzalike symptoms, fatigue, malaise, anorexia, neuropsychiatric side effects, and hepatic toxicity. The therapy was marginally effective at best and quite toxic at worst. The FDA approval was based largely on the Eastern Cooperative Oncology Group E1684 trial, in which high-risk patients with palpable nodal disease experienced short-term disease-free and overall survival benefit with adjuvant interferon; longer follow-up demonstrated a modest difference in disease-free survival only. Alternative dosing strategies, including intermittent dosing and use of pegylated interferon alfa-2b, were tried. The Sunbelt Melanoma Trial demonstrated that in lower-risk patients with a single positive SLN, there was no benefit to adjuvant interferon in terms of disease-free or overall survival. The summary assessment of adjuvant interferon for melanoma is that it reproducibly improved disease-free survival, with minimal effect on overall survival at the cost of serious toxicity. Better adjuvant therapy options were needed; these options came in the form of targeted therapy and immunotherapy.  Targeted Therapy. The first successful targeted therapy developed for melanoma was vemurafenib, a small molecule tyrosine kinase inhibitor targeted against the BRAF  V600E mutation. BRAF is one of the recognized driver mutations in melanoma that is present in about half of all cutaneous melanoma. Building on the initial successful trials in metastatic melanoma, BRAF inhibition as a treatment concept evolved into dual BRAF-MEK inhibition in order to overcome some of the resistance issues seen with single-agent BRAF inhibition (Fig. 31.18). The promising experience with BRAF-MEK inhibition in metastatic melanoma led to the development of an adjuvant trial for patients with resected stage III BRAF-mutant melanoma. The landmark COMBI-AD trial was published by Long and colleagues in 2017.19 In this multicenter, international study, 870 patients with completely resected stage III melanoma with either the BRAF V600E or V600K mutation were randomly assigned

to dual BRAF (dabrafenib) and MEK (trametinib) inhibition therapy or placebo for 12 months after resection. The initial findings were simply remarkable: 3-year relapse-free survival was improved from 39% to 58% in the treatment group (HR, 0.47) and 3-year overall survival was improved from 77% to 86% (HR, 0.57). Subgroup analyses showed that the benefit of dual BRAFMEK inhibition was consistent across multiple cohorts, including age, disease stage (IIIA, IIIB, and IIIC), micrometastatic versus macrometastatic disease, ulceration, and number of nodal metastases. The therapy was well tolerated, with a reasonable adverse event profile. Importantly, the trial enrolled patients with stage III disease who had undergone a completion lymphadenectomy for SLN-positive disease. High-risk micrometastatic disease was selected by only enrolling patients with a lymph node metastasis of more than 1 mm. This trial has established the potential role of adjuvant targeted BRAF-MEK inhibition for stage III melanoma in patients with BRAF-mutant melanoma; however, there are some issues with how we incorporate this strategy in light of some of the other adjuvant therapy options. There is some concern about the long-term durability of this strategy, as we know that patients who initially respond to targeted therapy often eventually develop resistance. Long-term follow-up of this study will shed some light on this issue. Adjuvant immunotherapy is also very promising (discussed below). Thus, it is not clear what the optimal adjuvant treatment strategy is for BRAF-mutant melanoma patients who are also candidates for adjuvant immunotherapy. Finally, one must reconcile the findings of this trial with the current paradigm for managing SLN-positive melanoma. All patients in this study underwent completion lymphadenectomy for SLN-positive disease; however, the current treatment strategy for SLN-positive disease in light of the MSLT-II and DeCOG studies is to forgo completion lymphadenectomy in favor of nodal surveillance.  Immunotherapy. Adjuvant immunotherapy developed in a simi­ lar manner to BRAF-targeted therapy, in which early experience with treatment of metastatic disease developed into an adjuvant therapy concept. The first immunotherapy agent to gain approval for adjuvant therapy was the monoclonal anti-CTLA-4 antibody

CHAPTER 31  Melanoma and Cutaneous Malignancies Receptor tyrosine kinase

721

Resistance mechanisms

RTK upregulation PIP3

PIP2

PTEN

RAS

P85 p110

NF1 RAF

BRAFV600E amplification BRAFV600E splice variants CRAF overexpression

PI3K AKT

MAP3K8

mTOR

RAS mutation NF1 loss PTEN loss

MEK

ERK

MAP3K8 upregulation AKT mutation MEK mutation

FIG. 31.18  BRAF-MEK signaling pathway and potential mechanisms of resistance. (From Welsh SJ, Rizos H, Scolyer RA, et al. Resistance to combination BRAF and MEK inhibition in metastatic melanoma: where to next? Eur J Cancer. 2016;62:76–85.)

ipilimumab in 2015. The FDA approved ipilimumab based on the initial findings of the EORTC 18071 study published in 2015.20 In this trial, 951 patients with resected stage III melanoma were randomized to treatment with ipilimumab at a dose of 10 mg/kg for up to 3 years or placebo. All patients with SLN-positive disease underwent a completion lymphadenectomy and patients with micrometastatic lymph node disease of 1 mm or less were excluded. Median recurrence-free survival was improved from 17.1 months to 26.1 months in the ipilimumab group (HR, 0.75). With longer follow-up (median follow-up, 5.3 years), the recurrence-free survival benefit was maintained and an overall survival benefits was demonstrated.21 Five-year recurrence-free survival was 40.8% in the ipilimumab group compared to 30.3% (HR, 0.76) and the 5-year overall survival rate was improved from 54.4% to 65.4% (HR, 0.72). The rate of distant metastasis-free survival was also improved. These benefits did not come without increased risk of serious adverse events and even death from adjuvant ipilimumab. Serious adverse events occurred in 54% of the patients treated with ipilimumab compared to 26% of the placebo group. Five patients (1.1%) died due to complications from adjuvant ipilimumab. The promising results from this trial led to the first new drug approved by the FDA for adjuvant therapy of melanoma in nearly 20 years. However, the side effects and risk of death were of significant concern. The newer programmed death 1 (PD-1) inhibitors nivolumab and pembrolizumab offered the promise of safer, better-tolerated immunotherapy with just as effective and durable a response as ipilimumab. The Checkmate 238 trial demonstrated that adjuvant nivolumab was more effective than ipilimumab at preventing recurrence in resected stage III and stage IV melanoma.22 In this trial, 906 patients with complete resection of stage IIIB, IIIC, or IV (as defined by AJCC seventh edition) melanoma were randomly assigned to 1 year of adjuvant nivolumab or ipilimumab. At a minimum follow-up of 18 months, the 12-month recurrence-free survival was 70.5% in the nivolumab group and 60.8% in the ipilimumab group (HR, 0.65). Serious (grade 3 or 4) adverse events were lower in the nivolumab group (14%) compared to the ipilimumab group (46%). The relative benefit of nivolumab compared to ipilimumab was consistent across multiple subgroups, including age, gender, stage (IIIB, IIIC, and IV), ulceration, and micro- versus macrometastatic lymph node disease. Adjuvant

pembrolizumab has also been reported to improve recurrencefree survival in resected stage III melanoma. In the EORTC 1325 (KEYNOTE-054) trial, 1019 patents with resected stage III melanoma (by seventh edition AJCC) were randomized to 1 year of adjuvant pembrolizumab or placebo.23 With a median followup of 15 months, adjuvant pembrolizumab was associated with improved 1-year recurrence-free survival compared to placebo (75.4% vs. 61.0%; HR, 0.57). The low rate of serious adverse events reported in the pembrolizumab group (14.7%) was similar to that of nivolumab in the Checkmate 238 trial. Like nivolumab, pembrolizumab was effective across multiple subgroups, including PD-1 ligand (PD-L1) expression, gender, stage (IIIA, IIIB, IIIC), number of positive lymph node, micro- versus macrometastatic lymph node disease, ulceration, and BRAF mutation status. Based on these landmark trials, the PD-1 inhibitors nivolumab and pembrolizumab have become the preferred adjuvant immunotherapy option for patients with resected stage III and IV melanoma. Ipilimumab has fallen out of favor because of its toxicity profile compared to the PD-1 inhibitors, but it may still play a role in salvage therapy or in combination with PD-1 inhibitors (discussed in more detail below). Preference for nivolumab or pembrolizumab is usually institution specific, as there are no data to suggest one is more effective than the other. The issue that surgeons and medical oncologists face, as alluded to in the Targeted Therapy section previously, is the reconciliation of the adjuvant trial study populations, in which all SLN-positive patients underwent CLND, with the current treatment paradigm of omission of CLND in most SLN-positive patients. Checkmate 238 excluded stage IIIA patients, and EORTC 1325/KEYNOTE-054 allowed IIIA patients, but only if the micrometastatic lymph node burden was larger than 1 mm in diameter (using the seventh edition AJCC staging criteria). The majority of patients with nodal metastases detected by SLN biopsy have a single microscopically positive lymph node. We are thus facing a population of stage III patients that are mostly IIIA, with an adjuvant treatment strategy that we know is effective in IIIB and IIIC patients. The risk stratification of these single positive SLN patients into groups that will and will not benefit from adjuvant immunotherapy will be the focus of a great deal of research in the future as we try to tailor our adjuvant treatment strategy to maximize effectiveness and minimize excess utilization. 

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SECTION V  Surgical Oncology

Radiation Therapy. Although melanoma has been historically believed to be relatively resistant to radiation, several newer studies suggest that there may be roles for radiation treatment in the adjuvant and palliative settings as well as a potential adjunct to systemic immunotherapy. Adjuvant radiation therapy may have a role in select patients at high risk for lymph node basin recurrence after lymphadenectomy. In long-term follow-up of the ANZMTG 01.02/TROG 02.01 trial, adjuvant radiation therapy after regional lymphadenectomy reduced the cumulative incidence of lymph node field relapse from 36% to 21% (adjusted HR, 0.52).24 The trial randomized 250 patients considered to be at high risk for nodal recurrence to either adjuvant radiotherapy (48 Gy in 20 fractions) or observation following lymphadenectomy. High risk was defined as one or more involved parotid nodes, two or more cervical or axillary nodes, three or more involved inguinal nodes, presence of extranodal extension, or maximum diameter of the largest lymph node greater than 4 cm (3 cm for cervical nodes). After long-term follow-up, there remained no difference in overall survival or relapse-free survival. Adjuvant radiation therapy does appear to offer some improvement in control of regional lymph node disease in high-risk patients after lymphadenectomy; however, the importance of this regional control with disease that is clearly high risk for systemic metastases is not clear. It is likely that patients with high-risk regional nodal disease would derive more benefit from better adjuvant systemic therapy (immunotherapy) to reduce the risk of metastatic recurrence rather than adjuvant radiation therapy to improve nodal basin disease control. 

Surveillance There are no definitive guidelines on appropriate follow-up for patients with resected melanoma who are disease free, although the NCCN does offer some suggested surveillance approaches. The general principle that should be considered is that the intensity of the surveillance strategy and incorporation of imaging studies should be individualized according to the patient’s risk and likely site of recurrence. Most recurrences are detected within the first 5 years after treatment, although melanoma is notorious for delayed recurrences, sometimes decades after treatment, in seemingly lowrisk lesions. Patients with early stage, localized disease (0–II) are at low risk of recurrence and should be observed by history and physical examination at least every 6 months for the first 3 years and at least annually thereafter. A careful history is necessary to elicit symptoms such as new skin lesions, nodal masses, pain, headaches, neurologic changes, weight loss, and gastrointestinal and pulmonary symptoms. Patients should be educated about common symptoms and signs of recurrence so that they can report any important changes that arise between scheduled visits. Physical examination should include a complete skin inspection, including palpation to detect regional nodal or in-transit recurrence. Most recurrences in these patients will be reported by the patients themselves.25 For stage III melanoma and those with high-risk stage II disease (thick and/or ulcerated primaries), a reasonable follow-up schedule is a history and physical examination every 3 or 4 months for the first 3 years, every 6 months for the next 2 years, and annually thereafter. The use of laboratory tests and imaging tests such as CT, MRI, or PET/CT is controversial but not unreasonable for these patients. Even though there has never been any proven benefit to early detection of recurrent melanoma with radiographic or laboratory studies, it stands to reason that in this age of effective immunotherapy for metastatic melanoma, there may be some utility in early detection of low-volume disease. Patients with stage

FIG. 31.19  Local recurrence of melanoma within the scar of the primary melanoma excision.

IV melanoma will have regular clinical, laboratory, and radiologic evaluations to monitor the response to treatment. The survivorship team, which will likely include the surgeon, dermatologist, and potentially the medical oncologist, should consider both recurrence of the primary melanoma and development of a second primary melanoma. Survivors of melanoma continue to exhibit high-risk UV exposure and suboptimal risk reduction behavior.26 Melanoma survivors have a ten fold increased risk of a subsequent melanoma compared to the general population and a cumulative risk of the development of a second primary melanoma of approximately 5%.27 Melanoma survivors should have regular skin exams for the rest of their lives.  Treatment of Locoregional Recurrent Disease Local recurrence. Recurrences within 5 cm of the WLE scar or skin graft are considered local recurrences and represent aggressive tumor biology associated with a poor overall survival (Fig. 31.19). Recurrence risk increases with tumor thickness and has been estimated as 0.2%, 2%, 6%, and 13% for melanomas less than 0.75 mm, 0.75 to 1.5 mm, 1.5 to 4 mm, and larger than 4 mm, respectively. Treatment for local recurrence is operative resection to histologically negative margins. Although WLE guidelines for primary tumors do not apply, at least a 1-cm margin should be attempted with complete resection of the prior WLE scar. SLN biopsy of local recurrences is technically feasible, and the results may have some prognostic value. The rate of a positive SLN biopsy when performed for recurrence may be as high as 40%, and this may offer valuable risk stratification to select patients for additional surgery or adjuvant therapy.28  In-transit disease. In-transit tumors, either at presentation or as a recurrence after initial local therapy, are subcutaneous or cutaneous tumor nodules between the primary tumor site and draining nodal basin formed by tumor deposits within the lymphatic channels (Fig. 31.20). They are often subtle in appearance, lack pigmentation, and may only be appreciated as a palpable

CHAPTER 31  Melanoma and Cutaneous Malignancies

FIG. 31.20  In-transit metastases (circled on left flank) between the large primary tumor of the mid lower back and the draining nodal basin.

nodule. Fine needle aspiration or core biopsy can confirm the diagnosis. Once diagnosed, whole body imaging should be performed, as there is a high risk of distant metastatic disease. Limited in-transit disease may be adequately treated with simple excision to negative margins, but a high suspicion for a more aggressive disease biology that will require additional treatment must be in the mind of the surgeon. In approximately 20% of patients, local excision alone may be sufficient treatment, but they may require repeat excision in the future. SLN biopsy in the setting of in-transit disease should be considered, as the results carry prognostic significance.28 Historically, extensive or recurrent in-transit disease confined to the extremity was treated with regional chemotherapy. Methods of delivering high-dose chemotherapy into the limb that was otherwise isolated from the rest of the body included hyperthermic isolated limb perfusion or isolated limb infusion. Melphalan was the most common chemotherapy agent delivered into the circuit. Isolated limb infusion was developed as a less invasive, less resource-intensive technique with comparable oncologic outcomes and less limb toxicity. These treatments are used less often now, as intralesional and systemic immunotherapies are now preferred as an effective way to achieve locoregional disease control of in-transit disease with less morbidity for patients. Unresectable stage III disease, including in-transit disease, was included in many of the early immunotherapy trials that evaluated CTLA-4 or PD-1 inhibition. Both agents showed good response rates and improved progression-free survival, used alone or in combination. Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1–derived oncolytic immunotherapy that is serially injected into palpable target lesions to induce both a direct local effect and potentially a systemic response. In the OPTiM

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trial, 436 patients with unresected stage IIIB to IV melanoma by the seventh edition AJCC staging were randomized to either serial intralesional T-VEC injection or granulocyte macrophage colony-stimulating factor as a control.29 A durable response rate of 16% was seen in the T-VEC group compared to 2% in the control group (odds ratio, 8.9). The overall response rate was also greater in the T-VEC group (26% vs. 6%) and median overall survival was marginally improved (23 months vs. 19 months). The best responses were seen in IIIB, IIIC, and M1a disease. There were systemic, off-target responses as well. Investigators observed a 34% response rate in uninjected nonvisceral lesions and 15% response rate in uninjected visceral lesions, defined by a size reduction of at least 50%. Based on this trial, T-VEC received FDA approval for intralesional therapy of stage III or IV cutaneous melanoma. The addition of T-VEC to systemic immunotherapy appears to improve the response rate to immunotherapy in unresectable stage III/IV disease; this combination strategy will continue to be investigated.30–32 Given the successes seen with intralesional and systemic immunotherapies, these have become the first-line treatment for patients with extensive in-transit disease that is not amenable to simple resection. Regional infusion of chemotherapy continues to have a role, mostly in salvage situations in which immunotherapy has been ineffective and the disease remains isolated to an extremity. These situations are increasingly uncommon, as our experience with intralesional and systemic immunotherapy continues to grow.  Regional nodal recurrence. Therapeutic lymph node dissection for isolated regional nodal recurrences was historically the preferred treatment in patients who had not previously had a lymph node dissection. Strictly following the protocols used in the adjuvant immunotherapy trials discussed above, this strategy is still acceptable. After confirming the absence of metastatic disease, a therapeutic lymph node dissection of the involved nodal basin can be performed to achieve reasonable disease control, followed by adjuvant immunotherapy. If nodal recurrence occurs after adjuvant immunotherapy, an alternative adjuvant therapy strategy can be considered after regional lymphadenectomy. An alternative strategy can be considered, which takes lessons from the treatment of other solid organ malignancies in which a neoadjuvant treatment strategy is used. The approach recognizes that patients with regional nodal recurrences in fact have a form of systemic metastatic disease. Most of these patients will eventually develop systemic recurrences. Recognizing that the concern in these patients should be first and foremost systemic disease control, a neoadjuvant treatment strategy can be used in which disease biology and treatment response can be assessed prior to surgery. The first group to show the potential effectiveness of this strategy is the group from the MD Anderson Cancer Center, using targeted BRAF-MEK inhibition in high-risk, resectable stage III and oligometastatic stage IV melanoma. In this study, 21 patients with BRAF-mutant melanoma with resectable stage III or oligometastatic stage IV melanoma were randomized to upfront surgical resection and adjuvant dabrafenib/trametinib or neoadjuvant dabrafenib/trametinib, followed by surgical resection and adjuvant BRAF-MEK inhibition.33 The trial was stopped early because of the remarkable benefit seen in the neoadjuvant group, who enjoyed a median event-free survival of 19.7 months versus 2.9 months in the surgery first group (HR, 0.016). With a median follow-up of 18 months, 71% of the neoadjuvant treatment group were alive without disease progression compared to none in the upfront resection group.

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SECTION V  Surgical Oncology

The next logical extension of this experience is to apply a neoadjuvant immunotherapy treatment strategy that can be used regardless of BRAF mutation status in patients with regional nodal recurrences. Several clinical trials are underway, evaluating the safety and efficacy of neoadjuvant immunotherapy in patients with stage III or oligometastatic stage IV melanoma followed by resection. These studies will give us some insight into the pathologic response rate that can be expected with this approach and the potential markers that can be identified to predict a favorable response with this treatment strategy. Operative resection of these patients for persistent or recurrent regional lymph node recurrence still plays a role; however, we predict that these operations will become less common in the future as our immunotherapy treatments improve. However, the surgeon must still be able to offer a safe, effective operation that often will improve a patient’s quality of life with bulky nodal disease. This may often be in a palliative situation in which short-term relief from pain may be enjoyed by the patient, even though recurrence is almost certain.  Treatment of Metastatic Disease Treatment options for metastatic melanoma have expanded greatly in the last decade (Table 31.4). Metastatic melanoma, which once carried a dismal prognosis measured in months, can now be treated effectively with multiple agents that prolong survival and improve quality of life. It is indeed an exciting time to be treating melanoma as our therapies expand and our ability to treat patients with metastatic disease continues to improve. Historical. Historically, the only two agents approved for metastatic melanoma were dacarbazine and high-dose interleukin-2. These agents were found to induce moderate response rates without any benefit in overall survival. Biochemotherapy, which was a highly toxic combination of cytotoxic chemotherapy with interleukin-2 and interferon, would sometimes result in limited successes. This approach was never able to demonstrate a consistent improvement in overall survival. Some individuals would respond well and achieve a durable response; however, these events were too infrequent to demonstrate a benefit to a large population of patients. These therapies were associated with significant toxicity and potential fatal complications. Better therapies for metastatic melanoma were desperately needed.  Immunotherapy. Melanoma was always considered a cancer that was susceptible to immunotherapy treatment strategies. Prior to the development of immune checkpoint blockade, interleukin-2, interferon, granulocyte-macrophage colony-stimulating factor, and multiple vaccines were tried in an attempt to boost the inherent immune response to melanoma. Through a better understanding of the regulation of the immune response, newer strategies focusing on blocking the negative feedback systems that suppress T-cell activity were developed, specifically the CTLA-4 and PD-1 pathways (Fig. 31.21). Ipilimumab is a monoclonal anti–CTLA-4 antibody that was the first systemic agent to demonstrate improved overall survival in patients with metastatic melanoma. In activated T cells, the CTLA-4 receptor traffics to the extracellular membrane, where it inhibits costimulatory ligands on antigen-presenting cells and thereby prevents continued antigen-presenting cell stimulation of the T cell. By blocking CTLA-4, ipilimumab effectively prolongs the T-cell response. In one of the early-randomized trials to show that ipilimumab could improve survival, 502 patients with metastatic melanoma were randomized to standard of care dacarbazine or dacarbazine plus ipilimumab.34 The group treated with ipilimumab had improved overall survival at 1 and 3 years (HR, 0.72).

Based on this study and other subsequent studies, ipilimumab was approved by the FDA for metastatic melanoma. Significant autoimmune toxicities, including potentially fatal bowel perforations, prompted additional studies to find less toxic but equally effective immunotherapy options. The PD-1 inhibitors represent a newer family of immune checkpoint regulators that work to suppress the natural inhibitory system of the T-cell immune response. The interaction of PD-1 receptor with its ligands PD-L1 and PD-L2 promote T-cell anergy and apoptosis. Some tumors express PD-L1 as a mechanism to promote T-cell tolerance and evade the immune system. Multiple randomized clinical trials have demonstrated that PD-1 inhibitors can improve survival in patients with metastatic melanoma. Patients treated with pembrolizumab alone or nivolumab alone have improved overall survival compared to those treated with ipilimumab alone.35,36 The PD-1 inhibitors have an improved safety profile compared to ipilimumab and are more effective; thus, they have become the preferred first line agents for metastatic melanoma. Combining PD-1 inhibitors (nivolumab) with CTLA-4 inhibition has been attempted to improve response rates. There does appear to be marginally improved response rates and survival when nivolumab is combined with ipilimumab, but at the cost of increased risk of serious adverse events. When nivolumab or ipilimumab alone is used, the rates of serious adverse treatmentrelated events were 21% and 28%, while when used in combination, the rates of serious adverse treatment-related events doubled to 59%.36 The next generation of immunotherapy for melanoma will likely include the use of TIL or chimeric antigen receptor T-cell therapy. The TIL technique involves the isolation and expansion of tumor-specific T cells collected from the peritumor stroma. With this technique, these melanoma-specific TIL cells are clonally expanded, then reinfused into the patient after lymphodepletion. The TIL cells then enhance the patient’s own adoptive immunity in order to evoke a heightened immune response to the tumors. Current studies are underway evaluating the safety and efficacy of this technique. Chimeric antigen receptor T-cell therapy involves genetically engineering an extracellular antigenbinding domain that targets melanoma or other target malignant cells with the intracellular signaling portion of the T cell receptor. Initial experience with chimeric antigen receptor T-cell therapy in hematologic malignancies is promising, but more work needs to be done to understand its potential role for treating metastatic melanoma.  Targeted therapy. The first agent used to target metastatic melanoma with the BRAF V600E mutation was vemurafenib. For BRAF-mutant patients, vemurafenib demonstrated significant improvement in overall and progression-free survival and was approved by the FDA for treatment of BRAF-mutant metastatic melanoma. The major issue with single-agent BRAF inhibition, including vemurafenib and dabrafenib, is the development of treatment resistance. This is not the result of a change in the target BRAF gene, rather it is felt to be the result of upregulation of alternative signaling pathways, including the MAPK pathway. Dual BRAF-MEK inhibition with trametinib and dabrafenib has been shown to improve overall response rates and survival compared to single agent trametinib or dabrafenib in BRAF-mutant metastatic melanoma.37,38 Long-term follow-up for these studies is ongoing, as there remain concerns regarding the durability of the response to targeted therapy inhibition. Dual BRAF-MEK inhibition is a good treatment option for patients with BRAF-mutant metastatic melanoma who cannot

CHAPTER 31  Melanoma and Cutaneous Malignancies

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TABLE 31.4  Summary of important targeted therapy and immunotherapy trials for metastatic

melanoma. TRIAL NAME

STUDY POPULATION

INTERVENTION TREATMENT

CONTROL PRIMARY TREATMENT OUTCOME

Hodi et al51

Unresectable stage III or IV Ipilimumab 3 mg/kg with or without gp100

Robert et al34

Previously untreated, unresectable IIIB or IV

Ipilimumab 10 mg/kg + Dacarbazine dacarbazine

COMBI-d (Long et al)37

Unresectable stage III or IV melanoma with BRAF V600E or V600K mutations Unresectable stage III or IV melanoma with BRAF V600E or V600K mutations Previously untreated, unresectable stage III or IV melanoma without BRAF mutations Previously untreated, unresectable stage III or IV melanoma Previously untreated, unresectable stage III or IV

Dabrafenib + trametinib Dabrafenib + placebo

COMBI-v (Robert et al)38

CheckMate 066 (Robert et al)52

CheckMate 069 (Postow et al)53 CheckMate 067 (Wolchok et al)36

KEYNOTE-006 (Schachter et al)35

gp100

NOTES

Improved overall survival with Ipilimumab alone as effective ipilimumab plus gp100 vs. gp100 as ipilimumab + gp100 alone (median OS, 10 vs. 6.4 months; HR, 0.68) Improved overall survival with ipilimumab + dacarbazine (median OS, 11.2 vs. 9.1 months; HR, 0.72) Improved progression-free survival Improved response rate (67% (HR, 0.75; 95% CI, 0.57–0.99) vs. 51%) and 6-month OS (93% vs. 85%; HR, 0.63)

Dabrafenib + trametinib Vemurafenib

Improved overall survival at 12 months Stopped early for efficacy, (72% vs. 65%; HR, 0.69; 95% CI, improved objective response 0.53–0.89) rate (64% vs. 51%)

Nivolumab

Improved overall survival (HR, 0.42; 99.79% CI, 0.25–0.73)

Improved progression-free survival and improved objective response rate

Improved objective response rate in BRAF wild type (61% vs. 11%, P < 0.001) Improved overall survival in nivolumab/ipilimumab (HR, 0.55) and nivolumab alone (HR, 0.65) vs. ipilimumab alone

Increased serious adverse events with nivolumab + ipilimumab (54% vs. 24%) Similar 3-year OS in nivolumab alone (52%) compared to nivolumab/ ipilimumab (58%), both better than ipilimumab alone (34%) No differences in every 2 week or every 3 week pembrolizumab

Dacarbazine

Nivolumab + ipilimumab Ipilimumab

Nivolumab + ipilimumab Ipilimumab Nivolumab alone

Unresectable stage III or IV Pembrolizumab every 2 orIpilimumab melanoma? 3 weeks

Overall survival better in both pembrolizumab groups compared to ipilimumab (HR, 0.68 compared to ipilimumab for both treatment regimens)

CI, Confidence interval; gp100, glycoprotein 100; HR, hazard ratio; OS, overall survival. T-cell or APC

Tumor cell CD28 CTLA-4

Ipilimumab

TCR

B7

MHC Neoantigen presentation

Antigen

Activation and proliferation

Mutation PD-1

Anti-PD-1 antibody

PD-L1/2

CTL effector function

FIG. 31.21  The CTLA-4 and PD-1 pathways that are integral to immunotherapy for melanoma. APC, Antigen-presenting cell; CTL, cytologic T lymphocyte; CTLA, cytotoxic T lymphocyte antigen; MHC, major histocompatibility complex; PD-1, programmed death 1; TCR, T cell receptor. (From Herzberg B, Fisher DE. Metastatic melanoma and immunotherapy. Clin Immunol. 2016;172:105–110.)

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SECTION V  Surgical Oncology

tolerate immunotherapy, usually because of existing autoimmune comorbidities. Immunotherapy is probably the preferred treatment strategy for those patients who are BRAF-mutant but also eligible for immunotherapy in most centers. Patients not eligible for immunotherapy with BRAF-wild type melanoma continue to have limited effective treatment options.  Metastasectomy. Although most patients with stage IV melanoma will present with disseminated lesions that are not amenable to resection, patients with limited metastatic disease should be considered for resection if the disease is stable or responds to systemic therapy. Operative resection may not only offer symptom palliation, but also in some highly selected patients, it may provide a survival advantage similar to that seen after lymphadenectomy for advanced stage III patients. Resection of oligometastatic disease in well-selected patients can lead to 5-year survival rates ranging from 15% to 40%. Even patients with brain metastases may benefit from complete resection, further emphasizing that complete extirpation of all disease may be the best treatment, even for advanced disease. Careful selection of patients is paramount. Important things to consider in evaluating a patient for resection of metastatic disease include the patient’s underlying functional status and comorbidities, the location and number of metastatic lesions, and the features reflective of the underlying tumor behavior, such as the disease-free interval from the time of primary resection. Failure to respond to systemic immunotherapy is usually a poor prognostic sign that signifies aggressive disease biology. However, medical and surgical oncologists are more often encountering the phenomenon of mixed response to immunotherapy. Oftentimes, in patients with multiple sites of metastatic disease, there will be a good radiologic response to immunotherapy in most, but not all, of the distant metastases. In these situations, if these nonresponding sites are amenable to resection, it makes sense to perform metastasectomy to remove the nonresponding lesions. 

Special Situations and Noncutaneous Melanoma Unknown Primary Melanoma In rare cases, patients will present with stage III or stage IV melanoma and no preceding diagnosis of a primary cutaneous melanoma. This occurs in less than 2% of melanoma cases overall and in less than 5% of all cases involving metastatic disease. A diagnosis of unknown primary melanoma should prompt a thorough skin examination, including the perianal area, external genitalia, nail beds, scalp, and external auditory canal. Endoscopic evaluation of the oral cavity and nasopharynx as well as of the anus and rectum can identify mucosal melanoma. Women should undergo a thorough pelvic examination, and an ophthalmology examination may be required to rule out ocular melanomas. PET/CT and MRI of the brain are warranted to assess the extent of disease. Some hypothesize that unknown primary melanomas arise from benign nevus cells already trapped within lymph nodes. Alternatively, cutaneous melanoma is known to undergo spontaneous regression in rare cases, presumably as a result of an immune response to the primary tumor. Therefore, a history of a prior pigmented skin lesion that has disappeared or clinical evidence of vitiligo should not be dismissed. Patients may provide a history of pigmented skin lesions that have been excised, cauterized, or treated with lasers. Pathology review of any previously excised skin lesions should be performed.

In the setting of lymph node metastasis without a primary lesion, the patient should be treated as a patient with stage III melanoma, as discussed above. Interestingly, patients with unknown primary melanomas who present with lymph node involvement have equivalent or possibly better overall survival compared with patients with a known primary lesion. This may suggest a stronger immune response in these patients that resulted in regression of the primary melanoma.  Melanoma and Pregnancy As many as one third of women diagnosed with melanoma are of childbearing age; treatment of melanoma in pregnant women involves some difficult decision-making. Whether there is a link between pregnancy and the overall risk for development of melanoma is not well understood. Early studies suggested that hormonal changes during pregnancy led to increasing pigmentation and an environment conducive to melanoma development; however, current evidence does not support this theory. Any nevus or pigmented lesion with suspicious changes during pregnancy should not be attributed to hormones or the expected physiology of pregnancy; appropriate workup is required. Some evidence has suggested worse outcomes for melanoma in pregnancy; however, after controlling for other relevant risk factors, it appears that the prognosis of patients with melanoma treated during pregnancy is no different from that of nonpregnant patients.39 The evaluation and treatment of a pregnant patient with melanoma should follow guidelines similar to those for the nonpregnant patient. There is no therapeutic benefit to early termination of the pregnancy. WLE can be safely performed under local anesthesia. Based on experience with pregnant patients with breast cancer, SLN biopsy may be performed if indicated by the pathologic factors of the primary tumor, although vital blue dye should not be used. Not only is there an unknown risk to the fetus, but also there is an estimated 1 in 10,000 risk of an anaphylactic reaction if isosulfan blue dye is used. Lymphoscintigraphy is considered safe since the dose used is well below the teratogenic threshold. Nevertheless, some physicians and patients are uncomfortable with the use of radioactive materials during pregnancy. In such situations, WLE under local anesthesia with a 1-cm margin can be performed, with wider margin excision and SLN biopsy reserved until after the baby is delivered. The placenta should be examined pathologically for evidence of melanoma in women who develop melanoma during pregnancy as a marker for metastasis as well as possible transmission to the child. For patients who have tumors with poor prognostic factors, it may be advisable to wait 2 to 3 years before the next pregnancy as this represents the time during which recurrence is most likely.  Noncutaneous Melanoma The neural crest cells from which melanocytes develop migrate predominantly to the skin during fetal development; however, they will also localize to several other organs and tissues. As a result, melanoma may arise in other locations, including the mucosal surfaces, within the eye, or in the leptomeninges.  Ocular Melanoma. Within the eye, melanocytes are found in the retina and uveal tract (iris, ciliary body, and choroids). In the United States, ocular melanoma is the most common intraocular malignant neoplasm in adults. Primary treatment consists of enucleation or iodine-125 brachytherapy, although other options include photocoagulation and partial resection. Unlike cutaneous melanoma, given the lack of lymphatic vessels in the

CHAPTER 31  Melanoma and Cutaneous Malignancies uveal tract, metastatic spread of ocular melanoma occurs hematogenously. Metastases develop almost exclusively in the liver. Resection is rarely possible because the pattern of metastases is often a diffuse, miliary one. Dedicated liver imaging is needed to detect these lesions. Ocular melanoma is less responsive to immunotherapy compared to cutaneous melanoma. One hypothesis is that ocular melanoma carries less of a mutational burden compared to cutaneous melanoma, thus rendering immunotherapy less effective.  Mucosal Melanoma. The most common sites for mucosal melanoma are the head and neck (oral cavity, oropharynx, nasopharynx, and paranasal sinuses), anal canal, rectum, and female genitalia. Because of the occult location of many of these lesions, patients tend to present with more advanced disease and have a poor prognosis. These tumors should be excised to negative margins when possible. Given the high risk of metastatic disease, extensive local resections, such as abdominoperineal resection or pelvic exenteration, do not improve overall survival. These procedures may still be necessary for local disease control. Radiation therapy may be used to improve locoregional disease control. In general, the role for SLN biopsy has not been well established. We perform SLN biopsy routinely for anal and other mucosal melanomas when feasible. For anal melanoma, a negative SLN biopsy in the superficial inguinal region would omit that region from the radiation fields. Unlike ocular melanoma, it appears that the response rate to immunotherapy for mucosal melanoma is similar to that of cutaneous melanoma, thus some have recommended that these agents be considered for use in the adjuvant setting or for treatment of metastatic disease. 

NONMELANOMA SKIN CANCERS NMSC represents the most common type of malignant neoplasm in the world. In the United States, it is estimated that almost one in five Americans will develop NMSC during their lifetime. Approximately 80% are BCCs, with SCC representing nearly 20%. Much rarer types of NMSC make up the remainder of cases. Sun exposure is the predominant risk factor. Similar to cutaneous melanoma, the overall incidence of NMSC is increasing. Accurate estimates of NMSC incidence are difficult to ascertain as many are treated without obtaining a histologic diagnosis, and most cases are not reported in cancer registries. The American Cancer Society estimated that there are more than 5 million cases of BCC and SCC diagnosed in over 3 million people per year in the United States. Patients diagnosed with a BCC or SCC have an increased risk of additional cancers, including a second NMSC, melanoma, and nonskin cancers. For this reason, patients with a prior diagnosis of skin cancer require long-term surveillance.

Squamous Cell Carcinoma Presentation and Risk Factors Risk factors for the development of SCC include exposure to sunlight, susceptible skin types, compromised immunity, environmental exposures, and underlying genetic disorders. Most SCCs occur on sun-exposed surfaces, particularly the head and neck. In susceptible individuals (those with fair skin, blond hair, and blue eyes), prolonged sun exposure correlates directly to an increased risk for SCC. In contrast to melanoma or BCC, the cumulative effect of chronic UV radiation likely plays a larger role in SCC than intermittent, intense exposures. As with melanoma, individuals with dark complexions have a lower risk of SCC, even with

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prolonged sun exposure. The risk for SCC increases with occupational or recreational sun exposure, advancing age, and proximity to the equator. The amount of sun exposure is also proportional to the incidence of known precursor lesions for SCC, including actinic keratosis. UV radiation, and UVB in particular, increases the risk of SCC through several mechanisms. There is the direct carcinogenic effect of UV light on the frequently dividing keratinocytes within the basal layer of the epidermis. Unrepaired mutations from UV light damage can drive tumor proliferation and growth. UVBinduced silencing of the p53 tumor suppressor gene occurs in more than 90% of SCCs. With loss of p53, keratinocytes are unable to arrest the cell cycle or to initiate apoptosis in the face of cellular damage from UV radiation. With subsequent mutations, cells can then progress from dysplasia to in situ or invasive disease. Occupational and environmental carcinogens, including arsenic, organic hydrocarbons, ionizing radiation, and cigarette smoke are associated with an increased risk for SCC. Genetic disorders, including xeroderma pigmentosum and albinism, are associated with increased risk for many types of skin cancer, including SCC. A history of chronic inflammation from burn scars (Marjolin ulcer), draining sinuses, infections (including osteomyelitis), and nonhealing ulcers can precede the development of SCCs. In the setting of chronic nonhealing wounds, or even with previously healed wounds that subsequently break down, biopsy may be prudent to rule out SCC. Immunosuppression is a well-established risk factor for SCCs of the skin, particularly with the suppression of cell-mediated immunity after solid organ transplantation. Skin cancer is the most frequent malignant neoplasm in organ transplant recipients, with SCC and BCC representing 95% of these cancers. Whereas the risk of BCC increases ten fold after transplantation, the incidence of SCC in posttransplant patients is 65 times that of the normal population (Fig. 31.22). SCC that develops in immunosuppressed patients are more aggressive and have an increased risk of systemic metastases. The intensity of immunosuppression and the duration of therapy both correlate with the risk of malignancy. Whereas malignant neoplasms develop in 10% to 27% of patients after 10 years of immunosuppression, this number increases to 40% to 60% after 20 years. Other conditions associated with impairments of cell-mediated immunity (lymphoma, leukemia, autoimmune disease, etc.) are associated with an increased risk of SCC. Human papillomavirus, an infection associated with immunosuppression, is a proposed risk factor for the development of SCCs. BRAF inhibition used to treat melanoma is also associated with the development of SCC. Most SCCs begin with a proliferation of keratin cells in the basal layer of the epidermis that appear as red or pink areas, clinically termed actinic keratoses (solar keratoses). Local symptoms may wax and wane for a period of many months. Lesions are scaling, with an uneven surface and an erythematous base (Fig. 31.23). Individual lesions are usually smaller than 1 cm in diameter and appear in chronically sun-damaged skin. The diagnosis is both clinical and histologic as actinic keratoses share many microscopic features with SCC in situ. The risk of malignant transformation of actinic keratosis to SCC is approximately 0.01%– 0.6% over 1 year and up to 2.5% over 4 years. Bowen disease, which appears histologically as SCC in situ, initially manifests as a reddened area that progresses to thickened plaques of variable size. When it is confined to the glans penis or vulva, Bowen disease is sometimes referred to as erythroplasia of Queyrat.

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SECTION V  Surgical Oncology

FIG. 31.22  Multiple squamous cell carcinomas on the forearm of a patient on immunosuppression after kidney transplant.

Field therapies, which treat a generalized area but do not define the status of the margin, can also be used. Examples of field therapies include radiation therapy, cryosurgery, photodynamic therapy, electrodessication and curettage, and topical agents like imiquimod. Cryotherapy is best suited for small superficial lesions and can be expected to achieve local control rates greater than 90%. Treated areas are allowed to heal slowly by secondary intention, often resulting in pale scars. Curettage may be used for patients with superficial lesions less than 2 cm. In precursor lesions of SCC, such as actinic keratosis, cryotherapy is a commonly performed therapy. Alternative treatments include topical 5-fluorouracil, electrodessication and curettage, carbon dioxide laser, dermabrasion, and chemical peel. Tissue biopsy is indicated when the actinic keratosis is raised or recurrent after topical therapy. SLN biopsy may have a role in high-risk lesions, as clinically occult lymph node metastases may be identified in 7% to 20% of patients. The indications for SLN biopsy and subsequent nodal management strategy (completion lymphadenectomy with or without radiation therapy) are not as well defined as they are for cutaneous melanoma. Adjuvant radiation to the primary tumor is recommended by the NCCN for any SCC with extensive perineural or large nerve involvement.40 Locally advanced or metastatic SCC of the skin is fortunately rare; advanced disease is difficult to treat. Systemic cytotoxic chemotherapies are usually platinum based with variable response rates. Targeted epidermal growth factor receptor agents have been used with moderate success as primary and salvage systemic therapy for metastatic SCC.41–43 A new PD-1 inhibitor, cemiplimab, was recently approved by the FDA based on a phase 1 study using PD-1 inhibition in refractory advanced cutaneous SCC in which a response rate of 50% was observed, with the duration of response exceeding 6 months in over half of the responders.44 

Basal Cell Carcinoma

FIG. 31.23  Squamous cell carcinoma with red, scaling skin.

Invasive SCCs are palpable scaling lesions that become ulcerated centrally and have elevated, firm edges. In addition to spreading horizontally, these lesions may grow vertically and become fixed to underlying tissue. They may be confused with keratoacanthoma, a benign lesion that can also thicken and ulcerate. Biopsy may be required to differentiate between these two conditions.  Treatment Unlike melanoma, SCC T category is based on the diameter of the lesion. Other high-risk features for SCC of the skin have been defined by the NCCN (Table 31.5). These high-risk features include assessment of size, location, histology, and individual patient factors. Most SCCs can be treated with local excision with excellent results. The typical margin of excision is a gross 5-mm resection, although MMS can be used when a cosmetically sensitive area demands skin conservation. MMS may also be preferred for recurrent or high-risk tumors. For higher-risk lesions, 10 mm margins are recommended.

Presentation and Risk Factors BCC is the most common NMSC, and lesions are most commonly found on the sun-exposed areas of the head and neck. Risk factors for the development of BCC are similar to those for SCC, although basal cell lesions are more often associated with intense, intermittent exposure to UV radiation. The hedgehog-signaling pathway is a key signaling pathway in embryonic development but is largely inactive in mature adult tissue. The pathway is mutated in up to 90% of BCCs. In the presence of hedgehog signaling peptides, the Patched receptor releases the transmembrane Smoothened (SMO) protein, allowing SMO to initiate a signaling cascade that activates the expression of several target genes. Normally, Patched will inhibit SMO in the absence of hedgehog signals. Both activating mutations in SMO and inactivating mutations in Patched have been linked to BCC, ultimately leading to unrestricted growth signaling. In contrast to SCCs and actinic keratoses, there is no precursor skin lesion for BCCs. These lesions may have an appearance that varies from nodules in the skin to a large nonhealing sore with drainage and crusting. In comparison to SCCs, they have a slow growth rate, often leading to a delay in diagnosis. BCCs commonly infiltrate locally but rarely metastasize. Metastases are associated with advanced age and large, neglected lesions. The primary site will often undergo resection multiple times before metastases appear. Once metastatic disease develops, the median survival decreases to less than 1 year. BCCs grow in multiple distinctive patterns, and although there is not a universally accepted classification system, there are several common subtypes. The nodular growth pattern is characterized

CHAPTER 31  Melanoma and Cutaneous Malignancies

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TABLE 31.5  Risk factors for local recurrence or metastases in squamous cell carcinoma of the

skin.

LOW RISK

HIGH RISK

Location/size

Area L 15 cm.7 The superficial versus deep anatomic designation of the tumor with respect to the investing fascia has been eliminated. Compared with extremity STS, visceral and retroperitoneal STS appears to have a lower disease-specific survival. In the case of visceral STS, this decreased disease-specific survival is driven by the likelihood for distant metastasis; but for retroperitoneal STS, the low disease-specific survival is driven by the risk of local recurrence.1 The importance of the size of the primary STS to prognosis is well described (Fig. 32.2), but the current size thresholds specified by the AJCC eighth edition have been challenged. Greater prognostic discrimination is proposed by designating all low grade tumors as stage I, high-grade tumors less than 7.5 cm as stage II, high-grade tumors greater than 7.5 cm as stage III, and metastatic as stage IV.8

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SECTION V  Surgical Oncology

Overall, regional lymph node involvement for STS is uncommon (2% to 10%). The most common STS subtypes undergoing lymphadenectomy for nodal metastases are angiosarcoma, rhabdomyosarcoma, MFH (recently reclassified as undifferentiated pleomorphic sarcoma), epithelioid sarcoma, clear cell sarcoma, and liposarcoma. Although regional nodal involvement is an important prognosticator of survival, patients with a single lymph node, multiple positive nodes, and distant metastatic disease all have similar survival.1 Some groups have proposed the use of sentinel lymph node dissection for epithelioid sarcoma, clear cell sarcoma, and rhabdomyosarcoma in the pediatric population, but the accuracy is generally unacceptable, and the technique has never been successfully applied to STS in a well-designed clinical trial. Nomograms have been developed in response to the fact that standard staging systems, like the AJCC, do not adequately consider the relevant parameters and therefore may not accurately estimate prognosis of patients with STS. No fewer than 13 different nomograms have been published for STS alone. The nomograms were developed to address a number of oncologic outcomes but most typically predict local recurrence or overall survival (Fig. 32.3). In general, the nomograms are reported to more accurately prognosticate outcome than traditional staging systems, but few have been validated in a data set beyond that which was used to generate the nomogram. Nonetheless, they can provide meaningful information that, when used appropriately, can have an impact on the care of patients with STS. It remains to be seen how the proliferation of these nomograms will affect future editions of traditional staging systems. 

in the differential diagnosis, appropriate oncologic staging should be undertaken. This staging starts by performing a detailed history and physical examination. These are important in determining the likelihood of STS versus other more common mimicking diagnoses, such as hypertrophic scar, myositis ossificans, hematoma, or cyst (Box 32.1). Small, superficial, and mobile masses highly suggestive of STS that are separate from skeletal or neurovascular structures may be taken to the operating room for resection with wide gross margins, depending on the location relative to vital structures. Tumors close to vital structures may be referred to a center with expertise treating STS. In these patients, a preoperative biopsy is unnecessary. The undesirable consequences of an unnecessary preoperative biopsy include a pathology report that provides the incorrect non-STS diagnosis because of an insufficient specimen, a nonideal placement of the biopsy site leading to a larger incision than otherwise necessary, and delay in therapy. Larger or otherwise more complicated lesions require additional oncologic staging. The extent of staging is highly individualized and adapted to each patient. In general, the indications for preoperative imaging and biopsy include the following; • Inability to determine the extent of the mass on physical examination. • Suspected neurovascular involvement. • Suspicion for regional or distant metastasis. • Need for operation that would likely result in a significant functional deficit. • Suspicion that the mass is unresectable or resectable with questionable surgical margins at presentation. Rigorous studies evaluating the utility of MRI versus CT are dated. Whereas MRI is generally considered the most informative imaging modality for trunk and extremity STS, there are important roles for the use of contrast-enhanced CT and ultrasound. In addition to imaging of the primary STS site, a chest

Clinical Evaluation There are dozens of STS subtypes that affect the trunk and extremities. The most common clinical presentation is of a patient with a painless mass without prior evaluation. If STS is included Points Age: ≥65 Presentation Tumor Size: ≥15 cm Multifocal Complete Resection Histology Total Points

0

10

20

30

40

60

70

Yes No Recur. Prim. Yes No Yes No No Yes WD LPS 0

20

40

60

80

100

Median Survival Time (Yrs)

120

8 6

3-Year Survival Probability 5-Year Survival Probability

50

0.95 0.95

0.8 0.8

0.7

5 0.7

0.6

140 4 0.6

160 3

180

200

2

0.5 0.4 0.3 0.2

0.5 0.4 0.3 0.2

0.1

FIG. 32.3  Postoperative nomogram for median, 3- and 5-year overall survival prediction in patients with nonmetastatic, resectable, retroperitoneal sarcoma. WD LPS, Well-differentiated liposarcoma. (From Anaya DA, Lahat G, Wang X, et al. Postoperative nomogram for survival of patients with retroperitoneal sarcoma treated with curative intent. Ann Oncol. 2010;21:397–402. Oxford University Press, European Society of Medical Oncology.)

CHAPTER 32  Soft Tissue Sarcoma CT scan should generally be obtained as this is the most frequent site of metastasis. When they are available, the biopsy results may prompt consideration of additional imaging. For example, a CT scan of the abdomen and pelvis should be considered for patients with more aggressive histologic types, such as myxoid or round cell liposarcoma, epithelioid sarcoma, angiosarcoma, and leiomyosarcoma. Brain imaging may be considered to exclude metastasis from alveolar soft part sarcoma, clear cell sarcoma, and angiosarcoma. The surgeon may choose from a variety of biopsy methods. Given the rarity of STS and the scant amount of tissue procured, a fine-needle aspirate is generally unsatisfactory except in the diagnosis of a local recurrence. An image-guided core needle biopsy is more likely to provide a reliable diagnosis, but when it is applied to large cystic lesions or lesions with a considerable myxoid component, a core needle biopsy may still be nondiagnostic. To decrease the risk of local recurrence, the core biopsy approach should be planned so that the entire needle trajectory can be easily incorporated into the forthcoming surgical resection volume. If the core needle biopsy attempts are still nondiagnostic, an incisional

biopsy may be necessary. Here, again, it is critical to plan the incision so that the entire biopsy trajectory is ultimately included within the resection volume. Armed with radiographic and pathologic information, a multidisciplinary team at a high-volume STS center, with representatives from surgical oncology, medical oncology, diagnostic radiology, pathology, and radiation oncology in attendance, ideally discusses the case. The goal of this discussion is to assess which treatment modalities are most appropriate for each patient and in what sequence each modality should be implemented (Fig. 32.4). Up to 74% of patients who undergo an unplanned trunk or extremity sarcoma resection have residual disease at the time of re-resection. Thirty-day mortality, rates of limb preservation, and overall survival have been linked to care delivered at high-volume STS centers.9 Because of the considerable risk for recurrence, close postoperative surveillance is important for STS patients. In general, these patients should undergo a physical examination every 3 to 6 months for 2 or 3 years, then every 6 months for the next 2 years, and then annually. Radiographic surveillance of the chest,

History and physical exam CT/MRI of primary site Biopsy–core vs. incisional Determine prognosis based on histologic type, size, grade, patient age

Ewing/Rhabdo Preop chemo

High grade

Low grade

>5 to 5 to 10 cm

No adjuvant therapy

Consider perioperative BRT or postoperative IMRT

Postoperative IMRT

Consider perioperative BRT or postoperative IMRT

Perioperative BRT or postoperative IMRT

Postoperative IMRT

FIG. 32.4  Algorithm for the management of primary (with no metastases) extremity or trunk soft tissue sarcoma using a biologic rationale (i.e., size and grade of tumor). BRT, Brachytherapy; CT, computed tomography; EBRT, external beam radiation therapy; IMRT, intensity-modulated radiation therapy; MRI, magnetic resonance imaging; RC/Pleo LS, round cell–pleomorphic liposarcoma; SS, synovial sarcoma.

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SECTION V  Surgical Oncology

abdomen, and pelvis should also be undertaken at regular intervals. The modality (CT vs. MRI) and the frequency should be individualized to the patient and the tumor characteristics. The most informative preoperative imaging modality is favored, but consideration should also be given to avoiding unnecessary radiation exposure by ultrasound or MRI. The imaging frequency for STS patients has not been rigorously studied, but a shorter imaging frequency may be appropriate for a patient with close surgical margins or a patient with a particularly ominous histologic type. Lipomatous Tumors Lipomas are adipocytic tumors that can arise from any part of the body. By definition, they are benign neoplasms, but they can cause symptoms as a consequence of the adjacent structures that the lipoma displaces. Lipomas are encapsulated and devoid of nodularity or thick internal septations. They are generally homogeneous but may contain calcifications or hemorrhage as a result of trauma. There can be a great deal of clinical overlap between lipoma and the malignant liposarcoma. The CT and MRI features that have been demonstrated to be associated with liposarcoma over lipoma include tumor size larger than 10 cm, presence of thick (more than 2 mm) septa, presence of nonadipose areas, and lesions that are less than 75% adipose tissue. Lipomas are effectively treated by a simple excision beyond the capsule of the tumor, whereas the treatment of liposarcoma involves a more complex resection with attention to adequate margins, ideally in the setting of a multidisciplinary care team specializing in STS. Overall, liposarcoma is the most frequent STS subtype and represents 45% of all retroperitoneal sarcoma; it is composed of three histologic varieties: well-differentiated and dedifferentiated liposarcoma, pleomorphic liposarcoma, and myxoid/round cell liposarcoma, listed in order of decreasing frequency. Well-differentiated and dedifferentiated liposarcomas more typically arise from the retroperitoneum versus the extremities, whereas the inverse is true for pleomorphic and myxoid/round cell liposarcoma. Compared with well-differentiated liposarcoma, the dedifferentiated variety has a worse prognosis, largely because of its much greater risk of distant metastasis compared with well-differentiated liposarcoma. Local recurrence is common in both types. The malignant behavior of well-differentiated and dedifferentiated liposarcomas is attributable to the amplification of chromosome 12q13-15, which accounts for the upregulation of MDM2 and CDK4. Both welldifferentiated and dedifferentiated retroperitoneal liposarcomas are often multifocal. Myxoid and round cells are descriptive terms based on their histologic appearance. These liposarcoma varieties are characterized by distinct translocations such as FUS-DDIT3 located at t(12;16)(q13;p11) and more rarely EWSR1-DDIT3

A

B

located at t(12;22)(q13;q12). Multiple tumor-promoting pathways including MET, RET, and PI3K/Akt are activated as a result of these translocations. Myxoid liposarcoma is unusual in its relative sensitivity to radiation and chemotherapy, resulting in a 10year disease-specific survival of 87%. Considered a poorly differentiated form of the myxoid variety, the round cell variety has a worse outcome than myxoid liposarcoma, with metastasis developing in 21% of patients in one large series. Pleomorphic liposarcoma is another example of a poorly differentiated liposarcoma with a poor outcome. It displays a variety of genetic abnormalities, none as reliable as those described for the preceding liposarcoma varieties. In routine practice, one of the key preoperative distinctions is between well-differentiated and dedifferentiated retroperitoneal liposarcomas because of differences in natural history and management. MRI and CT scan are useful in making this distinction but can be difficult because a given tumor may contain elements of both. The imaging characteristics that raised suspicion of a dedifferentiated histology in a cohort of 78 patients with retroperitoneal liposarcoma included tumor hypervascularity, areas of necrosis or cystic change, adjacent organ invasion, and areas of focal nodular or water density.10 These authors proposed a clinical algorithm in which patients with evidence of focal nodular or water density underwent biopsy of this suspicious area for definitive distinction between well-differentiated and dedifferentiated histology (Fig. 32.5). In their series, patients without the radiographic focal nodular or water density uniformly were definitively demonstrated to have well-differentiated tumors. In the event of equivocal microscopic tumor morphology, well-differentiated liposarcoma can be distinguished from benign lipoma and dedifferentiated liposarcoma can be distinguished from other poorly differentiated STS subtypes on the basis of MDM2 and CDK4 immunohistochemistry. For extremity liposarcoma, the goal is a limb-sparing resection with a negative surgical margin. Well-differentiated liposarcoma has an extremely low risk of distant metastasis and has a favorable overall survival. This, combined with its resistance to radiation therapy and most chemotherapy agents, essentially eliminates the need for adjuvant therapy. On the other hand, patients with dedifferentiated extremity liposarcoma should be referred for consideration of adjuvant radiation therapy. The treatment of patients with retroperitoneal liposarcoma is more complex. The principal goal is a gross complete resection as incomplete gross resection is associated with an increased risk of mortality.11 Traditionally, retroperitoneal sarcoma has been treated by resection with a generous gross margin, with resection of organs and structures that are contiguous with or invading the tumor when feasible. More recently, some have advocated for a

C

FIG. 32.5  Variability in computed tomography appearance of retroperitoneal liposarcoma. (A) Simple, predominantly fatty, well-differentiated tumor; the arrow marks the inferior mesenteric vein. Thin septa are appreciable within the tumor. (B) A hypercellular well-differentiated tumor with a focal nodular or water density area (arrow). (C) This tumor contains well-differentiated areas (star) as well as dedifferentiated elements (arrow).

CHAPTER 32  Soft Tissue Sarcoma “complete compartmental resection,” which mandates the resection of adjacent organs, even if they are not directly involved with the tumor.12 Although it is controversial, the concept that “the resection is only as good as the closest margin” is an important one. This takes into account the relationships between vital structures on one side of the tumor and not resecting contiguous but uninvolved organs. Understanding of the patterns of retroperitoneal liposarcoma recurrence is important in planning the optimal approach. For patients with well-differentiated retroperitoneal liposarcoma, a unifocal versus multifocal presentation does not appear to confer an adverse prognosis, but patients with dedifferentiated disease multifocality have a worse overall survival.13 Patients who develop recurrence after initial resection are likely to develop multifocal disease. This appears to be reflective of the tumor biology because an initial resection with positive margins does not appear to affect whether a patient develops a unifocal versus multifocal recurrence. The complete compartmental resection approach results in frequent multivisceral resections, with the following organs resected in more than 50% of cases: spleen, pancreas, diaphragm, adrenal gland, and kidney.12 Proponents of a more traditional approach in which only tumor-contiguous organs are removed point out that 15% of patients who have recurrence after undergoing standard resection do so beyond the compartmental bounds of their initial tumor.13 These out-of-field recurrences are unlikely to have been prevented with an aggressive complete compartmental resection strategy, and patients who may eventually benefit from nephrotoxic systemic chemotherapy are adversely affected by a potentially unnecessary complete compartmental resection–related nephrectomy. Although grossly incomplete resections are to be avoided, a margin-negative resection is not possible in some situations. At times, this can be predicted on the basis of the preoperative imaging, but at other times, the difficulty of the resection is not appreciated until during the operation. A single-institution retrospective study compared the outcome of patients with retroperitoneal liposarcoma who underwent an incomplete resection versus patients who underwent exploration and biopsy without tumor resection. Even incomplete resection provides a statistically significant improvement in survival compared with no resection, 26 versus 4 months. In addition, 75% of patients undergoing incomplete resection reported palliation of their presenting symptoms. In the setting of recurrent retroperitoneal liposarcoma, the rate of recurrent tumor growth is associated with prognosis. Patients whose recurrence grows less than 0.9 cm/mo benefitted from complete resection of the recurrence, whereas recurrent tumor growth of more than 0.9 cm/mo was associated with poor outcome.14 Palliative chemotherapy options are emerging for patients with unresectable recurrence who have already failed chemotherapy. A subgroup analysis of a randomized phase 3 trial comparing eribulin versus dacarbazine for either extremity or retroperitoneal liposarcoma showed that eribulin was associated with an improvement in overall survival (15.6 vs. 8.4 months). Based on these data, single-agent eribulin is approved in the palliative setting for patients with liposarcoma. Together, these observations contribute to the complexity of developing an individualized treatment plan for retroperitoneal liposarcoma.  Malignant Fibrous Histiocytoma Reclassification In past decades, MFH was considered the most common STS in adults. Improvements and innovations in the pathologic review of STS have drastically altered the definition of MFH. Various authors have retrospectively reevaluated tumors originally classified

743

as MFH and found that the majority merited reclassification. In one seminal manuscript, 63% were reclassified, and only 13% truly met pathologic criteria for MFH. These data shifted the diagnosis of MFH to one of exclusion, and this movement culminated in the 2013 World Health Organization classification of soft tissue tumors that completely eliminated the term. Tumors that still meet pathologic criteria for MFH are now referred to as unclassified or undifferentiated pleomorphic sarcoma. Careful histologic, immunohistochemical, and molecular analysis by a pathologist with STS expertise is crucial in the accurate diagnosis and treatment of these patients. With precise pathologic review, patients with tumors originally classified as MFH have demonstrably different prognoses based on the actual line of STS differentiation.15 

TRUNK AND EXTREMITY SARCOMA Extremity STS poses a particular challenge with respect to balancing the degree of limb function with tumor control. Historically, surgeons had a much lower threshold to recommend extremity amputation for STS. Data from clinical trials have prompted a shift toward limb preservation in these patients. The ability to offer limb preservation is a result of improvements in the multidisciplinary care of these patients. One of the seminal trials conducted at the National Cancer Institute (NCI) proposed that extremity STS resection might be addressed by a limb-sparing approach instead of amputation.16 Forty-three patients with highgrade extremity STS were randomized to undergo a limb-sparing operation followed by adjuvant radiation therapy versus amputation alone; both groups received adjuvant chemotherapy. This approach resulted in no statistical significant difference in local recurrence in the limb-sparing group as compared with the amputation group. Disease-free and overall survival rates were also equivalent between the two groups. These results were supported by a similar contemporary trial that compared 126 patients who were randomized to limb-sparing STS resection with or without adjuvant brachytherapy. In this trial, brachytherapy was associated with improved local recurrence, but subset analysis suggests that this result may have been driven by the favorable response in patients with high-grade tumors. In a later NCI study, patients demonstrated a decrease in local recurrence regardless of tumor grade with the addition of external beam radiation therapy. The STS literature lacks a randomized trial to identify in which patients adjuvant radiation therapy can be safely omitted because of the large sample size required to satisfy the accompanying power calculation.17 Retrospective data indicate that adjuvant radiation therapy may be omitted for T1 extremity STS that is resected with negative surgical margins, even considering that 58% of these patients had high-grade tumors.18 A large retrospective Scandinavian study of 1093 patients found that whereas a narrow or involved surgical margin does increase the risk of local recurrence, adjuvant radiation therapy improved local control independent of tumor grade, tumor depth (superficial or deep), or margin status. In the event that adjuvant radiation therapy is indicated, the surgeon should consider two technical maneuvers. The first is placement of a few metallic clips at the boundaries of the resection bed in the event that adjuvant radiation therapy is indicated; the second is that when a surgical drain is necessary, the skin exit site should be placed near the incision as the entire surgical drain track is usually included in the radiation field. Metallic clips within the resection bed will assist with radiation planning, and careful drain placement reduces an otherwise unnecessary expansion of the radiation field.

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SECTION V  Surgical Oncology

Above and beyond the established local control benefits of adjuvant radiation, delivery of neoadjuvant radiation for STS offers a number of conceptual advantages. Before surgical resection, the target tissue oxygenation is superior, which facilitates the generation of intratumoral free radicals and ultimately tumor cell destruction. When neoadjuvant radiation is administered, the radiation field includes a smaller volume of adjacent nontumor tissue compared with the radiation field after surgical resection.19 When radiation is delivered with the tumor in situ, a lower preoperative dose is required versus in the postoperative setting. If radiation is delivered preoperatively, patients would be predicted to complete all components of their therapy more promptly as delayed wound healing can delay initiation of postoperative radiation therapy. In contrast to other tumors, administration of neoadjuvant radiation therapy rarely results in measurable tumor shrinkage but may cause varying degrees of histologic tumor necrosis.20 A complete pathologic response after neoadjuvant therapy is an important prognostic factor in a variety of malignant neoplasms including breast cancer, esophageal cancer, and rectal cancer. Unfortunately, this relationship does not appear to hold true for STS. When most of the resected tumor is nonviable after neoadjuvant radiation therapy or chemoradiotherapy, patients with STS do not have improvements in overall survival or local recurrence.21 Patients with a positive surgical margin after undergoing preoperative radiation therapy do not appear to derive a significant reduction in local recurrence by administration of a postoperative radiation boost. Only one clinical trial has randomized patients with extremity STS to receive either neoadjuvant or postoperative radiation therapy. In this trial, neoadjuvant external beam radiation therapy was associated with an increased risk of wound complications.19 Although the authors reported a statistically significant difference in overall survival favoring the neoadjuvant arm, survival was a secondary end point, and the trial was not properly powered to evaluate this parameter. One would expect that another conceptual advantage of choosing a neoadjuvant approach would be to decrease the incidence and consequences of positive surgical margins by delivering tumoricidal doses preoperatively to the areas most at risk. In actuality, the existing randomized trial showed equivalent rates of negative surgical margins in patients receiving preoperative versus postoperative radiation therapy (83% and 85%, respectively).19 Using the existing retrospective data to explore this question is problematic as there are clear selection biases in which patients receive neoadjuvant therapy and their subsequent risk for positive surgical margins. Finally, the definition of a positive or negative surgical margin differs among manuscripts, which contributes to the difficulty in interpreting the reported data. The long-term implications of a positive margin are independent of whether radiation therapy is delivered preoperatively or postoperatively; positive margins are associated with an increased risk for local recurrence, whereas overall survival is generally unchanged. Preoperative regimens combining chemotherapy and radiation therapy have also been investigated. A retrospective review of 112 patients undergoing either neoadjuvant chemoradiation or neoadjuvant radiation versus surgery alone found equivalent oncologic outcomes among the three approaches. When stratified by size, the overall survival of patients with tumors larger than 5 cm was improved in treatment with either neoadjuvant chemoradiation or neoadjuvant radiation therapy compared with surgery alone. Preoperative chemoradiation therapy followed by surgical resection and additional chemotherapy was shown to be associated with an increased overall survival. This was suggested in a retrospective study of 48 patients whose chemotherapy included a combination of doxorubicin, ifosfamide,

and dacarbazine. All 48 patients had high-grade extremity STS measuring at least 8 cm, and additional postoperative radiation therapy was delivered in the event of positive surgical margins.22 Patients undergoing this intensive preoperative and postoperative chemotherapy regimen were matched to historical controls. In this study, the resection margin status was similar between the two groups. The outcomes of this preoperative and postoperative chemoradiation treatment schema were verified in radiation therapy oncology group (RTOG) 9514, a single-arm, multi-institutional phase 2 trial.23 The use of chemotherapy in the adjuvant setting for STS is controversial. European Organisation for Research and Treatment Center (EORTC) 62931 was a randomized multi-institutional trial that randomized 351 patients to receive adjuvant chemotherapy (doxorubicin, ifosfamide, and the hematopoietic growth factor lenograstim) versus no chemotherapy. The overall and relapse-free survivals were equivalent in both groups. A meta-analysis of 1953 patients who had participated in 18 trials showed that those patients who received adjuvant doxorubicin had statistically significant improvements in local, distant, and overall recurrence. A randomized phase 2 study of 150 patients showed that neoadjuvant chemotherapy (doxorubicin and ifosfamide) was not associated with improvements in disease-free or overall survival. Because of the abundance of conflicting data, consensus guidelines such as those of the National Comprehensive Cancer Network and the European Society for Medical Oncology remain guarded in their recommendation for adjuvant chemotherapy. Another treatment strategy that has been employed in patients with locally advanced extremity STS is regional chemotherapy, namely, limb perfusion. More commonly used in the treatment of locally advanced melanoma, this involves placement of both intravenous and intraarterial catheters that are positioned within the affected limb proximal to the tumor. The combination of the limb vasculature and the intravascular catheters completes a circuit through which hyperthermic chemotherapy is circulated. A tourniquet proximal to the tips of the catheters separates the limb circulation from the systemic circulation to minimize systemic chemotherapy toxicity. The most common perfusion agents used are melphalan, tumor necrosis factor-α, and interferon-γ. Isolated limb perfusion is often combined with other modalities, namely, surgical resection. The technical demands and potential for local toxicities limit the application of this therapy. Currently, only one randomized trial has compared regional chemotherapy with other standard STS therapies. Overall, the published data are insufficient to conclusively establish the role of regional chemotherapy in the care of extremity STS. The question as to what constitutes an adequate STS resection margin is complex, but the following is clear: the volume of tissue that is resected has clear implications as to the postoperative function of the limb, and a quantitative definition of an adequate surgical margin has never been defined in a randomized, prospective format. Whereas advances in rehabilitation medicine and prosthetic construction have significantly improved the functional capacity of patients who undergo extremity STS resection, the aforementioned data demonstrate that the goal of effective tumor extirpation with the smallest functional deficit is possible. Unlike in the melanoma literature, patients with extremity STS have never been randomized to compare surgical margin widths. Retrospectively, the local recurrence rate after resection of extremity STS with a microscopic margin of 1 cm or more is superior to when the margin is less than 1 cm.24 However, in a different retrospective study, the only factor associated with an increased risk of local recurrence was tumor at the margin of resection.25

CHAPTER 32  Soft Tissue Sarcoma Because reresection has been associated with improvements in local recurrence, patients with positive margins should be offered re-resection to achieve margins of 1 cm.26 In difficult anatomic situations, pursuit of clear surgical margins should be weighed against the natural history of extremity STS and the risk of an increased functional deficit. Even in the setting of multimodality therapy, the risk of distant metastasis consistently outweighs the risk of local recurrence in high-grade tumors. The gross morphology of STS is such that during resection, the plane of least resistance is usually along a tumor pseudocapsule. The pseudocapsule is a characteristic plane of thickened tissue that radiographically and during intraoperative palpation gives the impression of representing the interface between tumor and normal tissue. Resections that proceed along the pseudocapsule plane are generally enucleations with involved margins. Traditionally, a 1- to 2-cm grossly negative margin beyond the pseudocapsule is recommended, but this may be difficult or impossible to achieve in certain anatomic sites and may be unnecessary in dealing with low-grade tumors. Neoadjuvant therapy may be associated with formation of a more robust tumor pseudocapsule populated by fewer tumor cells.27 Ultimately, as discussed in the section on retroperitoneal sarcoma, the resection margin is only as good as the closest margin in any region of the tumor, so that extending resections to increase morbidity in one region is not necessary if a closer margin exists in another region. STS tumors tend to metastasize hematogenously principally not only to the lungs but also to the liver and bone. Tumor grade is the most important predictor of metastasis, with a 43% rate of metastasis-free survival in patients with high-grade tumors.28 Other important predictors of metastasis include tumor size, bone or neurovascular involvement, and tumor depth (superficial vs. deep). The prevalence of pulmonary metastases among patients previously treated for extremity STS is approximately 19%. Isolated pulmonary metastases should be resected whenever feasible.29 A prolonged disease-free interval between initial STS treatment and development of lung metastasis is generally a favorable prognostic factor. In the absence of effective systemic therapies, repeated pulmonary metastasectomy is also a consideration. Patients who are not candidates for metastasectomy should be evaluated for ablative or systemic therapies. Many types of STS are relatively chemoresistant; notable exceptions include angiosarcoma and synovial sarcoma. Typical agents for metastatic STS include doxorubicin, dacarbazine, ifosfamide, gemcitabine, docetaxel, eribulin, pazopanib, regorafenib, and olaratumab.

Malignant Peripheral Nerve Sheath Tumors MPNSTs occur in roughly equal frequency sporadically and as part of NF1. These tumors are the malignant form of the benign schwannoma. Although they arise from a peripheral nerve or the nerve sheath, they are often painless on presentation. The most common age at presentation is 20 to 50 years. Historically, other names have been applied to MPNST, such as malignant schwannoma, neurogenic sarcoma, and neurofibrosarcoma. The term malignant schwannoma is avoided because not all MPNSTs actually arise from Schwann cells. These are generally aggressive tumors; recent large series have shown a local recurrence rate of about 20% and a 10-year disease-specific survival of more than 40%. The key prognostic factors include tumor size at presentation and tumor grade. There is no consensus in the literature as to whether MPNST in the setting of NF1 carries a worse prognosis than spontaneous cases. Treatment of these tumors is similar to that of other STS subtypes, with a focus on margin-negative resection.

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Although it has not been studied prospectively in the MPNST population, most retrospective reports agree that adjuvant radiation therapy is indicated to decrease the rate of local recurrence in extremity and superficial trunk lesions. 

Desmoid Tumor Desmoid tumors, also known as aggressive fibromatosis, are an uncommon group of fibroblastic tumors that have a curious natural history in that distant metastases are extremely rare. Approximately 75% to 85% of cases arise sporadically; the others are related to FAP. Among the sporadic cases, recent pregnancy and antecedent trauma are recognized associations. These tumors are two to three times more common in women than in men and are most commonly diagnosed in patients aged 30 to 40 years. Approximately 20% of FAP patients develop desmoid tumors, and a common presentation involves a desmoid at the prior colectomy scar. Desmoid tumors are usually preceded by colonic polyposis in FAP patients and represent the second leading cause of death in FAP patients. A detailed family history should be obtained from patients presenting with desmoid tumors to rule out unappreciated FAP, and consideration should also be given to screening colonoscopy. The molecular underpinnings of desmoids, regardless of sporadic or syndromic association, are related to the Wingless and Int-1 (WNT) signaling pathway. In sporadic cases, CTNNB1 mutations result in the expression of a stabilized form of β-catenin, which ultimately accumulates and is transported to the nucleus, where it exerts its proliferative effects through activation of transcription factors. In the setting of FAP, APC mutations also cause β-catenin stabilization, which also activates nuclear transcription and cellular proliferation. Specific APC codon mutations appear to confer a higher desmoid risk than other codon mutations. Clinically, the most common areas of origin include the extremity, intraperitoneal, abdominal wall, and chest wall. Affected patients may present with a painful versus asymptomatic firm mass, bowel obstruction, or bowel ischemia. Desmoid tumors are usually slow-growing but on occasion do grow aggressively. On radiographic evaluation, these tumors are generally homogeneous and solid in appearance. They may have either a distinct or an infiltrating boundary. Both CT scan and MRI are useful imaging modalities. Especially in sporadic cases, desmoid tumors are indistinguishable from a variety of other STS subtypes based on imaging alone. Core needle biopsy is indicated in situations in which treatment recommendations will be altered on the basis of tumor histology. Treatment of these tumors can be challenging. When tumors are large or infiltrating crucial anatomic structures, surgical resection with widely negative margins may not be possible. Even when the tumors are adequately resected, especially in the FAP population, desmoid tumors show a high likelihood of local recurrence. These observations have prompted various recommendations for consideration of active surveillance for desmoid tumors rather than reflexive resection on diagnosis. In addition, the role of radiation may be appropriate, especially in recurrent extremity tumors. When considering that many desmoids are indolent and show very little growth after presentation and that resection may mandate significant functional deficits, an active surveillance strategy may be appropriate for selected patients. A small German trial enrolled 38 patients with progressive desmoid tumors and showed that 65% of patients treated with imatinib achieved progression arrest after 6 months, and 45%, after 24 months.30 

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SECTION V  Surgical Oncology

Angiosarcoma Angiosarcoma is a malignant tumor that arises from the endothelial lining of blood vessels and therefore can arise from almost any site. Overall, it accounts for 2% of all STS, but approximately 40% of all angiosarcomas are radiation associated.3 In decreasing order of frequency, the most important primary sites are the trunk, head, and neck (particularly the scalp) and the viscera. Within the head and neck, the scalp is often the site of angiosarcoma origin. Angiosarcoma typically is diagnosed in the seventh and eighth decades. Although most angiosarcoma is sporadic, risk factors include previous therapeutic radiation exposure and lymphedema (see previous section). Angiosarcoma, in contrast to other STS, does have a higher frequency of involved regional lymph nodes. Approximately 20% of patients present with metastasis, most frequently to the lung.31 On histologic evaluation, these tumors range from extremely well differentiated, mimicking hemangioma, to very poorly differentiated. Consistent with this, there is a wide variety of cytogenetic changes. On immunohistochemical examination, CD31 and FLI-1 are the most consistent markers. The primary therapy for these lesions is surgical resection with negative margins. On microscopic examination, these tumors often infiltrate well beyond the area of gross involvement. For patients with head and neck angiosarcoma, this can present a reconstructive challenge. Angiosarcoma that arises within the breast after breast-conserving therapy is managed with mastectomy. Even after surgical resection, the outcome is poor, with a 5-year disease-specific survival of 53%.31 In the cohort with resectable disease, tumor size larger than 5 cm and histologic evidence of an epithelioid component are indicators of poor prognosis. After resection, distant failure predominates over local failure, although both are common. These tumors are often locally advanced and unresectable at presentation; fortunately, these tumors are responsive to chemotherapy and radiation therapy, and a neoadjuvant approach may be feasible. The median survival of stage IV angiosarcoma is 8 to 12 months. Unlike other STS, metastatic angiosarcoma may be manifested with hemopneumothorax. Breast angiosarcoma may metastasize to the liver. The most typical agents employed in the unresectable or metastatic setting include paclitaxel and doxorubicin, followed by radiation therapy, except perhaps in patients whose tumor was incited by previous radiation therapy. A host of ongoing trials including angiosarcoma patients are underway that are exploring the utility of a range of agents including tyrosine kinase inhibitors and combination therapy of angiogenesis inhibitors with cytotoxic agents (https://clinicaltrials.gov/). 

Dermatofibrosarcoma Protuberans DFSP is an uncommon STS that affects approximately 1 in 4.2 million patients in the United States. This tumor affects men and women equally and appears to be more common in African American patients than in whites. The typical range of presentation is between the fourth and seventh decades. The trunk, upper extremity, and lower extremity are equally frequent sites of DFSP, followed by the head and neck. On physical examination, these are firm, indurated nodules that are reddish or brown in appearance. On histologic evaluation, DFSP is a dermal or subdermal tumor without penetration into the epidermis. Cytogenetically, the majority of DFSP displays the t(17;22)(q22;q13) translocation, which fuses the COL1A1 and platelet-derived growth factor B genes and accounts for its platelet-derived growth factor B overexpression. In difficult cases, this gene fusion can be detected by fluorescence in situ hybridization. Because of its somewhat bland

visual appearance and the lack of associated pain, it can often be large at presentation, having been mistaken for a hypertrophic scar or a keloid. DFSP frequently recurs locally, and consequently, the treatment is surgical resection with wide margins. As is true with most STS, there are no well-designed clinical trials to define an adequate margin. Recurrence can be successfully treated with resection. The 5-year survival is 99.2%. DFSP rarely metastasizes, but when it does, it often implies degeneration to fibrosarcoma. Because of the platelet-derived growth factor B upregulation, patients with unresectable disease may be treated with neoadjuvant imatinib. 

RETROPERITONEAL AND VISCERAL SARCOMA Retroperitoneal sarcoma represents approximately 15% of all STS. The sequestered location of the retroperitoneum probably accounts for the fact that the average tumor size at presentation is 15 cm.32 The most frequent retroperitoneal sarcoma subtypes are liposarcoma, leiomyosarcoma, and MFH undifferentiated pleomorphic sarcoma. The predominant intraperitoneal STS subtypes are GIST and leiomyosarcoma, which are discussed separately. The average age at presentation is 54 years, and there is an equal male-to-female distribution. In most series, the overall survival of patients presenting with retroperitoneal sarcoma is 33% to 39%. Even after optimal surgical resection, at least 70% of patients will relapse. In one large retrospective series, approximately 12% of patients presented with metastatic disease, predominantly pulmonary or hepatic. The presentation of retroperitoneal sarcoma is variable, depending on the size and location of the tumor. Some are asymptomatic and incidentally discovered. Symptomatic tumors may be manifested with abdominal pain, weight loss, early satiety, nausea, emesis, back or flank pain, paresthesias, and weakness. CT and MRI are widely used for the evaluation of retroperitoneal sarcoma because of their excellent spatial resolution and reproducible axial image acquisition. The advantages of CT scan include rapid image acquisition, nearly universal availability, and a concise image set that can be more intuitive for the nonradiologist to interpret. The advantages of MRI include a wider range of soft tissue differentiation, but the disadvantages include an increased susceptibility to claustrophobia and motion artifact, the more limited availability, and a greater number of implant-related contraindications compared with CT scan. These modalities can be complementary, and at times, both provide useful information. The patient must be carefully evaluated along with the imaging studies to verify that the retroperitoneal mass does not represent an unappreciated lymphoma, germ cell tumor, or metastasis from another primary tumor as the management of these tumors is quite different from that of retroperitoneal sarcoma. A number of consensus guidelines strongly recommend performing a preoperative biopsy, but as previously discussed with extremity STS, biopsy for retroperitoneal sarcoma is not mandatory and has drawbacks in certain situations. By definition, a surgical biopsy ruptures the tumor, seeding the operative field and potentially reducing the possibility of a margin-negative resection. Preoperative biopsy can be particularly misleading in patients with large tumors as the biopsy is susceptible to a significant degree of sampling bias. This sampling bias can provide inappropriately reassuring information. The preoperative CT scan often contains enough information to proceed with treatment without a preoperative biopsy as long as the other basic considerations in the differential diagnosis are considered excluded. This includes lymphoma,

CHAPTER 32  Soft Tissue Sarcoma germ cell tumors, and other metastatic disease (see Box 32.1). In a retrospective study from a large, single, tertiary care institution, the initial staging CT scan was sufficient in assessing the need for preoperative biopsy and assigning a treatment approach for those tumors for which biopsy is not indicated; this approach is discussed in greater detail in the lipomatous tumor section.10 For this reason, if preoperative biopsy is obtained from a heterogeneous mass, the specimen should be obtained from the most concerning region under image guidance. When possible, treatment should proceed with a complete gross resection. In the retroperitoneal sarcoma literature, the concept of margin status is different from that for extremity STS. Because extremity STS tumors are usually smaller than retroperitoneal sarcoma tumors, microscopic evaluation of the entire surgical specimen margin is often feasible. Given the much larger tumor dimensions of most retroperitoneal sarcomas, it is not practical and often impossible to microscopically evaluate 100% of the surgical specimen margin surface area. Consequently, most of the retroperitoneal sarcoma literature refers to complete gross resection. In one large series, complete gross resection was achieved in 80% of initial sarcoma resections, 57% of operations for first recurrence, 33% of operations at second recurrence, and 14% of operations at third recurrence. In 75% of patients, achieving complete gross resection may mean resecting contiguous or inseparable adjacent organs, such as the kidney, bowel, or pancreas and vascular structures. Resection requiring pancreaticoduodenectomy, major vascular resection, or splenectomy was more likely to result in a major postoperative complication, but a major postoperative complication does not appear to adversely affect long-term survival or recurrence.33 Predicting histologic invasion on the basis of gross intraoperative findings can be inaccurate. Before the era of modern CT technology, patients who underwent nephrectomy because of intraoperative evidence of suspected involvement during retroperitoneal sarcoma resection were further evaluated for histologic evidence of sarcoma invasion. In 73% of cases, the nephrectomy specimen did not contain STS. Improvements in the quality of preoperative imaging probably decrease the rate of adjacent organ resection based solely on intraoperative suspicion. As expected, predictors of poor prognosis include gross residual disease after resection, unresectable disease (either metastatic or locally advanced), and high tumor grade. Patients with a complete gross resection have a median survival of 103 months compared with 18 months for patients with incomplete resections. Even with optimal chemotherapy

A

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and radiation therapy, the median survival of patients with unresectable disease is 10 months.34 Patients who undergo complete resection should undergo active surveillance, as the risk of local recurrence and distant metastasis after 5 years is 23% and 21%, respectively. Although palliative resection may often be the only meaningful option in patients who develop recurrence, reresection of the recurrent disease was of limited value, resulting in 17% 3-year disease-free survival.35 In contrast to extremity sarcoma, the role of multimodality therapy is more controversial in retroperitoneal sarcoma. Given the success of adjuvant radiation in extremity STS, this approach has been applied to retroperitoneal sarcoma, but with fewer randomized data to support its efficacy. The 60- to 70-Gy dose that is considered sarcoma lethal and typically used for extremity STS is not feasible in the adjuvant setting for retroperitoneal sarcoma because of bowel toxicity. Even dose reduction to 50 to 55 Gy results in significant enteritis. These tolerability issues prompted consideration of neoadjuvant radiation for retroperitoneal sarcoma. An advantage of neoadjuvant radiation is that the in situ tumor displaces the bowel anteriorly, thus facilitating the delivery of a higher radiation dose posteriorly, which is the most likely site of a positive histologic margin (Fig. 32.6). This approach delivers 45 Gy to the planned target volume, and the projected at-risk margins are boosted up to 65 Gy. Two separate studies have demonstrated that the neoadjuvant approach is well tolerated and that long- and short-term oncologic outcomes are favorable compared with historical cohorts treated with resection alone.36,37 For patients with metastatic retroperitoneal sarcoma, there are few effective chemotherapeutic options. Single or combination therapy with anthracyclines can be used as first-line therapy. A second-line regimen is gemcitabine and docetaxel. Thus far, the experience with immunotherapy agents in STS patients has been disappointing. One encouraging finding is that patients with undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma have a somewhat more promising objective response rate than those with other STS subtypes when treated with pembrolizumab, a programmed death-1 inhibitor.38 In an open-label phase 2 trial, combined programmed death-1 inhibitor and cytotoxic T-lymphocyte (CTLA-4) inhibition showed very poor response rates in patients with metastatic sarcoma.39 Novel agents undergoing further study include trabectedin, tyrosine kinase inhibitors, MDM2 antagonists, peroxisome proliferator-activated receptor gamma agonists, and CDK4 antagonists.

B

FIG. 32.6  Liquefaction of a high-grade retroperitoneal sarcoma before (A) and after (B) administration of 60-Gy preoperative radiation therapy. The tumor was subsequently resected with negative surgical margins, and no viable tumor was histologically identifiable.

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SECTION V  Surgical Oncology

Gastrointestinal Stromal Tumor GIST is the most common variety of visceral STS. These tumors are believed to originate from the interstitial cells of Cajal within the gastrointestinal myenteric plexus and emanate from nearly any part of the alimentary tract, from esophagus to anus. The most prevalent GIST sites are the stomach, the small bowel, and the rectum. Cajal cells are thought to function as pacemaker cells in the viscera, mediating contractions. Cajal cells and GIST share common markers for CD117 and a calcium-activated chloride channel called DOG1. CD117 is another name for the KIT gene, which codes for a tyrosine kinase transmembrane receptor called c-kit. These molecular descriptions led to dramatic refinements in the diagnosis and treatment of patients with GIST. In morphologic appearance, GIST is classically a spindle cell neoplasm of smooth muscle origin. Although these tumors were previously described as leiomyoma or leiomyosarcoma, GISTs are differentiated on the basis of CD34, CD117, and DOG1 expression and the lack of smooth muscle staining. The c-kit receptor is a proto-oncogene that belongs to the platelet-derived growth factor receptor (PDGFR) superfamily. The natural c-kit ligand is a stem cell factor, and its binding causes tyrosine kinase receptor homodimerization, autophosphorylation, and activation of multiple pathways, including RAS, RAF, MAPK, AKT, and STAT3. Certain mutations of the c-kit receptor confer constitutive activation of the receptor, which ultimately results in cellular proliferation. The other relevant gene, also found on chromosome 4, that bears striking similarity to c-kit is the PDGFRα. Overall, about 70% of GISTs have KIT gene mutations, approximately 7% have PDGFRα mutations, and 15% have wild-type KIT and PDGFRα genotypes. These GISTs are characterized by a number of other mutations affecting succinate dehydrogenase (SDH), BRAF, KRAS, and NF1. SDH mutations are related to GIST in patients affected by the Carney-Stratakis syndrome, and NF1 mutations drive GIST formation in patients with NF1. The clinical presentation of these tumors is variable, ranging from incidental to symptomatic with respect to pain, nausea, vomiting, or, more rarely, gastrointestinal blood loss. On endoscopic examination, GIST usually appears as a smooth submucosal tumor that extrinsically impinges on the visceral lumen as opposed to an ulcerated mucosal mass. The endoscopic differential diagnosis of an intramural visceral mass includes GIST, neuroendocrine tumor, intramural lipoma, and lymphoma. Some GISTs are serosally pedunculated and do not contribute to intestinal obstruction. CT imaging shows that these tumors are well encapsulated and generally have heterogeneous contrast enhancement because of regions of necrosis within the tumor. Metastasis is not rare, but affected sites include the liver and peritoneal surface. The majority of GISTs are sporadic, but there are notable examples of syndromic involvement. These include NF1, germline SDH mutations, the Carney-Stratakis syndrome, von Hippel-Lindau disease, and other minor familial GIST syndromes. Because these are submucosal tumors, endoscopic forceps biopsies are often nondiagnostic. Tumors situated between the ligament of Treitz and the ileocecal valve can be localized by double-balloon enteroscopy or capsule endoscopy. Blood loss related to GIST may indicate that the tumor has ulcerated through the mucosa. An endoscopic ultrasound-guided needle biopsy generally shows a spindle cell neoplasm; if sufficient tissue is available, this can be submitted for CD117 evaluation. Preoperative biopsy for suspected GIST is not mandatory, but preoperative histologic verification

of GIST obviates the need for empirical lymphadenectomy at the time of resection, which would be crucial for neuroendocrine tumor or intestinal adenocarcinoma. Appropriate preoperative staging for GIST includes a contrast-enhanced CT scan of the chest, abdomen, and pelvis. Localized lesions are taken to the operating room for resection with grossly negative surgical margins. Obtaining wide surgical margins has not been demonstrated to improve local recurrence rates or overall survival. Given the rarity of lymph node involvement, lymphadenectomy is not mandatory for GIST. Care should be taken not to compromise the capsule of the tumor as rupture can seed the exposed tissues and adversely affect the prognosis of the patient. As long as the risk of tumor rupture is not elevated, consideration of minimally invasive surgical resection techniques is appropriate and may accelerate the recovery. The operative note should clearly document the integrity of the tumor capsule as it can profoundly affect recommendations for adjuvant therapy. Ideally, the pathology report follows a synoptic guideline to ensure that all relevant parameters are communicated to the multidisciplinary team. The key parameters include the tumor site organ of origin, tumor size, tumor focality, mitotic rate, immunohistochemical CD117 status, margin status, and results of molecular genetic studies, if performed. The mitotic rate is defined as the total count of mitoses per 5 mm2 on the glass slide section and is reported in the most proliferative area of the tumor. In GISTs, the mitotic rate parameter is synonymous with the tumor grade that is included with most other STS subtypes. Entities that can mimic GIST microscopically include melanoma, paraganglioma, neuroendocrine tumors, and nerve sheath tumors. Distinct from other STS subtypes, the AJCC eighth edition staging system has a schema that separates GISTs based on anatomic site of origin; gastric and omental tumors versus nongastric tumors (Tables 32.4 to 32.6). The anatomic site of origin

TABLE 32.4  American Joint Committee on

Cancer staging for gastrointestinal stromal tumor. Primary Tumor (T) TX T0 T1 T2 T3 T4

Primary tumor cannot be assessed No evidence for primary tumor Tumor 2 cm or less Tumor >2 cm, ≤5 cm Tumor >5 cm, ≤10 cm Tumor >10 cm

Regional Lymph Nodes (N) N0 No regional lymph node metastasis N1 Regional lymph node metastasis Distant Metastasis (M) M0 No distant metastasis M1 Distant metastasis Histologic Grade (G) GX Grade cannot be assessed G1 Low grade; mitotic rate ≤5 per 5 mm2 G2 High grade; mitotic rate >5 per 5 mm2 From Amin MB, Edge SB, Greene FL, et al. AJCC Cancer Staging Manual. 8th ed. New York: Springer; 2017.

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CHAPTER 32  Soft Tissue Sarcoma TABLE 32.5  Anatomic stage and prognostic

groups for gastric and omental gastrointestinal stromal tumor. GROUP

T

N

M

GRADE

Stage IA Stage IB Stage II

T1 or T2 T3 T1 T2 T4 T3 T4 Any T Any T

N0 N0 N0 N0 N0 N0 N0 N1 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M1

Low Low High High Low High High Any rate Any rate

Stage IIIA Stage IIIB Stage IV

From Amin MB, Edge SB, Greene FL, et al. AJCC Cancer Staging Manual. 8th ed. New York: Springer; 2017.

TABLE 32.6  Anatomic stage and prognostic

groups for nongastric* gastrointestinal stromal tumor. GROUP

T

N

M

GRADE

Stage IA Stage II Stage IIIA

T1 or T2 T3 T1 T4 T2 T3 T4 Any T Any T

N0 N0 N0 N0 N0 N0 N0 N1 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M1

Low Low High Low High High High Any rate Any rate

Stage IIIB

Stage IV

From Amin MB, Edge SB, Greene FL, et al. AJCC Cancer Staging Manual. 8th ed. New York: Springer; 2017. *Nongastric includes small bowel, colorectal, esophageal, mesentery, and peritoneal.

is important from a surgical planning standpoint, and from a prognostic standpoint. In order of decreasing prognosis are the following sites of tumor origin: gastric, jejunal/ileal, and colorectal GIST. A number of tools available to predict prognosis after resection can then be used on the basis of these pathologic and clinical parameters. The Memorial Sloan-Kettering Cancer Center (MSKCC) group developed a nomogram based on the size of the resected GIST, the mitotic rate, and the anatomic site of origin, which is validated to predict the probabilities of 2- and 5-year recurrence-free survival.37 The nomogram was developed using data from 127 patients treated at MSKCC and then validated in two independent GIST populations from other institutions. The target population of this nomogram is patients undergoing complete GIST resection who did not receive adjuvant therapy. Another prognostic tool is the Armed Forces Institute of Pathology criteria, designed to predict the risk of progressive disease after resection and based on data from more than 1900 patients with resected GIST who also did not receive adjuvant therapy. Inputs into this schema include mitotic rate, size, and anatomic site of origin. This series has not been validated to the same degree as the MSKCC nomogram but was developed using a more robust sample size. The modified NIH criteria were established on the basis of several data sets, including the Armed Forces Institute of Pathology criteria, and have subsequently been validated (Table 32.7).40,41

TABLE 32.7  Assessing the prognosis of

resected gastrointestinal stromal tumor.

TUMOR SIZE ≤2 cm >2 cm, ≤5 cm >5 cm, ≤10 cm >10 cm

RISK OF TUMOR PROGRESSION, WITHOUT ADJUVANT THERAPY

MITOTIC RATE (MITOSES/ MM2)

GASTRIC ORIGIN

SMALL BOWEL ORIGIN

≤5 >5 ≤5 >5 ≤5 >5 ≤5 >5

0% 0%* 1.9% 16% 3.6% 55% 12% 86%

0% 50%* 4.3% 73% 24% 85% 52% 90%

Adapted from Miettinen M, Lasota J. Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med. 2006;130:1466–1478. *These values are based on small sample sizes, which limits their clinical applicability.

As predictors of outcome after surgical resection, these risk assessment tools are routinely used to also assess the need for adjuvant therapy. Although none of these risk assessment tools includes it as an input parameter, the success of adjuvant therapy is dependent on the GIST molecular phenotype. Specific KIT mutations differentially affect long-term prognosis and response to therapy. The specific KIT exon in which the GIST mutation resides affects the molecular and clinical phenotype. For example, a KIT mutation in exon 13 resides within the tyrosine kinase domain and confers susceptibility to imatinib therapy. Exon 9 mutations correspond to the extracellular domain of the c-kit receptor, are observed principally in small bowel or colon GIST, and are less sensitive to imatinib. Routine genetic analysis at GIST diagnosis to determine the precise mutated exon is strongly recommended by consensus guidelines as this information may alter treatment recommendations and patient outcome.42 Systemic therapy is indicated for adjuvant therapy after GIST resection, for the treatment of metastatic GIST, and for the neoadjuvant therapy of unresectable or locally advanced tumors. Imatinib, the best studied of these systemic agents, is an oral tyrosine kinase inhibitor of c-kit. In general, the presence of a KIT mutation is highly associated with response to this oral medication. Again, because of the similarities to the c-kit and PDGFRαs, some patients with wild-type KIT are sensitive to imatinib. Dasatinib was associated with progression-free survival in patients with imatinib-resistant GIST, including the PDGFRα D842V mutation.43 Other available agents capable of GIST-related tyrosine kinase inhibition include sunitinib and regorafenib. The third major molecular GIST group is characterized by SDH mutations. Patients with these mutations are generally younger, have multiple gastric GISTs, and have a poor response to imatinib. Although it is not universally accepted as standard of care, advanced molecular analysis should be considered for all patients. This may affect the choice and dose of tyrosine kinase inhibitor for patients with KIT or PDGFRα mutations and in patients with wild-type KIT and PDGFRα GISTs; further molecular evaluation may identify clinically relevant SDH or BRAF mutations.

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SECTION V  Surgical Oncology

Imatinib was first developed to treat Philadelphia chromosome–positive chronic myelogenous leukemia. Soon after, its efficacy was demonstrated in the setting of metastatic GIST, adjuvant therapy for resected GIST, and neoadjuvant therapy for unresectable GIST. Imatinib was demonstrated to be associated with a dramatic improvement in the median overall survival of metastatic GIST from 20 months to 57 months.44 In the adjuvant setting after complete surgical resection, two randomized studies have demonstrated improved disease-free recurrence.45,46 Because these trials vary in their clinicopathologic inclusion criteria and study design, there remains debate as to which patients should receive imatinib and for what duration. The ACOSOG Z9001 was a double-blind trial that randomized patients with a grossly negative GIST resection to receive imatinib versus placebo for 1 year. All tumors were larger than 3 cm, and all were c-kit positive by immunohistochemistry. One year of adjuvant imatinib was associated with a statistically significant improvement in the recurrence-free survival versus placebo (98% vs. 83%, respectively).45 A subsequent Z9001 follow-up study demonstrated a persistent improvement in recurrence-free survival but did not demonstrate any improvement in overall survival.47 In a separate trial, patients were randomized to 1 versus 3 years of adjuvant imatinib after resection of c-kit–positive GIST. This trial stipulated that patients must have high-risk disease per the NIH consensus criteria. The 3-year duration of therapy was associated with improvements not only in recurrence-free survival but also in overall survival. Joensuu and colleagues48 published the first data describing the parameters associated with tumor recurrence after resection in patients already treated with adjuvant imatinib. Data sets from two of the aforementioned three randomized trials were used to construct and to validate a risk stratification score. Two such scores were developed. The five-parameter score includes mitotic count, organ of origin, size, tumor rupture, and duration of imatinib therapy; the two-parameter score includes mitotic count and organ of origin. These data support a 3-year duration of imatinib therapy and indicate that nongastric organ of origin and a high mitotic count adversely affect recurrence-free survival. Because the previous risk assessment schemas were developed using patient cohorts who had never been treated with adjuvant imatinib, this stratification score may prove to be clinically relevant. More recently, a single arm, phase 2 clinical trial (Postresection Evaluation of Recurrence-free Survival for Gastrointestinal Stromal Tumors with 5 Years of Adjuvant Imatinib [PERSIST-5]) showed that of the 46 patients who completed 5 years of adjuvant imatinib, no patient with sensitive mutations experienced tumor recurrence.49 

Leiomyosarcoma Leiomyosarcoma is a malignant smooth muscle tumor that can originate from virtually any part of the body. The most common sites affected are the retroperitoneum and the peritoneal cavity, namely, the uterus; about 25% rise from the trunk and extremities. Overall, after liposarcoma, leiomyosarcoma is the second most frequent STS subtype.1 The peak incidence of leiomyosarcoma is in the sixth and seventh decades. Retroperitoneal and uterine leiomyosarcoma is more common in women, but there is a male predominance in other leiomyosarcoma sites. Predisposing risk factors for leiomyosarcoma include prior radiation exposure and immunosuppression combined with Epstein-Barr virus–related tumor promotion. Leiomyosarcoma does not arise from a degenerated leiomyoma, a common benign soft tissue tumor.

Leiomyosarcoma is generally a heterogeneous, well-circumscribed tumor with an often cystic or necrotic central area. This tumor stains positive for desmin and smooth muscle actin. It has a wide variety of cytogenetic aberrations but no reliable or pathognomonic markers. Before the description of KIT mutations, tumors that are now appreciated to represent GIST were described as leiomyosarcoma. First-line therapy for leiomyosarcoma is surgical resection with negative margins. For uterine leiomyosarcoma, a total abdominal hysterectomy and bilateral oophorectomy is indicated. Resection of tumors that invade or are intimately associated with the inferior vena cava (IVC) require special planning. Depending on the size and position of the tumor, an approach including neoadjuvant radiation therapy may be a consideration. The intraoperative options include tumor resection with IVC ligation, patching of the IVC, and interposition graft of the IVC. Tumors involving the IVC typically have a great deal of collateralization already in place. For a tumor that requires segmental resection of the infrahepatic IVC, if the collaterals can be preserved, ligation without reconstruction may be an acceptable maneuver as postoperative lower extremity edema is well tolerated. Because of the rarity of IVC leiomyosarcoma, a future randomized trial further evaluating these maneuvers is unlikely. Regardless of the organ of origin, adjuvant therapy is not currently recommended, although this is the subject of ongoing trials, especially for uterine leiomyosarcoma. Affecting 44% of patients, metastasis is usually hematogenous in nature, mainly to the lung and liver. Historically, doxorubicin, ifosfamide, docetaxel, and gemcitabine have been used in the metastatic setting but recently olaratumab with doxorubicin was approved for advanced, unresectable STS. Olaratumab is a recombinant human monoclonal antibody that binds PDGFRα. In combination with doxorubicin, it showed an improvement in overall and progression-free survival for patients with advanced, unresectable STS. In subgroup analysis, the improvement in survival was greater for patients with leiomyosarcoma versus other histologic subtypes.50 

SUMMARY STS is a fascinating aspect of surgical oncology that requires an understanding of multiple tumor types. To effectively treat STS patients, the surgeon must have a strong understanding of tumor biology, the physiologic consequences of various resection strategies, and the ability to effectively work within the context of a multidisciplinary oncology team. Recent discoveries relating to the molecular and genetic underpinnings demonstrate that, although they are rare, these tumors may offer opportunities in the development of novel targeted therapies.

SELECTED REFERENCES Anya DA, Lahat G, Wang X, et al. Postoperative nomogram for survival of patients with retroperitoneal sarcoma treated with curative intent. Ann Oncol. 2010;21:397–402. A thoughtful, pragmatic, and easily applicable approach to the management of retroperitoneal sarcomas.

Brennan MF, Antonescu CR, Moraco N, et  al. Lessons learned from the study of 10,000 patients with soft tissue sarcoma. Ann Surg. 2014;260:416–421; discussion 421–422.

CHAPTER 32  Soft Tissue Sarcoma The largest surgical series of soft tissue sarcoma demonstrates a number of key concepts that relate to natural history and management of patients with this disease.

Fletcher CD, Gustafson P, Rydholm A, et al. Clinicopathologic re-evaluation of 100 malignant fibrous histiocytomas: prognostic relevance of subclassification. J Clin Oncol. 2001;19:3045–3050. This illustrates the concept that the historical term malignant fibrous histiocytoma is pathologically imprecise and fails to accurately predict outcome.

Heslin MJ, Lewis JJ, Nadler E, et al. Prognostic factors associated with long-term survival for retroperitoneal sarcoma: implications for management. J Clin Oncol. 1997;15:2832–2839. An important manuscript demonstrating the natural history of patients undergoing resection for retroperitoneal sarcoma.

Joensuu H, Eriksson M, Hall KS, et  al. Risk factors for gastrointestinal stromal tumor recurrence in patients treated with adjuvant imatinib. Cancer. 2014;120:2325–2333. Whereas most retrospective reviews focus on gastrointestinal stromal tumor (GIST) prognosis after resection alone, this paper describes a methodology to stratify the risk of GIST recurrence in patients treated with adjuvant imatinib.

Joensuu H, Eriksson M, Sundby Hall K, et al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA. 2012;307:1265–1272. In demonstrating superior recurrence-free and overall survival, this trial established the duration of adjuvant imatinib for patients with a high risk for gastrointestinal stromal tumor following resection.

O’Sullivan B, Davis AM, Turcotte R, et  al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet. 2002;359:2235–2241. The National Cancer Institute of Canada/Canadian Sarcoma Group SR2 clinical trial represents the only prospective randomized comparison of preoperative versus postoperative radiation therapy for extremity sarcoma.

Pisters PW, Pollock RE, Lewis VO, et  al. Long-term results of prospective trial of surgery alone with selective use of radiation for patients with T1 extremity and trunk soft tissue sarcomas. Ann Surg. 2007;246:675–681. Compelling data supporting the selective use of adjuvant radiation for early-stage soft tissue sarcoma.

Rosenberg SA, Tepper J, Glatstein E, et al. The treatment of softtissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg. 1982;196:305–315.

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This phase 3 National Cancer Institute (NCI) study paved the way for a generation of studies examining the role for limbsparing surgery in the setting of multimodal therapy.

Taylor BS, Barretina J, Maki RG, et  al. Advances in sarcoma genomics and new therapeutic targets. Nat Rev Cancer. 2011;11:541–557. A unique perspective on the taxonomy and classification of soft tissue sarcoma, driven by the molecular genetics of this diverse tumor family.

van Vliet M, Kliffen M, Krestin GP, et  al. Soft tissue sarcomas at a glance: clinical, histological, and MR imaging features of malignant extremity soft tissue tumors. Eur Radiol. 2009;19:1499–1511. This manuscript is a concise atlas of soft tissue sarcoma that correlates the natural history of the disease to the imaging and histologic characteristics.

REFERENCES 1. Brennan MF, Antonescu CR, Moraco N, et al. Lessons learned from the study of 10,000 patients with soft tissue sarcoma. Ann Surg. 2014;260:416–421; discussion 421–412. 2. Ballinger ML, Goode DL, Ray-Coquard I, et al. Monogenic and polygenic determinants of sarcoma risk: an international genetic study. Lancet Oncol. 2016;17:1261–1271. 3. Gladdy RA, Qin LX, Moraco N, et al. Do radiation-associated soft tissue sarcomas have the same prognosis as sporadic soft tissue sarcomas? J Clin Oncol. 2010;28:2064–2069. 4. Italiano A, Di Mauro I, Rapp J, et  al. Clinical effect of molecular methods in sarcoma diagnosis (GENSARC): a prospective, multicentre, observational study. Lancet Oncol. 2016;17:532–538. 5. Amin MB, Edge SB, Greene FL, et al. AJCC Cancer Staging Manual. 8th ed. New York: Springer; 2017. 6. Anaya DA, Lahat G, Wang X, et al. Establishing prognosis in retroperitoneal sarcoma: a new histology-based paradigm. Ann Surg Oncol. 2009;16:667–675. 7. Lahat G, Anaya DA, Wang X, et al. Resectable well-differentiated versus dedifferentiated liposarcomas: two different diseases possibly requiring different treatment approaches. Ann Surg Oncol. 2008;15:1585–1593. 8. Johnson AC, Ethun CG, Liu Y, et  al. A novel, simplified, externally validated staging system for truncal/extremity soft tissue sarcomas: an analysis of the US Sarcoma Collaborative database. J Surg Oncol. 2018;118:1135–1141. 9. Gutierrez JC, Perez EA, Moffat FL, et al. Should soft tissue sarcomas be treated at high-volume centers? An analysis of 4205 patients. Ann Surg. 2007;245:952–958. 10. Lahat G, Madewell JE, Anaya DA, et al. Computed tomography scan–driven selection of treatment for retroperitoneal liposarcoma histologic subtypes. Cancer. 2009;115:1081–1090. 11. Heslin MJ, Lewis JJ, Nadler E, et  al. Prognostic factors associated with long-term survival for retroperitoneal sarcoma: implications for management. J Clin Oncol. 1997;15:2832–2839.

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12. Bonvalot S, Rivoire M, Castaing M, et al. Primary retroperitoneal sarcomas: a multivariate analysis of surgical factors associated with local control. J Clin Oncol. 2009;27:31–37. 13. Tseng WW, Madewell JE, Wei W, et al. Locoregional disease patterns in well-differentiated and dedifferentiated retroperitoneal liposarcoma: implications for the extent of resection? Ann Surg Oncol. 2014;21:2136–2143. 14. Park JO, Qin LX, Prete FP, et al. Predicting outcome by growth rate of locally recurrent retroperitoneal liposarcoma: the one centimeter per month rule. Ann Surg. 2009;250:977–982. 15. Fletcher CD, Gustafson P, Rydholm A, et al. Clinicopathologic re-evaluation of 100 malignant fibrous histiocytomas: prognostic relevance of subclassification. J Clin Oncol. 2001;19:3045–3050. 16. Rosenberg SA, Tepper J, Glatstein E, et al. The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg. 1982;196:305–315. 17. Pisters PW, O’Sullivan B, Maki RG. Evidence-based recommendations for local therapy for soft tissue sarcomas. J Clin Oncol. 2007;25:1003–1008. 18. Pisters PW, Pollock RE, Lewis VO, et al. Long-term results of prospective trial of surgery alone with selective use of radiation for patients with T1 extremity and trunk soft tissue sarcomas. Ann Surg. 2007;246:675–681; discussion 681–672. 19. O’Sullivan B, Davis AM, Turcotte R, et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet. 2002;359:2235–2241. 20. Canter RJ, Martinez SR, Tamurian RM, et al. Radiographic and histologic response to neoadjuvant radiotherapy in patients with soft tissue sarcoma. Ann Surg Oncol. 2010;17: 2578–2584. 21. Mullen JT, Hornicek FJ, Harmon DC, et al. Prognostic significance of treatment-induced pathologic necrosis in extremity and truncal soft tissue sarcoma after neoadjuvant chemoradiotherapy. Cancer. 2014;120:3676–3682. 22. Mullen JT, Kobayashi W, Wang JJ, et al. Long-term followup of patients treated with neoadjuvant chemotherapy and radiotherapy for large, extremity soft tissue sarcomas. Cancer. 2012;118:3758–3765. 23. Kraybill WG, Harris J, Spiro IJ, et al. Phase II study of neoadjuvant chemotherapy and radiation therapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy Oncology Group Trial 9514. J Clin Oncol. 2006;24:619–625. 24. Baldini EH, Goldberg J, Jenner C, et al. Long-term outcomes after function-sparing surgery without radiotherapy for soft tissue sarcoma of the extremities and trunk. J Clin Oncol. 1999;17:3252–3259. 25. Heslin MJ, Woodruff J, Brennan MF. Prognostic significance of a positive microscopic margin in high-risk extremity soft tissue sarcoma: implications for management. J Clin Oncol. 1996;14:473–478. 26. Zagars GK, Ballo MT, Pisters PW, et  al. Surgical margins and reresection in the management of patients with soft tissue sarcoma using conservative surgery and radiation therapy. Cancer. 2003;97:2544–2553. 27. Grabellus F, Podleska LE, Sheu SY, et al. Neoadjuvant treatment improves capsular integrity and the width of the fibrous capsule of high-grade soft-tissue sarcomas. Eur J Surg Oncol. 2013;39:61–67.

28. Coindre JM, Terrier P, Guillou L, et  al. Predictive value of grade for metastasis development in the main histologic types of adult soft tissue sarcomas: a study of 1240 patients from the French Federation of Cancer Centers Sarcoma Group. Cancer. 2001;91:1914–1926. 29. Blackmon SH, Shah N, Roth JA, et al. Resection of pulmonary and extrapulmonary sarcomatous metastases is associated with long-term survival. Ann Thorac Surg. 2009;88:877–884; discussion 884–875. 30. Kasper B, Gruenwald V, Reichardt P, et al. Imatinib induces sustained progression arrest in RECIST progressive desmoid tumours: final results of a phase II study of the German Interdisciplinary Sarcoma Group (GISG). Eur J Cancer. 2017;76:60–67. 31. Lahat G, Dhuka AR, Hallevi H, et al. Angiosarcoma: clinical and molecular insights. Ann Surg. 2010;251:1098–1106. 32. Stoeckle E, Coindre JM, Bonvalot S, et al. Prognostic factors in retroperitoneal sarcoma: a multivariate analysis of a series of 165 patients of the French Cancer Center Federation Sarcoma Group. Cancer. 2001;92:359–368. 33. MacNeill AJ, Gronchi A, Miceli R, et al. Postoperative morbidity after radical resection of primary retroperitoneal sarcoma: a report from the Transatlantic RPS Working Group. Ann Surg. 2018;267:959–964. 34. Lewis JJ, Leung D, Woodruff JM, et al. Retroperitoneal softtissue sarcoma: analysis of 500 patients treated and followed at a single institution. Ann Surg. 1998;228:355–365. 35. Gronchi A, Miceli R, Allard MA, et  al. Personalizing the approach to retroperitoneal soft tissue sarcoma: histology-specific patterns of failure and postrelapse outcome after primary extended resection. Ann Surg Oncol. 2015;22:1447–1454. 36. Pawlik TM, Pisters PW, Mikula L, et al. Long-term results of two prospective trials of preoperative external beam radiotherapy for localized intermediate- or high-grade retroperitoneal soft tissue sarcoma. Ann Surg Oncol. 2006;13:508–517. 37. Gold JS, Gonen M, Gutierrez A, et al. Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis. Lancet Oncol. 2009;10:1045–1052. 38. Tawbi HA, Burgess M, Bolejack V, et al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol. 2017;18:1493–1501. 39. D’Angelo SP, Mahoney MR, Van Tine BA, et al. Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials. Lancet Oncol. 2018;19:416–426. 40. Rutkowski P, Bylina E, Wozniak A, et  al. Validation of the Joensuu risk criteria for primary resectable gastrointestinal stromal tumour—the impact of tumour rupture on patient outcomes. Eur J Surg Oncol. 2011;37:890–896. 41. Joensuu H, Vehtari A, Riihimaki J, et al. Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. Lancet Oncol. 2012;13:265–274. 42.  Soft tissue sarcoma. NCCN Evidence Blocks. National Comprehensive Cancer Network. 2018, Accessed December 28, 2018. https://www.nccn.org/professionals/physician_gls/ pdf/sarcoma_blocks.pdf. 43. Schuetze SM, Bolejack V, Thomas DG, et al. Association of dasatinib with progression-free survival among patients with advanced gastrointestinal stromal tumors resistant to imatinib. JAMA Oncol. 2018;4:814–820.

CHAPTER 32  Soft Tissue Sarcoma 44. Blanke CD, Demetri GD, von Mehren M, et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 2008;26:620–625. 45. Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373:1097–1104. 46. Joensuu H, Eriksson M, Sundby Hall K, et al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA. 2012;307:1265–1272. 47. Corless CL, Ballman KV, Antonescu CR, et  al. Pathologic and molecular features correlate with long-term outcome after

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adjuvant therapy of resected primary GI stromal tumor: the ACOSOG Z9001 trial. J Clin Oncol. 2014;32:1563–1570. 48. Joensuu H, Eriksson M, Hall KS, et al. Risk factors for gastrointestinal stromal tumor recurrence in patients treated with adjuvant imatinib. Cancer. 2014;120:2325–2333. 49. Raut CP, Espat NJ, Maki RG, et  al. Efficacy and tolerability of 5-year adjuvant imatinib treatment for patients with resected intermediate- or high-risk primary gastrointestinal stromal tumor: the PERSIST-5 Clinical Trial. JAMA Oncol. 2018;4:e184060. 50. Tap WD, Jones RL, Van Tine BA, et  al. Olaratumab and doxorubicin versus doxorubicin alone for treatment of softtissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet. 2016;388:488–497.

33

CHAPTER

Bone Tumors Herbert S. Schwartz, Ginger E. Holt, Jennifer L. Halpern

OUTLINE Overview Bone Microenvironment Drug Therapies Bone Macroenvironment Biopsy Staging Oncologic Resection Skeletal Reconstruction Skeletal Stabilization Utilized in Intralesional Resections Skeletal Reconstruction Utilized in Wide Resections Benign Bone Tumors

OVERVIEW Orthopedic oncology is a complex surgical discipline that involves the diagnosis, management, and surveillance of primary mesenchymal malignancies (sarcomas), benign bone and soft tissue masses, and secondary neoplasms of bone and soft tissue. The unique structural qualities of bone, along with its complex microenvironment, must be considered when formulating strategies for management of bone tumors. This chapter reviews the complex biology of the bone microenvironment as it relates to tumor progression, skeletal stability, and potential treatment options. It also presents a general approach to the diagnosis, management, and appropriate triage of primary and secondary bone tumors, both benign and malignant. Although making a diagnosis is paramount, the restoration of function in the setting of skeletal compromise/instability is also critical in the management of bone tumors. Therefore, a complex understanding of what the tumor is doing to the bone, what the bone is doing to the tumor, where the lesion is, and what the lesion is making impacts how bone tumors are managed (Table 33.1). 

BONE MICROENVIRONMENT An understanding of the bone microenvironment impacts the macroscopic management of skeletal tumors. In the absence of tumor, bone is a dynamic and symbiotic organ, actively maintained by cells that respond to stimuli such as injury, stress, or metabolic need. Osteoblasts represent a terminal differentiation of a mesenchymal stem cell. They generate a collagen matrix, which is then mineralized. When osteoblasts become surrounded by the matrix they create, they are deemed osteocytes—and serve to maintain the bony environment. Osteoclasts are multinucleated cells derived from a hematopoietic lineage (macrophages), which resorb

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Enchondroma Osteochondroma Osteoid Osteoma Giant Cell Tumor Skeletal Sarcomas Osteosarcoma Ewing Sarcoma Chondrosarcoma Bone Metastases Conclusion

bone. The constant interplay of those cells (osteoblast, osteocyte, osteoclast) is necessary to maintain bone health. The marrow space is also home to other significant cell populations, such as mesenchymal stem cells. The active and ongoing homeostasis of bone and its intramedullary inhabitants generate a microenvironment rich in growth factors and signaling molecules, making it an ideal soil for osteophilic tumors. In the setting of metastatic to bone neoplasms, intravascular tumor cells are attracted to the microenvironment of bone because it is both preconditioned for tumor cell arrival by circulating factors and because it is inherently attractive due to the proteins, signaling molecules, and cells that it contains (Fig. 33.1). That concept was first coined the “seed and soil” theory by Dr. Stephen Paget in 1889.1 For example, mesenchymal stem cells return (in part) to the bone marrow due to a signaling pathway involving the CXCL12 chemokine and the CXCR4 receptor. Intramedullary mesenchymal stem cells secrete CXCL12, and circulating stem cells that express the correlating CXCR4 receptor are recruited to the marrow space. Similarly, in the setting of metastatic breast cancer as an example, tumor cells express CXCR4 receptor and therefore can also be recruited to the marrow space via the chemokine CXCL12.2 In general, cell signaling molecules produced in the marrow space are recognized by tumor-based receptors and represent one example of how the bone microenvironment influences tumor deposition. Other players involved in homing of tumor cells to bone include, but are not limited to, exosomes/oncosomes, adhesion molecules, platelets, and circulating stem cells.3 Once in the bone microenvironment, in what is deemed the “vicious cycle,” tumor cells hijack the endogenous cells of bone to create an environment that fosters their own growth. Normally, the balance of lysis and bone formation in bone is maintained through the strategic production of signaling proteins. For

CHAPTER 33  Bone Tumors

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TABLE 33.1  Four questions asked to evaluate bone tumors. 1

2

QUESTION

ANSWER

CLINICAL SIGNIFICANCE

EXAMPLE

Where is the lesion—which bone and what part of that bone?

Which bone? (e.g., femur)

Some lesions occur most often in a specific bone.

Chondromyxoid fibroma—tibia

Where is the bone? (e.g., epiphyseal, metaphyseal, diaphyseal) Destructive

There is a specific differential for lesions that occur in specific regions of the bone.

Differential diagnosis of epiphyseal lesions is giant cell tumor, chondroblastoma, infection, and ganglion. Metastatic lung carcinoma essentially erases the cortex, destabilizing the bone.

What is the lesion doing to the bone?

No change in overall morphology 3

What is the bone doing to the lesion?

Failing to contain it Expanding and thinning

4

What is the lesion making?

Creating a sclerotic border around the lesion Matrix-cartilage, bone, fibrous tissue

If a lesion essentially erases the bone, it implies that the lesion is aggressive and therefore likely to be malignant. If the lesion does not deform, distort, or destroy the bone, it suggests that the lesion is benign. If the bone cannot respond to the assault of a tumor, the tumor is aggressive. If the lesion is growing but the bone is trying to contain it, the bone may appear expanded and thinned. It may fall into the benign aggressive differential. When the bone forms a sclerotic rim around a lesion, the lesion is typically benign. The matrix a tumor produces is part of its inherent classification.

An enchondroma is an eccentric cartilage deposit within the intramedullary canal. If covered up, the bone would look normal. Osteosarcoma breaks out of the bone and elevates periosteum. Aneurysmal bone cysts, giant cell tumors

Nonossifying fibroma, intraosseous ganglion Bone forming—osteoid osteoma, osteoblastoma, osteosarcoma

example, receptor activator of nuclear factor-κB ligand (RANKL) is generated by osteoblasts, and recognized by its osteoclast receptor (RANK). When bound, RANKL stimulates osteoclastogenesis.4 Osteoprotegerin is a decoy receptor secreted by osteoblasts, which inhibits RANKL binding and therefore inhibits osteoclastogenesis.5 Tumor cells can disturb bone homeostasis in a variety of ways. Tumor cells can directly stimulate osteoblasts to generate RANKL, which is the most prominent cytokine inducer of osteoclastogenesis.6,7 Alternatively, tumor-secreted matrix metalloproteinase-7 can cleave extracellular matrix where bound and inactive RANKL resides, thereby releasing the active form of RANKL.8 Once overactive osteoclastogenesis is initiated, tumor growth is fueled by this aggressive bone degradation, which frees an abundance of growth factors that can drive tumor proliferation. This chapter is not intended to cover all aspects of the microenvironment tumor-native bone interplay. However, an appreciation of those complex relationships is important. Medical therapies can target not only tumor cells (the seed) but also the soil—essentially preventing tumor growth by making the environment less favorable. In patients with bone metastases, and even in the setting of benign but locally aggressive lytic/osteoclast filled tumors, systemic medications designed to limit osteoclast function are now utilized. The goal of those medicines is to reduce the number of skeletally related events (SREs), which include hypercalcemia of malignancy, bone pain, pathologic fracture, spinal cord compression, or the need for palliative radiation.

small guanosine triphosphatases that are essential for the boneresorbing activity and survival of osteoclasts. Bisphosphonates are only taken up by active osteoclasts. Zoledronic acid (Zometa) is commonly used for oncology patients as a means of preventing SREs.10 Denosumab (Xgeva) is a monoclonal antibody generated against RANKL. This drug mimics the natural action of osteoprotegerin, which prevents RANKL binding to RANK, thereby preventing osteoclast maturation. However, it does not also block the tumor necrosis factor-related apoptosis-inducing ligand, which is the principal mediator of tumor cell death by the human host cells.11 Denosumab inhibits osteoclast recruitment, maturation, and function and ultimately induces apoptosis of activated osteoclasts and therefore stops bone resorption.12 Examination of denosumab-treated bone shows an absence of osteoclasts.13 Denosumab has been compared to zoledronic acid through a randomized double blind trial in men with metastatic prostate cancer and shown to be more effective in preventing SREs than zoledronic acid.14 Denosumab was also found to be superior to zoledronic acid in delaying time to SRE in patients with metastatic breast cancer.15 Although the aforementioned studies suggest that denosumab is superior to zoledronic acid in treatment of metastatic bone lesions in the case of breast and prostate cancer, denosumab is not universally used at this time for treatment of bone metastases. That fact likely relates to economic and availability issues, as well as the need for studies to assess longer term follow and ideal dosing protocols.13 

Drug Therapies

BONE MACROENVIRONMENT

Bisphosphonates are a class of drugs that inhibits bone resorption and can decrease the number of SREs.9 Nitrogen-containing bisphosphonates bind to and inhibit key enzymes of the intracellular mevalonate pathway, thereby preventing the prenylation and activation of

Primary tumors of bone, both benign and malignant, tend to form in specific geographic regions of bone (Fig. 33.2). The primary differential diagnosis of epiphyseal tumors includes giant cell tumor, chondroblastoma, infection, or intraosseous ganglion. Clear

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SECTION V  Surgical Oncology

Premetastatic niche conditioning

“Homing” of circulating tumor cells to the bone microenvironment

Exosome + HPC Osteoprotegerin

Cancer met

MSC

Osteoblast

Mets stimulate osteoblasts to release RANKL

Denosumab

RANKL

Osteoclast differentiation

RANKL receptor

Osteoclast activation Osteoclast

Bisphosphonate

FIG. 33.1  Circulating metastatic cancer cells find the bone microenvironment through a complex series of steps. Prior to their arrival, circulating factors optimize the bone (premetastatic niche conditioning). Cells are then recruited to the bone by signaling molecules called chemokines (homing). Once in the bone, tumor cells hijack normal bone metabolism (the vicious cycle). Medical therapies used in the treatment of metastatic bone cancers exploit the understanding of the vicious cycle. Denosumab is a human monoclonal antibody that binds the receptor activator of nuclear factor-κB ligand (RANKL) and directly inhibits osteoclastogenesis. Zoledronic acid is a bisphosphonate that is taken up by and then inhibits activated osteoclasts. (Adapted from Cook LM, Shay G, Araujo A, et al. Integrating new discoveries into the “vicious cycle” paradigm of prostate to bone metastases. Cancer Metastasis Rev. 2014;33:511–525.) HPC, Hematopoietic progenitor cell; MSC, mesenchymal stem cell.

cell chondrosarcoma is a less common epiphyseal lesion. Common diaphyseal lesions include adamantinoma, Ewing sarcoma, infection, osteoid osteoma/osteoblastoma, and fibrous dysplasia. Osteosarcoma most commonly forms in metaphyseal bone of the distal femur, proximal tibia, and proximal humerus. Metastatic bone disease can occur in all regions of the bone, although certain sites are considered more typical for specific cancers. Acral

metastases and intracortical metastases are typically lung carcinomas. The common locations of tumors and the structural integrity and demands of the bone in those locations are important facts to consider when formulating plans for biopsy and reconstruction. For example, biopsy of an intraosseous, diaphyseal femoral lesion through a transcortical approach, even with a large bore needle (core biopsy), can increase the risk of fracture at the site of

CHAPTER 33  Bone Tumors

Epiphysis

Metaphysis

Diaphysis

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Giant cell tumor Chondroblastoma Infection Intraosseous ganglion Metastatic disease

Osteosarcoma Metastatic disease

Adamantinoma Ewing sarcoma Infection Osteoid osteoma Fibrous dysplasia

Metaphysis Epiphysis

Fracture after diaphyseal core biopsy

High stress regions of femur Biopsy through greater trochanter start point

FIG. 33.2  The location of tumors helps to narrow the differential diagnosis. Biopsy in certain locations can increase the risk of fracture in long bones. Pictured is an example of a fracture created in the diaphyseal femur following a core-biopsy needle. Biopsy through the greater trochanter, an intramedullary nail starting point, is a biomechanically safer option.

biopsy (Fig. 33.2). An alternative, depending upon the proximity of the lesion to the greater trochanter, is to perform an intramedullary biopsy through a greater trochanteric starting point, using pituitary rongeurs to grab intramedullary bone at a predetermined location (Fig. 33.2). That biopsy entrance site does not destabilize the bone, and it still can be resected as part of a wide tumor resection if needed. Alternatively, lesions at the metaphyseal flare can often be biopsied directly, because the biomechanical stress in that area places it at much lower risk for fracture, even if a small bone window is created to obtain tissue. The relevance of tumor location is reflected in Mirels’ criteria, which allow for a more objective assessment of pathologic fracture risk in patients with bone tumors (Table 33.2). In that system, a numeric score is assigned to observed metastatic lesions in bone.16 Lesions are categorized by location, size, and nature (lytic vs. blastic). Based on a total score, recommendations can be made for operative prophylaxis. This classification/scoring system is designed to assist with decision making but in no way replaces clinical judgments made in consideration of each patient. However, it does capture the fact that lesions in high-stress, weight-bearing areas of the skeleton, such as the trochanteric femur, are at highest risk of fracture. 

BIOPSY Biopsy is a complex cognitive skill in the skeleton for two primary reasons. First, as previously mentioned, one must be aware of what approaches might further destabilize the bone in question. Second, one must place the biopsy tract in a location that accommodates future wide resection. Specifically, if a diagnosis of primary

malignancy is rendered, a wide resection must include the biopsy tract, which harbors malignant cells. If a significant hematoma forms after bone biopsy, then larger resection may be needed to obtain adequate margins (Fig. 33.3). There are different modalities of bone biopsy. Fine-needle aspirate is rarely used unless there is a significant extraosseous soft tissue component that is accessible or significant bony lysis. Core biopsy, often performed with computed tomography (CT) scan guidance, can be performed through intact cortices (with adjunct use of a combined biopsy/drill system) or through areas of soft tissue extension. Incisional biopsy is a surgical procedure during which a carefully planned small incision is made in line with the tumor, with respect to neurovascular structures and bone biomechanics. Open biopsy allows for acquisition of the most tissue as compared to other techniques. If the cortex is intact, a high-speed burr is often used to create a less than dime-sized window into the bone. Meticulous hemostasis must be obtained to prevent contamination of surrounding tissues. Often, Surgicel and Gelfoam are packed into defects created in the soft tissue extraosseous component of the tumor, and then the tumor capsule and superficial layers are closed meticulously. If the cortex has been violated, often bone wax or a small plug of bone cement is used to prevent intramedullary extravasation of blood and tumor into the biopsy tract. Inappropriately placed biopsy tracts can change the nature of surgery required—even changing a potential limb salvage candidate into a patient requiring an amputation. Biopsy placement and execution are critical. It has been conclusively shown in several studies that surgeons inexperienced in musculoskeletal oncology principles have a three to four times increased rate of complication from a poorly placed biopsy site.17–19

758

SECTION V  Surgical Oncology

TABLE 33.2  Mirels scoring system. SCORE

SITE OF LESION

1

Upper limb

2

Lower limb

3

Trochanteric

SIZE OF LESION >

1

1

3

>

2

3 2

cortex cortex 3

cortex 3

LESION TYPE

PAIN

Blastic

Mild

Mixed

Moderate

Lytic

Functional

The Mirels scoring system allows assessment of fracture risk. There are four factors (site, size, lesion type, pain) that are assigned a numeric score of 1 to 3. The four scores are added together. If the overall score is more than 9, prophylactic fixation is indicated. A score of less than 7 can often be treated with radiation and medical therapies. Despite the utility of the scoring system, clinical judgment must always be taken into consideration regarding a specific patient.16

A1

A2

B FIG. 33.3  When planning a biopsy location, one must consider that the biopsy tract will be contaminated and, in the case of malignant tumors, will require resection. In panel A1, a computed tomography–guided biopsy tract into the vertebral body is demonstrated by the arrow. In panel A2, the arrows indicate the extent of biopsy tract recurrence. Panel B is an excellent example of an inappropriate biopsy, which mandated an otherwise unnecessary amputation in the patient. Biopsies must be performed in line with the incision that will eventually be required to resect a tumor. The entire biopsy tract must be resected. Therefore, a biopsy incision is typically small and strategically placed.

The biopsy result is the most important factor driving a patient’s care. The tissue obtained allows one to render a diagnosis and build a treatment pathway. As such, when a biopsy is performed, it is critical that the surgeon has a basic understanding

of how to make a correct diagnosis. Surgical pathology tissue review includes histologic evaluation and immunohistochemistry. The challenge in sarcoma care has previously been interobserver reliability with regard to diagnosis. The molecular pathology of

759

CHAPTER 33  Bone Tumors bone tumors—identification of genetic signatures that correlate to skeletal neoplasia—allows for consistency in diagnoses and is emerging as a powerful tool in the care of bone tumor patients. Table 33.3 documents the pathognomonic mutations associated with various bone tumors.20 

STAGING A critical part of biopsy planning includes a global understanding of the nature of a tumor—whether it is localized or part of a more systemic process. Patient history and physical examination are vital parts of evaluation. Physical examination must include chaperoned breast examination or prostate examination in patients who potentially may have a metastatic to bone process. A series of radiologic studies are then performed to characterize the scope of the disease process. When a patient presents with an isolated bone lesion that may represent a malignancy, especially without antecedent history of cancer, the following studies or labs are typically obtained: 1. Magnetic resonance imaging (MRI) of the entire affected bone with contrast—identifies a soft tissue component of the tumor that, if present, may be easier to sample and also helps to identify skip metastases. 2. CT scan of the chest, abdomen, and pelvis with and without intravenous and oral contrast—screens for common osteophilic carcinomas including breast, lung, renal, thyroid, and prostate and also helps to establish whether solid organ metastases are present. 3.  CT with two-dimensional reconstructions of the affected bone—allows a better three-dimensional understanding of how the tumor has affected the bone. 4. Whole body bone scan—identifies other possible osseous sites/ metastases. 5. Plain radiographs of the affected bone—show where in the bone the tumor is located (epiphyseal, metaphyseal, diaphyseal), show what the tumor is doing to the bone (lytic, blastic), show what the bone is doing to the tumor (containment vs. failure to contain) and show the matrix of the lesion (bone, cartilage, fibrous, etc.) (Table 33.1). 6.  Laboratory evaluation to include prostate-specific antigen, serum electrophoresis, calcium to rule out hypercalcemia of malignancy, lactate dehydrogenase, alkaline phosphatase,

complete blood count with differential, comprehensive metabolic panel, sedimentation rate, and C-reactive. There are two primary staging systems used to describe skeletal sarcoma. In the Musculoskeletal Tumor Society Staging System, or Enneking system,21 Stage I refers to a low-grade skeletal sarcoma, Stage II refers to a high-grade skeletal sarcoma, and Stage III represents metastatic disease, either regional or distant. The letter A refers to intracompartmental tumor localization, whereas the letter B refers to extracompartmental extension. An example of extracompartmental extension would include an osteosarcoma with extraosseous soft tissue mass or a pathologic fracture through an osteosarcoma, resulting in hematoma contamination. The American Joint Committee on Cancer staging system has been updated.22 Tumors are described by grade (I, low; II, high; III, tumor of any grade with skip metastasis; IV, tumor of any grade with distant metastasis) and size (8 cm, B). Staging systems in general are designed to reflect prognosis and therefore guide treatment algorithms. Enneking also developed a staging system for benign bone tumors.23 In the Enneking system, tumors are characterized as latent (1), active (2), or aggressive (3). Aggressive benign tumors often have a higher risk of local recurrence. Although aggressive benign tumors still can be technically resected in an intralesional fashion, resection must be meticulous, often utilizing high-speed burrs and other adjuvants. The most important factor in preventing recurrence is likely to be adequacy of resection.24 

ONCOLOGIC RESECTION There are four types of surgical resection: (1) intralesional, (2) marginal, (3) wide, and (4) radical. The type of margin reflects the surgical dissection plane relative to the tumor or capsule of the tumor. Intralesional resections involve an incision made into the substance of tumor. Intralesional resections in bone are typically exemplified by curettage or debulking. They are used in the setting of benign bone tumors and metastatic to bone tumors. Marginal resections theoretically involve resection of the tumor around its capsule and by definition leave microscopic disease behind. Wide resections involve resection of the tumor with a surrounding rim of normal tissue, designed to remove the entirety of a tumor. Radical resections include not only the tumor and a rim of normal tissue but also the entirety of the compartment in which the tumor

TABLE 33.3  Skeletal neoplasia DNA alterations. TUMOR Osteosarcoma Ewing sarcoma Chondrosarcoma Osteochondroma Enchondroma Aneurysmal bone cyst Fibrous dysplasia Giant cell tumor

SUPPRESSOR GENE ONCOGENE RB, p53 INK4A, INK2A KCMF1

CDK4, FOS, cMYC MDM2, MET CD99

TRANSLOCATIONS

CHROMOSOME LOSS

CHROMOSOME GAIN

6q, 13q, 15q, 17p, 18q

1q, 5p, 6p, 7q, 8q, 12q, 17p, 19q

1p, 5q, 6p, 9p, 14q, 22q

7p, 12q, 21q

PROTEIN CHANGE

t(11;22)(q24;q12) EWS-FLI1 t(21;22)(q22;q12) EWS-ERG

IDH1, IDH2 EXT1, EXT2

12q

IHH-PTHrP

20q

GS RANKL Histone

t(16;17)(q22;p13) CDH11-USP6 GNAS1 TPX2 H3F3

Telomeric fusions

20q 1q

Gs, Mutation in alpha-subunit of the Gs stimulatory protein leading to activation and inappropriate cyclic adenosine monophosphate production (cAMP); IHH-PTHrP, Indian hedge-hog-PTH-related protein; RANKL, receptor activator of nuclear factor-κB ligand.

760

SECTION V  Surgical Oncology

resides. Wide resections are more commonly utilized in the treatment of skeletal sarcomas, as opposed to radical resections. 

disease with palliation as a goal, the reconstruction strategy selected should impart immediate stability and immediate full weightbearing potential whenever possible. 

SKELETAL RECONSTRUCTION

Skeletal Reconstruction Utilized in Wide Resections

The type of reconstruction needed often depends upon the type of resection that is indicated. It also depends greatly on the reparative potential of the bone. For example, children can regenerate bone at a higher rate than adults, and therefore in the setting of benign tumors like aneurysmal bone cyst, bone graft might be utilized in a child, whereas in an adult bone, cement might be used. Another important factor is the posttreatment impact of a tumor on bone. For example, a lytic lesion caused by multiple myeloma has a better chance of healing following medical therapies that a lytic lesion caused by lung cancer. The potential for bone regeneration at the site of tumor relates in many ways to the stromal content of the tumor. Lymphoma of bone is predominantly cellular, whereas lung carcinoma in bone has a significant stromal component. The footprint of the tumor cannot be erased in stromal-heavy tumors.

In the case of wide resection (skeletal sarcomas), large segments of bone are resected (Fig. 33.5B and C). In those cases, reconstruction often involves the use of intercalary allografts or metal components, osteoarticular allografts, allograft-prosthetic composites, arthroplasty utilizing megaprosthesis, or arthrodesis. Autologous vascularized free tissue transfer, such as vascularized free fibulas, can also be an option. Amputation is also always an alternative in select cases.

Skeletal Stabilization Utilized in Intralesional Resections Skeletal stabilization/reconstruction comes in many forms. Plates and screws that span defects can be used following curettage of lesions. Bone strength can be augmented through the insertion of polymethylmethacrylate (bone cement) into skeletal defects along with plates and screws (rebar) (Fig. 33.4). Intramedullary nail fixation is a common strategy for prophylaxis of diaphyseal lesions, especially in the femur (Fig. 33.5). In the setting of metastatic

Allograft When a patient is identified who will require a large bulk allograft, templated x-rays of the bone needed (or the contralateral bone if there is too much deformity) are obtained. Approved tissue banks harvest materials with meticulous sterility, and then can assess whether any in-stock cadaveric allografts match the bone being requested.25 Allografts can be harvested with soft tissue attachments, and in that case, the host tendons can be sewn into the allograft attachment sites. Allografts can be fortified with cement augmentation, if possible, and then secured to the native bone utilizing plates and screws (Fig. 33.6). Allografts are obviously nonviable scaffolds, and therefore, ultimate healing at the native bone-allograft interface depends upon the native bone use of the allograft as a scaffold through which new bridging bone is formed. Intercalary allografts are essentially bony place holders

A

B

C

D

FIG. 33.4  The patient had a prior right proximal femur metastatic lesion treated with proximal femur resection and megaprosthesis. She then developed a large, lytic, painful left iliac wing lesion, which required intralesional resection and reconstruction utilizing cement and 7.3 mm cannulated screws. (A) Anteroposterior pelvis x-ray shows the lytic defect (arrow). (B) Computed tomography scan two-dimensional coronal reconstruction view shows not only the bony defect, but also the associated soft tissue mass (arrow and dotted line). (C) Intraoperative view of the bony defect (arrows). (D) Postoperative anteroposterior pelvis.

CHAPTER 33  Bone Tumors

A

B

761

C

FIG. 33.5  This patient had intramedullary nail stabilization and palliative radiation of the left femur for treatment of a peritrochanteric metastatic renal cell carcinoma lesion. (A) Despite appropriate attempt at stabilization and adjuvant therapies, she had persistent pain. A left proximal femoral resection and proximal femur megaprosthesis was performed. (B) Gross specimen revealed persistent lysis of the bone (arrows). (C) A long-cemented stem proximal femur endoprosthesis was used for reconstruction.

and can often be secured in situ through the use of intramedullary stabilization. Osteoarticular allografts include implantation of a new joint surface. In weight-bearing joints, osteoarticular allograft fracture and collapse over time are common. However, especially in the growing child, they allow for delay of arthroplasty and generation of additional bone stock. The means of reconstruction is often dictated by the weightbearing demands of the bone in question. For example, an osteoarticular allograft is a good option for the proximal humerus—a technically non–weight-bearing limb. An allograft with soft tissue attachments allows the rotator cuff tendons to be sewn to the implant, thereby potentiating some overhead mobility. An osteoarticular allograft in the distal femur may be more problematic because of weight-bearing demands. Therefore, arthroplasty may be preferred.  Arthroplasty Arthroplasty is a common reconstruction strategy utilized following tumor resections that include portions of a joint (Fig. 33.7) The socalled megaprosthesis is named such because large modular metal implants are combined to restore length to the limb and replace large bone defects. Those metal replacements are either potted into the bone using bone cement or press fit into the long bone canal. Bone cement offers immediate stability, but increased chance of aseptic loosening over time.26 Press fit stems require ingrowth or ongrowth of host bone over time around the stem periphery. In the case of the proximal humerus and proximal femur, no additional resurfacing of the acetabulum or glenoid is typically done. For distal

femur or proximal tibia tumors, the tumor-unaffected side of the joint requires resurfacing to accommodate a hinge mechanism.  Amputation Amputation is indicated in the setting of primary tumors when an adequate margin cannot be obtained through the use of limb salvage or when the functional result achieved through limb salvage is worse than that achieved by amputation. Amputation may be indicated in the setting of metastatic or advanced cancers for the purposes of palliation. 

BENIGN BONE TUMORS The incidence of benign bone tumors far exceeds that of skeletal sarcomas. In these authors’ clinical experience, there are at least five benign bone tumors for every primary malignant bone neoplasm. Fifty-four percent of benign bone tumors are chondrogenic (enchondroma or osteochondroma).27 The true prevalence of these tumors is unknown because many go undetected and unreported. Aggressive benign bone tumors, such as giant cell tumor and aneurysmal bone cysts, have a local recurrence rate as high as 30% and require meticulous intralesional resection utilizing highspeed burr resection and other adjuvants.28

Enchondroma Enchondromas are benign proliferations of hyaline cartilage typically found in the appendicular skeleton, less likely detected in the

762

SECTION V  Surgical Oncology

C

Proximal

Whole graft

L: Length from the greater trochanter to the distal end W: Width of the condyle measured medial to lateral D: Diameter of the femoral head measured at the widest part W': Width of the shaft at mid shaft measured anterior to posterior A: Width of the shaft at mid shaft measured medial to lateral D': Diameter of the medullary canal at cut end

*

A

B

D

E

F

FIG. 33.6  Allograft reconstruction can be used in osteoarticular, intercalary, or allograft-prosthetic composite reconstructions. An 11 year old with an extensive left femoral diaphyseal osteosarcoma with multiple skip metastases. (A) Anteroposterior femur x-ray demonstrates periosteal reaction (yellow arrows). Anticipated resection is denoted with red lines. (B) Magnetic resonance imaging (MRI) shows the extent of tumor, which does not extend distal to the physis. Proximal extent of tumor extends to the inferior aspect of lesser trochanter. MRI allows planning of intercalary femoral resection. (C) Allograft matched. (D) Biopsy tract. (E) Resection performed with negative margins and includes the medial biopsy tract (*). (F) Anteroposterior femur x-ray postresection. Red arrows indicate allograft–native bone interfaces.

axial skeleton, which are centered in the metaphysis. They typically are incidental findings discovered during radiographic evaluations for other symptoms, except in the phalanges, where they can cause pathologic fracture (Fig. 33.8A). Enchondromas represent lobular cartilage islands, which retain chondroid features and continue to grow until skeletal maturity, at which time they begin to undergo calcification. Their long-term physiologic activity is the reason that they remain scintigraphically active decades later on a bone scan. Isolated lesions do not cause progressive deformity of the bone. Malignant transformation is rare. However, in patients with multiple enchondromas, such as Ollier disease or Maffucci syndrome (Ollier with subcutaneous hemangiomas), the risk of progressive bone deformity is higher, as is the risk of malignant transformation into a secondary chondrosarcoma. Interestingly, individuals with Maffucci syndrome also have a higher risk of developing occult carcinomas.29 Treatment of enchondromas remains conservative, and serial radiographic evaluation is the primary means of punctuated surveillance. Surgical intervention is only required if there is a question of malignant transformation. In that setting, albeit rare, the entire lesion is often curetted and submitted to surgical pathology. Cartilage lesions have areas of heterogeneity, therefore, in the case of malignant transformation, often only a small portion of the lesion appears malignant. The histopathologic interpretation of cartilage lesions depends on radiographic information and clinical information. For example, an enchondroma biopsied from the finger will look hypercellular but, because of its location, will be called an enchondroma. The same material, however, if biopsied from the pelvis, would be called a higher-grade chondrosarcoma. Clinical context is vital for proper evaluation of cartilage lesions (Fig. 33.8). If there is a question surrounding the diagnosis of

enchondroma and open biopsy is performed, the biopsy entrance site, along with the lesion, is often packed with bone cement and the bone is stabilized with a plate and screws. Bone grafting of the resected lesion is also an option. If lesions are called chondrosarcoma, then, depending on the grade of the tumor, further resection or wide resection may be indicated. 

Osteochondroma Although discussed as a benign bone tumor, an osteochondroma is better described as a hamartoma of bone. It develops from aberrant growth cartilage and radiographically is a “cartilage capped bony projection on the external surface of the bone” according to the World Health Organization (Fig. 33.9). It is typically detected in the second decade of life. It presents as a painless mass, or a mass associated with pain due to mechanical symptoms. There are two distinct radiographic types of osteochondroma—pedunculated and sessile. On three-dimensional imaging analysis, the intramedullary component of an osteochondroma should be confluent with the intramedullary canal of the affected bone. The lesion itself is capped by cartilage, and therefore, the lesion grows through skeletal development and stops growing at skeletal maturity. If a lesion continues to grow after skeletal maturity, or if radiographically a cartilage cap exceeds 2 cm in thickness after skeletal maturity, then there is concern for potential malignant transformation. The majority of osteochondromas are solitary, and in those cases, the chance of malignant transformation is less than 1%. However, osteochondromas can develop in a polyostotic fashion—as in hereditary multiple osteochondral exostosis or osteochondromatosis. Hereditary multiple osteochondral exostosis is an autosomal dominant condition. Three separate loci are implicated in its development: 1) EXT1 (8q24.1), 2) EXT2

CHAPTER 33  Bone Tumors

A

B

C

763

D

* E

G

F

FIG. 33.7  Endoprostheses are used to reconstruct periarticular malignant tumors. (A) Lateral x-ray distal femur shows aggressive bone tumor with large soft tissue extension. (B) Magnetic resonance imaging (MRI) T2 sagittal shows true extent of bone involvement and soft tissue mass. (C) Anteroposterior distal femur x-ray demonstrates osteoblastic matrix. (D) MRI T2 coronal shows planned biopsy trajectory—lateral to access soft tissue mass (arrow). (E) Resection specimen with biopsy tract (*). (F) Histology analysis shows malignant cells with lace-like osteoid matrix. (G) Right distal femur endoprosthesis utilizing press-fit fixation into the femoral canal.

(11p11-12), and 3) EXT3 (19p).30,31 Affected children present with mass lesions and skeletal growth anomalies, including short stature, limb length discrepancies, angular deformity of knees and ankles, radial bowing and wrist deviation, and subluxation of the radiocapitellar joint.32 The risk over time of malignant transformation of an osteochondroma in this scenario ranges from 10% to 30%. Osteochondromas that transform are called secondary chondrosarcomas. 

Osteoid Osteoma Osteoid osteoma is a benign osteoblastic tumor (Fig. 33.10). Although self-limited, the symptoms generated by this less than 1 cm in diameter lesion can be debilitating. Osteoid osteomas typically occur in the diaphysis of long bones, but can occur anywhere, such as the posterior elements of the spine. Osteoblastomas are essentially giant osteoid osteomas that occur primarily in the spine. Both conditions can lead to scoliosis if in the spine—related to pain and muscle spasm or joint pain and sympathetic effusion if in the proximity of a joint. Radiographically, these lesions show a radiolucent nidus, surrounded by an area of thickened cortical bone and sclerosis. On MRI, there is often extensive edema surrounding the lesions. The patient’s history elicited is classic, in that pain is worse at night and relieved with nonsteroidal anti inflammatory drugs. Although these self-limited lesions can be managed for a period of years with nonsteroidal anti inflammatory drug therapy, watchful waiting, given the profound associated symptoms, is unacceptable

to most patients. Osteoid osteoma can be treated with radiofrequency ablation using CT-guided percutaneous techniques. In that scenario, a lesion can be localized in three dimensions, biopsied to obtain definitive tissue for diagnosis, and then ablated using high-frequency radio waves that essentially heat the surrounding tissue around the probe. In areas not amenable to radiofrequency ablation, such as those that are too subcutaneous or near vital structures like the spinal cord, surgical resection of the lesion including the nidus is still performed. 

Giant Cell Tumor Giant cell tumor, which represents approximately 20% of benign bone tumors, is the most aggressive benign bone tumor (Fig. 33.11). Giant cell tumor occurs in the epiphyseal portion of a long bone or flat bones like the pelvis or sacrum in individuals between 20 and 40 years of age. Patients present with pain, which usually results from periarticular subchondral pathologic fractures. Along with eventual biopsy to rule out malignancy, preoperative evaluation also includes chest imaging and local site imaging. Surgical management requires exposure of the affected bone and creation of a large bony window allowing access to the entirety of the tumor cavity. Local recurrence rates after treatment of giant cell tumor in a bone can be as high as 40%, and, therefore, resection must be meticulous and often includes the use of adjuvants. Following gross resection through the use of curettage, a high-speed burr is used to resect tumor from characteristic bony pits. Additional adjuvants, such as polymethyl

764

SECTION V  Surgical Oncology

A

C1

B

C2

190

D1

D2

FIG. 33.8  The differential diagnosis of cartilage lesions depends upon clinical and radiographic information. (A) Middle phalanx expansile lesion with internal calcification presenting as pathologic fracture is a typical presentation for enchondroma. (B) Although the more distal a cartilage lesion is, the less likely it is malignant, another patient presented with an aggressive proximal phalanx lesion, marked by pain, periosteal reaction, and internal calcification, and she was diagnosed with chondrosarcoma. (C) Patient has a proximal humerus cartilage lesion with expected calcification on anteroposterior proximal humerus x-ray without destruction of surrounding cortex (C1). The lesion is lobular in nature as apparent on MRI (C2). The patient is being followed radiographically. (D) In comparison, another patient had an aggressive appearing lesion in the left proximal femur, causing bony distortion (D1), which on MRI was associated with surrounding bone edema (D2). The patient was diagnosed with a high-grade chondrosarcoma and treated with proximal femoral resection, megaprosthesis.

methacrylate bone cement, liquid nitrogen, phenol, or argon beam laser, are then used to try to decrease recurrence rates.28 Finally, periarticular stabilization is performed, typically with a combination of cement and hardware. Bone grafting in those cases is often inadequate to restore stability. Periarticular cement offers immediate stability but may be associated with thermal damage to articular cartilage.33 Giant cell tumors in the spine, sacrum, and pelvis present greater surgical challenges. Oftentimes, preoperative embolization is required because intraoperative tumor hemorrhage can be significant if the tumor has an aneurysmal bone cyst component. Despite its benign description, there are instances of giant cell tumor lung metastases, which occur in approximately 1% to 2% of cases.34 In those cases, the metastatic focus in the lung

does not histopathologically meet the criterion for malignancy and is identical in appearance to the benign bone tumor in the skeleton. Survival rates are approximately 80% with aggressive treatment. Patients require long-term follow-up because recurrences may develop several years postoperatively. Medical therapies, such as bisphosphonates and human monoclonal RANKL antibodies (denosumab), can be useful in refractory giant cell tumor as well.35,36 Those medicines target the role of osteoclasts in tumor development and decrease osteoclast function. However, their efficacy is not complete, as denosumab does not affect neoplastic stromal cell proliferation.37 Radiation treatment may have a role in primary giant cell tumors of the axial skeleton or in recurrent refractory giant cell tumors in a long bone. There is strong evidence, however, that irradiation of giant cell tumors

CHAPTER 33  Bone Tumors

765

*

FIG. 33.9  Osteochondromas are considered more a growth aberrancy than a tumor. Typical features in a skeletally mature individual are small cartilage cap less than 2 cm (arrow) and intramedullary canal of lesion confluent with intramedullary canal of the affected bone (*).

increases the chance for malignant transformation to a frank giant cell sarcoma decades later.38 

SKELETAL SARCOMAS The American Cancer Society estimates that 3500 new cases of primary bone cancers will be diagnosed in 2019.39 In adults, 40% of primary bone cancers are chondrosarcomas, 28% are osteosarcomas, 10% are chordomas, 8% are Ewing sarcomas, and 4% are skeletal sarcomas of bone not otherwise specified. In children, osteosarcoma is the most common primary bone tumor (56%), followed by Ewing sarcoma (28%) and chondrosarcoma (6%). The incidence of skeletal sarcomas is approximately equal in the pediatric and adult populations. The modern-day algorithm for treatment of bone sarcomas, which includes neoadjuvant chemotherapy, wide surgical resection, and adjuvant chemotherapy, was a serendipitous discovery in the 1970s.40 During that time, intensive chemotherapy was administered to many teenagers with nonmetastatic osteosarcoma of the extremities after biopsy, while they awaited fabrication of a custom endoprosthesis. After several months, the tumor was surgically removed and the implant inserted to preserve the limb. The resected bone was then examined histopathologically for evidence of chemotherapy effect. A survival benefit was noted in children who had received chemotherapy. That observation evolved into the modern day treatment algorithm for skeletal sarcoma, which includes neoadjuvant chemotherapy, wide surgical resection, and subsequent adjuvant chemotherapy. Wide surgical resections are mandated for skeletal sarcomas. The surgical goal is a local recurrence rate of less than 7%. Early studies by Simon et al.41 and Link et al.42 documented equivalent local recurrence and survival rates between limb salvage and amputation for distal femoral osteosarcoma. Cure rates are approximately 67% for extremity sarcomas, whereas axial tumors in the pelvis or spine have a worse prognosis (33%) for a similar tissue type.43,44

It has been demonstrated that limb salvage is more costeffective over a period of decades than immediate amputation in the teenage population.45 Implant survival is complicated in the short-term by infection (allografts) and in the long-term by aseptic loosening (metal).46 Ten-year implant survival rates for metallic prostheses range from 50% to 80% in the proximal tibia, distal femur, and proximal femur, respectively.47 Wound healing, especially while administering chemotherapy, is enhanced with healthy local flaps. Rotational flaps are often used around the knee to improve prosthetic coverage. For example, in proximal tibia resections, a medial gastrocnemius flap is needed to cover the prosthesis and to reconstruct the extensor mechanism.

Osteosarcoma Osteosarcoma, or osteogenic sarcoma, is defined as a malignant tumor that produces neoplastic osteoid. Neoplastic cartilage or fibrous tissue may be present. There are many types of osteosarcoma and they vary by location (intraosseous, surface, or extraskeletal), grade, or etiology. Spontaneous osteosarcomas are most common, but some osteosarcomas occur in the genetic syndromes of Li-Fraumeni, hereditary retinoblastoma, and in postradiation scenarios. There is a bimodal age of tumor occurrence. Conventional osteosarcomas occur in the first two decades of life, whereas posttreatment or secondary (malignant transformation) osteosarcomas occur much later. Survival is best predicted by the degree of chemotherapy-induced necrosis.48 Nonmetastatic extremity osteosarcoma with greater than 90% chemotherapy-induced necrosis has survival rates of 80% at 5 years. Pelvic osteosarcoma with less than 90% chemotherapy-induced necrosis has a survival rate of approximately 30%.43,44 

Ewing Sarcoma Ewing sarcoma and primitive neuroectodermal tumor are small blue cell (microscopic appearance) malignancies of bone that cytogenetically represent the same entity. They share a common

766

SECTION V  Surgical Oncology

B

D

A

C FIG. 33.10  Osteoid osteomas are benign bone-forming lesions, which, despite their small size, can cause significant pain. (A) Anteroposterior tibia x-ray shows new bone formation and cortical thickening (arrow). (B) Axial computed tomography scan shows thickened cortex with a central nidus (arrow). (C) In appropriate lesions, computed tomography–guided biopsy for diagnosis can be followed by radiofrequency ablation for definitive treatment. (D) An excised osteoid osteoma with a cherry red nidus and surrounding bone.

translocation, t(11;22)(q24;q12), in 85% of cases. Molecular cloning of the translocation reveals fusion between the 5′ end of the EWS gene from the 22q12 chromosome and the 3′ end of the 11q24 FLI1 gene.49 This tumor is exquisitely sensitive to chemotherapy and radiation treatment. Neither modality alone or in combination is sufficient to maximize the cure rate, however. Surgical extirpation in conjunction with chemotherapy is the preferred treatment. Reconstruction options follow those of other skeletal sarcomas. 

Chondrosarcoma Chondrosarcoma is a malignant skeletal neoplasm that produces hyaline cartilage (Fig. 33.8D1 and D2). Several pathologic subtypes exist in which the neoplastic cells produce unusual matrices. Histopathology alone does not predict biologic behavior. Rather, a combination of histopathology, age, location, and radiographic appearance yields the best predictor of tumor aggressiveness. A low-grade cartilage tumor of the phalanx may have the same microscopic appearance as a pelvic chondrosarcoma. It would be exceedingly rare to die of a phalanx cartilage tumor. However, local control is notoriously difficult to achieve in pelvic

chondrosarcomas, and long-term cure rates require massive resection. Secondary chondrosarcomas occur after malignant transformation of benign cartilage tumors such as enchondroma or osteochondroma. 

BONE METASTASES Skeletal metastases are approximately 500 times more common than skeletal sarcomas; 1.2 million new cases of carcinoma are diagnosed each year in the United States. The most common osteophilic carcinomas include prostate, thyroid, breast, lung, bladder, and renal carcinoma. As cancer therapeutics improve, the prevalence of patients living with metastatic cancer also increases. Displaced pathologic fractures and impending pathologic fractures represent common problems for the orthopedic oncologist. The workup for a metastatic skeletal carcinoma of unknown primary origin includes a detailed physical exam, including breast and prostate exam. The radiographic studies ordered include a computed axial tomographic scan of the chest, abdomen, and pelvis; a whole body bone scan; serum protein electrophoresis; and assay for prostate-specific

CHAPTER 33  Bone Tumors

A1

A2

B1

767

B2

FIG. 33.11  Giant cell tumors are destructive epiphyseal lesions that can cause articular surface compromise. (A1) They present as lytic lesions in the epiphyseal bone as on this anteroposterior distal femur x-ray. (A2) Intralesional resection and adjuvant treatment are performed and followed by cement, plate, and screw reconstruction. (B1) Although adjuvants are used, the most important part of limiting recurrence is meticulous resection. To accomplish that goal, a bony window often as large as the lesion itself must be created so that all aspects of the lesion can be addressed. (B2) Cement reconstruction allows for immediate stability as well as a means of radiographic monitoring for signs of recurrence.

antigen.50 If a diagnosis of metastatic to bone carcinoma is established, then there are certain medical therapies that can be used to decrease the number of SREs in a patient (or clinically significant bone metastases). Intralesional resection after tissue confirmation of the diagnosis and stabilization of bone lesions can provide excellent palliation of symptoms and improvements in quality of life. When considering surgical stabilization, often whole bone prophylaxis is performed utilizing metal implants and cement augmentation. Postoperative radiation therapy must include delivery to the entire bone from joint to joint. A surgical goal of a local recurrence rate less than 15% is preferred. Isolated metastases such as from renal cell carcinoma or melanoma can be treated aggressively if they are indeed isolated and occur after a long hiatus (several years) from initial diagnosis. Cures, in such instances, are not rare. Reconstructive goals consist of choosing an implant durable enough to outlive the patient and understanding what, if any, healing capacity the bone may have. A variety of surgical techniques are used to reconstruct the skeleton (Figs. 33.5 and 33.6). Palliative relief of pain and maximization of function are the goals of surgery. 

CONCLUSION The management of bone tumors requires an expertise and understanding of the bone microenvironment combined with a knowledge of macroscopic bone biomechanics. Tumor resections in the skeleton mandate concurrent plans for stable skeletal reconstruction. In the case of primary malignant bone tumors, studies demonstrate that patients have better outcomes when treated in a tertiary care facility with orthopedic oncology expertise. With regard to the management of secondary malignancies of bone, multiple factors—the nature of the tumor, the location of the lesion, and the demands of specific bone locations—may affect decisions regarding resection and reconstruction. Benign bone tumors often do not require surgical intervention, only surveillance. Aggressive benign tumors can be resected in an intralesional fashion, but that

resection must be meticulous, and those patients must be followed for evidence of recurrence. Skeletal sarcomas are treated with wide excision and appropriate reconstruction. An evolving understanding of the bone microenvironment has translated into better pharmaceutical options for the treatment of bone tumor lesions and a better understanding of the bone-specific and tumor-specific demands in tumor reconstruction.

SELECTED REFERENCES Baumhoer D, Amary F, Flanagan AM. An update of molecular pathology of bone tumors. Lessons learned from investigating samples by next generation sequencing. Genes Chromosomes Cancer. 2019;58:88–99. A majority of primary bone tumors, excluding high-grade osteosarcoma, can now be defined by molecular genetic alterations. The ability to identify distinct molecular markers in bone sarcoma allows one to more reliably determine definitive diagnosis. The right diagnosis has ramifications for developing appropriate treatment pathways and for generating meaningful research study groups.

Enneking WF, Spanier SS, Goodman MA. A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop Relat Res. 1980;153:106–120. This surgical staging system for musculoskeletal sarcomas stratifies bone and soft-tissue tumors of any by the grade of biologic aggressiveness, by the anatomic setting, and by the presence of metastasis. It consists of three stages: I— low grade; II—high grade; and III—presence of metastases. These stages are subdivided by whether the lesion is anatomically confined (a) within a compartment or (b) beyond a compartment in ill-defined fascial planes and spaces. It has proven to be the most correlative system for predicting sarcoma outcomes.

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SECTION V  Surgical Oncology

Fizazi K, Carducci M, Smith M, et  al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377:813–822. In this phase 3 randomized controlled trial, denosumab was shown to be better than zoledronic acid in the prevention of skeletally related events. The results reflect the importance of understanding the bone microenvironment in which tumors proliferate. Denosumab is a human monoclonal antibody targeted against receptor activator of nuclear factor κB ligand Zoledronic acid is a bisphosphonate that inhibits the activated osteoclasts.

Mankin HJ, Mankin CJ, Simon MA. The hazards of the biopsy, revisited. Members of the Musculoskeletal Tumor Society. J Bone Joint Surg Am. 1996;78:656–663. This investigation reviewed the hazards associated with biopsies of primary malignant musculoskeletal sarcomas and demonstrated that there were troubling rates in errors in diagnosis and technique, which adversely affected patient care. In addition, it was noted that patients had a decreased incidence of biopsy-related complications or adverse change in outcome when biopsy was performed in a sarcoma care center. On the basis of those observations, whenever possible, musculoskeletal tumor biopsies should be done in a tertiary-type sarcoma center by an orthopedic oncologist or collaborating musculoskeletal radiologist.

Rougraff BT, Kneisl JS, Simon MA. Skeletal metastases of unknown origin. A prospective study of a diagnostic strategy. J Bone Joint Surg Am. 1993;75:1276–1281. In 85% of patients, the primary site of metastatic origin was identified with the use of a computed tomography (CT) scan of the chest, abdomen, and pelvis. This diagnostic strategy was simple and highly successful for the identification of the site of an occult malignant tumor before biopsy in patients who had skeletal metastases of unknown origin. In a patient presenting with a skeletal lesion suspicious for a metastatic lesion with an unknown primary, CT scan is the test of choice to identify the primary lesion. In an era when insurance approval of such tests is increasingly more difficult, it is important to advocate for patients to receive this standard of care examination.

Simon MA, Aschliman MA, Thomas N, et al. Limb-salvage treatment versus amputation for osteosarcoma of the distal end of the femur. J Bone Joint Surg Am. 1986;68:1331–1337. This study compared three groups of patients who had a limbsparing procedure, an above-the-knee amputation, or disarticulation of the hip for osteosarcoma of the distal femur. The use of a limb-salvage procedure for osteosarcoma of the distal end of the femur did not shorten the disease-free interval or compromise long-term survival.

REFERENCES 1. Paget S. The distribution of secondary growths in cancer of the breast. Lancet. 1889;1:571–573. 2. Kang Y, Siegel PM, Shu W, et  al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell. 2003;3:537–549. 3. Cook LM, Shay G, Araujo A, et al. Integrating new discoveries into the “vicious cycle” paradigm of prostate to bone metastases. Cancer Metastasis Rev. 2014;33:511–525. 4. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423:337–342. 5. Morony S, Capparelli C, Sarosi I, et  al. Osteoprotegerin inhibits osteolysis and decreases skeletal tumor burden in syngeneic and nude mouse models of experimental bone metastasis. Cancer Res. 2001;61:4432–4436. 6. Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002; 2:584–593. 7. Weilbaecher KN, Guise TA, McCauley LK. Cancer to bone: a fatal attraction. Nat Rev Cancer. 2011;11:411–425. 8. Lynch CC, Hikosaka A, Acuff HB, et al. MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL. Cancer Cell. 2005;7:485–496. 9. Pavlakis N, Schmidt R, Stockler M. Bisphosphonates for breast cancer. Cochrane Database Syst Rev. 2005:CD003474. 10. Aapro M, Abrahamsson PA, Body JJ, et al. Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann Oncol. 2008;19:420–432. 11. Sheridan JP, Marsters SA, Pitti RM, et al. Control of TRAILinduced apoptosis by a family of signaling and decoy receptors. Science. 1997;277:818–821. 12. Body JJ, Facon T, Coleman RE, et  al. A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clin Cancer Res. 2006;12:1221–1228. 13. Rordorf T, Hassan AA, Azim H, et al. Bone health in breast cancer patients: a comprehensive statement by CECOG/ SAKK Intergroup. Breast. 2014;23:511–525. 14. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377:813–822. 15. Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, doubleblind study. J Clin Oncol. 2010;28:5132–5139. 16. Mirels H. Metastatic disease in long bones. A proposed scoring system for diagnosing impending pathologic fractures. Clin Orthop Relat Res. 1989;249:256–264. 17. Mankin HJ, Mankin CJ, Simon MA. The hazards of the biopsy, revisited. Members of the Musculoskeletal Tumor Society. J Bone Joint Surg Am. 1996;78:656–663. 18. Randall RL, Bruckner JD, Papenhausen MD, et  al. Errors in diagnosis and margin determination of soft-tissue sarcomas initially treated at non-tertiary centers. Orthopedics. 2004;27:209–212. 19. Trovik CK. Scandinavian Sarcoma Group Project. Acta Orthop Scand Suppl. 2001;300:1–31. 20. Baumhoer D, Amary F, Flanagan AM. An update of molecular pathology of bone tumors. Lessons learned from investigating

CHAPTER 33  Bone Tumors samples by next generation sequencing. Genes Chromosomes Cancer. 2019;58:88–99. 21. Enneking WF, Spanier SS, Goodman MA. A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop Relat Res. 1980;153:106–120. 22. American Joint Committee on Cancer. Bone. In: Edge SB, Greene FL, Byrd DR, et al., eds. AJCC Cancer Staging Manual. 7th ed. New York: Springer-Verlag; 2010:281–287. 23. Enneking WF. Staging Musculoskeletal Tumors in Musculoskeletal Tumor Surgery. New York: Churchill Livingstone; 1983. 24. Blackley HR, Wunder JS, Davis AM, et al. Treatment of giantcell tumors of long bones with curettage and bone-grafting. J Bone Joint Surg Am. 1999;81:811–820. 25. Joyce MJ. Safety and FDA regulations for musculoskeletal allografts: perspective of an orthopaedic surgeon. Clin Orthop Relat Res. 2005;435:22–30. 26. Myers GJ, Abudu AT, Carter SR, et al. The long-term results of endoprosthetic replacement of the proximal tibia for bone tumours. J Bone Joint Surg Br. 2007;89:1632–1637. 27. Unni KK. Dahlin’s Bone Tumors: General Aspects and Data on 11,087 Cases. ed 5. Philadelphia: Lippincott-Raven; 1996. 28. Turcotte RE, Wunder JS, Isler MH, et  al. Giant cell tumor of long bone: a Canadian Sarcoma Group study. Clin Orthop Relat Res. 2002;397:248–258. 29. Altay M, Bayrakci K, Yildiz Y, et al. Secondary chondrosarcoma in cartilage bone tumors: report of 32 patients. J Orthop Sci. 2007;12:415–423. 30. Wuyts W, Van Hul W. Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes. Hum Mutat. 2000;15:220–227. 31. Le Merrer M, Legeai-Mallet L, Jeannin PM, et al. A gene for hereditary multiple exostoses maps to chromosome 19p. Hum Mol Genet. 1994;3:717–722. 32. Vanhoenacker FM, Van Hul W, Wuyts W, et al. Hereditary multiple exostoses: from genetics to clinical syndrome and complications. Eur J Radiol. 2001;40:208–217. 33. Radev BR, Kase JA, Askew MJ, et  al. Potential for thermal damage to articular cartilage by PMMA reconstruction of a bone cavity following tumor excision: a finite element study. J Biomech. 2009;42:1120–1126. 34. Dominkus M, Ruggieri P, Bertoni F, et al. Histologically verified lung metastases in benign giant cell tumours—14 cases from a single institution. Int Orthop. 2006;30:499–504. 35. Chawla S, Henshaw R, Seeger L, et al. Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim analysis of an open-label, parallel-group, phase 2 study. Lancet Oncol. 2013;14:901–908.

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36. Balke M, Campanacci L, Gebert C, et  al. Bisphosphonate treatment of aggressive primary, recurrent and metastatic giant cell tumour of bone. BMC Cancer. 2010;10:462. 37. Mak IW, Evaniew N, Popovic S, et al. A translational study of the neoplastic cells of giant cell tumor of bone following neoadjuvant denosumab. J Bone Joint Surg Am. 2014;96:e127. 38. Rock MG, Sim FH, Unni KK, et  al. Secondary malignant giant-cell tumor of bone. Clinicopathological assessment of nineteen patients. J Bone Joint Surg Am. 1986;68:1073–1079. 39. Cancer Facts and Figures 2019. American Cancer Society, Accessed July 30, 2019. https://www.cancer.org/cancer/b one-cancer/about/key-statistics.html. 40. Rosen G, Marcove RC, Caparros B, et al. Primary osteogenic sarcoma: the rationale for preoperative chemotherapy and delayed surgery. Cancer. 1979;43:2163–2177. 41. Simon MA, Aschliman MA, Thomas N, et al. Limb-salvage treatment versus amputation for osteosarcoma of the distal end of the femur. J Bone Joint Surg Am. 1986;68:1331–1337. 42. Link MP, Goorin AM, Miser AW, et al. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med. 1986;314:1600–1606. 43. Pakos EE, Nearchou AD, Grimer RJ, et al. Prognostic factors and outcomes for osteosarcoma: an international collaboration. Eur J Cancer. 2009;45:2367–2375. 44. Goorin AM, Schwartzentruber DJ, Devidas M, et  al. Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma: pediatric Oncology Group Study POG-8651. J Clin Oncol. 2003;21:1574–1580. 45. Grimer RJ, Carter SR, Pynsent PB. The cost-effectiveness of limb salvage for bone tumours. J Bone Joint Surg Br. 1997;79:558–561. 46. Mankin HJ, Hornicek FJ, Raskin KA. Infection in massive bone allografts. Clin Orthop Relat Res. 2005;432:210–216. 47. Jeys LM, Kulkarni A, Grimer RJ, et al. Endoprosthetic reconstruction for the treatment of musculoskeletal tumors of the appendicular skeleton and pelvis. J Bone Joint Surg Am. 2008;90:1265–1271. 48. Picci P, Bacci G, Campanacci M, et  al. Histologic evaluation of necrosis in osteosarcoma induced by chemotherapy. Regional mapping of viable and nonviable tumor. Cancer. 1985;56:1515–1521. 49. Aurias A, Rimbaut C, Buffe D, et al. Chromosomal translocations in Ewing’s sarcoma. N Engl J Med. 1983;309:496–498. 50. Rougraff BT, Kneisl JS, Simon MA. Skeletal metastases of unknown origin. A prospective study of a diagnostic strategy. J Bone Joint Surg Am. 1993;75:1276–1281.

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VI

HEAD AND NECK

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34

Head and Neck Wendell G. Yarbrough, Adam Zanation, Samip Patel, Saral Mehra

OUTLINE Normal Histology Epidemiology Carcinogenesis Staging Clinical Overview Evaluation Lymphatic Spread Therapeutic Options Anatomic Sites Neck Oral Cavity Oropharynx Hypopharynx

Larynx Salivary Nasal Cavity and Paranasal Sinuses Nasopharynx Ear and Temporal Bone Head and Neck Reconstruction Reconstructive Goal 1: Separation of Upper Aerodigestive Tract From Sterile Compartments Reconstructive Goal 2: Optimizing Function Reconstructive Goal 3: Optimization of Form/Cosmesis Reconstructive Options in Head and Neck Surgery

Please access Elsevier eBooks for Practicing Clinicians to view the videos for this chapter https://expertconsult.inkling.com/.

cavity is lined by nonkeratinized, stratified squamous epithelium with minor salivary glands throughout the submucosa and within the muscular tissue of the tongue. The oral cavity transitions to the oropharynx at the junction between the hard and soft palates and at the anterior tonsillar pillar. Waldeyer ring is formed by lymphoid tissues of the palatine tonsils, adenoids, lingual tonsils, and adjacent submucosal lymphatics. Similar to the adenoids, the palatine tonsils contain germinal centers without capsules or sinusoids, but, in contrast to the adenoids, the tonsils have crypts lined by stratified squamous epithelium with the lymphoepithelial cells residing at the base of the crypts. The junction between the oropharynx and hypopharynx is a horizontal line at the top of the hyoid bone. The hypopharynx is lined by nonkeratinizing, stratified squamous epithelium. Seromucous glands are found throughout the submucosa of the hypopharynx, in the lower two-thirds of the epiglottis and in the potential space between the true and false vocal folds known as the ventricle. The lining of the larynx transitions from nonkeratinizing, stratified squamous epithelium of the epiglottis and true vocal folds to pseudostratified, ciliated respiratory epithelium of the false vocal fold, ventricle, and subglottis. The thyroid, cricoid, and arytenoid cartilages are composed of hyaline cartilage, whereas the epiglottis, cuneiform, and corniculate cartilages are composed of elastic-type cartilage. The external ear is a cutaneous structure lined with keratinizing squamous epithelium and associated adnexal structures. The external third of the external auditory canal is unique in that it contains modified apocrine glands that produce cerumen. The middle ear is lined with respiratory epithelium. Numerous noncancerous changes in squamous epithelium can be seen in the upper aerodigestive tract. Leukoplakia, which describes any white mucosal lesion, and erythroplakia, which describes

NORMAL HISTOLOGY The normal histology of the upper aerodigestive tract varies based on the cells, tissues, and function required of each site. A complete review of the thyroid and parathyroid glands is beyond the scope of this chapter. The upper aerodigestive tract can be conceptualized to start with the openings to the nose and mouth. The shape of the nasal vestibule is maintained by underlying septal, upper lateral, and lower lateral cartilages and is a cutaneous structure lined by keratinizing squamous epithelium that has sebaceous and sweat glands, as well as hair follicles. The limen nasi, or mucocutaneous junction, is where the epithelium changes to a ciliated pseudostratified columnar (respiratory) epithelium that lines the sinus and nasal cavities with the exception of the olfactory epithelium at the roof of the nasal cavity. The olfactory epithelium is a specialized tissue composed of supporting cells and bipolar olfactory neural cells with odorant receptors on cilia that face the nasal cavity and axons that coalesce to form the olfactory nerve (CN I) and pass through the cribriform plate on the deep surface. As with the nasal cavity, the paranasal sinuses are also lined by respiratory epithelium, but it tends to be thinner and less vascular than that of the nasal cavity. The nasopharyngeal lining varies from squamous to respiratory epithelium in an inconsistent manner. The adenoidal pad is a lymphoid tissue containing germinal centers without capsules or sinusoids and, like the palatine and lingual tonsils, contains a specialized lymphoepithelium with discontinuous basement membrane and intermixing of stromal, immune, and epithelial cells. The oral

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CARCINOGENESIS

FIG. 34.1  Leukoplakic lesion on the left mobile tongue. On biopsy, this lesion was determined to be hyperkeratosis without invasive cancer.

any red mucosal lesion, are clinical descriptions and should not be used as diagnostic terms (Fig. 34.1). Erythroplakia is more concerning than leukoplakia, since it is more often associated with an underlying malignant lesion. Hyperplasia refers to thickening of the epithelium, while parakeratosis is an abnormal presence of nuclei in the keratin layers, and dyskeratosis refers to any abnormal keratinization of epithelial cells and is found in dysplastic lesions. 

EPIDEMIOLOGY The American Joint Committee on Cancer (AJCC) staging system divides sites of malignancies originating in the upper aerodigestive tract (i.e., head and neck) into eight major sites: lip and oral cavity, oropharynx, hypopharynx, larynx, nasal cavity and ethmoid sinus, maxillary sinus, major salivary glands, and thyroid.1 Excluding salivary and thyroid, these cancers historically have been tightly associated with exposure to causative tobacco carcinogenesis. In the latter part of the twentieth century, the human papillomavirus (HPV) was identified as a cause of oropharyngeal and nasopharyngeal cancers and is also associated with a portion of sinonasal and nasopharyngeal cancers. Epstein-Barr virus (EBV) is responsible for a subset of nasopharyngeal cancers. While there remains a male preponderance in smoking-associated aerodigestive tract malignancies, the male-to-female ratio has been decreasing because of the direct association between tobacco as a causative agent and the increased incidence of female smokers. For reasons that are not totally understood, HPV-associated head and neck squamous cell carcinoma (HNSCC) has a 4:1 male preponderance.2 The increased risk associated with combined abuse of alcohol and tobacco is multiplicative. By 2012, HPV caused more oropharyngeal cancers than uterine cervical cancers, and by 2015, HPV-associated oropharyngeal cancers accounted for more than 40% of all HPV-associated cancers in the United States.2 HPVassociated cancer of the oropharynx affects younger individuals and is not associated with alcohol or tobacco use. According to the National Cancer Database, squamous cell carcinoma (SCC) is the most common head and neck tumor of the major head and neck sites (88.9%), adenocarcinoma is the most common of the major salivary glands (56.4%), SCC is the most common of the sinonasal tract (43.6%), and lymphoma is the most common of the sites classified as “other” (82.5%).4 

Tobacco exposure is associated with many human cancers and is the major dose-dependent carcinogen that causes head and neck cancers (HNCs) that are not associated with HPV. HPV infection is now the primary cause of oropharyngeal carcinoma in the United States. Evidence has amassed mandating that HPVpositive and HPV-negative HNSCCs be considered two distinct cancers.5 High-risk HPV types suppress apoptosis and activate cell growth through actions of the HPV oncogenes, E6 and E7. Malignant transformation requires expression of the HPV oncogenic proteins E6 and E7 that inactivate the p53 and retinoblastoma tumor suppressors, respectively.6 E6 binds the cellular E6-associated protein and this complex targets p53 for ubiquitination and degradation contributing to unregulated cell growth. Likewise, E7 associates with retinoblastoma and targets retinoblastoma for proteasomal degradation.6 The Cancer Genome Atlas (TCGA) has added immensely to understanding of carcinogenesis. Mutation profiles have been assigned based on mutation type, and analysis of HNCs has revealed that there are two major patterns. HPV-negative HNSCCs are associated with mutational profiles associated with tobacco carcinogens and those associated activity of apolipoprotein B mRNA-editing enzyme catalytic polypeptide (APOBEC), while HPV-positive cancers have mutational profiles associated with APOBEC.7 APOBECs are DNA editing enzymes that deaminate cytosine to form uracil in single-stranded DNA, thus creating a DNA mismatch. APOBECs, especially APOBEC3B, are important in innate immunity and A3B is upregulated in response to HPV, likely contributing to higher levels of APOBEC mutations in HPV-associated HNSCCs. APOBEC activity in HPV-positive HNSCC has been associated with the increased percentage of PIK3CA mutations in these tumors.8 Many years after Slaughter proposed field cancerization, the molecular basis of HNSCC began to be defined. Chromosomal gain and loss were initially studied, revealing that loss of heterozygosity at 9p21 and 3p21 was among the earliest detectable events leading to dysplasia, with further genetic alteration in 11q, 13q, and 14q being associated with carcinoma in situ.9 The high rate of recurrence, in part, results from histopathologically benign squamous cell epithelium harboring a clonal population with genetic alterations. Patients with HNSCC have a 3% to 7% annual incidence of secondary lesions in the upper aerodigestive tract, esophagus, or lung. A synchronous second primary lesion is defined as a tumor detected within 6 months of the index tumor. The occurrence of a second primary lesion more than 6 months after the initial lesion is referred to as metachronous. A second primary develops in the aerodigestive tract of 14% of patients with HNSCC over the course of their lifetime, with more than half of these lesions occurring within the first 2 years of the index tumor. Many individual studies identified important genetic defects that drive HNSCC or tumor maintenance. These studies culminated in a National Cancer Institute–led effort—TCGA—to molecularly characterize more than 500 HNSCCs through RNA sequencing, whole exome sequencing, methylation analysis, and reverse-phase protein analysis.10 TCGA characterization of HNSCC clearly identified that HPV-associated and HPV-negative HNSCCs were molecularly distinct. Despite this distinction, many copy number alterations were shared between HPV-positive and HPV-negative HNSCCs, including losses of 3p and 8p and gains of 3q and 8q. Some copy number variants were unique to HPV-negative HNSCC, such as amplification of CCND1 (cyclin

CHAPTER 34  Head and Neck D1) and loss of CDKN2A (p16INK4a), while amplification of FGFR 3 was observed primarily in HPV-associated SCC. Compared to many other tumor types, the number of structural alterations was high in HNSCC, averaging 141 amplifications or deletions and 62 chromosomal fusions per tumor genome. Gene mutation analysis confirmed defects in many known tumor suppressors and oncogenes, including p53, CDKN2A, PIK3CA, EGFR, and HRAS. While targeting of some frequently mutated oncogenes (MYC, HRAS) and tumor suppressor genes (TP53, CDKN2A, NOTCH) has not yet been successful for HNSCC, combined mutation and copy number analysis revealed that several receptor tyrosine kinases for which there are inhibitors (EGFR, FGFR1, ERBB2, IGF1R, FGFR2, FGFR3, MET) were altered in HPV-negative cancers. Unfortunately, these potential therapeutic targets in HNSCC have not advanced to clinical use. A novel finding of the TCGA was identification of deletions and truncating mutations of the tumor necrosis factor (TNF) receptor– associated factor 3 (TRAF3) that previously was found only in hematologic malignancies. These defects were only found in HPV-positive HNSCC, and further analysis of TCGA data revealed that a portion of HPV-positive HNSCCs also harbored defects in CYLD (cylindromatosis lysine 63 deubiquitinase), with close to 30% of these tumors having a defect in one of these genes. TRAF3 and CYLD share common functions to inhibit the nuclear factorκB (NF-κB) and activate innate immunity, and HPV-positive HNSCCs containing defects and TRAF3 or CYLD had increased expression of NF-κB regulated genes and downregulation of immune genes.11 HNSCC with TRAF3 or CYLD defects lacked integrated HPV and had distinct methylation, HPV gene expression, and somatic gene expression profiles. Interestingly, no other solid tumors carry such high levels of inactivating defects in TRAF3 or CYLD except for nasopharyngeal cancer associated with EBV.11 It is surprising that uterine cervical cancers, which are also caused by HPV, do not harbor a defect in these genes and that somatic mutations are largely not shared between HPV-associated HNSCC and uterine cervical cancer.12 Clinical differences between uterine and cervical cancer and HPV-positive HNSCC are highlighted by treatment response and cure rate, which are higher in HNCs. Together, these data suggest that uterine cervical cancer and HPVassociated HNC are distinct. The high rate of episomal HPV, coupled with defects in innate immunity found in HNSCC, suggests that HPV integration, as described in uterine cervical cancer, is not required in HNSCC, suggesting that HPV may cause cancer through a different mechanism in the oropharynx. The Centers for Disease Control and Prevention reported that by 2012, HNCs were more common than uterine cervical cancer and was the most common HPV-associated cancer reported in the United States,2 highlighting that HNSCC is a public health concern on par with uterine cervical cancer. Alterations in immune recognition are common in both HPVpositive and HPV-negative HNSCCs with defects in human leukocyte antigen (HLA)-A/B noted in both tumor types, and it is becoming clear that tumors alter many normal processes to evade immune recognition. Over the last several years, drugs targeting the programmed cell death receptor 1 (PD-1)/PD-1 ligand (PDL1) axis have been approved for use in recurrent and metastatic HNSCC. Response rates in these initial trials were approximately 20%, and promisingly, some responses persisted for years. There was a higher response rate in patients with a higher percentage of tumor cells or inflammatory cells in the tumor that expressed PDL1. Other markers associated with response to PD-axis inhibitors include mutational load, immune cell infiltrate, and neoantigen

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expression.13 Harnessing the immune system to control HNSCC has garnered great enthusiasm with many new and combination immune therapies emerging and being tested. Understanding of mutational drivers of HPV-associated and HPV-negative HNSCC, as well as modulators of immune recognition, provides great promise for future advances in treatment. We currently lack adequate tools to pair ideal treatments with each patient’s tumor. This shortcoming highlights the urgent need for identification of reliable prognostic biomarkers as we move toward personalized therapy of HNSCC. 

STAGING The AJCC creates criteria for tumor staging based on characteristics of the primary tumor (T) and nodal metastases (N), as well as the presence of distant metastases (M), accumulatively TNM. All tumors can have clinical TNM (cTNM) staging, and cancers that are treated surgically can have pathologic staging–designated pTNM.1 The T classification refers to the extent of the primary tumor and is specific to each of the six sites of origin, with subclassifications within each site. The N classification identifies the pattern of lymphatic spread within the neck nodes. Clinical staging of the neck is based on palpation for enlarged nodes and radiographic evaluation of the neck. Using the computed tomography (CT) criteria for identification of nodal metastases, central necrosis or size larger than 1.0 cm (>1.5 cm for level II), 7% of pathologically positive lymph nodes are misclassified as negative based on CT imaging, and these smaller nodes are most often found in necks with more extensive disease. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET)/CT scanning and advanced informatics techniques are being explored to improve detection of nodal metastases of HNSCC, especially for the clinically N0 (cN0) necks. Metastatic disease is reported as Mx (cannot be assessed), M0 (no distant metastases are present), or M1 (metastases present). The most common sites of distant spread are the lungs, whereas hepatic, bone, and brain metastases occur less frequently. The risk for distant metastases depends more on nodal staging than on primary tumor size. Classification of nodal metastases for thyroid, nasopharynx, mucosal melanoma, and skin has consistently differed from HNSCC because of differences in behavior of these distinct tumor types. Until the eighth edition of the AJCC staging manual, HPV-positive and HPV-negative cancers used identical criteria for TNM classification and had the same staging grid. As an acknowledgement that HPV-positive and HPV-negative HNSCC are distinct diseases, they now have distinct T and N classification in the eighth edition of the AJCC staging manual (Figs. 34.2 and 34.3). For the first time, the pathologic and clinical T and N classifications of HNSCC are based on different criteria (data not shown and Tables 34.1 and 34.2). Finally, HPV-positive and HPV-negative HNSCCs have different staging criteria, with one example being that stage IV in HPV-positive HNSCC applies only to patients with distant metastases, whereas in HPV-negative HNSCC, stage IV also encompasses all patients with T4, N2, or N3 disease (Figs. 34.2 and 34.3). In the eighth edition of the AJCC Cancer Staging Manual,1 a descriptor has been added as ECS+ or ECS−, depending on the presence or absence of nodal extracapsular spread (ECS). After complete resection of the primary and nodal disease, pathologic staging may be reported as pTNM. Pathologic T and N classification allows occult spread or microscopic disease to be considered and is useful in determining prognosis.

774

SECTION VI  Head and Neck N0 T1

N1

N2

N3

TABLE 34.1  Clinical metastatic

classification of regional lymph nodes (cN).

I

DESCRIPTION

III T2

IV-A T3

CATEGORY HPV POSITIVE

II IV-B

III

T4a

IV-A

T4b

IV-B

cN0 cN1 cN2

IV-C

M1

FIG. 34.2  Standard staging (human papillomavirus–negative head and neck squamous cell carcinoma) pathologic and clinical are identical. pN0

pN1

I

HPV NEGATIVE

Regional lymph nodes not assessed No regional lymph node 1+ ipsilateral lymph node, ≤6 cm Bilateral lymph node all ≤6 cm

cN2b cN2c

II

cN3 cN3a cN3b

Any lymph node >6 cm

Regional lymph nodes not assessed No regional lymph node Single ipsilateral lymph node, ≤3 cm Single ipsilateral lymph node >3–6 cm Multiple ipsilateral lymph nodes ≤6 cm Bilateral/contralateral lymph nodes with all ≤6 cm Any lymph node >6 cm Any lymph node over and ENE+

ENE, Extranodal extension; HPV, human papillomavirus

pT2 pT3 II

III

pT4 M1

cN2a

pN2

pT0 pT1

cNX

IV

FIG. 34.3  Human papillomavirus–positive pathologic staging.

Staging of HNCs changes as we more accurately identify determinants of outcome. The eighth edition of the AJCC Cancer Staging Manual highlights that the TNM classification system for HNCs is constantly evolving as new therapies and knowledge impacting outcome advance. 

CLINICAL OVERVIEW Evaluation Proper treatment of HNC requires careful evaluation of tumor and patient characteristics, as well as accurate clinical and radiographic staging. Patients with HNC are initially evaluated in a similar manner, regardless of the site of tumor. Patient histories focus on manifestations of the tumor, including the duration of symptoms, detection of masses, location of pain, and presence of referred pain. Special attention is paid to numbness, cranial nerve weakness, dysphagia, odynophagia, hoarseness, airway compromise, trismus, nasal obstruction, and bleeding. Alcohol and tobacco use histories are elicited. Office examination includes direct visual inspection of the oral cavity and upper oropharynx, fiberoptic visualization of the nasopharynx, lower oropharynx, larynx, and hypopharynx, as well as palpation of accessible tumors and neck to detect potential nodal spread. The examiner should be especially vigilant for second primary tumors and should not be preoccupied by the obvious primary lesion. Contrast-enhanced CT and/or magnetic resonance imaging (MRI) of the head and neck are performed for evaluation of the tumor and detection of clinically undetected lymphadenopathy. CT scanning is best at evaluating bony destruction, whereas MRI can determine soft tissue involvement and neural spread and is excellent at evaluating parotid and parapharyngeal space tumors. Chest CT scanning is

TABLE 34.2  Pathologic metastatic

classification of regional lymph nodes (pN). DESCRIPTION CATEGORY pNX pN0 pN1 pN2 pN2a

pN2b pN2c pN3a pN3b

HPV POSITIVE

HPV NEGATIVE

Regional lymph nodes not assessed No regional lymph node Up to four lymph nodes with metastasis ≥5 lymph nodes with metastasis

Regional lymph nodes not assessed No regional lymph node Single ipsilateral lymph node, ≤3 cm Single ipsilateral lymph node >3–6 cm or single ipsilateral lymph node ≤3 cm, ENE+ Multiple ipsilateral lymph nodes ≤6 cm Bilateral/contralateral lymph nodes with all ≤6 cm Any lymph node >6 cm Any non pN1 lymph node, ENE+

ENE, Extranodal extension; HPV, human papillomavirus.

performed to rule out synchronous lung lesions, be they second primaries of metastatic lesions. Alternatively, 18F-FDG PET imaging can be used for staging and detection of distant metastases, but anatomic detail at the primary site and nodal metastases frequently is not adequate to determine the extent of tumor spread. For HNC, excluding thyroid cancers, there are currently no blood markers that are used for diagnosis or prognosis of HNC. Circulating EBV DNA is used to follow tumor response for EBVpositive nasopharyngeal cancers and HPV DNA is being tested as a potential marker for following tumor response in HPV-positive HNSCC. Direct laryngoscopy and examination under anesthesia are commonly performed as part of the evaluation of HNC. These procedures allow the physician to evaluate tumors without patient discomfort and

CHAPTER 34  Head and Neck

FIG. 34.4  Diagram of cervical lymph node levels I through V. Level II is divided into regions A and B by the spinal accessory nerve. (Courtesy Cleveland Clinic Foundation, 2003.)

with muscle paralysis that aids in detection of tumors in areas that are difficult to palpate or visualize. Exam under anesthesia improves evaluation of the oropharynx, hypopharynx, and larynx and eases the ability to obtain biopsy samples. Pathologic confirmation of cancer is mandatory before initiating treatment, but this can be done by a biopsy with frozen section during the same anesthetic before a planned complete resection. Concurrent bronchoscopy and esophagoscopy have historically been recommended for the detection of synchronous second primaries of the aerodigestive tract, which occur in 4% to 8% of patients who have one head and neck malignancy. With a normal CT or PET scan, bronchoscopy and esophagoscopy have a low yield for discovering second primaries but are useful for determining direct tumor spread to the upper esophagus, subglottis, or trachea. Increases in HPV-positive HNSCC have increased the portion of patients presenting without an obvious primary site. These carcinomas of unknown primary typically present with cancer in neck nodes, but the primary site cannot be identified clinically or radiographically. Since excisional biopsies should be a last resort for diagnosis for neck nodes, fine-needle aspirations (FNAs) and cytology can identify SCC in cervical nodes. HPV testing of FNA from neck nodes can be very useful, both for identification of nodal metastasis when the specimen is acellular and for directing the search for the primary cancer site, the oropharynx. 

Lymphatic Spread The cervical lymphatic nodal basins contain 50 to 70 lymph nodes per side and are divided into seven levels (Figs. 34.4 and 34.5). Level I is subdivided: • Level IA is bounded by the anterior belly of the digastric muscle, hyoid bone, midline, and mandible. • Level IB is bounded by the anterior and posterior bellies of the digastric muscle and the inferior border of the mandible. Level IB contains the submandibular gland. Level II is bounded superiorly by the skull base, anteriorly by the stylohyoid muscle, inferiorly by a horizontal plane extending posteriorly from the hyoid bone, and posteriorly by the posterior edge of the sternocleidomastoid muscle. Level II is further subdivided:

775

FIG. 34.5  Diagram of anterior lymph node levels I, VI, and VII. Although large in area, most level VI lymph nodes are confined to the paratracheal region. (Courtesy Cleveland Clinic Foundation, 2003.)

• Level IIA is anterior to the spinal accessory nerve. • L  evel IIB, or the so-called submuscular triangle, is posterior to the nerve. Level III begins at the inferior edge of level II and is bounded by the laryngeal strap muscles anteriorly, by the posterior border of the sternocleidomastoid muscle posteriorly, and by a horizontal plane extending posteriorly from the inferior border of the cricoid cartilage. Level IV begins at the inferior border of level III and is bounded anteriorly by the strap muscles, posteriorly by the posterior edge of the sternocleidomastoid muscle, and inferiorly by the clavicle. Level V is posterior to the posterior edge of the sternocleidomastoid muscle, anterior to the trapezius muscle, superior to the clavicle, and inferior to the base of the skull. Level VI is bounded by the hyoid bone superiorly, the common carotid arteries laterally, and the sternum inferiorly. Although level VI is large in area, the few lymph nodes that it contains are mostly in the paratracheal regions near the thyroid gland. Level VII (superior mediastinum) lies between the common carotid arteries and is superior to the aortic arch and inferior to the upper border of the sternum. Lymphatic drainage usually occurs in a superior to inferior direction and follows predictable patterns based on the primary site. Primary tumors of the lip and oral cavity generally metastasize first to nodes in levels I, II, and III. The upper lip primarily metastasizes ipsilaterally, whereas the lower lip has ipsilateral and contralateral drainage. Tumors of the oropharynx, hypopharynx, and larynx usually metastasize to ipsilateral levels II, III, and IV with the exception of supraglottic larynx and base-of-tongue subsites that can spread bilaterally. Tumors of the nasopharynx spread to the retropharyngeal and parapharyngeal lymph nodes as well as to levels II through V. Other sites that metastasize to the retropharyngeal lymph nodes are the soft palate, posterior and lateral oropharynx, and hypopharynx. Scalp, ear, and posterior facial skin cancers can also metastasize to level V. Tumors of the subglottis, thyroid, hypopharynx, and cervical esophagus spread to levels VI and VII. 

776

SECTION VI  Head and Neck

Therapeutic Options Therapeutic options for patients with newly diagnosed HNSCC include surgery, radiation therapy, chemotherapy, and combination regimens. In general, early-stage disease (stage I or II) is treated by surgery or radiation therapy. Late-stage disease (stage III or IV) is best treated by a combination of surgery and postoperative radiation therapy, with upfront concurrent chemotherapy and radiation therapy, or all three modalities, depending on the site of the primary, nodal metastasis, HPV status, and pathologic tumor characteristics. Because the benefits and side effects of treatments vary based on characteristics of the patient and tumor, having an integrated team of specialists with expertise in surgery, radiation, and chemotherapy is critical to attain the best survival and quality of life.14 Although current practice generalizations are outlined in this chapter, they should not be considered as a statement that the authors endorse these as standard of care. Consideration of individual patient and tumor characteristics by multispecialty teams can result in personalized recommendations that vary from generalizations outlined herein. Because of the breadth of expertise needed and the intensity of therapy, it has become clear that outcome is improved when patients are treated at centers that treat large numbers of patients with HNSCC.14 Since the highest risk of failure for HNSCC is by recurrence at the primary site or in regional cervical lymphatics, characteristics of the primary tumor and nodal metastases must be considered for therapeutic decisions. The neck is generally treated when there are clinically positive nodes or the historical risk for occult disease in an N0 neck approaches or is more than 20%, based on the location and classification of the primary lesion. The nodal basins at risk can be treated with neck dissection, radiation, or concurrent chemotherapy and radiation. If nonoperative therapy is recommended, addition of chemotherapy to radiation is influenced by the tumor’s HPV status and the T and N classification with larger tumors or more advanced neck disease more frequently treated with concurrent radiation and chemotherapy, and early-stage disease with low T and low N classification more often treated with radiation alone. For surgically treated primary lesions, neck dissection is commonly performed if nodal disease is present or if the historical risk of occult nodal disease approaches or is more than 20%. For oral cancers, nodal dissection can be recommended for all patients or with consideration of depth of the primary tumor, which modifies the risk of nodal spread.15,16 Photon irradiation is effective for eradicating microscopic SCC and is an alternative to surgery for many early-stage, lowvolume lesions. Subsets of tonsil, tongue base, and nasopharyngeal primary tumors are especially responsive to photon irradiation, particularly those driven by oncogenic viruses. Neutron and proton irradiation are used much less often in the head and neck, although experience has grown with their role in salivary gland malignancies (neutron irradiation) and skull base cancers (proton irradiation). Electrons are not commonly used in the head and neck for noncutaneous tumors. Intensity-modulated radiation therapy, which can reduce the photon dosage to surrounding normal tissue through computer three-dimensional (3D) planning, has been widely implemented in the head and neck in attempts to minimize the side effects of radiation. Radiation therapy is not as effective in treating large-volume, low-grade neoplasms or tumors involving bone or cartilage or in close proximity to the mandible. A landmark chemotherapy trial for HNSCC was the Department of Veterans Affairs larynx trial, published in 1991.17 This study established that response to induction chemotherapy in laryngeal cancer could be used to predict sensitivity to radiation.

Two-thirds of patients treated with induction chemotherapy were able to keep their larynx. With surgical salvage used for radiation failures in this trial, survival was equal between patients treated with laryngectomy and radiation therapy. This success of larynx preservation by nonsurgical therapy led to further studies evaluating chemotherapy and radiation for primary treatment of HNC. The idea of using chemotherapy as a radiation sensitizer was tested by the Radiation Therapy Oncology Group (RTOG) and the Head Neck Intergroup in the RTOG 9111 trial. This trial found that organ preservation and locoregional control for advanced-stage laryngeal cancer was best with concurrent chemotherapy and radiation compared to radiation alone or the induction regimen used in the Veterans Affairs larynx trial.18 The superiority of concurrent chemotherapy with radiation compared to induction chemotherapy followed by radiation dampened enthusiasm for induction therapy, which is now being explored for tumor reduction before surgery to preserve vital organs. The French Head and Neck Oncology and Radiotherapy Group strengthened the argument for chemotherapy as a radiation sensitizer by finding that concomitant chemotherapy with radiation improved overall survival and locoregional control compared to radiation alone for advanced oropharyngeal cancer.19 Combined, these studies and others established cisplatin and radiation therapy as an alternative to surgery, followed by radiation therapy for primary treatment of SCC of the head neck. Short-term improvement in progression-free survival, locoregional control, and overall survival contributed to the establishment of concurrent platinum-based chemotherapy with radiation as a standard therapeutic option for previously untreated head neck cancer therapy. Ten-year results from the RTOG 91-11 trial revealed that while concurrent chemotherapy with radiationmaintained superiority for locoregional control, long-term laryngectomy-free and overall survival were better for patients treated with induction chemotherapy followed by radiation.20 Similarly, analyses using nationwide databases have indicated that relative to nonoperative therapy, total laryngectomy improves survival for advanced-stage larynx cancer.14 These findings indicate that for some head and neck tumors, concurrent chemotherapy and radiation may be associated with worse outcome due to less adequate therapy or long-term mortality unrelated to cancer recurrence. The balance between organ preservation, survival, and side effects of therapeutic modalities is another reason for personalization of therapy and further supports the multidisciplinary team model that is employed at high volume centers. The efficacy of chemotherapy as a radiation sensitizer for primary treatment of HNSCC led to testing the addition of chemotherapy to postoperative radiation. Because of the increased short-term morbidity, concurrent chemotherapy and radiation were reserved for postoperative patients at high risk for recurrence based on T and N classification or poor pathologic features such as perineural spread, positive margins, or extracapsular extension of lymphatic metastasis. The European Organization for Research and Treatment of Cancer (EORTC) Trial 22931 and the RTOG Trial 9501 compared postoperative treatment of advanced-stage, high-risk HNSCC with radiation alone or concurrent cisplatin and radiation therapy. In the RTOG, the 2-year locoregional control rate was 82% for the group receiving chemoradiation therapy versus 72% for the radiation therapy–alone group. Disease-free survival was significantly longer in the patients who received chemoradiation therapy, although overall survival was not significantly different between the groups. In the EORTC trial, locoregional control, disease-free survival, and overall survival were superior for patients

CHAPTER 34  Head and Neck treated with postoperative concurrent chemotherapy and radiation compared to radiation alone. As expected, more toxicity and treatment morbidity were seen in the combined-treatment group, and further prognostic indicators to determine which patients are at high risk for failure are needed to predict which groups warrant this more intensive adjuvant therapy. Standard therapy for recurrent or metastatic HNSCC has been cytotoxic chemotherapy, and the EXTREME trial established the combination of cisplatin, 5-fluorouracil, and the anti-EGFR antibody cetuximab as the most effective of the cytotoxic regimens.21 Although the response rate of the EXTREME regimen is close to 40%, median overall survival of patients with EXTREME was approximately 10 months and the regimen is very toxic, with high percentages of patients experiencing severe toxicities. Despite reasonable activity, the toxicity and relatively modest increase in survival have limited the adoption of the EXTREME regimen and led investigators to search for alternatives. The success of therapy to reactivate the immune system in an array of solid tumors prompted testing of immune therapy in HNSCC. Inhibition of the PD-1/PD-L1 axis, which normally inhibits the adaptive immune response, was initially tested for second-line therapy of recurrent/metastatic HNSCC after failure of platin-containing regimens. In these trials, antibodies targeting PD-1 have improved overall survival with a near doubling of the response rate compared to a single agent EGFR inhibitor, methotrexate, or taxane therapy.22 As compared to other therapies for recurrent or metastatic HNSCC, some patients treated with immunotherapy maintained long-term tumor-free status. Unfortunately, response in the recurrent or metastatic patient population to this promising therapy has been low, 13% to 20%, indicating that better prognostic markers or additional therapies are needed. Prognostic markers including immune infiltrate, PD-L1 expression in tumor cells, PD-L1 expression in tumor infiltrating immune cells, and mutational load are all currently being explored. PD-1–axis antibodies are now being tested in first-line therapy for patients with recurrent/metastatic head and neck cell carcinoma both as a single agent and in combination with standard cytotoxic chemotherapy or other therapies. Early results are promising, with response rates to immunotherapy slightly lower than that observed with EXTREME, but in patients with even modest PD-L1 expression in tumor or immune cells, overall survival was superior with immune therapy.23 When data are fully analyzed, immunotherapy may become the preferred first-line treatment for recurrent and metastatic HNSCC. 

ANATOMIC SITES Neck The neck is not an anatomic site for primary tumors within the upper aerodigestive tract; however, cervical lymph nodes must be treated if involved by metastatic HNC and are typically treated if the risk of metastatic lymphadenopathy is predicted to be greater than 20%. HNSCC has a relatively low propensity for distant metastatic spread but commonly spreads to lymph nodes within the anterior cervical chains, making treatment of local and regional disease of utmost importance for cure. Neck dissections have been categorized based on nonlymphatic structures that are removed and based on the levels of lymph nodes that are excised. Radical neck dissection (RND) is the most comprehensive procedure with removal of levels I to V, as well as the jugular vein, sternocleidomastoid muscle, and spinal accessory nerve (cranial nerve XI). Lateral neck dissections remove lymphatic tissue from

777

A

S

P

FIG. 34.6  Proper appearance of the right neck after a radical neck dissection. In addition to all lymphatic tissue, the three structures of the internal jugular vein, sternocleidomastoid muscle, and spinal accessory nerve have been resected. A, Anterior; P, posterior; S, superior.

levels II to IV, while lymphatic tissue excised with supraomohyoid neck dissection is limited to levels I to III. The anterior neck is a compact area packed with somatic and cranial nerves, named and unnamed vessels, lymphatics including the specialized thoracic duct, salivary glands, endocrine organs, and structures of the respiratory, digestive, and combined aerodigestive tracts. Excision of cervical lymph nodes requires identification of the many nerves, vessels, and other structures that can and should be preserved unless characteristics of the tumor mandate their removal. The RND was attributed to Crile in 1906 and, for many years, was the only described technique for oncologic removal of nodal metastases (Fig. 34.6). All modifications of neck dissection are described in relation to the standard RND, which removes nodal levels I through V and the sternocleidomastoid muscle, internal jugular vein, cranial nerve XI, cervical plexus, and submandibular gland. Preservation of the sternocleidomastoid muscle, internal jugular vein, or cranial nerve XI in any combination is referred to as a modified RND, and the structures preserved are specified for nomenclature. A modified neck dissection may also be referred to as a Bocca neck dissection, named after the surgeon who demonstrated that not only is modified RND equally as effective in controlling neck disease as RND, but also the functional outcomes of patients after modified RND are superior to functional outcomes after RND.24 Although resection of the sternocleidomastoid muscle or one internal jugular vein is relatively nonmorbid, loss of cranial nerve XI leaves a denervated trapezius muscle, which can cause a painful chronic frozen shoulder; however, physical therapy can prevent or limit pain and maximize mobility. Documentation that tumor control was equivalent with modified RND while sparing uninvolved structures within the neck has led to a wider adoption of modified RND and selective neck dissections for HNC. Selective neck dissection is a neck dissection that preserves any level (I–V) and is based on the knowledge of the patterns of regional metastatic spread to the cervical lymphatics. Oral cavity cancers mostly likely involve levels I to III, while pharyngeal and laryngeal most likely involve levels II to IV. Selective neck dissections are frequently used for clinically negative (cN0) necks to spare nodal groups carrying less than a 20% chance of being

778

SECTION VI  Head and Neck

involved with metastatic disease. Postoperative neck radiation or concurrent chemotherapy with radiation may be added based on pathologic staging of excised nodes removed during selective neck dissection. The movement toward more minimal surgery for clinically negative necks (cN0) has progressed to exploration of sentinel lymph node biopsy, which attempts to predict the disease status of the neck based on removal and pathologic examination of the first echelon of tumor-draining nodes. Although sentinel lymph node biopsy has been used extensively with melanoma, its use in HNSCC has been hindered by technical issues, including difficulties with injection of the primary site and proximity of the primary cancer to nodes of interest. A study by the American College of Surgeons Oncology Group examined stages I and II oral SCCs, with findings that sentinel lymph node biopsy and enhanced pathologic examination of sentinel nodes from N0 necks correctly predicted pathologically negative cervical metastasis in 96% of patients.25 Sentinel node technology continues to advance, with more specific detection now being explored in HNSCC. The neck is the site of metastases of HNSCC and is anatomically complex with many critical structures. Neck dissections are used to clear nodal disease or to stage the neck to determine if postoperative therapy is needed. If the neck contains no metastatic disease or only a single neck node is involved, and if there are no poor prognostic features, then the patient may be spared postoperative therapy. 

Oral Cavity There are many diseases of the oral cavity, and a number of systemic diseases can manifest with lesions in the oral cavity. Persistent oral lesions should be appropriately evaluated with history, possible biopsy, and/or follow-up to assess for premalignant or malignant oral lesions. Lesions that come and go, or move to different locations, are less worrisome for cancer. Biopsy to establish a diagnosis should be a relatively small in-office pinch, punch, or incisional biopsy, to allow appropriate work-up if carcinoma is identified. Oral leukoplakia is a white patch in the oral cavity that has a low, but clinically significant, risk of either being cancer or progressing to cancer. The risk of a red lesion (erythroplakia) in the mouth being malignant is higher compared to leukoplakia.26 Mucosal lesions in the oral cavity can be diagnosed on biopsy as dysplasia, which is a histopathologic diagnosis based on a number of architectural and cellular changes. Grading of dysplasia includes mild, moderate, severe, and carcinoma in situ. Severe dysplasia and carcinoma in situ are premalignant lesions and treated similarly by complete surgical excision while mild and moderate dysplasia may be observed or excised. There are a number of oral mucosal lesions that can look like carcinoma but are either selflimited or treated medically, such as lichen planus, midline glossitis, pseudoepitheliomatous hyperplasia, and necrotizing sialometaplasia. In addition to the stratified squamous epithelium lining the oral cavity, the mouth has nearly 1000 submucosal minor salivary glands, two sublingual salivary glands, bone, teeth, and neurovascular structures, all of which can lead to congenital, infectious, inflammatory, and neoplastic pathology. Examples of some rare but destructive or deforming oral cavity lesions that must be distinguished from oral cavity cancer include lymphovascular malformations (Fig. 34.7), granular cell tumors (with tongue as the most common site), hemangiomas, neuromas, neurofibromas, and leiomyomas. There are also a number of benign bone or dental tumors and cysts such as ameloblastoma, keratocystic odontogenic tumor, and dentigerous cyst that are treated surgically by

FIG. 34.7  Vascular malformation of the tongue.

either curettage or segmental mandibular or maxillary resection depending on various factors. Oral Cavity Malignancy The oral cavity is the most common site of head and neck malignancy, and over 90% of oral cavity cancers are SCCs. Additional types of malignancies include minor salivary gland, mucosal melanoma, sarcomas (including Kaposi sarcoma), and lymphoma. Risk factors specific for oral cavity squamous cell cancer include tobacco products, alcohol, areca nut (also known as betel nut), and (for lip cancer) ultraviolet light exposure. Familial predisposition to HNSCC, including oral cavity cancers, occurs in patients with CDKN2A (p16INK4a) mutations that are also predisposed to melanoma and in patients with Fanconi anemia, who are approximately 700 times more likely to develop HNSCC and can do so at a younger age.27,28 Staging of oral cavity cancer is based on tumor size and depth of invasion (DOI) beyond the basement membrane: T1, less than 2 cm and DOI less than 5 mm; T2, 2 to 4 cm and DOI less than 10 mm or less than 2 cm and DOI 5 to 10 mm; T3, greater than 4 cm or any size DOI greater than 10 mm; T4a, invading adjacent structures, such as mandible/maxilla bone (superficial erosion alone of bone or tooth socket by gingival primary does not count as bone invasion), deep muscle of tongue, or facial skin; and T4b, invading masticator space, pterygoid plates, skull base, encases internal carotid artery. For lip cancer, T4a is defined as invasion through the cortical bone and involvement of the inferior alveolar nerve, floor of mouth, or skin of the face.1 Minor salivary gland malignancies are staged according to the site of tumor origin.  Oral Cavity Cancer Treatment Upfront surgery remains the preferred initial treatment for oral cavity carcinoma 29 Surgery for oral cavity malignancy should include wide local resection of the primary tumor with negative margins. In most cases, positive margins in the oral cavity on final pathology should be re-resected if feasible. Reconstructive surgery should be an integral part of the treatment decision, as most oral cavity tumors are resectable, with suitable functional and cosmetic outcome if all reconstructive options are considered. Management of the neck for oral cavity cancer depends on the presence or risk of regional metastases; in general, for early-stage oral cavity SCC, when the DOI is larger than 3 mm, an elective neck dissection is indicated. The extent of neck dissection can be either a selective supraomohyoid neck dissection (levels I–III) for

CHAPTER 34  Head and Neck

779

Lip Alveolar ridge Hard palate Retromolar trigone Stensen duct (parotid papilla) Buccal mucosa Oral tongue Floor of mouth Wharton duct (submandibular papilla)

FIG. 34.8  Anatomy of the oral cavity and its subsites.

a clinically N0 neck or up to a modified RND (sparing all muscular and neurovascular structures if possible) for cN+ disease. If the primary tumor crosses the midline, bilateral neck treatment should be performed. Although not common practice in the United States for early-stage oral cancer, there are data to support elective neck dissection in all patients with T1 to T2 lateralized oral cavity SCC15 and sentinel lymph node biopsy in early-stage oral cavity cancer.25 The recommendation for adjuvant radiotherapy depends on particular pathologic factors, including the presence of perineural or lymphovascular invasion, T-stage, and regional nodal disease. Advanced-stage tumors are generally treated with adjuvant radiotherapy; chemotherapy is reserved for extranodal extension, close or positive margins (that cannot be re-resected), and, in some cases, high node burden or advanced T stage.  Subsites of the Oral Cavity There are seven subsites to the oral cavity (Fig. 34.8), and each should be understood separately because the surgical and reconstructive considerations can be quite distinct. Importantly, the base of tongue, tonsils, tonsillar pillars, soft palate, and posterior pharynx wall are all part of the oropharynx (not the oral cavity) and have distinct functions and often pathology than the oral cavity. While HPV-related cancers of the head and neck have seen a remarkable increase in incidence, HPV is not thought to contribute significantly to oral cavity SCC at this time. Lip. The lip starts at the junction of the facial skin and vermillion border and ends at the point where the upper and lower lips meet when the mouth is closed. The oral commissures are the lateral-most aspects of the lip and are important anatomic considerations as size and position are important for oral competence and mouth opening. In the United States, rates of lip cancer have decreased over the last 40 years, stabilizing at approximately

FIG. 34.9  Lip cancer.

0.7 per 100,000 population, with white males having the highest incidence per person.30 The incidence of lip cancer is much higher in countries that have higher rates of skin cancer (such as Australia) and in countries where tobacco use is more prevalent. Risk factors for lip cancer are similar to other oral cavity cancer sites, with the addition of ultraviolet exposure from sunlight and tanning beds (similar to skin cancers). Approximately 90% of lip tumors involve the lower lip (Fig. 34.9), and the most common type of lip cancer is SCC, but other cancers can include basal cell carcinoma (BCC), melanoma, and minor salivary gland tumors. In the United States, 5-year overall survival for cancers of the lip from 2008 to 2014 was 88.4%.30 The main reconstructive considerations following lip surgery are maintenance of oral competence and appearance. Reconstructive methods for the lips can range from primary closure, mucosal advancement flaps, lip-switch staged flaps, adjacent tissue transfer, nasolabial flaps, and free flaps for cases of total lip reconstruction.  Oral tongue. The oral tongue extends from the floor of mouth to the circumvallate papillae posteriorly. The base of tongue (and lingual tonsils) is not anatomically part of the oral tongue or the oral cavity. The tongue is a muscular organ made of four intrinsic muscles and four extrinsic muscles, which are anchored to bone and/or aponeurosis. Lesions in the tongue can be described by location, including lateral border, dorsal tongue, or ventral tongue. The oral tongue plays a critical function in speech articulation and the oral phase of swallowing. Partial glossectomy is appropriate surgery for tongue malignancy, and larger tumors can require resection of adjacent subsites such as the floor of mouth, alveolar mucosa, mandible, or maxilla. If bilateral lingual arteries and/or hypoglossal nerves are sacrificed as part of tumor extirpation, vascularity and function will be compromised; therefore, if the tumor extent allows, effort should be made to maintain neurovascular integrity to one side of the tongue. If total glossectomy is required for adequate tumor extirpation, the risk of aspiration is greatly increased and patients may require a total laryngectomy to avoid aspiration pneumonia. Reconstruction following glossectomy considers optimizing tongue mobility for speech and swallowing, maintenance of adequate oral bulk for propulsion of food boluses, and minimizing the risk of aspiration. In cases where the extrinsic tongue muscles are separated from the hyoid bone, a hyoid and/or laryngeal suspension procedure should be considered to decrease risk of aspiration. 

780

SECTION VI  Head and Neck

Floor of the mouth. The floor of mouth extends from the lingual surface of the mandible to the ventral tongue anteriorly, and to the glossotonsillar sulcus (or anterior tonsillar pillars) posteriorly. The left and right sides are separated by the lingual frenulum, and lateral to the frenulum on each side is the papilla of the submandibular duct (Wharton duct). The submandibular duct papilla should be cannulated and protected in surgeries involving the floor of mouth whenever possible, and redirection with sialodochoplasty can be performed to maintain submandibular gland salivary flow. The submandibular duct in the floor of mouth is also the most common site of salivary stones, which can oftentimes be successfully removed endoscopically.31 In addition, the lingual nerve (a branch of trigeminal V3 cranial nerve) travels in the floor of mouth quite superficially and is crossed by the duct. Finally, the sublingual gland lies in the floor of mouth and can be the source of a ranula or malignancy. The floor of mouth plays an important role in separating the tongue from the mandible, which is necessary for tongue mobility and a major consideration in oral cavity reconstruction.  Buccal mucosa. The buccal mucosa extends from the inner surfaces of the upper and lower lips to the labial aspect of the maxilla and mandible. Chewing tobacco, including snuff dipping, is especially associated with dysplasia and carcinoma of the buccal mucosa. Additionally, oral submucosal fibrosis commonly involves the buccal mucosa and is associated with consumption of areca nut (commonly referred to as betel nut), which is a fruit of areca palm. Oral submucosal fibrosis is an inflammatory, premalignant condition that leads to significant scarring and fibrosis in this region and resultant trismus. Surgical considerations for the buccal mucosa include the parotid duct (Stensen duct) and parotid papilla, which opens in the buccal mucosa adjacent to the upper second molar. Maintaining adequate mouth opening to avoid trismus is a major reconstructive consideration following ablative surgery of the buccal mucosa, and the use of mouth opening exercises and physical therapy as surgical adjuncts can help to improve function.  Palate. The hard palate is the area medial to the maxillary alveolar ridges and extends posteriorly to the soft palate (which is part of the oropharynx). The hard palate forms the roof of the mouth separating the mouth from the nose. Deep to the mucosal lining, the hard palate is formed by the palatine process of the maxillary bone and the palatine bone. For erosive, submucosal, and invasive lesions of the hard palate, the nasal cavity and sinuses should be examined because a small hard palate lesion could be just the tip of more substantial nasal or paranasal sinus pathology (Fig. 34.10). For example, in immunocompromised patients, invasive fungal sinusitis can present as a palatal erosion, and although not a cancer, it carries a high mortality and must be dealt with expeditiously. There are several benign conditions of the palate with some that mimic a mass or cancer. Torus palatini is a common and benign bone growth in the center hard palate, which only requires surgical removal if it interferes with function such as adequate fitting of upper dentures. Necrotizing sialometaplasia is a self-limited ulcerative inflammatory lesion of minor salivary glands that can mimic carcinoma on physical examination and requires clinical suspicion for appropriate diagnosis and avoidance of inappropriate treatment. Tumors of the hard palate can arise from the stratified squamous mucosa, with the most frequent malignancy being SCC or from minor salivary glands. Due to a thick mucoperichondrium that is fixed to the bone, hard palate malignancies typically require removal of bone for adequate margin, and surgical approaches

FIG. 34.10  Hard palate cancer with erosion into the nasal cavity.

include infrastructure maxillectomy or total maxillectomy depending on extent of tumor. The main reconstructive considerations are separation of the oral and nasal cavities for optimization of speech and swallowing, dental restoration for mastication and appearance, as well as upper alveolar arch reconstruction for midface form. Reconstruction of maxillectomy defects can include dental obturation, soft tissue regional/free flaps for posterolateral defects, or bone-containing free flaps with the possibility of subsequent dental implantation.  Alveolus. The alveolus (or alveolar ridge) and the accompanying gingiva extend from the gingivobuccal sulcus laterally to the floor of mouth and hard palate and make up the dental surfaces of the maxilla and mandible. SCC is the most common malignancy of the alveolus and is much more common at the lower gingiva. Upper gingival primaries often extend onto the hard palate and many surgical considerations are the same for both. Adequate tumor resection requires resection of the alveolar ridge mucosa and underlying periosteum. The periosteum of the mandible is a strong tumor barrier, and tumors that abut the bone may be resected along with the adjacent periosteum only. Tumors adherent to the periosteum should undergo excision with marginal mandibulectomy, which involves resection of the superior or inner cortical portions of the mandible, with preservation of a continuous rim. If there is more than superficial cortical erosion of the mandible, the marrow space is at risk of harboring malignancy, and thus, a segmental mandibulectomy is required for adequate margin control. In many cases of alveolar primary tumors, dental extraction is required for both exposure and osteotomies. Reconstructive considerations of the alveolus include maintaining tongue mobility if adjacent floor of mouth is also resected, vestibule height if adjacent buccal mucosa/inner lip is resected, and dental restoration with prosthesis or implants if possible. For marginal mandibulectomy defects involving adjacent floor of mouth, in many cases, lowering the mandible height can allow for closure by undermining and mobilizing floor of mouth without tethering the tongue. For segmental mandible defects (Fig. 34.11), obturation is not a

CHAPTER 34  Head and Neck

A

B

D

781

C

E

FIG. 34.11  Segmental mandible resection and osseocutaneous fibula free flap reconstruction for alveolar ridge primary carcinoma. (A) Mandible exposure with prebending of plate prior to resection. (B) Defect showing mandible resected along with floor of mouth defect into oral cavity. (C) Resected right mandible with additional piece for improved margin. (D) Fibula free flap in place under titanium plate prior to turning skin inside mouth. (E) Skin paddle flipped over plate for closure of intraoral defect.

suitable reconstructive option and vascularized osseocutaneous (or bone only) free flaps are the preferred reconstruction.  Retromolar trigone. The retromolar trigone is the region defined by the ascending ramus of the mandible starting on each side just posterior to the last molar tooth and ending adjacent to the tuberosity of the maxilla. Numerous adjacent subsites of the oral cavity (buccal mucosa, upper and lower alveolar ridge) and oropharynx (anterior tonsil pillar and soft palate) are immediately adjacent to the retromolar trigone, making exact identification of the primary site difficult. In addition, the attached gingiva in this region is extremely thin, and the inferior alveolar nerve enters the mandible through the mandibular foramen near this region of the mandible. For these reasons, tumors in the retromolar trigone have a higher propensity for bone invasion, and the inferior alveolar nerve is at greater risk when performing marginal mandibulectomy in this region. Reconstructive considerations are the same as those for mandibular or lower alveolar ridge reconstruction, issues inherent to multiple subsite involvement, and trismus. The buccal fat flap can be quickly and easily harvested to reconstruct defects of the retromolar trigone with vascularized tissue. 

Oropharynx Anatomy Until the epidemic of HPV-associated HNC hit the United States, the oropharynx was a low-volume site for HNSCC, with laryngeal cancer and oral cavity cancers far outnumbering those of the oropharynx. Since the epidemic, HPV-positive oropharyngeal SCC (OPSCC) has increased ∼225%, while HPV-negative OPSCC has decreased 50%. Likewise, the 1990s to the present have seen a

steadily decreasing incidence of oral cavity and larynx cancers.32 Since 2012, the incidence of HPV-positive OPSCC has been greater than the incidence of uterine cervical cancer, making oropharyngeal cancer the most commonly diagnosed HPV-associated cancer in the United States.2 In 2015, HPV-positive OPSCC was more common than HPV-associated vulvar, vaginal, anal, and penile cancers combined.33 Anatomic borders of the oropharynx include the circumvallate papillae anteriorly, plane of the superior surface of the soft palate superiorly, plane of the hyoid bone inferiorly, pharyngeal constrictors laterally and posteriorly, and medial aspect of the mandible laterally. Subsites within the oropharynx include the base of the tongue, inferior surface of the soft palate and uvula, anterior and posterior tonsillar pillars, glossotonsillar sulci, pharyngeal tonsils, and lateral and posterior pharyngeal walls. Unlike other sites within the upper aerodigestive tract and other subsites within the oropharynx, the tonsil and base of tongue are predisposed to develop HPV-associated cancers. The selectivity of HPV for the base of tongue and tonsil likely relates to the specialized reticular epithelium that is closely associated with lymphatic tissue that is designated lymphoepithelium. Lymphoepithelial cells are specialized for antigen presentation, and related to this function, they reside in the depths of tonsillar crypts, where they directly contact and intermingle with lymphatic and professional antigenpresenting cells in an area where there is a discontinuous basement membrane (Fig. 34.12). Although poorly understood, it has been suggested that unique molecular characteristics of lymphoepithelial cells or signaling with surrounding lymphatic cells permits or accelerates HPV carcinogenesis. Regardless, the pharyngeal and lingual tonsils within the oropharynx are sites that account for the vast majority of HPV-positive HNSCCs. 

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SECTION VI  Head and Neck

HPV

Superficial cell layer

Intermediate cell layer

APG

Basal cell layer Basement membrane Lymphocytes

FIG. 34.12  The specialized reticulated epithelium lining the tonsillar crypts. The basal, intermediate, and superficial layers are interrupted by migrating nonepithelial cells including lymphocytes and antigen-presenting cells. Destruction to the basement membrane causes contact to viral particles (Drawing by T. Phelps). APG, Antigen-presenting group; HPV, human papillomavirus.

Oropharyngeal Cancer and Treatment Of tumors of the oropharynx, 90% are SCCs. Other tumors include lymphoma of the pharyngeal tonsils or lingual tonsils at the tongue base or salivary gland neoplasms arising from minor salivary glands in the soft palate, tongue base, or less frequently the pharyngeal walls. Initial symptoms of oropharyngeal cancer include sore throat, bleeding, dysphagia and odynophagia, referred otalgia, globus sensation, and voice changes including a muffled quality or “hot potato” voice. HPV-positive cancers are more likely to be asymptomatic and present with a neck mass as the only sign. Trismus suggests spread outside of the oropharynx with involvement of the pterygoid musculature. For treatment decision-making, imaging studies are obtained to evaluate invasion through the pharyngeal constrictors, bony involvement of the pterygoid plates or mandible, invasion of the parapharyngeal space, relationship of the tumor to the carotid artery, relationship of the carotid artery to the pharyngeal wall, involvement of the prevertebral fascia and laryngeal extension. If present, lymph node metastases generally occur in levels II to IV of the jugular chain of nodes. Cystic metastatic nodes are frequently seen with HPV-positive OPSCC, and bilateral metastases are more common with tongue base involvement, especially as cancers approach the midline. Standard concurrent chemotherapy and radiation provide excellent local control and overall survival for nonsmokers with

HPV-positive OPSCC, even for patients with regional lymphatic metastases. For similar patients with HPV-positive OPSCC who have more than 10-pack years of smoking, survival following chemoradiation is not as favorable as patients with minimal smoking history, but still equivalent to patients with early-stage HPVnegative cancer.34 HPV-associated SCC accounts for more than 75% of oropharyngeal cancers in the United States, and the high rate of cure coupled with the toxicity of therapy in these patients has sparked interest in deintensification of therapy. The reasons and support for de-escalation approaches are that response and survival are high with standard therapies, but aggressive therapies currently used for treatment of HNSCC were developed to improve the survival of patients with HPV-negative HNSCC and carry significant morbidity. Patients with HPV-positive OPSCC are healthier, smoke less, are younger, and have longer expected survival compared to HPV-negative HNSCC patients, spurring investigators to seek less aggressive therapies with the goal of decreasing long-term morbidities. In addition to deintensification through limiting chemotherapy or decreasing radiation fields or dosage, transoral robotic surgery (TORS) has a role for de-escalation with excellent results as a single modality for early-stage disease. TORS can also be used to avoid concurrent chemotherapy and is being explored as a means to decrease radiation dosage. A cooperative group trial used pathologic stratification after TORS and neck dissection to assign deintensified radiation for HPV-associated

CHAPTER 34  Head and Neck OPSCC, but results are not yet mature. Other de-escalation trials for untreated advanced-stage HPV-positive HNSCC used response to induction chemotherapy to stratify patients to lower radiation doses, but results are not mature to determine if this strategy is advantageous.35 A randomized cooperative group trial (RTOG 1016) compared concurrent radiation and cetuximab versus cisplatin for patients with HPV-positive OPSCC and nodal metastasis.36 The trial’s goal was to determine if side effects and morbidity associated with cisplatin could be safely avoided by substitution of cetuximab. Unfortunately, the trial found that cetuximab and radiation were inferior to the standard, but more toxic, therapy of cisplatin and radiation. Exploratory trials targeting advanced-stage HPV-positive HNSCC have tested the efficacy of lower radiation doses combined with concurrent weekly cisplatin and found a high rate of pathologic complete response.37 Many of these early de-escalation studies for HPV-positive OPSCC have been promising, with results suggesting that therapy for HPVpositive HNSCC can be deintensified, but the results of the only randomized trial (RTOG 1016) are cautionary showing that some strategies designed to decrease side effects will also decrease efficacy and adversely impact survival. One central issue that hinders de-escalation studies is inability to select patients with low-risk HPV-positive HNSCC. The lone marker used clinically to predict response and survival in patients with HPV-associated HNSCC is patients’ tobacco smoking history. Those with more extensive smoking history have worse response and survival than those who smoked less. Why smoking history correlates with survival for HPV-positive HNSCC is unknown, especially since smoking is not a risk factor for this subset of HNSCC. New predictive biomarkers, especially molecular markers, are needed to appropriately choose low-risk patients with HPVassociated OPSCC for therapeutic deintensification while simultaneously identifying patients who need aggressive therapy. Recently, defects in TRAF3 and CYLD, genes that regulate innate immunity and NF-κB, were found in approximately 30% of HPV-positive, but not in HPV-negative, HNSCCs.11 Patients whose tumors harbored defects in these genes had improved survival compared to patients whose tumors lacked these defects. These results suggest that defects in TRAF3 or CYLD may be used as a predictive biomarker; however, additional confirmatory studies and trials are needed before they can be used for clinical decision-making. Regardless of HPV status, surgery is generally recommended for primary disease that involves bony structures such as the mandible or pterygoid plates, as well as for recurrent disease after radiation failure. However, some centers are individualizing treatment and recommending nonsurgical therapy for early bony invasion. Radiation, chemoradiation, and surgery with or without adjuvant treatment each have a role for management of OPSCC and therapy is commonly personalized based on the tumor characteristics, risk of recurrence, patient age and comorbidities, and expected side effects of therapy. Extensive surgery of the tongue base can significantly impair swallowing and in cases requiring excision of more than half of the base of tongue, chemoradiation is frequently recommended as the initial therapy. On the other hand, lateral cancers of the base of tongue, pharyngeal walls, or tonsil typically have good recovery of swallow and speech functions after surgical excision and secondary healing or reconstruction. Similar outcomes and functional recovery after surgery or nonsurgical therapy for lateralized oropharyngeal cancers makes either surgical and nonsurgical treatments reasonable. The development and adoption of TORS have revitalized surgical therapies of OPSCC. Scopes with angled or flexible optics,

783

combined with articulated or flexible instruments, is the innovation allowing surgeons to feel secure and adopt transoral resection of pharyngeal cancers. Wide-angle and high-quality visualization, coupled with retractors and instruments for exposure and retraction in the confined area of the pharynx, was required to assure margin negative resections for most pharyngeal tumors. With TORS, an assistant is at the head of the bed with the surgeon controlling the robot from a console (Fig. 34.13). The major advantage of TORS relative to traditional mandibular splitting approaches is that TORS avoids division and repair of soft tissues and bone and therefore has advantages for cosmesis, functional recovery, healing time, and complication rate. On the other hand, flap reconstruction is difficult without wider exposure provided by traditional lip and mandible splitting approaches, and following most TORS excisions, healing is by secondary intent. As surgeons have become more familiar with TORS, its utility has expanded, with it now being used or tested for excision of larger tumors, as well as for identification of the site of unknown primaries. 

Hypopharynx Anatomy The hypopharynx is posterior and lateral to the larynx and extends inferiorly from the horizontal plane of the top of the hyoid bone to a horizontal plane extending posteriorly from the inferior border of the cricoid cartilage. The hypopharynx is composed of three distinct subsites and includes bilateral piriform sinuses, posterior hypopharyngeal wall, and the postcricoid space. The postcricoid area extends inferiorly from the two arytenoid cartilages to the inferior border of the cricoid cartilage, connecting the piriform sinuses and forming the anterior hypopharyngeal wall. The piriform sinuses are inverted, pyramid-shaped potential spaces medial to the thyroid lamina; they begin at the pharyngoepiglottic folds and extend to the cervical esophagus at the inferior border of the cricoid cartilage.  Hypopharyngeal Cancer and Therapy Hypopharyngeal cancer is a rare cancer of the head and neck, with approximately 2500 to 3000 new cases diagnosed yearly in the United States. It is more common in older men with a history of alcohol abuse and smoking. The exception is in the postcricoid area in which cancers are more common worldwide in women; this is related to Plummer-Vinson syndrome, a combination of dysphagia, hypopharyngeal and esophageal webs, weight loss, and iron deficiency anemia usually occurring in middle-aged women. In patients who fail to undergo treatment consisting of dilation, iron replacement, and vitamin therapy, postcricoid carcinoma may develop just proximal to the web. Over 95% of all cancers arising in the hypopharynx are SCCs, and hypopharynx cancers are frequently diagnosed at later stages and have the poorest prognosis of all head and neck squamous cell cancers. The role of HPV in carcinogenesis of hypopharyngeal cancer is unclear, with HPV detected in fewer than 30% of tumors; however, a recent large population-based cohort study analyzing the National Cancer Database data revealed a large survival benefit for patients with the HPV-positive hypopharyngeal cancer (52.2% vs. 28.8%) similar to the benefit for HPV-positive oropharyngeal patients, suggesting that HPV is etiologic in a portion of these cancers.38 Hypopharyngeal tumors manifest most commonly with dysphagia, hoarseness, neck mass, weight loss, sore throat, referred otalgia, and hemoptysis, in descending order. A high index of suspicion should be maintained because similar symptoms may

784

SECTION VI  Head and Neck Electrocautery unit Screen

(Bedside assistant)

Nurse

Anesthesiologist Assistant Patient-side cart

Surgeon at console

Electrocautery unit (Surgeon console and patient cart)

FIG. 34.13  Operating room setup for da Vinci transoral robotic surgery.

be seen with the more common gastroesophageal reflux disease. In advanced disease, hoarseness may develop from direct involvement of the arytenoid cartilages, recurrent laryngeal nerves, or paraglottic spaces. The rich lymphatics that drain the hypopharyngeal region contribute to early lymphatic metastasis, with 70% of patients having palpable lymphadenopathy upon presentation. Patients with hypopharyngeal cancer have the highest rate of synchronous malignancies and the highest rate of development of second HNSCC primaries of any of the head and neck sites. Staging for hypopharyngeal cancer is based on the number of involved subsites or size of the tumor. Physical examination for hypopharyngeal lesions includes in-office fiberoptic flexible endoscopy. Having the patient blow against closed lips and closing the palate or pinching the nose inflates the potential spaces of the piriform sinuses and can assist in visualization of the tumor. Moving the larynx back and forth while pressing it against the spine may demonstrate a loss of laryngeal crepitus, and a fixed larynx suggests posterior extension into the prevertebral fascia and indicates that the tumor may not be resectable. Barium swallow may demonstrate mucosal abnormalities associated with an exophytic tumor and is useful for determining the extent of involvement of the cervical esophagus if esophagoscopy is not possible. It also assists in determining the presence and amount of aspiration present. CT or MRI is commonly performed to determine the local extent of the tumor, the presence of thyroid cartilage invasion, extralaryngeal spread, direct extension into the neck, and pathologic lymphadenopathy (Fig. 34.14). Direct laryngoscopy and biopsy under general anesthesia are usually required to obtain diagnostic material, and esophagoscopy can directly determine the inferior tumor extent.

Cancer of the left piriform sinus

FIG. 34.14  Computed tomography scan to review the local extent of the tumor, presence of thyroid cartilage invasion, extralaryngeal spread, direct extension into the neck, and pathologic lymphadenopathy.

The most common area for lymphatic spread is the upper jugular nodes, even with inferior tumors. Other lymphatic regions at risk are the lateral nodes and paratracheal and retropharyngeal nodes. The presence of contralateral cervical metastases or level V involvement is a poor prognostic indicator. With the exception of HPV-associated hypopharyngeal tumors, outcomes for

CHAPTER 34  Head and Neck hypopharyngeal cancers are worse than outcomes for other sites in the head and neck. It is unclear how molecular alterations of the tumor, differences in lymphatic density, or other anatomic characteristics of the hypopharynx contribute to the relatively poor prognosis for hypopharyngeal SCC. For early lesions confined to the medial wall of the piriform or posterior pharyngeal wall, radiation or chemoradiation therapy is effective as a primary treatment modality. Because of the high incidence of postoperative aspiration, laryngeal-sparing partial pharyngectomy is rarely possible for hypopharyngeal cancer. Small tumors of the medial piriform wall or pharyngoepiglottic fold may be amenable to conservation surgery, but they should not involve the piriform apex, and the patient must have mobile vocal cords and adequate pulmonary reserve. Concurrent chemotherapy with radiation for hypopharyngeal cancer is now the most common initial treatment and has resulted in decreased rates of laryngopharyngectomy.39 Surgery is recommended for advanced tumor stage when laryngeal function is already compromised or when posttreatment aspiration is expected. Hypopharyngeal cancer surgery usually requires laryngopharyngectomy, bilateral neck dissection, and central neck dissection, followed by adjuvant radiation plus or minus concomitant chemotherapy. Survival for patients whose initial therapy was chemoradiation or surgery followed by postoperative radiation or chemoradiation is less than 40% at 5 years.39 After total laryngectomy and partial pharyngectomy, primary closure may be possible if at least 4 cm of viable pharyngeal mucosa remains. Primary closure using less than 4 cm of mucosa generally leads to stricture and an inability to swallow effectively. A pedicled regional flap, such as a pectoralis major myocutaneous flap or supraclavicular fasciocutaneous flap, or free flaps can be used to augment any remaining mucosa in these cases. When total laryngopharyngectomy with esophagectomy has been performed, a gastric pull-up may be used for reconstruction, but more contemporary methods to reconstruct the total pharyngectomy defect include free flap reconstruction with enteric (jejunum) flaps or tubed cutaneous flaps. 

Larynx Anatomy The larynx serves critical functions for breathing, airway protection, and voice. To understand the pathology and surgical approaches to the larynx, thorough knowledge of the 3D anatomy of the larynx and its subsites is needed (Fig. 34.15). Using the cartilage framework of the larynx as the boundaries, the concept of a “voice box” becomes apparent. The anterior border of the larynx is composed of the lingual surface of the epiglottis, thyrohyoid membrane, anterior commissure, and anterior wall of the subglottis (which consists of the thyroid cartilage, cricothyroid membrane, and anterior arch of the cricoid cartilage). The posterior and lateral limits of the larynx are the arytenoids, interarytenoid region, aryepiglottic folds, and posterior wall of the subglottis (which is the mucosa covering the surface of the cricoid cartilage). The superior limit anteriorly is the tip and lateral borders of the epiglottis, laterally is the aryepiglottic folds, and posteriorly is the arytenoids and interarytenoid area. The inferior limit is defined as the plane passing through the inferior edge of the cricoid cartilage. The superior laryngeal nerve provides innervation to the larynx with an external branch that supplies the cricothyroid and inferior constrictor muscles and an internal branch with afferent sensory fibers from the mucosa of the false vocal folds and piriform sinuses. The recurrent laryngeal nerve supplies motor innervation to all the intrinsic muscles of the larynx and sensation to the mucosa

785

of the true vocal folds, subglottic region, and adjacent esophageal mucosa. The normal functions of the larynx are to provide airway patency, protect the tracheobronchial tree from aspiration, provide resistance for Valsalva maneuvers and coughing, and facilitate phonation. Therefore, laryngeal pathology is usually manifest with voice, breathing, and sometimes swallowing complaints. Tumors that involve the larynx impair these functions to a variable degree, depending on location, size, and DOI. Dysphonia that persists more than 4 to 6 weeks should be evaluated by direct or indirect laryngoscopy (Fig. 34.16). Vocal cord immobility is identified on flexible laryngoscopy and can be related to central pathology or peripheral pathology along the course of the recurrent laryngeal nerve extending from the skull base into chest and back to the larynx. Evaluation of vocal paralysis should be done before attributing this to viral or idiopathic causes. In addition to primary laryngeal pathology, primary malignancies of the thyroid, thymus, lung, and skull base can manifest as vocal cord paralysis. Metastatic cancers to the lungs, mediastinum, and central or lateral neck can also present with vocal cord paralysis. Benign pathology of the larynx includes respiratory papillomatosis, laryngeal cysts, vocal fold nodules and polyps, contact ulcers, subglottic stenosis, and systemic diseases such as amyloidosis and sarcoidosis. Benign neoplasms such as granular cell tumors, minor salivary gland neoplasms, and chondromas also affect the larynx. Exposure to carcinogens (e.g., tobacco) can cause a series of mucosal changes in the epithelium of the larynx, clinically referred to as leukoplakia (any white lesion of the mucosa) or erythroplakia (a red lesion), that consist of hyperplasia, metaplasia, or variable degrees of dysplasia, which are diagnosed by biopsy.  Laryngeal Cancer and Therapy While the most common malignant lesion of the larynx is SCC derived from the epithelial lining, mucous glands within the mucosa can give rise to malignant histologies associated with those of minor salivary gland origin such as adenocarcinoma, adenoid cystic carcinoma, and mucoepidermoid carcinoma. Other tumors found in the larynx include neuroendocrine carcinoma, adenosquamous carcinoma, chondrosarcoma, synovial sarcoma, and, rarely, distant metastases from other organ systems. Invasive thyroid cancers can also be associated with direct laryngeal invasion. For classification and staging of cancers, the larynx is separated into the supraglottis, glottis, and subglottis, reflecting differences in metastatic potential, treatment, and prognosis.39a The supraglottis includes all structures superior to the laryngeal ventricle, including the suprahyoid and infrahyoid epiglottis, aryepiglottic fold, arytenoids, and false vocal cords. The glottic larynx is formed by the true vocal cords, including the anterior and posterior commissures. The subglottis extends from the glottis to the bottom of the cricoid cartilage. Flexible laryngoscopy is commonly performed in the clinic to assess the extent of tumor involvement and vocal cord motion. Biopsy is frequently performed in the operating room under general anesthesia via direct laryngoscopy, where the tumor extent is determined for accurate clinical staging, and to plan for surgical excision. The extent and location of the tumor determine if partial laryngectomy is possible and if transoral endoscopic approaches are feasible. For T1 tumors with high suspicion of cancer preoperatively, patients can be counseled on the possibility of biopsy with frozen section diagnosis followed by transoral excision during the same anesthetic.

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SECTION VI  Head and Neck

Epiglottis Hyoid bone Thyrohyoid membrane Superior horn of thyroid cartilage Corniculate cartilage Arytenoid cartilage Superior thyroid notch Thyroid cartilage lamina Vocal ligament Median cricothyroid ligament Inferior horn of thyroid cartilage Cricoid cartilage Trachea

Anterior view

Cricoid cartilage

Posterior view Corniculate cartilage

Arytenoid articular surface

Muscular process Vocal process

Lamina

Arytenoid cartilage

Arch Anterosuperior view Epiglottis Hyoepiglottic ligament Hyoid bone Triticeal cartilage Thyrohyoid membrane Thyroid cartilage lamina Oblique line Laryngeal prominence Corniculate cartilage Arytenoid cartilage Median Lateral

Muscular process Vocal process Vocal ligament Thyroepiglottic ligament Cricothyroid ligament Cricoid cartilage

Right lateral view

Cricothyroid joint Trachea

Medial view, median (sagittal) section

FIG. 34.15  Framework anatomy of the larynx demonstrating the boundaries.

CHAPTER 34  Head and Neck

Median glossoepiglottic ligament

Root of tongue (lingual tonsil) Epiglottis Ventricular folds (false cords)

Vocal folds (true cords) Trachea

Aryepiglottic fold

Pyriform fossa Corniculate tubercle Esophagus

A

787

Cuneiform tubercle Interarytenoid incisure Normal larynx: Inspiration

B

Normal larynx: Phonation

FIG. 34.16  Endoscopic view of larynx during inspiration (A) and phonation (B).

CT or MRI with thin-cut slices through the larynx is useful to determine the extent of local and regional disease. Chest imaging is performed to identify second primary cancers and metastatic disease. If larynx-conserving surgeries are being considered, the patient should have adequate pulmonary reserve given the increased risk of aspiration after partial laryngectomy. Formal pulmonary function testing (PFT) can be performed, but guidelines have not been validated, so the need for PFTs is considered individually.  Treatment of Larynx Cancer Treatment decision-making in larynx cancer is complex because competing options can produce similar oncologic outcomes and because the risks to speech and swallow function with different therapies can be hard to predict. Therefore, treatment recommendations are best made with multidisciplinary evaluation taking into account functional outcomes, patient preference, surgical experience, and a number of patient and tumor characteristics. For example, poor pulmonary function may decrease enthusiasm for partial laryngectomy procedures, while a nonfunctional larynx on presentation (e.g., gastric tube and tracheotomy dependent) suggests that larynx preserving treatment options may not benefit the patient. There are many treatment options for tumors not requiring total laryngectomy for surgical management. For early-stage larynx cancer (T1–T2 N0, stage I–II), there is debate as to the difference in voice and swallowing outcomes following surgical versus nonsurgical treatment. T1 to T2 N0 (and select T3 tumors) can be treated with either radiation therapy or partial laryngectomy (+/− neck dissection) with adjuvant treatment guided by pathologic features or presence of nodal disease. T1 to T2 N+ (and select T3N1) tumors can be treated with surgery, radiation therapy, or concurrent chemoradiotherapy. For T3 tumors that would require total laryngectomy for tumor extirpation, an organ-preserving approach with chemotherapy and radiation is frequently recommended, reserving total laryngectomy for treatment failures. Induction chemotherapy options can also be considered in specific circumstances, assessing response to therapy as a harbinger for definitive treatment as surgical versus nonsurgical.

Cartilage invasion or extralaryngeal involvement (i.e., T4a tumors) suggests that the function of the larynx cannot be preserved, indicating that total laryngectomy may be preferred as initial therapy with adjuvant radiation or chemoradiation guided by pathology results.  Complications and Morbidity following Nonsurgical Treatment While the advantages of organ-preserving treatment for certain stage III to IV larynx cancers are obvious, there are a number of posttreatment issues. Standard concurrent chemoradiation regimens are based on cisplatin that is associated with hearing loss and renal injury, and failure of chemoradiation as a primary treatment usually excludes larynx preservation for salvage surgery. In addition, chemotherapy with high-dose radiation can cause laryngeal dysfunction due to chondronecrosis, fibrosis, or extensive lymphedema, even in the absence of recurrent tumor. Pharyngoesophageal stenosis is another complication of nonsurgical treatment of laryngeal cancer. Partial stenosis can be treated with serial dilations, while the rare patient with total stenosis requires anterograde/retrograde rendezvous procedures, open surgical procedures with lumen augmentation, or open surgical procedures with circumferential pharyngoesophageal reconstruction with tubed skin flaps, visceral flaps such as jejunum, or gastric pull-up.  Surgical Therapy Partial laryngectomy. If characteristics of the cancer allow laryngeal preservation surgery, patient factors such as pulmonary function and cardiovascular status are assessed because these patients often have to tolerate some amount of aspiration or airway compromise. Modern partial laryngectomy procedures include open and endoscopic approaches. In the current era, endoscopic (or transoral) laryngeal procedures are far more common than open partial laryngectomy procedures. Transoral laryngeal surgery is typically done with microsuspension laryngoscopy and use of the CO2 laser, called transoral laser microsurgery. TORS is also a promising tool for partial laryngectomy, but with current instrumentation,

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SECTION VI  Head and Neck

exposure, and access issues, TORS is limited given excellent results with transoral laser microsurgery. Currently, most partial laryngectomy procedures are performed endoscopically, but the surgeon should be aware of open partial laryngectomy procedures since there are specific situations in which these remain good options for patients. For T1 tumors of the glottis, a microsuspension laryngoscopy and tumor resection to negative margins with either cold steel or CO2 laser are the most common approaches. Open partial laryngectomy procedures for T1 glottic tumors can include open cordectomy and open anterior frontolateral partial laryngectomy, while larger glottic tumors can be excised with open vertical hemilaryngectomy. Reconstruction of vertical hemilaryngectomy requires strap muscle or fascial free flap to provide bulk against which with unaffected vocal cord can contact to prevent aspiration and for voice. Contraindications to vertical partial laryngectomy include subglottic extension greater than 10 mm anteriorly or 5 mm posteriorly, most T3 glottic cancers, involvement of an entire vocal cord, and more than one third of the contralateral vocal cord. For supraglottic tumors, open horizontal laryngectomy procedures can be done, including supraglottic horizontal partial laryngectomy and supracricoid horizontal partial laryngectomy for supraglottic tumors extending onto the glottis. Each of these procedures requires reconstruction with cricohyoidoepiglottopexy or cricohyoidopexy to suspend the larynx as high as possible to decrease the risk of postoperative aspiration. Open horizontal partial laryngectomies have a greater impact on swallowing, and prolonged rehabilitation is necessary to maximize postoperative recovery. Perioperative tracheotomy is a necessity for the more extensive open approaches, with the goal of decannulation within 2 to 4 weeks of surgery. Near-total laryngectomy is an uncommonly performed procedure, leaving patients dependent on tracheotomy for breathing, but gives them laryngeal voice ability via a tracheoesophageal conduit. There may be a value in parts of the world where speech rehabilitation following total laryngectomy is difficult to obtain.  Total laryngectomy. Total laryngectomy requires removal of the entire larynx (Fig. 34.17) and creation of a permanent tracheostoma by circumferentially sewing the superior trachea to the neck skin. Preservation of pharyngeal mucosa enables primary closure

Epiglottis

Superior cornu of thyroid cartilage Greater cornu hyoid bone

Left pharyngeal wall

Trachea

FIG. 34.17  Total laryngectomy specimen with left piriform sinus and pharyngeal wall also removed

of the pharynx. Adjunct procedures at the time of total laryngectomy can include neck dissection, cricopharyngeal myotomy, pharyngeal plexus neurectomy, hemithyroidectomy on the side of the tumor (preserving the contralateral thyroid to protect the parathyroid glands), primary tracheoesophageal puncture (with or without prosthesis placement), and dividing the sternal heads of the sternocleidomastoid muscle to prevent a deep stoma and assist with postoperative appliance placement. Immediate postoperative risks include pharyngocutaneous fistula and hypocalcemia. All healthcare providers should be aware that patients who have had laryngectomy cannot be intubated transorally; the airway can be secured or intubated only through the tracheostoma in patients who have had laryngectomy. Long-term issues after laryngectomy can include hypothyroidism and perceived loss of taste and smell. Stomal and pharyngoesophageal stenosis is increased if postoperative radiation or chemoradiation is required but can usually be managed with stomaplasty and pharyngeal dilation, respectively. Total laryngectomy can also be performed in the salvage setting for persistent/recurrent tumor after radiotherapy, chemoradiation, or for a nonfunctional larynx. In the setting of prior treatment with radiation with or without chemotherapy, there is a higher risk of pharyngocutaneous fistula and pharyngoesophageal stenosis, and these risks can be improved with use of on-lay or augmentation free or pedicled flaps (e.g., anterior lateral thigh, radial forearm, or pectoralis major flap).  Speech and Swallowing Rehabilitation Speech and swallowing rehabilitation is an integral part of laryngeal cancer treatment requiring preoperative planning. Prior to performing total laryngectomy, speech rehabilitation should be explained by surgeons and/or a speech language pathologist, and if possible, patients can discuss lifestyle implications of a permanent neck tracheostoma and changes in communication with a laryngectomy patient. There are currently a number of speech rehabilitation options following total laryngectomy. The creation of speech requires an air generator (e.g., pulmonary or esophageal exhalation), a sound source (e.g., a vibratory surface), and a set of resonator and articulators within a cavity to transform the sound into intelligible speech (e.g., vocal tract including tongue, mouth, nasal cavity). The main speech rehabilitation options after total laryngectomy include electrolarynx, esophageal speech, and tracheoesophageal puncture with prosthesis. With the electrolarynx, a vibratory sound wave generator is placed directly on the submandibular area, cheek, or oral cavity and the sound generated in this way is transformed in the vocal tract to create speech. The patient mouths words to produce a monotone, electronic-sounding speech that can take considerable time, coaching, and practice to maximize speech intelligibility. Esophageal speech is produced by swallowing air into the esophagus and expulsing the air back through the pharynx, which vibrates as the air passes. The ability to master esophageal speech requires a motivated patient who can control the release of air through the upper esophageal sphincter. Finally, tracheoesophageal puncture is a surgically created conduit between the tracheal stoma and pharynx that is made at the time of laryngectomy or secondarily. This conduit is fitted with a one-way valve that allows passage of air posteriorly from the trachea to the pharynx but prevents food and liquid from passing into the airway. By occluding the stomal opening with the thumb during exhalation, the patient can pass air from the trachea into the pharynx, which vibrates and allows remarkable clarity of

CHAPTER 34  Head and Neck speech. Hands-free mechanisms that do not require manual occlusion of the stoma are preferred by many patients. There are cost and maintenance associated with cleaning and changing the prosthesis on a regular basis. 

Salivary Anatomy There are three paired major salivary glands: the parotid glands, submandibular glands, and sublingual glands. There are also up to 1000 minor salivary glands located submucosally throughout the oral cavity, pharynx, and larynx as depicted (Fig. 34.18). Given the widespread location of salivary glands, tumors and lesions of salivary glands can be found almost anywhere in the head and neck region and upper aerodigestive tract. The parotid glands are the largest salivary glands, and salivary secretions are directed into the oral cavity via the parotid (Stensen) duct opening in the buccal mucosa next to the second maxillary molar. Although there is no capsular or fascial separation, the parotid gland is practically separated into superficial and deep lobes with the separation defined as the plane of the facial nerve. A feature unique to the parotid among the major salivary glands is the presence of lymph nodes within the fascial envelop. Treatment of intraparotid nodes must be considered for parotid cancers as well as for skin cancers of the face, temple, eyelid, ear, and scalp. The submandibular glands are the second largest salivary glands and secrete saliva through the submandibular (Wharton) duct, which opens in the anterior floor of mouth adjacent to the lingual frenulum. The final pair of major salivary glands, the sublingual glands, are found in the floor of mouth, superficial to the lingual nerve and mylohyoid muscle, and drain into the floor of mouth via the ducts of Rivinus, some of which also drain into the Wharton duct. Minor salivary glands drain individually through the mucosa without named ducts.  Nonneoplastic Salivary Disease Nonneoplastic diseases of salivary glands are most commonly obstructive, infectious, or inflammatory and typically manifest as enlargement and tenderness of the affected gland(s). Viruses and or aerobic/anaerobic bacteria are the most common infectious causes and are associated with acute onset and rapid resolution following appropriate therapy. More persistent and indolent granulomatous infections can be caused by typical or atypical tuberculosis, toxoplasmosis, actinomycosis, and Bartonella henselae (cat-scratch disease). Bacterial sialadenitis is typically unilateral and painful, and purulence can often be expressed from the ductal opening with deep palpation and sometimes skin changes are evident (Fig. 34.19). Bacterial salivary gland infections are associated with dehydration (or ductal obstruction) and are more common in elderly or infirm patients who may be on dehydrating medication. Sudden and acute swelling of a single major salivary gland typically indicates ductal obstruction and can be caused by salivary stones, strictures, thick saliva, or bacterial infection. Viral sialadenitis is typically bilateral and can be caused by the mumps virus as well a number of other more common viral infections that impact the upper aerodigestive tract. Multiple, large, bilateral cysts of the parotid glands (lymphoepithelial cysts) can be seen in poorly controlled HIV infection. A major cause of salivary obstruction is salivary stones (sialolithiasis) that cause gland swelling upon eating. Small

789

stones in the parotid or submandibular duct can be managed with salivary endoscopy (Video 34.3). Obstructive or inflammatory sialadenitis can also be manifestations of systemic diseases such as Sjogren syndrome, sarcoidosis, or immunoglobulin G4 (IgG4)-related disease. In addition, patients treated with radioactive iodine for thyroid cancer are much more prone to developing obstructive sialadenitis that can be immediately associated with treatment or up to 1 year following completion of therapy. Neoplasms of the Salivary Glands Salivary neoplasms manifest as masses either within one of the major salivary glands or submucosally when arising from a minor salivary gland. Deep lobe parotid tumors can present as what appears to be unilateral tonsil hypertrophy or soft palate bulge, which is actually caused by mass effect within the parapharyngeal space pushing the palatine tonsil medially within the oropharynx. Deep lobe parotid tumors may have no outward signs or symptoms and are frequently found incidentally on imaging. Warthin tumors are the second most common benign salivary neoplasm and are 18FFDG avid by PET imaging because of the high mitochondrial content of oncocytes within the tumor. When Warthin tumors are found by staging or restaging PET imaging of cancer patients, they raise concern for metastasis or second primary malignancy. Benign salivary neoplasms. Pretreatment evaluation of salivary gland masses may include cross-sectional imaging (CT or MRI) and/or FNA. FNA either with direct palpation or under image guidance (ultrasound or CT) can help identify benign versus malignant salivary tumors. The benefit of FNA in the work-up of salivary gland tumors is controversial since cytologic accuracy varies based on experience of the cytologist and is not definitive with the sensitivity of distinguishing benign from malignant tumors being approximately 80%.40 In addition, most parotid tumors are benign, and surgical removal is recommended for almost all regardless of pathology. Advocates of FNA tout the value of identifying a malignancy prior to surgery for improved patient counseling, patient expectations, and surgical planning (i.e., the likelihood of facial nerve sacrifice, the extent of parotidectomy, and the need for concomitant neck dissection). In addition, intraoperative frozen section pathologic analysis of the tumor can help the guide extent of surgery and avoid the need for reoperation following pathologic diagnosis. Most salivary neoplasms (∼75%) are found in the parotid gland, and the majority of parotid salivary tumors are benign. As a general rule, the larger the salivary gland, the more likely a tumor within that gland is benign; for example, the probability of a tumor being malignant in the parotid, submandibular, and sublingual/minor salivary glands is approximately 25%, 50%, and 75%, respectively. The most common benign neoplasm is pleomorphic adenoma, followed by Warthin tumor (also known as papillary cystadenoma lymphomatosum). Treatment for benign salivary tumors is surgical removal, either parotidectomy, submandibular gland excision, or wide local excision of the minor salivary gland with margin control. Removal of benign salivary gland tumors upon detection improves the accuracy of histopathologic diagnosis, avoids more difficult dissection, and lowers the risk of patient morbidity (e.g., facial nerve injury, aesthetic concerns) by removal of the tumor before it enlarges. Removal of benign tumors also prevents malignant transformation that can occur with some histologies, particularly transformation of pleomorphic adenoma to an aggressive cancer, carcinoma ex

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SECTION VI  Head and Neck

Facial nerve Parotid duct Parotid gland

Masseter muscle

Opening of submandibular duct

Digastric muscle (posterior belly) Submandibular gland Sternocleidomastoid muscle

Digastric muscle (anterior belly)

Submandibular duct Sublingual gland

Mylohyoid muscle

A Minor salivary glands (not encapsulated) Serous Mucus Seromucus (mixed)

B FIG. 34.18  Anatomic distribution of the major salivary glands (A) and minor salivary glands (B).

CHAPTER 34  Head and Neck

A

791

B

FIG. 34.19  (A) Acute right parotitis with infection caused by obstruction of Stensen duct by a salivary stone. (B) Computed tomography scan showing parotid stone within the left duct (not during active infection).

pleomorphic adenoma. On the other hand, some benign tumors may be observed based on patient preference, patient suitability for surgery, patient life expectancy, and histopathology. Patients with Warthin tumors that are not enlarging or that were incidentally found or that occur in patients with metastatic cancer or in patients with contraindications to surgery may be appropriate for observation since this tumor has no malignant potential.  Salivary Cancer and Therapy Salivary malignancy is rare but can be found almost anywhere in the head and neck due to the diverse location of the major and minor salivary glands. The most common presentation is a mass in the location of the salivary gland. Symptoms such as a facial nerve paralysis can indicate a parotid malignancy in the setting of a parotid mass and/or a history of head and neck skin cancers. Population studies have identified an increased relative risk of salivary gland cancer in patients with a history of thyroid cancer, particularly those treated with radioactive iodine.41 The most common primary salivary gland malignancies are mucoepidermoid carcinoma, adenoid cystic carcinoma, adenocarcinoma, carcinoma ex-pleomorphic adenoma, and acinic cell carcinoma. Secretory carcinoma (previously mammary-analog secretory carcinoma) is a recently described salivary malignancy with a translocation mutation that results in the fusion gene ETV6NTRK3.42 In the past, secretory carcinoma was categorized as other carcinomas, most commonly acinic cell carcinoma. Lymph nodes within the parotid gland are common sites of metastasis of the ear, face, and scalp SCC or melanoma. Lymphoma and metastases from other sites (kidney, lung, breast, prostate) can also be seen in the parotid salivary gland. A complete list of salivary tumors (malignant and benign) based on the 2017 World Health Organization (WHO) Classification of salivary gland tumors is shown in Table 34.3.43 Primary salivary malignancy is staged according to the location of the salivary glands. T-stage for the major salivary glands (parotid, submandibular, and sublingual) is based primarily on size: T1, less than 2 cm; T2, 2 to 4 cm; T3, more than 4 cm and/or extraparenchymal extension; T4a, invading skin, mandible, ear canal, and/ or facial nerve; and T4b, invading the skull base, pterygoid plates,

and/or encasing carotid artery.1 Staging of minor salivary gland malignancy is based on the staging systemic of the anatomic location of the minor salivary gland; for example, a salivary carcinoma of the hard palate is staged using the oral cavity cancer staging system. Following appropriate staging work-up, treatment for almost all primary salivary gland cancer is surgery with complete tumor resection. There is some controversy as to the extent of parotidectomy that should be performed for the treatment of malignant tumors. At a minimum, gross total tumor resection is the goal. For deep lobe parotid malignancy, a total parotidectomy (superficial and deep lobe) is usually required and includes removal of all parotid lymph nodes and mobilization of the facial nerve branches. For other malignant parotid tumors, total superficial parotid lobectomy and total parotidectomy have each been advocated. If possible, the facial nerve and its branches should be preserved except in cases of gross tumor invasion (Fig. 34.20). Radical parotidectomy, or extended radical parotidectomy to include resection of skin, facial nerve, or temporal bone, may be required for gross total tumor extirpation. For submandibular, sublingual, and minor salivary gland tumors, gross total tumor resection with negative margins is also the goal. Once again, major nerves whose sacrifice would cause functional deficits (lingual, hypoglossal, marginal mandibular branch of the facial, etc.) should be spared unless the tumor cannot be completely removed without removal of the nerves. Neck dissection is usually recommended for the clinically node positive necks, high-grade primary tumors, and T3 to T4 tumors. For incompletely resected tumors or those with gross residual disease, surgical re-resection should be offered if possible. Adjuvant radiation therapy is typically recommended for gross residual disease and/or adverse features such as intermediate or high-grade, close or positive margins, neural/perineural invasion, lymph node metastases, lymphatic/vascular invasion, and T3 to T4 tumors. Radiation therapy is typically recommended following removal of adenoid cystic carcinomas with radiation fields extended to cover adjacent or involved nerves due to its high propensity for perineural invasion and spread. The role of systemic therapy in salivary malignancy is less studied but can be considered for cases of gross residual disease or adverse pathologic features. 

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TABLE 34.3  2017 WHO classification of primary salivary gland tumors. MALIGNANT TUMORS

BENIGN TUMORS

Acinic cell carcinoma Secretory carcinoma Mucoepidermoid carcinoma Adenoid cystic carcinoma Polymorphous adenocarcinoma Epithelial-myoepithelial carcinoma Clear cell carcinoma Basal cell adenocarcinoma Sebaceous adenocarcinoma Intraductal carcinoma Cystadenocarcinoma Adenocarcinoma, NOS Salivary duct carcinoma Myoepithelial carcinoma Carcinoma ex pleomorphic adenoma Carcinosarcoma Poorly differentiated carcinoma Neuroendocrine and nonneuroendocrine undifferentiated carcinoma Large cell neuroendocrine carcinoma Small cell neuroendocrine carcinoma Lymphoepithelial carcinoma Squamous cell carcinoma Oncocytic carcinoma Sialoblastoma (borderline tumor)

Pleomorphic adenoma Myoepithelioma Basal cell adenoma Warthin tumor Oncocytoma Lymphadenoma Cystadenoma Sialadenoma papilliferum Ductal papillomas Sebaceous adenomas Canalicular adenoma and other ductal adenomas Soft Tissue Tumors Hemangioma Lipoma/sialolipoma Nodular fasciitis Hematolymphoid Tumors Extranodal marginal zone lymphoma of MALT Other Epithelial Lesions Sclerosing polycystic adenosis Nodular oncocytic hyperplasia Lymphoepithelial lesions Intercalated duct hyperplasia

From El-Naggar AK, Chan JKC, Takata T, et al. The fourth edition of the head and neck World Health Organization blue book: editors’ perspectives. Hum Pathol. 2017;66:10–12. MALT, Mucosa-associated lymphoid tissue; NOS, not otherwise specified; WHO, World Health Organization.

Masseter muscle Submandibular gland Facial nerve Diagastric muscle Sternocleidomastoid muscle Greater auricular nerve (divided)

FIG. 34.20  Total parotidectomy field with identification, mobilization, and preservation of all branches of facial nerve.

CHAPTER 34  Head and Neck Surgical Technique Submandibular gland excision is classically performed via a transcervical incision, raising subplatysmal flaps, and protecting the marginal mandibular branch of the facial nerve. The Hayes-Martin maneuver of dividing the facial vein at the inferior aspect of the gland and raising it with the gland fascia can protect the facial nerve branch because it travels superficial to this vein. The superior aspect of the gland is then dissected free (with division of the facial artery) and the inferior aspect of the gland is dissected off the anterior belly of the digastric muscle, and the gland is freed from the posterior border of the mylohyoid muscle, which is retracted medially-superiorly, revealing the lingual nerve, submandibular ganglion, and the submandibular duct. The hypoglossal nerve can be identified with medial-inferior retraction of the mylohyoid muscle. Finally, the gland is dissected free posteriorly, and the facial artery is once again divided along the posterior aspect of the gland. Parotidectomy is demonstrated in Video SALIV-2. The most common incision is a cervicomastoid incision as described by Blair in 1912 and modified by Bailey in 1941. Skin flaps are raised in a subplatysmal plane in the neck and over the parotid fascia in the face. The parotid gland is freed from the sternocleidomastoid muscle, often requiring division of the greater auricular nerve and external jugular vein, and the posterior belly of the digastric muscle is identified. Next, the parotid gland is dissected from the tragal cartilage proceeding deep to the tympanic and mastoid bones and the lateral aspect of the tympanomastoid suture line. The tissue between the digastric dissection and mastoid dissection is carefully divided, and the parotid gland retracted medially. The main trunk of the facial nerve is identified at the tympanomastoid suture line, at the level of the digastric muscle approximately 1 cm anterior, inferior, deep to the tragal pointer. The nerve and its branches are followed distally, dividing the overlying parotid tissue to expose the nerve. The tumor is removed en bloc with visualization and dissection of the nerve branches. Mobilization of nerve branches is required for large or deep lobe tumors as shown in Fig. 34.21. Facial nerve electromyographic monitoring can be used if available per surgeon preference. The parotidectomy defect, which can be deforming depending on the extent of parotidectomy the need for resection of skin, temporal bone, or facial nerve, can be reconstructed with considerations being tumor characteristics and patient wishes. For standard parotidectomy defects, the main goals of reconstruction are to cover the facial nerve, avoid contact of parotid parenchyma with sweat glands of the facial skin, and fill contour defects. Since most reconstructive methods create a barrier between the remaining parotid tissue and the skin, they reduce the risk of Frey syndrome (gustatory sweating). Reconstructive options include the use of acellular dermal matrix, free fat grafting, sternocleidomastoid muscle flap, digastric muscle flap, other regional buried flaps, or buried free flaps. The latter two are more typically used in the case of total parotidectomy defects, especially if a neck dissection is performed concomitantly. 

Nasal Cavity and Paranasal Sinuses Anatomy The nasal cavity and paranasal sinuses comprise a complex 3D structure that abuts critical structures including the orbit, cranium, and skull base. The anatomic boundaries are the palate and oral cavity inferiorly, the soft tissue of the face or nose anteriorly, and the cranial base or orbits laterally, superiorly, and posteriorly.

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FIG. 34.21  Deep lobe parotid tumor with mobilization of the facial nerve inferiorly to expose and remove the tumor.

The nasal cavity begins at the anterior nasal vestibules and contains the bony and cartilaginous nasal septum, structures of the lateral nasal wall, and the olfactory cleft. The paranasal sinuses are divided into paired maxillary and ethmoid sinuses and the central sphenoid and frontal sinuses that are usually completely separated by septae into right and left halves. Structures of the lateral nasal wall include the inferior, middle, and superior turbinates and the superior, middle, and inferior meatus named for the turbinate superior to them. The maxillary, anterior ethmoid, and frontal sinuses drain via the infundibulum into the middle meatus, while the nasolacrimal duct drains into the inferior meatus. The four paired paranasal sinuses lie lateral and superior to the nasal cavity. The frontal sinuses are the most anterior and superior air cavities that lie within the frontal bone and drain into the nasal cavity via the frontal recesses into the middle meatus. The ethmoid sinuses are a honeycomb-like bony labyrinth that are located medial to the orbits and inferior to the anterior cranial fossa. The lamina papyracea is the thin lateral wall of the ethmoid sinus that constitutes the medial wall of the orbit. The anterior and posterior ethmoid cavities are separated by the basal lamella of the middle turbinate with the anterior ethmoids draining into the middle meatus and the posterior ethmoids draining via the sphenoethmoidal recess into the posterior nasal cavity. The sphenoid sinus lies in the middle of the sphenoid bone and is the most posterior and central of the sinuses. The vital structures of the optic nerves, carotid arteries, and cavernous sinuses are immediately adjacent to the lateral walls of the sphenoid sinus, whereas the sella turcica and optic chiasm are immediately superior to the central and posterior superior sinus roof. Additionally, the very lateral boundaries of the sphenoid sinus are adjacent to the second division of the trigeminal nerves (V2) and the vidian nerves. The maxillary sinuses drain into the middle meatus and are bound posteriorly by the pterygopalatine fossa, laterally by the zygomatic process of the maxilla, superiorly by the orbital floor, and inferiorly by the palate. 

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SECTION VI  Head and Neck

Pathology of the Nasal Cavity and Paranasal Sinuses The most common diseases of the nasal cavity and paranasal sinuses are inflammatory in nature related to allergies or infections with viruses or bacterial. Although these inflammatory diseases can cause severe symptoms or even be life-threatening, most frequently, they are intermittent, mild, or self-limited when treated with anti inflammatory drugs and/or antibiotics. The majority of sinus infections resolve with no treatment or a short course of antibiotics; however, some infections require several weeks of antibiotic therapy combined with systemic steroids. On rare occasions, sinus infections can spread into the orbit or intracranially, resulting in the need for intravenous antibiotics and surgical procedures to open and drain the infected sinus. Tumors of the nasal cavity and paranasal sinuses most frequently present at late stages because common associated symptoms of nasal congestion, headache, and facial pain are attributed to more common diseases such as allergies and sinusitis. Tumors can also present with involvement of structures surrounding the paranasal sinuses such as the orbits, the infratemporal fossa, and the cranial fossa. Proptosis, orbital pain, diplopia, epiphora, and vision loss are symptoms of orbital invasion, whereas sensory nerve involvement is heralded by facial numbness in the distribution of the infraorbital nerve or the palate. Tumors that involve the infratemporal fossa often present with trismus from involvement of pterygoid muscles and numbness in the distribution of the third division of the trigeminal nerve (V3). Finally, tumors involving the anterior cranial fossa can cause various central nervous system symptoms such as seizure, personality changes, or meningitis. Both benign and malignant tumors arise within the sinonasal cavity with most arising from the epithelial lining. Schneiderian papilloma (also call sinonasal papilloma) is the most common benign tumor of the nasal cavity,44 and patients present with unilateral nasal congestion and/or epistaxis. This benign tumor is associated with local destruction and has potential for malignant transformation. Schneiderian papilloma should be on the differential diagnosis for any unilateral sinonasal mass (Fig. 34.22). Sinonasal papilloma is classified into three groups: 1. Septal papilloma. These tumors usually began growing on the septum; they are exophytic and not associated with malignant degeneration. 2.  Inverted papilloma (most common). Tumors usually arise along the lateral nasal wall and have an inverted growing pattern with local destruction. Inverted papillomas have an approximately 10% to 15% malignant degeneration rate. 3. Cylindrical cell papilloma (very rare). An oncocytic variant, and like inverted papilloma, these tumors most commonly originate from the lateral nasal wall. These tumors have equal or slightly higher potential for malignant transformation compared to inverted papilloma. The treatment of choice for sinonasal papillomas is complete resection with negative margins. In the case of inverted papilloma and cylindrical papilloma, removal of bone at the base of the tumor is important to prevent recurrence. With complete removal of sinonasal papilloma, recurrence rates are low. Open and endoscopic approaches are safe and effective for resection of these tumors; however, endonasal endoscopic approaches are preferred when possible since they avoid the lateral rhinotomy and associated facial scar. Other benign nasal lesions include hemangioma, benign fibrous histiocytoma, fibromatosis, leiomyoma, ameloblastoma, myxoma, fibromyxoma, and fibro-osseous and osseous lesions, such as fibrous dysplasia, ossifying fibroma, and osteoma. Growth of tumors, weakness of the skull base, or the combination can

allow intracranial tumors or normal tissues to extend into the nasal cavity presenting as encephaloceles, meningoceles, dermoids, or pituitary tumors. CT and MRI are each important imaging studies to obtain for evaluation of sinonasal and skull base tumors, since they provide complimentary information. Together, these imaging studies help clinicians narrow the potential differential diagnoses as they also assist in the identification of intracranial connections, involvement or impingement on critical structures (e.g., orbit, cranial nerves), and tumor vascularity. T2-weighted MRI images are more sensitive to differentiate tumors from obstructed secretions within the nasal or sinus cavities (Fig. 34.22), while CT images help identify bony destruction. Identification of structures involved by or adjacent to the tumor assists with diagnostic, treatment, and surgical planning. It is particularly important to determine if the tumor breeches the skull base, since intracranial involvement can increase the risk of cerebrospinal fluid (CSF) leak, even with diagnostic biopsy. Malignancies of the sinonasal cavity are extremely rare, accounting for less than 1% of all cancers and less than 5% of HNCs. There is a slight male predominance and the peak incidence varies by tumor histology, but patient age most frequently ranges from the 40s to the 60s. Because respiratory epithelium can differentiate into squamous or glandular histology, SCC and adenocarcinoma represent two of the most common sinonasal cancers.45 Risk factors for sinonasal cancer are woodworking or exposure to wood dust or metal/nickel most commonly from commercial smelting. Other sinonasal malignancies include olfactory neuroblastoma, neuroendocrine carcinoma, sinonasal undifferentiated carcinoma (SNUC), malignant fibrous histiocytoma, osteosarcoma, chondrosarcoma, mucosal melanoma, lymphoma, fibrosarcoma, leiomyosarcoma, angiosarcoma, teratocarcinoma, hemangiopericytoma, and metastases from other organ systems (e.g., renal cell carcinoma). In addition to tumor that arises in the nasal and sinus cavities, tumors of the central nervous system and primary skull base tumors such as chordomas, invasive pituitary adenomas, chondrosarcomas, and meningiomas can breech anatomic barriers to present in the sinonasal cavity. In the eighth edition of the AJCC staging manual, the nasal cavity, ethmoid, and maxillary sinuses are distinguished as separate primary sites. The staging system applies only to epithelial carcinomas excluding neuroendocrine and primary skull base pathologies. Additionally, staging currently does not include frontal or sphenoid sinus as separate sites. Primary site staging (T stage) depends on tumor extent, with a key distinction being invasion into adjacent sinonasal structures versus invasion into the orbit, soft tissues of the face, palate, or cribriform plate/brain. Lymph node metastases are uncommon (5%–15%), and elective neck dissection for primary sinonasal carcinomas is generally not recommended. However, if a carcinoma arising in the nasal or sinus cavity extends to the oral cavity or there is concern that the tumor arose in the oral cavity before extending into the sinonasal cavities, then a I through IV elective neck dissection should be considered. Additionally, neck dissection may be performed if neck surgery is needed for vessel control or to identify vessels for free flap reconstruction. Primary elective radiation to the upper neck nodal basins is often included with postoperative adjuvant therapy. Involved nodal groups may include the retropharyngeal, parapharyngeal, submental, and upper jugulodigastric nodes.  Evaluation and Treatment of Sinonasal Cancer Sinonasal cancers can involve or closely approximate the orbits, cranial base, carotid arteries, cavernous sinus, multiple cranial

CHAPTER 34  Head and Neck

A

C

P

FL

795

B

D

FIG. 34.22  (A) Axial computed tomography (CT) of an inverted papilloma showing base of the tumor in the lateral maxillary wall with hyperostosis noted. (B) Coronal CT of an inverted papilloma showing base of the tumor in the lateral maxillary wall with hyperostosis noted. (C) Coronal T1 magnetic resonance imaging (MRI) showing soft tissue boundaries of the tumor filling the maxillary sinus, abutting the orbital wall but without orbital soft tissue invasion. (D) Axial T2 MRI showing the soft tissue tumor filling the maxillary sinus but with T2 hyperintense signal in the sphenoid sinus showing mucous instead of tumor in the sphenoid.

nerves, palate, brain, or other critical structures. The complexity of resection, reconstruction, and radiation planning is hard to overstate speaking to the advantage of experienced multidisciplinary teams for treatment, reconstruction, and rehabilitation.

Preoperative workup consists of primary site imaging often with CT scans and MRI scans as well as local, regional, and distant staging with either CTs or PET/CTs. Biopsy of the primary site is required to establish pathologic diagnosis. Once a diagnosis

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SECTION VI  Head and Neck

A

B

FIG. 34.23  Postoperative (5 year) endoscopic craniofacial T1 magnetic resonance imaging showing no evidence of recurrent disease and a healthy nasoseptal flap skull base reconstruction

is established and staging completed, a multidisciplinary treatment plan is established. Treatment of most sinonasal malignancies relies on a negative margin surgical resection. Postoperative radiation is considered for high-stage disease or high-grade pathologies. For most sinonasal cancers, the utility of chemotherapy as a postoperative radiation sensitizer is unclear; however, concurrent chemotherapy with radiation is considered for treatment of tumors with high-risk pathologic features (e.g., positive margins, nodal disease, extracapsular nodal extension) or for those with high-grade histology (e.g., SNUC or small cell carcinoma). Clinical trials are currently underway to evaluate the utility of neoadjuvant preoperative chemotherapy to shrink tumors before surgery to aid with preservation of critical structures. Preoperative planning is particularly important for sinonasal tumors to identify structures involved or adjacent to the tumor, to plan reconstruction, to assemble the surgical team, and to inform patients of surgical risks that may alter appearance or function. Preoperative studies also identify highly vascular tumors allowing preoperative embolization to decrease intraoperative blood loss and aid with complete tumor removal. Identification of tumors that transgress the dura alerts the treatment team of the potential need for perioperative lumbar drainage and for dural repair. Placement of a tracheotomy for craniofacial surgery to reduce the risk for postoperative pneumocephalus is controversial; however, depending on the planned reconstruction, it can be considered if there is risk of oral swelling, large skull base defects, or in patients who are obese or have obstructive sleep apnea. Endoscopic techniques continue to evolve and allow for control of resection margins for many primary ethmoid as well as anterior skull base malignancies. Primary maxillary carcinoma involving the medial wall can also be performed endoscopically; however, if the palate or lateral maxilla is involved, then a radical maxillectomy with traditional approaches is preferred. Endoscopic techniques have evolved beyond dissection within the sinonasal cavities and now include dissection of the orbital lamina, periorbital, and intraorbital tumors. Additionally, resections of the bony skull base, dura, and intradural olfactory tracts can be

performed via an endoscopic endonasal route (Fig. 34.23). Sinonasal cancers that involve the skin, palate, or intraconal orbit and that have far lateral extent or excessive intracranial extent are not ideal for endoscopic resection. Advancement in reconstruction using endoscopic techniques has been a driver of more aggressive endoscopic resections and has increasingly relied on the pedicled nasoseptal flap.46 This flap is based on the posterior nasal artery that is a reliable branch of the sphenopalatine artery. Increased use of the posteriorly based nasoseptal flap has resulted in a marked decrease of CSF leak rates to less than 5% following endoscopic resection of intracranial pathologies such as craniopharyngiomas, meningiomas, and other primary neural tumors. However, the nasal septum is often involved with sinonasal carcinomas, and margins should not be compromised to preserve the blood supply to the nasal septal flap. In situations that the pedicled nasoseptal flap cannot be used, a tunneled pericranial flap can be used for endonasal skull base reconstruction. This flap is harvested with either a coronal incision or with endoscopic techniques before tunneling it through the nasion.47 For more lateral defects, tunneled temporoparietal fascial flaps are also useful. Endoscopic resection and reconstruction techniques have been remarkably advanced and now offer a less morbid treatment option with outcomes comparable to open surgery for many sinonasal cancers. Primary radiation therapy with concurrent chemotherapy for sinonasal malignancies continues to be studied, and these nonsurgical therapies are used for unresectable tumors and tumors whose excision would cause unacceptable morbidity. In addition, neoadjuvant chemotherapy or chemoradiation therapy plays an integral role for some aggressive histologies (e.g., SNUC, rhabdomyosarcoma, and midline reticulocytosis). Recent data suggest that chemoselection may be used to identify patients with sinonasal undifferentiated cancers who are best treated surgically or nonsurgically. Given the low incidence of sinonasal cancer, trials to advance therapy for this orphan disease have been difficult to complete; however, molecular analysis of these tumors is providing insight into sinonasal carcinogenesis that is changing tumor categorization with future treatment implications. Retrospective analysis of

CHAPTER 34  Head and Neck sinonasal cancers has revealed that as many as one in five are associated with high-risk HPV. Most HPV-associated tumors are SCCs, but HPV is also detected in tumors with adenoid cysticlike features. Identification of HPV in sinonasal tumors is associated with improved overall and disease-free survival, possibly related to increased sensitivity to DNA damaging agents.48 Analysis of SNUCs or nonkeratinizing SCC found loss of SMARCB1 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily B, member 1) expression. These tumors have poor outcomes, and currently, there is no therapy targeting loss of SMARCB1. Poor prognosis is also characteristic of undifferentiated or poorly differentiated squamous cell sinonasal tumors that contain fusions genes of NUT (nuclear protein in testis gene) and BRD4 or BRD3 (bromodomain containing 4 or 3). Although there are currently no targeted therapies for NUT carcinoma, bromodomain inhibitors are a logical choice for patients who fail standard therapy. Finally, IDH2 (isocitrate dehydrogenase 2) hotspot mutations have been identified in a significant portion (∼50%) of SNUCs. Identification of this mutation in a large portion of SNUCs has therapeutic implications since inhibitors of mutant IDH are available. 

Nasopharynx Anatomy The nasopharynx is positioned at the posterior aspect of the nasal cavity and at the superior aspect of the pharynx, is anatomically distinct from the nasal cavity and sinuses, and unlike the sinonasal complex, it contains lymphatic tissue and lymphoepithelial cells. Superiorly, the nasopharynx is defined by the mucosally covered bony choana and sphenoid rostrum. From this superior border, the nasopharynx extends inferiorly to the soft palate comprised largely by the adenoid pad bounded posteriorly by the clivus and upper spine. The lateral walls include the fossae of Rosenmuller, as well as the eustachian tube orifices.  Pathology of the Nasopharynx Inflammatory disease of the nasopharynx is primarily centered on the lymphatic tissue and lymphoepithelial cells of the adenoids. Bacterial and viral infections that cause tonsillitis also infect the adenoids that can lead to nasal obstruction. Persistently enlarged adenoids can contribute to obstructive sleep apnea in pediatric patients, and because of the proximity of adenoids to the eustachian tube orifices, infected adenoids contribute to eustachian tube dysfunction resulting in otitis media with effusion, acute, or chronic otitis media. Treatment of recurrent acute or chronic otitis media may include removal of adenoid tissue in addition to pressure equalization tube insertion. Tumors of the nasopharynx arise from the structures it comprises, including the epithelium, the adenoids (lymphoid and epithelial tissues), and deeper tissues, including fascia, cartilage, bone, and muscle. Although all tumors of the nasopharynx are rare, papillomas, teratomas, and fibromas are among the most commonly diagnosed benign tumors in this area. Angiofibroma, a benign vascular tumor that affects young male patients, is the most common benign tumor of the nasopharynx in children (Fig. 34.24). Although these tumors frequently involved the nasopharynx, juvenile nasopharyngeal angiofibromas (JNAs) originate from the cells surrounding the sphenopalatine artery and extend into the pterygomaxillary space, pushing the posterior wall of the maxillary sinus anteriorly. Molecular analysis of JNA shows frequent activating mutations in beta-catenin, and mutations in the adenomatous polyposis coli (APC) gene are also described by

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possibly explaining why these tumors occur up to 25 times more frequently in adolescents affected by familial adenomatous polyposis. Thornwaldt cyst is a midline mass of the inferior nasopharynx that originates from a remnant of the caudal notochord containing a jelly-like material that can become chronically inflamed. Rarely tumors of the central nervous system and upper spine can also involve the nasopharynx. Nasopharyngeal tumors cause symptoms of nasal obstruction, serous otitis with effusion (often unilateral), and associated conductive hearing loss, epistaxis, and nasal drainage. Findings such as cervical lymphadenopathy, pain, trismus, and cranial nerve involvement suggest malignancy. Diagnosis is aided by clinic examination of the nasopharynx using flexible or rigid nasopharyngoscopes under topical anesthesia. If the mass is easily visualized, exophytic, and not vascular or pulsatile, then in-clinic biopsies can be considered with epistaxis being the primary risk. Otherwise, biopsy is performed in the operating room. CT scanning can identify widening of cranial nerve foramina, indicating nerve involvement, and bony destruction, especially around the clivus and upper spine, and contrast can give an indication of the vascularity of the tumor. MRI is complimentary to assess soft tissue involvement, intracranial extension, perineural spread, cavernous sinus extension, and carotid involvement. Surgery is the primary treatment for benign tumors of the nasopharynx. Endoscopic techniques have evolved to allow for complete negative margin resections of most benign nasopharyngeal pathology without the need for palatal splitting or facial incisions. JNA is a prime example of tumors whose treatment has shifted from open to endoscopic approaches (Fig. 34.24). If tumors are embolized, excision of JNAs is performed 1 to 2 days after embolization of the arterial supply, which most frequently arises from the internal maxillary artery. In addition to benign tumors, cancers arise in the nasopharynx, including nasopharyngeal carcinoma, low-grade nasopharyngeal papillary adenocarcinoma, lymphoma, plasmacytoma, rhabdomyosarcoma, malignant schwannoma, liposarcoma, chondrosarcoma, and chordoma. The staging system of malignant tumors of the nasopharynx only applies to epithelial tumors and is based on confinement of the tumor within the nasopharynx or spread to surrounding structures.1 Although nasopharyngeal carcinoma accounts for much less than 1% of cancers diagnosed in North America, it represents between 15% and 20% of all malignancies in China and Sub-Saharan Africa. There is a strong correlation with EBV in these countries, but the association of EBV and nasopharyngeal carcinoma in the United States is less frequent. The WHO histopathologic grading system describes three types of nasopharyngeal cancer: I. Keratinizing SCC II. Nonkeratinizing SCC III. Undifferentiated carcinoma (most common subtype) WHO type I accounts for 20% of tumors in the United States and is associated with tobacco and alcohol exposure rather than EBV. WHO types II and III represent the remainder of cases in the United States, as well as the endemic form seen in Southeast Asia. In addition to EBV, another virus, HPV, has been found in up to 20% of nasopharyngeal cancers. HPV-positive nasopharyngeal tumors have a trend toward improved overall survival, but analyses have been difficult due to inability to control for EBV status of these tumors. The most common presenting sign of a primary nasopharyngeal cancer is cervical node metastases, particularly to level

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B

A

C

D

E

FIG. 34.24  (A) Axial T1 magnetic resonance imaging (MRI) of a juvenile nasopharyngeal angiofibromas (JNAs) showing infratemporal fossa involvement. (B) Coronal T1 MRI of a JNA showing infratemporal fossa involvement. (C) Sagittal MRI of a JNA showing clival and nasopharyngeal involvement. (D) Postoperative axial T1 MRI of a JNA after infratemporal fossa resection. (E) Postoperative sagittal T1 MRI of a JNA after clival and nasopharyngeal resection.

V and to the posterior cervical triangle. High-dose radiation therapy with concurrent chemotherapy to the primary tumor and bilateral necks including the retropharyngeal nodal basins is the primary treatment. Intensity-modulated radiation therapy has become a standard for nasopharyngeal carcinoma treatment since it results in a lower incidence of xerostomia and may provide a better quality of life compared to conventional 3D or 2D radiation therapy. A phase II RTOG study (RTOG-0225) showed the feasibility of intensity-modulated radiation therapy in a multi-institutional setting with a positive impact on xerostomia marked by low rates of grade III and IV xerostomia rates.49 Surgery is most commonly used for persistent neck disease and for selected cases of local recurrence. Surgery for small and/or midline recurrent tumors can be performed via endonasal endoscopic techniques; however, endoscopic techniques can be limited by inability to control feeding vessels, inability to obtain adequate margins, and limited access the infratemporal fossa (see below). Additionally, vascularized reconstructive options after radiation and/or reirradiation are limited within the nose. Transfacial maxillary swing-type operations are preferred for larger or lateral tumors since they provide much broader access for tumor excision and reconstruction with unirradiated free tissue transfer. A nasopharyngeal mass in pediatric patients should be aggressively pursued since the nasopharynx is the second most

common site for rhabdomyosarcoma. Rhabdomyosarcoma is the most frequent soft tissue sarcoma in pediatric patients and is the most common sarcoma occurring in the head and neck. Radiotherapy plus multiagent chemotherapy is the cornerstone of treatment, with surgery being reserved for recalcitrant or recurrent lesions. Although surgery of the nasopharynx is performed primarily for benign pathologies, numerous open approaches are described for excision of malignant tumors of the nasopharynx and surrounding skull base region. Transoral transpalatal and transfacial with lateral rhinotomy are direct approaches that may be extended to swing of the anterior face of the maxilla and palate or mobilization of the orbit. As adjuncts to the transoral approach, transmandibular or LeFort I osteotomies with midfacial degloving and palatal drop can increase access and visualization. Lastly, lateral approaches that include transmandibular and transparotid as well as far lateral approaches through the temporal bone and jugular fossa can be used for tumors involving the clivus, petroclival synchondrosis, and petrous apex. Endoscopic skull-based tumor surgery of the nasopharynx has evolved significantly over the last decade and indications for its use continue to expand. Endoscopic approaches have advantages of illumination and magnified visualization, allowing curative resections of benign nasopharyngeal and control rates for malignant pathologies that frequently equal open approaches. A key

CHAPTER 34  Head and Neck for control of benign and malignant nasopharyngeal tumors with endoscopic approaches is adherence to oncologic principles of obtaining negative margins.  Parasellar and Pituitary Skull Base Surgery In the late twentieth and early twenty-first century, approaches to the pituitary and pituitary tumor extirpation evolved from transseptal/transsphenoid with microscopic visualization to endonasal transsphenoid with endoscopic visualization. The endoscopic approaches are quicker and less invasive, with less morbidity. Highly functioning skull base programs rely on multidisciplinary collaboration between otolaryngology and neurosurgery to manage diseases of the sellar and parasellar areas. Primary pathologies involving the sella and parasellar region are pituitary adenomas, Rathke cleft cyst, craniopharyngioma, and meningiomas. In addition to being less invasive, the endoscopic techniques provide better visualization of the suprasellar and cavernous sinus areas. Reconstruction using vascularized tissue, such as the nasal septal flap, has reduced postoperative CSF leak rates following sellar or parasellar endoscopic surgery to less than 3%.50 With appropriate otolaryngology follow-up and postoperative care, sinonasal function can be maintained equivalent to baseline. 

Ear and Temporal Bone Anatomy The external ear is made up of the skin and cartilage of the auricle or pinna and the cartilaginous and bony external auditory canal to the tympanic membrane. The middle ear is a space that starts medial to the tympanic membrane and goes to the labyrinthine structures and eustachian tube orifice. It contains the ossicular chain and the facial nerve. The inner ear is contained within the petrous portion of the temporal bone and consists of the cochlea, semicircular canals, and balance organs. The inner ear spans to the internal auditory canal through which cranial nerves VII and VIII pass to the midbrain.  Pathology of the Ear and Temporal Bone Inflammatory and infectious ear disease is very common particularly in the pediatric population due to the frequency of eustachian tube dysfunction and recurrent viral infections. Viral and bacterial infections cause otitis media and are usually self-limited or easily treated with available antibiotics; however, more resistant community-acquired bacteria are becoming more common. Resistant, recurrent, or chronic infections are managed with tympanostomy tube insertion that can be accompanied by adenoidectomy for recalcitrant infections. Guidelines for placement of tympanostomy tubes in children are published by the American Academy of OtolaryngologyHead and Neck Surgery (https://www.entnet.org/sites/default/ files/July2013_TubesFactSheet.pdf ). Tumors of the ear can involve the external ear, ear canal, middle ear, or inner ear structures. Progressively, the tumors become higher stage and are associated with worse survival as they involve deeper more internal structures. Primary neoplasms of the pinna and external ear are most often skin cancers, with sun exposure being the primary risk factor. SCCs have a worse overall prognosis than BCCs. In the external auditory canal, ceruminous gland adenocarcinomas and minor salivary gland carcinomas can also arise but are rare. Within the temporal bone, benign neoplasms include adenoma, bony tumors, schwannomas, paragangliomas, acoustic neuroma, and meningioma. Squamous cell cancer is the most common

799

primary cancer of the temporal bone, with other histologies being adenocarcinoma of middle ear or endolymphatic sac origin, and osteosarcomas. The temporal bone can also be invaded by adjacent parotid cancers and metastatic disease from distant sources.  Evaluation of Ear and Temporal Bone Tumors Evaluation of primary cancers of the ear and temporal bone usually includes pathologic analysis and imaging for anatomic staging. When evaluating skin cancers of the external ear, the external auditory canal should be evaluated for involvement. Evaluation of ear cancers frequently includes audiometric analysis of hearing function in both the affected and nonaffected ears since treatments such as surgery, chemotherapy, and radiation can adversely affect hearing. Fine-cut CT scans including the ears and temporal bones are excellent for determining bony involvement, and MRIs with gadolinium can detect perineural spread and intracranial involvement. Although only 10% of primary ear and temporal bone tumors present with lymph node or distant metastasis, staging with either parotid, neck and chest CT scans, or PET/CT scans is standard. Depending on the location and extent of the cancer within the ear or temporal bone, primary echelon nodal drainage can be to the parotid lymph nodes and/or the upper neck.  Treatment of Ear and Temporal Bone Tumors Primary treatment of ear and temporal bone tumors involves surgery with surgical goals of obtaining negative soft tissue and bony margins while maintaining functional preservation of the facial nerve and potential hearing structures. Involvement of the ear canal by an external ear tumor usually changes the surgical planning from auriculectomy to an auriculectomy with a primary lateral temporal bone resection, but minimal involvement or wellcircumscribed ear canal involvement can be safely removed with a sleeve resection. Parotidectomy and neck dissection or postoperative radiation should be considered for extensive SCCs involving the tragus or anterior external auditory canal to control direct or lymphatic spread to the parotid or parotid lymph nodes and to gauge the need for adjuvant therapy. Radiation therapy is less frequently used as primary treatment for primary ear and temporal bone malignancies; however, it is effective for skin malignancies of the pinna without bone involvement. Postoperative adjuvant radiotherapy should be considered for stage III and IV disease, as well as for poor pathologic prognosticators of perineural spread or metastatic spread to multiple lymph nodes. Chemoradiation can be considered for patients with positive margins or ECS of their involved lymph nodes. Reconstruction of ear and temporal bone defects ranges from local primary closures to pedicled temporoparietal fascial or temporalis flaps to extensive microvascular free flap reconstructions. If the facial nerve has to be sacrificed, primary reconstruction as well as facial reanimation goals should be considered. The paramount consideration after sacrifice of the facial nerve is to protect the patient’s ipsilateral eye from corneal abrasions. Planning for reconstruction must include coverage of exposed bone and neurovascular structures, potential CSF leak closure, and cosmesis. 

HEAD AND NECK RECONSTRUCTION Reconstructive surgery for the head and neck (upper aerodigestive tract and soft tissues) presents unique surgical challenges, although one that has shown great improvement over the last several

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decades. Advancements in technology, skills, and training have given surgeons more leeway in ablative procedures for locoregional control of head and neck neoplasms and in performing salvage procedures after failure of radiation therapy. The goals of reconstructive surgery for defects created by oncologic head and neck surgery, in order of priority, are 1) separation of upper aerodigestive tract contamination from other critical compartments, such as intradural, mediastinal, and deep neck contents; 2) maximization of function, including breathing, speech, swallowing, vision, and hearing; and 3) optimization of form or cosmesis.

Reconstructive Goal 1: Separation of Upper Aerodigestive Tract From Sterile Compartments Without thoughtful and advanced reconstructive surgery, contamination from the upper aerodigestive tract after tumor extirpation can lead to life-threatening complications such as meningitis, encephalitis, mediastinitis, persistent deep neck infection, hemorrhage, pharyngocutaneous fistula, and carotid artery blowout. Therefore, reconstruction of the upper aerodigestive tract should prioritize watertight closure of mucosal wounds and, in some cases (especially areas at high risk of leak), second layer onlay coverage. 

Reconstructive Goal 2: Optimizing Function Of these three major reconstructive goals, perhaps the most challenging is planning a reconstructive method that maximizes function. The most common functional problems following HNC extirpation are related to speech and swallowing. Resection of tissues of the oral cavity, oropharynx, hypopharynx, larynx, or cervical esophagus frequently alters swallowing function. Surgery for oral cancer or pharyngeal cancers can impede tongue motion, mouth opening, and oral competence. Loss of innervation—sensory or motor, locally or at the skull base—can also severely impair swallowing. Complicating matters further is that swallowing and speech rehabilitation are very closely related to airway (including patency of airway and aspiration). Other issues such as orbital position, patency of the external auditory canal, flow of tears into the nose, and eustachian tube patency are functional issues that must also be considered. 

Reconstructive Goal 3: Optimization of Form/Cosmesis The third important goal of head and neck reconstruction is to restore form and appearance. Resection of some HNCs causes cosmetic disfigurement that can have a major impact on patients’ quality of life. Understanding all available reconstruction options, including free tissue transfer, allows the reconstructive surgeons to choose a donor site that optimizes all three goals. Prioritization of reconstructive goals assists in optimizing reconstructive plans. Of course, the size, shape, and location of the expected defect are important in decision-making; however, patient comorbidities, surgeon experience, and the need for postoperative treatment also factor into reconstructive decision-making. For example, reconstruction of a scalp defect with exposed bone resulting from excision of an aggressive malignancy may be optimally reconstructed with hair bearing coverage by tissue expansion with delayed adjacent tissue transfer; however, the reconstructive surgeon must be aware of the impact that this may have in delaying adjuvant treatment such as radiation therapy and thus potentially oncologic outcomes. Thus, reconstructive surgeons should

be an integral part of the multidisciplinary team involved in treatment planning for patients with HNC. 

Reconstructive Options in Head and Neck Surgery For reconstruction in many parts of the body, the simplest method is usually the best. Functional implications inherent to head and neck reconstruction frequently mandate that the simplest reconstructive method may not be the best option. The framework of the reconstructive ladder and reconstructive elevator systematically organize various reconstructive options. The concept of the elevator is particularly important for planning reconstruction of head and neck defects, purporting that more advanced reconstructive techniques that lead to improved function or oncologic outcome may be preferred.51 Secondary Intention Healing by secondary intention is an excellent option in several clinical scenarios in the head and neck. Mucosal defects with an underlying layer of vascularized muscle, fat, or bone that will not contract to the point of impeding function may be left to close by secondary intention. One major advantage of many transoral procedures, including transoral laser microsurgery and TORS, is that significant defects of the larynx and pharynx heal by secondary intention with good functional results. If healing by secondary intent is planned following resection of oropharyngeal tumors, major vessels including internal and external carotid arteries and major branches should be covered. In addition, there should be no connections between the pharynx and neck if a concomitant neck dissection is performed. Healing by secondary intention is frequently used for small to moderate size defects of the lateral pharyngeal wall, hard palate, base of tongue, superficial tongue, external nose, scalp, and larynx.  Primary Closure Primary closure is an option for reconstruction of cutaneous defects and select oral cavity and pharyngeal defects. For facial reconstruction with primary closure, attempts should be made to keep incisions within the relaxed skin tension lines. Incisions that parallel these lines respect facial esthetic units and can be closed with the less tension to decrease scarring. Z-plasty can be used to reorient an unfavorable line of closure into a relaxed skin tension line. For oral cavity and oropharynx reconstruction, attention must be given to risk of dehiscence associated with mobility and muscular forces. Avoiding decreased tongue motion is a primary concern with oral reconstruction since it can lead to difficulties with swallowing or speech. In addition to skin, primary closure can be used for tongue-wedge resections without any significant floor of mouth involvement, minimal lateral tongue defects, and alveolar resections particularly if mandibular height is decreased by a marginal mandibulectomy.  Nonvascularized Grafts Nonvascularized grafts including split-thickness and full-thickness skin grafts, cartilage grafts, and bone grafts can be used in select situations where there is underlying or surrounding healthy vascularized tissue. Prior radiation therapy to the recipient area limits the use of some nonvascularized grafts, particularly bony and cartilaginous grafts. Skin grafts are completely dependent for nutrition from the underlying tissue bed and can heal well over muscle, perichondrium,

CHAPTER 34  Head and Neck and periosteum. They do not take well over bone or cartilage or on tissue that has been irradiated or that is infected or hypovascular. Skin grafts are generally used for superficial oral cavity, ear, or maxillectomy defects. Split-thickness skin grafts contain the epidermis and a portion of the dermis and are harvested with a dermatome at approximately 0.012-inch to 0.018-inch thickness. Thinner grafts require fewer nutrients to remain viable but also contract more when healing. A nonadherent antibiotic-impregnated bolster is commonly used to maintain stability between the split-thickness skin graft and recipient bed for 5 days to allow transmission of nutrients and capillary ingrowth while healing. Harvest sites include the anterior and lateral aspects of the thighs and buttocks. Full-thickness skin grafts are characterized by a better color match, texture, contour and less contracture, but success rates are lower than with split-thickness skin grafts due to increased thickness needed for diffusion. Commonly used donor sites include the postauricular, upper eyelid, neck, and supraclavicular fossa skin. Composite grafts are occasionally needed for cartilage and skin reconstruction of the nasal ala and may be harvested from the conchal bowl without significantly affecting the appearance of the pinna. Similarly, nonvascularized bone grafts from the hip or rib can be used in highly selected laryngeal, nasal, or mandibulomaxillary augmentation but not typically in the setting of previous or anticipated radiation therapy. Acellular cadaveric human dermis that has been prepared by removing immunogenic cells while leaving the collagen matrix intact can be used as a skin graft substitute and avoids donor site morbidity.  Adjacent Tissue Transfer and Local Flaps Local skin flaps can have an excellent tissue match because of their proximity to the defect. Commonly used designs include advancement, rotation, transposition, rhomboid, and bilobed flaps (Fig. 34.25). Similar to primary closure, local flaps should be designed to be incorporated into the lines of relaxed skin tension. Although most local flaps depend on the subdermal plexus of capillaries, there are axial based interpolated local flaps such as the paramedian forehead flap, nasolabial flap, facial artery myomucosal, and nasoseptal flaps that can be used for a variety of defects of the face, nose, oral cavity, and skull base. 

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Regional Flaps Regional flaps are based on axial blood flow and are located at a significant distance from the donor site. Harvest of the flap requires maintenance of the axial blood supply and reaching the defect frequently requires creation of a subcutaneous tunnel. The degree of dissection of the feeding vessels depends on mobility and reach required and care should be taken to avoid kinking or compression of the blood supply. Despite many advances in head and neck reconstruction over the past 40 years, the pectoralis major myocutaneous regional flap first described for head and neck reconstruction in 1979 remains an important reconstructive option due to its ease of harvest, long reach to many parts of the head and neck, and healthy muscle and skin components. The pectoralis flap can be harvested as a musculocutaneous flap or muscle only flap and is based on the pectoral branch of the thoracoacromial artery which enters the muscle from the deep surface and skin perforators through the muscle to supply the skin. Following flap harvest, a subcutaneous tunnel is created from the donor site, over the clavicles, to the defect. Division of the pectoral nerve branches ensures atrophy of the muscle to reduce the bulge over the clavicle over time. Regional flaps commonly used in head and neck reconstruction are shown in Table 34.4, some of which are also depicted in Fig. 34.26. Currently, less commonly used regional flaps in head and neck reconstruction include the deltopectoral flap, infraclavicular artery island flap, trapezius flap, and platysma flap, among others.  Free Tissue Transfer Free tissue transfer entails removal of composite tissue from a distant site, along with its blood supply, and revascularization through microvascular anastomosis of one or more arteries and veins within or near the reconstructive field. Contemporary head and neck microvascular free flap success rates are over 95% at high-volume centers, reflecting incremental improvements in technology, surveillance, training, and experience. Free tissue transfer allows for reconstruction of essentially any head and neck defect, and the choice for the donor site depends on the characteristic of the tissue needed for reconstruction (e.g., size, bone, bulk, epithelial lining) as well as patient and surgeon considerations. Commonly used free flaps used in head and neck reconstruction are the radial forearm, lateral arm, and anterolateral thigh when soft tissue and epithelial lining is needed. Fibula and

FIG. 34.25  Adjacent tissue transfer used for large scalp defect in a young, unirradiated patient.

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A

C

B

FIG. 34.26  Example of regional flaps used in head and neck reconstruction. (A) Pectoralis major myocutaneous flap. (B) Supraclavicular artery island flap. (C) Temporoparietal fascia flap and temporalis muscle flap.

TABLE 34.4  Commonly used regional flaps in head and neck reconstruction. FLAP NAME

VASCULAR SUPPLY

COMPONENTS

Pectoralis major

Pectoral branch of thoracoacromial artery

Supraclavicular artery island Submental artery island Temporalis Temporoparietal fascia

Supraclavicular branch of transverse cervical artery Submental branch of facial artery Deep temporal artery Superficial temporal artery

Latissimus dorsi

Thoracodorsal artery

Deltopectoral flap

Intercostal perforators of the internal mammary artery

Muscle Musculocutaneous Fasciocutaneous Fasciocutaneous Muscle Fascia Fasciocutaneous Muscle Musculocutaneous Fasciocutaneous

TABLE 34.5  Commonly used free flaps in head and neck reconstruction. FASCIAL AND/OR FASCIOCUTANEOUS Radial forearm Anterolateral thigh Lateral arm Ulnar forearm Temporoparietal fascia Lateral thigh

MUSCLE AND/OR MYOCUTANEOUS

BONE-CONTAINING FREE FLAPS

VISCERAL

Rectus abdominis Latissimus dorsi Gracilis Anterolateral thigh with vastus lateralis

Fibula Scapula (lateral border or tip) Radial forearm Iliac crest/external oblique

Jejunal Omentum Gastro-omentum

scapula free flaps are frequently used when soft tissue, epithelial lining, and bone are needed. Rectus and latissimus can be useful for large defects requiring muscle only or muscle with skin. Because of the complexity of reconstruction in the head and neck and because the first choice for free flap reconstruction of a defect may not be possible due to previous therapy or patient considerations, the reconstructive surgeon should have a grasp of many potential donor sites as indicated in Table 34.5. Figs. 34.27 and 34.28 depict some of the commonly used flaps and insets. Additional flaps have also been described in case series such as the medial sural artery perforator free flap, the anterolateral thigh osteomyocutaneous free flap, and a number of perforator-type skin flaps. In addition to the characteristics and composition of the defect that will guide flap selection, patient and donor site considerations include previous surgeries, preoperative testing (such as Allen test

for radial forearm free flap, and arterial imaging for the fibula free flap), pedicle length, pedicle caliber, donor site morbidity, patient preference, and the expectation for osseointegrated implants into bone. Age itself is not a contraindication to free flap reconstruction, although a history of prior failed free flaps, clotting disorders, or of vascular disease should raise caution. Perhaps the most versatile donor site for head and neck free flap reconstruction is the system of flaps from the subscapularis vascular system.52 The subscapularis artery, from the axillary artery, has a number of branches and can thus allow for multiple soft and hard tissue components that have a good amount of independent mobility yet a single arterial and single venous anastomosis (Fig. 34.29). From the pedicled subscapularis artery and vein, the reconstructive surgeon can obtain a large number of flaps based on branches: thoracodorsal artery and circumflex scapular artery (Table 34.6). This system of flaps has further

A

C

B

D

F

E

FIG. 34.27  Commonly used free flaps in head and neck reconstruction. (A) Radial forearm free flap. (B) Fibula free flap. (C) Anterolateral thigh free flap (in this case with a large cuff of vastus lateralis muscle). (D) Scapula free flap. (E) Rectus abdominis free flap. (F) Scapula and latissimus dorsi free flap.

A

B

C FIG. 34.28  (A) Inset of radial forearm free flap for posterolateral hard palate defect. (B) Inset of a supraclavicular artery island flap (regional) for floor of mouth and tongue. (C) Inset of a fibula-free flap and floor-of-mouth/tongue defect.

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SECTION VI  Head and Neck TABLE 34.6  Individual flaps based on the

subscapular artery and vein. FLAP COMPONENTS Scapular fasciocutaneous flap Parascapular fasciocutaneous flap Scapular-parascapular osteofasciocutaneous flap Scapula tip osteofasciocutaneous flap Latissimus dorsi muscle or myocutaneous flap Latissimus dorsi osteomusculocutaneous flap Serratus anterior muscular flap Serratus anterior musculocutaneous flap Serratus anterior with rib flap

Subscapular artery Circumflex scapular artery

Scapular skin flap

Thoracodorsal artery

Range of possible resected bone

Angular branch

Latissimus dorsi muscle

BLOOD SUPPLY (ALL FROM THE SUBSCAPULARIS ARTERY) Circumflex scapular (transverse branch) Circumflex scapular (vertical branch) Circumflex scapular (bone perforators) Thoracodorsal (angular artery branch) Thoracodorsal Thoracodorsal and bone component Thoracodorsal Thoracodorsal Thoracodorsal

These individual flaps can be combined into a mega-flap with multiple components revascularized with a single arterial and single venous anastomosis of the subscapularis artery and vein.

FIG. 34.29  Subscapularis system of flaps.

additional burring needed here

B

A

2 cuts will be guided for this segment Anterior

C

D FIG. 34.30  A virtual surgical plan for mandible reconstruction. (A) Plan for surgical resection. (B) Plan for fibula reconstruction. (C): Patient-specific fibula cutting plan for ostectomy and osteotomies. (D) Three-dimensional model and prebent plate ready prior to surgery (different case).

CHAPTER 34  Head and Neck advantages of rarely being affected by atherosclerosis and minimal donor site morbidity especially in the lame, very elderly, or frail population, in which fibula harvest could severely impact early ambulation and is important for a healthy postoperative recovery.  Virtual Surgical Planning for Reconstruction of the Facial Skeleton Virtual surgical planning (VSP) for maxillomandibular reconstruction is increasingly used, although the exact indications, advantages, and disadvantages are still debated. There is general consensus of value for reconstruction of facial skeletal defects if they are too distorted from trauma or pathology to prebend a plate. In these cases, VSP optimizes occlusion and projection by either prebending or 3D printing reconstruction plates and providing osteotomy cutting guides. The value of 3D planning has been extolled for all maxillomandibular reconstruction to decrease operative time and increased accuracy in occlusion and bone-bone contact. The main disadvantages for VSP are the added cost and, in cases of malignancy, the increased time required to plan the surgery as well as the possibility of not adhering to the preoperative plan because of intraoperative findings related to unrecognized tumor extent and/or margin status. Fig. 34.30 depicts VSP for mandibular reconstruction.

SELECTED REFERENCES Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24–35. This classic article used results of a randomized clinical trial (Radiation Therapy Oncology Group [RTOG] 0129) to analyze survival in the subset of patients with oropharyngeal squamous cell carcinoma (OPSCC) based on human papillomavirus (HPV) status. Findings clarified that patients with HPV-associated OPSCC have improved overall and progression-free survival. The study also identified smoking history of greater than 10 pack-years as a negative prognostic factor in HPV-positive OPSCC.

Chen AY, Fedewa S, Pavluck A, et al. Improved survival is associated with treatment at high-volume teaching facilities for patients with advanced stage laryngeal cancer. Cancer. 2010;116:4744–4752. This article was amongst the earliest to identify the type of treatment center as a significant factor that impacts patient survival. Analysis of patients from the National Cancer Database with advanced laryngeal cancer revealed improved survival for patients treated at high volume teaching/research facilities compared to low volume teaching/research facilities, community facilities, or community cancer centers. The value of multidisciplinary care was implied since high volume for surgical treatment and nonsurgical treatment for laryngeal cancer independently correlated with improved survival.

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Ferris RL, Blumenschein Jr G, Fayette J, et  al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375:1856–1867. The U.S. Food and Drug Administration (FDA) approval of the first immune therapy for head and neck squamous cell carcinoma (HNSCC) was based on this study. The randomized phase 3 trial of recurrent HNSCC after platinum therapy revealed that overall survival was improved in patients treated with nivolumab compared to the standard of care single-agent therapy. Response rate and 6-month progression-free survival were approximately doubled in patients treated with nivolumab, whereas high-grade toxicity was decreased.

Forastiere AA, Zhang Q, Weber RS, et  al. Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol. 2013;31:845–852. Long-term results of a phase 3 clinical trial (Radiation Therapy Oncology Group [RTOG] 91-11) in advanced laryngeal cancer were used to compare survival between patients in the three treatment arms: (1) induction cisplatin/fluorouracil (PF) followed by radiation therapy (RT), (2) concomitant cisplatin/ RT, and (3) RT alone. Short-term results of this trial revealed superior laryngeal preservation and locoregional control for patients in the concomitant treatment arm; however, long-term results revealed no difference in laryngectomy-free survival (at 10 years) with a strong trend toward improved overall survival at 10 years in patients treated in the induction arm compared to concurrent cisplatin/RT. This report shows that early and long-term results of trials may conflict and that delayed analysis may alter impressions about optimal therapy.

Marur S, Li S, Cmelak AJ, et al. E1308: phase II trial of induction chemotherapy followed by reduced-dose radiation and weekly cetuximab in patients with HPV-associated resectable squamous cell carcinoma of the oropharynx—ECOG-ACRIN Cancer Research Group. J Clin Oncol. 2017;35:490–497. This article describes a phase 2 trial (E1308) that used response to induction chemotherapy as a marker to select patients for lower dose radiation therapy in advanced stage human papillomavirus (HPV)associated oropharyngeal squamous cell carcinoma (OPSCC). The trial revealed significantly improved swallowing function for patients treated with deintensified radiation therapy and identified a low-risk group (1.66%; prior ADH, ALH, or LCIS; or prior DCIS with mastectomy) were randomly assigned to exemestane or placebo. After a median follow-up of 35 months, exemestane was associated with a 65% relative reduction in the annual incidence of invasive breast cancer, with 11 invasive cancers detected in the exemestane group and 32 detected in the placebo group. Adverse events occurred in 88% of subjects in the exemestane group and 85% of subjects in the placebo group (P = 0.003), with significant differences noted in the development of endocrine, gastrointestinal, and musculoskeletal symptoms. Exemestane has not been approved by the U.S. Food and Drug Administration as a chemopreventive agent; however, it has a category 1 recommendation for breast cancer prevention in the National Comprehensive Cancer Network clinical practice guidelines.  Prophylactic Mastectomy Prophylactic mastectomy has been shown to reduce the chance of breast cancer development in high-risk women by 90%. Hartmann and colleagues performed a retrospective review of 639 women with a family history of breast cancer who underwent prophylactic mastectomy. The women were divided into high-risk (n = 214) and moderate-risk (n = 425) groups, with women at high risk defined as women with a family history suggestive of an autosomal-dominant predisposition to breast cancer. For women at moderate risk, the number of expected breast cancers was calculated according to the Gail model. On the basis of this model, 37.4 breast cancers were expected to develop, but only 4 cancers occurred, for an incidence risk reduction of 89%. For women in the high-risk cohort, the Gail model would underestimate the risk for development of breast cancer. The expected number of breast

825

cancers was calculated by using three different statistical models from a control study of the high-risk probands (sisters). Three breast cancers developed after prophylactic mastectomy, for an incident risk reduction of at least 90%. Several groups reported on prospective studies in BRCA1 and BRCA2 mutation carriers treated with prophylactic mastectomy versus surveillance and showed that mastectomy is highly effective in preventing breast cancers. More recently, results of riskreducing mastectomy and risk-reducing salpingo-oophorectomy were reported in BRCA1 and BRCA2 mutation carriers followed in 22 centers as part of the PROSE consortium. None of the participants who underwent risk-reducing mastectomy developed a subsequent breast cancer compared with 7% of the women who did not undergo this surgery. The use of risk-reducing salpingooophorectomy reduced the incidence of ovarian cancers from 5.8% to 1.1% and the incidence of breast cancers from 19.2% to 11.4%. Risk-reducing salpingo-oophorectomy was associated with a significant reduction in breast cancer–specific mortality, ovarian cancer–specific mortality, and all-cause mortality. The available data suggest that BRCA mutation carriers should be counseled to consider risk-reducing surgeries as a strategy to reduce cancer incidence and improve survival. Women who undergo annual mammographic screening have an overall 80% chance of surviving breast cancer after it has been detected. Given the penetrance in the range of 50% to 60% for BRCA1 or BRCA2 mutation carriers, the chance of a BRCA1 or BRCA2 mutation carrier dying of breast cancer is approximately 10% if she chooses not to undergo risk-reducing surgery. The use of risk-reducing surgery in women who are not known to have deleterious mutations in BRCA1 or BRCA2 is controversial. Trends have suggested that more women with newly diagnosed breast cancer are choosing to undergo contralateral prophylactic mastectomy as a strategy for reducing the risk of contralateral breast cancer, but it also reduces quality of life. The American Society of Breast Surgeons does not recommend the routine use of contralateral mastectomy in the sporadic cancer patient, but as many women request such procedures, it favors a shared-decision model.10 

Summary: Risk Assessment and Management Understanding risk factors for the development of disease provides clues to pathogenesis and identifies patients likely to benefit from risk-reducing strategies. Although breast cancer can develop in both sexes, the risk of breast cancer development is much higher in women; breast cancer in men is uncommon. Age is a strong determinant of risk and is part of the NCI risk assessment tool. Family history is most significant when breast cancer affects firstdegree relatives (mothers, sisters, and daughters) at a young age and when cases of ovarian cancer are found on the same side of the family. This type of family history may preclude the use of the NCI tool for accurate risk assessment. The most significant histologic risk factors for the development of breast cancer are LCIS, ADH, and ALH. A personal history of breast cancer predisposes to contralateral breast cancer, although adjuvant therapy (endocrine therapy and chemotherapy) reduces this risk. 

BENIGN BREAST TUMORS AND RELATED DISEASES Breast Cysts Cysts within the breast parenchyma are fluid-filled, epitheliallined cavities that vary in size from microscopic to large palpable

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masses containing 20 to 30 mL of fluid. A palpable cyst develops in at least 1 in every 14 women, and 50% of cysts are multiple or recurrent. The pathogenesis of cyst formation is not well understood; however, cysts appear to arise from destruction and dilatation of lobules and terminal ductules. Microscopic studies showed that fibrosis at or near the lobule, combined with continued secretion, results in unfolding of the lobule and expansion of an epithelial-lined cavity containing fluid. Cysts are influenced by ovarian hormones, a fact that explains their variation with the menstrual cycle. Most cysts occur in women older than 35 years; the incidence steadily increases until menopause and sharply declines thereafter. New cyst formation in older women is generally associated with exogenous HRT. Intracystic carcinoma is exceedingly rare. Rosemond reported that only three cancers were identified in more than 3000 cyst aspirations (0.1%). Other investigators confirmed this low incidence. There is no evidence of increased risk for breast cancer associated with cyst formation. A palpable mass can be confirmed to be a cyst by direct aspiration or ultrasonography. Cyst fluid can be straw-colored, opaque, or dark green and may contain debris. Given the low risk for malignancy within a cyst if it appears to be a simple cyst without internal perturbation and smooth borders an aspiration is not necessary. If the mass is complex, then aspiration may be necessary. If the cyst resolves after aspiration and the cyst contents are not grossly bloody, the fluid does not need to be sent for cytologic analysis. If the cyst recurs multiple times (more than twice is a reasonable rule), CNB should be performed to evaluate any solid elements. The entire cystic structure can be percutaneously removed with a vacuum-assisted core needle device.11 Surgical removal of a cyst is usually not indicated but may be required if the cyst recurs multiple times or if needle biopsy reveals findings of atypia, incompletely removes the mass, or if the cyst is large and painful for the patient. 

Fibroadenomas and Other Benign Tumors Fibroadenomas are benign solid tumors composed of stromal and epithelial elements. Fibroadenoma is the second most common tumor in the breast (after carcinoma) and is the most common tumor in women younger than 30 years. In contrast to cysts, fibroadenomas most often arise during the late teens and early reproductive years. Fibroadenomas are rarely seen as new masses in women after age 40 or 45 years. Clinically, fibroadenomas manifest as firm masses that are easily movable and may increase in size over several months and wax and wane with the menstrual cycle. They slide easily under the examining fingers and may be lobulated or smooth. On excision, fibroadenomas are well-encapsulated masses that may detach easily from surrounding breast tissue. Mammography is of little help in discriminating between cysts and fibroadenomas; however, ultrasonography can readily distinguish between them because each has specific characteristics. Fibroadenomas are benign tumors, although neoplasia may develop in the epithelial elements within them. Cancer in a newly discovered fibroadenoma is exceedingly rare (0.2%); 50% of findings in fibroadenomas are LCIS, which is no longer considered stage 0 breast cancer in the eighth edition of the American Joint Committee on Cancer (AJCC) staging system but signifies a high risk for developing breast cancer, 35% are invasive carcinomas, and 15% are intraductal carcinoma. When a tissue diagnosis confirms that the breast mass is a fibroadenoma, the patient can be reassured, and surgical excision is not needed. If the patient is

bothered by the mass or it continues to grow, the mass can be removed with open excisional biopsy or via percutaneous approach.11 Two subtypes of fibroadenoma are recognized. Giant fibroadenoma is a descriptive term applied to a fibroadenoma that attains an unusually large size (typically >5 cm). The term juvenile fibroadenoma refers to a large fibroadenoma that occasionally occurs in adolescents and young adults and histologically is more cellular than the usual fibroadenoma. Although these lesions may display remarkably rapid growth, surgical removal is curative. 

Hamartomas and Adenomas Hamartomas and adenomas are benign proliferations of variable amounts of epithelium and stromal supporting tissue. A hamartoma is a discrete nodule that contains closely packed lobules and prominent, ectatic extralobular ducts. On physical examination, mammography, and gross inspection, a hamartoma is indistinguishable from a fibroadenoma. Page and Anderson described an adenoma or tubular adenoma as a benign cellular neoplasm of ductules packed closely together so that they form a sheet of tiny glands without supporting stroma. During pregnancy and lactation, adenomas may increase in size, and histologic examination shows secretory differentiation. Biopsy is required to establish the diagnosis. 

Breast Infections and Abscess There are two general categories of infections of the breast: lactational infections and chronic subareolar infections associated with duct ectasia. Lactational infections are thought to arise from entry of bacteria through the nipple into the duct system and are characterized by fever, leukocytosis, erythema, and tenderness. Infections of the breast are most often caused by Staphylococcus aureus and may manifest as cellulitis with breast parenchymal inflammation and swelling, termed mastitis, or as abscesses. Treatment requires antibiotics and frequent emptying of the breast. True abscesses require drainage. Initial attempts at drainage should include needle aspiration; surgical incision and drainage should be reserved for abscesses that do not resolve after aspiration and treatment with antibiotics. In such cases, abscesses are generally multiloculated. Ultrasound evaluation can assist in characterizing a breast abscess and help to guide needle aspiration. In women who are not lactating, a chronic relapsing form of infection may develop in the subareolar ducts of the breast that is variously known as periductal mastitis or duct ectasia. This condition appears to be associated with smoking and diabetes. The infections are most often mixed infections that include aerobic and anaerobic skin flora. A series of infections with resulting inflammatory changes and scarring may lead to retraction or inversion of the nipple, masses in the subareolar area, and occasionally a chronic fistula from the subareolar ducts to the periareolar skin. Palpable masses and mammographic changes may result from the infection and scarring; these can make surveillance for breast cancer more challenging. Subareolar infections may initially manifest as subareolar pain and mild erythema. Warm soaks and oral antibiotics may be effective treatment at this stage. Antibiotic treatment generally requires coverage for aerobic and anaerobic organisms. If an abscess has developed, needle aspiration is required in addition to antibiotics. Surgical incision and drainage are reserved for abscesses that do not resolve with these more conservative measures. Repeated infections are treated by excision of the entire subareolar duct complex after the acute infection has resolved completely, together

CHAPTER 35  Diseases of the Breast with intravenous antibiotic coverage. Rarely, patients have recurrent infections requiring excision of the nipple and areola. A presumed infection of the breast generally clears promptly and completely with antibiotic therapy. If erythema or edema persists, a diagnosis of inflammatory carcinoma should be considered and biopsy of the skin as well as underlying breast tissue will be needed. 

Papillomas and Papillomatosis Solitary intraductal papillomas are true polyps of epithelial-lined breast ducts. Solitary papillomas are most often located close to the areola but may be present in peripheral locations. Most papillomas are smaller than 1 cm but can grow to 4 or 5 cm. Larger papillomas may appear to arise within a cystic structure, probably representing a greatly expanded duct. Papillomas are the benign tumor most associated with the development of DCIS. Papillomas located close to the nipple are often accompanied by bloody nipple discharge. Less frequently, they are discovered as a palpable mass under the areola or as a density seen on a mammogram. Treatment is excision through a circumareolar incision. For peripheral papillomas, the differential diagnosis is between papilloma and invasive papillary carcinoma. It is important to distinguish papillomatosis from solitary or multiple papillomas. Papillomatosis refers to epithelial hyperplasia, which commonly occurs in younger women or is associated with fibrocystic change. Papillomatosis is not composed of true papillomas but rather consists of hyperplastic epithelium that may fill individual ducts similar to a true polyp but has no stalk of fibrovascular tissue. 

Sclerosing Adenosis Adenosis refers to an increased number of small terminal ductules or acini. Adenosis is frequently associated with a proliferation of stromal tissue that produces a histologic lesion, sclerosing adenosis, which can be confused with carcinoma grossly and histologically. Sclerosing adenosis can be associated with deposition of calcium, which can be seen on a mammogram in a pattern indistinguishable from the microcalcifications of intraductal carcinoma. In many series, sclerosing adenosis is the most common pathologic diagnosis in patients undergoing needle-directed biopsy of microcalcifications. Sclerosing adenosis is frequently listed as one of the component lesions of fibrocystic disease; it is common and is not believed to have significant malignant potential. 

Radial Scars Radial scars belong to a group of abnormalities known as complex sclerosing lesions. Radial scars can appear similar to carcinomas mammographically because they create irregular spiculations in the surrounding stroma. Radial scars contain microcysts, epithelial hyperplasia, and adenosis and have a prominent display of central sclerosis. The gross abnormality is rarely more than 1 cm in diameter. Larger lesions may form palpable tumors and appear as spiculated masses with prominent architectural distortion on a mammogram. These tumors can cause skin dimpling by producing traction on surrounding tissues. Radial scars generally require excision to rule out an underlying carcinoma. Radial scars are associated with a modestly increased risk for breast cancer. 

Fat Necrosis Fat necrosis can mimic cancer on mammography by producing a palpable mass or density that may contain calcifications. Fat necrosis may follow an episode of trauma to the breast or be related

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to a prior surgical procedure or radiation therapy. Calcifications are characteristic of fat necrosis and can often be visualized on ultrasonography as well. Histologically, fat necrosis is composed of lipid-laden macrophages, scar tissue, and chronic inflammatory cells. This lesion has no malignant potential. 

EPIDEMIOLOGY AND PATHOLOGY OF BREAST CANCER Epidemiology It has been estimated that 266,120 cases of invasive breast cancer and 63,960 cases of in situ breast cancer would be diagnosed in 2018 in the United States. Breast cancer is the second leading cause of cancer-related deaths, second to lung cancer, with approximately 40,920 deaths caused by breast cancer annually. Breast cancer is also a global health problem, with more than 2 million cases of breast cancer diagnosed worldwide each year. The overall incidence of breast cancer was increasing until approximately 1999 because of increases in the average life span, lifestyle changes that increase the risk for breast cancer, and improved survival rates for other diseases. Breast cancer incidence decreased from 1999 to 2006 by approximately 2% per year. This decrease may be attributed to a reduction in the use of HRT after the initial results of the Women’s Health Initiative were published but may also be the result of a reduction in the use of screening mammography (70.1% of women ≥40 years old were screened in 2000 vs. 66.4% in 2005). During the years 2006 to 2010, breast cancer incidence rates were stable. Survival rates in women with breast cancer have steadily improved over the last several decades, with 5-year survival rates of 63% in the early 1960s, 75% during the years 1975 to 1977, 79% during 1984 to 1986, and 90% during 1995 to 2005. The largest decreases in death rates from breast cancer have been in women younger than 50 years (decreases of 3.2% per year), although breast cancer death rates have also decreased in women older than 50 years (by 2% per year). The decreased mortality from breast cancer is thought to be the result of earlier detection via mammographic screening, a decreased incidence of breast cancer, and improvements in therapy. The survival rate for stage I breast cancer is 98.7%. The current treatment of breast cancer is guided by pathology, staging, and more recent insights into breast cancer biology. There is an increased emphasis on defining disease biology and status in individual patients, with the subsequent tailoring of therapies. 

Pathology Noninvasive Breast Cancer Noninvasive neoplasms of the breast were previously broadly divided into two major types, LCIS and DCIS (Box 35.3). LCIS is no longer regarded as a neoplasm of the breast in the eighth edition of the AJCC staging system but is regarded as a risk factor for the development of breast cancer. LCIS is recognized by its conformity to the outline of the normal lobule, with expanded and filled acini (Fig. 35.8A). One variant of LCIS, pleomorphic LCIS, has been recognized more recently as a distinct, more aggressive histopathologic subtype. Pleomorphic LCIS shows marked nuclear pleomorphism compared with classic LCIS. One or more lobules are distended by discohesive cells with irregularly shaped, high-grade nuclei. Pleomorphic LCIS may or may not be associated with comedonecrosis and calcifications. If pleomorphic LCIS is associated with calcifications, it may be detected mammographically. The natural history of pleomorphic LCIS is unknown, and there is debate regarding treatment; many experts

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BOX 35.3  Classification of primary breast

cancer.

Noninvasive Epithelial Cancers Lobular carcinoma in situ Ductal carcinoma in situ or intraductal carcinoma • Papillary, cribriform, solid, and comedo types  Invasive Epithelial Cancers (Percentage of Total) Invasive lobular carcinoma (10%) Invasive ductal carcinoma • Invasive ductal carcinoma, not otherwise specified (50%–70%) • Tubular carcinoma (2%–3%) • Mucinous or colloid carcinoma (2%–3%) • Medullary carcinoma (5%) • Invasive cribriform carcinoma (1%–3%) • Invasive papillary carcinoma (1%–2%) • Adenoid cystic carcinoma (1%) • Metaplastic carcinoma (1%)  Mixed Connective and Epithelial Tumors Phyllodes tumors, benign and malignant Carcinosarcoma Angiosarcoma Adenocarcinoma

suggest that pleomorphic LCIS be treated with surgical excision similar to DCIS. DCIS is more morphologically heterogeneous than LCIS, and pathologists recognize four broad types of DCIS: papillary, cribriform, solid, and comedo. The latter three types are shown in Fig. 35.8. DCIS is recognized as discrete spaces filled with malignant cells, usually with a recognizable basal cell layer composed of presumably normal myoepithelial cells. The four morphologic types of DCIS are rarely seen as pure lesions; DCIS lesions are usually of mixed morphology. The papillary and cribriform types of DCIS are generally lower-grade lesions and may take longer to transform to invasive cancer. The solid and comedo types of DCIS are generally higher-grade lesions. As the cells inside the ductal membrane grow, they have a tendency to undergo central necrosis. The necrotic debris in the center of the duct undergoes coagulation and finally calcifies, leading to the tiny, pleomorphic, and frequently linear forms of microcalcifications that can be seen on mammograms. In some patients, an entire ductal tree may be involved in the malignancy, and the mammogram shows typical calcifications that can span from the nipple extending posteriorly into the interior of the breast (termed segmental calcifications).If not treated, DCIS can transform into an invasive cancer, usually recapitulating the morphology of the cells inside the duct. In other words, low-grade cribriform DCIS tends to be associated with low-grade invasive lesions that retain some cribriform features. DCIS frequently coexists with invasive cancers, and when this is the case, the two phases of the malignancy are usually morphologically similar.  Invasive Breast Cancer Invasive breast cancers are recognized by their lack of overall organized architecture with infiltration of cells haphazardly into a variable amount of stroma, or formation of sheets of continuous and monotonous cells without respect for form and function of a

glandular organ. Pathologists broadly divide invasive breast cancer into ductal and lobular histologic types, which probably does not reflect histogenesis and imperfectly predicts clinical behavior. Invasive ductal cancer tends to grow as a cohesive mass; it appears as discrete abnormalities on mammograms and is often palpable as a discrete lump in the breast. Invasive lobular cancer tends to permeate the breast in a single-file nature, which explains why it remains clinically occult and often escapes detection on mammography or physical examination until the disease is extensive. The growth patterns of invasive ductal and lobular carcinomas are shown in Fig. 35.9. Invasive ductal cancer, also known as infiltrating ductal carcinoma, is the most common form of breast cancer; it accounts for 50% to 70% of invasive breast cancers. Invasive lobular carcinoma accounts for 10% of breast cancers, and mixed ductal and lobular cancers have been increasingly recognized and described in pathology reports. When invasive ductal carcinomas take on differentiated features, they are named according to the features that they display. If the infiltrating cells form small glands lined by a single row of bland epithelium, they are called infiltrating tubular carcinoma (see Fig. 35.9C). The infiltrating cells may secrete copious amounts of mucin and appear to float in this material. These lesions are called mucinous or colloid tumors (see Fig. 35.9D). Tubular and mucinous tumors are usually low-grade (grade I) lesions; these tumors each account for approximately 2% to 3% of invasive breast carcinomas. Medullary cancer is characterized by bizarre invasive cells with high-grade nuclear features, many mitoses, and lack of an in situ component (see Fig. 35.9E). The malignancy forms sheets of cells in an almost syncytial fashion, surrounded by an infiltrate of small mononuclear lymphocytes. The borders of the tumor push into the surrounding breast rather than infiltrate or permeate the stroma. In its pure form, medullary cancer accounts for only approximately 5% of breast cancers; however, some pathologists have described a so-called medullary variant that has some features of the pure form of the cancer. These tumors are uniformly high grade, ER and progesterone receptor (PR) negative, and negative for the human epidermal growth factor receptor 2 (HER-2/neu; HER-2) cell surface receptor. Another rare subtype of breast cancer that is typically high grade and negative for ER, PR, and HER-2 is metaplastic carcinoma. Most metaplastic carcinomas are node negative, but they have high potential for metastatic spread, and 10% of patients present with de novo metastatic disease. Even patients presenting with localized metaplastic carcinoma have a poor prognosis: Approximately 50% experience local or distant relapse. Tumors that lack expression of ER, PR, and HER-2 are often called triple-negative breast cancers. Gene expression profiling and microarray analysis of breast cancers have revealed that triple-negative breast cancers are distinctly different from other ductal breast cancers and may also express molecular markers found in basal or myoepithelial cells. There may be some overlap between triplenegative breast cancer and basal-like breast cancer, but these categories were developed using differing technologies, and the two categories do not exactly overlap. The term basal-like breast cancer describes a specific subtype of breast cancer defined by microarray analysis, whereas triple-negative breast cancer is defined by lack of immunohistochemical detection of ER, PR, and HER-2. The different histologic subtypes of breast cancer have some relationship with prognosis, although this is influenced by tumor size, histologic grade, hormone receptor status, HER-2 status, lymph node status, and other prognostic variables. The prognosis

CHAPTER 35  Diseases of the Breast

A

B

C

D

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FIG. 35.8  Noninvasive breast cancer. (A) Lobular carcinoma in situ (LCIS). The neoplastic cells are small with compact, bland nuclei and are distending the acini but preserving the cross-sectional architecture of the lobular unit. (B) Ductal carcinoma in situ (DCIS), solid type. The cells are larger than in LCIS and are filling the ductal rather than the lobular spaces. However, the cells are contained within the basement membrane of the duct and do not invade the breast stroma. (C) DCIS, comedo type. In comedo DCIS, the malignant cells in the center undergo necrosis, coagulation, and calcification. (D) DCIS, cribriform type. In this type, bridges of tumor cells span the ductal space and leave round, punched-out spaces.

of invasive ductal carcinoma, not otherwise specified, is variable, modified by histologic grade and expression of molecular markers. Basal-like breast cancer is commonly aggressive, and because it is triple receptor negative, there are no targeted treatments for this form of cancer. Invasive lobular breast cancers carry an intermediate prognosis, and tubular and mucinous cancers have the best overall prognosis. These generalizations about the prognosis associated with different histologic subtypes are useful only in the context of tumor size, grade, and receptor status. Modern classification schemes based on determination of molecular markers and breast cancer subtype by microarray analysis are replacing these older morphologic descriptions.  Molecular Markers and Breast Cancer Subtypes Numerous molecular markers have been reported to affect breast cancer outcomes, including molecules in the steroid hormone receptor pathway (ER and PR), molecules in the HER pathway (HER family), angiogenesis-related molecules, cell cycle–related molecules (e.g., cyclin-dependent kinases), apoptosis modulators, proteasomes, cyclooxygenase-2, peroxisome-proliferator-activated receptor γ, insulin-like growth factors (insulin-like growth factor

family), transforming growth factor-γ, platelet-derived growth factor, and p53. Most of these markers are not routinely tested on breast cancer specimens at the time of diagnosis; such testing would not be feasible. Categorizing breast cancer according to the expression of molecular targets of treatments is practical, and the resulting classifications appear to agree with nonbiased classifications based on gene expression. Classification schemes reflect biology and predict treatment efficacy. Incorporating predictive markers into the routine testing of breast cancers can help predict which patients would be most likely to benefit from therapies directed at those markers. The best example of this is testing for ER. Before the discovery of ER, all breast cancers were considered potentially sensitive to endocrine therapy. Pathologic assessment of ER is now performed on all primary tumors and predicts which patients may benefit from and should receive endocrine therapy. Patients whose tumors are ER negative can be spared endocrine therapy. A second important predictive factor in breast cancer, discovered in 1985, is HER-2. This protein is the product of the erb-B2 gene and is amplified in approximately 20% of human breast cancers. The extracellular domain of the receptor is present on the surface

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A

B

C

D

E FIG. 35.9  Invasive breast cancer. (A) Invasive ductal carcinoma, not otherwise specified. The malignant cells invade in haphazard groups and singly into the stroma. (B) Invasive lobular carcinoma. The malignant cells invade the stroma in a characteristic single-file pattern and may form concentric circles of single-file cells around normal ducts (targetoid pattern). (C) Invasive tubular carcinoma. The cancer invades as small tubules, lined by a single layer of well-differentiated cells. (D) Mucinous or colloid carcinoma. The bland tumor cells float like islands in lakes of mucin. (E) Medullary carcinoma. The tumor cells are large and very undifferentiated with pleomorphic nuclei. The distinctive features of this tumor are the infiltrate of lymphocytes and the syncytium-appearing sheets of tumor cells.

of breast cancer cells, and an intracellular tyrosine kinase enzyme links the receptor to the internal machinery of the cell. HER-2 is a member of the epidermal growth factor receptor family of receptor tyrosine kinases. The tyrosine kinase of HER-2 is activated when

the HER-2 receptor heterodimerizes with other members of the family that have been bound by growth factors or when the HER-2 receptor homodimerizes. There is no known ligand that binds to the HER-2 receptor. HER-2 protein overexpression is measured

CHAPTER 35  Diseases of the Breast Samples Grade ER HER-2 BRCA1 ER-associated and other luminal cell genes

Genes

Normal breast epithelial and myoepithelial genes HER-2 amplicon T-cell and B-cell lymphocyte genes Basal cell and proliferation genes

–3 –2 .0 . –1 5 . –1 9 . –0 4 . –0 8 .3 0. 3 0. 8 1. 4 1. 9 2. 5 3. 0

clinically by immunohistochemistry and scored on a scale from 0 to 3+. Alternatively, fluorescence in situ hybridization, which directly detects the number of HER-2–gene copies, can be used to detect gene amplification. Inhibiting the function of the HER-2 receptor slows the growth of HER-2–positive tumors in laboratory models and in clinical trials. Trastuzumab and pertuzumab are antibodies directed against the extracellular domain of the HER-2 surface receptor and are effective treatment for HER-2–positive breast cancer (see “HER-2–Based Targeted Therapy” later on). HER-2 testing is now a standard part of pathologic reporting on the primary tumor and is a predictive marker for HER-2–directed therapies. A logical classification scheme for invasive breast cancer is based on the expression of ER status and HER-2. This classification has the advantage of directing treatment choices. Patients with ER-positive tumors receive endocrine therapies, and patients with HER-2–positive tumors receive HER-2–targeted therapy generally with systemic chemotherapy. However, breast cancer is a heterogeneous disease, and different breast cancers behave in different ways. For example, some ER-positive tumors are indolent and not life-threatening, whereas other ER-positive tumors are very aggressive. In an attempt to subclassify the disease further, investigators are turning to global assessment of gene expression using microarrays; these are composed of oligonucleotide probes to almost every known expressed sequence of DNA in the human genome. Similar technologies based on single-nucleotide polymorphisms in the cancer DNA and profiles of expressed proteins are being developed to subclassify cancers and direct treatment. A typical microarray experiment, commonly known as a heat map, is shown in Fig. 35.10; the colors indicate levels of gene expression. Such a portrayal of the disease shows how different ER-positive tumors are from ER-negative tumors and underscores the modern concept that subclassification is needed not only to define different groups of breast cancer but also to guide treatment. In Fig. 35.10, HER-2–positive tumors form two clusters (in green at the top), although these clusters are fused together in many depictions. HER2–positive tumors cluster similarly and are responsive to inhibitors of the HER-2 receptor (e.g., trastuzumab and pertuzumab). An unexpected finding is the uniqueness of tumors that are both ER negative and HER-2 negative. These tumors, also negative for PR, are called triple-negative cancers. They express proteins in common with myoepithelial cells at the base of mammary ducts and are also called basal-like cancers (see earlier). Women who carry a deleterious mutation in BRCA1 (but not BRCA2) are much more likely to contract a basal-like cancer (triple-negative) than other subtypes. In addition to being used to classify breast cancer subtypes, molecular markers are used to select patients for systemic treatment (e.g., chemotherapy, endocrine therapy) and to predict the tumor response to these pharmacologic treatments. The simplest example is the use of ER or HER-2 status to predict the response to endocrine treatment or trastuzumab. Microarray experiments use thousands of gene transcripts (messenger RNAs) to provide a snapshot of the molecular phenotype of an individual cancer. To adapt this technology for clinical application, investigators selected critical assemblies of gene products that provide the same predictive ability as a nonbiased, genome-wide analysis. The most utilized in the United States is a 21-gene test that can be used on paraffin-embedded tumor material from breast surgical specimens (Oncotype DX assay, a 21-gene recurrence score assay). Originally designed to predict the recurrence of ER-positive, node-negative breast cancer treated with adjuvant endocrine therapy, the 21gene recurrence score assay provides a recurrence score for ERpositive breast cancer that is used clinically to determine whether

831

FIG. 35.10  Microarray representation of human breast cancer. This portrayal of global gene expression is called a heat map, with shades of red indicating high gene expression and shades of blue indicating low gene expression relative to a mean across tissue samples. Tissue samples are present across the top in columns, and individual genes are in rows down the side; the intersection is an individual gene in a particular sample. A computer-clustering algorithm aligns samples with similar gene expression and genes with similar expression patterns in the samples (two-way clustering). This illustration provides an unbiased look at breast cancer according to gene expression. The dendrogram at the top depicts the degree of similarity of the tissue samples: yellow, normal breast epithelium; blue, predominantly ER-positive cancers; red, basal-like or triple-negative cancers; and green, HER-2–positive cancers (in two clusters defined by the degree of lymphocytic infiltrate). The stripes at the top indicate grade (shades of darker purple are higher grades), ER expression (purple is positive; green is negative), and HER-2 (purple is positive; green is negative). BRCA1 mutation was determined for other reasons in this experiment. (Courtesy Dr. Andrea Richardson, Department of Pathology, Brigham and Women’s Hospital, Boston, MA.) ER, Estrogen receptor; HER-2, human epidermal growth factor receptor 2.

women with high-risk ER-positive breast cancer should receive adjuvant chemotherapy in addition to tamoxifen or other endocrine therapies (see “Endocrine Therapy” later on). Another multigene assay for determining prognosis is the MammaPrint assay. The MammaPrint assay analyzes data from 70 genes to develop a risk profile. The test provides a simple readout of low-risk or highrisk disease. This tool can be used for risk assessment in patients with ER-positive or ER-negative tumors. Tests based on critical combinations of genes will likely increasingly be used to guide clinical decision-making regarding breast cancer treatment.  Other Tumors of the Breast Phyllodes tumors. Tumors of mixed connective tissue and epithelium constitute an important group of unusual primary breast tumors. On one end of the spectrum are benign fibroadenomas,

832

SECTION VII  Breast

which are characterized by a proliferation of connective tissue and a variable component of ductal elements that may appear compressed by the swirls of fibroblastic growth. Clinically more challenging are phyllodes tumors, which contain a biphasic proliferation of stroma and mammary epithelium. First called cystosarcoma phyllodes, these tumors are now called phyllodes tumors in recognition of their usually benign course. However, with increasing cellularity, an invasive margin, and sarcomatous appearance, these tumors may be classified as malignant phyllodes tumors. Benign phyllodes tumors are firm lobulated masses that can range in size, with an average size of approximately 5 cm (larger than average fibroadenomas). Histologically, benign phyllodes tumors are similar to fibroadenomas, but the whorled stroma forms larger clefts lined by epithelium that resemble clusters of leaf-like structures. The stroma is more cellular than in a fibroadenoma, but the fibroblastic cells are bland, and mitoses are infrequent. Phyllodes tumors are seen on mammography as round densities with smooth borders and are indistinguishable from fibroadenomas. Ultrasonography may reveal a discrete structure with cystic spaces. The diagnosis is suggested by the larger size, history of rapid growth, and occurrence in older patients. Cytologic analysis is unreliable in differentiating a low-grade phyllodes tumor from a fibroadenoma. CNB is preferred, although it is difficult to classify phyllodes tumors with benign or intermediate malignant potential on the basis of a limited sampling. The final diagnosis is best made by excisional biopsy followed by careful pathologic review. Local excision of a benign phyllodes tumor, similar to local excision of a fibroadenoma, is curative. Intermediate tumors, also called borderline phyllodes tumors, are tumors to which it is difficult to assign a benign classification. These tumors are treated by excision with negative margins (often suggested to be at least 1 cm) to prevent local recurrence. Affected patients are at some risk for local recurrence, most often within the first 2 years after excision. Close follow-up with examination and imaging allows early detection of recurrence. At the other end of the spectrum of tumors of mixed connective tissue and epithelium are frankly malignant stromal sarcomas. Malignant phyllodes tumors are characterized by features such as cellular atypia, high number of mitoses, and stromal overgrowth, the extent of which is the main predictor of survival. These tumors are treated similarly to soft tissue sarcomas that occur on the trunk or extremities. Complete surgical excision of the entire tumor with a margin of normal tissue is advised. When the tumor is large with respect to the size of the breast, total mastectomy may be required. If mastectomy is performed and the margins are negative, radiation therapy is not recommended. If the margins are concerning or close, if the tumor involves the fascia or chest wall, or if the tumor is very large (>5 cm), irradiation of the chest wall is considered. If only wide local excision is performed, adjuvant radiation therapy is recommended. As with other soft tissue sarcomas, regional lymph node dissection is not required for staging or locoregional control. Metastases from malignant phyllodes tumors occur via hematogenous spread; common sites of metastasis include lung, bone, abdominal viscera, and mediastinum. Systemic therapeutic agents used for sarcomas have resulted in minimal success.  Angiosarcoma. Angiosarcoma, a rare vascular tumor (1% of all breast tumors), may occur de novo in the breast parenchyma or within the dermis of the breast after irradiation for breast cancer. Angiosarcoma has also been seen to develop in the upper extremity of patients with lymphedema, historically 10 to 15 years after radical mastectomy and irradiation. Angiosarcomas arising in the

absence of previous radiation therapy or surgery (primary angiosarcomas) generally form an ill-defined mass within the parenchyma of the breast. In contrast, angiosarcomas caused by prior radiation therapy (secondary angiosarcomas) arise in the irradiated skin as purplish vascular proliferations that may go unrecognized for a period of time. The development of angiosarcoma in the ipsilateral arm to surgery is called Stewart-Treves syndrome and is secondary to long-standing lymphedema. The differential diagnosis is frequently between malignant angiosarcoma and atypical vascular proliferations in irradiated skin. Histologically, angiosarcoma is composed of an anastomosing tangle of blood vessels in the dermis and superficial subcutaneous fat. The atypical and crowded vessels invade through the dermis and into subcutaneous fat. These tumors are graded by the appearance and behavior of the associated endothelial cells. Pleomorphic nuclei, frequent mitoses, and stacking of the endothelial cells lining neoplastic vessels are features seen in highergrade lesions. Necrosis, rarely seen in hemangiomas, is common in high-grade angiosarcomas. Clinically, radiation-induced angiosarcoma is identified as a reddish brown to purple raised rash within the radiation portals and on the skin of the breast or chest wall. As the disease progresses, tumors protruding from the surface of the skin may predominate. Mammography is unrevealing in most cases of angiosarcoma. In the absence of metastatic disease at initial evaluation, surgery is performed to secure negative skin margins and usually involves a total mastectomy. A split-thickness skin graft or myocutaneous flap may be needed to replace a large skin defect created by the resection. Metastasis to regional nodes is extraordinarily rare, and axillary dissection is not required. Patients remain at high risk for local recurrence after resection of angiosarcoma. For patients who present with primary angiosarcoma of the breast, radiation therapy is beneficial in locoregional treatment. Metastatic spread occurs hematogenously, most commonly to the lungs and bone and less frequently to the abdominal viscera, brain, and contralateral breast. Adjuvant chemotherapy is generally recommended and may improve outcomes of patients with angiosarcoma. Angiosarcomas can be divided into low-, intermediate-, and high-grade lesions with the commensurate survival being 91%, 68%, and 14%, respectively 

STAGING OF BREAST CANCER Breast cancer stage is determined clinically by physical examination and imaging studies before treatment, and breast cancer stage is determined pathologically by pathologic examination of the primary tumor and regional lymph nodes after definitive surgical treatment. Staging is performed to group patients into risk categories that define prognosis and guide treatment recommendations for patients with a similar prognosis. Breast cancer is classified with the tumor-nodemetastasis (TNM) classification system, which groups patients into four stage groupings based on the size of the primary tumor (T), status of the regional lymph nodes (N), and presence or absence of distant metastasis (M). The most widely used system is that of the AJCC. This system is updated every 6 to 8 years to reflect current understanding of tumor behavior. The TNM classification is shown in Table 35.4.12 Staging with the eighth edition of the AJCC has become much more complex as it includes T, N, and M as well as biologic markers (ER, PR, and HER-2), histologic grade, and, where applicable, Oncotype Dx score. For example, a tumor with the same TNM staging and molecular markers but with different Oncotype Dx scores can have different stages. A staging website is best utilized to determine stage (https://cancerstaging.org/About/news/Pages/

CHAPTER 35  Diseases of the Breast

833

TABLE 35.4  TNM classification for breast cancer (pathologic staging). Primary Tumor (T) TX T0 Tis Tis (DCIS) Tis (LCIS) Tis (Paget) T1 T1mi T1a T1b T1c T2 T3 T4 T4a T4b T4c T4d Regional Lymph Nodes (N) pNX pN0 pN0(i−) pN0(i+) pN0(mol−) pN0(mol+) pN1 pN1mi pN1a pN1b pN1c pN2 pN2a pN2b pN3

Distant Metastases (M) M0 cM0(i+)

M1

Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ DCIS LCIS Paget disease of the nipple not associated with invasive carcinoma or carcinoma in situ (DCIS and/or LCIS) in underlying breast parenchyma Tumor ≤20 mm in greatest dimension Tumor ≤1 mm in greatest dimension Tumor >1 mm but ≤5 mm in greatest dimension Tumor >5 mm but ≤10 mm in greatest dimension Tumor >10 mm but ≤20 mm in greatest dimension Tumor >20 mm but ≤50 mm in greatest dimension Tumor >50 mm in greatest dimension Tumor of any size with direct extension to the chest wall and/or to the skin Extension to the chest wall, not including only pectoralis muscle adherence or invasion Ulceration and/or ipsilateral satellite nodules and/or edema of the skin Both T4a and T4b Inflammatory carcinoma

Regional lymph nodes cannot be assessed No regional lymph node metastasis No regional lymph node metastasis histologically, negative IHC Malignant cells in regional lymph nodes no greater than 0.2 mm No regional lymph node metastasis histologically, negative molecular findings (IHC) Positive molecular findings (RT-PCR), but no metastasis detected by histology or IHC Micrometastases; or metastases in one to three axillary nodes and/or in internal mammary nodes with metastases detected by sentinel lymph node biopsy but not clinically detected Micrometastases (>0.2 mm and/or >200 cells but none >2.0 mm) Metastases in one to three axillary nodes; at least one metastasis >2.0 mm Metastases in internal mammary nodes with micrometastasis or macrometastases detected by sentinel lymph node biopsy (not clinically detected) Metastases in one to three axillary nodes and in internal mammary nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected Metastases in four to nine axillary nodes or in clinically detected internal mammary lymph nodes in the absence of axillary lymph node metastases Metastases in four to nine axillary nodes (at least one tumor deposit >2.0 mm) Metastases in clinically detected internal mammary lymph nodes in the absence of axillary lymph node metastases Metastases in ≥10 axillary nodes; or in infraclavicular (level III axillary nodes) or in clinically detected ipsilateral internal mammary lymph nodes in the presence of one or more positive level I, II axillary nodes; or in >3 axillary lymph nodes and internal mammary lymph nodes, with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected; or in ipsilateral supraclavicular lymph nodes

No clinical or radiographic evidence of distant metastases No clinical or radiographic evidence of distant metastases, but deposits of molecularly or microscopically detected tumor cells in circulating blood, bone marrow, or other nonregional nodal tissue that are no larger than 0.2 mm in a patient without symptoms or signs of metastases Distant detectable metastases as determined by classic clinical and radiographic means and/or histologically proven larger than 0.2 mm

DCIS, Ductal carcinoma in situ; IHC, immunohistochemistry; LCIS, lobular carcinoma in situ; RT-PCR, reverse transcriptase polymerase chain reaction. From Edge SB, Byrd DR, Compton CC, et al, eds. AJCC Cancer Staging Manual. 7th ed. New York: Springer-Verlag; 2010.

Updated-Breast-Chapter-for-8th-Edition.aspx). Metastasis to ipsilateral axillary nodes predicts outcome after surgical treatment more powerfully than tumor size. Before the incorporation of systemic therapies in the management of breast cancer, when treatment was

with surgery alone, the survival rate decreased almost linearly with increasing nodal involvement. Although staging is an important part of the initial assessment of breast cancer patients, it has traditionally been based

834

SECTION VII  Breast

on anatomic variables without other important prognostic factors. The new staging form has a place to record other variables, including tumor grade, ER status, PR status, HER-2 status, circulating tumor cells, disseminated tumor cells (in bone marrow), multigene recurrence score, and response to chemotherapy. Some prefixes and suffixes are used with the cTNM (clinical) and pTNM (pathologic) staging systems to designate special cases. These do not affect the stage group but indicate that they must be analyzed separately. These prefixes and suffixes include the “m” suffix, which signifies multiple primary tumors, pT(m) NM; the “y” prefix, which denotes patients who have received systemic therapy before surgery, ypTNM; and the “r” prefix, which indicates a recurrent tumor, rTNM. In clinical practice, physicians use the anatomic stage grouping in addition to important biologic factors to determine risk and guide treatment recommendations. 

SURGICAL TREATMENT OF BREAST CANCER Historical Perspective Through the mid-twentieth century, breast cancer was thought to arise in the breast and progress to other sites largely via centrifugal spread. In this model, more extensive surgical procedures were expected to reduce mortality by resecting locoregional disease before it could spread to distant sites. This model was supported, in part, by the results of the Halsted radical mastectomy, which was the first procedure that demonstrated improvements in breast cancer survival relative to the local excision of tumors. Introduced in the 1890s, the radical mastectomy included removal of the breast, overlying skin, and underlying pectoralis muscles in continuity with the regional lymph nodes along the axillary vein up to the costoclavicular ligament. The procedure often required a skin graft to cover the large skin defect that was created. This approach was well suited to breast cancer biology of the time, when most tumors were locally advanced, frequently with chest wall or skin involvement and extensive axillary nodal disease. Radical mastectomy provided improved local control and led to an increasing population of long-term survivors. Radical mastectomy continued to be the mainstay of surgical therapy into the 1970s. Numerous women continued to die of metastatic breast cancer after radical mastectomy and even after more extensive surgical procedures, including radical mastectomy with en bloc resection of the internal mammary and supraclavicular nodes. This situation eventually led to a shift in the theory of primary centrifugal spread to the more modern theory that breast cancer spreads centrifugally to adjacent structures and via lymphatics and blood vessels to distant sites. In the modern era, breast cancer treatment includes local and regional approaches (surgery and radiation therapy) in addition to medical therapies designed to treat systemic disease. Multimodality treatment approaches were the first to show significant improvements in locoregional control and survival. As breast cancer was being recognized at earlier stages, radical mastectomy was abandoned in favor of more conservative surgical approaches in combination with radiation therapy. The result was dramatic reductions in the extent of surgery required for local control of breast cancer and decreases in treatment-related morbidity. Breast cancer is a heterogeneous disease, and current treatment is guided by molecular properties of the individual patient’s tumor as well as the size and location of the tumor. 

Surgical Trials of Local Therapy for Operable Breast Cancer Radical Mastectomy Versus Total Mastectomy With or Without Radiation Therapy In the NSABP B-04 trial, patients with clinically negative nodes were randomly assigned to radical mastectomy, total mastectomy with irradiation of the chest wall and regional nodes, or total mastectomy alone with delayed axillary dissection if nodes became clinically enlarged. Patients did not receive systemic therapy. Patients with clinically positive nodes were randomly assigned to radical mastectomy or total mastectomy with irradiation of the chest wall and regional lymphatics. At 25 years of follow-up, overall survival (OS) and disease-free survival (DFS) were equivalent in all treatment arms within the node-positive and node-negative groups. Of the patients with clinically node-negative disease who underwent radical mastectomy, 38% were found to have nodal metastases at surgery, yet only 18% of patients undergoing total mastectomy without axillary dissection or radiation therapy developed axillary recurrence requiring delayed dissection. Those individuals with axillary bed recurrences and delayed axillary node resection did very poorly. However, OS was equivalent in all three groups.  Mastectomy Versus Breast-Conserving Therapy Six prospective clinical trials that included more than 4500 patients compared mastectomy versus breast-conserving therapy (Table 35.5). In all these trials, there was no survival advantage for the use of mastectomy over breast preservation. The largest of these trials, NSABP B-06, enrolled 1851 patients with tumors up to 4 cm in diameter and clinically negative lymph nodes. Patients were randomly assigned to undergo modified radical mastectomy, lumpectomy alone, or lumpectomy with postoperative irradiation of the breast without an extra boost to the lumpectomy site. All patients with histologically positive axillary nodes received chemotherapy. At 20 years of follow-up, OS and DFS were the same in all three treatment groups. NSABP B-06 provided valuable information about rates of ipsilateral breast cancer recurrence after lumpectomy, with or without breast irradiation. At 20 years of follow-up, local recurrence rates were 14.3% in women treated with lumpectomy and radiation therapy and 39.2% in women treated with lumpectomy alone (P < 0.001). For patients with positive nodes who received chemotherapy, the local recurrence rate was 44.2% for lumpectomy alone and 8.8% for lumpectomy plus radiation therapy. Another important trial that evaluated breast-conserving therapy was the Milan I trial. This trial enrolled patients with smaller tumors and used more extensive surgery and radiation therapy than the NSABP B-06 trial. There were 701 women with tumors up to 2 cm and clinically negative nodes randomly assigned to undergo radical mastectomy or quadrantectomy with axillary dissection and postoperative irradiation. Patients with pathologically positive nodes received chemotherapy. OS at 20 years did not differ between the two groups. Locoregional failure rates differed between the groups: Chest wall recurrence occurred in 2.3% of women who underwent radical mastectomy, and ipsilateral breast tumor recurrence occurred in 8.8% of women who underwent quadrantectomy and radiation therapy (20-year follow-up). After quadrantectomy, local failure rates were higher in younger women, with rates of 1% per year in women younger than 45 years and 0.5% per year in older women.

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CHAPTER 35  Diseases of the Breast TABLE 35.5  Randomized trials comparing breast conservation versus mastectomy.

TRIAL NSABP B-06a Milan Cancer Instituteb Institute GustaveRoussyc National Cancer Instituted EORTCe Danish Breast Cancer Groupf

MAXIMUM TUMOR SIZE (CM)

SYSTEMIC THERAPY

FOLLOW-UP (YEARS)

% SURVIVAL LUMPECTOMY + XRT

1851 701

4 2

Yes Yes

20 20

47 44

46 43

14* 8.8*

179

2

No

14

73

65

13

237

5

Yes

10

77

75

16

868 905

5 None

Yes Yes

10 6

65 79

66 82

17.6 3

NO. PATIENTS

% SURVIVAL MASTECTOMY

LOCAL RECURRENCE (BCT) (%)

BCT, Breast-conserving therapy; EORTC, European Organization for Research and Treatment of Cancer; NSABP, National Surgical Adjuvant Breast and Bowel Project; XRT, radiation therapy. *Includes only women whose excision margins were negative. aFisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med. 2002;347:1233. bVeronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med. 2002;347:1227. cArriagada R, Le M, Rochard F, et al. Conservative treatment versus mastectomy in early breast cancer: Patterns of failure with 15 years of followup data. J Clin Oncol. 1996;14:1558. dJacobson J, Danforth D, Cowan K, et al. Ten-year results of a comparison of conservation with mastectomy in the treatment of stage I and II breast cancer. N Engl J Med. 1995;332:907. evan Dongen J, Voogd A, Fentiman I, et al. Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 Trial. J Natl Cancer Inst. 2000;92:1143. fBlichert-Toft M, Rose C, Andersen J, et al: Danish randomized trial comparing breast conservation therapy with mastectomy: six years of life-table analysis. Danish Breast Cancer Cooperative Group. J Natl Cancer Inst Monogr. 1992;11:19.

Three other randomized trials in patients with operable breast cancer found no survival benefit of mastectomy over breastconserving therapy. In the European Organization for Research and Treatment of Cancer (EORTC) Trial 10801, in which 868 women were randomly assigned to modified radical mastectomy or lumpectomy and irradiation, there was no difference in survival at 10 years. This trial included patients with tumors up to 5 cm, and 80% of women enrolled had tumors larger than 2 cm. Positive margins were allowed, and the results showed lower rates of local recurrence with clear versus involved margins. In the Institut Gustave-Roussy trial, 179 women with tumors smaller than 2 cm were randomly assigned to modified radical mastectomy or lumpectomy with a 2-cm margin of normal tissue around the cancer. No differences were observed between the two surgical groups in risk for death, metastases, contralateral breast cancer, or locoregional recurrence at 15 years of follow-up. In the U.S. NCI trial, 237 women with tumors 5 cm or smaller were randomly assigned to lumpectomy with axillary dissection and radiation therapy or modified radical mastectomy. No differences were seen in OS or DFS rates at 10 years. 

Planning Surgical Treatments It is critical to establish the diagnosis of breast cancer firmly before initiation of definitive surgical treatment. CNB of a palpable or image-detected lesion is the preferred approach for diagnosis. Open surgical biopsy is reserved for lesions not amenable to CNB and cases in which CNB has proved nondiagnostic. Examination of biopsy material should provide information about tumor histologic type and grade, ER and PR status, and HER-2 status. Oncotype DX is indicated for patients with ER-positive, nodenegative disease.

A history and physical examination, in addition to appropriate imaging studies, are important to establish the extent of disease and assign a clinical stage. The most common sites of distant metastases from breast cancer are the bone, liver, and lungs followed by brain. The National Comprehensive Cancer Network provides guidelines regarding the use of laboratory and radiologic testing in patients at initial diagnosis based on clinical stage. Computed tomography scans, bone scans, and other imaging studies are generally reserved for patients with clinically positive nodes, abnormalities on blood chemistry tests or chest radiographs, and for patients with locally advanced or inflammatory breast cancer. Thorough imaging of the ipsilateral and contralateral breast is performed to look for areas of concern other than the index lesion. Breast MRI may be used in selected cases to define the extent of tumor and look for additional breast lesions or to document response to neoadjuvant chemotherapy; however, there is no high-level evidence demonstrating that use of MRI to guide decisions regarding local therapy improves local recurrence rates or survival. In the absence of metastatic disease, the first intervention for patients with early-stage breast cancer is surgery for excision of the tumor and surgical staging of the regional lymph nodes. Assessment of the primary tumor size and regional lymph nodes defines the pathologic stage and provides an estimate of the prognosis to inform decisions about systemic therapy. Patients with locally advanced and inflammatory breast cancers should receive systemic therapy before surgery (see “Neoadjuvant Systemic Therapy for Operable Breast Cancer” later on). The selection of surgical procedures takes into account patient characteristics and other clinical and pathologic variables. Patient characteristics, including age, family history, menopausal status, and overall health, are assessed. Some patients may undergo

836

SECTION VII  Breast

BOX 35.4  Contraindications to radiation. Absolute • Pregnancy Relative • Systemic scleroderma* • Active systemic lupus erythematosus* • Prior radiation to breast or chest wall • Severe pulmonary disease • Severe cardiac disease (if tumor is left sided) • Inability to lie supine • Inability to abduct arm on affected side • p53 mutation† *Other collagen vascular diseases are not contraindications to radiation, although patients should not be taking immunosuppressants such as methotrexate because they are radiosensitizers. †Patients with p53 mutations are highly susceptible to radiationinduced cancers.

genetic testing for BRCA or other gene mutations at the time of diagnosis. Patients with a known BRCA mutation are generally counseled toward bilateral mastectomy for treatment of the index breast and reduction of the risk of contralateral breast cancer. The location of the tumor within the breast and tumor size relative to breast size are evaluated. Patient preferences for breast preservation versus mastectomy are determined. For patients considering mastectomy, options for immediate reconstruction are discussed. 

Selection of Surgical Therapy Mastectomy and breast-conserving therapy have been shown to be equivalent in terms of patient survival, and the choice of surgical treatment is individualized. Patients who desire breast-conserving surgery must be willing to attend postoperative radiation therapy sessions and to undergo postoperative surveillance of the treated breast. Consultation with a radiation oncologist may be arranged before the planned surgery. Patients are advised about the risks and long-term sequelae of radiation therapy. A mastectomy is generally recommended for patients who have contraindications to radiation therapy (Box 35.4). Although pregnancy is an absolute contraindication to radiation therapy, many patients pregnant at diagnosis can complete their pregnancy and receive radiation therapy after delivery. A significant factor in determining whether breast-conserving therapy is feasible is the relationship between tumor size and breast size. In general, the tumor must be small enough in relation to the breast size so that the tumor can be resected with adequate margins and acceptable cosmesis. In patients with large tumors for whom adjuvant (postoperative) systemic chemotherapy will likely be recommended, the use of preoperative chemotherapy may be considered. Chemotherapy administered before surgery may decrease the tumor size sufficiently to permit breast-conserving surgery in patients who would not otherwise appear to be good candidates. Another strategy is to consider oncoplastic breast surgery with local tissue rearrangement or pedicled myocutaneous flaps (latissimus dorsi) to fill the defect resulting from breast-conserving surgery.13 Patients with multicentric tumors are usually served best by mastectomy because it is difficult to perform more than one breast-conserving surgery in the same breast with acceptable cosmesis, although clinical trials are ongoing to determine

the feasibility of multiple resections followed by radiation therapy. Although high nuclear grade, presence of lymphovascular invasion, and negative steroid hormone receptor status all have been linked to increased local recurrence rates, none of these factors are considered contraindications to breast conservation. 

Factors Influencing Eligibility for Breast Conservation Randomized trials have demonstrated the efficacy of breast-conserving therapy for a wide variety of breast cancers and have defined eligibility criteria for breast conservation. With these criteria and current surgical and radiation therapy approaches, local recurrence rates after lumpectomy and radiation therapy are less than 5% at 10 years at many large centers. Tumor Size Tumors smaller than 5 cm tumors with clinically positive nodes, and tumors with lobular and ductal histology were included in the randomized trials of mastectomy versus breast-conserving therapy. In current practice, lumpectomy is considered when the tumor, regardless of size, can be excised with clear margins and an acceptable cosmetic result.  Margins The appropriate margin width for lumpectomy specimens has been debated. Although the NSABP B-06 trial defined a negative margin as “no ink on tumor,” other trials evaluating breastconserving therapy did not specify a required margin width or did not evaluate microscopic margins. The optimal margin width has been open to interpretation, resulting in substantial variability in treatment and recommendations regarding the need for reexcision for wider margins. The Society of Surgical Oncology and American Society for Radiation Oncology convened a multidisciplinary panel to address the question of what margin width is required to minimize the risk of ipsilateral breast tumor recurrence.14 The panel used a meta analysis of margin width and ipsilateral breast tumor recurrence from a systematic review of 33 studies including 28,162 patients. They found that positive margins, defined as ink on invasive carcinoma or DCIS, were associated with a twofold increase in ipsilateral breast tumor recurrence risk compared with negative margins. The risk was not affected by any specific clinicopathologic features, including favorable biology, use of endocrine therapy, or administration of a radiation boost. In addition, more widely clear margins than no ink on tumor did not significantly decrease the ipsilateral breast tumor recurrence risk, including in patients with unfavorable biology, lobular cancers, or cancers with an extensive intraductal component. The panel concluded that “no ink on tumor” should be used as the standard for an adequate margin in invasive breast cancer. European consensus groups vary on their recommendations for margin width ranging from 2 mm to 5 mm.  Histology Invasive lobular cancers and cancers with an extensive intraductal component can be treated with lumpectomy if clear margins can be achieved. Atypical hyperplasia (ductal and lobular) and LCIS at resection margins do not increase local recurrence rates.  Patient Age Local recurrence rates after breast-conserving surgery are higher for younger women than for older women. Local recurrence rates are reduced in patients of all ages with the use of radiation therapy. A radiation boost to the tumor bed has been shown to reduce local

CHAPTER 35  Diseases of the Breast

837

A

Incision closure

B

Sentinel node biopsy

FIG. 35.11  Breast-conserving surgery. (A) Incisions to remove malignant tumors are placed directly over the tumor or around the areola. After the partial mastectomy has been completed, the parenchymal defect is closed (inset) to prevent a cosmetic deformity. (B) A transverse incision below the axillary hairline is used for sentinel node biopsy or axillary dissection. The boundaries of the axillary dissection are the axillary vein superiorly, the latissimus dorsi muscle laterally, and the chest wall medially. The inferior dissection enters the tail of Spence (the axillary tail of the breast). In sentinel node biopsy, a similar transverse incision is made, which may be located by percutaneous mapping with the gamma probe to detect a hot spot from the radiolabeled colloid. It is extended through the clavipectoral fascia, and the true axilla is entered. The sentinel node is located by staining with blue dye (inset), radioactivity, or both and is dissected free as a single specimen.

failures after lumpectomy with negative margins, particularly in younger women. 

Breast-Conserving Surgery Technical Aspects Excision of the primary tumor with preservation of the breast has been referred to by many terms, including lumpectomy, partial mastectomy, segmental mastectomy, segmentectomy, tylectomy, and wide local excision. Breast-conserving surgery removes the malignancy with a surrounding rim of grossly normal breast parenchyma. This procedure is depicted in Fig. 35.11, which shows the completed lumpectomy and skin incision for the axillary component of the procedure. The breast specimen that is removed is oriented and its edges are inked before sectioning. Specimen radiography should be performed for all nonpalpable lesions or if there are microcalcifications associated with the palpable tumor. If a margin appears to be close or is positive histologically on intraoperative assessment, reexcision to remove more tissue frequently achieves a clear margin and allows conservation of the breast. Orientation of the surgical specimen allows focal reexcision of involved margins rather than global reexcision and improves the cosmetic result by reducing the amount of normal breast parenchyma that is excised. There is level I evidence that shaved margins at the time of the lumpectomy reduces the need for reexcision.15 The larger the

volume of excision, the better the margin clearance, but the poorer the cosmetic result. The surgical defect created after lumpectomy is closed in cosmetic fashion. There is increasing interest in the use of advancement flap closure and other oncoplastic surgical techniques to maximize the cosmetic result. Surgical staging of the axilla is performed through a separate incision in most patients undergoing breast conservation. SLND (see Fig. 35.11) has replaced anatomic axillary node dissection in patients with clinically negative axillary nodes. For patients who require axillary dissection, the extent of the dissection is identical to the axillary component of the modified radical mastectomy (see Fig. 35.11).  Cosmetic Challenges The term oncoplastic surgery has been popularized to stress the importance of achieving the best possible esthetic result in the context of resecting the tumor with adequate oncologic margins. The goal is to retain as much of the natural breast size and contour as possible to provide optimal cosmesis and symmetry with the opposite breast. When the primary tumor is resected using an incision directly over the tumor and closure of the skin without reapproximation of any breast tissue, several deformities can occur, including volumetric deformity from a large parenchymal resection (retraction deformity when the seroma resorbs at the operative site); skin–pectoral muscle adherence deformity, in which

838

SECTION VII  Breast

the skin adheres to the underlying pectoral muscle; and lower pole deformity with downward turning of the nipple (bird beak deformity) caused by excision of a tumor in the lower hemisphere of the breast. These deformities can make it difficult for patients to wear tight-fitting clothing because significant asymmetry may be evident. It is important to correct these deformities before radiation therapy because the irradiation may further accentuate any asymmetry and make it more challenging to correct the defect in the future. The surgeon should consider oncoplastic techniques in the following situations: (1) a significant area of skin is to be resected with the tumor, (2) a large-volume resection is expected, (3) the tumor is in an area associated with poor cosmetic outcomes (e.g., lower hemisphere below the nipple), or (4) resection may lead to nipple malposition. Extent of breast resection. When oncoplastic surgery techniques are considered, it is not the absolute breast volume that will be resected but rather the ratio of the anticipated defect to the volume of the remaining breast parenchyma and the type of parenchyma present (fatty replaced vs. dense) that is important. In general, oncoplastic surgery should be considered when the size of the surgical defect is likely to be greater than 20% to 30% of the breast volume and for any tumor resection in the lower breast.  Breast size and body habitus. Patients with large breasts are often good candidates for tumor resection and bilateral reduction mammaplasty. Breast reduction can allow for improved esthetic outcomes after resection of large volumes of breast tissue at any location. Obese patients should be considered for this approach because they are often poor candidates for autologous tissue reconstruction after mastectomy, and implants are often not large enough to recreate a breast proportional in size to the contralateral breast. Breast reduction surgery is a good option because this can relieve the symptoms of macromastia and allow for improved outcomes after breast irradiation.  Tumor location. Tumors lying directly under the nipple-areolar complex and tumors located between the nipple-areolar complex and inframammary fold require special attention to avoid nippleareolar complex distortion and contour deformity. In general, the skin and well-vascularized breast parenchyma must be adjusted to correct for the removal of breast tissue in these areas. As noted, deformities in the contour will be exacerbated by radiation and may be more challenging to correct at a later date. Fig. 35.12 shows the various incisions for tumors located in different parts of the breast. Upper pole lesions can be served by a variety of techniques (Fig. 35.12A), including round block (one or more lesion in any quadrant but especially nice for upper inner quadrant lesions), crescent mastopexy (for those who need a minor lift), and batwing or hemi-batwing (for those who need more of a lift). Lower pole lesions (Fig. 35.12B) may use techniques that require a mastopexy based on a superior pedicle flap. Lower outer lesions may require a J or V plasty to retain the shape of the breast. A Benelli includes a deepithelization circumferentially around the areola and is especially useful for the lower inner quadrant of the breast as well as a minor reduction in breast volume. These techniques can also be used to correct defects left from previous surgeries. Short-term follow-up shows that oncoplastic techniques have greater patient satisfaction, less complications, and less local recurrence.16  Timing of Oncoplastic Surgery Immediate repair of a partial mastectomy defect is almost always preferred to a delayed approach. Oncoplastic techniques

such as tissue advancement and local tissue rearrangement at the time of the initial surgical procedure tend to provide the optimal solution. This approach has not been associated with delay in delivery of adjuvant systemic therapy or radiation. In general, local tissue transfer and breast reduction surgery cannot be performed on the irradiated breast; it is preferable to perform the procedure before radiation therapy. Tissue expanders and implants are not recommended to fill partial mastectomy defects because radiation may lead to capsular contracture, distortion, and infection. If a cosmetic defect occurs after breast-conserving surgery and radiation therapy, reconstruction of the treated breast is generally not recommended for 1 to 2 years after radiation therapy has been completed. In fatty replaced and irradiated tissue, there is a higher rate of tissue necrosis, seroma formation, and infection. The use of vascularized tissue from outside the radiation field is the favored approach. If the main deformity is caused by asymmetry with the contralateral breast, a mastopexy of the contralateral breast can be considered. In general, surgical procedures on the irradiated breast should be minimized because healing and recovery are impaired even when the skin appears healthy. 

Mastectomy Indications Certain tumors still require mastectomy, including tumors that are large relative to breast size, tumors with extensive calcifications on mammography, tumors for which clear margins cannot be obtained on wide local excision, and tumors in patients with contraindications to breast irradiation (see Box 35.4). Patient preference for mastectomy or a desire to avoid radiation is also a valid indication for mastectomy.  Postmastectomy Breast Reconstruction Breast reconstruction may be performed immediately—that is, the same day as mastectomy—or as delayed reconstruction, months or years later. Immediate reconstruction has the advantages of preserving the maximum amount of breast skin for use in reconstruction, combining the recovery period for both procedures, and avoiding a period of time without a breast mound. Immediate reconstruction does not have a detrimental effect on long-term survival, local recurrence rates, or detection of local recurrence. Reconstruction may or may not be delayed in patients who might require postmastectomy radiation therapy. Reconstruction options include tissue expander/implant and autologous tissue reconstructions, most often with transverse rectus abdominis muscle flaps, latissimus dorsi flaps, or muscle-preserving perforator abdominal flaps.  Technical Details Simple or total mastectomy refers to complete removal of the mammary gland, including the nipple and areola. Modified radical mastectomy refers to removal of the mammary gland, nipple, and areola, with the addition of a complete axillary lymph node dissection (ALND) (Fig. 35.13). For either a total mastectomy or a modified radical mastectomy, an elliptical skin incision is planned to include the nipple and areola and usually any previous excisional biopsy scars (see Fig. 35.13). Skin flaps are raised to separate the underlying gland from the overlying skin along the subdermal plexus (see Fig. 35.13). If immediate reconstruction is not planned, sufficient skin is taken to allow smooth closure of skin flaps without redundant skin folds; this facilitates comfortable use of a breast prosthesis.

CHAPTER 35  Diseases of the Breast

• Round block technique • Crescent mastopexy • Batwing resection • Hemi-batwing

839

Upper pole lesions

A Lower pole lesions • Reduction mastopexy • Triange incision • Inframammary J or V plasty • Benneli

B FIG. 35.12  The various incisions for tumors located in different parts of the breast. (A) Upper pole lesions can be served by a variety of techniques, including round block, crescent mastopexy, and batwing or hemi-batwing. (B) Lower pole lesions may use techniques that require a mastopexy based on a superior pedicle flap. Including reduction mastopexy, triangle insision, J or V plasty, and Benneli. (Adapted from Fitoussi A, Berry MG, Couturaud B, et al. Oncoplastic and reconstructive surgery for breast cancer: The Institut Curie Experience. Paris: Springer; 2008.)

If immediate reconstruction is planned, a skin-sparing mastectomy may be performed in which only the nipple-areola complex is removed and the maximum amount of skin is left for use in the reconstruction. Nipple-areola–sparing mastectomy has been used with increasing frequency for selected patients with breast cancer. Multiple studies have shown the safety and feasibility of this approach, with many series showing comparably low recurrence rates in patients undergoing nipple-areola–sparing mastectomy (Table 35.6). Nipple-areola–sparing mastectomy has also been demonstrated to be safe in patients undergoing prophylactic mastectomy for risk reduction, including BRCA1 and BRCA2 gene mutation carriers.17 Breast tissue is separated from the underlying pectoralis muscle, and the pectoral fascia is generally taken with the breast specimen. In a total mastectomy (see Fig. 35.13), breast tissue is separated from the axillary contents, and all breast tissue superficial to the fascia of the axilla is removed. In a modified radical mastectomy,

the level I and II axillary lymph nodes are taken with the axillary breast tissue (see Fig. 35.13). Level I nodes are nodes inferior to the axillary vein and lateral to the pectoralis minor muscle, and level II nodes are nodes anterior or posterior to the pectoralis minor. 

Lymph Node Staging The pathologic status of the axillary lymph nodes is one of the most important prognostic factors in patients with breast cancer. Identification of metastatic tumor deposits in the axillary nodes indicates a poorer prognosis and often prompts a recommendation for more aggressive systemic and locoregional therapies. Historical Perspective Historically, ALND was a routine component of the surgical management of breast cancer. It provides prognostic information about axillary nodal status and plays a therapeutic role in

840

SECTION VII  Breast Skin sparing

A

B A

Nipple sparing

B FIG. 35.13  Total mastectomy with and without axillary dissection. For patients undergoing mastectomy without reconstruction, skin incisions are generally transverse and surround the central breast and nipple-areolar complex. (A) Circumareolar incisions are most common for patients undergoing skin-sparing mastectomy with immediate reconstruction. Skin flaps are raised to separate the gland from the overlying skin and then the gland from the underlying muscle. Simple mastectomy divides the breast from the axillary contents and stops at the clavipectoral fascia. If axillary staging is planned, this is generally performed through a separate transverse axillary incision. (B) An inframammary incision is shown for nipple-areolar–sparing mastectomy.

removing axillary disease in patients with positive nodes. The surgical procedure includes clearance of node-bearing tissue between the pectoralis major and latissimus dorsi muscles from the edge of the breast tissue in the low axillary region to the axillary vein and removal of the nodes posterior to the pectoralis minor muscle. Axillary dissection is the main source of morbidity in patients with early-stage breast cancer. The immediate problems include acute pain and paresthesias, need for hospitalization, reduced range of motion at the shoulder joint, and need for a drain in the surgical bed for 7 to 10 days. Long-term problems resulting from axillary dissection include lymphedema of the ipsilateral arm, numbness, chronic pain, and reduced range of motion at the shoulder joint.  Sentinel Lymph Node Dissection Identification of the first, or sentinel, node draining the area of the primary tumor in the breast allows for a more selective approach to the axilla. The sentinel node is the most likely node to contain metastatic disease, if present, and the pathologist can focus the examination on the sentinel node(s) without the added cost and time required to examine the full axillary contents. The technique of SLND was developed to reduce the morbidity associated with axillary surgery, while still providing accurate staging information. Many patients now present with clinically node-negative disease, and SLND can identify those patients with node-positive disease

who may benefit from completion of ALND. Patients with negative sentinel lymph nodes can avoid the morbidity of axillary dissection. In sentinel node surgery, radiolabeled colloid, blue dye, or both are injected into breast tissue at the site of the primary tumor; the material passes through the lymphatics to the first draining node(s), where it accumulates. The procedure can also be performed with injection of the mapping agents that can be injected subareolar position or in a subdermal location overlying the site of the primary tumor. The sentinel node is identified as a blue, radioactive, fluorescent, or magnetic node or a combination of these. If the pathologic analysis of the sentinel node is negative for evidence of metastasis, the likelihood that other nodes are involved is sufficiently low that ALND is not required. The NSABP B-32 trial was a critical study evaluating SLND.18 In that study, 5611 patients with clinically node-negative breast cancer were randomly assigned to undergo SLND plus ALND or SLND with ALND only if the sentinel node was positive. The sentinel node was positive in 26% of patients in both groups. For patients with a pathologically negative sentinel node (n = 3986), in whom the primary analysis was performed, there was no difference in OS, DFS, or regional control rates, demonstrating that when the sentinel node is negative, SLND alone without further ALND is appropriate for patients with clinically negative lymph nodes. A randomized trial conducted at the European Institute of Oncology

CHAPTER 35  Diseases of the Breast

841

TABLE 35.6  Studies on nipple and local recurrence rates in patients undergoing nipple-

areola–sparing mastectomy.

AUTHOR

YEAR

PROCEDURES N

FOLLOW-UP (MONTHS)

NAC RECURRENCE (%)

Crowea Marguliesb Bonetic Filhod Jensone Peledf Loshiriwatg Coopeyh Krajewskii Orzalesij Smithk Radovanovicl Galimbertim

2004 2005 2011 2011 2011 2012 2012 2013 2015 2016 2017 2018 2018

54 50 281 157 127 412 934 156 226 755 2182 441 1989

NA 7.9 25.3 10 60 28 64 22 24 36 51 108 94

10* 0 0 0 0 0 0 0 0 0.6 0 5.4* 1.8

LOCAL RECURRENCE (%) NA 0 7 0 0 2 0 2.6 1.7 2.9 3.7 7.3 5.3

*Nipple-areolar complex involved at the time of surgery and excised. aCrowe JP Jr, Kim JA, Yetman R, et al. Nipple-sparing mastectomy: technique and results of 54 procedures. Arch Surg. 2004;139:148–150. bMargulies AG, Hochberg J, Kepple J, et al. Total skin-sparing mastectomy without preservation of the nipple-areola complex. Am J Surg. 2005;190:907–912. cBoneti C, Yuen J, Santiago C, et al. Oncologic safety of nipple skin-sparing or total skin-sparing mastectomies with immediate reconstruction. J Am Coll Surg. 2011;212:686–693; discussion 693–685. dde Alcantara Filho P, Capko D, Barry JM, et al. Nipple-sparing mastectomy for breast cancer and risk-reducing surgery: the Memorial SloanKettering Cancer Center experience. Ann Surg Oncol. 2011;18:3117–3122. eJensen JA, Orringer JS, Giuliano AE. Nipple-sparing mastectomy in 99 patients with a mean follow-up of 5 years. Ann Surg Oncol. 2011;18:1665– 1670. fWarren Peled A, Foster RD, Stover AC, et al. Outcomes after total skin-sparing mastectomy and immediate reconstruction in 657 breasts. Ann Surg Oncol. 2012;19:3402–3409. gLohsiriwat V, Martella S, Rietjens M, et al. Paget’s disease as a local recurrence after nipple-sparing mastectomy: clinical presentation, treatment, outcome, and risk factor analysis. Ann Surg Oncol. 2012;19:1850–1855. hCoopey SB, Tang R, Lei L, et al. Increasing eligibility for nipple-sparing mastectomy. Ann Surg Oncol. 2013;20:3218–3222. iKrajewski AC, Boughey JC, Degnim AC, et al. Expanded indications and improved outcomes for nipple-sparing mastectomy over time. Ann Surg Oncol. 2015;22:3317–3323. jOrzalesi L, Casella D, Santi C, et al. Nipple sparing mastectomy: surgical and oncological outcomes from a national multicentric registry with 913 patients (1006 cases) over a six year period. The Breast. 2016;25:75–81. kSmith BL, Tang R, Rai U, et al. Oncologic safety of nipple-sparing mastectomy in women with breast cancer. J Am Coll Surg. 2017;225:361–365. lRadovanovic Z, Ranisavljevic M, Radovanovic D, et al. Nipple-sparing mastectomy with primary implant reconstruction: surgical and oncological outcome of 435 breast cancer patients. Breast Care (Basel). 2018;13:373–378. mGalimberti V, Morigi C, Bagnardi V, et al. Oncological outcomes of nipple-sparing mastectomy: a single-center experience of 1989 patients. Ann Surg Oncol. 2018;25:3849–3857.

and numerous single-institution reports confirmed the findings from the NSABP B-32 trial showing that the technique is accurate. Identification of the sentinel node allows for a more detailed analysis of the lymph node most likely to have a positive yield. In general, pathologists section the sentinel node along its short axis and submit all the sections for paraffin embedding of the tissues. The paraffin blocks can be sectioned and examined with hematoxylin-eosin staining of sections from each block. Some pathologists perform more detailed analysis of the sentinel nodes with step-sectioning of the paraffin blocks and immunohistochemical staining for cytokeratin, which enhances sensitivity by allowing detection of micrometastases. However, the clinical relevance of these micrometastases and small tumor deposits detected by immunohistochemical techniques has been questioned. The NSABP B-32 trial provided an opportunity to investigate the clinical significance of occult metastatic disease. For patients with negative sentinel nodes by hematoxylin-eosin staining, additional sections were evaluated by immunohistochemistry to identify occult metastases. The 5-year DFS rate was 86.4% for patients with occult metastases compared with 89.2% for patients without occult metastases (absolute

difference = 2.8%), and the 5-year OS rate was 94.6% for patients with occult metastases compared with 95.8% for patients without occult metastases (absolute difference = 1.2%). These differences were statistically significant given the large number of patients enrolled in the study; however, because the absolute differences were small, the NSABP investigators concluded that the presence of occult metastases was not clinically significant. This conclusion was confirmed by the American College of Surgeons Oncology Group (ACOSOG) Z0010 trial, which was designed to evaluate the significance of sentinel node and bone marrow micrometastases in patients with early-stage breast cancer undergoing breast-conserving therapy.19 In that study, the 5-year DFS rates for patients with immunohistochemistry-positive and immunohistochemistry-negative sentinel nodes were 90% and 92%, respectively (P = 0.82), whereas the 5-year OS rates were 95% and 96%, respectively (P = 0.64).  Lymphatic Mapping Technique and Selection of Patients for Sentinel Lymph Node Dissection Lymphatic mapping can be performed with a combination of 99mTc-labeled sulfur colloid and a vital blue dye, isosulfan

842

SECTION VII  Breast

blue (Lymphazurin), fluorescence, magnetic particles, or with a single agent for localization of the sentinel node(s). Studies indicate that using the combination technique may result in the lowest possible false-negative rate. Preoperative lympho‑ scintigraphy can provide information on the specific nodal basins draining the primary tumor. Using a peritumoral injection technique, approximately 70% of patients have drainage to the axilla, 20% have drainage to the axilla and the internal mammary nodal basin, 2% to 3% have drainage to the internal mammary nodal basin alone, and 8% do not show any drainage to the regional nodal basins. If a subareolar or subdermal injection technique is used, drainage is seen almost exclusively in the axillary nodal basins. A dose of 2.5 mCi of 99mTc-labeled sulfur colloid can be injected on the day before surgery for preoperative lymphoscintigraphy; this allows for adequate activity to remain in the sentinel nodes for the intraoperative lymphatic mapping procedure the following day without the need for reinjection. Alternatively, for surgeons not using preoperative lymphoscintigraphy, 0.5 to 1.0 mCi of 99mTc-labeled sulfur colloid can be injected in the operating suite and avoids the preoperative pain and vasovagal events. In the operating suite, 3 to 5 mL of blue dye can be injected peritumorally, and the injection site is massaged to facilitate passage of the dye through the lymphatics. A handheld gamma probe is used to localize transcutaneously the area of increased radioactivity; this helps to guide placement of the incision for the sentinel node procedure. After the incision is made, an area of increased radioactivity is localized with the handheld gamma probe, and the surgeon visualizes blue lymphatic channels leading to the sentinel node. Dissection is performed to avoid prematurely disrupting the afferent lymphatics. If a blue-stained lymphatic channel or a specific area of radioactivity (“hot spot”) cannot be identified, the primary tumor can be resected to remove the site of injection, decreasing the background shine-through radioactivity. The sentinel node may be identified and removed, after which the nodal basin is checked again to confirm that the level of radioactivity has decreased. If the level of radioactivity remains high, additional sentinel nodes may remain in the nodal basin, and additional dissection should be completed to remove all sentinel nodes. Published studies have demonstrated an average of two or three sentinel nodes per patient. Surgeons experienced in SLND can identify a sentinel node in more than 95% of patients. The false-negative rate for sentinel node surgery ranges from 0% to 11%, as reported in the NSABP B-32 trial.18 Surgeons should be trained in SLND before using this procedure as a staging tool. Patients who present with clinically palpable lymph nodes should be evaluated with axillary ultrasonography and fine-needle aspiration biopsy (FNAB) of the nodes. If axillary metastasis is confirmed, patients can proceed directly to standard axillary node dissection or be considered for preoperative chemotherapy. If axillary metastasis is not confirmed by FNAB, patients can proceed to sentinel node surgery for staging. Some studies have shown that patients who have undergone previous excisional biopsy of the primary tumor are more likely to have a false-negative sentinel node.18 The lymphatics may be disrupted by the biopsy, which can affect drainage patterns of the area surrounding the excisional biopsy site. To avoid this scenario, CNB is the preferred diagnostic approach in patients suspected to have breast cancer. In older studies, SLND was reported to be less accurate in patients treated with preoperative chemotherapy. A meta analysis of the published studies on sentinel node surgery after chemotherapy

suggested that this technique is accurate; a more recent comparison showed that false-negative rates after chemotherapy compared favorably with false-negative rates observed in patients who undergo surgery first.20  Outcomes of Sentinel Lymph Node Dissection Morbidity rates are substantially lower with SLND than with ALND. Another advantage is that SLND can be performed as an outpatient procedure and does not require a drain. Patients have more rapid return to full mobility and are able to return to work and other activities weeks sooner than after axillary dissection. Long-term morbidity, including lymphedema, numbness, and chronic pain, is greatly reduced. SLND has been shown to provide reliable pathologic staging of the axilla, with false-negative rates generally less than 5% in experienced hands. Axillary recurrence rates have been shown to be extremely low after a negative sentinel node biopsy without axillary dissection. A negative sentinel node is now widely accepted as sufficient to establish node-negative disease in a patient, with no further axillary treatment required.18 When the sentinel node contains metastatic disease, the likelihood of additional involved nodes is directly proportional to the size of the primary breast tumor, presence of lymphatic vascular invasion, and size of the lymph node metastasis. Although ALND has been standard practice for patients with positive sentinel nodes, the need for ALND in all patients with a positive sentinel node has been called into question because many patients have smallvolume metastases, and the sentinel node is often the only positive node. A meta analysis of studies evaluating patients with positive sentinel nodes showed that 53% of patients have additional positive nodes at ALND. In the case of micrometastatic disease in the sentinel nodes, the rate of nonsentinel node involvement is 20%, and for patients with isolated tumor cells, it is less than 12%. These findings led to a trend of omitting ALND in selected patients with positive sentinel nodes. An analysis of SEER data from the years 1998 to 2004 revealed that 16% of patients with sentinel node–positive disease did not undergo ALND. These patients were more commonly older patients with low-grade, ER-positive tumors. During this time period, the proportion of patients with micrometastasis in the sentinel node who did not undergo ALND increased from 21% to 38%. A review of the National Cancer Data Base data from the years 1998 to 2005 revealed similar findings, with 20.8% of patients with sentinel node–positive disease avoiding ALND. There were no differences in axillary recurrence rates or survival between patients who had sentinel node surgery only and patients who underwent ALND. The ACOSOG initiated a prospective randomized trial in 1999 designed specifically to evaluate the impact of ALND on locoregional recurrence and survival in patients with early-stage breast cancer.21,22 The trial now with 10-year follow-up, ACOSOG Z0011, enrolled patients with clinical T1 or T2 breast cancer with one or two positive sentinel nodes who were planning to undergo breast-conserving surgery and whole breast irradiation (WBI). Patients were randomly assigned to undergo completion ALND or no further surgery (sentinel node surgery alone). The primary end point of the Z0011 study was OS; secondary end points were locoregional recurrence and lymphedema. Patients enrolled in the Z0011 study had relatively favorable disease characteristics: The median age was 55 years, 70% of patients had T1 tumors, 82% had ER-positive tumors, 71% had only one positive sentinel node, and 44% had micrometastases. At a median follow-up of 9.3 years, the 10-year OS was 86.3% in the SLND-alone group

CHAPTER 35  Diseases of the Breast and 83.6% in the ALND group (P = 0.02). The 10-year DFS was 80.2% in the SLND-alone group and 78.2% in the ALND group (P = 0.32). Ten-year regional recurrence did not differ significantly between the two groups. The Z0011 study investigators concluded that ALND may be safely omitted in patients with early-stage breast cancer with a positive sentinel node who are undergoing breast-conservation surgery (BCS), have one to two positive nodes, and receive whole breast radiation and systemic therapy. This study did not include mastectomy patients. Trials are ongoing to determine the feasibility of omitting ALND in mastectomy patients. It should be noted, however, that there was no significant difference in lymphedema seen between the groups. This may be because this trial included WBI, which in most patients included the Level I axilla or higher. Conventional wisdom teaches that the lymphatics reside juxtaposed to the vein, and if the surgeon can avoid skeletonizing the vein, then the risk of lymphedema could be minimized or avoided (Fig. 35.2). If this were the case, then SLND should have cured the problem of surgical lymphedema. In fact, lymphatics are seen from the SLN incision nearly one-third of the time. In the more than 10 randomized studies of SLND versus ALND for breast cancer, the lymphedema rate varies between 0% and 13% for SLND and 7% and 77% for ALND. From these varying rates, it is obvious that not everyone is performing the same procedure. Klimberg and colleagues developed the axillary reverse mapping (ARM) procedure to intraoperatively recognize the lymphatic drainage of the upper extremity and preserve it. The procedure consists of radioactivity in the breast and blue dye in the arm (split mapping) in order to identify and protect the lymphatics draining the upper extremity. In a 26-month median followup of a phase II trial of 654 patients receiving SLND or ALND with ARM, the rate of lymphedema was less than 1% and 6%, respectively.23 When any cut lymphatics were reapproximated, the rate of lymphedema was nil for either group. Alliance 221702 is a randomized trial that will further determine the efficacy of ARM. ALND remains the standard of care for patients with locally advanced breast cancer or inflammatory breast cancer, patients with a positive sentinel node who are scheduled for mastectomy, patients with a positive sentinel node who are scheduled for accelerated partial breast irradiation (PBI), and patients with clinically positive nodes as well as a positive sentinel node after neoadjuvant chemotherapy. 

TREATMENT OF DUCTAL CARCINOMA IN SITU DCIS, or intraductal cancer, accounts for approximately 25% of all newly diagnosed breast cancers. It was anticipated that more than 63,960 new cases of DCIS would be diagnosed in 2016. Most cases of DCIS are detected as an area of clustered calcifications on a screening mammogram without an associated palpable abnormality. Rarely, DCIS manifests as a palpable mass or as unilateral, single-duct nipple discharge. Findings on mammography in patients with DCIS include clustered calcifications without an associated density in 75% of patients, calcifications coexisting with an associated density in 15%, and a density alone in 10%. The calcifications seen on a mammogram generally correspond to areas within the central involved duct in which there is often necrosis and debris. DCIS calcifications tend to cluster closely together, are pleomorphic, and may be linear or branching, suggesting their ductal origin. DCIS is viewed as a precursor to invasive ductal cancer, and treatment aims to remove the DCIS to prevent progression to invasive disease. Because the prevalence of metastatic disease in

843

patients with DCIS without demonstrable invasion is low (45

Minimally invasive parathyroidectomy with IOPTH or bilateral exploration

>45

En bloc resection

pHPT (95%) in third decade, pNETs 25–45 (40%), pituitary adenomas (30%), adrenocortical and thyroid tumors, meningioma, facial angiofibromas, lipomas pHPT (15%–35%), MTC (99%), 38 pheochromocytoma (50%), lichen planus, amyloidosis, Hirschsprung disease pHPT (80%), pituitary adenoma (40%), 50 pNETs, adrenal, thyroid, gonadal and renal tumors Isolated pHPT, parathyroid carcinoma 39 (GCM2 mutation)

pHPT in second or third decade, 32 parathyroid carcinoma (35%), ossifying fibromas of mandible and maxilla, renal cysts, hamartomas and Wilms tumor, and uterine tumors

Subtotal parathyroidectomy and transcervical thymectomy

Resection of only visibly enlarged parathyroid glands. Address or rule out pheochromocytoma first Same as MEN1

Bilateral neck exploration with resection of enlarged glands only versus subtotal parathyroidectomy En bloc resection for parathyroid cancer Minimally invasive parathyroidectomy with IOPTH or bilateral exploration En bloc resection for parathyroid cancer

Adapted from Silva BC, Cusano NE, Bilezikian JP. Primary hyperparathyroidism. Best Pract Res Clin Endocrinol Metab. 2018;32:593–607; Bilezikian JP, Cusano NE, Khan AA, et al. Primary hyperparathyroidism. Nat Rev Dis Primers. 2016;2:16033; Wilhelm SM, Wang TS, Ruan DT, et al. The American Association of Endocrine Surgeons guidelines for definitive management of primary hyperparathyroidism. JAMA Surg. 2016;151:959– 968; and El Lakis M, Nockel P, Gaitanidis A, et al. Probability of positive genetic testing results in patients with family history of primary hyperparathyroidism. J Am Coll Surg. 2018;226:933–938. AD, Autosomal dominant; HPT, hyperparathyroidism; HPT-JT, hyperparathyroidism-jaw tumor syndrome; IOPTH, intraoperative parathyroid hormone; MEN, multiple endocrine neoplasia; MTC, medullary thyroid cancer; pHPT, primary hyperparathyroidism; PTH; parathyroid hormone; pNET, pancreatic neuroendocrine tumors. *Age = mean age at presentation of primary HPT in years. †Surgical approach to HPT associated with the disorder.

other associated findings of a particular syndrome (see “Familial Primary HPT” section). 

Clinical Manifestations Up to 80% of patients with primary HPT are diagnosed as a result of incidental hypercalcemia found on routine bloodwork. However, patients with primary HPT can have diverse symptoms, which are the result of calcium effects on multiple organ systems, including the renal, skeletal, gastrointestinal, cardiac, and neuromuscular systems (Table 38.3). In a recent cohort study of over 9000 patients, 35% of patients had objective findings of end-organ effects at the time of diagnosis, including osteoporosis, nephrolithiasis, or hypercalciuria. In addition, 62% of patients developed end-organ effects within 5 years of diagnosis.21 Up to 20% of patients with primary HPT have symptomatic nephrolithiasis, 10% of patients have recurrent kidney stones, and up to 12% of patients have

“silent nephrolithiasis” when they are screened with abdominal imaging.17,18 Primary HPT results in loss of bone mass, which is most pronounced at sites of cortical bone in the distal third of the radius and the femoral neck. However, recent studies using high-resolution peripheral quantitative CT (HRpQCT) have demonstrated that both cortical and trabecular bone are affected by primary HPT, with increased fractures seen in the vertebral bodies in patients with primary HPT compared to a control population.19,20 Up to 15% of patients with HPT have osteopenia in the lumbar spine.18 In a longitudinal observational study, patients with untreated primary HPT followed for 15 years had a decline in bone mineral density of 35% at the distal radius and 10% at the femoral neck.22 All patients with primary HPT should be screened for osteopenia and osteoporosis with measurement of bone mineral density of the distal third of the radius, the lumbar spine, the femoral neck, and the hip.

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SECTION VIII  Endocrine

TABLE 38.3  Signs and symptoms of primary hyperparathyroidism. TARGET ORGAN OR SYSTEM Renal Skeletal

Neuromuscular Gastrointestinal

Neuropsychiatric

Cardiovascular

SYMPTOMS

COMMENTS

Nephrolithiasis, nephrocalcinosis, polyuria, polydipsia, renal insufficiency Fragility fractures Osteopenia/osteoporosis Bone pain Osteitis fibrosa cystica

15%–20% of patients have kidney stones

Proximal muscle weakness, muscular atrophy, gait disturbance Easy fatigability, generalized weakness Gastroesophageal reflux, constipation, abdominal pain, peptic ulcer disease Nausea, vomiting, acute pancreatitis Fatigue, depression, anxiety, emotional lability, sleep disturbances, lethargy, memory loss, inability to concentrate, mental status change, psychosis, obtundation, and coma Exacerbation of hypertension, valvular disease, myocardial calcifications, premature atherosclerosis, left ventricular hypertrophy, shortened QT interval, conduction abnormalities, and heart block

Neuromuscular and neuropsychiatric symptoms are often reported by patients with primary HPT. Many of these symptoms may improve with surgical intervention, and include easy fatigability, generalized weakness, depression, anxiety, memory loss, and inability to concentrate. Three randomized controlled trials show neurocognitive benefits of surgery when compared with observation in patients with primary HPT.17 

Diagnosis and Evaluation The diagnostic evaluation of primary HPT should include measurements of serum total calcium, intact PTH, creatinine, and 25(OH)D levels (Table 38.4). Serum phosphorus, alkaline phosphatase, and 24-hour urine calcium and creatinine levels may also be of value. Classic primary HPT is defined by hypercalcemia associated with an elevated intact PTH level or an inappropriately normal intact PTH level. Patients with hypercalcemia from most other causes have a low (suppressed) PTH level. In a patient with hypercalcemia, if the PTH level is greater than 25 pg/mL, primary HPT remains a consideration. These patients should be asked about biotin supplementation, which should be stopped a few weeks prior to PTH testing, as biotin can falsely lower PTH test results.19 Calcium measurements should be repeated to ensure persistent elevation. Total serum calcium levels should be corrected for abnormal serum albumin using the following equation: corrected calcium (mg/dL) = (0.8[4.0 – patient’s albumin (g/dL)] + total calcium (mg/dL).17 In patients with primary HPT, vitamin D deficiency is associated with more significant hypercalcemia, more severe bone disease, and increased parathyroid adenoma weight.17 Measurement of blood urea nitrogen, serum creatinine, and glomerular filtration rate (GFR) is essential because renal insufficiency is a known complication of primary HPT and to rule out chronic kidney disease, which is associated with a secondary increase in PTH levels. A 24-hour urine calcium and creatinine measurements are checked to evaluate for elevated urine calcium greater than 400 mg, which is associated with an increased risk of nephrolithiasis and is an

Unrelated to significant trauma Cortical bone > trabecular bone (distal third of radius most affected) Common Rare, but may occur with advanced disease, characterized by bone pain and multiple skeletal deformities including salt and pepper appearance of the skull, bone cysts, and brown tumors of bone Rare Common Common Rare Rare, can be seen in cases of severe hypercalcemia Often reported Rare, can be seen with severe hypercalcemia Conflicting data on improvement of cardiac parameters after parathyroidectomy

established indication for parathyroidectomy, and to help rule out FHH, which can mimic primary HPT. Patients with FHH have a 24-hour urine calcium less than 100 mg and a calcium creatinine clearance ratio (CCCR) less than 0.01 (Table 38.4). The usefulness of routine measurement of CCCR to differentiate primary HPT from FHH has recently been called into question by a large study of 1000 patients with surgically confirmed primary HPT. Nineteen percent of patients with primary HPT had CCCR less than 0.01, 63% had a CCCR less than 0.02%, and none of them had FHH. Thus, calculating CCCR to differentiate FHH from primary HPT should not be prioritized in the workup of primary HPT unless there is high clinical suspicion of FHH.23 Normocalcemic primary HPT is a recognized variant of primary HPT that presents with high PTH levels and normal total and ionized serum calcium levels in the absence of secondary causes for HPT. Most patients with normocalcemic primary HPT are diagnosed as a result of evaluation for kidney stones or osteoporosis. There is increased recognition of this variant, particularly in centers where all patients with osteopenia or osteoporosis are screened for primary HPT.19 Up to 16% of patients may progress over time to hypercalcemic primary HPT.17 An ionized calcium level should be obtained in all patients with suspected normocalcemic primary HPT but it is not necessary to make the diagnosis of primary HPT in hypercalcemic patients. In patients with a normal serum calcium level and an elevated PTH level, other causes for an increased PTH level should be investigated, including, vitamin D deficiency, renal insufficiency, primary hypercalciuria, malabsorption syndromes, and medications such as bisphosphonates and denosumab. Normocalcemic primary HPT is associated with complications similar to those of hypercalcemic HPT, and thus, the management is no different for normocalcemic primary HPT than for classical primary HPT.24 Normohormonal primary HPT is another variant of primary HPT characterized by hypercalcemia and normal but inappropriately high intact PTH levels (>30 pg/mL). Rarely, patients with normohormonal primary HPT may have PTH levels less than 30 pg/

CHAPTER 38  The Parathyroid Glands TABLE 38.4  Evaluation of patients with

suspected or confirmed primary HPT. TESTS Lab Tests Serum total calcium Intact PTH Creatinine, GFR 25-hydroxyvitamin D Ionized calcium Albumin

Serum phosphate Alkaline phosphatase

Urine Tests 24-hour urine calcium and creatinine If urine calcium 1 mg/dL above the upper limit of normal • Age 160 pg/mL Normal = 20 mitoses/10 HPF >20% Aggressive

HPF, High-power field.

TABLE 39.3  American Joint Committee on Cancer (AJCC) and European Neuroendocrine

Tumor Society (ENETS) staging for pancreatic neuroendocrine tumors. AJCC 8TH EDITION

ENETS

Primary Tumor (T) T1 T2 T3

Maximum tumor diameter 2 but 4 cm

T4

Tumor involves the celiac axis or superior mesenteric artery

Tumor limited to the pancreas 4 cm, or invading the duodenum or common bile duct Tumor invades adjacent structures

Nodal Metastases (N) N0 N1 N2

No regional lymph node metastases Metastasis in one to three regional lymph nodes Metastasis in four or more regional lymph nodes

No regional lymph node metastasis Regional lymph node metastasis

Metastatic Disease (M) M0 M1

No distant metastasis Distant metastasis

No distant metastasis Distant metastasis

T1, N0, M0 (Ia) T2, N0, M0 (Ib) T3, N0, M0 (IIa) T1-3, N2, M0 (IIb) Any T, N2, M0 T4, any N, M0 Any T, any N, M1

T1, N0, M0 (Ia) T2, N0, M0 (Ib) T3, N0, M0 (IIa) T1-3, N2, M0 (IIb) T4, any N, M0

Stage I II III IV

Any T, any N, M1

Adapted from Li X, Gou S, Liu Z, et al. Assessment of the American Joint Commission on Cancer 8th edition staging system for patients with pancreatic neuroendocrine tumors: a surveillance, epidemiology, and end results analysis. Cancer Med. 2018;7:626–634.

rates, invasion of other organs, angioinvasion, and the Ki-67 proliferative index (Table 39.2). G1 and G2 tumors are considered well differentiated, and G3 tumors are poorly differentiated and is by far the most important prognostic indicator. High-grade/poorly differentiated PNETs are sometimes referred to as “neuroendocrine carcinoma” and account for fewer than 3% of PNETs. However, it is important to emphasize that well-differentiated tumors do still have malignant potential, but that the differences in behavior persist, even for patients with metastatic disease. The American Joint Committee on Cancer (AJCC) and European Neuroendocrine Tumor Society (ENETS) also have proposed staging schemes for PNETs. Neither system includes tumor grade, and both apply staging similar to that of exocrine pancreatic cancers to PNETs (Table 39.3). In another study, a tumor, grade, metastases (TGM) staging system was proposed as a more

accurate prognostic tool.3 In a recent study using the Surveillance, Epidemiology, and End Results databases, the 8th edition AJCC staging system exhibited good prognostic discrimination across stages in both resected and unresected patients.4 Molecular Genetics of PNETs Although most PNETs occur sporadically, others can be associated with genetic syndromes. The most common genetic syndrome associated with PNETs is multiple endocrine neoplasia type 1 (MEN1), characterized by PNETs, parathyroid adenomas or hyperplasia, and pituitary adenomas. MEN1 is caused by mutations or allelic deletions in the tumor suppressor gene, menin, on chromosome 11q13 and is inherited in an autosomal dominant fashion. Menin is a component of the histone methyltransferase complex and is involved in control of G1 to S phase cell cycle

946

SECTION VIII  Endocrine Cell Growth Glucose (obesity/pregnancy/ MEN1 mutation)

Cell−Cell Communication

EC

Glu4

Laminin 5 PI3K/Akt mTOR Foxo1

ATRX

Integrin 3/6 1

DAXX Chromatin HBA1/NO

p53

FAK/Src

Menin

p27/p18 inhibitor G1/S progression (cell sizes) G2 S

M G1

G2

M G1

B

Telomeres PI3K/Raf/JNK mTOR

Notch Rho/Rac/PAK

Proliferation Apoptosis

Survival, Invasion, and Metastasis

S

A FIG. 39.3  Common genetic mutations and impacted signal transduction pathways in pancreatic neuroendocrine tumors (PNETs). (A) Cell growth. MEN1 mutations decrease Menin-regulated p27/p18 expression, which abrogates the glucose sensor. DAXX mutations decrease p53 levels, diminishing the checkpoint for cellular/DNA damages. Both MEN1 and DAXX mutations promote cell cycle progression from the G1 to S phase, regardless of glucose levels and damage. (B) Cell–cell communications. Endocrine cells, such as beta or alpha cells, relay on the endothelium to provide extracellular matrix, which disables the attachment requirement needed for cancer cells to invade and migrate. ATRX mutation-modulated chromatin modification may play a role in the abnormal activation of FAK/Src and mTOR pathways in PNET. Underlines indicate the mutated genes or activated protein. (With permission from Zhang J, Francois R, Iyer R, et al. Current understanding of the molecular biology of pancreatic neuroendocrine tumors. J Natl Cancer Inst. 2013;105:1005–1017, p 1008.) EC, Endothelial cell; FAK, focal adhesion kinase; HBA1, hemoglobin-α; JNK, c-Jun N-terminal kinase; MEN1, multiple endocrine neoplasia type 1; mTOR, mammalian target of rapamycin; NO, nitric oxide; PAK, p21-activated kinase; PI3K/Akt, phosphoinositide-3-kinase/protein kinase B.

progression. Mutation or allelic deletion causes loss of tumor suppressor function and predisposes patients to neoplastic growth in the parathyroid, pituitary, and pancreatic endocrine tissue. Von Hippel-Lindau (VHL) syndrome is also associated with PNETs. Patients with inherited mutations of the VHL gene are at risk for the development of renal cell carcinoma, pheochromocytoma, benign tumors of the central nervous system, retina, epididymis, and inner ear and pancreatic lesions, including NETs, microcystic adenomas, and simple cysts. Similar to MEN1, the management of PNETs can be challenging, since they are often multifocal and associated with tumors in other locations. PNETs associated with VHL generally behave in an indolent fashion, and it has been suggested that these tumors can be observed until they reach at least 2 3 cm in size. However, specific germline mutations in exon 3 of the VHL gene may be associated with a more aggressive phenotype and warrant earlier treatment and closer surveillance.5 Most PNETs, however, are not associated with a known genetic syndrome and occur sporadically. Other than family history, risk factors for PNETs are not well defined. As in other neoplastic processes, tumorigenesis of PNETs involves an accumulation of a number of genetic events. The common genetic mutations

and impacted signal transduction pathways in PNETs is shown in Fig. 39.3. Complete exomic sequencing of a discovery set of 10 sporadic PNETs revealed mutations in 149 genes, of which 6 were selected for further analysis in a validation set of 58 PNETs.6 Inactivating mutations in MEN1 were seen in 44% of sporadic tumors. Mutations in death-domain associated protein (DAXX) and alpha thalassemia-mental retardation syndrome X-linked (ATRX), whose protein products are involved in p53-mediated DNA damage repair, were seen in 25% and 18%, respectively. Patients with mutations in MEN1 or DAXX/ATRX had prolonged survival compared to those who did not. Previous expression analyses had suggested dysregulation of the mammalian target of rapamycin (mTOR) pathway in a large proportion of tumors.7,8 The mTOR protein is serine/threonine kinase and a key component of a cellular pathway playing an important role in the regulation of cell growth and proliferation. mTOR is upregulated in several tumors, including PNETs. This has potential clinical implications since the mTOR inhibitor everolimus has been U.S. Food and Drug Administration (FDA) approved for advanced NETs. Potentially, mutational testing will allow selection of patients most likely to benefit from this targeted therapy. Overall,

CHAPTER 39  Endocrine Pancreas TABLE 39.4  Comparison of commonly

mutated genes in PNET and PDAC. GENES MEN1 DAXX, ATRX Genes in mTOR pathway TP53 KRAS CDKN2A TGFBR1, SMAD3, SMAD4

PNET 44% 43% 15% 3% 0% 0% 0%

PDAC 0% 0% 0.8% 85% 100% 25% 38%

Adapted from Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331:1199–1203. mTOR, Mammalian target of rapamycin; PDAC, pancreatic ductal adenocarcinoma; PNET, pancreatic neuroendocrine tumor.

the mutational analysis was most remarkable for how distinct the genetic abnormalities were from those observed in a similar study of pancreatic adenocarcinoma (Table 39.4).9 Mutations in KRAS were not seen in PNETs and mutations in P53 were seen only rarely, at least not in these well-differentiated tumors. In a separate study comparing well- and poorly differentiated PNETs, MEN1 and DAXX/ATRX expression by immunohistochemistry was abnormal in approximately half of well-differentiated tumors. In contrast, staining of DAXX/ATRX was normal in poorly differentiated tumors, but there was a high incidence of abnormal p53 and retinoblastoma expression as well as overexpression of the antiapoptotic protein Bcl2, implicating it as a target for therapy in these tumors.10 

General Principles of Diagnosis and Treatment of PNETs Diagnosis and Evaluation The diagnosis and evaluation of PNETs are dependent on the history, symptoms, and imaging available at the time of presentation. Patient presentation can vary widely and include an incidental finding in an asymptomatic patient: functional hormonal syndromes, abdominal symptoms due to mass effect or metastatic disease such as abdominal or back pain, jaundice, anorexia, and weight loss. Until nonfunctional tumors grow large enough to cause symptoms related to mass effect, they often have no or vague symptoms and present at a more advanced stage. Finally, with the increase in the number of incidentally found PNETs on imaging done for other reasons, patients may be completely asymptomatic. All patients with suspected PNETs, regardless of presentation, need, at minimum, 1) a careful history screening for functional tumor symptoms, with biochemical confirmation if indicated, 2) cross-sectional or more advanced imaging when necessary to localize the PNET, 3) evaluation for metastatic disease, and 4) a thorough family history to rule out associated genetic syndromes. A general algorithm for the management of patient with suspected PNET is shown in Fig. 39.4.  Screening for Functional Tumors The diagnosis of functional PNETs can be detected by elevated serum levels of the suspected peptide based on symptoms (Table 39.1). In patients presenting with a hyperenhancing pancreatic mass on cross-sectional imaging suggestive of PNET, the history should screen for neuroglycopenic symptoms, diarrhea, ulcer diathesis, rash, and other symptoms suggestive of a classic hormonal

947

syndrome. A family history should also be obtained to rule out the possibility of MEN1-associated PNET. In the absence of symptoms, a full hormonal screen is not necessary. PNETs often produce distinct gastrointestinal peptides including chromogranin A, neurotensin, and PP. While these peptides are not associated with clinical symptoms or syndromes, they can aid in the confirmation of the diagnosis. Chromogranin A levels have been shown to correlate with tumor presence in both functional and nonfunctional PNETs. Similar to other biomarkers, chromogranin A is useful for both confirmation of the diagnosis in a patient with suspected PNET on imaging as well as posttreatment surveillance for recurrence. Chromogranin A levels can also be elevated in patients on proton pump inhibitors (PPIs), with atrophic gastritis, and in patients with hepatic or renal insufficiency.  Localization The vast majority of noninsulinoma or nongastrinoma pancreatic endocrine tumors will be identified on cross-sectional imaging. Once the diagnosis of a functional PNET is made, cross-sectional imaging with CT or MRI is the first step in localization. Because of their rich vascular supply, PNETs are hyperattenuating when compared with surrounding pancreatic tissue on contrast-enhanced multidetector CT (MDCT; Figs. 39.5A and 39.6A–D). Insulinomas and gastrinomas, which are smaller at presentation, can be more difficult to localize. CT technique, including thinner collimation (1.25-mm cuts) and multiple-phase imaging, is critical to improving sensitivity of CT for these small lesions. Capturing the vascular blush in the arterial phase is critical for identification and differentiation from other types of pancreatic tumors, which is less pronounced in the venous phase. In addition, the use of water instead of oral contrast may assist in identifying small duodenal gastrinomas. The sensitivity of MDCT in the localization of PNETs, in general, is 73% to 96% and is directly related to the size and location of the tumor.11 MRI can also be used for localization (Fig. 39.5B). Pancreatic endocrine tumors demonstrate low-signal intensity on T1-weighted images and high-signal intensity on T2-weighted images. As with CT, size is directly related to sensitivity. In one large series of insulinomas, contrast-enhanced MRI identified all lesions larger than 3 cm, 50% of lesions 1 to 2 cm, and no lesions smaller than 1 cm.12 The overall sensitivity of MRI for detecting PNETs is between 80% and 90%.11,13 If unable to localize a pancreatic endocrine tumor on CT or MRI, endoscopic ultrasound (EUS) should be performed. EUS has an overall sensitivity of approximately 90% for tumors of all sizes and better sensitivity for detecting tumors smaller than 3 cm than CT or MRI.13 EUS has the best diagnostic performance in detection and localization of insulinoma. However, EUS has a limited ability to detect small duodenal tumors, with a sensitivity of only 50% in this setting. EUS also allows for fine-needle aspiration of tumors for a pathologic diagnosis. This is especially useful for nonfunctional tumors without a classic CT appearance of pancreatic endocrine tumors (Fig. 39.6A–D). The abundance of somatostatin receptors on most PNETs makes somatostatin receptor scintigraphy (SRS) a useful adjunct in localization, if tumors are not evident on CT or MRI. The sensitivity for SRS is over 80% for all pancreatic endocrine tumors excluding insulinomas. SRS has an overall sensitivity of 80% to 100% and specificity higher than 90% for gastrinomas, as somatostatin receptors are present in more than 90% of gastrin-secreting PNETs. Somatostatin receptors are also present in a significant

948

SECTION VIII  Endocrine

Patient with suspected PNET

Patient presented with symptoms suggesting functional PNET

Found on CT

Symptoms consistent with functional PNET?

Yes

Send appropriate biochemical markers consistent with syndrome

No Is tumor 0.2

>>>5

+

No

≤2.7

No

With administration of inappropriate insulin With administration of oral agents Fasting

5 years* >5 years*

Y Y Y Y Y Y Y Y Y Y Y N Y Y Y Y N

N Y Y N Y Y Y Y Y N N N N Y Y Y N

AGE TO INITIATE SCREENING, YEARS 11 11 11 16 16 16 16 16 16 16 16 16 16 16 16 16 16

OTHER CONDITIONS CLA HD HD HD HD CLA -

Adapted from Wells SA Jr, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25:567–610. ATA categories: HST, ATA highest; H, ATA high; MOD, ATA moderate; CLA, Cutaneous lichen amyloidosis; HD, Hirschprung disease; MEN2, multiple endocrine neoplasia type 2 syndromes; Pheo, pheochromocytoma; PHPT, rimary hyperparathyroidism; TT, prophylactic thyroidectomy. p*Screening begins at age 5 and timing of TT may be based on calcitonin levels.

form of MTC will have bilobar, multifocal disease. Initial operation should also always include a compartment-oriented bilateral central (level VI) lymph node dissection, that is, removal of all lymph node tissue en bloc in the compartment bounded by the hyoid bone superiorly, the innominate vein inferiorly, the carotid sheaths laterally, and anterior to the trachea, recurrent laryngeal nerves, and deepest layer of cervical fascia whether or not they appear to be clinically involved. The rate of lymph node metastases to level VI is excessively high, found in both the ipsilateral and contralateral compartments ranging from 50% to 80%.40 Even nodes that are apparently normal should be removed as intraoperative surgeon-performed inspection has a low sensitivity and specificity for detection of involved nodes at 65% and 47%, respectively.41 Both the ipsilateral and contralateral lateral nodal compartments, levels II to V, are also frequently involved. The occurrence rates of lateral node metastases depend on primary tumor size as well as extent of involvement of the central compartment, and preoperative calcitonin and CEA levels positively correlate with the presence of lateral node metastases.31 Ideally, the central compartment should be addressed at the time of the initial operation as reoperations in level VI are higher risk, with increased rates of both recurrent laryngeal nerve injury and permanent hypoparathyroidism in reoperations. Ultrasound has a high sensitivity and specificity, 83.5% and 97.7%, respectively, for the lateral neck compartment. Further, the lateral neck compartments are anatomically separate from the central neck and the implications of increased rates of both recurrent nerve injury and hypoparathyroidism do not apply as they do in the central compartment. Therefore, guidelines recommend a patient-tailored approach when considering lateral neck dissection at the time of the initial operation. Careful attention should be paid to the identification of the parathyroid glands at operation in order to maintain function. Ideally, they should

be maintained in situ, but in situations where this is not possible, they may be autotransplanted into either sternocleidomastoid muscle or to the brachioradialis muscle of the forearm depending on the familial setting and likelihood of developing PHPT. The goal of preventative surgery in those known to carry RET mutations is to limit the potential for metastatic spread of MTC and to improve overall survival as essentially all MEN2 patients will develop MTC at some point in their lifetime. Improved survival is linked to performing thyroidectomy and central node dissection when calcitonin levels are either undetectable or very low and when there is no clinically apparent MTC. Therefore, preventative or “prophylactic” thyroidectomy is recommended in infants, children, and adolescents, and recommendations are stratified according to mutation present. With the publication of the 2015 American Thyroid Association guidelines, the management of MTC was updated. In previous editions, categories A, B, C, and D were used to define risk, where risk is related to the aggressiveness of MTC, A being the lowest and D being the highest. With the revised edition, these have been changed to moderate (ATA-MOD), high (ATA-H), and highest (ATA-HST) risk categories. Patients with MEN2B all fall into the ATA-HST risk, previously D, category due to the early onset of MTC in these patients and the more aggressive course of the disease. Category C is now ATA-H and includes patients with codon C634 and A883F mutations. Categories A and B are now merged into the category ATA-MOD and include patients with all other RET mutations, excluding M918T, C634, and A883F.31 Recommendations for management are then stratified based on risk category, summarized in Table 41.1. Recommendations are similar to those published by other societies. Carriers in the ATA-MOD risk category should begin annual screening with physical and ultrasound examination as well as

1008

SECTION VIII  Endocrine

calcitonin measurements done at 6- to 12-month intervals beginning at the age of 5. The timing of thyroidectomy can then be determined using calcitonin levels.31 In one database series of young patients, those operated on with calcitonin levels less than 30 pg/mL had no persistent or recurrent disease at follow-up.42 In another series of patients who underwent preventative surgery, the mean age at detection of no nodal metastases was age 10.43 Therefore, for this category, the type of operation may be individualized based on calcitonin levels and age at the time of operation and the extent of surgery may only need to be total thyroidectomy rather than total thyroidectomy with a central lymph node dissection. The follow-up period in this group may extend for several years and there is potential for loss of continuity, and these factors should be considered when timing preventative surgery.31 Those in the ATA-H risk category should have a preventative thyroidectomy performed at the age of 5 years or earlier if serum calcitonin levels dictate otherwise. Inclusion of central lymph node dissection at the time of total thyroidectomy is based on preoperative calcitonin levels as well as intraoperative inspection of lymph nodes.31 The recommendation for children in the ATA-HST risk category, limited to those with MEN2B and an M918T mutation, should have a total thyroidectomy in the first year of life. The decision to perform central lymph node dissection at the time of operation is dictated based on the presence of clinically suspicious level VI lymph nodes and the ability of the surgeon to identify and preserve parathyroid glands.31 Children operated on at an earlier age are more likely to have a biochemical cure, with undetectable calcitonin levels, and improved survival. Most will develop MTC by age 16 and are likely to possess physical characteristics associated with MEN2B. Therefore, screening for MEN2B or MTC should be considered in children with the typical physical phenotype. Outcomes of the familial forms of MTC are largely dependent on the age and stage at the time of surgical management. In a population of patients with MEN2-associated MTC, overall survival at 5 and 10 years was 100% and 94%, respectively, and diseasefree survival at 5 and 10 years was 92.9% and 71.6%, respectively, with a mean age at diagnosis of 43.9 years. Age, preoperative calcitonin levels, and presence of vascular invasion were all predictors of survival.44 In another series of patients, approximately one third of patients achieved biochemical cure, or normalization of calcitonin, with appropriate surgical management,45 which has been linked to improved survival. Ultimately, though, carriers of RET mutations require lifelong follow-up not only for detection of recurrent MTC, but following total thyroidectomy, patients require thyroid hormone replacement to physiologic levels. Calcitonin and CEA levels should be measured every 3 months postoperatively, or, if undetectable after surgery, the interval can be lengthened to 6 to 12 months.  Recurrent and Metastatic Disease Approximately 50% of patients with MTC will have either persistent or recurrent disease after initial operation. These patients are identified by either a palpable neck mass following surgery or as evidenced by calcitonin levels. Depending on the degree to which calcitonin is elevated or if it is rising, distant metastatic disease should be considered and evaluated as previously stated. Regional recurrences, that is, those limited to the neck, are best managed with repeat operation. Benefits of reoperation in the neck include potential for achieving biochemical cure, known to

correlate with survival, as well as potentially identifying patients who may have calcitonin elevations as a result of distant metastasis once the neck is free of disease. Reoperative neck surgery should be focused on treating compartments with imageable or biopsy-proven disease, with the operation done in a compartment-oriented fashion. Beyond surgery, limited options exist for management. Postoperative RAI is not indicated as C-cells do not take up iodine. External beam radiation therapy is of little benefit for the management of recurrent disease in the neck and does not improve survival. It may play a role in the palliation of bone metastases. Single-agent or combination cytotoxic chemotherapies have a low response to treatment and are typically not used as first-line therapy.31 Understanding the genetics of MTC has allowed for the development of targeted therapies primarily falling into the class of agents known as tyrosine kinase inhibitors. Vandetanib is the primary agent used, and in clinical trials, both partial and complete responses have been observed. It has also been demonstrated to improve progression-free survival and its use in metastatic MTC is Food and Drug Administration approved.46 

Pheochromocytoma Pheochromocytomas are tumors arising from the chromaffin cells of the adrenal medulla. These cells secrete catecholamines, which are produced in excess in the setting of a pheochromocytoma. Typical symptoms of pheochromocytoma include sweating, tremulousness, headache, flushing, palpitations, and anxiety. Typical age at diagnosis is in the 30s or 40s, although they may also be identified in children and adolescents. Identification of a pheochromocytoma prior to surgical management of MTC is critical to avoid intraoperative hypertensive crisis and death, and evaluation is done by measuring plasma or timed urinary metanephrines prior to surgery. If a pheochromocytoma is identified prior to thyroidectomy, then in almost all situations, an adrenalectomy would be done first to normalize catecholamine levels. Compared to patients with sporadic pheochromocytoma, MEN2-pheochromocytoma occur in younger patients, are often bilateral, and have higher baseline metanephrine levels. In one series of patients, MEN2-pheochromocytoma patients were more than 10 years younger on average and had bilateral tumors approximately 50% of the time.47 In another series of patients, pheochromocytoma was diagnosed synchronously with MTC in 34% of patients, highlighting the importance of screening for pheochromocytoma prior to thyroidectomy. In the same group, survival was equivalent in patients with MTC with and without pheochromocytoma.48 The most common mutation identified in patients with pheochromocytoma is a codon 634 mutation followed by codon 918 mutations.47,48 In patients with a codon 634 mutation, penetrance is 25% by age 30, 52% by age 50, and 88% by age 77, while all patients with a codon 918 mutation (MEN2B) developed a pheochromocytoma by age 56 years. In all other mutations, the penetrance is 32%. MEN2-pheochromocytoma tend to be benign, but given the potential for recurrence and bilaterality, patients require lifelong monitoring. They can be malignant, but it is uncommon, occurring less than 5% of the time. All patients with MEN2A or MEN2B should be screened for pheochromocytoma. Recommendations for screening are stratified according to the ATA risk categories where HST, H, and

CHAPTER 41  The Multiple Endocrine Neoplasia Syndromes

A

1009

B FIG. 41.7  (A) Typical computed tomography appearance of pheochromocytoma, indicated by arrow. (B) Resected adrenal pheochromocytoma.

MOD risk patients begin screening at the ages of 11, 11, and 16, respectively.31 Measurements of plasma free metanephrines and normetanephrines or 24-hour urinary metanephrines and normetanephrines should be done at a minimum annually. If there is any abnormality with testing, that is, elevated levels of either, further investigatory imaging should be done with either CT or MRI of the abdomen to evaluate for the presence of an adrenal mass. Patients confirmed to have a pheochromocytoma should undergo surgical resection. The procedure of choice for operative management is either a laparoscopic or retroperitoneoscopic adrenalectomy, and the selection of the procedure depends on the expertise of the surgeon (Fig. 41.7). The safety of either of these procedures is well established, and they are comparable to one another. Minimally invasive adrenalectomies are associated with a shorter hospital stay and less postoperative pain compared to open adrenalectomy. Laparoscopic transabdominal adrenalectomy may be better for larger lesions; however, and it is still an appropriate choice for pheochromocytoma that are larger as well. If there is any radiologic evidence of invasion of adjacent organs or structures, the pheochromocytoma would then be presumed to be malignant, and an open adrenalectomy is preferred. A major concern surrounding operation for MEN2-pheochromocytoma is that they are likely to either be bilateral or recur over time, and patients will potentially need multiple operations. Because of this, when feasible, a cortical-sparing or partial adrenalectomy should be performed. The safety of this procedure is established, and it is done in an effort to avoid adrenal insufficiency. Situations where cortical-sparing adrenalectomy is preferred include patients who have had the contralateral adrenal gland removed and small tumors where there is a portion of normal-appearing adrenal gland that could potentially be left in situ. Approximately 90% of patients after cortical-sparing adrenalectomy will remain steroid-independent.49 The decision to perform a cortical-sparing adrenalectomy should be weighed

against the risks of developing another pheochromocytoma over the lifetime of the patient, and treatment decisions should be individualized based on patient-specific details. All patients undergoing surgery for a pheochromocytoma should receive appropriate preoperative preparation with an alpha-blocker or calcium-channel blocker. 

Primary Hyperparathyroidism Up to a third of patients with MEN2A can develop PHPT, and the likelihood of development is predictable based on which mutation is present. PHPT is not found in patients with MEN2B or with FMTC; therefore, screening and surveillance are not indicated. PHPT tends to occur earlier and is most commonly found in patients with codon 634 mutations, ATA-H category.50 The recommended age at which screening and annual surveillance should begin follows the recommendations for pheochromocytoma. ATA-H and ATA-MOD category patients should begin annual testing of calcium levels and PTH at the ages of 11 and 16 years, respectively.31 Options for surgical management include subtotal parathyroidectomy, leaving a portion of one gland in situ, total parathyroidectomy with autotransplantation into the brachioradialis muscle of the forearm, or parathyroidectomy with removal of only abnormal-appearing glands guided by intraoperative PTH measurements in order to establish that the patient has been biochemically cured. Over time, the surgical management of PHPT in the setting of MEN2A has evolved to the latter procedure, where only abnormal-appearing glands are removed at the time of surgery. The rate of both persistent and recurrent disease is low even with focused or image-guided parathyroidectomy. In planning for a focused parathyroidectomy, preoperative imaging should be obtained based on surgeon comfort and experience with interpretation of the study. Patients who develop PHPT following a thyroidectomy for MTC should have imaging prior to undergoing reoperative neck surgery in order to localize the abnormal gland or glands.31 

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CONCLUSION Management of MEN has evolved over time and has been greatly impacted by both better understanding of the natural history of the disease, as well as discovery and characterization of the related genetic mutations. Identification of a mutation in either the MEN1 gene or in the RET gene offers a way for the clinician to predict the course of the disease over time and tailor care to the individual patient. Patients with MEN2 may be offered preventative surgery and be cured of MTC. Those with MEN1 can be offered appropriate surveillance to avoid sequelae of malignant progression of NETs. Exclusion of the presence of a mutation in known kindreds can avoid lifelong unnecessary testing. Surveillance and treatment will continue to be tailored over time as more is learned about the pathogenesis of these diseases, resulting in improved outcomes in those affected.

SELECTED REFERENCES Alesina PF, Hinrichs J, Meier B, et al. Minimally invasive corticalsparing surgery for bilateral pheochromocytomas. Langenbecks Arch Surg. 2012;397:233–238. This report of a single-institution experience of patients undergoing bilateral cortical-sparing adrenalectomy for pheochromocytoma demonstrates that patients undergoing this procedure have a low recurrence rate and few have adrenal insufficiency postoperatively.

Elaraj DM, Skarulis MC, Libutti SK, et  al. Results of initial operation for hyperparathyroidism in patients with multiple endocrine neoplasia type 1. Surgery. 2003;134:858–864; discussion 864–855. This is a single-institution series evaluating the outcomes of parathyroidectomy and patient characteristics in patients undergoing parathyroidectomy for primary hyperparathyroidism with a known diagnosis of multiple endocrine neoplasia type 1.

Nell S, Verkooijen HM, Pieterman CRC, et al. Management of MEN1 related nonfunctioning pancreatic NETs: a shifting paradigm: results from the DutchMEN1 Study Group. Ann Surg. 2018;267:1155–1160. Using a prospectively collected database of patients known to have multiple endocrine neoplasia type 1, these data compare the outcomes and characteristics of patients with nonfunctional pancreatic neuroendocrine tumors (NETs) stratified by size managed with surgery versus observation.

Neumann HP, Bausch B, McWhinney SR, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002;346:1459–1466. These data evaluated a population of patients with apparent nonsyndromic pheochromocytoma and found that up to 25% possess a previously unknown genetic mutation.

Wells Jr SA, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25:567–610. These are the most recently published management guidelines for medullary thyroid carcinoma written by a consensus group of experts in the field.

REFERENCES 1. Thakker RV, Newey PJ, Walls GV, et  al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012;97:2990–3011. 2. Ito T, Igarashi H, Uehara H, et al. Causes of death and prognostic factors in multiple endocrine neoplasia type 1: a prospective study: comparison of 106 MEN1/Zollinger-Ellison syndrome patients with 1613 literature MEN1 patients with or without pancreatic endocrine tumors. Medicine (Baltimore). 2013;92:135–181. 3. Larsson C, Skogseid B, Oberg K, et  al. Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature. 1988;332:85–87. 4. Chandrasekharappa SC, Guru SC, Manickam P, et  al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 1997;276:404–407. 5. Dreijerink KM, Goudet P, Burgess JR, et  al. Breast-cancer predisposition in multiple endocrine neoplasia type 1. N Engl J Med. 2014;371:583–584. 6. Lemos MC, Thakker RV. Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Hum Mutat. 2008;29:22–32. 7. Marini F, Giusti F, Brandi ML. Genetic test in multiple endocrine neoplasia type 1 syndrome: an evolving story. World J Exp Med. 2015;5:124–129. 8. Thevenon J, Bourredjem A, Faivre L, et al. Higher risk of death among MEN1 patients with mutations in the JunD interacting domain: a Groupe d’etude des Tumeurs Endocrines (GTE) cohort study. Hum Mol Genet. 2013;22:1940–1948. 9. Pardi E, Mariotti S, Pellegata NS, et  al. Functional characterization of a CDKN1B mutation in a Sardinian kindred with multiple endocrine neoplasia type 4 (MEN4). Endocr Connect. 2015;4:1–8. 10. Elaraj DM, Skarulis MC, Libutti SK, et al. Results of initial operation for hyperparathyroidism in patients with multiple endocrine neoplasia type 1. Surgery. 2003;134:858–864; discussion 864–855. 11. Lairmore TC, Govednik CM, Quinn CE, et  al. A randomized, prospective trial of operative treatments for hyperparathyroidism in patients with multiple endocrine neoplasia type 1. Surgery. 2014;156:1326–1334; discussion 1334–1325. 12. Cohen MS, Dilley WG, Wells Jr SA, et al. Long-term functionality of cryopreserved parathyroid autografts: a 13-year prospective analysis. Surgery. 2005;138:1033–1040; discussion 1040–1031. 13. Kwekkeboom DJ, Krenning EP. Somatostatin receptor imaging. Semin Nucl Med. 2002;32:84–91. 14. Haug AR, Cindea-Drimus R, Auernhammer CJ, et  al. The role of 68Ga-DOTATATE PET/CT in suspected neuroendocrine tumors. J Nucl Med. 2012;53:1686–1692.

CHAPTER 41  The Multiple Endocrine Neoplasia Syndromes 15. Fendrich V, Langer P, Waldmann J, et al. Management of sporadic and multiple endocrine neoplasia type 1 gastrinomas. Br J Surg. 2007;94:1331–1341. 16. Norton JA. Surgical treatment and prognosis of gastrinoma. Best Pract Res Clin Gastroenterol. 2005;19:799–805. 17. Norton JA, Jensen RT. Resolved and unresolved controversies in the surgical management of patients with Zollinger-Ellison syndrome. Ann Surg. 2004;240:757–773. 18. Guettier JM, Kam A, Chang R, et  al. Localization of insulinomas to regions of the pancreas by intraarterial calcium stimulation: the NIH experience. J Clin Endocrinol Metab. 2009;94:1074–1080. 19. Albright SV, McCart JA, Libutti SK, et al. Rapid measurement of insulin using the Abbott IMx: application to the management of insulinoma. Ann Clin Biochem. 2002;39:513–515. 20. Christakis I, Qiu W, Hyde SM, et  al. Genotype-phenotype pancreatic neuroendocrine tumor relationship in multiple endocrine neoplasia type 1 patients: a 23-year experience at a single institution. Surgery. 2018;163:212–217. 21. Triponez F, Dosseh D, Goudet P, et al. Epidemiology data on 108 MEN 1 patients from the GTE with isolated nonfunctioning tumors of the pancreas. Ann Surg. 2006;243: 265–272. 22. Vinault S, Mariet AS, Le Bras M, et al. Metastatic potential and survival of duodenal and pancreatic tumors in multiple endocrine neoplasia type 1: a GTE and AFCE cohort study (Groupe d’etude des Tumeurs Endocrines and Association Francophone de Chirurgie Endocrinienne) [published online ahead of print 2018]. Ann Surg. 23. Nell S, Verkooijen HM, Pieterman CRC, et al. Management of MEN1 related nonfunctioning pancreatic NETs: a shifting paradigm: results from the DutchMEN1 Study Group. Ann Surg. 2018;267:1155–1160. 24. Falconi M, Eriksson B, Kaltsas G, et  al. ENETS consensus guidelines update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology. 2016; 103:153–171. 25. de Laat JM, Dekkers OM, Pieterman CR, et  al. Long-term natural course of pituitary tumors in patients with MEN1: results from the DutchMEN1 Study Group (DMSG). J Clin Endocrinol Metab. 2015;100:3288–3296. 26. Christakis I, Qiu W, Silva Figueroa AM, et  al. Clinical features, treatments, and outcomes of patients with thymic carcinoids and multiple endocrine neoplasia type 1 syndrome at MD Anderson Cancer Center. Horm Cancer. 2016;7:279–287. 27. Gatta-Cherifi B, Chabre O, Murat A, et al. Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d’etude des Tumeurs Endocrines database. Eur J Endocrinol. 2012;166:269–279. 28. Callender GG, Rich TA, Perrier ND. Multiple endocrine neoplasia syndromes. Surg Clin North Am. 2008;88:863–895, viii. 29. Steiner AL, Goodman AD, Powers SR. Study of a kindred with pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism and Cushing’s disease: multiple endocrine neoplasia, type 2. Medicine (Baltimore). 1968;47: 371–409.

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30. Eng C, Clayton D, Schuffenecker I, et  al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET Mutation Consortium analysis. JAMA. 1996;276:1575–1579. 31. Wells Jr SA, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25:567–610. 32. Farndon JR, Leight GS, Dilley WG, et al. Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity. Br J Surg. 1986;73:278–281. 33. Jasim S, Ying AK, Waguespack SG, et al. Multiple endocrine neoplasia type 2B with a RET proto-oncogene A883F mutation displays a more indolent form of medullary thyroid carcinoma compared with a RET M918T mutation. Thyroid. 2011;21:189–192. 34. Elisei R, Romei C, Cosci B, et  al. RET genetic screening in patients with medullary thyroid cancer and their relatives: experience with 807 individuals at one center. J Clin Endocrinol Metab. 2007;92:4725–4729. 35. Neumann HP, Bausch B, McWhinney SR, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002;346:1459–1466. 36. Noone AM, Howlader N, Krapcho M, et  al. SEER Cancer Statistics Review, 1975–2015. National Cancer Institute; 2018. https://seer.cancer.gov/archive/csr/1975_2015/. Accessed June 13, 2019. 37. Torresan F, Cavedon E, Mian C, et al. Long-term outcome after surgery for medullary thyroid carcinoma: a single-center experience. World J Surg. 2018;42:367–375. 38. Wells Jr SA, Pacini F, Robinson BG, et al. Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. J Clin Endocrinol Metab. 2013;98: 3149–3164. 39. Castroneves LA, Coura Filho G, de Freitas RMC, et  al. Comparison of 68Ga PET/CT to other imaging studies in medullary thyroid cancer: superiority in detecting bone metastases. J Clin Endocrinol Metab. 2018;103: 3250–3259. 40. Moley JF, DeBenedetti MK. Patterns of nodal metastases in palpable medullary thyroid carcinoma: recommendations for extent of node dissection. Ann Surg. 1999;229:880–887; discussion 887–888. 41. Laird AM, Gauger PG, Miller BS, et al. Evaluation of postoperative radioactive iodine scans in patients who underwent prophylactic central lymph node dissection. World J Surg. 2012;36:1268–1273. 42. Rohmer V, Vidal-Trecan G, Bourdelot A, et al. Prognostic factors of disease-free survival after thyroidectomy in 170 young patients with a RET germline mutation: a multicenter study of the Groupe Francais d’Etude des Tumeurs Endocrines. J Clin Endocrinol Metab. 2011;96:E509–518. 43. Machens A, Niccoli-Sire P, Hoegel J, et al. Early malignant progression of hereditary medullary thyroid cancer. N Engl J Med. 2003;349:1517–1525. 44. Jayakody S, Reagh J, Bullock M, et al. Medullary thyroid carcinoma: survival analysis and evaluation of mutation-specific immunohistochemistry in detection of sporadic disease. World J Surg. 2018;42:1432–1439.

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45. Cupisti K, Wolf A, Raffel A, et  al. Long-term clinical and biochemical follow-up in medullary thyroid carcinoma: a single institution’s experience over 20 years. Ann Surg. 2007;246:815–821. 46. Wells Jr SA, Robinson BG, Gagel RF, et  al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30:134–141. 47. Rajan S, Zaidi G, Agarwal G, et al. Genotype-phenotype correlation in Indian patients with MEN2-associated pheochromocytoma and comparison of clinico-pathological attributes with apparently sporadic adrenal pheochromocytoma. World J Surg. 2016;40:690–696.

48. Thosani S, Ayala-Ramirez M, Palmer L, et al. The characterization of pheochromocytoma and its impact on overall survival in multiple endocrine neoplasia type 2. J Clin Endocrinol Metab. 2013;98:E1813–E1819. 49. Alesina PF, Hinrichs J, Meier B, et al. Minimally invasive cortical-sparing surgery for bilateral pheochromocytomas. Langenbecks Arch Surg. 2012;397:233–238. 50. Schuffenecker I, Virally-Monod M, Brohet R, et  al. Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene. Groupe D’etude des Tumeurs a Calcitonine. J Clin Endocrinol Metab. 1998;83:487–491.

SECTION

IX

Esophagus

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CHAPTER

Esophagus Ravi Rajaram, Jonathan D. Spicer, Rajeev Dhupar, Jae Y. Kim, Boris Sepesi, Wayne L. Hofstetter

OUTLINE Anatomy Esophageal Inlet Esophageal Layers Anatomic Narrowing Gastroesophageal Junction Vasculature Lymphatics Innervation Physiology Swallowing Reflux Mechanism Diagnosis and Management of Esophageal Motility Disorders Diagnosis Motility Disorders of the Esophageal Body Motility Disorders of the Lower Esophageal Sphincter Motility Disorders Affecting Both Body and Lower Esophageal Sphincter Diverticular Disorders Pharyngoesophageal (Zenker) Diverticulum Midesophageal Diverticula Epiphrenic Diverticula

Gastroesophageal Reflux Disease Medical Management Workup Surgical Therapy Acquired Benign Disorders of the Esophagus Acquired Esophageal Disease Benign and Rare Tumors of the Esophagus Benign Tumors of the Esophagus Rare Malignant Tumors of the Esophagus Esophageal Cancer Epidemiology of Esophageal Cancer Diagnosis and Staging of Esophageal Cancer Approach to Early-Stage Esophageal Cancer High-Grade Dysplasia and Superficial Cancers Locally Advanced Esophageal Cancer The Role of Surgery in Trimodality Therapy and Salvage Surgery Surveillance Palliative Options for Esophageal Cancer Summary

An organ that spans the distance of neck to stomach, the esophagus for all of its tube-like simplicity is in actuality a complex and relatively durable organ. It traverses the outside world and passes through precious territory in the mediastinum. The esophagus functions within areas that transition through pressure changes ranging from atmospheric to vacuum. Yet, the precision of a normal esophagus is virtually unrecognized. We swallow without effort, pain, or thought; but introduce disease within the organ, and we incur various degrees of malady, some quite severe and invariably chronic. We have yet to come up with perfect solutions for most of the dysfunction that is described in the forthcoming section, and replacement of the esophagus at this point is accomplished only by substitution of tissues rather than a renewal. Ultimately, among the “fixes” that are described, nothing functions as well as the original healthy organ. However, advances in perioperative care, surgical safety, and minimally invasive as well as endoscopic techniques have improved patient outcomes for many esophageal pathologies. Nevertheless, future generations of esophagologists have the opportunity to further innovate and contribute to the management of this complex organ. Our hope is that this chapter serves as an introduction to the esophagus and its various forms of function and dysfunction. One could literally spend a lifetime delving into each of these areas.

ANATOMY

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The esophagus is a two-layered, mucosa-lined muscular tube that travels through the neck, chest, and abdomen and rests unobtrusively in the posterior mediastinum. It commences at the base of the pharynx at C6 and terminates in the abdomen, where it joins the cardia of the stomach at T11 (Fig. 42.1). Along its 25- to 30cm course, it winds its way through a path yielding to structures of more vital efforts. The cervical esophagus begins as a midline structure that deviates slightly to the left of the trachea as it passes through the neck into the thoracic inlet. At the level of the carina, it deviates to the right to accommodate the arch of the aorta. It then winds its way back under the left mainstem bronchus and remains slightly deviated to the left as it enters the diaphragm through the esophageal hiatus at the level of the eleventh thoracic vertebra. In the neck and upper thorax, the esophagus is secured between the vertebral column posteriorly and the trachea anteriorly. At the level of the carina, the heart and pericardium lie directly anterior to the thoracic esophagus. Immediately before entering the abdomen, the esophagus is pushed anteriorly by the descending thoracic aorta that accompanies the esophagus through the diaphragm into the abdomen separated by the median arcuate ligament.

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CHAPTER 42  Esophagus

C4 C6 Trachea

Diaphragm

Squamocolumnar junction Z-line

T1 Esophagus T3

Rugal folds T5 Aorta

Heart

T7

FIG. 42.2 Z-line. Epithelium Basement membrane Lamina propria Muscularis mucosae Submucosa

T9

T11

Muscularis propria

Diaphragm

Periesophageal tissue (adventitia)

FIG. 42.1  Course of the esophagus.

The journey through the muscular esophagus begins and ends with two distinct high-pressure zones, the upper (UES) and lower esophageal sphincter (LES). After passing through the UES, four esophageal segments are encountered: the pharyngeal, cervical, thoracic, and abdominal esophagus. The LES is the outlet through which passage into the stomach is then facilitated.

Esophageal Inlet The high-pressure zone at the inlet of the esophagus is the UES, which anatomically marks the end of a complex configuration of muscles that begins in the larynx and posterior pharynx and ends in the neck. The pharyngeal constrictor muscles are three consecutive muscles that begin at the base of the palate and end at the crest of the esophagus. The superior and middle pharyngeal constrictor muscles, as well as the oblique, transverse, and posterior cricoarytenoid muscles, are immediately proximal to the UES and serve to anchor the pharynx and larynx to structures in the mouth and palate. These muscles also aid in deglutition and speech but are not responsible for the high pressures noted in the UES. The inferior pharyngeal constrictor muscle is the final bridge between the pharyngeal and esophageal musculature. Inserting into the median pharyngeal raphe, the inferior pharyngeal constrictor muscle is composed of two consecutive muscle beds—the thyropharyngeus and cricopharyngeus muscles—that originate bilaterally from the lateral portions of the thyroid and cricoid cartilages, respectively. The transition between the oblique

FIG. 42.3  Layers of the esophagus. (Adapted from Pearson FG, Cooper JD, Deslauriers J, et al. Esophageal surgery. 2nd ed. New York, NY: Churchill Livingstone; 2002:124.)

fibers of the thyropharyngeus muscle and the horizontal fibers of the cricopharyngeus muscle creates a point of potential weakness, known as Killian triangle (site of a Zenker diverticulum). The cricopharyngeus muscle is responsible for generating a high-pressure zone that marks the position of the UES and esophageal introitus. Its distinctive bowing array of muscle fibers is unique and serves to transition into the circular esophageal musculature. This point of transition is flanked by the longitudinal esophageal muscles that extend superiorly to attach to the midportion of the posterior surface of the cricoid cartilage and form the V-shaped area of Laimer. 

Esophageal Layers The esophagus is comprised of two proper layers, the mucosa and muscularis propria. It is distinguished from the other layers of the alimentary tract by its lack of a serosa. The mucosa is the innermost layer and consists of squamous epithelium for most of its course. The distal 1 to 2 cm of esophageal mucosa transitions to cardiac mucosa or junctional columnar epithelium at a point known as the Z-line (Fig. 42.2). Within the mucosa, there are four distinct layers: the epithelium, basement membrane, lamina propria, and muscularis mucosae. Deep to the muscularis mucosae lays the submucosa (Fig. 42.3). Within it is a plush network of

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SECTION IX  Esophagus Circular esophageal muscle Cricoid cartilage (posterior surface) Tendinous attachment of longitudinal esophageal muscle Posterior cricoarytenoid muscle Inferior pharyngeal constrictor muscle Pharyngeal aponeurosis (cut away) Zone of sparse muscle fibers (Killian triangle)

Squamocolumnar junction Z-line

Fat pad

Rugal folds

Cricopharyngeus muscle (part of inferior pharyngeal constrictor) Esophageal mucosa and submucosa Circular muscle in V-shaped area (of Laimer) Right recurrent laryngeal nerve Longitudinal esophageal muscle

Window cut in longitudinal muscle exposes circular muscle layer Posterior view with pharynx opened and mucosa removed

FIG. 42.4  Muscles of the esophagus.

lymphatic and vascular structures, as well as mucous glands and Meissner neural plexus. Enveloping the mucosa, directly abutting the submucosa, is the muscularis propria. Below the cricopharyngeus muscle, the esophagus is composed of two concentric muscle bundles: an inner circular and outer longitudinal (Fig. 42.4). Both layers of the upper third of the esophagus are striated, whereas the layers of the lower two-thirds are smooth muscle. The circular muscles are an extension of the cricopharyngeus muscle and traverse through the thoracic cavity into the abdomen, where they become the middle circular muscles of the lesser curvature of the stomach. The collar of Helvetius marks the transition of the circular muscles of the esophagus to oblique muscles of the stomach at the incisura (cardiac notch). Between the layers of esophageal muscle is a thin septum comprised of connective tissue, blood vessels, and an interconnected network of ganglia known as Auerbach plexus. Enshrouding the inner circular layer, the longitudinal muscles of the esophagus begin at the cricoid cartilage and extend into the abdomen, where they join the longitudinal musculature of the cardia of the stomach. The esophagus is then wrapped by a layer of fibroalveolar adventitia. 

Anatomic Narrowing The esophageal silhouette resembles an hourglass. There are three distinct areas of narrowing that contribute to its shape. Measuring 14 mm in diameter, the cricopharyngeus muscle is the narrowest point of the gastrointestinal tract and marks the superiormost portion of the hourglass-shaped esophagus. Located just below the carina, where the left mainstem bronchus and aorta abut the esophagus, the bronchoaortic constriction at the level of the fourth thoracic vertebra creates the center narrowing and measures 15 to 17 mm. Finally, the diaphragmatic constriction, measuring 16 to 19 mm, marks the inferior portion of the hourglass and is located where the esophagus passes through the diaphragm. Between these three distinct areas of anatomic constriction are two areas of

FIG. 42.5  Identifiers of the gastroesophageal junction.

dilatation known as the superior and inferior dilatations. Within these areas, the esophagus resumes the normal diameter for an adult and measures approximately 2.5 cm. 

Gastroesophageal Junction The UES and LES mark the entrance and exit to the esophagus, respectively. These sphincters are defined by a high-pressure zone but can be difficult to identify anatomically. The UES corresponds reliably to the cricopharyngeus muscle, but the LES is more complex to discern. There are four anatomic points that identify the gastroesophageal junction (GEJ): two endoscopic and two external. Endoscopically, there are two anatomic considerations that may be used to identify the GEJ. The squamocolumnar epithelial junction (Z-line) may mark the GEJ provided that the patient does not have a distal esophagus replaced by columnar-lined epithelium, as seen with Barrett esophagus. The transition from the smooth esophageal lining to the rugal folds of the stomach may also identify the GEJ accurately. Externally, the collar of Helvetius (or loop of Willis), where the circular muscular fibers of the esophagus join the oblique fibers of the stomach, and the gastroesophageal fat pad are consistent identifiers of the GEJ (Fig. 42.5). 

Vasculature The rich vascular and lymphatic structures that nourish and drain the esophagus serve as a surgical safety net and a highway for metastases. The vasculature is divided into three segments: cervical, thoracic, and abdominal. The cervical esophagus receives most of its blood supply from the inferior thyroid arteries, which branch off of the thyrocervical trunk on the left and the subclavian artery on the right (Fig. 42.6). The cricopharyngeus muscle, which marks the inlet of the esophagus, is supplied by the superior thyroid artery. The thoracic esophagus receives its blood supply directly from four to six esophageal arteries coming off the aorta, as well as esophageal branches off the right and left bronchial arteries. It is supplemented by descending branches off the inferior thyroid arteries, intercostal arteries, and ascending branches of the paired inferior phrenic arteries. The abdominal esophagus receives its blood supply from the left gastric artery and paired inferior phrenic arteries. All the arteries that supply blood to the esophagus terminate in a fine capillary network before they penetrate the muscular wall of the esophagus. After penetrating and supplying the muscular layers, the capillary network continues the length of the esophagus within the submucosal layer.

CHAPTER 42  Esophagus

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Inferior thyroid artery

Esophageal branch of inferior thyroid artery

Thyrocervical trunk

Aorta Right bronchial artery

Intercostal arteries

Esophageal branch of right bronchial artery

Aortic esophageal arteries

Diaphragm

Left gastric artery

Paired phrenic arteries

Celiac axis

Splenic artery

FIG. 42.6  Arterial supply to the esophagus.

The venous drainage parallels the arterial vasculature and is just as complex. In all parts of the esophagus, the rich submucosal venous plexus is the first basin for venous drainage of the esophagus. In the cervical esophagus, the submucosal venous plexus drains into the inferior thyroid veins, which are tributaries of the left subclavian vein and right brachiocephalic vein (Fig. 42.7). The drainage of the thoracic esophagus is more intricate. The submucosal venous plexus of the thoracic esophagus joins with the more superficial esophageal venous plexus and the venae comitantes that envelop the esophagus at this level. This plexus, in turn, drains into the azygos and hemiazygos veins on the right and left sides of the chest, respectively. The intercostal veins also drain into the azygos venous system. The abdominal esophagus drains into the systemic and portal venous systems through the left and right phrenic veins and left gastric (coronary) vein and short gastric veins, respectively. 

Lymphatics The lymphatic drainage of the esophagus is extensive; it consists of two interconnecting lymphatic plexuses arising from the submucosa and muscularis layers. The submucosal lymphatics penetrate the muscularis propria and drain into the plexus that runs longitudinally in the esophageal wall. They then egress and drain into regional lymph node beds. In the upper two-thirds of the esophagus, lymphatic flow is upward, whereas in the distal third,

flow tends to be downward. Esophageal lymphatics begin in the neck with drainage to the paratracheal lymph nodes anteriorly and deep lateral cervical and internal jugular nodes laterally and posteriorly. Once inside the chest, the lymphatics form a matrix of interconnecting channels that drain into the mediastinal lymph nodes and thoracic duct. Anteriorly, the paratracheal and subcarinal lymph nodes and the paraesophageal, retrocardiac, and infracardiac nodes all drain the esophagus. Other mediastinal stations, such as the para-aortic and inferior pulmonary ligament nodes, can also receive drainage from the thoracic esophagus. Posteriorly, nodes along the esophagus and azygos veins are the primary sites of drainage (Fig. 42.8). The intricate lymphatic network of the esophagus allows for rapid spread of infection and tumor into three body cavities. It stands to reason that the rich arterial supply to the esophagus makes it one of the more durable organs in the body with respect to surgical manipulation, whereas its comprehensive venous and lymphatic drainage create an oncologic challenge to controlling cellular migration. These anatomic complexities lead to surgical challenges when treating esophageal cancer and other esophageal diseases. 

Innervation The innervation to the esophagus is sympathetic and parasympathetic (Fig. 42.9). The cervical sympathetic trunk arises from the

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SECTION IX  Esophagus Internal jugular vein Inferior thyroid vein Subclavian vein Esophageal plexus

Superior vena cava Intercostal veins

Submucosal venous plexus

Azygos vein Hemiazygos vein

Short gastric veins

Inferior vena cava

Portal vein Left gastroepiploic vein Left gastric (coronary) vein

Superior mesenteric vein

Right gastroepiploic vein

Inferior mesenteric vein

FIG. 42.7  Venous drainage of the esophagus.

superior ganglion in the neck. It extends next to the esophagus into the thoracic cavity, where it terminates in the cervicothoracic (stellate) ganglion. Along the way, it gives off branches to the cervical esophagus. The thoracic sympathetic trunk continues on from the stellate ganglion, giving off branches to the esophageal plexus, which envelops the thoracic esophagus anteriorly and posteriorly. Inferiorly, the greater and lesser splanchnic nerves innervate the distal thoracic esophagus. In the abdomen, the sympathetic fibers lay posteriorly alongside the left gastric artery. The parasympathetic fibers arise from the vagus nerve, which gives rise to the superior and recurrent laryngeal nerves. The superior laryngeal nerve branches into the external and internal laryngeal nerves that supply motor innervation to the inferior pharyngeal constrictor muscle and cricothyroid muscle and sensory innervation to the larynx, respectively (Fig. 42.10). The right and left recurrent laryngeal nerves come off the vagus nerve and loop underneath the right subclavian artery and aortic arch, respectively. They then travel upward in the tracheoesophageal groove to enter the larynx laterally underneath the inferior pharyngeal constrictor muscle. Along the way, they innervate the cervical esophagus, including the cricopharyngeus muscle. Unilateral injury to the superior or recurrent laryngeal nerve results in hoarseness and aspiration from laryngeal and UES dysfunction. In the thorax, the vagus nerve sends fibers to the striated muscle and parasympathetic preganglionic fibers to the smooth muscle of the esophagus. A weblike nervous plexus envelops the esophagus throughout

its thoracic extent. These sympathetic and parasympathetic fibers penetrate through the muscular wall, forming networks between the muscle layers to become Auerbach plexus and within the submucosal layer to become Meissner plexus (Fig. 42.11). They provide an intrinsic autonomic nervous system within the esophageal wall that is responsible for peristalsis. The parasympathetic fibers coalesce 2 cm above the diaphragm into the left (anterior) and right (posterior) vagus nerves, which descend anteriorly onto the fundus and lesser curvature and posteriorly onto the celiac plexus, respectively. 

PHYSIOLOGY Chicago architect Louis Sullivan is well known for his progressive philosophy that form should follow function. In anatomy this is demonstrated often, and there is no better illustration of this principle in the human body than the esophagus. The primary function of the esophagus is to transport material from the pharynx to the stomach. Secondarily, the esophagus needs to constrain the amount of air that is swallowed and the amount of material that is refluxed. Its form has evolved nicely to enable it to function seamlessly. The esophagus usually measures 30 cm, extending from the pharynx down onto the cardia of the stomach. Under ideal physiologic conditions, the concentric muscular configuration permits effortless unidirectional flow of material from the top to the bottom of the esophagus. The UES, 4 to 5 cm in length, remains in

CHAPTER 42  Esophagus

1019

Deep cervical nodes (internal jugular)

Paratracheal nodes

Thoracic duct

Tracheobronchial nodes

Retrocardiac nodes

Diaphragmatic nodes Left gastric nodes

Celiac nodes

FIG. 42.8  Lymphatic drainage of the esophagus.

a constant state of tone (mean, 60 mm Hg), preventing a steady flow of air into the esophagus, whereas the tone in the LES (mean, 24 mm Hg) remains elevated just enough to prevent excessive material from refluxing back up into the esophagus (Table 42.1). Transport of a food bolus from the mouth through the esophagus into the stomach begins with swallowing and ends with postrelaxation contraction of the LES, requiring coordinated peristaltic contractions in transit. The material in transit can move easily because the esophageal neuromuscular form provides all functions necessary to power the food bolus through three body cavities.

3. Elevation of the soft palate. Simultaneously, as the tongue moves the food bolus into the hypopharynx, the soft palate is elevated to close off the passage into the nasopharynx. 4. Elevation of the hyoid. To help bring the epiglottis under the tongue, the hyoid bone moves anteriorly and upward. 5. Elevation of the larynx. The change in position of the hyoid elevates the larynx and opens up the retrolaryngeal space, further facilitating the movement of the epiglottis under the tongue. 6. Tilting of the epiglottis. Finally, the epiglottis tilts back, covering the opening of the larynx to prevent aspiration.

Swallowing

Esophageal Phase

There are three phases to swallowing: oral, pharyngeal, and esophageal. Six events occur during the oropharyngeal phase of swallowing (Fig. 42.12). These rapid series of events last about 1.5 seconds and, once initiated, are completely reflexive. 1. Elevation of the tongue. Food is taken into the mouth and mixed with saliva to prepare a soft bolus for transport. The tongue pushes the bolus into the posterior oropharynx. 2. Posterior movement of the tongue. The tongue moves posteriorly and thrusts the food bolus into the hypopharynx.

Upper esophageal sphincter. The esophageal phase of swallowing is initiated by the actions during the pharyngeal phase. To allow passage of the food bolus, the UES relaxes and the peristaltic contractions of the posterior pharyngeal constrictors propel the bolus into the esophagus. The pressure differential generated between the positive pressure in the cervical esophagus and the negative intrathoracic pressure sucks the bolus into the thoracic esophagus. Within 0.5 second of the initiation of swallowing, the UES closes, reaching close to 90 mm Hg. This postrelaxation

1020

SECTION IX  Esophagus

Superior ganglion of vagus nerve Vagus nerve (X)

Superior laryngeal nerve

Right recurrent laryngeal nerve

Left recurrent laryngeal nerve Stellate ganglion

Thoracic sympathetic ganglion

Thoracic sympathetic trunk Anterior esophageal plexus

Anterior (left) vagus nerve

Greater thoracic splanchnic nerves

Celiac plexus and ganglia

FIG. 42.9  Innervation of the esophagus.

Superior laryngeal nerve

Internal branch of superior laryngeal nerve Sensory branches to larynx

Internal branch External branch

Inferior pharyngeal constrictor muscle

Transverse and oblique arytenoid muscles Thyroarytenoid muscle

Cricothyroid muscle

Lateral cricoarytenoid muscle

Cricopharyngeus muscle (part of inferior pharyngeal constrictor)

Posterior cricoarytenoid muscle

Recurrent laryngeal nerve

Anterior and posterior branches of inferior laryngeal nerve Recurrent laryngeal nerve

FIG. 42.10  Innervation of the larynx.

CHAPTER 42  Esophagus Longitudinal muscle Intermuscular connective and elastic tissue Circular muscle Myenteric (Auerbach) plexus Submucous (Meissner) plexus Submucosa

1021

1. Elevation of tongue 2. Posterior movement of tongue 3. Elevation of soft palate 4. Elevation of hyoid 5. Elevation of larynx 6. Tilting of epiglottis

FIG. 42.11  Intrinsic esophageal innervation.

TABLE 42.1  Normal manometric values. PARAMETER

VALUE

Upper Esophageal Sphincter Total length Resting pressure Relaxation time Residual pressure

4.0–5.0 cm 60.0 mm Hg 0.58 sec 0.7–3.7 mm Hg

Lower Esophageal Sphincter Total length Abdominal length Resting pressure Relaxation time Residual pressure

3–5 cm 2–4 cm 6–26 mm Hg 8.4 sec 3 mm Hg

1

3 2

4 5

6

FIG. 42.12  Phases of oropharyngeal swallowing. (Adapted from ZuideEsophageal Body Contractions Amplitude Duration

40–80 mm Hg 2.3–3.6 sec

contraction lasts 2 to 5 msec, initiates peristalsis, and prevents reflux of the bolus back into the pharynx. The UES pressure returns to resting pressure (60 mm Hg) as the wave travels into the midesophagus (Fig. 42.13).  Peristalsis. There are three types of esophageal contractions: primary, secondary, and tertiary. Primary peristaltic contractions are progressive and move down the esophagus at a rate of 2 to 4 cm/sec and reach the LES about 9 seconds after the initiation of swallowing (Fig. 42.14). They generate an intraluminal pressure from 40 to 80 mm Hg. Successive swallows will follow with a similar peristaltic wave unless swallowing is repeated rapidly, at which time the esophagus will remain relaxed until the last swallow occurs, and peristalsis will follow. Secondary peristaltic contractions are also progressive but are generated from distention or irritation of the esophagus rather than voluntary swallowing. They can occur as an independent local reflex to clear the esophagus of material that was left behind after the progression of the primary peristaltic wave. Tertiary contractions are nonprogressive, nonperistaltic, monophasic or multiphasic, simultaneous waves that can occur after voluntary swallowing or spontaneously between swallows throughout the esophagus. They represent uncoordinated contractions of the smooth muscle that are responsible for esophageal spasm.  Lower esophageal sphincter. The final phase of esophageal bolus transit occurs through the LES. Although this is not a true sphincter, there is a distinct high-pressure zone that measures 2 to 5 cm in length and generates a resting pressure of 6 to 26 mm Hg.

ma GD, Orringer MB. Shackelford’s surgery of the alimentary tract. 3rd ed. Philadelphia, PA: WB Saunders; 1991:95.)

The LES is located in the chest and abdomen. A minimum total length of 2 cm, with at least 1 cm of intraabdominal length, is required for normal LES function. The transition from the intrathoracic to the intraabdominal sphincter is noted on a manometric tracing and is known as the respiratory inversion point (RIP; Fig. 42.15). At this point, the pressure of the esophagus changes from negative to positive with inspiration and positive to negative with expiration. Peristaltic contractions alone do not generate enough force to open up the LES. Vagal-mediated relaxation of the LES occurs 1.5 to 2.5 seconds after pharyngeal swallowing and lasts 4 to 6 seconds. This flawlessly timed relaxation is needed to allow efficient transport of a food bolus out of the esophagus and into the stomach. A postrelaxation contraction of the LES occurs after the peristaltic wave has passed through the esophagus, allowing the LES to return to its baseline pressure (Fig. 42.16), reestablishing a barrier to reflux. 

Reflux Mechanism Not all reflux is abnormal. Healthy individuals have occasional episodes of gastroesophageal reflux that is a result of spontaneous opening of the LES. The competence of the LES and its ability to establish a barrier to reflux depends on several factors: adequate pressure and length, radial symmetry, and motility of the esophagus and stomach. A competent sphincter is at least 2 cm and carries a pressure between 6 and 26 mm Hg. Radial asymmetry and abnormal peristalsis prevent proper closure and allow free refluxing of gastric material into the distal esophagus. Abnormal esophageal motility and poor gastric emptying result in inadequate esophageal clearance that also encourages reflux. Finally,

1022

SECTION IX  Esophagus DS

Pharynx

mm Hg 40

20

0

UES

100

50

0

Proximal esophagus

40

20

0

5 sec

FIG. 42.13  Manometry of the upper esophageal sphincter (UES). (Adapted from Pearson FG, Cooper JD, Deslauriers J, et al. Esophageal surgery. 2nd ed. New York, NY: Churchill Livingstone;2002:480.)

neurotransmitters, hormones, and peptides that regulate the LES can increase or decrease tone. All these anatomic and physiologic disruptions can result in reflux through the LES and are implicated in the development of gastroesophageal reflux disease (GERD). 

DIAGNOSIS AND MANAGEMENT OF ESOPHAGEAL MOTILITY DISORDERS Diagnosis Esophageal motility disorders constitute a relatively rare group of conditions, the underlying causes of which remain poorly understood. Patients with these conditions will present with a variety of symptoms including dysphagia, chest pain, heartburn, regurgitation, and weight loss. By definition, esophageal motility disorders are diagnosed when manometric findings exceed two standard deviations from normal. Unfortunately, symptom severity does not always correlate well with manometry, which is of critical importance in planning for surgical intervention in these generally complicated patients. Esophageal motility disorders are best classified by the Chicago classification, which was derived from data obtained by high-resolution manometry (HRM) with esophageal pressure topography (Table 42.2).1 Because this classification is purely based on differentiating patterns of manometric findings, the exact clinical

utility of this classification remains under investigation. Nevertheless, the findings from these ultramodern diagnostic modalities correlate well with those from conventional, water-perfused manometry. From a practical standpoint, the primary difference between HRM and conventional manometry is that in HRM, the pressure sensors are no more than 1 cm apart rather than every 3 to 5 cm. Up to 36 sensors can be found distributed radially and longitudinally, allowing a three-dimensional spatial pressure map to be drawn during deglutition. The graphic representation of this is what is referred to as esophageal pressure topography. Whereas manometry is diagnostic for patients with named esophageal motility disorders, their presenting complaints are frequently vague and nonspecific. Hence, a complete workup including careful exclusion of other organ systems (cardiac, respiratory, peptic ulcer disease, and pancreaticobiliary disease) as the source of symptoms is paramount. In addition, attention to systemic symptoms of connective tissue disorders such as scleroderma is key as the surgical management of such patients requires specific modifications to avoid disastrous outcomes. With respect to the esophageal portion of the workup, a barium esophagram continues to be a highly useful road map to guide further investigations. A timed barium esophagram in which images are taken at 1, 2, and 5 minutes after the initial swallow may further characterize esophageal emptying and be particularly helpful in evaluating a patient with suspected achalasia. When the esophagus is thought to be the cause of the patient’s symptoms, upper endoscopy is necessary to rule out mucosal abnormalities and to provide improved visualization of the defects in question (stricture, hernia, diverticulum, esophagitis, masses). A computed tomography (CT) scan of the chest and abdomen is not uniformly required but may be helpful, particularly when there is suspicion of an extrinsic cause for the presenting symptoms. The addition of pH testing in the context of a documented esophageal motility disorder is necessary only when the motility disorder is thought to be the result of end-stage GERD as a means of documenting this. Classically, esophageal motility disorders have been classified into primary and secondary causes. Primary disorders fall into five categories of motor disorders: achalasia, diffuse esophageal spasm (DES), nutcracker (jackhammer) esophagus, hypertensive LES, and ineffective esophageal motility (IEM). Secondary conditions result from progressive damage induced by an underlying collagen vascular or neuromuscular disorder; they include scleroderma, dermatomyositis, polymyositis, lupus erythematosus, Chagas disease, and myasthenia gravis. Whereas such a classification is rooted in the basic etiology of this collection of diseases, it does not help much with interpreting manometric results, nor is it helpful as a guide to treatment strategies. For this reason, we suggest an anatomic approach to classifying esophageal motility disorders based on involvement of the esophageal body or LES as this is the basis for understanding basic esophageal manometry and often the key to guide surgical therapy. 

Motility Disorders of the Esophageal Body Diffuse Esophageal Spasm DES is a poorly understood hypermotility disorder of the esophagus. Under the Chicago classification, this is now called distal esophageal spasm. Although it is manifested in a similar fashion to achalasia, it is five times less common. It is seen most often in women and is often found in patients with multiple medical complaints. The cause of the neuromuscular physiology is unclear. The basic pathology is related to a motor abnormality

CHAPTER 42  Esophagus

Swall 80 60 40 20 0 Press 2 20 * 10 0 –10

41w(1)

1 *

w(2)

1023

w(3)

Press 3 20 * 10 0 –10 Press 4 30 * 20 10 0 –10 Press 5 30 * 20 10 0 –10 Press 6 20 * 10 0 –10 8 *

Resp 50 30 10 –10

Respiratory variation

FIG. 42.14  Normal esophageal peristalsis. (From Bremner CG, DeMeester TR, Bremner RM, et al. Esophageal motility testing made easy. St Louis: Quality Medical Publishing; 2001:35.) Overall length

Relaxation of the LES

mm Hg

Abdominal length 40 30 20 10 0

Pharyngeal peak

RIP

Onset Esophageal baseline Gastric baseline 47

46

Time of relaxation End

45

44

43

Postrelaxation contraction

42

cm

FIG. 42.15  Normal lower esophageal sphincter. (From Bremner CG, DeMeester TR, Bremner RM, et al. Esophageal motility testing made easy. St Louis: Quality Medical Publishing; 2001:15.) RIP, Respiratory inversion point.

of the esophageal body that is most notable in the lower twothirds of the esophagus. Muscular hypertrophy and degeneration of the branches of the vagus nerve in the esophagus have been observed. As a result, unlike the normally organized peristaltic contractions typically seen with swallowing (Fig. 42.14), DES esophageal contractions are repetitive, simultaneous, and of high amplitude.

FIG. 42.16  Relaxation of the lower esophageal sphincter (LES). (From Bremner CG, DeMeester TR, Bremner RM, et al. Esophageal motility testing made easy. St Louis: Quality Medical Publishing; 2001:24.)

The clinical presentation of DES is typically that of chest pain and dysphagia. These symptoms may be related to eating or exertion and may mimic those of angina. Patients will complain of a squeezing pressure in the chest that may radiate to the jaw, arms, and upper back. The symptoms are often pronounced during times of heightened emotional stress. Regurgitation of esophageal contents and saliva is common, but acid reflux is not. However, acid reflux can aggravate the symptoms, as can cold liquids. Other functional gastrointestinal complaints, such as irritable bowel syndrome and pyloric spasm, may accompany DES, whereas other

1024

SECTION IX  Esophagus

TABLE 42.2  The Chicago classification of esophageal motility, v3.0. CRITERIA Achalasia and Esophagogastric Junction Outflow Obstruction Type I achalasia (classic) Median IRP >15 mm Hg, 100% failed peristalsis (DCI 15 mm Hg; no normal peristalsis, spastic contractions with DCI >450 mm Hg·s·cm with ≥20% of swallows Esophagogastric junction outflow obstruction (achalasia in evolution) Median IRP >15 mm Hg; sufficient evidence of peristalsis such that criteria for types I-III are not met Major Disorders of Peristalsis Absent contractility Distal esophageal spasm Hypercontractile esophagus (nutcracker or jackhammer)

Normal median IRP, 100% failed peristalsis Normal median IRP; ≥20% premature contractions with DCI >450 mm Hg·s·cm At least 2 swallows with DCI >8000 mm Hg·s·cm

Minor Disorders of Peristalsis Ineffective esophageal motility Fragmented peristalsis Normal esophageal motility

≥50% ineffective swallows ≥50% fragmented contractions with DCI >450 mm Hg·s·cm None of the above criteria are met

Data from Roman S, Gyawali CP, Xiao Y, et  al. The Chicago classification of motility disorders. Gastrointest Endosc Clin N Am. 2014; 24:545–561.

Integrated relaxation pressure (IRP) is the mean of the 4 seconds of maximal deglutitive relaxation in the 10-second window beginning at the upper esophageal sphincter relaxation referenced to gastric pressure; distal contractile integral (DCI) is the amplitude × duration × length (mm Hg·s·cm) of the distal esophageal contraction exceeding 20 mm Hg from the transition zone to the proximal margin of the lower esophageal sphincter.

gastrointestinal problems, such as gallstones, peptic ulcer disease, and pancreatitis, all trigger DES. The diagnosis of DES is made by radiographic and manometric studies. The classic picture of the corkscrew esophagus or pseudodiverticulosis on an esophagram is caused by the presence of tertiary contractions and indicates advanced disease (Fig. 42.17). A distal bird beak narrowing of the esophagus and normal peristalsis can also be noted. HRM findings in DES are a normal median integrated relaxation pressure (IRP), a measure of esophagogastric junction (EGJ) relaxation with swallowing, in addition to at least 20% premature contractions. Additionally, the distal contractile integral, which is a composite measure of distal esophageal contraction, is greater than 450 mm Hg·s·cm in DES (Table 42.2).1 Correlation of subjective complaints with evidence of spasm (induced by a vagomimetic drug, bethanechol) on manometric tracings is convincing evidence of this capricious disease. The treatment for DES is far from ideal as symptom relief is often partial. Traditionally, the mainstay of treatment for DES is nonsurgical, and pharmacologic or endoscopic intervention is preferred. All patients are evaluated for psychiatric conditions, including depression, psychosomatic complaints, and anxiety. Control of these disorders and reassurance of the esophageal nature of the chest pain that the patient is experiencing is often alleviating to distressed patients. If dysphagia is a component of a patient’s symptoms, steps must be taken to eliminate trigger foods or drinks from the diet. Similarly, if reflux is a component, acid suppression medications are helpful. Nitrates, calcium channel blockers, sedatives, and anticholinergics may be effective in some cases, but the relative efficacy of these medicines is not known. Peppermint may also provide temporary symptomatic relief. Bougie dilatation of the esophagus up to 50 or 60 Fr provides relief for severe dysphagia and is 70% to 80% effective. Botulinum toxin injections have also been tried with some success, but the results are not sustainable.

FIG. 42.17  Barium esophagram of diffuse esophageal spasm. (Adapted from Peters JH, DeMeester TR. Esophagus and diaphragmatic hernia. In: Schwartz SI, Fischer JE, Spencer FC, et al, eds. Principles of surgery. 7th ed. New York, NY: McGraw-Hill;1998.)

Surgery is indicated for patients with incapacitating chest pain or dysphagia who have failed to respond to medical and endoscopic therapy or in the presence of a pulsion diverticulum of the thoracic esophagus. Historically, a long esophagomyotomy is performed either through the abdomen or a left thoracotomy or video-assisted

CHAPTER 42  Esophagus thoracoscopic approach in the chest is used. While some surgeons advocate extending the myotomy up into the thoracic inlet, most agree that the proximal extent generally should be high enough to encompass the entire length of the abnormal motility, as determined by manometric measurements. The distal extent of the myotomy is extended down onto the LES, but the need to include the stomach is not agreed on uniformly. A Dor fundoplication is recommended to provide reflux protection as the surgery itself interrupts the phrenoesophageal ligament and encourages reflux. Results of a long esophagomyotomy for DES are variable, but it is reported to provide relief of symptoms in up to 80% of patients. Recently, several authors have reported their experience with the use of peroral endoscopic myotomy (POEM) in the treatment of motility disorders of the esophageal body. In this natural orifice approach, an operating endoscope is used to perform a mucosotomy and a submucosal tunnel is created. Through this tunnel, the circular muscular layer of the esophagus is visualized and divided, effectively performing an endoscopic myotomy. In one series, 73 patients with medically refractory motility disorders of the esophageal body, including nine with DES, underwent POEM and had a clinical response rate of 93%.2 Furthermore, in the 44 patients with repeat manometry available after POEM, all demonstrated resolution of the abnormal manometric findings seen on initial testing. Though POEM has most often been described in motility disorders of the LES, in particular achalasia (see Achalasia section below), this technology represents a novel surgical approach for performing a long esophagomyotomy in DES patients with early promising results.  Nutcracker Esophagus Recognized in the late 1970s as a distinct entity and known as hypercontractile esophagus in the Chicago classification, nutcracker or jackhammer esophagus is a disorder characterized by excessive contractility. It is described as an esophagus with hypertensive peristalsis or high-amplitude peristaltic contractions. It is seen in patients of all ages, with equal gender predilection and is the most common of all esophageal hypermotility disorders. Like DES, the pathophysiologic process is not well understood. It is associated with hypertrophic musculature that results in high-amplitude contractions of the esophagus and is the most painful of all esophageal motility disorders. Patients with nutcracker esophagus present in a similar fashion to those with DES and frequently complain of chest pain and dysphagia. Odynophagia is also noted, but regurgitation and reflux are uncommon. An esophagram may or may not reveal any abnormalities, depending on how well “behaved” the esophagus is during the examination. The Chicago classification characterizes the diagnosis of nutcracker esophagus as the subjective complaint of chest pain with at least two swallows showing a distal contractile integral greater than 8000 mm Hg·s·cm with single or multipeaked contractions on HRM. The LES pressure is normal, and relaxation occurs with each wet swallow. Ambulatory monitoring can help distinguish this disorder from DES. Similar to DES, the primary initial treatment of nutcracker esophagus is medical. Calcium channel blockers, nitrates, and antispasmodics may offer temporary relief during acute spasms. Bougie dilatation may offer some temporary relief of severe discomfort but has no long-term benefits. Patients with nutcracker esophagus may have triggers and are counseled to avoid caffeine, cold, and hot foods. Although surgery was not historically included in the management of this disease, early results from POEM demonstrating excellent clinical responses have led gastroenterologists and surgeons to rethink this conventional wisdom.2 

1025

Motility Disorders of the Lower Esophageal Sphincter Hypertensive Lower Esophageal Sphincter Hypertensive LES has been renamed in the Chicago classification as EGJ outflow obstruction and is defined on HRM as a median IRP greater than 15 mm Hg (ineffective EGJ relaxation with swallowing). Thought by some to be achalasia in evolution, the diagnosis differs by evidence of effective peristalsis that is not present in achalasia. Hypertensive LES may be observed in patients presenting with dysphagia, chest pain, and, less frequently, heartburn and regurgitation. The diagnosis is made by manometry with a hypertensive, poorly relaxing sphincter. Localization of the LES may be aided by identification of the RIP (Fig. 42.15). Motility of the esophageal body may be hyperperistaltic or normal. An esophagram may show narrowing at the GEJ with delayed emptying and abnormalities of esophageal contraction; however, these are nonspecific findings. About 50% of the time, peristalsis in the esophageal body is normal. In the remainder, abnormal contractions are noted to be hypertensive peristaltic or simultaneous waveforms. The pathogenesis is not well understood. The treatment of hypertensive LES is with endoscopic and surgical intervention. Botox injections alleviate symptoms temporarily, and hydrostatic balloon dilatation may provide long-term symptomatic relief. Surgery is indicated for patients who fail to respond to interventional treatments and those with significant symptoms. Historically, a laparoscopic Heller esophagomyotomy is the operation of choice. In patients with normal esophageal motility, a partial antireflux procedure (e.g., Dor or Toupet fundoplication) is added to prevent postoperative reflux. Additionally, the use of POEM for such patients has also been described with several studies supporting its use. 

Motility Disorders Affecting Both Body and Lower Esophageal Sphincter Achalasia The literal meaning of the term achalasia is “failure to relax.” It is the best understood of all esophageal motility disorders. The incidence is 6/100,000 persons/year with a predilection to affect young women. Its pathogenesis is presumed to be idiopathic or infectious neurogenic degeneration. Severe emotional stress, trauma, drastic weight reduction, and Chagas disease (parasitic infection with Trypanosoma cruzi) have also been implicated. Regardless of the cause, the muscles of the esophagus and LES are affected. Prevailing theories support the model that the destruction of the nerves to the LES is the primary pathologic process and that degeneration of the neuromuscular function of the body of the esophagus is secondary. This degeneration results in hypertension of the LES and failure of the LES to relax on pharyngeal swallowing as well as pressurization of the esophagus, esophageal dilatation, and resultant loss of progressive peristalsis. The classic triad of presenting symptoms of achalasia consists of dysphagia, regurgitation, and weight loss. Heartburn, postprandial choking, and nocturnal coughing are commonly seen. The dysphagia that patients experience often begins with liquids and progresses to solids. Most patients describe eating as a laborious process during which they must pay special attention to the process. They eat slowly and use large volumes of water to help wash the food down into the stomach. As the water builds up pressure, retrosternal chest pain is experienced and can be severe

1026

SECTION IX  Esophagus

Bird’s beak

FIG. 42.18  Barium swallow showing achalasia. (Adapted from Dalton CB. Esophageal motility disorders. In: Pearson FG, Cooper JD, Deslauriers J, et al, eds. Esophageal surgery. 2nd ed. New York, NY: Churchill Livingstone; 2002.)

until the LES opens, which provides quick relief. Regurgitation of undigested, foul-smelling food is common, and with progressive disease, aspiration can become life-threatening. Pneumonia, lung abscess, and bronchiectasis often result from long-standing achalasia. The dysphagia progresses slowly during years, and patients adapt their lifestyle to accommodate the inconveniences that accompany this disease. Patients often do not seek medical attention until their symptoms are advanced and will present with marked distention of the esophagus. Achalasia is also known to be a premalignant condition of the esophagus. During a 20-year period, a patient will have up to an 8% chance for development of carcinoma. Squamous cell carcinoma (SCC) is the most common type identified and is thought to be the result of long-standing retained undigested fermenting food in the body of the esophagus, causing mucosal irritation. If the histology is adenocarcinoma, it tends to appear in the middle third of the esophagus, below the air-fluid level, where the mucosal irritation is the greatest. In contrast to these theories of carcinogenesis, it appears that, even in patients with treated achalasia, there is an ongoing cancer incidence risk. Although no specific surveillance program for patients with treated achalasia has yet been endorsed by any of the gastroenterology societies, long-term surveillance is strongly recommended to monitor for recurrent achalasia and cancer. The diagnosis of achalasia is usually made from an esophagram and a motility study. The findings may vary, depending on the degree to which the disease has advanced. The esophagram will often show a dilated esophagus with a distal narrowing referred to as the classic bird beak appearance of the barium-filled esophagus (Fig. 42.18). Sphincter spasm and delayed emptying through the LES as well as dilatation of the esophageal body are observed. A lack of peristaltic waves in the body and failure of relaxation of the LES (the sine qua non of this disease) are noted. Lack of a gastric air bubble is a common finding on the upright portion of the

FIG. 42.19  Barium swallow showing megaesophagus. (From Orringer MB. Disorders of esophageal motility. In: Sabiston DC, ed. Textbook of surgery. 15th ed. Philadelphia, PA: WB Saunders; 1997.)

esophagram and is a result of the tight LES not allowing air to pass easily into the stomach. In the more advanced stage of disease, massive esophageal dilatation, tortuosity, and sigmoidal esophagus (megaesophagus) are seen (Fig. 42.19). Manometry is the “gold standard” test for diagnosis and distinguishes achalasia from other potential esophageal motility disorders (Fig. 42.20). Achalasia is defined by a median IRP greater than 15 mm Hg (failure of LES relaxation with deglutition) and absence of normal peristalsis. Additional manometric findings associated with achalasia include esophageal body pressurization from incomplete air evacuation, simultaneous mirrored contractions without evidence of progressive peristalsis, and low-amplitude waveforms indicating a lack of muscle tone. The Chicago classification further subdivides achalasia into three types based on characteristic HRM findings (Table 42.2).1 In type I (classic) achalasia, the median IRP greater than 15 mm Hg and there is 100% failed peristalsis with minimal esophageal pressurization. In type II achalasia, the median IRP greater than 15 mm Hg, 100% failed peristalsis, and panesophageal pressurization with at least 20% of swallows. In type III (spastic or vigorous) achalasia, the median IRP greater than 15 mm Hg without normal peristalsis and there are spastic contractions (distal contractile integral >450 mm Hg·s·cm) with at least 20% of swallows (Fig. 42.20). The amplitude of the contractions in response to swallowing is normal or high and patients oftentimes present with chest pain. It is postulated that patients in the early phases of achalasia may not have abnormalities in the esophageal body that are seen in later stages of the disease. Patients presenting with spastic achalasia may be in this early phase and will go on to develop abnormal esophageal body contractions predicated on the presence of outflow obstruction of the esophagus. Endoscopy must also be performed in

CHAPTER 42  Esophagus

1027

A

B

C

FIG. 42.20  High-resolution esophageal manometry. (A) A normal swallowing pattern. (B) and (C) Classic (type I) achalasia and atypical spastic or vigorous achalasia (type III). The arrows denote initiation of swallowing.

all suspected achalasia patients to evaluate the mucosa for esophagitis and rule out secondary causes of distal esophageal narrowing (“pseudoachalasia”) such as GEJ tumors, neuropathy, and strictures. There are surgical and nonsurgical treatment options for patients with achalasia; all are directed toward relieving the obstruction caused by the LES. Because none of them are able to address the issue of decreased motility in the esophageal body, they are all palliative treatments. Nonsurgical treatment options include medications and endoscopic interventions but usually are only a short-term solution to a lifelong problem. In the early stage of the disease, medical treatment with sublingual nitroglycerin, nitrates, or calcium channel blockers may offer hours of relief from chest pressure before or after a meal. Pneumatic dilatation has been shown to provide excellent relief of symptoms although frequently requiring multiple interventions and with a risk of esophageal perforation. Injection of botulinum toxin (Botox) directly into the LES blocks acetylcholine release, prevents smooth muscle contraction, and effectively relaxes the LES. With repeated treatments, Botox may offer symptomatic relief for years, but symptoms recur more than 50% of the time within six months. In comparing balloon dilatation to Botox injections, remission of symptoms occurred in 89% versus 38% of patients at one year, respectively. Surgical esophagomyotomy offers excellent results that are durable. The current technique is a modification of the Heller myotomy that was described originally through a laparotomy in 1913. Various changes have been made to the originally described procedure, but the modified laparoscopic Heller myotomy is now the operation of choice. A robotic-assisted approach may also be performed. The decision to perform an antireflux procedure remains controversial. Most patients who have undergone a myotomy will experience some amount of reflux, either symptomatic or not. The addition of a partial antireflux procedure, such as a Toupet or Dor fundoplication, will restore a barrier to reflux and decrease postoperative symptoms. Studies done to compare balloon ­dilatation versus surgery have shown perforation rates of 4% and 1% and mortality rates of 0.5% and 0.2%, r­espectively. Results were historically considered excellent in 60% of patients undergoing

balloon dilatation and in 85% of those undergoing surgery. However, in a randomized controlled trial of the E ­ uropean Achalasia Trial Investigators, pneumatic dilatation was found to be equivalent to laparoscopic Heller myotomy and Dor fundoplication with therapeutic success rates of 86% versus 90% at two years.3 Perforation occurred in 4% of the patients during pneumatic dilatations and mucosal tears occurred in 12% during l­aparoscopic Heller myotomy, but all were repaired intraoperatively. Notably, patients in the pneumatic dilatation cohort had a 25% rate of redilation to achieve treatment success. Clinicians need to remain wary and vigilant with achalasia patients, even ­after “­successful” intervention. Continued asymptomatic outflow obstruction will lead to dilatation. Close monitoring of these patients is a­ ppropriate. The use of POEM in the treatment of achalasia has been well described. Through the submucosal tunnel, the muscular layer of the distal esophagus, LES, and cardia is visualized and divided. Although concern for the lack of an antireflux procedure and the possibility of symptomatic reflux remains, results thus far have been encouraging. This is a promising new technique and outcomes thus far suggest equivalency with Heller myotomy in the short-term.4 However, it remains to be seen if POEM outcomes will compare favorably in the long-term to the excellent results reported in multiple large series of Heller myotomy patients. Esophagectomy is considered in any symptomatic patient with a tortuous dilated esophagus (megaesophagus), sigmoid esophagus, failure of more than one myotomy, or reflux stricture that is not amenable to dilatation. Less than 60% of patients undergoing repeated myotomy benefit from surgery, and fundoplication for treatment of reflux strictures has even more dismal results. In addition to definitively treating the end-stage achalasia patient, esophageal resection also eliminates the risk for carcinoma in the resected area. A transhiatal esophagectomy with or without preservation of the vagus nerve offers a good long-term result. However, in the setting of megaesophagus, a total esophagectomy incorporating a transthoracic dissection may be safest, given the difficulty in palpating the borders of the esophagus through a transhiatal approach. Notably, POEM in end-stage achalasia patients with

1028

SECTION IX  Esophagus

sigmoid esophagus has also been reported. In a recent study, two-year outcomes after POEM demonstrated treatment success in 96.8% of patients.5 Use of POEM may obviate the need for esophagectomy in this malnourished, often high-risk, patient population.  Ineffective Esophageal Motility IEM was first recognized as a distinct motility disturbance by Castell in 2000. It is defined as a contraction abnormality of the distal esophagus and is usually associated with GERD. It may be secondary to inflammatory injury of the esophageal body because of increased exposure to gastric contents. Dampened motility of the esophageal body leads to poor acid clearance in the lower esophagus. The symptoms of IEM are mixed, but patients usually present with symptoms of reflux and dysphagia. Heartburn, chest pain, and regurgitation are noted. Diagnosis is made by manometry. IEM is defined by greater than 50% of swallows being deemed ineffective (distal contractile integral 100 beats/min) Leukocytosis (>10,000 white blood cells/mL) Pleural effusion Fever (>38.5°C) Noncontained leak (barium swallow or CT scan) Respiratory compromise (respiratory rate >30, increasing oxygen requirement, or mechanical ventilation) Time to diagnosis >24 hours Presence of cancer Hypotension

SCORE 1 1 1 1 2 2 2

2 3 3

CT, Computed tomography. Score ranges 0 to 18 with higher scores indicating greater morbidity with worse prognosis. Data From Abbas G, Schuchert MJ, Pettiford BL, Pennathur A, Landreneau J, Landreneau J, et al. Contemporaneous management of esophageal perforation. Surgery. 2009;146:749–755.

The principles of management after diagnosis include (1) treatment of contamination, (2) wide local drainage, (3) source control, and (4) enteral feeding access. In the circumstance of small perforations with contained leaks and no fluid collections in the mediastinum or chest, contamination might be minimal. In general, though, perforation is treated with broad-spectrum antibiotics, including antifungals, with duration that will vary on the basis of control of infection and the patient’s condition. Drainage of the area with chest tubes is most common, with the number, location, and duration to vary by the degree of leak. In select cases, radiologically guided drains can be

CHAPTER 42  Esophagus TABLE 42.4  Pittsburgh esophageal

perforation severity score. SCORE Morbidity (%) Mortality (%) Median length of stay (days)

5

53 2 10

65 6 16

81 27 28

Score ranges 0 to 18 with higher scores indicating greater morbidity with worse prognosis. Data from Abbas G, Schuchert MJ, Pettiford BL, et al. Contemporaneous management of esophageal perforation. Surgery. 2009;146:749–755.

used as well. Video-assisted thoracoscopic surgery (VATS) or open thoracic washout with decortication may be necessary, depending on the duration of the leak and amount of pleural space soiling. Source control will also depend on the patient’s condition, the severity and location of perforation, and the surgeon’s experience. Endoluminal therapy with covered stents has become more widely popularized and can give good results when it is used in the appropriate patient population.17 Stent migration is a concern, however, and frequent chest X-rays are typically performed to evaluate the position of the stent. In a systematic review, plastic stents had higher rates of migration and required more reinterventions, albeit with lower stricture rates, when compared to metallic stents.17 Although the criteria are still debated, stents can be considered in patients with early, small perforations, with minimal contamination in a location amenable to stenting. Additionally, if there is a delay between injury and diagnosis then stents are still an option given the poor tissue quality likely to be found if approached surgically. However, in these patients, VATS is also often used for drainage and decortication of the lung in addition to chest tube placement. Use of stents, with or without VATS, in esophageal perforation may be as effective as open surgery with evidence suggesting less morbidity, shorter lengths of stay, and less costs associated with an endoluminal approach. If the decision is made to intervene surgically, the approach depends on the location of the leak. In general, high perforations are approached through a left-sided neck incision, midesophageal through a right thoracotomy, and distal esophageal through a left thoracotomy or thoracoabdominal approach. Radiographic studies that demonstrate a right- or left-sided leak may modify the approach. Minimally invasive approaches are reasonable, depending on the surgeon’s preference. After the area of perforation is identified, assessment continues with myotomy to expose the full extent of mucosal injury, debridement of devitalized tissues, assessment of injury, and considerations for repair. Any sign of obstruction (achalasia, stricture, tumor) must be remedied at the time of the initial operation, else the perforation will not heal. In the setting of achalasia or a hypertensive LES, a contralateral myotomy should be performed to relieve the distal obstruction. Small injuries with healthy tissues can be repaired primarily in two layers with tissue flap coverage (intercostal muscle, pericardial fat, pleura, omentum), but extensive injuries with devitalized areas can be managed with controlled fistulization by T-tube. Very large or devitalized defects will require esophageal exclusion with creation of a cervical esophagostomy and gastrostomy tube, with plans for future reconstruction by esophagectomy with typically a substernal gastric, colon, or small bowel conduit. Gastrostomy and jejunostomy tubes at the first operation are important to provide decompression and drainage near the perforation as well as enteral access for nutrition.

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Recently, endoscopic vacuum therapy (EVT) has emerged as an option for surgeons in the management of esophageal perforation.18 Borrowing traditional principles of wound healing in vacuum therapy for skin and soft tissue defects, EVT has been described for both esophageal perforation and anastomotic leak after esophagectomy. This technique involves endoscopic placement of a sponge into the site of esophageal injury. Tubing from the sponge is connected externally to a vacuum device with continuous negative pressure applied to the site of perforation. Serial endoscopies are then performed every several days to weeks to examine the site of injury and to evaluate for appropriate granulation tissue and for exchange of the sponge. Once the mucosa has sufficiently healed, the sponge is removed and diet liberalized. Another recent endoscopic option for esophageal perforation, particularly those identified acutely, is placement of over-the-scope clips to seal the site of injury.18 Use of EVT and over-the-scope clips still mandates that basic principles of esophageal perforation are adhered to, namely wide local drainage, decortication, and feeding access. However, early evidence suggests these therapies may be safe and viable options with good outcomes in appropriately selected patients.18 Mortality from esophageal perforation may be decreasing over time.14 Use of minimally invasive and endoluminal techniques, in addition to improved imaging and perioperative care, are important contributing factors. Additionally, regionalization of esophageal perforation to high-volume centers may also translate into improved survival.14  Caustic Ingestion The majority of caustic ingestion is accidental small-volume drinking of household products by young children. In adults, it is more commonly a suicide attempt with large volumes, and therefore more extensive injury is usually present. The injury pattern can vary from short-segment superficial injury to full-thickness necrosis of the proximal gastrointestinal tract. There are many factors that affect the extent of injury (pH, volume, duration of exposure), and the evaluation and management after the ingestion are challenging and require experience and sound judgment. The initial evaluation should involve a surgeon immediately. Physical examination findings of upper airway compromise (dyspnea, drooling, stridor, hoarseness) will likely require endotracheal intubation. However, this should be done with bronchoscopic guidance and preparation to perform cricothyroidotomy as there is danger of inability to secure a safe airway or iatrogenic perforation. Nasogastric and orogastric tubes should not be inserted blindly. Subsequent evaluation should include radiographic studies to guide the first procedure, ideally a CT scan of chest and abdomen with intravenous and oral administration of contrast material, followed by a barium swallow study. Evaluation continues in the operating room. With rare exception, most patients should have an endoscopic evaluation of the degree and extent of injury. It is recommended that this be done early in the hospital course as the risk of perforation increases after 48 hours. Pediatric endoscopes are useful to minimize insufflation and mechanical stresses. The traditional teaching is that endoscopy should not proceed past an area of circumferential injury; however, an experienced endoscopist can cautiously proceed to complete the evaluation if it is thought that management will change with additional information. It is important to note the severity and degree of injury at all locations because subsequent evaluations are frequently necessary. A classification system for endoscopic grading of injuries from caustic ingestions has been described (Table 42.5).

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SECTION IX  Esophagus

TABLE 42.5  Classification scheme for

caustic ingestion.

ENDOSCOPIC FINDING Normal Superficial edema/erythema Mucosal/submucosal ulceration   Superficial edema/erythema   Deep or circumferential Transmural ulcerations with necrosis   Focal necrosis   Extensive necrosis Perforation

GRADE 0 1 2 2A 2B 3 3A 3B 4

Data from Zargar SA, Kochhar R, Mehta S, et al. The role of fiberoptic endoscopy in the management of corrosive ingestion and modified endoscopic classification of burns. Gastrointest Endosc. 1991;37:165– 169.

All patients should be treated with broad-spectrum antibiotics. Depending on the clinical course, patients may benefit from repeated endoscopy 48 to 72 hours after the event to assess for signs of worsening injury. Of paramount importance is frequent clinical reassessment as deterioration at any time should prompt resumption of workup and surgical intervention as indicated. Surgical intervention can vary from endoscopy only to placement of gastrostomy or jejunostomy tubes or esophagectomy, gastrectomy, and small bowel resection with proximal diversion and feeding tube. Reconstruction can be complicated, sometimes requiring several months of recovery and the use of colon or small bowel conduits. In the long term, patients may develop strictures that require repeated dilatation or eventual resection, fistulas that require surgical interventions, or esophageal cancer (>1000 times increased risk). The use of routine corticosteroids is no longer advocated. Early dilatation, esophageal stents, and other adjunctive measures must be considered on a case-by-case basis.  Foreign Body Ingestion, Benign Tracheoesophageal Fistula, and Schatzki Ring The patient with foreign body ingestion can require technical expertise to prevent iatrogenic perforation. If the object is lodged in the esophagus, careful endoscopy under general anesthesia is preferred. Forceful pushing to move the object into the stomach can result in perforation. Full relaxation, lubrication with water, and gentle pressure can sometimes be enough. Bringing the object proximally requires special large endoscopic graspers, nets, or lassoes along with patience and full visualization as the object is removed to prevent injury in the esophagus and oropharynx. Over-tubes are frequently useful in this setting, as is rigid esophagoscopy. If the object is not retrievable, laparoscopy or laparotomy with gastrotomy may be necessary. Evaluation of the full gastrointestinal tract is recommended with radiographs and CT scan before an intervention. For patients with repeat foreign body ingestions, or those ingesting objects for the purpose of self-harm, inpatient psychiatric evaluation is warranted. Benign tracheoesophageal fistula can be seen in patients with multiple procedures or foreign bodies in the upper mediastinum. A classic example of benign tracheoesophageal fistula is in the patient with endotracheal tube (or tracheostomy) and nasogastric tube. It is manifested most commonly with recurrent or persistent respiratory infection and bilious or salivary contents emanating from the tracheostomy. CT scan and barium swallow can be

helpful in determining the diagnosis. Further evaluation is done with bronchoscopy and endoscopy, ensuring that bronchoscopy is performed such that the entire airway is evaluated. The tracheostomy balloon will have to be deflated and usually temporarily removed during the evaluation for visualization. If tracheoesophageal fistula is identified, treatment principles are (1) discontinuation of the causative agent, (2) consideration of exclusion of the fistula by stent or diversion, and finally (3) repair or delayed healing. In a stable patient, definitive repair may preclude the need for temporary exclusion or diversion. If the fistula was caused by a tracheostomy balloon, a longer or cuffless tracheostomy will be required. Antibiotics are usually employed as well. Enteral access and gastric decompression can be achieved with gastrostomy and jejunostomy tubes. Repair can be undertaken when the patient is medically suitable by either thoracotomy or cervical approach with resection of the fistula, possible primary repair or resection, and vascularized tissue interposition. Attempts at definitive repair in a compromised patient are not optimal. Delayed healing can occur if the offending agents are removed and diversion is successful. Esophageal stents can occasionally be used in this setting as well, although this must be determined on a case-by-case basis. Placement of simultaneous esophageal and airway stents (“kissing stents”) is typically reserved for only the most moribund patients as they have the potential to worsen the size of the fistula due to radial forces. EVT has also been described in the management of tracheoesophageal fistula, though clinical experience with this application is still relatively new. A Schatzki ring is a concentric, nonmalignant, fibrous thickening and narrowing of the GEJ with squamous epithelium above and columnar cells below (Fig. 42.26). The cause is unknown, with correlations to reflux disease. The majority of patients with a Schatzki ring have a concomitant finding of hiatal hernia. Presence of a ring is not pathologic, but these can be seen in patients suffering from dysphagia or obstruction. In the symptomatic patient, whether the diagnosis is by esophagram or endoscopy, treatment is usually with dilatation (bougie or balloon). The area should always be biopsied to rule out malignancy. Repeated dilatation is often necessary and is a reasonable way to manage symptomatic rings as there are few permanent surgical options. Persistent strictures should always raise suspicion for malignant disease. 

BENIGN AND RARE TUMORS OF THE ESOPHAGUS Benign Tumors of the Esophagus Benign tumors of the esophagus are less common than esophageal cancer. Among benign lesions, tumors of the submucosa and muscularis propria occur more frequently than mucosal tumors. Most of these lesions are asymptomatic and are identified incidentally on endoscopy. Barium esophagram characteristically demonstrates a smooth defect in the lumen. Benign mucosal tumors include granular cell tumors and fibrovascular polyps. Granular cell tumors may be found in a variety of locations, including the skin, respiratory tract, gastrointestinal tract, breast, and tongue. These tumors derive from Schwann cells of nerve sheath origin and most often emanate from the mucosa or submucosa.19 Within the gastrointestinal tract, the distal third of the esophagus is the most common location. They can appear as either sessile or bulging whitish-grey lesions with often normal-appearing mucosa. Up to 11% of patients may have multiple tumors.19 On endoscopic ultrasound (EUS), lesions typically have regular borders and arise within the first and second sonographic layers. Because these lesions are usually covered by a layer of normal squamous

CHAPTER 42  Esophagus

1037

Squamous mucosa Columnar gastric mucosa Schatzki ring

B

A

FIG. 42.26  (A) Histology of a Schatzki ring. (B) Barium esophagram of a Schatzki ring. (Adapted from Wilkins EW Jr. Rings and webs. In: Pearson FG, Cooper JD, Deslauriers J, et al, eds. Esophageal surgery. 2nd ed. New York, NY: Churchill Livingstone; 2002.)

epithelium, standard biopsies may be nondiagnostic. Tunneled biopsies will reveal eosinophilic granules. The tumors stain positive for S100, further supporting their origin from Schwann cells. Granular cell tumors are largely benign lesions, with only 1% to 2% having been described as malignant. Atypical features on EUS, large size (>2 cm), and presence of symptoms are reasonable indications for excision. Endoscopic resection is a valuable tool for these lesions when diagnosis is in question and to rule out malignancy. Fibrovascular polyps are a heterogeneous group of soft tissue tumors most often found in the cervical esophagus at or near the cricopharyngeus. They appear cylindrical or elongated, with a stalk. Symptoms are rare, but large tumors may cause dysphagia and some may even prolapse into the hypopharynx, causing airway obstruction. Even large tumors can usually be resected endoscopically after securing the airway. Squamous papillomas most often occur in the distal esophagus and are usually associated with some underlying inflammation. They appear as colorless, exophytic projections, with a wart-like projection.20 Additionally, they are often seen with a crossing vessel on the surface of the lesion. There is also evidence suggesting a link between squamous papillomas and human papillomavirus (HPV).20 Complete excision is warranted to rule out carcinoma and can usually be performed endoscopically with little morbidity. Benign submucosal tumors include lipomas, hemangiomas, and neural tumors. Lipomas have a characteristic, homogeneous, hyperechoic, smooth appearance on EUS. Symptoms are rare even with large tumors. Resection is seldom warranted. Hemangiomas typically appear as a purple or reddish nodule. EUS will demonstrate a smooth, hypoechoic, submucosal mass. Most tumors are asymptomatic. Lesions causing either dysphagia or bleeding can usually be treated endoscopically. Neural tumors including neurofibromas and schwannomas are rare in the esophagus. The majority are benign, with a handful of case reports on malignant esophageal schwannoma.21 Symptomatic tumors can usually be resected by enucleation. Large tumors may require esophagectomy.

FIG. 42.27  Computed tomography image of an 8-cm leiomyoma that was causing dysphagia. The lesion was enucleated thoracoscopically, and the patient’s dysphagia resolved.

Leiomyomas are the most common benign tumors of the esophagus. They have a 2:1 male predominance. Although they are usually asymptomatic, large tumors may cause dysphagia or discomfort (Fig. 42.27). The tumors arise in the muscularis propria and are usually found in the mid to distal esophagus. Like most other benign esophageal tumors, they will demonstrate a smooth filling defect on barium esophagram. The endoscopic appearance is a round protrusion into the lumen of the esophagus with smooth, normal mucosa. On EUS, leiomyomas are hypoechoic, have regular borders, and arise from the fourth endosonographic

SECTION IX  Esophagus

layer. Tumors with EUS characteristics suggestive of a leiomyoma should not be biopsied as this will complicate subsequent attempts at enucleation. Small, asymptomatic lesions with this appearance may be safely observed without biopsy. Symptomatic lesions may be enucleated, and even large lesions can usually be removed with a VATS approach. Additionally, endoscopic resection with creation of a submucosal tunnel for leiomyomas up to 5.5 cm has been described. Oncologic outcomes appear to be similar to VATS with the added benefits of shorter lengths of stay and less cost.22 As technology continue to improve, many benign esophageal tumors may be approached endoscopically in the future. Regardless of the surgical approach, one must keep in mind the differential diagnosis of a large smooth esophageal tumor, including leiomyosarcoma, gastrointestinal stromal tumor (GIST), and leiomyoma. 

Rare Malignant Tumors of the Esophagus Although SCC and adenocarcinoma represent the overwhelming majority of esophageal cancers, a variety of other malignant histologic types may be encountered. Small cell carcinomas of the esophagus account for 0.6% of esophageal cancers. These tumors have the same aggressive phenotype and histologic appearance of other poorly differentiated neuroendocrine cancers. The tumors typically present with lymph node involvement and at an advanced stage.23 Long-term survival is possible in earlier stage tumors treated with surgery, although the overall prognosis is poor. Systemic chemotherapy is often used to impact survival. Stage at diagnosis is the most important prognostic factor.23 Primary melanoma of the esophagus is even rarer than small cell carcinoma, accounting for 0.1% to 0.2% of esophageal malignant neoplasms. Similar to small cell carcinoma, most tumors are manifested at a late stage, and prognosis is generally poor. Sarcomas and GISTs of the esophagus are far less common than benign leiomyomas. Although well-differentiated leiomyosarcomas may be difficult to distinguish from leiomyomas, these are rare tumors that often erode through the mucosa, appearing as an ulcerated or exophytic mass on endoscopy. EUS may show more irregular borders or a heterogeneous appearance that is uncharacteristic for leiomyoma. In general, esophagectomy with radical lymphadenectomy is the treatment of choice for leiomyosarcomas.24 GISTs have similar appearance to leiomyomas but can be distinguished histologically by CD117 (c-kit) and CD34 stain positivity. Additionally, compared to leiomyomas, GISTs tend to be larger, with uptake of IV contrast on CT, and often have significant positron emission tomography (PET) avidity.25 GISTs may be enucleated provided that negative margins can be obtained. However, if concerns about margin status or tumor recurrence persist, formal esophagectomy should be performed.26 Imatinib should be considered for any GIST larger than 3 cm or with other high-risk features. Imatinib may also be considered in the neoadjuvant setting for locally advanced tumors. Lymph node metastasis is an unusual event in these mesenchymal tumors. Compared to the more commonly found gastric GISTs, esophageal GISTs tend to have worse disease-free and overall survival.26 Other sarcomas of the esophagus have been reported but are much rarer. 

ESOPHAGEAL CANCER Epidemiology of Esophageal Cancer Nearly 18,000 cases of esophageal cancer occur annually in the United States and about 572,000 cases occur worldwide.27,28 Unfortunately, esophageal cancer is typically manifested at an advanced stage and current 5-year survival is only approximately

35 30 Rate per 1,000,000

1038

25 20 15 10 5 0 1975

1980

1985

1990

1995

2000

FIG. 42.28  Trends in incidence of esophageal cancer histologic types (1975-2001). Red line, Adenocarcinoma; blue line, squamous cell carcinoma; green line, not otherwise specified. (From Pohl H, Welch HG. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. J Natl Cancer Inst. 2005;97:142–146.)

19%, with the majority of patients dying of their disease.28 Adenocarcinoma is the most common histology in Westernized counties, including the United States. During the last several decades there has been a concomitant decline in the incidence of SCC both worldwide and in the United States (Fig. 42.28).29 These histologic changes are thought to reflect the increasing obesity epidemic and GERD contributing to adenocarcinoma in conjunction with global reductions in cigarette smoking, a key risk factor for SCC.27 This appears to be a true increase in incidence of adenocarcinoma rather than overdiagnosis as the overall stage distribution has not significantly shifted during this time. Other types of esophageal tumors, including mesenchymal tumors, neuroendocrine cancers, and benign tumors, are much rarer. Tobacco and alcohol are strong risk factors for SCC, and they have a synergistic effect on risk.27 The disease is three to four times more prevalent in men, and race also appears to be a factor.28 The incidence of SCC is much higher amongst African Americans compared with their white counterparts, even after adjusting for socioeconomic status, tobacco, and alcohol use. Worldwide, parts of the Middle East, central Asia, and China have the highest rates of SCC, after adjusting for tobacco and alcohol use, indicating that there may be some genetic predisposition or other environmental factors. The recognition of the importance of HPV in the pathogenesis of SCC in other organs has spurred an interest in its role in esophageal SCC. Currently, it appears that HPV-related SCC represents only a small subset of esophageal SCC. For those tumors that are HPV related, the clinical implications of HPV association are unclear. SCC is associated with certain intrinsic disorders of the esophagus, such as Plummer-Vinson syndrome and achalasia. Other hereditary cancer syndromes associated with esophageal SCC include tylosis and Fanconi anemia. Patients with a history of caustic ingestion or achalasia are at significantly increased risk for SCC. The incidence of esophageal adenocarcinoma has increased dramatically in the last four decades, amongst the highest of any cancer in the United States. It is now the most common histologic type of esophageal cancer in the United States.30 Though overall incidence rates of adenocarcinoma have stabilized to decreased in the last 10 to 15 years, within the subpopulation of younger non-Hispanic whites, the incidence is increasing.30 It continues to

CHAPTER 42  Esophagus be relatively uncommon in African Americans. Adenocarcinoma often arises in the setting of Barrett esophagus. The frequency and duration of GERD symptoms is significantly associated with the risk of developing adenocarcinoma. As with SCC, there is a male predominance. There are also familial forms of Barrett esophagus that increase the risk of adenocarcinoma. SCC may arise in any part of the esophagus, but the majority of cases arise in the proximal and middle esophagus. In contrast, the majority of adenocarcinomas arise in the distal esophagus or GEJ. Under current American Joint Committee on Cancer (AJCC) and National Comprehensive Cancer Network (NCCN) staging guidelines, GEJ adenocarcinomas are staged and classified as esophageal cancers, with the exception of Siewert III tumors (tumors with an epicenter 2–5 cm below the GEJ) which are classified with gastric cancers.31,32 The majority of esophageal cancers are symptomatic at the time of diagnosis. Dysphagia is the most common symptom, with the majority of patients reporting difficulty in swallowing at the time of presentation. Often, patients will report progressive dysphagia, beginning with an initial episode after eating solid food. After the initial episode of dysphagia, many patients will adapt by chewing more thoroughly, avoiding hard foods, or drinking liquids with swallows. Thus, it is only after the dysphagia has worsened significantly that patients seek medical attention, by which point the majority have weight loss. Many patients with adenocarcinoma will endorse a long history of reflux symptoms including heartburn and regurgitation. Other associated findings may include fatigue, retrosternal pain, and anemia. Locally advanced tumors may be manifested with laryngeal nerve involvement causing hoarseness or with tracheoesophageal fistula. A careful physical examination should be performed with particular attention to cervical and supraclavicular lymph nodes. Early-stage tumors are often asymptomatic and are sometimes discovered during endoscopy done for Barrett esophagus. 

Diagnosis and Staging of Esophageal Cancer Barium esophagram may demonstrate irregular narrowing or ulceration (Fig. 42.29). The classic “apple-core” filling defect is seen only if there is symmetrical, circumferential narrowing. Instead, there is often an asymmetric bulge seen with an infiltrative appearance. The diagnosis of esophageal cancer is almost always made by endoscopic biopsy. Endoscopy should be performed in any patient with dysphagia, even if the barium esophagram is suggestive of a motility disorder. Classically, esophageal cancers appear as friable, ulcerated masses, but the endoscopic appearance can be varied. Early-stage tumors may appear as ulcerations or small nodules. More advanced tumors are more likely to be friable masses but may also appear as strictures or ulcerations. In many cases, the initial endoscopist may not recognize the presence of cancer and a single biopsy may not be diagnostic. Therefore, multiple biopsies should be performed for any suspicious lesions. During endoscopy, the location of the tumor relative to the incisors and GEJ should be noted, as well as the length of the tumor and degree of obstruction. The most proximal extent and circumferential extent of any Barrett esophagus should also be noted according to the Prague criteria.12 For small tumors or nodules, an experienced endoscopist should perform endoscopic mucosal resection (EMR) to provide a specimen that accurately assesses depth of invasion. Once a diagnosis of esophageal cancer is made, accurate staging is essential to guide appropriate therapy and to predict prognosis. The eighth edition AJCC staging system acknowledges differences

1039

FIG. 42.29  Barium esophagram demonstrating advanced carcinoma with abrupt, irregular narrowing in the distal esophagus with more proximal dilatation and air-fluid level.

in the biology of adenocarcinoma and SCC by creating separate stage groupings for the two histologic types (Tables 42.6 to 42.11). Additionally, this is the first edition to separate staging into clinical, pathologic, and postneoadjuvant staging groups.32 The inclusion of postneoadjuvant tumor, node, metastasis stage (ypTNM) is a response to the increasing proportion of operable patients undergoing induction therapy prior to resection. Pathologic stage is included for those patients undergoing resection that did not have neoadjuvant therapy. Tumor location affects pathologic stage for SCC but not for adenocarcinoma (Fig. 42.30). The cervical esophagus begins at the hypopharynx and extends to the thoracic inlet, which is the level of the sternal notch. On endoscopy, this corresponds to approximately 15 to 20 cm from the incisors. The upper thoracic esophagus begins at the thoracic inlet and extends to the azygos vein. This is approximately 20 to 25 cm from the incisors. Midthoracic tumors arise from the lower border of the azygos vein to the inferior pulmonary vein. This is approximately 25 to 30 cm from the incisors. Lower tumors arise distal to the lower border of the inferior pulmonary vein to the GEJ. This is usually more than 30 cm from the incisors. Tumor grade is included in pathologic stage classification for earlier stage tumors for both adenocarcinoma and SCC.32 In both histologies, clinical and postneoadjuvant staging includes only the TNM classification without use of tumor location or grade. Nodal classification is based on the total number of involved nodes. The eighth edition staging system introduces an esophagus-specific regional lymph node map for descriptive purposes.32 The depth of invasion of the tumor defines the T-status (Fig. 42.31). High-grade dysplasia includes malignant cells confined to the epithelium by the basement membrane and is by definition noninvasive (Tis). T1a tumors invade the lamina propria or muscularis mucosa, whereas T1b tumors invade into the submucosa. T2 tumors invade the muscularis propria, and T3 tumors invade the adventitia but not surrounding structures. T4a tumors invade adjacent structures that are usually

1040

SECTION IX  Esophagus

TABLE 42.6  Esophageal carcinoma stage classifications. Primary Tumor (T) TX T0 Tis T1a T1b T2 T3 T4a

Tumor cannot be assessed No evidence of tumor High-grade dysplasia Tumor invades the lamina propria or muscularis mucosa Tumor invades the submucosa Tumor invades into but not beyond the muscularis propria Tumor invades the adventitia Tumor invades adjacent structures that are usually resectable (diaphragm, pleura, azygos vein, peritoneum, or pericardium) Tumor invades structures that are usually unresectable (aorta, vertebral body, or trachea)

T4b

Regional Lymph Nodes (N) NX N0 N1 N2 N3

Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastasis in 1–2 regional lymph nodes Metastasis in 3–6 regional lymph nodes Metastasis in ≥ 7 regional lymph nodes

Distant Metastasis (M) M0 M1

No distant metastasis Distant metastasis

Histologic Grade (G) GX G1 G2 G3

Grade cannot be assessed Well differentiated Moderately differentiated Poorly differentiated or undifferentiated

Location (L) – Applicable to Squamous Cell Carcinoma Only LX Upper Middle Lower

Location unknown Cervical esophagus to lower border of azygos vein Lower border of azygos vein to lower border of inferior pulmonary vein Lower border of inferior pulmonary vein to stomach, including esophagogastric junction

Adapted from Rice TW, Ishwaran H, Ferguson MK, et al. Cancer of the esophagus and esophagogastric junction: An eighth edition staging primer. J Thorac Oncol. 2017;12:36–42.

TABLE 42.7  Clinical stage groupings

(cTNM) for esophageal adenocarcinoma. Stage 0 Stage I Stage IIA Stage IIB Stage III

Stage IVA   Stage IVB

T

N

M

Tis T1 T1 T2 T2 T3 T4a T1-4a T4b Any T Any T

N0 N0 N1 N0 N1 N0-1 N0-1 N2 N0-2 N3 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

Adapted from Rice TW, Ishwaran H, Ferguson MK, et al. Cancer of the esophagus and esophagogastric junction: An eighth edition staging primer. J Thorac Oncol. 2017;12:36–42. T, Tumor status; N, lymph node status; M, metastasis.

resectable (diaphragm, pleura, and pericardium). T4b tumors invade adjacent structures that are typically unresectable (trachea and aorta). Small, superficial lesions that are evaluated by an experienced endoscopist may be resected by EMR. In this setting, EMR often provides accurate staging for depth of penetration (T-status) and may provide additional information about the risk of nodal metastasis such as finding of lymphovascular invasion. EUS has less accuracy for superficial disease and will seldom obviate the need for EMR.33 For T1a tumors resected by EMR, the risk of lymph node metastasis is very low, and additional staging studies are not required. Most tumors, however, will be manifested as larger lesions. For these, further staging with a contrast-enhanced CT scan of the chest and abdomen and PET/CT to evaluate for distant metastatic disease should be performed. If there is no evidence of distant metastatic disease, EUS should be done to assess T-status and regional lymph nodes. Coupling EUS with fine needle aspiration of any suspicious nodes further increases the accuracy of this test.31 Obtaining the PET/CT scan before EUS has several advantages.

CHAPTER 42  Esophagus TABLE 42.8  Pathologic stage groupings

(pTNM) for esophageal adenocarcinoma. Stage 0 Stage IA Stage IB

Stage IC Stage IIA   Stage IIB Stage IIIA Stage IIIB

Stage IVA

Stage IVB

T

N

M

G

Tis T1a T1a T1a T1b T1b T1 T2 T2 T2 T1 T3 T1 T2 T2 T3 T4a T4a T4b Any T Any T

N0 N0 N0 N0 N0 N0 N0 N0 N0 N0 N1 N0 N2 N1 N2 N1–2 N0–1 N2 N0–2 N3 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

N/A G1 GX G2 G1-2 GX G3 G1–2 G3 GX Any Any Any Any Any Any Any Any Any Any Any

T, Tumor status; N, lymph node status; M, metastasis; G, grade. Adapted from Rice TW, Ishwaran H, Ferguson MK, et al: Cancer of the esophagus and esophagogastric junction: An eighth edition staging primer. J Thorac Oncol 12:36-42, 2017.

TABLE 42.9  Clinical stage groupings

(cTNM) for esophageal squamous cell carcinoma. Stage 0 Stage I Stage II Stage III Stage IVA Stage IVB

T

N

M

Tis T1 T2 T3 T3 T1–3 T4 Any T Any T

N0 N0–1 N0–1 N0 N1 N2 N0–2 N3 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M1

T, Tumor status; N, lymph node status; M, metastasis. Adapted from Rice TW, Ishwaran H, Ferguson MK, et al: Cancer of the esophagus and esophagogastric junction: An eighth edition staging primer. J Thorac Oncol 12:36-42, 2017.

The PET/CT scan may demonstrate distant metastatic disease, eliminating the need for the patient to undergo EUS. The PET/ CT scan may also identify a suspicious lymph node that can be specifically examined and sampled during the EUS procedure (Fig. 42.32). EUS is superior to CT or PET for assessment of both T and N-status. It is highly accurate for celiac nodal status, though slightly lower for other regional lymph nodes due to difficulty accessing the node without traversing the tumor. Obstructing lesions may preclude EUS assessment. In these cases, dilatation to perform EUS is associated with a risk of perforation. These risks must be weighed against the benefits of obtaining additional staging information. Most tumors with such tight stenoses are

1041

locally advanced and should likely be treated with multimodality therapy. Although EUS provides information about invasion of adjacent structures, bronchoscopy should also be performed for proximal and middle third esophageal tumors to assess for direct tracheal invasion. It is important to remember that for more superficial tumors (T1a–T2), the accuracy of EUS is significantly diminished and EMR provides the most accurate staging information.31,33 Appropriate staging is critical for treatment decisions. Superficial T1a tumors can usually be treated with EMR. Locally advanced tumors (T3 tumors or T2 tumors with nodal involvement) require multimodality therapy. Stage IV disease requires systemic or palliative therapy. Without accurate staging, patients are likely to be either undertreated or overtreated, leading to decreased survival and quality of life. 

Approach to Early-Stage Esophageal Cancer In the last 15 years, there has been a significant shift in the way early-stage esophageal cancers are treated. Improved endoscopic technology as well as a better understanding of the biology of early-stage tumors has led to the increased use of endoscopic therapies for the diagnosis, staging, and treatment of early-stage esophageal cancers. It is likely that surgery will play a smaller role for superficial cancers as endoscopic and ablative therapies continue to evolve and biomarkers of prognosis are refined. Given the changing nature of these treatments, multidisciplinary care with surgeons, gastroenterologists, and pathologists is essential to providing patients with the best long-term outcomes. 

High-Grade Dysplasia and Superficial Cancers Barrett esophagus is a significant risk factor for the development of esophageal adenocarcinoma. However, the absolute annual risk of developing cancer in a patient with Barrett has been estimated to be as low as 0.12%.34 Thus, increasing attention has been paid towards those with findings of dysplasia and eradication therapies to prevent the development of invasive malignancy in this subpopulation. Dysplasia arising in Barrett esophagus is characterized by cytologic malignant changes including atypical nuclei, increased mitoses, and lack of surface maturation. High-grade dysplasia is distinguished from low-grade dysplasia by more prominent cytologic or architectural derangements. As long as the cells are confined to the epithelium without invasion of the basement membrane, the pathology should be described as dysplasia regardless of the degree of abnormality. This encompasses what was previously referred to as carcinoma in situ. Historically, esophagectomy was often recommended for patients with high-grade dysplasia for a number of reasons. In the past, endoscopic biopsies were relatively inaccurate, and up to 50% of patients who underwent esophagectomy for high-grade dysplasia were found to have invasive cancer in the surgical specimen. Also, therapies to reverse or to halt the progression of dysplasia to invasive cancer were unavailable. Although esophagectomy had very high rates of cure for high-grade dysplasia, it was associated with significant morbidity. Overtreatment has also been a concern. Despite the historical data that many patients with high-grade dysplasia have invasive cancer found on esophagectomy, there is evidence from other groups reporting that only a minority of patients with flat high-grade dysplasia develop invasive cancer on follow-up endoscopy. Some of the conflict may be due to interobserver

1042

SECTION IX  Esophagus

TABLE 42.10  Pathologic stage groupings (pTNM) for esophageal squamous cell carcinoma. Stage 0 Stage IA Stage IB

Stage IIA   Stage IIB

Stage IIIA Stage IIIB

Stage IVA

Stage IVB

T

N

M

G

L

Tis T1a T1a T1a T1b T1b T2 T2 T2 T3 T3 T3 T3 T3 T1 T1 T2 T2 T3 T4a T4a T4b Any T Any T

N0 N0 N0 N0 N0 N0 N0 N0 N0 N0 N0 N0 N0 N0 N1 N2 N1 N2 N1–2 N0–1 N2 N0–2 N3 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

N/A G1 GX G2–3 G1–3 GX G1 G2–3 GX Any G1 G2–3 GX Any Any Any Any Any Any Any Any Any Any Any

Any Any Any Any Any Any Any Any Any Lower Upper/middle Upper/middle Any Location X Any Any Any Any Any Any Any Any Any Any

G, grade; L, Location; M, metastasis; N, lymph node status; T, Tumor status. Adapted from Rice TW, Ishwaran H, Ferguson MK, et al. Cancer of the esophagus and esophagogastric junction: An eighth edition staging primer. J Thorac Oncol. 2017;12:36–42.

TABLE 42.11  Postneoadjuvant therapy

stage groupings (ypTNM) for esophageal adenocarcinoma and squamous cell carcinoma. Stage I Stage II Stage IIIA Stage IIIB

Stage IVA

Stage IVB

T

N

M

T0–2 T3 T0–2 T3 T0–3 T4a T4a T4a T4b Any T Any T

N0 N0 N1 N1 N2 N0 N1–2 NX N0–2 N3 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

T, Tumor status; N, lymph node status; M, metastasis. Adapted from Rice TW, Ishwaran H, Ferguson MK, et al. Cancer of the esophagus and esophagogastric junction: An eighth edition staging primer. J Thorac Oncol. 2017;12:36–42.

variation in the diagnosis of high-grade dysplasia versus invasive adenocarcinoma on biopsy specimens and the practice of diligent search for cancer at some institutions. Any biopsy specimens with high-grade dysplasia or invasive adenocarcinoma should be reviewed by a specialty pathologist experienced with Barrett esophagus and esophageal cancer. In contrast to the high rates of cancer development in patients with high-grade

dysplasia, the incidence of cancer with nondysplastic Barrett esophagus appears to be low. The largest study of endoscopic surveillance in patients with Barrett esophagus found that the annual risk for development of cancer was 0.39% in patients with no dysplasia versus 0.77% in patients with low-grade dysplasia.35 The Seattle biopsy protocol is still widely accepted for mapping of Barrett esophagus with high-grade dysplasia. This involves four-quadrant biopsies at 1-cm intervals along the entire length of Barrett esophagus in addition to targeted biopsies of all visible lesions. Emerging endoscopic imaging techniques increase the sensitivity for detection of dysplasia. Many specialty centers routinely use high-resolution endoscopy and some sort of chromoendoscopy or simulated chromoendoscopy, such as narrow-band imaging (Olympus), to evaluate Barrett esophagus. Narrow-band imaging uses light filters to allow more narrow wavelengths of light. The wavelengths penetrate only superficially and are absorbed well by hemoglobin, better revealing irregular mucosal vascular patterns (Fig. 42.33). Use of narrow-band imaging is associated with high accuracy is diagnosing dysplasia.36 Additional technologies include autofluorescence endoscopy and optical coherence tomography. Notably, confocal endomicroscopy was shown in a randomized trial to reduce the need for random biopsies and improve the diagnostic yield and accuracy of identifying dysplasia in patients with Barrett esophagus.37 These techniques hold promise for even greater resolution but require more specialized training and equipment compared with the relatively user-friendly technology of high-resolution endoscopy and narrow-band imaging.

CHAPTER 42  Esophagus Length in centimeters 0

5

10 Upper esophageal sphincter 15 Thoracic inlet

Sternal notch

Cervical esophagus

20 Upper thoracic esophagus Azygos vein 25 Middle thoracic esophagus

30

Inferior pulmonary vein

Lower thoracic esophagus/ esophagogastric junction (EGJ)

35

Diaphragm

40

EGJ Abdominal esophagus

45

FIG. 42.30  Regions of the esophagus. The cervical esophagus extends from the upper esophageal sphincter to the thoracic inlet. The upper thoracic esophagus extends from the thoracic inlet to the azygos vein. The midthoracic esophagus extends from the lower border of the azygos vein to the inferior pulmonary vein. The lower thoracic esophagus extends from the lower border of the inferior pulmonary vein to the gastroesophageal junction.

1043

1044

SECTION IX  Esophagus Epithelium Basement membrane

T1 intramucosal T1 submucosal

Lamina propria

HGD T2

T3

T4

Muscularis mucosa Submucosa

Muscularis propria Periesophageal tissue

Aorta

N0 N1

FIG. 42.31  Tumor classification for esophageal carcinoma as defined by depth of invasion. HGD, High-grade dysplasia.

FIG. 42.32  Fused transaxial positron emission tomography/computed tomography image demonstrating increased fluorodeoxyglucose activity in a gastroesophageal junction tumor and celiac lymphadenopathy.

Therapeutic Approaches to Esophageal Cancer Ablation. Various endoscopic ablative and resection techniques have been developed that have largely supplanted the role of esophagectomy for high-grade dysplasia. The most commonly used technology today is radiofrequency ablation (RFA). RFA is much more effective than photodynamic therapy with a lower stricture (and overall complication) rate. RFA

may be delivered with a circumferential balloon or an electrical plate using a bipolar electrode that transmits radiofrequency energy, which generates heat and destroys superficial tissue (Fig. 42.34). The treated mucosa is replaced by neosquamous mucosa. The standard ablation program uses two double pulses of 12 J/cm2. The balloon is then repositioned distally, and the procedure is repeated until the entire segment of Barrett esophagus is treated. If there are areas of residual Barrett esophagus on follow-up endoscopy, those segments may be treated with more focal ablation. Multiple studies have demonstrated the effectiveness of RFA for eradicating Barrett esophagus and dysplasia. In the Ablation of Intestinal Metaplasia (AIM-II) trial, 81% of patients with high-grade dysplasia and 90% of patients with low-grade dysplasia had eradication of dysplasia.38 Only 4% of patients had their dysplasia progress to a higher grade of dysplasia or cancer. In a European trial of patients with Barrett esophagus and low-grade dysplasia, 136 patients were randomized to RFA versus surveillance. Only 1.5% of ablated patients progressed to cancer versus 8.8% in the surveillance arm.39 RFA was able to eradicate dysplasia in 92.6% of patients. Finally, in a registry study of patients undergoing RFA for Barrett esophagus, only 2% developed cancer and only 0.2% died of their disease.40 American College of Gastroenterology guidelines recommend all patients with low-grade dysplasia undergo endoscopic eradication therapy, with yearly endoscopic surveillance being an acceptable alternative.12 All patients with high-grade dysplasia should undergo endoscopic therapy if medically able to tolerate the procedure.  Cryotherapy. Cryotherapy is an alternative ablative technique that uses extreme cold rather than heat to destroy tissue

CHAPTER 42  Esophagus

A

1045

B

FIG. 42.33  Traditional, white light view of Barrett esophagus with high-grade dysplasia (A) and narrow-band imaging of the same area (B).

A

B FIG. 42.34  Radiofrequency ablation performed in a patient with Barrett esophagus. (A) Preablation with catheter seen adjacent to area of metaplastic disease. (B) Posttreatment after radiofrequency ablation. (From Rajaram R, Hofstetter WL. Mucosal ablation techniques for Barrett’s esophagus and early esophageal cancer. Thorac Surg Clin. 2018;28:473–480.)

(Fig. 42.35). Cryotherapy is generally well tolerated with little pain and low stricture rates. One advantage of cryotherapy compared with RFA is that cryotherapy does not require a probe to be in contact with the tissue. Endoscopists typically use either an endoscopic spray catheter or in some cases, an endoscopic balloon, to deliver cold liquid nitrogen (–196°C). A decompression tube is typically required to prevent overdistention of the stomach and intestine with gas. In a large registry series, cryotherapy eradicated low- and high-grade dysplasia in 91% and 81% of patients, respectively.41 In another study, use of cryotherapy, in conjunction with EMR, for patients with high-grade dysplasia and intramucosal adenocarcinoma resulted in eradication rates of dysplasia of nearly 90% at five years.42 Additionally, cryotherapy has been used as salvage therapy after prior failed RFA. There have been no head-to-head comparisons between cryotherapy and RFA, but reports indicate similar efficacy to RFA. Regardless of what ablation technology is used, patients should have close surveillance and long-term acid suppression after

ablation. In patients with high-grade dysplasia, a repeat endoscopy should be performed three months after ablative therapy has completely eradicated their dysplasia/Barrett esophagus, preferably with high-resolution endoscopy and some form of chromoendoscopy.12 In those with low-grade dysplasia, the first surveillance endoscopy should be performed 6 months after their Barrett esophagus/dysplasia is completely eradicated.12 Many patients will require more than one ablation session to eradicate all Barrett esophagus. There is also a small risk that areas of Barrett epithelium could be hidden beneath areas of the new squamous epithelium, known as buried glands. Malignancy can arise within these buried glands, and these cancers may be more difficult to identify during endoscopy. The clinical significance of this phenomenon is unknown, and the incidence of malignancy developing within these areas of buried glands appears to be very low. Nevertheless, the potential implications of unrecognized incomplete eradication justifies future surveillance of ablated patients.  Endoscopic mucosal resection. One limitation of ablative therapies is the limited depth of penetration. Another

1046

SECTION IX  Esophagus

A

B

C

D FIG. 42.35  Liquid nitrogen spray cryotherapy performed in a patient with Barrett esophagus and dysplasia. (A) Dysplastic segment in background of Barrett esophagus seen anteriorly. (B) and (C) Targeted delivery of liquid nitrogen spray cryotherapy. (D) Posttreatment after liquid nitrogen spray cryotherapy. (From Rajaram R, Hofstetter WL: Mucosal ablation techniques for Barrett’s esophagus and early esophageal cancer. Thorac Surg Clin. 2018;28:473–480.)

disadvantage is the lack of definitive pathologic analysis. Therefore, patients with nodular or raised Barrett esophagus or other abnormalities suggestive of superficial invasive cancer should undergo EMR rather than ablation. EMR provides larger specimens to accurately determine the depth of invasion. EMR resects the full thickness of the mucosa, down into the submucosa (Fig. 42.36). Thus, it is a good therapeutic option for superficial lesions with a low risk of nodal metastases. In a study of 1000 patients with mucosal adenocarcinoma, use of EMR was found to achieve long-term eradication rates of 93.8% at near 5-year median follow-up.43 However, use of EMR needs to be individualized as it does not address the potential for nodal disease. Depending on the size of the lesion (>2 cm), degree of differentiation (intermediate/high-grade), and lymphovascular invasion, the overall risk of nodal metastasis for lesions confined to the mucosa (T1a) ranges from less than 2% to more than 15% (Table 42.12).44 For selected T1a lesions, EMR is highly effective (Fig. 42.37). Although EMR can technically remove lesions involving the submucosa (T1b), the risk of lymph node involvement increases with depth of submucosal invasion. Therefore, EMR is generally not considered adequate for tumors involving the deeper submucosa. However, lesions involving only the most

superficial third of the submucosa (SM1) have relatively low rates of nodal metastases, possibly less than 10%. On the other hand, lesions involving the deepest two-thirds of the submucosa (SM2/SM3) may have nodal involvement in nearly 40% of cases, with some studies finding significantly higher rates of nodal disease.45 T1b cancers with squamous cell histology also appear to have a higher risk of nodal metastasis compared with adenocarcinoma (45% vs. 26%).46 EUS has low accuracy for assessing T-status for superficial tumors, so patients with suspected T1 lesions should have EMR performed by a qualified endoscopist to obtain accurate staging. Thorough and accurate pathologic assessment is critical to formulating treatment plans. NCCN guidelines currently recommend use of EMR ± ablation in patients with Tis and T1a tumors as a preferred therapy over esophagectomy.31 Additionally, in superficial T1b (SM1) patients with adenocarcinomas and low-risk features, endoscopic eradication is a reasonable alternative to surgery. Complications of EMR include bleeding, stricture, pain, and perforation. The stricture risk is increased for patients requiring circumferential resection. In a study of EMR use in high-grade dysplasia and early esophageal cancer, approximately one-third of patients required dilatation though very few had long-term dysphagia.47 Although EMR may be performed for the entire segment

1047

CHAPTER 42  Esophagus

FIG. 42.36  A superficial T1a adenocarcinoma arising in the setting of Barrett esophagus (left) and submucosal defect after endoscopic mucosal resection (right).

TABLE 42.12  Nomogram for prediction of

1.00

lymph node metastases in early-stage esophageal cancer.

.90 .80

POINTS

.70

Size, per cm Depth T1a T1b Differentiation Well Moderate Poor Lymphovascular invasion

+ 1 (per cm)

.60

RISK CATEGORY Low Moderate High

0-1 2–4 5+

.50 .40 .30

+0 +3 +3 +6

POINTS

Survival

VARIABLE

+0 +2

++++++++++++++ +++++++++++++++++++++++++++ ++ +

.20 .10 0.00 0

PREDICTED RISK OF LYMPH NODE METASTASES (%) ≤2 3–6 ≥7

Adapted from Lee L, Ronellenfitsch U, Hofstetter WL, et al. Predicting lymph node metastases in early esophageal adenocarcinoma using a simple scoring system. J Am Coll Surg. 2013;217:191–199.

of Barrett esophagus, complication rates are lower if EMR is focused on specific areas combined with ablation for residual Barrett esophagus. EMR may be performed with a submucosal lifting technique, which raises the target lesion by injecting fluid into the submucosa beneath the lesion. This allows the lesion to be suctioned more easily into a cap, creating a pseudopolyp, allowing resection with a snare. Another technique uses suction to raise the lesion, allowing a band to be placed at the base of the pseudopolyp that is created and then using a snare to resect. One drawback of EMR is that larger lesions are typically removed piecemeal. Reports describe the efficacy of endoscopic submucosal dissection using an endoscopic needle knife that allows greater submucosal dissection and en-bloc resection of larger lesions.48 The safety of this technique outside a few specialized centers is unknown.

20

40 60 Follow-up [months]

80

100

FU [months]

12

24

36

48

60

72

Number of pts at risk

99

80

43

21

11

3

FIG. 42.37  Survival curve of patients undergoing endoscopic mucosal resection for low-risk, superficial esophageal adenocarcinoma. (From Ell C, May A, Pech O, et al. Curative endoscopic resection of early esophageal adenocarcinomas [Barrett’s cancer]. Gastrointest Endosc. 2007;65:3–10.)

Surveillance is an important component of the treatment for superficial esophageal cancers. Patients should receive high-dose acid suppression therapy with a PPI to help EMR and ablation sites to heal. Many patients require multiple procedures to completely eradicate Barrett epithelium. Short-interval follow-up endoscopy should be performed three months after endoscopic treatment is completed. Any residual Barrett epithelium may be focally ablated at that time. Surveillance endoscopies should be performed frequently (i.e., every three months) for the first year after endoscopic treatment for high-grade dysplasia or intramucosal cancer, after which time the frequency of endoscopic surveillance may be spaced out.12 For superficial lesions treated endoscopically, radiologic imaging, such as fluorodeoxyglucose (FDG) PET, has no value.  Esophagectomy. The role of esophagectomy as a singlemodality treatment for esophageal cancer is diminishing. Most tumors are found after symptoms develop, at which point they

1048

SECTION IX  Esophagus

are usually locally advanced or metastatic. Locally advanced tumors should be treated with multimodality therapy. Asymptomatic tumors are usually found during surveillance for Barrett esophagus. These are typically superficial and can be treated with EMR with lower complication rates than with esophagectomy. This leaves a relatively narrow subset of tumors that are treated appropriately with surgery only. As discussed earlier, T1b tumors have significant risk for nodal metastasis and, with exception of some SM1 tumors, most should be treated with esophagectomy. High-risk T1a lesions (larger tumors or lesions with lymphovascular invasion) could also be considered for esophagectomy. Extensive, multifocal lesions and ulcerated tumors may also be difficult to eradicate endoscopically and would be appropriate candidates for esophagectomy. An area of controversy is the optimal treatment for clinical T2N0 tumors. Esophagectomy with an adequate lymphadenectomy would be expected to confer an overall 5-year survival of anywhere between 40% and 65% for a pathologic T2N0 cancer, depending on histology, grade, and location of tumor.31 Unfortunately, a clinical stage of T2N0 is inaccurate in the majority of cases, and many patients are found to have node-positive disease on final pathology after esophagectomy.49 Clinical T2N0 patients were included in the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) trial, which compared neoadjuvant chemoradiation followed by surgery versus surgery alone for esophageal and GEJ cancer. Although the trial demonstrated a survival benefit for the neoadjuvant chemoradiation arm, clinical T2N0 patients represented only a small subset of the study cohort, and it is unclear how much benefit these patients in particular received.50 It is clear that many patients with clinical T2N0 disease are understaged, but retrospective analyses indicate that there may not be a survival advantage for neoadjuvant therapy in this group.51 One management strategy may be to selectively offer neoadjuvant therapy to patients with clinical T2N0 disease based on the patient’s pretest probability of upstaging. In a recent decision analysis, the authors found that if the risk of upstaging is more than 48.1%, there is a survival advantage to induction chemoradiation.52 Furthermore, they identified long tumors (>3 cm), presence of lymphovascular invasion, and high-grade as clinical factors associated with meeting this threshold and benefiting from induction therapy. It is important to also note that an equal number of patients with cT2N0 are actually overstaged, so liberal use of diagnostic EMR is appropriate.49 The advent of EMR also influences the type of esophagectomy that should be performed in early-stage esophageal cancer. Because of the potential for decreased complication and improved physiologic outcomes, vagal-sparing esophagectomy has been advocated by some for intramucosal adenocarcinoma and highgrade dysplasia. However, most low-risk lesions are now resected by EMR. Regarding surgical technique, a randomized trial of transhiatal esophagectomy compared to an extended transthoracic approach with en-bloc lymphadenectomy found lower perioperative morbidity in the transhiatal group with a trend towards increased overall and disease-free survival in transthoracic patients.53 The benefit of a transthoracic approach is the ability to perform an extensive lymphadenectomy, with some suggesting a minimum of 23 lymph nodes should be removed to maximize survival benefit.54 Minimally invasive esophagectomy (MIE) is also an approach gaining favor. Use of MIE is associated

with shorter lengths of stay with similar 30-day mortality and 3-year survival outcomes as open esophagectomy.55 While MIE involves a completely minimally invasive approach, a hybrid esophagectomy is one in which the abdominal portion is approached laparoscopically and an open right thoracotomy is performed (Ivor Lewis esophagectomy). In a recent randomized controlled trial, hybrid Ivor Lewis esophagectomy was associated with almost half as many major complications as open surgery with differences in pulmonary events being a driving factor.56 Additionally, 3-year overall and disease-free survival was similar in the two groups. Surgeons have also reported using a robotic-assisted approach for MIE with excellent oncologic outcomes, albeit with a significant learning curve associated with this technology. Perioperative outcomes after esophagectomy have been reported from the Society of Thoracic Surgeons General Thoracic Surgery Database.57 Postoperative 30-day mortality was 3.4% and major morbidity was 33.1%, and included return to the operating room (15.6%), anastomotic leaks (12.9%), reintubation (12.2%), and pneumonia (12.2%). In an attempt to address perioperative morbidity, several centers have implemented enhanced recovery or fast-track programs with results suggesting less ICU days, shorter lengths of stay, reduced costs, and fewer postoperative complications.58 Patients have increasing endoscopic and surgical options for the treatment of early-stage esophageal cancers. Care needs to be individualized so patients may make informed decisions, balancing the effectiveness of therapies with their risks and impact on quality of life. 

Locally Advanced Esophageal Cancer Despite improved awareness of the increasing trend in esophageal adenocarcinoma and more frequent detection of early esophageal adenocarcinoma on surveillance endoscopies, the majority of patients with esophageal cancer still present with locally advanced or metastatic disease. Usually, it is not until patients experience dysphagia, which generally signifies transmural tumor involvement (T3), that an esophageal cancer is diagnosed. In this setting, the probability of lymph node metastases reaches 80%, so the majority of patients present with clinical stage T3N1–3 according to the eighth edition (AJCC) of esophageal cancer staging. It should be reiterated that the eighth edition staging criteria includes not only clinical and pathologic stage, but also ypTNM stage.32 Inclusion of postneoadjuvant therapy stage reflects the significant survival benefit patients with locally advanced esophageal cancer have experienced from multimodality therapy in the current era.50 Current staging recognizes the prognostic value in the number of metastatic lymph nodes and groups patients into three categories: N1 (one to three positive nodes), N2 (four to six positive nodes), and N3 (seven or more positive nodes). The anatomic location of the regional nodal disease relative to the primary tumor is not a factor involved in staging. However, recent evidence suggests that nodal location, such as celiac axis or upper mediastinum, may significantly affect survival.59 In clinical practice, nodal disease location continues to influence treatment decisions. This confusion is partly due to the lack of consensus and definition of which nodal stations represent regional versus distant metastatic disease. In the era of multimodality therapy and selective surgery, the rigorous definition of locally advanced esophageal cancer is necessary to guide pretreatment therapeutic decisions before committing to either

CHAPTER 42  Esophagus aggressive locoregional therapy or initiating systemic treatment. For esophageal adenocarcinoma, mostly located in the distal esophagus or GEJ, we consider nodal disease located in the area from the celiac axis up to the paratracheal region to represent regional disease; nodal disease located outside of these boundaries is regarded as distant disease. For esophageal SCC, which mostly arises in the mid or proximal esophagus, periesophageal cervical lymphadenopathy is still considered a regional disease. Whereas the current staging system takes the tumor differentiation into account, it is mainly the disease burden that dictates the decisions about the treatment strategy, and therapeutic decisions are best discussed in a multidisciplinary setting. Principles of Multimodality Therapy for Locally Advanced Esophageal Cancer Surgical resection of the esophagus was the mainstay of esophageal cancer treatment in the past. However, we have learned that even the most radical resections with extensive lymph node dissections are not adequate to cure locoregionally advanced disease in the majority of cases. Distant recurrence or metastatic disease continues to be the main cause of death in patients with esophageal cancer. Our understanding and treatment of esophageal cancer have evolved significantly during the last 100 years. The initial recognition that a localized esophageal cancer may be cured with surgical resection dates back to the first successful esophagectomy performed by Franz Torek in 1913. Despite rather poor perioperative outcomes at that time, surgery became a supplement to radiation as the treatment of choice for localized esophageal cancer in the early twentieth century. Over time, more extensive en-bloc esophageal resections and lymphadenectomy became favored with the hope that radical resection of disease would result in a cure more frequently. However, similar to Halstead radical mastectomy, we have learned that whereas extended esophagectomy may lead to better locoregional control, it fails to achieve cure in patients destined to die of metastatic disease. Today, technical aspects of esophagectomy are still passionately debated as the technological advances enable us to perform these procedures safely even with less invasive or robotically assisted techniques. From an oncologic standpoint, however, surgical therapy has its limits in what it can contribute to the cure rate of esophageal cancer. Moreover, there continues to be a tremendous variability in the performance of surgical resection of the esophagus among surgeons, with some favoring transthoracic and some transabdominal approaches with varied extents of lymph node dissections. This lack of procedural standardization confounds the analysis of esophageal cancer treatment outcomes. Increased understanding of cancer biology led to the development of nonsurgical treatment strategies for solid organ malignant neoplasms, including esophageal carcinoma. Chemotherapy was combined concomitantly with radiation therapy to improve the local-regional efficacy and potentially for systemic effect. Intuitively, this strategy targets both local disease and systemic micrometastases. The demonstrated efficacy of this treatment paradigm subsequently stimulated interest in combining surgery, radiation, and chemotherapy to maximize the treatment effect. The combination of these treatment modalities became the focus of several clinical trials investigating the role and timing of each method. 

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Treatment Modalities Used in Locally Advanced Esophageal Cancer Radiation therapy. Radiation was employed as the first treatment modality for esophageal cancer. Early experiences with radium bougies and external beam radiation demonstrated esophageal tumor regression with occasional complete tumor responses. With the evolution of surgical care, radiation became a part of a multidisciplinary approach to esophageal cancer therapy with the goal of sterilizing areas within or around the operative field. Early randomized trials of neoadjuvant radiation administered doses of 20 to 40 Gy before resection in an attempt to decrease local recurrence and to improve survival rates. With one exception, all of these trials included patients with SCC only, and none of the trials demonstrated significant benefits of adding radiation therapy to resection. Although the lower radiation doses (20–40 Gy) may have been inadequate, clinicians were wary of combining higher dose radiation before surgery, given the toxicity risks (note that radiation delivery and particles used in therapy were very different in the past compared with current therapy). Nonetheless, high rates of locoregional recurrence after surgery led to the consideration of adjuvant radiation therapy for esophageal cancer. The rationale for this approach was the ability to deliver higher doses (40–60 Gy) of radiation postoperatively without worsening perioperative complications. Postoperative radiation therapy for esophageal cancer appeared to be potentially beneficial in several trials, although the data are conflicting and subject to selection bias.  Chemotherapy. The cause of death from esophageal cancer is mainly due to metastatic disease. Intuitively, systemic chemotherapy has the potential to target micrometastatic deposits. Even in the setting of a seemingly localized disease, it usually downstages marginally resectable tumors, allowing improved complete (R0) resection rates, and decreases the incidence of locoregional recurrence. The synergistic effect of chemotherapy with radiation strengthens the argument for its use. Importantly, when it is administered preoperatively, the biologic response can be evaluated and quantified pathologically in terms of pathologic tumor histoviability, and the degree of this response has been correlated as an indicator of outcome. Current chemotherapeutic regimens are based on platinum compounds (cisplatin and carboplatin) in combination with 5-fluorouracil or taxanes as a doublet. In several prospective randomized trials, researchers compared chemotherapy followed by surgery with surgery alone for both esophageal adenocarcinoma and SCC (Table 42.13).60 The landmark trial by Roth and colleagues demonstrated longer median survival durations in patients with major or complete response to chemotherapy, which highlighted the biologic diversity of esophageal cancers and their varied susceptibility to chemotherapy.61 In a phase 3 study run by the Medical Research Council (MRC) in the United Kingdom, patients with locally advanced esophageal cancer randomized to chemotherapy plus surgery, versus surgery alone, experienced a survival benefit.62 The largest trial of its kind, the MRC trial included 802 patients randomized to receive chemotherapy plus esophagectomy versus esophagectomy alone. The survival benefit of chemotherapy persisted at the updated median follow-up duration of six years, with 5-year survival rates of 23% with chemotherapy plus surgery and 17% with surgery alone (P = 0.03). Both adenocarcinoma and SCC patients experienced benefit. Another commonly referenced trial that demonstrated survival advantage and better R0 resection rate of neoadjuvant chemotherapy and surgery over surgery alone was the MRC Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial by Cunningham and

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TABLE 42.13  Randomized trials comparing chemotherapy and surgery versus surgery alone. TRIAL MRC CT-Sx Sx RTOG 8911 CT-Sx Sx MAGIC CT-Sx Sx FFCD CT-Sx Sx

N

HISTOLOGY

CHEMOTHERAPY

SCC, ADC

Cisplatin, 5-FU

400 402

R0 (%) 60 54

SCC, ADC

Cisplatin, 5-FU

213 227 ADC

Epirubicin, cisplatin, 5-FU

ADC

Cisplatin, 5-FU

63 59 NA

250 253 113 111

84 74

SURVIVAL Median (months) 17 13 Median (months) 14.9 16.1 5 years (%) 36* 23 5 years (%) 38* 24

*P < 0.05. ADC, Adenocarcinoma; CT, chemotherapy; 5-FU, 5-fluorouracil; MRC, Medical Research Council; SCC, squamous cell carcinoma; Sx, surgery. Adapted from Cools-Lartigue J, Spicer J, Ferri LE. Current status of management of malignant disease: Current management of esophageal cancer. J Gastrointest Surg. 2015; 19:964–972.

colleagues.63 The majority of the enrolled patients had gastric carcinoma, with only a subgroup having esophageal or GEJ tumors. In the adjuvant setting, the results of chemotherapy have not been convincing. The majority of trials were in the esophageal SCC setting, such as a phase 3 multicenter Japan Clinical Oncology Group trial (JCOG 9907), which randomized 330 patients comparing the effects of neoadjuvant (164 patients) and adjuvant (166 patients) chemotherapy for stage II and stage III esophageal SCC.64 Patients received two cycles of cisplatin and 5-fluorouracil before or after radical resection. The interim analysis demonstrated a significantly better (P = 0.044) median progression-free survival duration in the neoadjuvant group (three years) than in the adjuvant group (two years) and the difference in estimated 5-year overall survival rate of 60% versus 38% in the neoadjuvant and adjuvant arms, respectively (P = 0.013). On the basis of these findings, it was recommended to terminate the trial.  Definitive chemoradiation. Chemoradiation may be administered in a preoperative or postoperative setting, as definitive bimodality therapy, or as part of trimodality therapy when combined with surgery. Concomitant administration of chemotherapy and radiation has a synergistic effect with increased tumor cytotoxicity at low doses. The validity of chemoradiation use for all locations of esophageal cancer is based on encouraging results of definitive chemoradiation for cervical esophageal SCC. Randomized trials of chemoradiation versus radiation alone include RTOG 85-01 by Herskovic and colleagues, which established that a group of patients with esophageal SCC or adenocarcinoma could be cured with bimodality therapy alone. To improve on the favorable outcomes observed in the RTOG 85-01 trial, researchers attempted to increase locoregional disease control rates in the subsequent Intergroup 0123/RTOG 94-05 trial by modifying the intensity of radiation therapy to high-dose 64.8 Gy given concurrently with chemotherapy. Unfortunately, at a median follow-up duration of 16 months, the survival and locoregional disease control rates with the higher radiation dose did not differ significantly from those in the RTOG 85-01 trial, but the toxicity and treatment-related deaths were worse in the high-dose radiation therapy group. This study established that 50.4 Gy of radiation used concomitantly with chemotherapy is both a neoadjuvant and potentially definitive dose.65 

Chemoradiation and surgery. When used alone, each cancer treatment modality has its limitations, ranging from inadequate therapeutic effect to excessive toxicity. The synergistic effect of chemoradiation combined with surgical resection maximizes the chances of effectively treating both locoregional disease and potential undetectable metastases (Table 42.14). Early clinical trials testing a trimodality treatment paradigm did not demonstrate a survival advantage over surgery alone. Many of these trials were underpowered and mixed SCC and esophageal adenocarcinoma histology as well as varied radiation and chemotherapy regimens. Some trials suffered from poor patient accrual or inconsistent surgical outcomes. However, in locally advanced esophageal cancer the effect of trimodality therapy in well-selected patient populations appears to be significant. The most notable and frequently quoted trial that compared chemoradiation followed by surgery with surgery alone for esophageal and EGJ cancer was the CROSS trial.50 This trial enrolled an impressive 368 patients during a 4-year period, and 366 patients were included in the final analysis. The surgery-alone group consisted of 188 patients, whereas 178 underwent chemoradiation followed by surgery. The majority (75%) of the patients had adenocarcinoma, and 22% had SCC. The chemoradiation regimen consisted of a 5-week course of carboplatin and paclitaxel administered concurrently with radiation therapy at a dose of 41.4 Gy given in 23 fractions five days a week. Esophagectomy was performed within 4 to 6 weeks in the treatment group and immediately after randomization in the control group. The completeness (R0) of resection was higher in the trimodality group than in the surgeryalone group (92% vs. 69%; P < 0.001). Patients undergoing trimodality therapy with SCC experienced complete pathologic response (ypT0N0M0) significantly more than patients with adenocarcinoma (49% vs. 29%; P < 0.001). Expectedly, nodal positivity was higher in patients with surgery alone compared with the trimodality group (75% vs. 31%; P < 0.001). At a median follow-up duration of 45 months, patients receiving the trimodality therapy had significantly longer median overall survival duration (49.4 months) than did patients undergoing surgery alone (24 months; hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.49–0.87; P = 0.003). The estimated 5-year survival rate in the trimodality therapy group was 47%

CHAPTER 42  Esophagus

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TABLE 42.14  Randomized trials comparing chemoradiation and surgery versus surgery alone. TRIAL Walsh CT-RT-Sx Sx Bosset CT-RT-Sx Sx Urba CT-RT-Sx Sx Lee CT-RT-Sx Sx Burmeister CT-RT-Sx Sx Tepper CT-RT-Sx Sx CROSS CT-RT-Sx Sx Mariette CT-RT-Sx Sx Yang CT-RT-Sx Sx

N

HISTOLOGY

CHEMOTHERAPY

RT (GY)

PCR (%)

R0 (%)

SURVIVAL

ADC

Cisplatin, 5-FU

40

25

NA

SCC

Cisplatin

37

26

NA

SCC, ADC

Cisplatin, 5-FU, vinblastine

45

28

90 90

SCC

Cisplatin, 5FU

45.6

43

3 years (%) 32* 6 Median (months) 18.6 18.6 3 years (%) 30* 16 Median (months) 27.3 28.2 Median (months) 22.2 19.3 5 years (%) 39* 16 5 years (%) 47* 34 3 years (%) 47.5 53 Median (months) 100.1* 66.5

58 55 143 149 50 50 51 50

100 87.5 SCC, ADC

Cisplatin, 5-FU

35

16

128 128 SCC, ADC

Cisplatin, 5-FU

50.4

33

SCC, ADC

Carboplatin, paclitaxel

41.4

29

80* 59 NR

30 26 178 188

92* 69 SCC, ADC

Cisplatin, 5-FU

45

33.3

98 97

93.8 92.1 SCC

Cisplatin, vinorelbine

224 227

40

43.2 98.4* 91.2

*P < 0.05. ADC, Adenocarcinoma; CROSS, chemoradiotherapy for Oesophageal Cancer Following Surgery Study; CT, chemotherapy; 5-FU, 5-fluorouracil; NA, not available; NR, not reported; pCR, pathologic complete response; RT, radiotherapy; SCC, squamous cell carcinoma; Sx, surgery. Edited and adapted from Cools-Lartigue J, Spicer J, Ferri LE. Current status of management of malignant disease: Current management of esophageal cancer. J Gastrointest Surg. 2015;19:964–972.

compared with 34% (HR, 0.65; 95% CI, 0.49–0.87; P = 0.003) in the surgery group. Interestingly, trimodality therapy did not significantly benefit patients with adenocarcinoma histology (HR, 0.74; 95% CI, 0.53–1.02; P = 0.07) in the initial analysis. However, in a subsequent study with longer follow-up, the survival benefit of trimodality therapy in both SCC and adenocarcinoma was confirmed.50,66 

The Role of Surgery in Trimodality Therapy and Salvage Surgery Subsequent to the CROSS trial report, many Western centers adopted the trimodality therapy as the standard of care for the treatment of esophageal carcinoma. However, this trial still left many questions unanswered about the treatment strategy for locoregional esophageal carcinoma. Whereas we have observed that neoadjuvant chemoradiation improves R0 resection and locoregional recurrence rates and results in pathologic complete responses in many patients, other subgroups of patients clearly derive no benefit from neoadjuvant therapy over surgery alone. Equally, patients who are “cured” by neoadjuvant chemoradiation derive no additional survival benefit from further surgical extirpation of the esophagus. We are currently unable to identify these groups of patients and must search for simple, reproducible, and validated surrogate markers predictive of treatment outcome. So far, only histopathologic tumor response after neoadjuvant therapy has

emerged as a predictor of survival in esophageal cancer patients.67 Surgical resection and evaluation of histopathologic tumor response will therefore continue to play a role in the treatment of esophageal cancer in upcoming years. Studies have been published comparing preoperative chemotherapy versus preoperative chemoradiation. In a randomized trial of patients with adenocarcinoma of the EGJ, trimodality therapy had significantly higher pathologic complete response rates and higher probability of tumor-free lymph nodes compared to induction chemotherapy.68 Additionally, trimodality patients had much higher survival at 3-years compared to induction chemotherapy patients (47.4% vs. 27.7%, P = 0.07). However, these results did not meet statistical significance due to poor accrual and early trial closure. A metaanalysis inclusive of 24 trials and 4188 patients focusing on survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable esophageal carcinoma provided strong evidence for survival benefit of multimodality therapy versus surgery alone.69 The results of this metaanalysis also suggested a reduction in mortality with trimodality therapy compared to induction chemotherapy, although this did not meet statistical significance (HR, 0.88; 95% CI, 0.76–1.01; P = 0.07). Some authors have debated the value of surgery after bimodality therapy. Murphy and colleagues subsequently showed that surgical resection and tumor differentiation were the only independent predictors of survival in a retrospective analysis.70

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Clearly, impeccable perioperative outcomes are necessary to demonstrate oncologic benefit of surgical therapy. Hence, one strategy is to use esophageal resection selectively, only in the setting of disease persistence or recurrence after definitive chemoradiation. This treatment paradigm was the focus of the RTOG 0246 phase 2 trial by Swisher and colleagues.71 The study was designed to detect improvement in 1-year survival in patients undergoing selective or salvage esophagectomy. More than 70% of enrolled patients had T3 or N1 disease stage. Forty-one patients were included in the analysis and underwent chemoradiation. Subsequently, 21 (51%) underwent salvage esophagectomy because of residual or recurrent disease; one patient requested resection. Patients with complete clinical response after definitive chemoradiation had overall survival of 53%, with clinical incomplete response of 33% and clinical incomplete response salvaged by surgery of 41%. The estimated one-year survival was 71% and the study failed to achieve the prespecified 77.5% survival at one year. However, more recent studies suggest that salvage esophagectomy may confer survival that approaches planned trimodality therapy, albeit with higher postoperative morbidity and mortality.72 Differences in outcomes appear to exist for whether salvage surgery is undertaken for persistent versus recurrent disease, likely reflecting tumor biology. The role of salvage esophagectomy after definitive chemoradiation may be a potentially feasible treatment strategy and prospective studies are needed to identity patients best suited for this approach. 

Surveillance Patients who have received definitive chemoradiation therapy (bimodality therapy) for esophageal cancer continue to suffer from the fear that the disease may reappear again either as locoregional or distant metastatic recurrence. The purpose behind the periodic surveillance of patients who completed definitive bimodality therapy is to potentially implement salvage therapy for locoregional failure. High-level evidence-based surveillance algorithms are not available. However, per NCCN guidelines and expert opinion, providers should consider observing patients every three to six months with clinical examination, endoscopy studies, and a variety of imaging studies (CT chest/abdomen ± PET).31 This strategy is often costly and anxiety-provoking for patients, and it may not change the ultimate outcome for the patient. Considering the fact that more than 98% of local recurrences occur in the first 36 months, most authors suggest vigilant surveillance during this time after bimodality therapy to potentially catch recurrences early enough to render salvage surgery a feasible strategy. 

Palliative Options for Esophageal Cancer Patients with poor performance status or distant metastatic disease at the time of diagnosis are not candidates for aggressive locoregional therapy. The goal of treatment in these circumstances is either to palliate existing symptoms or potentially to avoid future complications related to the disease extent. Metastatic esophageal carcinoma may be manifested with a variety of symptoms, depending on the disease spread; however, dysphagia, odynophagia, chest pain, fatigue, and weight loss are likely to be among the most common symptoms. Palliative treatment is always individualized on the basis of a patient’s physiologic status, symptoms, disease extent, and wishes. Options for palliation range from best supportive care for symptom control to the use of chemotherapy or radiation, esophageal stent

placement, and enteral nutrition support. With advancements in image-guided percutaneous and endoscopic procedures, surgical procedures for palliation of esophageal carcinoma have become exceedingly rare. Recently, immunotherapy in the form of checkpoint inhibitors has been used in patients with advanced esophageal carcinoma and demonstrated promising results.73 Further investigational use of immunotherapy is ongoing and may represent a novel treatment approach in patients with metastatic disease. 

SUMMARY Multimodality therapy using a combination of neoadjuvant chemotherapy typically with concurrent radiation followed by surgery is presently regarded as the standard of care for either locally advanced esophageal adenocarcinoma or SCC. Whereas some patients benefit from this aggressive locoregional treatment strategy, many patients continue to develop distant metastatic disease, which is presently incurable. As the search for molecular predictors and targeted therapies for this cancer continues, we will have to rigorously test novel agents to determine their places in the therapeutic armamentarium. Standardized perioperative care in well-designed clinical trials will be imperative so the potential therapeutic benefit of surgery is not offset by unacceptably high perioperative mortality rates. Minimally invasive and hybrid approaches to esophagectomy may further mitigate perioperative risk while preserving the oncologic benefits of surgical resection. The heterogeneity of esophageal cancer will require novel treatment strategies to personalize and improve upon treatment outcomes for future patients.

ANNOTATED REFERENCES Gu Y, Swisher SG, Ajani JA, et al. The number of lymph nodes with metastasis predicts survival in patients with esophageal cancer or esophagogastric junction adenocarcinoma who receive preoperative chemoradiotherapy. Cancer. 2006;106:1017–1025. This paper discusses the notion that, in addition to location and response to neoadjuvant therapy, the number of lymph nodes may be one of the most significant predictors of outcome.

Hulscher JB, van Sandick JW, de Boer AG, et al. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med. 2002;347:1662–1669. This randomized trial evaluated two different approaches for esophagectomy and demonstrated: (1) less morbidity with a transhiatal approach and (2) a trend towards improved longterm survival in the transthoracic group with en-bloc lymphadenectomy.

Kahrilas PJ, Bredenoord AJ, Fox M, et al. The Chicago classification of esophageal motility disorders, v3.0. Neurogastroenterol Motil. 2015;27:160–174. The Chicago classification has provided a framework to understand and categorize esophageal motility disorders through the use of precise definitions involving high-resolution manometry.

CHAPTER 42  Esophagus Orringer MB, Sloan H. Esophagectomy without thoracotomy. J Thorac Cardiovasc Surg. 2002;76:643–654. This landmark paper was the first to describe the transhiatal esophagectomy and to document the outcomes in detail.

Park W, Vaezi MF. Cause and pathogenesis of achalasia: the current understanding. Am J Gastroenterol. 2006;101:202–203. This concise review of achalasia gives a thorough overview of the evolution of the cause and pathogenesis of this disease.

Shaheen NJ, Sharma P, Overholt BF, et al. Radiofrequency ablation in Barrett’s esophagus with dysplasia. N Engl J Med. 2009;360:2277–2288. This randomized trial demonstrated that endoscopic ablation of dysplastic Barrett esophagus not only could eradicate intestinal metaplasia, but also could significantly reduce the likelihood of disease progression and subsequent invasive cancer from developing.

van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366:2074–2084. This landmark randomized controlled study (Chemoradiotherapy for Oesophageal Cancer Following Surgical Study [CROSS] trial) is one of the most cited papers demonstrating a significant survival benefit from induction chemoradiotherapy prior to surgical resection.

Yammamoto S, Kawahara K, Maekawa T. Minimally invasive esophagectomy for stage I and II esophageal cancer. Ann Thorac Surg. 2005;80:2070–2075. This is one of the largest series of esophageal cancer patients undergoing a minimally invasive procedure to treat early-stage disease. It has become an important study, suggesting that minimally invasive surgery may be a viable option in these patients.

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SECTION IX  Esophagus

23. Deng HY, Ni PZ, Wang YC, et  al. Neuroendocrine carcinoma of the esophagus: clinical characteristics and prognostic evaluation of 49 cases with surgical resection. J Thorac Dis. 2016;8:1250–1256. 24. Mege D, Depypere L, Piessen G, et al. Surgical management of esophageal sarcoma: a multicenter European experience. Dis Esophagus. 2018;31:dox146. 25. Winant AJ, Gollub MJ, Shia J, et al. Imaging and clinicopathologic features of esophageal gastrointestinal stromal tumors. AJR Am J Roentgenol. 2014;203:306–314. 26. Lott S, Schmieder M, Mayer B, et al. Gastrointestinal stromal tumors of the esophagus: evaluation of a pooled case series regarding clinicopathological features and clinical outcome. Am J Cancer Res. 2015;5:333–343. 27. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424. 28. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7–34. 29. Pohl H, Welch HG. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. J Natl Cancer Inst. 2005;97:142–146. 30. Islami F, DeSantis CE, Jemal A. Incidence trends of esophageal and gastric cancer subtypes by race, ethnicity, and age in the United States, 1997-2014. Clin Gastroenterol Hepatol. 2018. 31. Esophageal and Esophagogastric Junction Cancers - Version 2.2018. National Comprehensive Cancer Network - Clinical Practice Guidelines in Oncology; 2018. www.nccn.org. Accessed December, 2018. 32. Rice TW, Ishwaran H, Ferguson MK, et  al. Cancer of the esophagus and esophagogastric junction: an eighth edition staging primer. J Thorac Oncol. 2017;12:36–42. 33. Dhupar R, Rice RD, Correa AM, et al. Endoscopic ultrasound estimates for tumor depth at the gastroesophageal junction are inaccurate: implications for the liberal use of endoscopic resection. Ann Thorac Surg. 2015;100:1812–1816. 34. Hvid-Jensen F, Pedersen L, Drewes AM, et  al. Incidence of adenocarcinoma among patients with Barrett’s esophagus. N Engl J Med. 2011;365:1375–1383. 35. de Jonge PJ, van Blankenstein M, Looman CW, et al. Risk of malignant progression in patients with Barrett’s oesophagus: a dutch nationwide cohort study. Gut. 2010;59:1030–1036. 36. Song J, Zhang J, Wang J, et al. Meta-analysis of the effects of endoscopy with narrow band imaging in detecting dysplasia in Barrett’s esophagus. Dis Esophagus. 2015;28:560–566. 37. Canto MI, Anandasabapathy S, Brugge W, et al. In vivo endomicroscopy improves detection of Barrett’s esophagus-related neoplasia: a multicenter international randomized controlled trial (with video). Gastrointest Endosc. 2014;79:211–221. 38. Shaheen NJ, Sharma P, Overholt BF, et al. Radiofrequency ablation in Barrett’s esophagus with dysplasia. N Engl J Med. 2009;360:2277–2288. 39. Phoa KN, van Vilsteren FG, Weusten BL, et al. Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized clinical trial. JAMA. 2014;311:1209–1217. 40. Wolf WA, Pasricha S, Cotton C, et al. Incidence of esophageal adenocarcinoma and causes of mortality after radiofrequency ablation of Barrett’s esophagus. Gastroenterology. 2015;149:1752–1761. e1751.

41. Ghorbani S, Tsai FC, Greenwald BD, et  al. Safety and efficacy of endoscopic spray cryotherapy for Barrett’s dysplasia: results of the National Cryospray Registry. Dis Esophagus. 2016;29:241–247. 42. Ramay FH, Cui Q, Greenwald BD. Outcomes after liquid nitrogen spray cryotherapy in Barrett’s esophagus-associated high-grade dysplasia and intramucosal adenocarcinoma: 5-year follow-up. Gastrointest Endosc. 2017;86:626–632. 43. Pech O, May A, Manner H, et al. Long-term efficacy and safety of endoscopic resection for patients with mucosal adenocarcinoma of the esophagus. Gastroenterology. 2014;146:652–660. e651. 44. Lee L, Ronellenfitsch U, Hofstetter WL, et al. Predicting lymph node metastases in early esophageal adenocarcinoma using a simple scoring system. J Am Coll Surg. 2013;217:191–199. 45. Manner H, Wetzka J, May A, et  al. Early-stage adenocarcinoma of the esophagus with mid to deep submucosal invasion (pT1b sm2-3): the frequency of lymph-node metastasis depends on macroscopic and histological risk patterns. Dis Esophagus. 2017;30:1–11. 46. Gockel I, Sgourakis G, Lyros O, et  al. Risk of lymph node metastasis in submucosal esophageal cancer: a review of surgically resected patients. Expert Rev Gastroenterol Hepatol. 2011;5:371–384. 47. Bahin FF, Jayanna M, Hourigan LF, et  al. Long-term outcomes of a primary complete endoscopic resection strategy for short-segment Barrett’s esophagus with high-grade dysplasia and/or early esophageal adenocarcinoma. Gastrointest Endosc. 2016;83:68–77. 48. Hirasawa K, Kokawa A, Oka H, et al. Superficial adenocarcinoma of the esophagogastric junction: long-term results of endoscopic submucosal dissection. Gastrointest Endosc. 2010;72:960–966. 49. Crabtree TD, Kosinski AS, Puri V, et al. Evaluation of the reliability of clinical staging of T2 N0 esophageal cancer: a review of the society of thoracic surgeons database. Ann Thorac Surg. 2013;96:382–390. 50. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366:2074–2084. 51. Speicher PJ, Ganapathi AM, Englum BR, et  al. Induction therapy does not improve survival for clinical stage T2N0 esophageal cancer. J Thorac Oncol. 2014;9:1195–1201. 52. Semenkovich TR, Panni RZ, Hudson JL, et al. Comparative effectiveness of upfront esophagectomy versus induction chemoradiation in clinical stage T2N0 esophageal cancer: a decision analysis. J Thorac Cardiovasc Surg. 2018;155:2221– 2230. e2221. 53. Hulscher JB, van Sandick JW, de Boer AG, et al. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med. 2002;347:1662–1669. 54. Peyre CG, Hagen JA, DeMeester SR, et  al. The number of lymph nodes removed predicts survival in esophageal cancer: an international study on the impact of extent of surgical resection. Ann Surg. 2008;248:549–556. 55. Yerokun BA, Sun Z, Yang CJ, et al. Minimally invasive versus open esophagectomy for esophageal cancer: a populationbased analysis. Ann Thorac Surg. 2016;102:416–423. 56. Mariette C, Markar SR, Dabakuyo-Yonli TS, et  al. Hybrid minimally invasive esophagectomy for esophageal cancer. N Engl J Med. 2019;380:152–162.

CHAPTER 42  Esophagus 57. Raymond DP, Seder CW, Wright CD, et  al. Predictors of major morbidity or mortality after resection for esophageal cancer: a society of thoracic surgeons general thoracic surgery database risk adjustment model. Ann Thorac Surg. 2016;102:207–214. 58. Shewale JB, Correa AM, Baker CM, et al. Impact of a fast-track esophagectomy protocol on esophageal cancer patient outcomes and hospital charges. Ann Surg. 2015;261:1114–1123. 59. Anderegg MC, Lagarde SM, Jagadesham VP, et al. Prognostic significance of the location of lymph node metastases in patients with adenocarcinoma of the distal esophagus or gastroesophageal junction. Ann Surg. 2016;264:847–853. 60. Cools-Lartigue J, Spicer J, Ferri LE. Current status of management of malignant disease: current management of esophageal cancer. J Gastrointest Surg. 2015;19:964–972. 61. Roth JA, Pass HI, Flanagan MM, et al. Randomized clinical trial of preoperative and postoperative adjuvant chemotherapy with cisplatin, vindesine, and bleomycin for carcinoma of the esophagus. J Thorac Cardiovasc Surg. 1988;96:242–248. 62. Medical Research Council Oesophageal Cancer Working G. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet. 2002;359:1727–1733. 63. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355:11–20. 64. Ando N, Kato H, Igaki H, et al. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol. 2012;19:68–74. 65. Minsky BD, Pajak TF, Ginsberg RJ, et  al. INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: highdose versus standard-dose radiation therapy. J Clin Oncol. 2002;20:1167–1174.

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66. Shapiro J, van Lanschot JJB, Hulshof M, et al. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol. 2015;16:1090–1098. 67. Davies AR, Gossage JA, Zylstra J, et al. Tumor stage after neoadjuvant chemotherapy determines survival after surgery for adenocarcinoma of the esophagus and esophagogastric junction. J Clin Oncol. 2014;32:2983–2990. 68. Stahl M, Stuschke M, Lehmann N, et  al. Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol. 2005;23:2310–2317. 69. Sjoquist KM, Burmeister BH, Smithers BM, et  al. Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol. 2011;12:681–692. 70. Murphy CC, Correa AM, Ajani JA, et al. Surgery is an essential component of multimodality therapy for patients with locally advanced esophageal adenocarcinoma. J Gastrointest Surg. 2013;17:1359–1369. 71. Swisher SG, Winter KA, Komaki RU, et al. A phase II study of a paclitaxel-based chemoradiation regimen with selective surgical salvage for resectable locoregionally advanced esophageal cancer: initial reporting of RTOG 0246. Int J Radiat Oncol Biol Phys. 2012;82:1967–1972. 72. Markar S, Gronnier C, Duhamel A, et  al. Salvage surgery after chemoradiotherapy in the management of esophageal cancer: is it a viable therapeutic option? J Clin Oncol. 2015;33:3866–3873. 73. Shah MA, Kojima T, Hochhauser D, et  al. Efficacy and safety of pembrolizumab for heavily pretreated patients with advanced, metastatic adenocarcinoma or squamous cell carcinoma of the esophagus: the Phase 2 KEYNOTE-180 Study. JAMA Oncol. 2018.

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CHAPTER

Gastroesophageal Reflux Disease and Hiatal Hernia Robert B. Yates, Brant K. Oelschlager

OUTLINE Gastroesophageal Reflux Disease Pathophysiology Clinical Presentation Preoperative Diagnostic Testing Additional Preoperative Considerations Treatment of GERD Alternative Operative Therapies for GERD

Paraesophageal Hernia Pathophysiology Clinical Presentation Preoperative Evaluation Operative Repair Acute Gastric Volvulus Summary

Please access Elsevier eBooks for Practicing Clinicians to view the videos for this chapter https://expertconsult.inkling.com/.

assisted laparoscopic surgery and the use of magnetic sphincter augmentation devices (MSADs) at the lower esophageal sphincter (LES). These options hold promise for further advancement of the care of patients with these conditions; however, they do not supplant the need for comprehensive understanding of these disease processes, perioperative patient management, and technical expertise in operative correction of these conditions.

Gastroesophageal reflux disease (GERD) is the most common benign medical condition of the stomach and esophagus. In patients with GERD who experience persistent life-limiting symptoms despite maximal medical therapy, antireflux surgery should be strongly considered. The application of laparoscopy to antireflux surgery has decreased perioperative morbidity, hospital length of stay, and cost compared with open operations. Conceptually, laparoscopic antireflux surgery (LARS) is straightforward; however, the correct construction of a fundoplication requires significant operative experience and skills in complex laparoscopy. In patients who present with late complications of antireflux surgery, including recurrent GERD and dysphagia, reoperative antireflux surgery can be effectively performed. Compared with first-time operations, however, reoperative antireflux surgery is technically more challenging, is associated with higher risk of perioperative complications, and results in less durable symptom improvement. Consequently, surgeons should have a higher threshold for performing reoperative antireflux surgery, and reoperations should be performed by experienced, high-volume gastroesophageal surgeons. To decrease perioperative risk and to maximize long-term relief of GERD symptoms, surgeons must be familiar with all aspects of preoperative evaluation and operative management of patients with GERD. Hernias at the esophageal hiatus span the spectrum from a small sliding hiatal hernia to a large paraesophageal hernia (PEH). Similarly, the symptoms of PEH can vary from mild GERD and gastroesophageal obstructive symptoms to severe, acute complications, including gastric volvulus, which requires immediate evaluation by a surgeon. The repair of a large PEH is challenging, but when it is performed at high-volume centers by experienced surgeons, hiatal hernia and PEH can be repaired safely and provide patients with long-lasting control of gastroesophageal symptoms. Technologic advancements in the surgical management of benign gastroesophageal disease include the application of robotic

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GASTROESOPHAGEAL REFLUX DISEASE Pathophysiology Endogenous antireflux mechanisms include the LES and spontaneous esophageal clearance. GERD results from the failure of these endogenous antireflux mechanisms. The LES has the primary role of preventing reflux of gastric contents into the esophagus. Rather than a distinct anatomic structure, the LES is a zone of high pressure located in the lower end of the esophagus. The LES can be identified with esophageal manometry. The LES is made up of four anatomic structures: 1. The intrinsic musculature of the distal esophagus is in a state of tonic contraction. Within 500 milliseconds of the initiation of a swallow, these muscle fibers relax to allow passage of liquid or food into the stomach, and then they return to a state of tonic contraction. 2. Sling fibers of the gastric cardia are oriented diagonally from the cardia-fundus junction to the lesser curve of the stomach. Located at the same anatomic depth as the circular muscle fibers of the esophagus, the sling fibers contribute significantly to the high-pressure zone of the LES (Fig. 43.1). 3. The crura of the diaphragm surround the esophagus as it passes through the esophageal hiatus. During inspiration, intrathoracic pressure decreases relative to intra abdominal pressure, favoring the movement of intra abdominal gastric contents into the esophagus located in the posterior mediastinum of the thorax. To counteract this pressure differential during inspiration,

CHAPTER 43  Gastroesophageal Reflux Disease and Hiatal Hernia

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Phrenoesophageal ligament Peritoneum (reflected)

Diaphragm Outer longitudinal muscle Anterior vagal trunk Inner circular muscle

A

GE junction

C

GE junction

B

GE junction

Sling fibers

FIG. 43.1  Schematic drawing of the muscle layers at the gastroesophageal junction. The intrinsic muscle of the esophagus, diaphragm, and sling fibers contribute to lower esophageal sphincter pressure. The circular muscle fibers of the esophagus are at the same depth as the sling fibers of the cardia.

the anteroposterior diameter of the crural opening is decreased, compressing the esophagus and increasing the measured pressure at the LES. Because of this fluctuation in LES pressure, it is important to measure the LES pressure at mid-expiration or end-expiration. 4. When the gastroesophageal junction (GEJ) is firmly anchored in the abdominal cavity, increased intra abdominal pressure is transmitted to the GEJ, which increases the pressure on the distal esophagus and prevents spontaneous reflux of gastric contents. Gastroesophageal reflux (GER) occurs when intragastric pressure is greater than the high-pressure zone of the distal esophagus. This can develop under two conditions: the LES resting pressure is too low (i.e., hypotensive LES) and the LES with normal resting pressure inappropriately relaxes in the absence of peristaltic contraction of the esophagus (i.e., spontaneous LES relaxation). Hypotensive LES is frequently associated with hiatal hernia because of displacement of the GEJ into the posterior mediastinum. However, hypotensive LES can occur in its normal anatomic position, and even small changes in this high-pressure zone can compromise its effectiveness. Not all GER is pathologic—in fact, it is a normal physiologic process that occurs even in the setting of a normal LES. Physiologic GER provides us the ability to rapidly evacuate swallowed air from the stomach that would otherwise cause unwanted bloating and flatus. The distinction between physiologic reflux (i.e., GER) and pathologic reflux (i.e., GERD) hinges on the total amount of esophageal acid exposure, the patient’s symptoms, and the presence of mucosal damage of the esophagus. Hiatal hernias are often associated with GERD because their abnormal anatomy compromises the efficacy of the LES. Hiatal hernias are classified into four types (I to IV). Type I hiatal hernia (Fig. 43.2A), also called a sliding hiatal hernia, is the most common. A type I hernia is present when the GEJ migrates cephalad into the posterior mediastinum. This occurs because of laxity of the phrenoesophageal membrane, a continuation of the

FIG. 43.2  The three types of hiatal hernia. (A) Type I is also called a sliding hernia. (B) Type II is known as a rolling hernia. (C) Type III is referred to as a mixed hernia. GE, Gastroesophageal.

endoabdominal peritoneum that reflects onto the esophagus at the hiatus (Fig. 43.3). A small sliding hernia does not necessarily imply an incompetent LES, but the larger its size, the greater the risk for abnormal GER. Furthermore, the presence of a type I sliding hiatal hernia alone does not constitute an indication for operative repair. In fact, many patients with small type I hiatal hernias do not have symptoms and do not require treatment. Hiatal hernia types II to IV, also referred to as PEH, are frequently associated with gastroesophageal obstructive symptoms (e.g., dysphagia, early satiety, and epigastric pain). However, they can also be associated with GERD. A type II hernia (Fig. 43.2B) occurs when the GEJ is anchored in the abdomen, and the gastric fundus migrates into the mediastinum through the hiatal defect. A type III hernia (Fig. 43.2C) is characterized by both the GEJ and fundus located in the mediastinum. Finally, a type IV hernia occurs when the stomach and any other visceral structure (e.g., colon, spleen, pancreas, or small bowel) migrates cephalad to the esophageal hiatus and into the mediastinum. For more information on PEH, refer to the last section of this chapter. 

Clinical Presentation Typica Symptoms of GERD The prevalence of symptoms among 1000 patients with GERD is presented in Table 43.1. Heartburn, regurgitation, and water brash are the three typical esophageal symptoms of GERD. Heartburn and regurgitation are the most common presenting symptoms. Heartburn is specific to GERD and described as an epigastric or retrosternal caustic or stinging sensation. Typically, it does not radiate to the back and is not described as a pressure sensation, which are more characteristic of pancreatitis and acute coronary syndrome, respectively. It is important to ask the patient about

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SECTION IX  Esophagus Phrenoesophageal ligament upper and lower limbs Thoracic aorta

Diaphragm Subhiatal fat ring Peritoneum

Liver

GE junction

FIG. 43.3  Section of the gastroesophageal (GE) junction demonstrates the relationship of the peritoneum to the phrenoesophageal membrane. The phrenoesophageal membrane continues as a separate structure into the posterior mediastinum. The parietal peritoneum continues as the visceral peritoneum as it reflects onto the stomach.

TABLE 43.1  Prevalence of symptoms

occurring more frequently than once per week in 1000 patients with gastroesophageal reflux disease. SYMPTOM Heartburn Regurgitation Abdominal pain Cough Dysphagia for solids Hoarseness Belching Bloating Aspiration Wheezing Globus

PREVALENCE (%) 80 54 29 27 23 21 15 15 14 7 4

his or her symptoms in detail to differentiate typical heartburn from symptoms of peptic ulcer disease, cholelithiasis, or coronary artery disease. The presence of regurgitation often indicates progression of GERD. In severe cases, patients will be unable to bend over or lie supine without experiencing an episode of regurgitation. Regurgitation of gastric contents to the oropharynx and mouth can produce a sour taste that patients will describe as either acid or bile. This phenomenon is referred to as water brash. In patients who report regurgitation as a frequent symptom, it is important to distinguish between regurgitation of undigested food and regurgitation of digested food. Regurgitation of undigested food is not common in GERD and suggests the presence of a different pathologic process, such as an esophageal diverticulum or achalasia.  Extraesophageal Symptoms of GERD Extraesophageal symptoms of GERD arise from the respiratory tract and include both laryngeal and pulmonary symptoms (Box 43.1). Two mechanisms may lead to extraesophageal symptoms of

BOX 43.1  Extraesophageal symptoms of

gastroesophageal reflux disease. Laryngeal Symptoms of Reflux Hoarseness or dysphonia Throat clearing Throat pain Globus Choking Postnasal drip Laryngeal and tracheal stenosis Laryngospasm Contact ulcers 

Pulmonary Symptoms of Reflux Cough Shortness of breath Wheezing Pulmonary disease (asthma, idiopathic pulmonary fibrosis, chronic bronchitis, and others)

GERD. First, proximal esophageal reflux and microaspiration of gastroduodenal contents cause direct caustic injury to the larynx and lower respiratory tract; this is the most common mechanism. Second, distal esophageal acid exposure triggers a vagal nerve reflex that results in bronchospasm and cough. The latter mechanism is due to the common vagal innervation of the trachea and esophagus. Unlike typical GERD symptoms (i.e., heartburn and regurgitation), extraesophageal symptoms of reflux are not specific to GERD. Before LARS is considered for a patient with primarily extraesophageal symptoms, it is necessary to determine whether those symptoms are due to abnormal GER or a primary laryngeal, bronchial, or pulmonary cause. This can be challenging. A lack of response of extraesophageal symptoms to proton pump inhibitor (PPI) therapy cannot reliably refute GERD as the cause of these symptoms.

CHAPTER 43  Gastroesophageal Reflux Disease and Hiatal Hernia Although PPI therapy can improve or completely resolve typical GERD symptoms, patients with extraesophageal symptoms experience variable response to medical treatment. This may be explained by recent evidence suggesting that acid is not the only underlying caustic agent resulting in laryngeal and pulmonary injury.1 PPI therapy will suppress gastric acid production, but microaspiration of nonacid refluxate, which contains caustic bile salts and pepsin, can cause ongoing injury and symptoms. Therefore, in patients with extraesophageal symptoms of GERD, a mechanical barrier to reflux (i.e., esophagogastric fundoplication) may be necessary to prevent ongoing laryngeal, tracheal, or bronchial injury. In patients who present with abnormal GER and bothersome extraesophageal symptoms, a thorough evaluation must be completed to rule out a primary disorder of the upper or lower respiratory tract. This should be completed whether or not typical GERD symptoms are also present. At the University of Washington Center for Esophageal and Gastric Surgery, we frequently refer patients with GERD and extraesophageal symptoms to a laryngologist or a pulmonologist to determine if a nongastrointestinal condition is causing these symptoms. If a nonreflux cause of the extraesophageal symptoms cannot be identified, then proceeding with an antireflux operation is acceptable. We counsel these patients a 70% likelihood of improvement in extraesophageal symptoms after LARS.2 If a patient’s laryngeal or pulmonary symptoms are not due to abnormal GER, an antireflux operation is not performed.  Pulmonary Disease, GERD, and Antireflux Surgery Increasing evidence suggests that GERD is a contributing factor to the pathophysiologic mechanism of several pulmonary diseases. In their extensive review, Bowrey and colleagues3 examined medical and surgical antireflux therapy in patients with GERD and asthma. In these patients, the use of antisecretory medications is associated with improved respiratory symptoms in only 25% to 50% of patients with GERD-induced asthma. Furthermore, less than 15% of these patients experience objective improvement in pulmonary function. One explanation for these results is that most of these studies lasted 3 months or less, which is potentially too short to see any improvement in pulmonary function. In addition, in several trials, gastric acid secretion was incompletely blocked by acid suppression therapy, and patients experienced ongoing GERD. In patients with asthma and GERD, antireflux surgery appears to be more effective than medical therapy at managing pulmonary symptoms. Antireflux surgery is associated with improvement in respiratory symptoms in nearly 90% of children and 70% of adults with asthma and GERD. Several randomized trials have compared histamine 2 receptor antagonists and antireflux surgery in the management of GERD-associated asthma. Compared with patients treated with antisecretory medications, patients treated with antireflux surgery were more likely to experience relief of asthma symptoms, to discontinue systemic steroid therapy, and to improve peak expiratory flow rate. Idiopathic pulmonary fibrosis (IPF) is a severe, chronic, and progressive lung disease that generally results in death within 5 years of diagnosis. Proximal esophageal reflux with microaspiration of acid and nonacid gastric contents has been implicated as one possible cause of alveolar epithelial injury that can lead to IPF. The incidence of GERD in patients with IPF has been reported to be as high as 94%.4 Because typical symptoms of GERD are not sensitive for abnormal reflux in patients with IPF, the threshold for testing patients with IPF for GERD should be low.

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Medical treatment of GERD in patients with IPF is associated with longer survival and slower pulmonary decline.5 Whereas this is promising, PPI therapy does not prevent reflux of nonacid gastroduodenal contents, which may contribute to ongoing pulmonary injury in some patients. Therefore, in IPF patients with significant GERD, the argument can be made that a mechanical barrier to both acid and nonacid reflux (i.e., LARS) is more appropriate than PPI therapy. Although very little literature exists on LARS in patients with IPF, it appears to be safe and to provide effective control of distal esophageal acid exposure, and it may mitigate decline in pulmonary function.6 Laparoscopic antireflux surgery for the treatment of idiopathic pulmonary fibrosis (WRAP-IPF) is a multicenter controlled phase 2 trial and the only randomized study comparing LARS to PPI therapy in patients with IPF and GERD confirmed by 24-hour pH probe.7 Of 72 eligible patients, 58 were equally randomized into surgery and no surgery groups (29 each group). The primary endpoint was change in forced vital capacity (FVC) at 48 weeks of treatment. Even in this patient population with severe systemic disease, LARS was deemed generally safe and well tolerated. Intention-totreat analysis failed to show a difference between the two groups for FVC at 48 weeks (P = 0.28), which was the primary endpoint. However, a more nuanced analysis of the data is necessary. The surgery group had one death and the no surgery group had four deaths, and all deaths were preceded by acute IPF exacerbation. The specified statistical analytic method assumes that any missing data (those from patients who died during the trial) is random. However, given that these deaths appeared directly due to progression of the underlying pulmonary disease, this missing data did not appear random. Consequently, a post hoc analysis was performed using an approach to this data (Lachin’s worst-rank analysis) that assumes missing data are not random and may be informative to the outcome of the study. Performing the analysis with this approach revealed a significant difference in FVC decline (P = 0.017) that favored the LARS group. Furthermore, the surgery group showed less pulmonary disease progression as measured by 10% FVC decline, acute exacerbation, or death (P = 0.048). Taken together, these results suggest that LARS may still play an important role in the mitigation of pulmonary decline in IPF patients with GERD. The failure to show a statistically significant difference in the intention to treat analysis may have resulted from an underpowered study, inappropriate choice of statistical analytic tool, or placing too much emphasis on decline of FVC. Future efforts to elucidate the role of LARS in IPF should take these considerations into account during study design and analysis.  Physical Examination Except in patients with severely advanced disease, the physical examination rarely contributes to confirmation of the diagnosis of GERD. In such patients, several observations may suggest the presence of GERD. For example, a patient who constantly drinks water during the interview may be facilitating esophageal clearance, which can suggest frequent reflux. Other patients with advanced disease will sit leaning forward and carry out the interview with their lungs inflated to almost vital capacity. This maneuver flattens the diaphragm, narrows the anteroposterior diameter of the hiatus, and increases the LES pressure to counteract GER. Patients who have severe proximal esophageal reflux and regurgitation of gastric contents into the mouth may develop erosion of their dentition (revealing yellow teeth caused by the loss of dentin), injected oropharyngeal mucosa, or signs of chronic sinusitis. Although physical examination findings are generally not specific for GERD, the physical examination may be helpful in

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determining the presence of other disease processes. For example, supraclavicular lymphadenopathy in a patient with heartburn and dysphagia may suggest esophageal or gastric cancer. Similarly, if the patient’s retrosternal pain is reproducible with palpation, a musculoskeletal source of the pain should be investigated. Short of these extreme presentations, the physical examination is generally not helpful in confirming or excluding GER as a pathologic entity. 

rn

SECTION IX  Esophagus

H ea

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8 1: pH Pharynx

Preoperative Diagnostic Testing Frequently, the diagnosis of GERD is based on the presence of typical symptoms and improvement in those symptoms with PPI therapy. However, when a surgeon evaluates a patient for antireflux surgery, four diagnostic tests are useful to establish the diagnosis of GERD and to identify abnormalities in gastroesophageal anatomy and function that may have an impact on the performance of LARS. Ambulatory pH and Impedance Monitoring Ambulatory pH monitoring quantifies distal esophageal acid exposure and is the “gold standard” test to diagnose GERD. A 24-hour pH monitoring is conducted with a thin catheter that is passed into the esophagus through the patient’s nares. The simplest catheter is a dual-probe pH catheter, which contains two solidstate electrodes that are spaced 10 cm apart and detect fluctuations in pH between 2 and 7. To ensure valid study results, the distal electrode must be placed 5 cm proximal to the LES; the location of the LES is identified on esophageal manometry (see next section). Alternatively, 48-hour ambulatory pH monitoring can be performed using an endoscopically placed wireless pH monitor. Ambulatory pH monitoring generates a large amount of data concerning esophageal acid exposure, including total number of reflux episodes (pH MRI US > MRI > CT US > MRI > CT Plain films > CT US > MRI > CT US > MRI > CT MRI > CT US > MRI MRI > CT US > CT> MRI

Adapted from Baheti AD, Nicola R, Bennett GL, et al. Magnetic resonance imaging of abdominal and pelvic pain in the pregnant patient. Magn Reson Imaging Clin N Am. 2016;24:403–417. CT, Computed tomography; MRI, magnetic resonance imaging; US, ultrasound.

a full stomach whenever intubation is planned.28 Intraoperative care during pregnancy is focused on optimal care of the mother. If the fetus is previable, fetal heart tones should be measured before and after the surgery. If the fetus is viable, fetal heart tones should be measured throughout the surgery with a provider capable of performing an intervention available. The safety of laparoscopic surgery in pregnancy has been extensively studied and established. Laparoscopy allows for decreased manipulation of the uterus, and as a result, less uterine irritability with lower risk of contractions, spontaneous abortions, preterm labor, and premature delivery.30 In order to safely enter the abdomen, the open Hassen technique is considered standard, with care to avoid injury to the enlarging uterus.31 Additional causes of acute abdomen include biliary disease, bowel obstruction, and pancreatitis, among others. Biliary disease is common, as sex steroids interfere with gallbladder emptying resulting in bile stasis.28 Ultrasound is the diagnostic test of choice. Treatment is recommended in the second trimester to avoid complications of biliary disease as the pregnancy progresses. Gallstone pancreatitis and acute cholecystitis should be managed more carefully. Gallstone pancreatitis has been associated with a fetal loss as high as 60%. If a woman does not respond quickly to conservative treatment with hydration, bowel rest, analgesia, and judicious use of antibiotics, further evaluation should be performed as surgical intervention may be indicated. Endoscopic retrograde cholangiopancreatography is considered safe and low radiation risk to the fetus, should the patient present with cholangitis or choledocholithiasis. Small bowel obstruction is often confused with the normal nausea and vomiting associated with pregnancy. It is important to remember that peritoneal signs in the presence of nausea and vomiting is never considered normal and should prompt further workup.28 Abdominal distention with colic should key the clinician to the diagnosis. 

Pediatrics Evaluating a child with an acute abdomen can be difficult for the clinician not accustomed to performing an abdominal exam in children. In contrast to performing an examination on an adult who is able to communicate with the clinician and give feedback when abdominal pain is elicited, much of the examination on a child occurs through observation. Children can be poor historians

because of their age, being afraid of the situation, and being unable to verbalize their symptoms. Clues to the extent of peritoneal irritation include a child’s willingness or unwillingness to stand or move about the hospital bed freely. Children with peritonitis will demonstrate abdominal pain with standing, jumping, or coughing.3 The abdominal exam should be performed thoughtfully and only to the extent to identify the presence of abdominal wall spasm in response to intraabdominal pathology. The most common cause of acute surgical abdomen in the pediatric population remains acute appendicitis and occurs most commonly in older children and adolescents with a presentation of anorexia, low-grade fever, and right-lower quadrant pain similar to adult patients.32 Younger children may present differently and pose a challenge to the clinician with reports from parents of a vague onset of symptoms. Their inability to characterize their pain, nonspecific signs, and difficulty in eliciting a physical exam results in imaging playing a crucial role in diagnosis. Almost all children, 99% in some reports, with appendicitis will have preoperative imaging before surgical intervention.32–34 Ultrasound often demonstrates pathologic concordance when performed in the hands of an experience ultrasonographer, especially those performed at a free-standing children’s hospital.34 Children presenting to a nonchildren’s hospital are more likely to have a CT scan diagnosis of appendicitis, despite the recommendations from multiple pediatric societies on the risks of radiation.34 Additional causes of acute abdomen are broken down by age and listed in Table 46.4. Intussusception should be considered in the differential of abdominal pain in children less than 3 years old. Gastroenteritis, Meckel diverticulitis, and C. difficile colitis are among other causes of abdominal pain, and presentation is similar to adult patients. Inconsolable crying and lethargy in small infants can be ominous. Any history of emesis in a newborn should prompt careful questioning regarding the character and timing of emesis episodes; bilious emesis is a surgical emergency and prompts urgent evaluation for midgut volvulus. A history of fever, passage of currant jelly stools, and lower gastrointestinal track bleeding should prompt further workup.35 

Critical Illness Establishing a diagnosis of an acute abdomen in the critically ill can be challenging. The clinician must navigate an environment of deep-sedation, multiple etiologies of sepsis, multiorgan failure,

CHAPTER 46  Acute Abdomen

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TABLE 46.4  Differential diagnosis of abdominal pain in children by age. < 2-YEARS OLD

2- TO 5-YEARS OLD

5- TO 12-YEARS OLD

>12-YEARS OLD

Intussusception Gastroenteritis Constipation Infantile colic Malrotation with midgut volvulus Incarcerated inguinal hernia Obstruction due to Hirschsprung disease UTI Meckel diverticulum

Intussusception Appendicitis Gastroenteritis Constipation Mesenteric adenitis Malrotation with midgut volvulus Sickle cell crisis

Appendicitis Gastroenteritis Constipation Mesenteric adenitis Functional abdominal pain Pneumonia Sickle cell crisis

Appendicitis Gastroenteritis Constipation Ovarian/testicular torsion Dysmenorrhea Pelvic inflammatory disease Ectopic pregnancy

Henoch-Schonlein purpura UTI Trauma Meckel diverticulum

Henoch-Schonlein purpura UTI Trauma

Adapted from Yang WC, Chen CY, Wu HP. Etiology of non-traumatic acute abdomen in pediatric emergency departments. World J Clin Cases. 2013;1:276–284. UTI, Urinary tract infection.

TABLE 46.5  Differential diagnosis of acute abdomen in transplant patients. LIVER37

LUNG38

HEMATOPOIETIC STEM CELL39

Biliary complications of transplant Vascular complications of transplant Small bowel obstruction Acute appendicitis Urinary tract infection Acute diverticulitis Acute pancreatitis

Gastroesophageal reflux Infectious enterocolitis Peptic ulcer disease Gastroparesis Diverticulitis Pancreatitis Gastrointestinal bleed

Acute graft versus host disease Cholangitis Neutropenic enterocolitis Infectious enterocolitis Pneumatosis

and absent or subtle clinical exam findings. Unrecognized abdominal pathology can cause patients to persist in their critical state or even progress to their demise. Critically ill patients may not be able to demonstrate the typical signs and symptoms of acute abdomen due to narcotic analgesia, blunting of the inflammatory response due to antibiotics or immunosuppression, and nutritional deficiency. Imaging is often necessary to establish a diagnosis as multiple causes for abdominal distention, sepsis, or organ failure may be at play in the intensive care unit (ICU) patient.36 Some patients, will be unstable for transport and the clinician will be challenged with the risks and benefits of obtaining advancing imaging, such as CT, versus operative exploration with the potential of a nontherapeutic laparotomy. Determining which patients are stable enough to survive an operation, potentially a nontherapeutic intervention, can be unpredictable.37 A small cohort of clinicians advocate for diagnostic laparoscopy in the ICU as a mode of both diagnosis and treatment of the acute abdomen in the critically ill patient. However, this is coupled with the difficulties of performing bedside laparoscopic surgery, the invasive nature of procedure, and the costs of the equipment and anesthesia.37 As technology continues to advance, this is an area where change is likely to occur. 

Immunocompromised Transplant patients often present to the emergency room with abdominal complaints. In one study, researchers found that 33% to 60% of transplant patients sought care in the emergency room after their procedure.38 Inflammation is necessary in the pathophysiology of abdominal pain and peritonitis, and this may

be blunted in the transplant patient. This can result in unreliable leukocytosis, delayed development of fever, and subjectively decreased abdominal symptoms. They may also present in a delayed fashion, which may be very quickly followed by overwhelming systemic collapse. As a result, although the abdominal pathology is similar to that seen in healthy adult patients, the immunosuppressed may have atypical presentations with very minimal symptoms. In one study of over 70,000 transplant patients, the incidence of emergency surgery was found to be 2.5%. The indications for surgical intervention were biliary disease (80%), gastrointestinal perforation (9%), complicated diverticulitis (6%), small bowel obstruction (2%), and appendicitis (2%). Overall mortality in this patient cohort was 5.5%.38 A differential diagnosis of abdominal pathology is listed in Table 46.5 broken down by type of transplant. Routine blood work should be performed in addition to checking serum levels of immunosuppressive drugs. These medications can cause many side effects that may cloud the presentation of acute abdomen, including loss of gastrointestinal mucosal integrity and regeneration, alterations in gastric acidity, and impaired immune response to illness. This often presents as diarrhea, abdominal pain, nausea, vomiting, and weight loss.38 Transplant patients may not mount an inflammatory response to illness, and serum markers may not be elevated despite ongoing abdominal pathology. Pseudomembranous colitis has increasingly been seen in the immunocompromised patient, independent of a recent association with broad-spectrum antibiotics. Typical presentations

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include diarrhea, abdominal pain, fever, and leukocytosis; however, this may not be seen in this patient cohort. A high index of suspicion, reliance on CT imaging and stool assays should be considered early. Cytomegalovirus infection is another important pathogen to consider in the transplant patient. The presentation can vary, including diarrhea, dysphagia, nausea, vomiting, abdominal pain, gastrointestinal bleeding, and intestinal perforation. Cytomegalovirus is diagnosed by biopsy demonstrating virus in the gastric or intestinal mucosa and is treated with antivirals. Atypical infections, including peritoneal tuberculosis, fungal infections, and endemic mycoses, can also be seen in this group. Due to the decreased inflammatory response, an abdominal infection may not present with a typically walled off abscess and CT scan imaging may not demonstrate classic findings.39 Immunosuppressed patients with suspicious abdominal pathology should have inpatient monitoring with a low threshold for operative intervention if an atypical infection that is not improving despite adequate therapy. 

Cardiac Patients

BOX 46.6  Risk factors for the

development of gastrointestinal complications after cardiothoracic surgery. • Age >70 • Low cardiac output • Peripheral vascular disease • Need for reoperation due to hemorrhage • Acute/chronic renal failure • Cardiopulmonary bypass time >150 minutes • Intraaortic balloon pump • Preoperative inotropic support • Active smoker • Chronic obstructive pulmonary disease • Prolonged ventilation • Valve surgery • Sepsis/sternal wound infections • Liver failure • Myocardial infarction

Abdominal emergencies in the cardiac patient can be easily masked by their postoperative recovery, ongoing management of their cardiac dysfunction, mechanical ventilation, arrhythmias, hemodynamic instability, and sedation.40 Risk factors are associated with the procedure performed, such as length of cardiopulmonary bypass, interventions on valvular heart disease, and need for intraaortic balloon pump. In addition, the patient’s preoperative physiology also has some effect, such as arrhythmias, hypertension, hypercholesterolemia, diabetes, renal disease, and need for preoperative inotropic support.41 Patients undergoing an open abdominal aortic aneurysm repair have the highest incidence, especially those repaired through a transabdominal approach. The highest mortality is seen in patients with intestinal ischemia and in those patients who required a valve repair.40 The pathophysiology of gastrointestinal complications is thought to be associated with disturbances in the superior mesenteric artery blood flow during cardiopulmonary bypass.42 The most common gastrointestinal diagnoses are ileus, pancreatitis, mesenteric ischemia, bowel obstruction, acute cholecystitis, and perforation.41 Risk factors for development of an abdominal complication after cardiothoracic surgery are listed in Box 46.6. 

From Buczacki SJA, Davies J. The acute abdomen in cardiac intensive care unit. In: Valchanov K, Jones N, Hogue CW, eds. Core topics in cardiothoracic critical care. 2nd ed. Cambridge: Cambridge University Press; 2018:294–300.

Morbidly Obese

may require multiple films to image the entire abdomen. CT may be limited due to weight restrictions on the examination table, although this is increasingly becoming less of an issue due to the increasing numbers of morbidly obese patients. Early laparoscopy, especially in the postoperative bariatric patient, is often used for both diagnosis and treatment. Examples of concerning CT imaging findings are listed in Box 46.7. 

The classic presentation of an acute abdomen is not a reliable indicator of intraabdominal pathology in the morbidly obese. The presentation is often subtle, leading to rapid progression to sepsis, organ failure, and death.42 In contrast to normal weight patients, the morbidly obese can mask the signs of peritonitis, even in the setting of abdominal catastrophes, such as anastomotic leaks, until very late in the disease process, leading to a high incidence of complications and increased mortality.42 Physical examination findings are difficult to interpret. Abdominal sepsis may only be associated with malaise, shoulder pain, hiccups, and shortness of breath.43 Severe abdominal pain is uncommon. Appreciation of abdominal distention or a mass is difficult because of their increased abdominal girth. The presence of anorexia is also highly unpredictable, and their reported symptoms or abdominal complaints can be exceedingly vague. With an unreliable physical exam, clinicians must rely on laboratory exams, tachycardia, x-ray imaging findings, and subtle clinical symptoms to make the diagnosis of an abdominal problem.42 Abdominal x-rays have reduced clarity and

BOX 46.7  Concerning CT imaging findings

in the postbariatric surgery patient. • Dilated alimentary limb • Dilated excluded stomach • Dilated biliopancreatic limb • Transition between dilated and nondilated bowel • Mesenteric swirl sign • Cluster of small bowel loops • Horizontal position of the superior mesenteric artery

From Karila-Cohen P, Cuccioli F, Tammaro P, et al. Contribution of computed tomographic imaging to the management of acute abdominal pain after gastric bypass: correlation between radiological and surgical findings. Obes Surg. 2017;27:1961–1972. CT, Computed tomography.

Elderly The diagnosis of an acute abdomen in the elderly patient is no different from that of the adult patient. This patient population, however, is unique in that they often suffer from delay in surgical treatment as a result of their age due to biases regarding the morbidity of the proposed intervention. This often occurs despite data to suggest that increased age does not independently affect mortality, morbidity, or length of hospital stay.44 With an aging population, surgeons and clinicians are now challenged with how to care for this patient cohort, and they must let go of their strong-held beliefs that patients can be “too old,” “too high risk,”

CHAPTER 46  Acute Abdomen

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BOX 46.8  Differential diagnosis of acute

BOX 46.9  Differential diagnosis of acute

• Peptic ulcer disease • Gastrointestinal bleed • Biliary disease • Pancreatitis • Bowel obstruction (large and small) • Volvulus • Diverticulitis • Appendicitis • Abdominal aortic aneurysm • Mesenteric ischemia

• Tumor infiltration • Gastrointestinal bleed • Bowel obstruction • Biliary disease • Appendicitis • Neutropenic enterocolitis • Invasive aspergillosis • Digestive tract graft versus host disease • Mesenteric ischemia • Diverticulitis

abdomen in the elderly patient.

From Rubinfeld I, Thomas C, Berry S, et al. Octogenarian abdominal surgical emergencies: not so grim a problem with the acute care surgery model? J Trauma. 2009;67:983–989; and Magidson PD, Martinez JP. Abdominal pain in the geriatric patient. Emerg Med Clin North Am. 2016;34:559–574.

or “nonsurvivable.”45 Approaching these patients with a “damagecontrol” mentality of aggressive resuscitation and careful attention to hypothermia, coagulopathy, acidosis, or hypotension and returning after adequate resuscitation are suggested to improve outcomes.45 Box 46.8 lists the most common indications for surgical intervention in the elderly patient population. 

Advanced Disease Surgery in patients with advanced or disseminated cancer can be fraught with complications with little chance of prolonging their survival. Emergency procedures, such as for perforation or obstruction, are performed in this patient population with grave risks, as their disseminated disease has little chance of cure. One study demonstrated that those that undergo an operation for perforation have an approximate 1 in 3 chance of mortality; this is only slightly improved to 1 in 6 for those undergoing an operation for obstruction.46 These complications may occur as a side effect of cancer treatment or it may represent disease progression. Regardless the cause, frank discussion with patients and their families are fundamental, and decisions regarding the patient’s goals of care, overall survival, and prolonged institutionalization should be discussed with respect to the patient’s wishes.46 Emergency surgery in patients with advanced disease often heralds an inflection point in their care and these patients are unlikely to obtain their goal of discharge home.46 Box 46.9 lists the differential diagnosis of acute abdomen in the oncologic patient. 

SUMMARY Despite improvements in laboratory examinations and imaging, the evaluation and management of the patient with acute abdominal pain remains a challenging part of a surgeon’s practice. However, a careful history and thorough physical examination continue to remain the most important part of the evaluation of the patient with acute abdominal pain. The surgeon continues to be required to make the decision to perform laparoscopy or laparotomy with some degree of uncertainty as to the expected findings. The increased morbidity and mortality associated with a delay in the treatment of many of the surgical causes of the acute abdomen argue for an aggressive and expeditious surgical approach.

abdomen in the oncology patient.

From Mokart D, Penalver M, Chow-Chine L, et al. Surgical treatment of acute abdominal complications in hematology patients: outcomes and prognostic factors. Leuk Lymphoma. 2017;58:2395–2402; and Cauley CE, Panizales MT, Reznor G, et al. Outcomes after emergency abdominal surgery in patients with advanced cancer: Opportunities to reduce complications and improve palliative care. J Trauma Acute Care Surg. 2015;79:399–406.

SELECTED REFERENCES Bouyou J, Gaujoux S, Marcellin L, et al. Abdominal emergencies during pregnancy. J Visc Surg. 2015;152:S105–115. This paper reviews the presentations of abdominal emergencies in pregnant patients as well as the best way to approach these conditions.

de Burlet KJ, Ing AJ, Larsen PD, et al. Systematic review of diagnostic pathways for patients presenting with acute abdominal pain. Int J Qual Health Care. 2018;30:678–683. An excellent resource for systematic evaluation and diagnosis in a patient with an acute abdomen.

Malbrain ML, Cheatham ML, Kirkpatrick A, et al. Results from the international conference of experts on intra-abdominal hypertension and abdominal compartment syndrome. I. Definitions. Intensive Care Med. 2006;32:1722–1732. A consensus statement that defines abdominal compartment syndrome and provides evidence-based algorithm on its diagnosis and treatment.

Navez B, Navez J. Laparoscopy in the acute abdomen. Best Pract Res Clin Gastroenterol. 2014;28:3–17. This paper highlights the usefulness of minimally invasive surgery in approaching the acute abdomen.

Steinheber FU. Medical conditions mimicking the acute surgical abdomen. Med Clin North Am. 1973;57:1559–1567. This classic article nicely reviews the various medical conditions that can manifest as an acute abdomen. It is well written and remains pertinent to the evaluation of these patients.

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REFERENCES 1. Al-Mane N, Al-Mane F, Abdalla Z, et  al. Acute surgical abdomen: an unusual presentation of pulmonary embolus. J Investig Med High Impact Case Rep. 2014;2:1–4. 2. Hijaz NM, Friesen CA. Managing acute abdominal pain in pediatric patients: current perspectives. Pediatric Health Med Ther. 2017;8:83–91. 3. Nakayama DK. Examination of the acute abdomen in children. J Surg Educ. 2016;73:548–552. 4. Medford-Davis L, Park E, Shlamovitz G, et  al. Diagnostic errors related to acute abdominal pain in the emergency department. Emerg Med J. 2016;33:253–259. 5. Maraolo AE, Gentile I, Pinchera B, et al. Current and emerging pharmacotherapy for the treatment of bacterial peritonitis. Expert Opin Pharmacother. 2018;19:1317–1325. 6. Van Bree SW, Prins MC, Juffermans NP. Auscultation for bowel sounds in patients with ileus: an outdated practice in the ICU. Neth J Crit Care. 2018;26:142–146. 7. Hatipoglu S, Hatipoglu F, Abdullayev R. Acute right lower abdominal pain in women of reproductive age: clinical clues. World J Gastroenterol. 2014;20:4043–4049. 8. Treskes N, Persoon AM, van Zanten ARH. Diagnostic accuracy of novel serological biomarkers to detect acute mesenteric ischemia: a systematic review and meta-analysis. Intern Emerg Med. 2017;12:821–836. 9. Reveles KR, Pugh MJV, Lawson KA, et al. Shift to community-onset clostridium difficile infection in the national veterans health administration, 2003-2014. Am J Infect Control. 2018;46:431–435. 10. Erkurt MA, Berber I, Berktas HB, et al. A life-saving therapy in Class I HELLP syndrome: therapeutic plasma exchange. Transfus Apher Sci. 2015;52:194–198. 11. Hanbidge AE, Buckler PM, O’Malley ME, et  al. From the RSNA refresher courses: imaging evaluation for acute pain in the right upper quadrant. Radiographics. 2004;24: 1117–1135. 12. Binkovitz LA, Unsdorfer KM, Thapa P, et al. Pediatric appendiceal ultrasound: accuracy, determinacy and clinical outcomes. Pediatr Radiol. 2015;45:1934–1944. 13. Drake FT, Kotagal M, Simmons LE, et  al. Single institution and statewide performance of ultrasound in diagnosing appendicitis in pregnancy. J Matern Fetal Neonatal Med. 2015;28:727–733. 14. Park J, Young-Hoon Y, Horeczko T, et al. Changes of clinical practice in gastrointestinal perforation with the increasing use of computed tomography. J Korean Soc Traumatol. 2017;30:25–32. 15. Geng WZM, Fuller M, Osborne B, et  al. The value of the erect abdominal radiograph for the diagnosis of mechanical bowel obstruction and paralytic ileus in adults presenting with acute abdominal pain. J Med Radiat Sci. 2018;65:259–266. 16. de Burlet KJ, Ing AJ, Larsen PD, et  al. Systematic review of diagnostic pathways for patients presenting with acute abdominal pain. Int J Qual Health Care. 2018;30:678–683. 17. Shogilev DJ, Duus N, Odom SR, et al. Diagnosing appendicitis: evidence-based review of the diagnostic approach in 2014. West J Emerg Med. 2014;15:859–871. 18. Gardner CS, Jaffe TA, Nelson RC. Impact of CT in elderly patients presenting to the emergency department with acute abdominal pain. Abdom Imaging. 2015;40:2877–2882.

19. Othman AE, Bongers MN, Zinsser D, et  al. Evaluation of reduced-dose CT for acute non-traumatic abdominal pain: evaluation of diagnostic accuracy in comparison to standarddose CT. Acta Radiol. 2018;59:4–12. 20. Cocorullo G, Falco N, Tutino R, et al. Open versus laparoscopic approach in the treatment of abdominal emergencies in elderly population. G Chir. 2016;37:108–112. 21. Navez B, Navez J. Laparoscopy in the acute abdomen. Best Pract Res Clin Gastroenterol. 2014;28:3–17. 22. Malbrain ML, Cheatham ML, Kirkpatrick A, et  al. Results from the international conference of experts on intra-abdominal hypertension and abdominal compartment syndrome. I. Definitions. Intensive Care Med. 2006;32:1722–1732. 23. Abbasi N, Patenaude V, Abenhaim HA. Management and outcomes of acute appendicitis in pregnancy-population-based study of over 7000 cases. BJOG. 2014;121: 1509–1514. 24. Kort B, Katz VL, Watson WJ. The effect of nonobstetric operation during pregnancy. Surg Gynecol Obstet. 1993;177:371–376. 25. Sadot E, Telem DA, Arora M, et  al. Laparoscopy: a safe approach to appendicitis during pregnancy. Surg Endosc. 2010;24:383–389. 26. Skubic JJ, Salim A. Emergency general surgery in pregnancy. Trauma Surg Acute Care Open. 2017;2:e000125. 27. Bouyou J, Gaujoux S, Marcellin L, et al. Abdominal emergencies during pregnancy. J Visc Surg. 2015;152:S105–S115. 28. Kilpatrick CC, Monga M. Approach to the acute abdomen in pregnancy. Obstet Gynecol Clin North Am. 2007;34:389–402, x. 29. Baheti AD, Nicola R, Bennett GL, et al. Magnetic resonance imaging of abdominal and pelvic pain in the pregnant patient. Magn Reson Imaging Clin N Am. 2016;24:403–417. 30. Kirshtein B, Perry ZH, Avinoach E, et  al. Safety of laparoscopic appendectomy during pregnancy. World J Surg. 2009;33:475–480. 31. Chung JC, Cho GS, Shin EJ, et al. Clinical outcomes compared between laparoscopic and open appendectomy in pregnant women. Can J Surg. 2013;56:341–346. 32. Aydin D, Turan C, Yurtseven A, et al. Integration of radiology and clinical score in pediatric appendicitis. Pediatr Int. 2018;60:173–178. 33. Kotagal M, Richards MK, Flum DR, et al. Use and accuracy of diagnostic imaging in the evaluation of pediatric appendicitis. J Pediatr Surg. 2015;50:642–646. 34. Yang WC, Chen CY, Wu HP. Etiology of non-traumatic acute abdomen in pediatric emergency departments. World J Clin Cases. 2013;1:276–284. 35. Fui SL, Lupinacci RM, Tresallet C, et al. How to avoid nontherapeutic laparotomy in patients with multiple organ failure of unknown origin. The role of CT scan revisited. Int Surg. 2015;100:466–472. 36. Gagne DJ, Malay MB, Hogle NJ, et  al. Bedside diagnostic minilaparoscopy in the intensive care patient. Surgery. 2002;131:491–496. 37. Cesaretti M, Dioguardi Burgio M, Zarzavadjian Le Bian A. Abdominal emergencies after liver transplantation: presentation and surgical management. Clin Transplant. 2017;31: e13102. 38. de’Angelis N, Esposito F, Memeo R, et al. Emergency abdominal surgery after solid organ transplantation: a systematic review. World J Emerg Surg. 2016;11:43.

CHAPTER 46  Acute Abdomen 39. Grass F, Schafer M, Cristaudi A, et al. Incidence and risk factors of abdominal complications after lung transplantation. World J Surg. 2015;39:2274–2281. 40. Chaudhry R, Zaki J, Wegner R, et al. Gastrointestinal complications after cardiac surgery: a nationwide population-based analysis of morbidity and mortality predictors. J Cardiothorac Vasc Anesth. 2017;31:1268–1274. 41. Buczacki SJA, Davies J. The acute abdomen in cardiac intensive care unit. In: Valchanov K, Jones N, Hogue CW, eds. Core Topics in Cardiothoracic Critical Care. 2nd ed. Cambridge: Cambridge University Press; 2018:294–300. 42. Byrne TK. Complications of surgery for obesity. Surg Clin North Am. 2001;81:1181–1193, vii-viii.

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43. Karila-Cohen P, Cuccioli F, Tammaro P, et al. Contribution of computed tomographic imaging to the management of acute abdominal pain after gastric bypass: correlation between radiological and surgical findings. Obes Surg. 2017;27:1961–1972. 44. Rubinfeld I, Thomas C, Berry S, et al. Octogenarian abdominal surgical emergencies: not so grim a problem with the acute care surgery model? J Trauma. 2009;67:983–989. 45. Magidson PD, Martinez JP. Abdominal pain in the geriatric patient. Emerg Med Clin North Am. 2016;34:559–574. 46. Mokart D, Penalver M, Chow-Chine L, et al. Surgical treatment of acute abdominal complications in hematology patients: outcomes and prognostic factors. Leuk Lymphoma. 2017;58:2395–2402.

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CHAPTER

Acute Gastrointestinal Hemorrhage Kevin J. Chiang, Noelle N. Saillant, Richard Hodin

OUTLINE Acute Management of Patients With Gastrointestinal Hemorrhage Initial Evaluation Acute Exsanguination Localization Obscure Bleeding

Specific Causes of UGIB Nonvariceal Bleeding Variceal Hemorrhage Acute Lower Gastrointestinal Hemorrhage Diagnosis Surgical Management Specific Causes of Lower Gastrointestinal Tract Bleeding

Gastrointestinal bleeding (GIB) is a term that describes the loss of blood from along the alimentary canal. GIB is classified by its anatomic location relative to the ligament of Treitz. Upper GIB (UGIB) is defined as being proximal to the ligament of Treitz. Upper intestinal hemorrhage is the most common presentation of GIB and is commonly from peptic ulcer disease (PUD) or esophageal varices. Pancreatic, liver, and other biliary origins of blood loss also are encompassed by this term. Lower GIB (LGIB) accounts for 30% to 40% of all bleeds and is defined as distal to the ligament of Treitz. This most often originates from the colon from diverticular disease or angiodysplasias. The term massive GIB refers to intestinal blood loss leading to hemodynamic instability or transfusion requirement, whereas occult GIB refers to anemia that persists or recurs after negative endoscopic evaluation and imaging workup. Overall, bleeding is the most common cause of hospitalization from gastrointestinal (GI) disease in the United States, accounting for over 507,000 admissions annually with a total cost of over $5.8 billion.1 The reported median length of hospital stay for GI hemorrhage is 3 to 6 days, with median cost ranging from $6700 to $20,370.1–3 The peak incidence has steadily decreased by 1% annually since the mid-1990s due to the advent of proton pump inhibitors (PPIs), increased treatment of Helicobacter pylori, and avoidance of nonsteroidal antiinflammatory drugs (NSAIDs). Following this trend, mortality has dramatically decreased from the historical rates of 6% to 12% for UGIB to more contemporary rates of less than 2%.1,3 While these advancements have steadily decreased hospital admissions for UGIB, admissions related to LGIB have increased.4

Depending on the manifestation, treatment may take place in the outpatient setting or be emergently managed. Regardless, a multidisciplinary approach is required to fully tend to the condition and to determine the location and best therapeutic approach for the blood loss. 

ACUTE MANAGEMENT OF PATIENTS WITH GASTROINTESTINAL HEMORRHAGE Initial Evaluation GIB may present in a subtle way as a diagnosis of unexplained microcytic anemia or the finding of a positive hemoccult stool study. In contrast, it may also present as massive life-threatening exsanguination.

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Acute Exsanguination Rapid triage of hemorrhaging patients while localizing the areas of blood loss is essential for resuscitation and prompt intervention. Assessment should adhere to the ABCDEs: airway, breathing, circulation, disability, and exposure. Patency of the airway and adequacy of breathing are the priority. Severe hematemesis or decreased mental status from shock or hepatic encephalopathy may compromise oxygenation, ventilation, and airway protective reflexes. If an airway is needed, it should be secured with attention to the patient’s hemodynamic status. Intravenous (IV) access with two large-bore (14- or 16- gauge) catheters should be obtained. Occasionally, in the massively hemorrhaging patient, central access with resuscitative lines is needed to maintain hemodynamic support. Invasive hemodynamic monitoring should also be considered in such patients. A urinary catheter should be placed to follow adequacy of resuscitation and preservation of renal function. The severity of hemorrhage can generally be determined quickly using simple clinical parameters. Tachypnea, tachycardia, hypotension, agitation, and mental status changes are all indicators of a severe degree of hemorrhage. Hypotension is a harbinger of death. Systolic blood pressures under 90 mm Hg do not typically manifest until a patient has experienced a 30% to 40% blood loss. In well-compensated hosts, many of these signs may be absent or subtle, manifesting only as anxiety, tachypnea, or cool skin. The clinical response may be further blunted in patients taking beta blockers5 or those patients who are at the extremes of age. Additional management priorities include obtaining a type and crossmatch, complete blood count, metabolic panel, coagulation profile, and liver function tests. Serum lactate can be utilized as an endpoint of resuscitation when elevated. It is important to note that in acute severe blood loss, the serum hematocrit is not a reliable marker of the amount of blood loss as it may take hours to

CHAPTER 47  Acute Gastrointestinal Hemorrhage dilute as fluid shifts from the interstitium and the patient receives volume resuscitation. The strategy for fluid resuscitation should be guided by the severity of hemorrhage. With large volume blood loss, the utilization of massive transfusion protocols can make universal donor blood products rapidly available in prespecified ratios with proven survival benefit in bleeding patients.5 The ideal ratio of these products for GIB has not been well studied, although evidence suggests that a ratio of blood constituents (plasma and platelets) that approximates the whole blood (one unit fresh-frozen plasma per two units of packed red blood cells [RBCs] administered) lost during hemorrhage may be beneficial.6,7 Furthermore, rapid blood loss can be complicated by preexisting or hemorrhage-related coagulopathy with deficiencies in both pro- and antithrombotic factors. Normalization of prothrombin time, partial thromboplastin time, fibrinogen levels, and platelet count are important adjuncts in management A role for viscoelastic tests such as thromboelastography or thromboelastometry has not been well studied in GIB but has shown benefit in other hemorrhage-related clinical scenarios.8 Use of a rapid infuser can be utilized to keep up with rapid blood loss and may help warm products to minimize hypothermia. These patients often require admission to the intensive care unit and urgent intervention to localize and control hemorrhage. Clinical response to volume to support mentation, radial pulse

pressure, and at least a systolic blood pressure of 90 mm Hg, while following endpoints of resuscitation, such as lactate clearance and urine output, guides adequacy of resuscitation. It is important to distinguish massively hemorrhaging patients from stable patients with GIB in whom a restrictive transfusion strategy should be employed. A landmark study by Villanueva compared a restrictive transfusion threshold of a hemoglobin level of 7 to 9 g/dL to a liberal threshold of 9 to 11 g/dL. This randomized controlled trial found lower rates of mortality, rebleeding, and other adverse outcomes with the restrictive strategy of 7 g/ dL.9 Importantly, this trial specifically excluded patients who were massively exsanguinating. In light of this study, such massively hemorrhaging patients should be considered a different patient population in terms of management strategy. 

Localization Running parallel with the active resuscitation of the patients is the equally important search to localize the site of blood loss (Fig. 47.1). History and physical exam guide the assessment and may direct the examiner to a presumptive diagnosis. This information, combined with the characteristic of the blood loss, is helpful for determining an upper versus lower source. Hematemesis is the emesis of blood or coffee ground gastric secretions, most commonly from a UGIB. Bleeding from the nasal or oropharyngeal space also may be swallowed or pool

Localization 2.0

Acute GI hemorrhage

+ – Yes No

NGT with lavage

Bilious

Clear or bloody aspirate Clinical signs of UGIB

LGIB suspected UGIB suspected Hemodynamically unstable despite resuscitation?

Hemodynamically unstable despite resuscitation? Yes

Yes

Yes

No

No

Stigmata or history cirrhosis or varices

CTA EGD within 24 hours

UGIB

LGIB

Bowel prep and colonoscopy

No Nondiagnostic

Suspect variceal bleeding

Balloon tamponade to bridge to stability Emergent TIPS

Nonvariceal bleeding

OR with intraoperative angiography

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Video capsule endoscopy, deep endoscopy, surgical consult, angiography, Meckel scan, scintigraphy

Surgery +/– with intraoperative angiography

FIG. 47.1  Algorithm for the diagnosis of acute GI hemorrhage. CTA, Computed tomography angiogram; EGD, esophagogastroduodenoscopy; GI, gastrointestinal; LGIB, lower GI bleed; NGT, nasogastric tube; TIPS, transjugular intrahepatic portosystemic shunt; UGIB, upper GI bleed.

1152

SECTION X  Abdomen

dependently in the stomach and thus lead to a non-GI source of hematemesis. Melena, a malodorous, black stool with a tar-like quality, is also indicative of a proximal source of bleeding. Melena is the byproduct of hemoglobin degradation by digestive enzymes and intestinal bacterial flora. Hematin is produced from the degradation of hemoglobin, leading to a brownish blue coloration. Over 90% of melena arises from a UGIB, though it can originate from anywhere in the GI tract10 if intestinal transit is slow. Hematochezia, the passage of bright red blood from the anus, is most commonly from hemorrhoidal disease. However, brisk UGIB with swift transit through the intestinal tract may also manifest as bright red blood per rectum and is an important etiology to rule out upon evaluation. The first steps in differentiating a UGIB from a LGIB is aided by a nasogastric tube (NGT) lavage (Fig. 47.1). It can detect the presence of blood above the ligament of Treitz while also irrigating the stomach in preparation for an endoscopy. Aspiration of bile is required to assure sampling of postpyloric secretions. An aspiration, which is bilious and nonbloody, can effectively rule out an active UGIB. However, a nonactive upper GI (UGI) source is not definitively ruled out by a negative lavage if hemostasis occurred several hours prior.10 The next localization steps after NGT lavage is then based on clinical suspicion, patient stability, and bleeding rate. Given enough clinical history or suspicion, one may target treatment to the most likely diagnosis, for instance, performing endoscopy for suspected ulcer disease or other therapeutic interventions without further localization. In an actively bleeding patient in whom further localization is needed, the balance between patient stability and timely evaluation is essential. The goal is to efficiently localize the area of bleeding prior to hemodynamic instability to avoid the rare but difficult circumstance of a forced procedure without source identification. An exsanguinating or moribund patient with unlocalized bleed should proceed to a hybrid room for visceral angiography and/or operative intervention. In patients whose hemodynamics can support further workup, the multidetector computed tomography angiogram (CTA) is emerging as the first-line study for localization of GIB. CTA can detect bleeding rates as low as 0.3 mL/min11 when performed under specific protocols that include three-phase IV contrast, multidetector scanners (64 slice) with no enteral contrast.11,12 The sensitivity and specificity of CTA approaches 100% and over 90%, respectively, and may reduce overall radiation and IV contrast of a visceral angiogram.12 In contrast to the CTA, technetium-99-m-labeled RBC scintigraphy can detect bleeding as low as 0.04 mL/min. A second advantage of tagged RBC scans is that repeat images can be acquired up to 24 hours after the initial labeling of RBCs. However, use of this modality sacrifices the precision of hemorrhage localization since it generally can only suggest the quadrant of the abdomen from where the bleeding is occurring. Regardless, in a stable patient with a slow intermittent bleed, RBC scintigraphy can sometimes provide a valuable estimation of bleeding site that can guide endoscopic or angiographic interventions.11,13,14 Patients with bleeding localized to the UGI tract should proceed to upper endoscopy within 24 hours of presentation, if not sooner, to diagnose and treat the source. If bleeding cannot be localized with imaging or angiography and UGIB has been ruled out, a colonoscopy should be performed if the patient is stable and can tolerate a full bowel preparation. A mechanical bowel prep assures a high-quality colonoscopy, as any stool or retained blood

will often obscure the bleeding site. Diverticular bleeding is statistically the most common source of LGIB and visualization of bleeding within diverticula is severely impaired by the presence of stool and old blood. The exception to this is if a brisk bleed from the descending colon or rectum is suspected. In this case, a careful LGI endoscopy may be undertaken, as any colonoscopy without prep increases the risk of perforation. To aid in the preparation of the colon to improve diagnostic accuracy, the patient should receive a “rapid prep,” which is a minimum of 4 L of polyethylene glycol solution given within a period of approximately 4 hours, followed by colonoscopy within 1 to 2 hours.14 This large volume of fluid is often difficult to tolerate, so administration through an NGT may be necessary. Administering prokinetics to improve gastric emptying can also reduce nausea and discomfort associated with the high volume of prep solution. The colonoscopy should always include intubation of the terminal ileum to rule out a more proximal source of bleeding. A large working channel is highly recommended to facilitate suctioning of stool and clots. Water-jet irrigation should also be used to flush debris from the mucosa and improve visualization. If UGI and colonic sources of bleeding have been excluded, the next most common location for bleeding is the small bowel, sometimes referred to as “middle GIB.” This accounts for 5% of acute GIBs. CTA remains the first test of choice. In a stable patient, there are additional options for further localization of bleeding if the CTA is nondiagnostic. These include video capsule endoscopy and push, device-assisted (balloon or spiral enteroscopy), or intraoperative enteroscopy. Video capsule endoscopy is noninvasive and is designed for imaging of the small bowel. It is the diagnostic modality of choice for overt GIB in a stable patient when upper and lower sources have been ruled out.15,16 Bleeding is the most common indication for capsule endoscopy.15 The diagnostic rates are reported to be between about 35% to 67% and highest in acute GIB rather than obscure blood loss. Other factors that are associated with a positive capsule study are male sex, age over 60 years, and hospitalization at the time of test performance. A full bowel preparation maximizes visualization of the mucosa. If there is recurrent bleeding, the capsule endoscopy can be repeated. The results should be used to guide further endoscopic or surgical therapy. If deep enteroscopy or deviceassisted enteroscopy is performed, the transit time of the capsule can aid in determining the starting point of the endoscopy. The main risk of capsule endoscopy is capsule retention that can occur in up to 1.5% of patients when used for overt GIB.15 Patients at high risk for capsule retention are those with heavy NSAID use, tumors, Crohn disease, prior small bowel radiation, or surgery. A dissolvable “test” capsule is sometimes used first to ensure that the video capsule will not get stuck. These higher-risk patients may be better served by the alternative diagnostic strategies of computed tomography (CT) enterography or magnetic resonance (MR) enterography.16 Multiphase CT enterography can be superior to capsule endoscopy in detecting bleeding from tumors. Typically, it is performed with a neutral or low-density oral contrast to distend the small bowel and includes IV contrast. Scans are performed in the arterial, enteral, and delayed phase. If a patient is stable and can tolerate capsule endoscopy and CT enterography, these studies are complementary to each other in discovering a small bowel source of bleeding.16 A positive study with capsule endoscopy or CT/MR enterography should be followed with a push or device-assisted enteroscopy as these have therapeutic capability.

CHAPTER 47  Acute Gastrointestinal Hemorrhage Push enteroscopy using a small-caliber colonoscope can reach about 50 to 70 cm past the ligament of Treitz and leads to successful diagnosis in 40% of patients with obscure small bowel bleeding. Double-balloon endoscopy is quickly gaining favor in the diagnosis and treatment of small bowel lesions. The procedure uses the peristaltic “push/pull” motions from inflation and deflation of two balloons to course the small intestine along its length. This technique is capable of examining the entire small bowel, with successful identification of 77% to 85% of occult bleeding sources. Although technically challenging, it has a diagnostic efficacy greater than that of video capsule endoscopy. Patients with altered anatomy, for example, Roux-en-Y bypasses, should undergo device-assisted endoscopy to evaluate the excluded portions of bowel. Intraoperative endoscopy, during laparotomy or laparoscopy, is a last resort when other modalities have failed to localize a source of small bowel bleeding and the patient continues to require transfusions or repeat hospitalizations. Surgery may also be necessary if a device-assisted enteroscopy cannot be performed without lysis of adhesions. This typically uses a sterile, small caliber colonoscope that is passed bidirectionally with the surgeon assisting to pass the bowel over the endoscope. Any suspicious areas are marked for possible resection or are dealt with endoscopically if feasible.16 

Obscure Bleeding The cause of obscure-overt bleeding is often a common lesion that is missed on initial evaluation. Repeated upper endoscopy and lower endoscopy should be performed and may identify lesions in up to 35% of patients. Tagged RBC scan and angiography can be helpful next steps but require ongoing hemorrhage. Small bowel enteroclysis, which uses barium, methylcellulose, and air to assist in image resolution, has been replaced largely in practice by CT enterography. CT enterography can identify gross lesions such as small bowel tumors and inflammatory conditions such as Crohn disease but cannot visualize angiodysplasias, the main cause of obscure small bowel hemorrhage. Provocative angiographic testing, which involves administration of anticoagulants, fibrinolytics, or vasodilators to increase hemorrhage during angiography, has been employed in small series with favorable results, but reluctance to induce uncontrolled hemorrhage has limited its use. Surgical backup and the ability to salvage the patient in an operating room is essential to the planning of such a procedure. 

SPECIFIC CAUSES OF UGIB Due to the divergence in diagnostic and therapeutic maneuvers, UGIB is often further subdivided into either nonvariceal or variceal bleeding.

Nonvariceal Bleeding Peptic Ulcer Disease PUD is responsible for up to two-thirds of UGIBs and can develop in the stomach or duodenum.17 Approximately 10% to 15% of patients with PUD will develop bleeding as part of their disease course.18 PUD results from an imbalance between mucosal barriers and other aggravating factors. The major etiologic factors in PUD are H. pylori and NSAIDs, and in some patients, these can act synergistically in the development of ulcers through their additive insults to the gastroduodenal mucosa. Worldwide, it is estimated that up to 77% of duodenal ulcers are associated with H. pylori infection. The bacterium causes an inflammatory reaction

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within the mucosa that impairs mucosal defense and allows ulcer formation. NSAIDs also disrupt the mucosal barrier but via a different mechanism. NSAIDs inhibit cyclooxygenases (i.e., COX-1 and COX-2), thus impairing prostaglandin synthesis, enhancing neutrophil adherence and subsequent mucosal injury. NSAIDs additionally inhibit the release of nitric oxide (NO) and hydrogen sulfide (H2S), further inhibiting protective mechanisms of the mucosa. In those patients with regular NSAID use, PUD has a prevalence of 15% to 20%.17 Erosion of the mucosal surface leads to injury, ulceration, and chronic blood loss that can be further exacerbated by antiplatelet agents, anticoagulants, and selective serotonin reuptake inhibitors. Significant bleeding does not occur until the erosion reaches an artery of the submucosa or an even larger vessel in the case of a penetrating ulcer. The most significant hemorrhage occurs when duodenal or gastric ulcers penetrate branches of the gastroduodenal or left gastric arteries, respectively.17 Treatment of PUD begins with effective prophylaxis. Aggressive treatment of H. pylori, reduction of NSAIDs, and the use of alternative NSAIDS preparations such as COX-2 inhibitors for chronic therapy have further decreased the incidence of PUD. However, it has been the landmark discovery of PPIs that has most drastically impacted the treatment of PUD. Since their introduction in 1989, PPIs have become a mainstay in the treatment of acid-related disorders. Multiple randomized controlled trials have proven their efficacy in healing ulcers compared to placebo as well their superiority over H2-inhibitors. PPIs inhibit the final common pathway of acid secretion by targeting the H+/ K+-ATPase of parietal cells. Acid is suppressed until replacement pumps are synthesized (up to 36 hours), well beyond the required 18 to 20 hours of a pH greater than 3 required for effective ulcer healing. Management. See localization algorithm for an outline of approach (Fig. 47.2). After initial resuscitation, patients should undergo esophagogastroduodenoscopy (EGD). Those with high clinical risk may benefit from EGD as soon as possible, with evidence supporting intervention within 12 hours of presentation,19 rather than the more liberal time frame of 24 hours. While awaiting EGD, patients should be treated with a PPI.20 Prokinetics should be considered, as a metaanalysis has supported erythromycin prior to endoscopy to reduce the need for second endoscopy, amount of blood transfusion, and hospital length of stay. An NGT can be helpful for diagnosis, but it is unlikely to clear enough clot to improve endoscopic visualization of the gastric mucosa. The next steps after index endoscopy depend on the findings. The Forrest classification was developed to assess the risk of rebleeding based on endoscopic findings and groups patients into high, intermediate, and low risk of rebleeding (Table 47.1). Endoscopic therapy is recommended for ulcers with active bleeding as well as those with a visible ulcer (Forrest I–IIa). In cases with an adherent clot (Forrest IIb), the clot is removed and the ulcer evaluated. Ulcers with a clean base or black spot secondary to hematin deposition (Forrest IIc–III) do not require endoscopic treatment and are managed medically. Approximately 25% of patients undergoing EGD for UGIB will require an endoscopic intervention.18 If the endoscopy is unable to achieve hemostasis, angiography should be performed. Surgery is the next step if angiography fails or is not available.  Medical management. All patients with confirmed peptic ulcer bleed should receive PPI therapy. Preendoscopic high-dose IV PPI therapy has been associated with decreased frequency of high-risk findings on endoscopy (Forrest Ia–IIa), leading to less

1154

SECTION X  Abdomen EGD shows PUD bleeding

No

High risk features endoscopic findings Forrest classification la, Ib, IIa, IIb Yes Endoscopic therapy No

Hemostasis? Yes Monitor, clears, PPI Assess for H. Pylori PPI Repeat EGD later if gastric ulcer

No

Rebleed?

Angiography

Surgery

Yes Repeat endoscopy Hemostasis?

No

Yes Monitor, clears, PPI No

Rebleed?

Yes

FIG. 47.2  Algorithm for the diagnosis and management of nonvariceal upper gastrointestinal bleeding. EGD, Esophagogastroduodenoscopy, PPI, proton pump inhibitor; PUD, peptic ulcer disease.

TABLE 47.1  The Forrest classification for

endoscopic findings and rebleeding risks in peptic ulcer disease. Grade Ia Grade Ib Grade IIa Grade IIb Grade IIc Grade III

CLASSIFICATION

REBLEEDING RISK

Active, pulsatile bleeding Active, nonpulsatile bleeding Nonbleeding visible vessel Adherent clot Ulcer with black spot Clean, nonbleeding ulcer bed

High High High Intermediate Low Low

need for endoscopic intervention. If PPI has not been started prior to endoscopy, a bolus of 80 mg should be given, followed by an infusion at 8 mg an hour for 72 hours. This approach has been shown to reduce risk of further bleeding, need for surgery, and mortality. Continuing PPI therapy postendoscopy also has been associated with reduced risk of further bleeding, need for surgery, and mortality.19 Interestingly, no difference in these outcomes was established between oral and IV preparations in a recent metaanalysis. However, heterogeneity in the study design, PPI dosing, and endoscopic findings limit absolute conclusions in the absence of a well-designed noninferiority trial. Eradication of H. pylori infection, if present, has been shown in multiple studies and metaanalysis to result in less rebleeding. Confirmation of successful therapy should be confirmed by breath or stool test or by biopsy on repeat endoscopy. Once H. pylori has been eradicated, there is no need for long-term acid suppression as it does not decrease the rebleed risk of 1.3%.21

All ulcerogenic medications such as NSAIDs or selective serotonin reuptake inhibitors should be discontinued in favor of alternatives. NSAIDs should be avoided as much as possible, although if they must be resumed, a combination of COX-2 selective NSAID and PPI should be used. Rebleeding rates with COX-2 inhibitors alone versus traditional NSAIDs plus a PPI are similar at 4% to 9%.19 A double-blind trial showed that COX-2 inhibitors plus PPI has a much lower rebleed risk as compared to COX-2 selective NSAIDs alone (0% vs. 8.9%).22 H. pylori eradication further improves the risk profile of NSAIDs. The benefits of low-dose aspirin (ASA) for cardiovascular risk reduction are outweighed in some patients by the risk for GIB. The decision to continue ASA is based on its clinical indication for primary or secondary risk reduction. When used for primary risk reduction, the risk of recurrent GIB outweighs the benefit of ASA prophylaxis. A recent randomized controlled trial studied the benefits of ASA in primary prevention of cardiovascular events.23 An analysis of secondary endpoints showed that ASA did not reduce cardiovascular events when compared to placebo but did increase the risk of significant hemorrhage in multiple areas of the body, including upper and lower GI.23 However, ASA for secondary risk should be restarted in combination with a PPI within 1 to 7 days after bleeding cessation.19 This recommendation is based on a randomized trial that compared patients who had high-risk features on endoscopy and resumed ASA immediately with those on placebo for 8 weeks. All patients received PPI infusion followed by oral therapy. At 30 days, the group receiving ASA did have a nonsignificant increased risk of bleeding. This risk was far outweighed by the notable finding that patients receiving ASA, compared to placebo, had a lower mortality at 30 days (1.3% vs. 9%) and 8 weeks (1.3% vs. 12.9%).24  Endoscopic management. Multiple endoscopic therapies have been used to treat PUD, including injection, thermal coagulation, plasma argon coagulation, mechanical clips, and fibrin glue. The recommended approach is to use thermal coagulation or clips, with or without epinephrine injection. This is based on metaanalysis showing that epinephrine monotherapy has a higher risk of rebleed compared to clipping or thermal coagulation. Injection therapy should be combined with other modalities such as heat or clipping.25 Epinephrine is diluted 1:10,000 or 1:20,000 and is injected into all four quadrants of a bleeding lesion. The rate of initial hemostasis with epinephrine monotherapy is as high as 100%, although the risk of rebleeding remains high and thus mandates use of another modality. The ideal volume of injection is unknown, although generally, 0.2 to 2 mL is injected in each quadrant. Large volume injection (>13 mL) is associated with improved hemostasis, suggesting that part of the mechanism is by tamponade and compression of the bleeding vessel. In addition to injection, heat or mechanical therapy is usually added and together can achieve initial hemostasis in up to 90% of bleeding ulcers. Heat can be in the form of monopolar or bipolar cautery, heater probe, or argon plasma coagulation. All heat modalities have similar efficacy and are effective in achieving initial hemostasis, reducing recurrent bleeding, surgery, and mortality.26 Hemoclips are less effective than thermal therapy, although they may be advantageous in dealing with a spurting vessel for which they can provide immediate control of hemorrhage. Limitations of hemoclips are the difficulty in applying to fibrotic lesions and prolonged procedure time as only one clip can be applied at a time. It is important to properly place the first clip as improperly placed clips can impede placement of subsequent clips.27 Clips can be useful if subsequent angiographic intervention is done, as they can assist in localizing the bleeding.

CHAPTER 47  Acute Gastrointestinal Hemorrhage A less commonly used hemostatic therapy is sclerosant injection, such as absolute alcohol. This modality is effective but risks tissue damage, thus making it less attractive. Rebleeding of an ulcer is associated with a significant increase in mortality. Patients at high risk of rebleeding should be identified early using previously described criteria and observed under higher levels of care such as in an intensive care unit. With rebleeding, a second attempt at endoscopic control is recommended and is successful in 75% of patients.  Angiographic management. Angiography is diagnostic as well as therapeutic and should be considered if a patient has failed endoscopic management or if the bleeding has not been localized. Access is obtained through the common femoral artery. The vessel interrogated first is based on clinical suspicion for location of the bleed. For suspected UGIB, the celiac artery and its branches are interrogated first as most UGIB is from gastric or duodenal ulcers supplied by branches of the celiac artery. The superior mesenteric artery and inferior mesenteric artery can also be evaluated if no bleeding is identified. The presence of clips or prior imaging can help guide further subselective catheterization. In patients with repetitive, nondiagnostic workups, provocative maneuvers with systemic anticoagulation must be weighed against the risk of uncontrolled hemorrhage. Transcatheter arterial embolization is effective at hemorrhage control when a bleeding source is found. Superselective embolization allows control of bleeding while maintaining adequate collateral flow to prevent bowel infarct. Examples include selective embolization of the left gastric artery or gastroduodenal artery for bleeding ulcers or the vasa recta or terminal branches of the inferior mesenteric artery for LGIB. There are various embolic agents such as coils, polyvinyl alcohol particles, Gelfoam, glue, and plugs. Coils and polyvinyl alcohol particles are most commonly used. Gelfoam is unique in that it is a temporary agent made of porcine adipose tissue and will recanalize over weeks to months, although the actual time course is often unpredictable. Success rates for UGIB embolization are cited at 44% to 100% and 88% to 93% for LGIB.28 Vasopressin infusion is less frequently used now that improved methods of transcatheter embolization are available. The mechanism of action is that vasopressin constricts arteries to reduce blood flow to the site of hemorrhage. Downsides to its use are cardiac side effects and high rates of rebleeding after cessation of infusion and the need to maintain vascular access in situ for 24 to 48 hours to continue the infusion. The cardiac effects can be mitigated to some degree with a nitroglycerin infusion to maintain coronary perfusion. Vasopressin infusion can be useful if there is diffuse bleeding or as a bridge to surgical intervention if superselective cannulation cannot be achieved.  Surgical management. Despite significant advances in endoscopic therapy, approximately 10% of patients with bleeding ulcers still require surgical intervention for effective hemostasis.18 To assist in this decision making, several clinical and endoscopic parameters have been proposed that are thought to identify patients at high risk for failed endoscopic therapy. The Forrest classification is the best predictor of rebleeding (see Table 47.1). Other endoscopic factors associated with increased risk of rebleeding are active bleeding at time of endoscopy, large ulcer size (i.e., >2 cm), posterior duodenal wall ulcer, and lesser gastric curve ulcer.29 Patients with these characteristics need closer monitoring and possibly earlier surgical intervention. Clearly, clinical judgment and local expertise must play a critical role in this decision. Indications for surgery have traditionally been based on the blood transfusion requirements, success of endoscopic therapy,

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BOX 47.1  Indications for surgery in

gastrointestinal hemorrhage.

Hemodynamic instability despite vigorous resuscitation (>6-unit transfusion) Failure of endoscopic techniques to arrest hemorrhage Recurrent hemorrhage after initial stabilization (with up to two attempts at obtaining endoscopic hemostasis) Shock associated with recurrent hemorrhage Continued slow bleeding with a transfusion requirement exceeding 3 units/ day

and recurrent bleeding after repeat endoscopy. Increased blood transfusions have been clearly associated with increased mortality. Although a less definitive criterion than it was in the past, most surgeons still consider an ongoing blood transfusion requirement more than 6 units as an indication for surgical intervention, particularly in the elderly, although an 8- to 10-unit loss may be more acceptable for the younger population. Current indications for surgery for peptic ulcer hemorrhage are summarized in Box 47.1. Secondary or relative indications include a rare blood type or difficult crossmatch, refusal of transfusion, shock on presentation, advanced age, severe comorbid disease, and a bleeding chronic gastric ulcer for which malignancy is a concern.  Surgical management of duodenal ulcers. The first step in the operative management for a duodenal ulcer is exposure of the bleeding site. Most of these lesions are in the duodenal bulb; stay sutures are placed on either side of a longitudinal duodenotomy or duodenopyloromyotomy. Hemorrhage typically can be controlled initially with pressure and then direct suture ligation with nonabsorbable suture. Anterior ulcers can be directly ligated. More commonly, a posterior ulcer erodes into the pancreaticoduodenal or gastroduodenal artery. Suture ligature of the vessel proximal and distally, typically in a superior and inferior orientation, as placement of medial-stitch to control the pancreatic branches typically arrests the bleed. The duodenotomy is closed transversely with an NGT above and a nasojejunal tube placed beyond the repair for distal enteral access. Omental buttressing of the suture line may assist in healing. A surgical drain can be left in place if there is significant concern for a potential leak. Traditionally, a definitive acid-reducing operation was considered if the patient was hemodynamically stable. This practice has largely been abandoned in the era of H. pylori eradication and PPI therapy, such that there has been a dramatic reduction in the rates of definitive ulcer therapy (gastrectomy or vagotomy). The choice between various acid-reduction operations was guided by the hemodynamic condition of the patient and the presence or absence of long-standing history of refractory ulcer disease. The various operations for PUD are discussed in greater detail in Chapter 49. A pyloroplasty combined with truncal vagotomy is the most frequently performed acid-reduction surgery used in the setting of a bleeding duodenal ulcer. There is some evidence to suggest that a parietal cell vagotomy may represent a better therapy for a bleeding duodenal ulcer in the stable patient, although some of this benefit may be abrogated if the pylorus has been divided. In a patient who has a known history of refractory duodenal ulcer disease or who has failed to respond to more conservative surgery, antrectomy with truncal vagotomy may be more appropriate. However, this procedure is more complex and should generally not be done in a hemodynamically unstable patient.  Surgical management of gastric ulcer. Surgical control of a bleeding gastric ulcer begins with a gastrotomy and suture ligation.

1156

SECTION X  Abdomen

This alone is associated with 30% risk of rebleeding. Gastric ulcer resection is generally indicated due to the 10% incidence of malignancy. Simple excision alone is associated with rebleeding in as many as 20% of patients, so distal gastrectomy is generally preferred. Alternatively, ulcer excision combined with vagotomy and pyloroplasty may be considered in high-risk patients. Bleeding ulcers of the proximal stomach near the gastroesophageal junction are more difficult to manage. Proximal or near-total gastrectomies are associated with a particularly high mortality in the setting of acute hemorrhage. Other options include distal gastrectomy combined with resection of a tongue of proximal stomach inclusive of the ulcer. Vagotomy and pyloroplasty combined with either wedge resection or a buttressed oversewing of the ulcer also may be appropriate. Again, the possibility of malignancy must be kept in mind, especially in gastric ulcers remote from the pylorus.  Esophagitis The esophagus is an infrequent site of nonvariceal hemorrhage. When it does occur, it is most commonly the result of esophagitis. Esophageal inflammation secondary to repeated exposure of the esophageal mucosa to the acidic gastric secretions in gastroesophageal reflux disease leads to an inflammatory response that can result in chronic blood loss. Ulceration may accompany this, but the superficial mucosal ulcerations generally do not bleed acutely and are more commonly manifested as anemia or guaiac-positive stools. Various infectious agents may also cause esophagitis, particularly in the immune-compromised host (Fig. 47.3). With infection, hemorrhage can occasionally be massive. Other causes of esophageal bleeding include medications, Crohn disease, and radiation. Treatment typically includes acid suppressive therapy. Endoscopic control of the hemorrhage, usually with electrocoagulation or heater probe, is often successful. In patients with an infectious cause, targeted therapy is appropriate. Surgery is seldom necessary.  Gastritis Stress-related gastritis is characterized by the appearance of multiple superficial erosions of the entire stomach, most commonly in the body. It is thought to result from the combination of acid and pepsin injury in the context of decreased mucosal protection from hypoperfusion, NSAIDs, chemotherapy, or other agents. Classically, gastritis commonly afflicted the critically ill. These lesions are different from the solitary ulcerations related to acid hypersecretion from severe head injury (i.e., Cushing ulcers). When stress ulceration is associated with major burns, these lesions are referred to as Curling ulcers. Significant hemorrhage from stress ulceration was common prior to improvements in the management of shock and prophylactic use of acid suppression in high-risk patients. In those who develop bleeding, acid suppressive therapy is often successful in controlling the hemorrhage. In rare cases when this fails, consideration should be given to the administration of octreotide or vasopressin, endoscopic therapy, or even angiographic embolization. Historically, such cases were more commonly seen and, at times, dealt with surgically. The surgical choices included vagotomy and pyloroplasty with oversewing of the hemorrhage or near-total gastrectomy. These procedures carried mortality rates as high as 60%. Fortunately, they are seldom necessary today.  Mallory-Weiss Tears Mallory-Weiss tears are partial-thickness tears of the mucosa and submucosa that occur near the gastroesophageal junction. Classically, these lesions develop in alcoholic patients after a period of intense retching and vomiting following binge drinking, but

FIG. 47.3  Bleeding esophageal ulcer secondary to herpes esophagitis. (Courtesy Scott A. Hande, MD, Brigham and Women’s Hospital.)

they can occur in any patient who has a history of repeated emesis. The mechanism, proposed by Mallory and Weiss in 1929, is forceful contraction of the abdominal wall against an unrelaxed cardia, resulting in mucosal laceration of the cardia as a result of the increased intragastric pressure. Such lesions account for 5% to 10% of cases of UGIB. They are usually diagnosed by history, and endoscopy is used to confirm the diagnosis. A retroflexion maneuver is necessary to view the area just below the gastroesophageal junction and should be performed routinely so as to not miss this diagnosis in UGIB patients. Most tears occur along the lesser curvature and can extend into the esophagus. Supportive therapy with acid suppression therapy is successful in 90% of bleeding episodes, the mucosa often healing within 72 hours. In rare cases of severe ongoing bleeding, endoscopic therapy with injection or electrocoagulation may be effective. Angiographic embolization, usually with absorbable material such as a gelatin sponge, has been successfully employed in cases of failed endoscopic therapy. If these maneuvers fail, high gastrotomy and suturing of the mucosal tear are indicated. It is important to rule out the diagnosis of variceal bleeding in cases of failed endoscopic therapy by a thorough examination of the gastroesophageal junction. Recurrent bleeding from a Mallory-Weiss tear is uncommon.  Gastric Antral Vascular Ectasia Gastric antral vascular ectasia is characterized by a collection of dilated venules that appear as a linear red streak converging on the antrum, giving the appearance of a watermelon. Severe hemorrhage is rare in gastric antral vascular ectasia, and most patients present with persistent, iron deficiency anemia from continued occult blood loss. Endoscopic therapy is indicated for persistent anemia or transfusion-dependent bleeding. The success rate is upward of 90% with argon plasma coagulation (Fig. 47.4). Patients failing to respond to endoscopic therapy should be considered for antrectomy.  Dieulafoy Lesion Dieulafoy lesions are vascular malformations found primarily along the lesser curve of the stomach within 6 cm of the gastroesophageal junction, although they can occur elsewhere in the GI

CHAPTER 47  Acute Gastrointestinal Hemorrhage

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A

B

C FIG. 47.4  (A) Gastric antral vascular ectasia (GAVE) can be seen in the gastric antrum, giving the stomach a watermelon appearance. (B) Argon plasma coagulation therapy of GAVE. (C) Posttherapy appearance of GAVE. (Courtesy David L. Carr-Locke, MD, Brigham and Women’s Hospital.)

tract (Fig. 47.5). Erosion of the gastric mucosa overlying these sizable vessels (1 to 3 mm) found in the gastric submucosa leads to bleeding. The mucosal defect is usually small (2 to 5 mm), without an associated ulcer, thus making it difficult to identify.30 Given the large size of the underlying artery, bleeding from a Dieulafoy lesion can be massive (Fig. 47.6). Initial attempts at endoscopic control are often successful. Application of thermal or sclerosant therapy is effective in 80% to 100% of cases. In cases that fail endoscopic therapy, angiographic coil embolization can also be successful. If these approaches are unsuccessful, surgical intervention may be necessary; because of difficulties in visualization and palpation of these lesions, prior endoscopic tattooing or clipping can facilitate the procedure. A gastrotomy is performed, and attempts are made at identifying the bleeding source. The lesion can then be oversewn. In cases in which the bleeding point is not identified, a partial gastrectomy may be necessary.  Hemobilia Hemobilia is often a difficult diagnosis to make. It is typically associated with trauma, recent instrumentation of the biliary tree,

FIG. 47.5  Dieulafoy lesion of the stomach. (Courtesy Linda S. Lee, MD, Brigham and Women’s Hospital.)

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SECTION X  Abdomen is treated as such. More commonly, bleeding complications of IBD are self-limited and related to Crohn ileitis. They present as a LGIB that is responsive to medical therapy. 

FIG. 47.6  Bleeding Dieulafoy lesion with a spurting vessel. (Courtesy Marvin Ryou, MD, Brigham and Women’s Hospital.)

or hepatic neoplasms. Hemobilia remains uncommon but is gradually increasing in incidence with expanded use of advanced endoscopy and other minimally invasive hepatopancreaticobiliary procedures.31 This unusual cause of GIB should be suspected in anyone with suggestive history or those with right upper quadrant pain and/or jaundice. CT with angiography protocol is the preferred modality for diagnosis in those with an equivocal presentation. Endoscopy can be helpful by demonstrating blood at the ampulla or other biliary abnormalities suggestive of hemobilia and can offer numerous therapeutic options. However, angiography remains the gold standard for diagnosis and intervention and should be considered as the first step in patients with swift bleeding and a suggestive history. If angiographic embolization is performed, the portal vein must be verified to be patent. Surgical intervention is rarely needed except when all other therapies have failed, although it is still used occasionally for infected pseudoaneurysms or compression of surrounding vascular structures.31  Malignancy Malignant neoplasms of the UGI tract are usually associated with chronic anemia or hemoccult-positive stool rather than episodes of significant hemorrhage. On occasion, malignant neoplasms will be manifested as ulcerative lesions that bleed persistently. This is perhaps most characteristic of the GI stromal tumor (GIST), although it may occur with a variety of other lesions including adenocarcinoma, leiomyomas, and lymphomas. Although endoscopic therapy is often successful in controlling these bleeds, the rebleeding rate is high; therefore, when a malignant neoplasm is diagnosed, surgical resection is indicated. The extent of resection is dependent on the specific lesion and whether the resection is believed to be curative or palliative. Palliative resections for control of bleeding usually entail wedge resections. Standard cancer operations are indicated when possible, although this may depend on the hemodynamic stability of the patient.  Inflammatory Bowel Disease UGIB from inflammatory bowel disease (IBD) is exceedingly rare, with a few reported cases of duodenal Crohn disease. This type of bleeding can be the result of an ulcer eroding into a vessel and

Aortoenteric Fistula Aortoenteric fistulas can be classified as primary or secondary and most often involve the duodenum. These are usually fatal as they represent free rupture of the aorta into the bowel. Primary aortoenteric fistulas are rare and most commonly form as the result of an aortic aneurysm compressed against the bowel. Secondary fistulas are much more common and are the result of an aortic graft-enteric erosion and may develop in up to 0.4% to 4% of aortic graft cases. The interval between surgery and hemorrhage can be days to years, with the median interval about 3 years. The pathogenesis is poorly understood, although the sequence of formation is thought to involve the development of a pseudoaneurysm at the proximal anastomotic suture line in the setting of an infection with subsequent fistulization into the overlying duodenum. With endovascular stent-grafts, the mechanism may involve stent graft failure with an endoleak or fracture of the stent that allows aneurysm expansion or mechanical erosion into the adjacent bowel. This diagnosis of an aortoenteric fistula should be considered in all bleeding patients with a known abdominal aortic aneurysm or any prior aortic reconstruction. Hemorrhage in this situation is often massive and fatal unless immediate surgical intervention is undertaken. Typically, patients with bleeding from an aortoenteric fistula will present first with a “sentinel bleed.” This is a selflimited episode that heralds the subsequent massive and often fatal hemorrhage. These episodes can be separated by hours to months, and some patients may experience multiple sentinel bleeds. In stable patients, EGD is always the first-line test for UGIB. However, if the suspicion for an aortoenteric fistula is high, CTA should be the first-line study. One case series found CTA to have a sensitivity of 79%, whereas EGD had a sensitivity of 50%.32 Any evidence of bleeding in the distal duodenum (third or fourth portion) on EGD in a patient at risk for an aortoenteric fistula should be considered diagnostic. A CT with IV contrast will often show air around the graft, which is suggestive of infection, possible pseudoaneurysm, and occasionally extravasation of IV contrast into the bowel lumen. Therapy includes ligation of the aorta proximal to the graft, removal of the infected prosthesis with debridement of surrounding tissue, and extra-anatomic bypass. One must assume that the graft is infected, and treatment should include long-term antibiotics. Endovascular repair may be used as a bridge to definitive open repair.  Hemosuccus Pancreaticus Bleeding from the pancreatic duct is one of the rarest causes of UGIB. Hemosuccus pancreaticus is bleeding from the pancreatic duct through the ampulla of Vater, most typically from a pancreatic source such as a malformation, ductal wall ulceration, or a pancreatic pseudocyst that erodes into a pseudoaneurysm. Angiography is the diagnostic gold standard and first therapeutic line of action due to high efficacy (75%–100%) and low-associated mortality. Operative interventions may occasionally be required to treat the pseudocyst and should be aided by intraoperative ultrasonography or pancreatoscopy to diagnose the site of hemorrhage to guide operative planning. Other surgical procedures such as pancreatic resection and/or arterial ligation have largely been replaced by endovascular intervention.33 

CHAPTER 47  Acute Gastrointestinal Hemorrhage Procedure-Related Bleeding Percutaneous endoscopic gastrostomy tube placement is an increasingly common procedure that allows enteral nutrition in various acute and chronic disorders where patients are unable to have intake by mouth. Bleeding from percutaneous endoscopic gastrostomy placement is estimated to be as high as 3%. The bleeding most often occurs from puncture of a superficial vessel in the skin and is easily controlled with pressure. Bleeding from a punctured gastric vessel or mucosa is easily controlled by compression from traction on the bumper, although this should be temporary, with care taken to avoid pressure necrosis of the gastric wall. If these maneuvers are ineffective, then the tube may need to be removed and hemostasis achieved endoscopically. Endoscopic sphincterotomy has similar bleeding rates to percutaneous endoscopic gastrostomy and represents another example of iatrogenic bleeding, with a bleeding complication rate of approximately 2%. Bleeding is often mild and self-limited. Delayed hemorrhage usually occurs within the first 48 hours and may require injection of the area with epinephrine. Surgical intervention is rarely required. Hemobilia, as previously noted, may be iatrogenic in nature, particularly after percutaneous transhepatic procedures. Bleeding may also occur in any patient who has a suture or staple line from a gastric or intestinal resection and anastomosis. Risk factor reduction is largely based on the bariatric surgical literature and has revealed the following measures: maintaining systolic blood pressure control less than 140 mm Hg, staple line reinforcement with built-in pericardial strips or absorbable polymers, and intraoperative evaluation of resection lines at a reduced insufflation pressure (10 mm Hg) to diminish the tamponade effect of pneumoperitoneum during laparoscopic cases. Most surgical anastomotic bleeding resolves with nonoperative management In patients in whom bleeding persists, diagnostic and therapeutic endoscopy can be performed safely as long as insufflation is minimal and attention is paid to staple line stress. Reoperation for surgical anastomotic bleeding is rarely needed and has been estimated to occur in less than 1.4% of cases.34 

Variceal Hemorrhage Hypertension within the venous system of the GI tract can occur due to prehepatic (portal or splenic vein thrombus), intrahepatic (cirrhosis) or posthepatic (Budd-Chiari) pathology. By far, the most common clinical scenario leading to variceal hemorrhage is portal hypertension from the sinusoidal fibrosis associated with cirrhosis. Portal hypertension is defined as a hepatic venous pressure gradient of more than 5 mm Hg; however, a pressure greater than 12 mm Hg is generally required to develop varices. Increased resistance to flow of the portal vein and its tributaries leads to engorgement of portacaval collaterals in the esophagus, stomach, and the hemorrhoidal plexus. This state is exacerbated by the hyperaldosteronism and expanded plasma volume, as well as splanchnic vasodilatation that congests the intestinal circulation. Due to the large capacitance of the venous system, veins may pathologically dilate to diameters upward of 1 to 2 cm with increased wall tension stressing the overlying mucosa. Catastrophic bleeding can occur with disruption of the overlying mucosa, which, despite medical advancement in the field, still has an associated 6-week mortality of 10% to 20%.35 Management of variceal hemorrhage begins with prevention. Identifying the at-risk population has been aided by the introduction of transient elastography. Liver stiffness measured by transient elastography values of more than 15 to 20 kPa suggests compensated

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advanced chronic liver disease and thus should prompt EGD to evaluate for gastric varices and measurement of hepatic venous pressure gradient. EGD findings then dictate the appropriate prophylaxis. Patients without varices should be surveyed every 2 years, whereas those with small varices should be scoped annually. If small varices are noted to have high-risk features such as red wale marks (longitudinal red streaking), patients may benefit from starting a nonselective beta blocker. Patients with medium or large varices benefit from treatment with nonselective beta blockade (propranolol, nadolol, and carvedilol) or prophylactic banding.35 In the acute hemorrhage, attention to the ABCDEs of resuscitation is of utmost importance and has been described earlier in the chapter. Bleeding from varices can be brisk and is often complicated by coagulopathy and thrombocytopenia. The goal of resuscitation is to maintain tissue perfusion. Transfusions should be based on hemodynamic status and tissue perfusion assessment, but a hemoglobin target between 7 and 8 g/dL is generally recommended to minimize increasing the hepatic venous pressure gradient.9 Best evidence for reversal of coagulopathy has yet to be established, but the degree of hemostatic dysfunction may be belied by the international normalized ratio (INR) and partial thromboplastin time. Generally, attempts at an INR less than 2 and platelet count greater than 50,000 should be attempted. Vasoactive drugs such as terlipressin, somatostatin, octreotide, and vapreotide should be used prior to endoscopic evaluation and continued for up to 5 days. These medications decrease the flow to the mucosa and may decrease venous pressure. Importantly, antibiotics should be administered in any patient with UGIB and cirrhosis to guard against infection and spontaneous bacterial peritonitis. Current recommendations are for oral fluoroquinolones or IV Ceftriaxone (1 g every 24 hours) for patients with advanced disease or nil per os status. In rare circumstances, patients may present with such severe instability that a device for mechanical tamponade of the esophageal varices must be placed to prevent imminent exsanguination. The Sengstaken-Blakemore tube is equipped with two inflatable balloons to provide mechanical pressure. The first balloon is a gastric balloon. With confirmed placement of the uninflated tube into the stomach, the gastric port is inflated and placed on tension by securing it to a fixed helmet. The tension is applied to the gastroesophageal junction and often may arrest hemorrhage. However, if bleeding continues, the second balloon (the esophageal port) may be inflated to further tamponade the lower esophageal venous plexus. These tubes are temporary measures reserved for pronounced hemodynamic instability as a bridge to more definitive therapy. It is estimated that over 50% of patients will rebleed with deflation. Furthermore, by virtue of the balloon tamponade, local esophageal trauma and ischemia may result from prolonged inflation. Recent trials using self-expanding esophageal stents to control massive variceal hemorrhage have been encouraging, and a randomized controlled trial is examining hemostasis failure and rebleeding rates with this approach, but as of now, their clinical use remains experimental.36 Endoscopy is the first recommended step in any patient with cirrhosis and UGIB. Endoscopic venous ligation is preferred over sclerotherapy for acute esophageal bleeding. Definitive long-term management with early transjugular intrahepatic portosystemic shunt (TIPS) should be performed within 24 hours for high-risk patients and within 72 hours for other patient populations. TIPS is a procedure that connects the hepatic vein with the portal vein via an image-guided deployment of a metal stent though the hepatic parenchyma. This effectively decreases the venous pressure and achieves definitive hemostasis in greater than 90% of patients.

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Salvage therapy with this modality may be necessary in medically refractory or dying patients as this will immediately decrease the portal venous gradient. The incidence of encephalopathy is increased with TIPS, and there can be technical complications such as bleeding, arrhythmia, and stenosis. TIPS is contraindicated in patients with hepatocellular carcinoma (relative), heart failure, pulmonary hypertension, or tricuspid regurgitation. Failure of hemorrhage control is predicted by venous pressures greater than 20 mm Hg, Model for End-Stage Liver Disease (MELD) score greater than 20, Child-Pugh class C cirrhosis, and active bleeding at the time of intervention. Surgical decompression of the portal system is accomplished by creating an anastomosis from the portal system to a caval tributary. Surgical intervention is an effective, oftentimes superior, long-term therapy for variceal hemorrhage but is associated with a mortality rate in excess of 50%. Shunts are characterized by the degree of diversion of flow. Shunts that decompress the entire portal tree are considered a nonselective shunt. Other surgical shunts, such as the distal splenorenal shunt, selectively decompress the gastroesophageal varices while leaving the superior mesenteric and portal veins intact. Nonshunt operations are reserved for the moribund patients that are failing resuscitation efforts. These procedures include either esophageal transection in which the distal esophagus is transected and then a stapled reanastomosis performed in a delayed fashion after varices have been ligated or the Sugiura procedure, which entails devascularization of the gastroesophageal junction and splenectomy. Since the advent of TIPS, which similarly decompresses the portal system with less upfront mortality risk, operative interventions for variceal management are much less common and nonshunt operations are exceedingly rare. 

ACUTE LOWER GASTROINTESTINAL HEMORRHAGE LGIB is defined as bleeding originating distal to the ligament of Treitz, although, in some cases, it may refer specifically to bleeding distal to the ileocecal valve due to its unique nature when compared to small bowel bleeding.14 The most common presentation is painless hematochezia, defined as bright red blood, clots, or burgundy stools. A brisk UGIB can also present in the same way, and initial evaluation of hematochezia should always begin by ruling out a UGIB, as discussed previously in this chapter. Melena, a common presentation of UGIB, can occasionally be a sign of LGIB. Information from a directed history and physical can suggest specific causes of LGIB. For example, abdominal pain with diarrhea suggests inflammatory, ischemic, or infectious-type colitis. Altered bowel habits, iron-deficiency anemia, or unexplained weight loss may suggest malignancy.13 LGIB is a less common reason for hospitalization in the United States when compared to UGIB and accounts for 30% to 40% of GIB1 or an annual incidence of 35 per 100,000 persons.37 The mortality rate associated with LGIB is slightly below that of UGIB at just below 2% and increases to about 5% in those individuals older than 85 years old. In patients with LGIB, more than 95% will have a source in the colon (Table 47.2). In general, the incidence of hospitalization, morbidity, and mortality for LGIB increases with age. The cause is also often related to age. Vascular lesions and diverticular disease affect all age groups but have an increasing incidence in middle-aged and elderly adults. In the pediatric population, intussusception is most commonly responsible, whereas Meckel diverticulum must be considered in the differential in the young adult. The clinical presentation of LGIB ranges from severe hemorrhage with diverticular disease or vascular lesions to a minor bleeding secondary to anal fissure or hemorrhoids.

TABLE 47.2  Differential diagnosis of lower

gastrointestinal hemorrhage. COLONIC BLEEDING

95%

Diverticular disease Anorectal disease

30%–40% 5%–15%

Ischemia Neoplasia Infectious colitis Postpolypectomy Inflammatory bowel disease Angiodysplasia Radiation colitis or proctitis Other Unknown

5%–10% 5%–10% 3%–8% 3%–7% 3%–4%

SMALL BOWEL BLEEDING

5%

Angiodysplasias Erosions or ulcers (potassium, nonsteroidal antiinflammatory drugs) Crohn disease Radiation Meckel diverticulum Neoplasia Aortoenteric fistula

3% 1%–3% 1%–5% 10%–25%

Diagnosis Hemorrhage from the lower GI tract tends to be less severe and intermittent, often spontaneously resolving between attempts at localization with endoscopy or other modalities. Additionally, over 40% of patients with LGIB have multiple lesions identified as the potential source of bleeding. If more than one lesion is identified, it is critical to confirm the responsible lesion before initiating aggressive therapy. Due to these factors, there is no diagnostic modality as sensitive or specific in LGIB as endoscopy is in UGIB. Additionally, these patients may need longer observations and suffer several episodes of bleeding before a definitive diagnosis is made. In up to 25% of patients with LGIB, the source of bleeding is never accurately identified. An algorithm for evaluation and management of LGIB is shown in Fig. 47.7. As always, one should begin with an initial evaluation and resuscitation as discussed previously. Anticoagulation should be reversed, and coagulation disorders treated aggressively. The exception to this rule is in the patient with high-risk cardiovascular disease in whom current guidelines support the continuation of ASA. The first step in further workup is to rule out anorectal bleeding with a digital rectal examination and anoscopy or sigmoidoscopy and to provide appropriate treatment if positive. With significant bleeding, it is also important to eliminate a UGI source. Up to 15% of patients with hematochezia had a UGI source to account for the bleed.37 A nasogastric aspirate that contains bile and no blood effectively rules out an active upper tract bleeding site. However, when emergent surgery for life-threatening hemorrhage is being contemplated, preoperative or intraoperative EGD can be appropriate even when LGIB is suspected. Subsequent evaluation depends on the magnitude of the hemorrhage and can be classified as minor, major, or massive. Patients with minor LGIB are hemodynamically stable and generally can be evaluated as outpatients. The most common causes of minor LGIB are anorectal lesions such as hemorrhoids or fissures, although IBD, infectious colitis, arteriovenous malformations, polyps, and malignancy can also be potential sources. Major LGIB can be defined as hemorrhage associated with hemodynamic instability, altered mental status, or the need for two or more units

CHAPTER 47  Acute Gastrointestinal Hemorrhage

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Acute lower GI bleeding

Initiate appropriate therapy

Yes

Rule out anorectal outlet bleeding: Positive digital rectal exam or anoscopy? No Rule out UGI bleeding: Positive NGT aspirate? EGD positive?

Bowel prep and colonoscopy No Active bleeding impairs colonoscopy unable to prep

Angiography CTA Scintigraphy

No localization

Evaluation of small bowel with video capsule endoscopy, deep endoscopy, angiography, Meckel scan, scintigraphy

Localization of bleeding

Colonoscopic hemostasis

Yes

UGI bleeding algorithm

No Hemodynamically unstable despite resuscitation? Yes Surgery, hybrid room with angiography

Unsuccessful Bleeding localized in colon or small bowel

Localization

Yes Angiographic treatment or surgery with segmental resection

Segmental resection, angiographic treatment

No Localization with serial clamping, intraoperative enteroscopy. Subtotal colectomy if necessary.

FIG. 47.7  Algorithm for diagnosis and management of lower GI hemorrhage. CTA, Computed tomography angiogram; EGD, esophagogastroduodenoscopy; GI, gastrointestinal; NGT, nasogastric tube; UGI, upper GI.

of blood. Massive LGIB is when a patient requires 10 or more units of blood products. The truly unstable patient who continues to bleed and requires ongoing aggressive resuscitation belongs in the operating room for expeditious diagnosis and surgical intervention. In facilities equipped with hybrid operating rooms, angiography can be helpful to localize bleeding or attempt endovascular therapy in the presence of immediate surgical intervention. Intraoperative endoscopy is also a useful adjunct to identify a source of bleeding. When the hemorrhaging patient responds to resuscitation and is hemodynamically stable, the evaluation and therapeutic intervention can be more directed. Colonoscopy is the mainstay here because it allows both visualization of the pathologic process and therapeutic intervention in colonic, rectal, and distal ileal sources of bleeding. CTA, mesenteric angiography, and tagged RBC scintigraphy are important components of the evaluation, provided there are no contraindications. If these modalities are nondiagnostic and UGIB has been ruled out, then the source of the hemorrhage is considered obscure and further evaluation is detailed previously the chapter. Colonoscopy For patients who are stable, colonoscopy is almost always the initial examination of choice for LGIB. Exceptions include patients who are unable to tolerate a bowel prep or if the bleeding is severe enough to limit the visualization through the colonoscope. Colonoscopy should only be performed after an adequate bowel prep, such as the “rapid prep” protocol described previously. Similar to

endoscopy for UGIB, colonoscopy should be performed within 24 hours. The causes of LGIB most likely to have successful endoscopic treatment are diverticular, angioectasia, and postpolypectomy. Overall endoscopic success is good with one review showing a hemostasis rate of 92% and early and late rebleed rates of 8% and 12%, respectively.38 The most common source of bleeding is diverticular, and even though an actively bleeding diverticulum may not be seen during endoscopy, certain features are predictive of high risk of rebleeding. Findings of active bleeding, a visible vessel, or adherent clot that cannot be dislodged by irrigation and suctioning are associated with a high risk of rebleed and should undergo endoscopic treatment.39 An India ink tattoo should be placed to identify the area of bleeding in case repeat intervention is needed. Other endoscopic therapeutic interventions include polypectomy, epinephrine injection, direct contact thermal coagulation, argon plasma coagulation, application of metal clips to lesions, and band ligation of internal hemorrhoids or rectal varices  Angiography When endoscopy is unable to localize a LGIB, angiography is an important diagnostic as well as therapeutic tool. Other imaging modalities that complement and help direct angiography are CTA and tagged RBC scintigraphy (see discussion above in “Localization”). When used prior to angiography, CTA and tagged RBC scans improve the localization of angiography.11 Because it relies on active bleeding, angiography is most useful in the setting of brisk bleeding. Using superselective embolization, it is possible to

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isolate bleeding from one specific diverticulum. The hemostatic techniques available are the same as those discussed for UGIB. The superior mesenteric artery is usually the first artery interrogated; however, if LGIB is suspected, the inferior mesenteric artery may be interrogated first. When used to treat diverticular bleeding, the rate of successful hemostasis approaches 100%, with rebleed rates as low as 0%.39 Other modalities may be utilized to localize lower intestinal bleeding. In a retrospective review of 600 cases, tagged RBC scan was positive in only about 39% to 45% of LGIB,40,41 with a significant false-positive rate of 10%.41 Despite its low sensitivity, the ability to perform repeat testing can be helpful in the diagnostic armamentarium, particularly in intermittent bleeding. Similarly, capsule endoscopy can also reveal bleeding lesions in the prepped colon. 

Surgical Management Persistent hemodynamic instability despite resuscitation attempts or administering more than 4 units of blood in 24 hours or more than10 units of blood during the hospital stay are considered indications for surgery. Preoperative identification of the culprit lesion is particularly important in LGIB because, without localization, the empiric surgery for unlocalized LGIB is a total abdominal colectomy and end ileostomy. Evidence in support of this practice of “blind subtotal colectomy” is limited and based on the high rebleeding rate with segmental resection (18% vs. 4% with total abdominal colectomy) and is associated with 20% to 30% mortality in the emergent setting. In the unstable patient with high transfusion requirements, intestinal anastomosis is to be avoided due to the conferred mortality of an anastomotic leak.42,43 Consideration for an oncologic resection in scenarios suspicious for malignancy is important when hemodynamic stability allows. An alternative management strategy in the dying patient is a damage control operation with delayed definitive therapy in order to support the patient’s physiology to “fight another day.” 

Specific Causes of Lower Gastrointestinal Tract Bleeding Diverticula In the United States, diverticula are the most common cause of significant LGIB. Among all with colonic diverticula, 3% to 15% will experience bleeding.39 The incidence of diverticula increases with age, with 20% at age 40 and increasing to 60% and beyond at age 60.44 In the past, diverticula were thought to be rare in patients younger than 40 years, but it is now an increasingly common diagnosis in this age group. Diverticula form at points of weakness in the bowel wall, where the vasa recta penetrate the circular muscle layer. As the dome of the diverticulum expands, the penetrating vessel is stretched and undergoes changes that can lead to vessel rupture and bleeding. In western countries, left-sided disease is far more common than right-sided disease; however, right-sided disease is responsible for over 50% of significant diverticular bleeding. Of those that bleed, more than 75% stop spontaneously, although approximately 10% will rebleed within a year and almost 50% within 10 years.44 Colonoscopy is the best modality for diagnosis and therapy. The endoscopic treatment options are similar to those for PUD and include injection, thermal coagulation, plasma argon coagulation, mechanical clips, and fibrin glue. Use of clips have an added advantage in that they can mark the location of bleeding if repeat

intervention is required. An actively bleeding vessel, or stigmata of recent bleeding, should prompt treatment. Like UGIB, monotherapy with injection of epinephrine should always be combined with another modality. The bleeding diverticulum should be marked with a tattoo if no clip was placed. With recurrent bleeding, colonoscopy can be repeated, or mesenteric angiography can be performed. If colonoscopy is unable to isolate or visualize bleeding or there is recurrent bleeding, angiography with superselective cannulation and embolization can be considered. A clip placed during colonoscopy can be used to help localize the site of bleeding. Surgical intervention should be considered a last resort when all other therapeutic options have failed, and the patient remains hemodynamically unstable despite aggressive resuscitation. Colonic resection should never be undertaken purely on clinical suspicion. Some mode of localization must be performed to rule out upper and small bowel bleeding and ensure that the bleeding lesion is resected. Blind total abdominal colectomy for GI hemorrhage carries with it high morbidity and mortality and does not entirely remove the risk for rebleed, which is approximately 4%. Segmental resection can be performed if bleeding is identified at a specific portion of the colon, although it does carry a higher risk of rebleeding (i.e., approximately 18%) compared to total abdominal colectomy.43  Colitis Inflammation of the colon can result from multiple disease processes, including IBD, infectious colitis, radiation proctitis after treatment for pelvic malignancies, and ischemia. Ulcerative colitis (UC) is much more likely than Crohn disease to manifest with GIB. Most UC patients and about one-third of Crohn patients will experience gross bleeding at some point in their disease course.45 Major acute hemorrhage from either form of IBD is rare. UC is a mucosal disease that begins in the rectum and can progress proximally to occasionally involve the entire colon. Patients typically present with diarrhea that may be bloody. Rectal inflammation results in small frequent bowel movements of up to 20 times a day, usually accompanied by crampy abdominal pain and tenesmus. Diagnosis is by careful history and colonoscopy with biopsy. The mainstays of treatment are supportive care with steroids, 5-aminosalicyclic acid compounds, immunomodulators, biologics, and antibiotics if indicated. Major hemorrhage from UC is rare. Bleeding will almost always be from a diffuse colitis with no discrete lesions amenable to endoscopic treatment. Urgent surgical therapy is occasionally needed because of ongoing bleeding but is more commonly indicated because of other complications of UC such as toxic megacolon or symptoms that are refractory to medical treatment. Crohn disease is more typically associated with guaiac-positive diarrhea and mucous stools without gross blood. It can affect any portion of the GI tract and is characterized by skip lesions, transmural thickening and inflammation of the bowel wall, and granulomas. Diagnosis is by endoscopy, biopsy, and contrast studies. Medical management consists of steroids, 5-aminosalicylic acid compounds, antibiotics, immunomodulators, and biologics. Similar to UC, significant bleeding requiring intervention is rare in Crohn disease. In contrast, Crohn disease is more likely to have discrete lesions that can undergo endoscopic or angiographic intervention, usually in the form of an ulcer that has eroded into a vessel. These ulcers can occur anywhere in the upper or lower GI tract, including the small bowel.45 Patients

CHAPTER 47  Acute Gastrointestinal Hemorrhage with long-standing disease may have strictures that impede passage of an endoscope.  Angiodysplasia/Arteriovenous Malformation Angiodysplasias of the intestine are also referred to as arteriovenous malformations, angiectasias, and vascular ectasia. These are thought to be acquired degenerative lesions secondary to progressive dilatation of normal submucosal blood vessels due to venous obstruction and are distinct from true congenital arteriovenous malformations. They can be found anywhere in the GI tract, although typically they occur in the cecum, and accordingly, this is where they most often cause bleeding. Their prevalence increases with age, and they are associated with aortic stenosis and renal failure. There is no gender predilection. The presentation is similar to diverticular bleeding in that it is painless, usually self-limiting, and intermittent. Unlike diverticular bleeding, this tends to be venous bleeding, so it is less brisk and often occult and will present more often as chronic bleeding. Nevertheless, the hemorrhage can be significant in up to 15% of cases. Diagnosis is by colonoscopy or angiography. CT scan is emerging as another reliable modality for diagnosis. On colonoscopy, these lesions appear as flat, bright-red, stellate lesions with a surrounding rim of pale mucosa. Angiography demonstrates dilated, slowly emptying veins and sometimes early venous filling. Incidentally discovered lesions do not require any further treatment. When treated endoscopically, noncontact thermal therapy with argon plasma coagulation is the preferred method. Angiographic techniques can also be used for hemostasis. If the bleeding has been localized and these attempts at hemostasis fail or bleeding recurs, segmental colon resection, most commonly right colectomy, is also effective.  Neoplasms Colon cancer is an uncommon cause of significant LGIB, but it is essential to rule out the possibility of a colon malignancy in any patient with LGIB or iron-deficient anemia. The bleeding is usually painless, intermittent, and slow in nature. Colonoscopy is the gold standard for diagnosis, except in massive hemorrhage, where CTA, angiography, or emergent surgery may be necessary. Another neoplastic cause for bleeding is GIST. GISTs are the most common soft tissue sarcoma in the digestive tract, with bleeding evident in 20% to 30% of cases. GISTs tend to present more frequently in the stomach and small intestine but can also affect the colon. Erosion into a blood vessel or alteration of the mucosal blood supply by local tumor growth leads to hemorrhage. Endoscopy is the best diagnostic tool. Oncologic resection based on the malignant risk of the tumor is needed to address this source. Small bowel tumors are not common but can be sources of occult or frank GIB. Small bowel tumors are typically diagnosed by small bowel contrast series or spiral CT scan. Treatment involves surgical resection. Intestinal polyps are rare sources of blood loss and more commonly present as an iatrogenic bled after polypectomy. In the pediatric population, they represent the second most common cause of bleeding. If the bleeding is attributable to a polyp, it can usually be treated with endoscopic therapy.  Ischemia Insufficient blood flow to the intestinal tract may be due to cardiogenic shock or low flow states, mesenteric vascular disease, or

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diversion of flow from the splanchnic circulation (embolism, vasopressors, vascular surgery). Mesenteric ischemia should be considered in any patient with bleeding with a past medical history of cardiovascular disease, peripheral vascular disease, or vasculitis. Additionally, the diagnosis should be entertained in any patient with recent abdominal vascular surgery, shock, or hypercoagulable states or on high-dose vasopressors. Acute colonic ischemia is the most common form of mesenteric ischemia. It tends to occur in the watershed areas of the splenic flexure and the rectosigmoid colon but can be right sided in up to 40% of patients. Patients present with a characteristic “pain out of proportion to exam” and diarrhea that is often guaiac positive or bloody from mucosal degradation. CT may show thickened bowel wall, pneumatosis, or more subtle signs of vascular disease such as calcification of the takeoff of the mesenteric vasculature. The diagnosis is generally confirmed with flexible endoscopy, which reveals an abnormal mucosa. Treatment is supportive and consists of bowel rest, IV antibiotics, support of blood pressure, and correction of the low-flow state. In 85% of cases, the ischemia is self-limited and resolves without incident, although some patients develop a delayed colonic stricture. In the other 15% of cases, surgery is indicated because of progressive ischemia and gangrene. Marked leukocytosis, fever, ongoing resuscitation, lactic acidosis, or severe pain indicate ongoing ischemia and the likely need for surgical resection and an end ostomy creation.46  Infectious Infectious colitis may present with bleeding. History, laboratory assessment, and culture data can inform the diagnosis. The two most notable organisms that can lead to LGIB are Clostridium difficile and cytomegalovirus. C. difficile colitis represents the overgrowth of a pathogenic clostridial bacterium that thrives after disruption of the normal gut microflora after antibiotic use. Explosive, voluminous, and, at times, bloody bowel movements can result from severe cases with associated mucosal sloughing. Profound leukocytosis is often observed as well as a characteristic foul smell. Treatment consists of stopping antibiotics, supportive care, and taking oral or IV metronidazole, oral vancomycin, or fidaxomicin. Cytomegalovirus colitis should be suspected in any immunocompromised patient who presents with bloody diarrhea. Endoscopy with biopsy confirms the diagnosis; treatment is IV ganciclovir.  Diverticula Meckel diverticula are congenital remnants of the vitelline duct that may contain either gastric or pancreatic ectopic tissue. Bleeding results from ulceration of the neighboring ileal tissue from irritation from an active focus of gastric mucosa. Bleeding is typically painless LGIB. Diagnosis can be made with capsule studies, CT, or with angiography in the setting of active bleeding. Angiographic findings aside from bleeding may include the presence of the vitelline artery, a superior mesenteric artery branch that is pathognomonic. A Meckel diverticulum scan, performed by administration of 99mTc-pertechnetate, can demonstrate ectopic gastric mucosa that can be localized with scintigraphy. Definitive treatment is surgical resection of the segment with care to incorporate the ulcerated ileal tissue, typically on the intestinal wall opposite the diverticulum.47 Small bowel diverticula are also occasionally the source of bleeding, which is often occult. Diagnosis may be suspected based on a history of known small bowel diverticula, capsule endoscopy, or angiography. Definitive management is surgical resection. 

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Radiation Therapy The use of radiation to treat pelvic cancers can be associated with bleeding-related complications. Bleeding from enteritis and, more commonly, proctitis complicates 1% to 5% of treated patients. Bleeding results from mucosal changes that, on endoscopy, reveal friability, angioectasias, and ulcerations. The American Society of Colon and Rectal Surgeons has published guidelines for therapy, which include strong recommendations for treatment with formalin 4% to 10%, sucralfate enemas, and hyperbaric oxygen. Endoscopic therapy with argon coagulation is additionally recommended as an effective treatment but is associated with fistula and stricture formation in 3% of patients.48

SELECTED REFERENCES de Franchis R. Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension. J Hepatol. 2015;63:743–752. This consensus paper is the result of the most recent Baveno Consensus Workshop, a recurring meeting of international experts in the field of portal hypertension. The 2015 meeting focused on the topics of invasive and noninvasive methods for screening and surveillance of gastroesophageal varices and of portal hypertension, the impact of etiologic therapy for cirrhosis, the primary prevention of decompensation, the management of the acute bleeding episode, the prevention of recurrent hemorrhage and other decompensating events, and vascular diseases of the liver in cirrhotic and noncirrhotic patients.

Gurudu SR, Bruining DH, Acosta RD, et al. The role of endoscopy in the management of suspected small-bowel bleeding. Gastrointest Endosc. 2017;85:22–31. Practice guidelines from the American Society for Gastrointestinal Endoscopy for the use of gastrointestinal endoscopy in small bowel bleeding.

Pasha SF, Leighton JA. Evidence-based guide on capsule endoscopy for small bowel bleeding. Gastroenterol Hepatol (N Y). 2017;13:88–93. Capsule endoscopy is the test of choice to evaluate for small bowel bleeding when other gastrointestinal sources have been ruled out. This paper provides a comprehensive review of capsule endoscopy, covering topics a clinician should be familiar with when considering the use of this diagnostic tool.

Strate LL, Gralnek IM. ACG clinical guideline: management of patients with acute lower gastrointestinal bleeding. Am J Gastroenterol. 2016;111:755. American College of Gastroenterology guidelines and literature review for management of acute lower gastrointestinal bleeding. It includes evidenced-based recommendations for resuscitation, risk stratification, diagnosis, and specific treatment modalities.

Tielleman T, Bujanda D, Cryer B. Epidemiology and risk factors for upper gastrointestinal bleeding. Gastrointest Endosc Clin N Am. 2015;25:415–428. Describes historical as well as more recently identified risk factors for upper gastrointestinal bleeding.

Villanueva C, Colomo A, Bosch A, et  al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013;368:11–21. Randomized trial comparing restrictive to liberal transfusion strategies in patients with acute upper gastrointestinal bleeding.

Wang YR, Richter JE, Dempsey DT. Trends and outcomes of hospitalizations for peptic ulcer disease in the United States, 1993 to 2006. Ann Surg. 2010;251:51–58. This study describes the changes in epidemiology and outcomes of peptic ulcer disease as the approach to medical and surgical treatment has changed over time.

REFERENCES 1. Peery AF, Crockett SD, Barritt AS, et  al. Burden of gastrointestinal, liver, and pancreatic diseases in the United States. Gastroenterology. 2015;149:1731–1741.e1733. 2. Nguyen NH, Khera R, Ohno-Machado L, et  al. Annual burden and costs of hospitalization for high-need, highcost patients with chronic gastrointestinal and liver diseases. Clin Gastroenterol Hepatol. 2018;16:1284–1292. e1230. 3. Abougergi MS, Travis AC, Saltzman JR. The in-hospital mortality rate for upper GI hemorrhage has decreased over 2 decades in the United States: a nationwide analysis. Gastrointest Endosc. 2015;81:882–888.e881. 4. Lanas A, Garcia-Rodriguez LA, Polo-Tomas M, et  al. Time trends and impact of upper and lower gastrointestinal bleeding and perforation in clinical practice. Am J Gastroenterol. 2009;104:1633–1641. 5. Cannon JW. Hemorrhagic shock. N Engl J Med. 2018;378:370–379. 6. Etchill EW, Myers SP, McDaniel LM, et al. Should all massively transfused patients be treated equally? An analysis of massive transfusion ratios in the nontrauma setting. Crit Care Med. 2017;45:1311–1316. 7. Fabricius R, Svenningsen P, Hillingso J, et  al. Effect of transfusion strategy in acute non-variceal upper gastrointestinal bleeding: a nationwide study of 5861 hospital admissions in Denmark. World J Surg. 2016;40:1129– 1136. 8. Gonzalez E, Moore EE, Moore HB, et  al. Goal-directed hemostatic resuscitation of trauma-induced coagulopathy: a pragmatic randomized clinical trial comparing a

CHAPTER 47  Acute Gastrointestinal Hemorrhage viscoelastic assay to conventional coagulation assays. Ann Surg. 2016;263:1051–1059. 9. Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013;368:11–21. 10. Cappell MS, Friedel D. Initial management of acute upper gastrointestinal bleeding: from initial evaluation up to gastrointestinal endoscopy. Med Clin North Am. 2008;92:491– 509, xi. 11. Jacovides CL, Nadolski G, Allen SR, et al. Arteriography for lower gastrointestinal hemorrhage: role of preceding abdominal computed tomographic angiogram in diagnosis and localization. JAMA Surg. 2015;150:650–656. 12. Marti M, Artigas JM, Garzon G, et al. Acute lower intestinal bleeding: feasibility and diagnostic performance of CT angiography. Radiology. 2012;262:109–116. 13. Gralnek IM, Neeman Z, Strate LL. Acute lower gastrointestinal bleeding. N Engl J Med. 2017;376:1054–1063. 14. Strate LL, Gralnek IM. ACG clinical guideline: management of patients with acute lower gastrointestinal bleeding. Am J Gastroenterol. 2016;111:755. 15. Pasha SF, Leighton JA. Evidence-based guide on capsule endoscopy for small bowel bleeding. Gastroenterol Hepatol (N Y). 2017;13:88–93. 16. Gurudu SR, Bruining DH, Acosta RD, et  al. The role of endoscopy in the management of suspected small-bowel bleeding. Gastrointest Endosc. 2017;85:22–31. 17. Tielleman T, Bujanda D, Cryer B. Epidemiology and risk factors for upper gastrointestinal bleeding. Gastrointest Endosc Clin N Am. 2015;25:415–428. 18. Wang YR, Richter JE, Dempsey DT. Trends and outcomes of hospitalizations for peptic ulcer disease in the United States, 1993 to 2006. Ann Surg. 2010;251:51–58. 19. Laine L. Clinical practice. Upper gastrointestinal bleeding due to a peptic ulcer. N Engl J Med. 2016;374:2367–2376. 20. Sreedharan A, Martin J, Leontiadis GI, et  al. Proton pump inhibitor treatment initiated prior to endoscopic diagnosis in upper gastrointestinal bleeding. Cochrane Database Syst Rev. 2010:CD005415. 21. Gisbert JP, Khorrami S, Carballo F. H.pylori eradication therapy vs. antisecretory non-eradication therapy (with or without long-term maintenance antisecretory therapy) for the prevention of recurrent bleeding from peptic ulcer. Cochrane Database Syst Rev. 2003:CD004062. 22. Chan FK, Wong VW, Suen BY, et  al. Combination of a cyclo-oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomised trial. Lancet. 2007;369:1621–1626. 23. McNeil JJ, Wolfe R, Woods RL, et al. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med. 2018;379:1509–1518. 24. Sung JJ, Lau JY, Ching JY, et al. Continuation of low-dose aspirin therapy in peptic ulcer bleeding: a randomized trial. Ann Intern Med. 2010;152:1–9. 25. Laine L, McQuaid KR. Endoscopic therapy for bleeding ulcers: an evidence-based approach based on meta-analyses of randomized controlled trials. Clin Gastroenterol Hepatol. 2009;7:33–47; quiz 31–32.

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26. Lau JY, Sung JJ, Lam YH, et al. Endoscopic retreatment compared with surgery in patients with recurrent bleeding after initial endoscopic control of bleeding ulcers. N Engl J Med. 1999;340:751–756. 27. Kim JS, Park SM, Kim BW. Endoscopic management of peptic ulcer bleeding. Clin Endosc. 205;48:106–111. 28. Ramaswamy RS, Choi HW, Mouser HC, et al. Role of interventional radiology in the management of acute gastrointestinal bleeding. World J Radiol. 2014;6:82–92. 29. Elmunzer BJ, Young SD, Inadomi JM, et  al. Systematic review of the predictors of recurrent hemorrhage after endoscopic hemostatic therapy for bleeding peptic ulcers. Am J Gastroenterol. 2008;103:2625–2632; quiz 2633. 30. Nguyen DC, Jackson CS. The Dieulafoy’s lesion: an update on evaluation, diagnosis, and management. J Clin Gastroenterol. 2015;49:541–549. 31. Berry R, Han J, Girotra M, et  al. Hemobilia: perspective and role of the advanced endoscopist. Gastroenterol Res Pract. 2018;2018:3670739. 32. Deijen CL, Smulders YM, Coveliers HME, et  al. The Importance of early diagnosis and treatment of patients with aortoenteric fistulas presenting with Herald bleeds. Ann Vasc Surg. 2016;36:28–34. 33. Ferreira J, Tavares AB, Costa E, et al. Hemosuccus pancreaticus: a rare complication of chronic pancreatitis. BMJ Case Rep. 2015;2015. 34. Silecchia G, Iossa A. Complications of staple line and anastomoses following laparoscopic bariatric surgery. Ann Gastroenterol. 2018;31:56–64. 35. de Franchis R. Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension. J Hepatol. 2015;63:743–752. 36. Zehetner J, Shamiyeh A, Wayand W, et  al. Results of a new method to stop acute bleeding from esophageal varices: implantation of a self-expanding stent. Surg Endosc. 2008;22:2149–2152. 37. Laine L, Yang H, Chang SC, et  al. Trends for incidence of hospitalization and death due to GI complications in the United States from 2001 to 2009. Am J Gastroenterol. 2012;107:1190–1195; quiz 1196. 38. Strate LL, Naumann CR. The role of colonoscopy and radiological procedures in the management of acute lower intestinal bleeding. Clin Gastroenterol Hepatol. 2010;8:333–343; quiz e344. 39. Niikura R, Nagata N, Shimbo T, et  al. Natural history of bleeding risk in colonic diverticulosis patients: a long-term colonoscopy-based cohort study. Aliment Pharmacol Ther. 2015;41:888–894. 40. Zuckerman GR, Prakash C. Acute lower intestinal bleeding, part I: clinical presentation and diagnosis. Gastrointest Endosc. 1998;48:606–617. 41. Tabibian JH, Wong Kee, Song LM, et al. Technetium-labeled erythrocyte scintigraphy in acute gastrointestinal bleeding. Int J Colorectal Dis. 2013;28:1099–1105. 42. Bender JS, Wiencek RG, Bouwman DL. Morbidity and mortality following total abdominal colectomy for massive lower gastrointestinal bleeding. Am Surg. 1991;57:536–540; discussion 540–531.

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43. Farner R, Lichliter W, Kuhn J, et  al. Total colectomy versus limited colonic resection for acute lower gastrointestinal bleeding. Am J Surg. 1999;178:587–591. 44. Strate LL. Lower GI bleeding: epidemiology and diagnosis. Gastroenterol Clin North Am. 2005;34:643–664. 45. Pardi DS, Loftus Jr EV, Tremaine WJ, et  al. Acute major gastrointestinal hemorrhage in inflammatory bowel disease. Gastrointest Endosc. 1999;49:153–157. 46. Walker AM, Bohn RL, Cali C, et  al. Risk factors for colon ischemia. Am J Gastroenterol. 2004;99:1333–1337.

47. Hansen CC, Soreide K. Systematic review of epidemiology, presentation, and management of Meckel’s diverticulum in the 21st century. Medicine (Baltimore). 2018;97:e12154. 48. Paquette IM, Vogel JD, Abbas MA, et  al. The American Society of Colon and Rectal Surgeons clinical practice guidelines for the treatment of chronic radiation proctitis. Dis Colon Rectum. 2018;61:1135–1140.

CHAPTER

48

Morbid Obesity William O. Richards, Leena Khaitan, Alfonso Torquati

OUTLINE Obesity: The Magnitude of the Problem Pathophysiology and Associated Medical Problems Medical Versus Surgical Therapy Metabolic Surgery Versus Medical Therapy for Diabetes Bariatric Surgery Mechanism of Action The Enteroencephalic Endocrine Axis Enteroinsular Endocrine Axis Preoperative Evaluation and Selection Eligibility General Bariatric Preoperative Evaluation and Preparation Evaluation of Specific Comorbid Conditions Special Equipment Operative Procedures Laparoscopic Adjustable Gastric Banding Roux-en-Y Gastric Bypass Biliopancreatic Diversion Duodenal Switch Laparoscopic Sleeve Gastrectomy Postoperative Care and Follow-Up Laparoscopic Adjustable Gastric Banding

Roux-en-Y Gastric Bypass, Biliopancreatic Diversion, Duodenal Switch, and Laparoscopic Sleeve Gastrectomy Bariatric Surgery Results Laparoscopic Adjustable Gastric Banding Roux-en-Y Gastric Bypass Biliopancreatic Diversion and Duodenal Switch Complications of Bariatric Surgery Laparoscopic Adjustable Gastric Banding Roux-en-Y Gastric Bypass Biliopancreatic Diversion and Duodenal Switch Laparoscopic Sleeve Gastrectomy Reoperative Surgery Endoscopic Procedures in Bariatric Surgery Preoperative Use of Endoscopy Intraoperative Endoscopy Postoperative Endoscopy Primary Endoscopic Weight Loss Procedures Controversies in Bariatric Surgery Conclusion

Please access Elsevier eBooks for Practicing Clinicians to view the videos for this chapter https://expertconsult.inkling.com/.

National Health and Nutrition Examination Survey (NHANES). The percentage of obese adults (BMI >30) in the United States increased 16 percentage points from 1980 to 2000, and increased by another 9 percentage points from 2000 to 2016.1 There are also significant differences in the prevalence of obesity in adults by sex, race, and Hispanic origin. Non-Hispanic Asians (12.7%) had significantly lower rates of obesity than all other race and non-Hispanic origin groups. Non-Hispanic whites (37.9%) had a lower prevalence of obesity than non-Hispanic black (46.8%) and Hispanic adults (47%). Hispanic men (43.1%) had a greater prevalence of obesity compared to nonHispanic Asian (10.1%) and non-Hispanic black men (36.9%).1 Worldwide, from 1975 to 2016, there has been a trend of increasing obesity in children and adolescents (age 5–19) in most regions of the world. The rate of increase in BMI has decreased in most high-income countries since 2000 albeit remaining at a high level. The rate of BMI increase, however, has accelerated in East, South, and Southeast Asia and is expected to surpass moderate to severe underweight children in those areas by 2022. Several countries (Nauru, Cook Islands, Palau, Niue, American Samoa) surpassed the United States in prevalence of obesity, while obesity was more than 20% or more in the United States, Polynesia, Micronesia, Middle East, and North Africa.2 The prevalence of morbidly obese adults (BMI >40) has increased to 6.3% of the adult United States population and is the second leading cause of preventable death in the United States. Morbid

OBESITY: THE MAGNITUDE OF THE PROBLEM Until very recently, obesity was not recognized as a disease, which confounded the ability of physicians to be compensated for treatment they delivered and to treat the condition effectively. The American Medical Association (AMA) officially recognized obesity as a disease in 2013 and in 2014 voted to approve the resolution “that our AMA, advocate for patient access to the full continuum of care of evidence-based obesity treatment modalities (including surgical interventions).” Morbid obesity is defined as being 100 lbs above ideal body weight, twice ideal body weight, or body mass index (BMI; measured as weight in kilograms divided by height in meters squared) of 40 kg/m2. The last definition is more accepted internationally and has essentially replaced the former ones for all practical and scientific purposes. A consensus conference by the National Institutes of Health (NIH) in 1991 suggested that the term severe obesity is more appropriate for defining people of such size. This term is used interchangeably with morbid obesity in the remainder of this chapter. The obesity epidemic in America continues to the point where nearly 40% of the U.S. adult population is obese, and prevalence of obesity in adolescents has increased to 18.5% in the most recent

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obesity is second only to smoking on the list of preventable factors responsible for increased health care costs. It is a sobering thought to realize that a 40-year-old morbidly obese man has a 12.4% reduction in life expectancy, or 9.1 years of life lost, compared with a normal-sized man. Moreover, the cost of care is staggering and may be as high as 9% of annual medical expenditures or $147 billion per year. There appears to be significant population heterogeneity between BMI and mortality that is attenuated by increasing age of the individual. Mortality also increases significantly even for individuals with minimal increases in BMI greater than 30.0. Thus, it appears that age, gender, race, and income level all play a role in the development of obesity and obesity-related mortality.2 

PATHOPHYSIOLOGY AND ASSOCIATED MEDICAL PROBLEMS The pathophysiology of severe obesity is multifactorial and has at its basis some genetic predisposition to obesity. There is a clear familial predisposition, and it is rare for a single-family member to have severe obesity. Scientists have identified specific genes that are associated with obesity, including the FTO gene (fat mass and obesity related) that plays a role in controlling feeding behavior and energy expenditure, the MC4R deficiency gene (melanocortin 4 receptor), which is associated with obesity, increased fat mass, and insulin resistance.3 Single gene mutations causing obesity are rare, and expressed during early childhood (Table 48.1). The most common single gene etiology of severe obesity is the MC4R, which induces appetite suppression (anorexigenic) effects on the hypothalamus in the regulation of energy homeostasis.3 Recent studies have suggested that the cilium of MC4R neurons in the hypothalamus is the most common pathway underlying the genetic causes of human obesity (Table 48.1).3 Another theory suggests that bacteria within the gut, known as the microbiome, play an essential role in the metabolism and immune system. Simply giving subtherapeutic antibiotic treatment to mice for 4 weeks increases adiposity, plasma levels of insulin, leptin, and triglycerides when the mice are later fed a high-fat diet. The predilection to obesity is transferrable to other mice when the low-dose penicillin-selected gut bacteria are transferred to germfree hosts, thus identifying that it is the action of the altered gut bacteria, not the antibiotics, that causes the obesity.4 Recent studies have demonstrated that the gut microbiome circadian rhythm is disrupted by lifestyle differences in developed countries (shift work or jet lag), which provokes the development of altered microbial community, thus predisposing the host to obesity and glucose intolerance. Other studies have shown that degradation of dietary flavonoids through the altered microbiome results in diminished energy expenditure, which leads to obesity. It is fascinating to hypothesize that the current epidemic of obesity relates

to changes in the microbiome created by the lifestyle changes and increased use of antibiotics in childhood seen in people who reside in developed countries. Although there is no definitive answer to the pathophysiology of severe obesity, it is clear that a severely obese individual has, in general, persistent hunger that is not satiated by amounts of food that satisfy the nonobese. This lack of satiety or maintenance of hunger with corresponding increases in calorie intake may be the single most important factor in the process. There appear to be fundamental differences in the satiety and appetite hormonal control of eating that have created the current epidemic. This is hypothesized to occur when the brain’s energy “set-point” rises to increase energy intake, through modulation of the individual’s appetite. We know that hormones, peptides, and vagal afferents to the brain have a major influence on satiety, appetite, and energy intake. Ghrelin, the only known orexigenic gut hormone, is also known as the hunger hormone and is secreted by P/D1 cells of the gastric fundus. Ghrelin stimulates release of various neuropeptides, such as neuropeptide Y (NPY) and growth hormone, from the hypothalamus, which creates an orexigenic or increased appetite state.5 Increased levels of ghrelin produce increased food intake, and increased levels of ghrelin develop in individuals after low-calorie diets, thus suggesting that one possible mechanism for the failure of most diets after 6 months is the increase in the appetite hormone ghrelin. One evolving concept is that the environment causes heritable change in gene function without modification of DNA sequences termed gene-environment interactions. The changes in the epi­ genome lead to the development of obesity and are much more common than either the monogenetic or the syndromic forms of obesity.5 Morbid obesity is a metabolic disease associated with numerous medical problems, some of which are virtually unknown in the absence of obesity. Box 48.1 lists the most common. These problems must be carefully considered when one is contemplating offering a patient weight reduction surgery. The most frequent problem is the combination of arthritis and degenerative joint disease, present in at least 50% of patients seeking surgery for severe obesity. The incidence of sleep apnea is high. Asthma is present in more than 25%, hypertension in more than 30%, diabetes in more than 20%, and gastroesophageal reflux in 20% to 30% of patients. The incidence of these conditions increases with age and the severity and duration of severe obesity. The metabolic syndrome includes type 2 diabetes mellitus (insulin resistance), dyslipidemia, and hypertension. Patients with this constellation of problems are obese, with central body obesity being the primary essential feature (waist circumference >35 inches in women or >40 inches in men). The syndrome is characterized by impaired hepatic uptake of insulin, systemic hyperinsulinemia,

TABLE 48.1  Gene mutations associated with obesity. GENE

EFFECT

ACTION ON

INHERITANCE

LINKED TO

Leptin/leptin receptor Ghrelin receptor Melanocortin 4 receptor Proopiomelanocortin (POMC)

Appetite stimulant Appetite stimulant Appetite inhibitor Appetite inhibitor

Autosomal recessive Autosomal recessive Autosomal dominant Autosomal recessive

Neuropeptide Y (NPY)

Appetite stimulant

Hypothalamus Hypothalamus Hypothalamus Melanocortin 4 receptor in hypothalamus Hypothalamus

Severe childhood obesity Short stature and obesity Increased fat mass, insulin resistance Severe early onset obesity by age 1 and excessive eating caused by insatiable hunger Hypertension, high low-density lipoprotein cholesterol, triglycerides, increased food intake and hunger

Autosomal recessive

CHAPTER 48  Morbid Obesity BOX 48.1  Medical conditions associated

with severe obesity.

Cardiovascular Hypertension Sudden cardiac death myocardial infarction Cardiomyopathy Venous stasis disease Deep venous thrombosis Pulmonary hypertension Right-sided heart failure  Pulmonary Obstructive sleep apnea Hypoventilation syndrome of obesity Asthma  Metabolic Metabolic syndrome (abdominal obesity, hypertension, dyslipidemia, insulin resistance) Type 2 diabetes Hyperlipidemia Hypercholesterolemia Nonalcoholic steatotic hepatitis (NASH) or nonalcoholic fatty liver disease (NAFLD)  Gastrointestinal Gastroesophageal reflux disease Cholelithiasis  Musculoskeletal Degenerative joint disease Lumbar disk disease Osteoarthritis Ventral hernias  Genitourinary Stress urinary incontinence End-stage renal disease (secondary to diabetes and hypertension)  Gynecologic Menstrual irregularities  Skin/Integumentary System Fungal infections Boils, abscesses  Oncologic Cancer of the thyroid, prostate, esophagus, kidney, stomach, colon, rectum, gallbladder, pancreas, female cancers of the breast, ovaries, cervix, and endometrium  Neurologic/Psychiatric Pseudotumor cerebri Depression Low self-esteem Stroke  Social/Societal History of physical abuse History of sexual abuse Discrimination for employment Social discrimination

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and tissue resistance to insulin. Patients with metabolic syndrome are at high risk for early cardiovascular death. Obesity has been shown to increase the risk of developing cancer of the thyroid, colon, rectum, esophagus, stomach, kidney, prostate, gallbladder, pancreas, breast (postmenopausal), endometrium, ovaries, and cervix.5 There are several mechanisms that may be responsible for the increased risk of cancer. Obesity increases chronic inflammation, which is linked to the development of esophageal adenocarcinoma through chronic inflammation from gastroesophageal reflux disease (GERD). Fat produces excess levels of estrogen, which is linked to increased risk of endometrial, ovarian, and postmenopausal breast cancer. Increased levels of insulin and insulin-like growth factor 1 is hypothesized to be linked to the development of colon, prostate, kidney, endometrial, and postmenopausal breast cancer.5 Not listed in Box 48.1 are the associated societal discriminatory problems that severely obese individuals face. Public facilities in terms of seating, doorways, and restroom facilities often make access to events held in such settings unavailable to a severely obese person. Travel on public transportation is sometimes difficult, if not impossible. Employment discrimination clearly exists for these individuals. Finally, the combination of low self-esteem, a frequent history of sexual or physical abuse, and these social difficulties coalesce to create a very high incidence of depression in the population of morbidly obese patients. 

MEDICAL VERSUS SURGICAL THERAPY Medical therapy for severe obesity has limited short-term success and almost nonexistent long-term success. Once severely obese, the likelihood that a person will lose enough weight by dietary means alone and remain at a BMI below 35 kg/m2 is estimated at 3% or less. The NIH consensus conference recognized that for this population of patients, medical therapy has been largely unsuccessful in treating the problem. Review of the clinical trials of lifestyle interventions for prevention of obesity demonstrated that the majority of trials were completely ineffective, and the few that were marginally effective had an extremely small impact on BMI. One of the most remarkable stories in modern medicine has been the absolute superiority of bariatric surgery over medical therapy for the treatment of morbid obesity and its comorbidities. Multiple long-term follow-up trials comparing morbidly obese diabetics who underwent bariatric surgery with those who did not have shown decreased mortality long term after bariatric surgery as shown in Table 48.2. The Swedish Obese Subjects (SOS) study is the first prospective controlled trial to provide long-term data on the effects of bariatric surgery on diabetes, cardiovascular events, cancer, and overall mortality. The study enrolled 2010 bariatric surgery subjects (gastric bypass, 13%; banding, 19%; vertical banded gastroplasty, 68%) and 2037 matched controls who received standard medical treatment and observed the subjects for 10 to 20 years. The SOS study was able to obtain follow-up on 98.9% of the subjects and found at 15 years after initiation that the surgery patients had lost 18% of their body weight, whereas the control group had only a 1% weight loss at 15 years. The long-term sustained weight loss and reduction in comorbid conditions after bariatric surgery resulted in a 29% reduction in mortality in the bariatric surgery patients (adjusted hazard ratio [HR], 0.71; 95% confidence interval, 0.54–0.92; P = 0.01), as shown in Fig. 48.1. The most common cause of death in the SOS study was cancer (47 in the control group and 29 in the surgery group). The incidence of myocardial infarction was significantly reduced in the surgery

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TABLE 48.2  Results of bariatric surgery compared to medically treated controls.

SURGERY MORTALITY RATE

STUDY

MEDICAL MORTALITY RATE

ODDS RATIO OR HAZARD RATIO SURGICAL REDUCTION IN MORTALITY NOTES

Swedish Obesity Study6

5.0%

6.3%

0.71 HR

Adams7

2.7%

4.1%

0.63 HR

Guidry RYGB versus propensity-matched controls9 Arteburn8

6.5%

12.7%

0.48 Odds ratio

13.8%

23.9%

0.47 HR

3.6%

15.2%

0.74 HR

Kauppilia10

Prospective trial of 2010 bariatric surgery and 2037 matched control patients, 15-year follow-up Retrospective matched cohort of 7925 RYGB and 7925 severely obese control patients, mean follow-up 7.1 years Retrospective matched cohort of 401 RYGB and 401 matched control patients, 10-year follow-up Veterans Affairs multisite cohort of 2500 bariatric surgery patients and 7462 matched control patients, 10-year follow-up 5 Nordic countries, population-based study of 49,977 bariatric surgery patients and 494,842 who did not have surgery, 15-year follow-up

HR, Hazard ratio; RYGB, Roux-en-Y gastric bypass.

Cumulative mortality (%)

14 12

Control

10 8 6

Surgery

4 P = 0.04

2 0

No. at Risk Surgery Control

0

2

4

6

2010 2037

2001 2027

1987 2016

1821 1842

8 10 Years 1590 1455

1260 1174

12

14

16

760 749

422 422

169 156

FIG. 48.1  Swedish obese subjects study weight loss for control and surgical subjects. (From Sjostrom L, Narbro K, Sjostrom CD, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med. 2007;357:741-752.)

group compared with the control group (HR, 0.56), and the surgery group had a lower number of first-time cardiovascular events (HR, 0.67) compared with the control group. Most strikingly, the SOS trial showed an 80% decrease in the annual mortality of diabetic individuals in the surgical weight loss group versus the matched control patients (9% mortality in the surgery group vs. 28% mortality in a control group).6 As can be seen in in Table 48.2, there are multiple studies with long-term follow-up comparing bariatric surgery to matched control groups and found the surgical groups have significant survival advantage (all cause, cancer, cardiovascular), associated with improvement in diabetes, obstructive sleep apnea, dyslipidemia, and hypertension.6–10 These studies are convincing evidence that bariatric surgery provides long-term weight loss, resolution of comorbidities, and improvement in mortality. While the SOS study found

improvement in all-cause mortality after 10 years of follow-up, the majority of procedures performed were vertical banded gastroplasty but Roux-en-Y gastric bypass (RYGB), a much more effective procedure comprised only 13% of the operations performed.6 Since RYGB is a more effective procedure, it is not surprising that the Adams7 and Guidry9 studies, which compared RYGB to medical treatment, showed convincing mortality differences as early as 3 to 5 years after surgery, much earlier than the Swedish Obesity Study.6 Similarly, Kauppila10 studied 49,977 patients undergoing bariatric surgery, of which RYGB made up 73.4% of the operative procedures, and compared to a cohort of obese persons in five Nordic countries and found that all-cause mortality was reduced by 4 years and improved further at 15 years later. Moreover, in the Adams study, the mortality for the first year was equal in the surgery and control groups (0.53% vs. 0.52%, respectively).7 The Arterburn study8 was from the Veterans Affairs (VA) hospitals in the United States, so it had a predominance of males (74% male) as opposed to all of the other reported trials having a majority of female subjects, but it also identified all-cause reduction in mortality at 5 years. The VA study is also remarkable for the higher first year mortality rate in the 2000 to 2005 period (HR, 1.66) than in the 2006 to 2011 period (HR, 0.88), which points to the improvements in surgical care occurring during this period. Despite the higher first year, mortality rate the all-cause mortality rate was lower for the surgery patients than the medical treated group after 5 to 14 years (HR, 0.47).8 Adams and colleagues11 have recently updated the results of the trial reported in 2007 with outcomes measured 12 years after gastric bypass (N = 418) compared to 417 matched patients who sought but did not undergo surgery and to 321 patients who were matched but never sought to undergo surgery. The improvements in weight and comorbidity were continued at 12 years postRYGB, as seen in Table 48.3. The data from multiple studies comparing medical to surgical treatment strongly supports that bariatric surgery reduces longterm mortality. But does this long-term effect hold true for older patients who have a higher operative mortality and shorter time to see long-term benefits? Surprisingly, a cohort of 7925 morbidly

CHAPTER 48  Morbid Obesity TABLE 48.3  Adjusted mean change from

baseline at 12 years after RYGB in the Utah study.11

Weight loss Body mass index Glucose, mg/dL Systolic blood pressure LDL cholesterol HDL cholesterol Triglycerides

RYGB

CONTROL GROUP 1

CONTROL GROUP 2

−26.9% −11.5 −8.0 +0.1 −11.0 +12.9 −62.8

−2.0% +0.1 +14.4 +10.1 +19.3 −2.3 +11.2

0.0% +1.2 +10.5 +8.3 +16.5 −3.3 +11.7

HDL, High-density lipoprotein; LDL, low-density lipoprotein; RYGB, Roux-en-Y gastric bypass.

obese patients matched to an equal number of matched control patients not undergoing surgery showed that long-term mortality was lower in the surgery groups for patients age 35 and older. Patients younger than 35 had a significant increase in externally caused deaths (HR = 2.53, P = 0.009), which was even higher in young women (HR = 3.08, P = 0.005). Nevertheless, this study shows that older patients aged 55 to 74 years old had a significant reduction in long-term mortality and the highest reduction of long-term mortality was in men aged 55 to 74 years.12 One perception of bariatric surgery is that it may induce profound unalterable changes in eating that negatively affect the patients’ health-related quality of life (HRQOL). A welldone 12-year prospective study evaluated HRQOL changes after gastric bypass surgery compared to two nonsurgical groups matched for similar demographics. The patients who underwent bariatric surgery had greatly improved QOL in the physical component from before surgery. There were also significant differences between the surgery patients and both nonsurgical groups for both the weight-related HRQOL and the physical HRQOL. The magnitude of improvement after 12 years after gastric bypass surgery from before surgery and between matched control groups supports the conclusion that bariatric surgery improves the patient’s quality of life (QOL).13 However, this study and the SOS study identified an increase in suicides and self-harm in patients undergoing bariatric surgery. The SOS study suicide and nonfatal health self-harm events were greater in the surgery group than in the matched controls (N = 87 and 49, respectively, out of 68,528 personyears, adjusted HR = 1.78). Analysis of the Utah long-term study7 revealed that suicide and nonfatal self-harm events were more frequent after gastric bypass than in the intensive lifestyle group (n = 341 and 84, respectively, out of 149,582 personyears). The authors concluded that bariatric surgery, in particular gastric bypass, was associated with increased risk of suicide or self-harm, but the absolute risk and numbers of patients do not support not offering bariatric surgery to patients. They recommend that preoperative psychiatric mental health assessment and postoperative monitoring for mental health particularly substance abuse is needed.14

Metabolic Surgery Versus Medical Therapy for Diabetes The Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial15 is 1 of 11 randomized controlled trials (RCTs) that have demonstrated the superiority of bariatric surgery over intensive medical therapy

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in type 2 diabetes. These trials have shown bariatric surgery to be more effective in glycemic control, weight loss, medication reduction, improvement in lipids, and in QOL, as shown in Fig. 48.2.15–18 Metabolic surgery reduced hemoglobin A1c (HgbA1c) by 2% to 3.5% while medical therapy was only able to reduce HgbA1c by 1% to 1.5%. Short- and long-term (2- to 5- year) results shown in Table 48.4 demonstrate that a significant number of patients (28%–43%) undergoing laparoscopic RYGB (LRYGB) achieved HgbA1c levels less than 6 compared to only 5% to 7% of medically treated patients.15–18 It is even more remarkable that the medically treated patients still required intensive medical therapy while the surgery patients had reduced or eliminated diabetic medications. Weight loss for both LRYGB and laparoscopic sleeve gastrectomy (LSG) was far superior to medical therapy. In the case of RYGB, the effect of duodenal bypass on the improvement in diabetes appears to be partially unrelated to weight loss, although in the STAMPEDE trial, the percentage weight loss attained at 1-year postoperative LRYGB was significantly associated with achieving HgbA1c less than 6 at 5 years postoperatively.15 Thus, whereas there may be a benefit to bypassing the duodenum, the sustained long-term weight loss appears to be an essential element of the salutatory effects of RYGB on type 2 diabetes. LRYGB also improves the other associated medical conditions of the metabolic syndrome, including improvements in hypertension and high-density lipoprotein (HDL) cholesterol, as shown in Table 48.3, which results in reduced cardiovascular events/deaths. Specifically, diabetic patients who undergo bariatric surgery have a lower rate of incident microvascular disease (16.9% surgery vs. 34.7% medical), with an adjusted odds ratio (AOR) of 0.41. The reduced incidence rate of microvascular disease was largest in the reduction of nephropathy (59% reduction) but also present in diabetic neuropathy (63% reduction) and diabetic retinopathy (45% reduction).19 The authors of this multi-institution study concluded that bariatric surgery not only improves glycemic control but also significantly reduced the incidence of microvascular disease, which improves survival. The authors argue that this additional evidence of improvement in microvascular disease should push primary care providers to talk to their obese diabetic patients about the benefits of bariatric surgery.19 

BARIATRIC SURGERY MECHANISM OF ACTION The first study reporting on the effectiveness of surgery in treating obesity and related comorbid conditions, published by Surgery, Gynecology & Obstetrics, in 1955 reported observing “the amelioration of diabetes mellitus following subtotal gastrectomy.” A few decades later, the wide acceptance of bariatric surgery as treatment for severe obesity has given significant momentum to study the physiology of weight loss surgery. The initial prevailing theory behind bariatric surgery was based on two primary mechanisms for surgically induced weight loss: caloric restriction and nutrient malabsorption. There is little question that the reduction in caloric intake and resulting weight loss are responsible for much of the improvement in comorbidit-comorbidities after bariatric surgery. However, after taking into account the more recent scientific evidence, the concepts of restriction and malabsorption do not fully explain the metabolic effects of bariatric surgery. In fact, the mechanisms seem to extend beyond the magnitude of weight loss alone to include effects on central nervous system regulation of appetite and metabolism and improvements in insulin secretion and

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SECTION X  Abdomen

Glycated hemoglobin

Glycated hemoglobin level (%)

10

Patients taking diabetes medications (%)

9 8 P 200 pg/mL), and values higher than 1000 pg/ mL are diagnostic. Diagnosing ZES in patients with marginally elevated gastrin levels is difficult because PPI use, H. pylori infection, and renal failure all can cause an elevation of fasting serum gastrin. In patients with gastrin levels in this equivocal range, the most sensitive diagnostic test is the secretin-stimulated gastrin level. Serum gastrin samples are measured before and after IV secretin administration. An increase in the serum gastrin level of greater than 200 pg/mL above basal levels is suggestive of gastrinoma versus other causes of hypergastrinemia, which normally do not demonstrate this response. After diagnosis of gastrinoma, acid suppression therapy is initiated, preferably with a high-dose PPI. Medical management is indicated preoperatively and for patients with metastatic or unresectable gastrinoma. The next step in management is localization and staging of the tumor. Most ZES gastrinomas are located in the duodenum or pancreas, within the “gastrinoma triangle”; the points of this triangle are made up of the cystic-common bile duct junction, the pancreas body-neck junction, and the junction between the second and third portions of the duodenum (Fig. 49.18). The best initial imaging study to localize the gastrin-secreting tumor is either triple-phase CT or MR imaging (MRI) of the abdomen. However, these imaging modalities have a relatively low sensitivity in detecting tumors that are less than 1 cm in diameter as well as small liver metastases. If initial imaging is nondiagnostic, localization can sometimes be achieved using somatostatin receptor scintigraphy or endoscopic ultrasound (EUS). If still unable to localize tumor, patients can be offered a surgical exploration. Localized gastrinomas should be resected; however, long-term cure rates are only about 50%. Once the tumor is located intraoperatively, a resection according to oncologic principles should

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SECTION X   Abdomen

Liver metastases n=4 Pancreatic head n = 2 (13, 12 mm)

Stomach

Pancreas D1 n = 18 (x=8mm, ¯ 4–15mm) D2 n = 17 (x¯ = 8mm, 3–18 mm)

Tail n = 4 (x¯ = 20mm, 2–30 mm) Body n = 3 (x¯ = 19mm, 8–25 mm) Duodenum

D3 n=2 (5, 5 mm)

Lymph node pancreatic head area n = 7 (x¯ = 17 mm, 5–25 mm)

FIG. 49.18  The location of gastrinomas at surgery that were not detected on preoperative imaging. Most tumors were located in the first and second portions of the duodenum and the head of the pancreas, within the so-called gastrinoma triangle. (From Norton JA, Fraker DL, Alexander HR, et al. Value of surgery in patients with negative imaging and sporadic Zollinger-Ellison syndrome. Ann Surg. 2012;256:509–517.)

be performed (rather than a tumor enucleation) with at least 10 lymph nodes removed. Small case series suggest that patients who are not operative candidates may have symptom palliation and slower disease progression with radiation therapy. Patients with tumor recurrence or metastatic disease can be treated with a variety of treatments. The most commonly utilized are somatostatin analogs and/or chemotherapy (streptozocin/doxorubicin or temozolomide-based regimen). For patients with liver metastases, liver-directed therapies (radiofrequency ablation, cryoablation, embolization, resection, or transplantation) can be considered. 

STRESS GASTRITIS Stress gastritis can occur after physical trauma, shock, sepsis, hemorrhage, or respiratory failure and may lead to life-threatening gastric bleeding. Stress gastritis is characterized by multiple superficial (nonulcerating) erosions that typically begin in the proximal portion of the stomach and progress distally. They may also occur in the setting of a central nervous system disease elevating intracranial pressure with resultant vagal nerve stimulation (Cushing ulcer) or as a result of thermal burn injury involving more than 30% of the body surface area leading to gastric ischemia (Curling ulcer). Stress gastritis lesions typically change with time. Early lesions are typically multiple and shallow, with discrete areas of erythema along with focal hemorrhage or an adherent clot. If the lesion erodes into the submucosa, which contains the blood supply, frank bleeding may result. They are almost always seen in the fundus of the stomach and only rarely in the distal stomach. Late lesions appear identical to regenerating mucosa around a healing gastric ulcer. Both types of lesions can be seen endoscopically.

Pathophysiology Although the precise mechanisms responsible for the development of stress gastritis remain to be fully elucidated, evidence suggests a multifactorial cause related to an imbalance between acid production and mucosal protection. Examples of impaired mucosal defense mechanisms against luminal acid are reduction in blood flow, mucus, or bicarbonate secretion by mucosal cells, or decreased endogenous prostaglandins. All these factors render the stomach more susceptible to damage from luminal acid, with the resultant hemorrhagic gastritis. Stress is considered present when hypoxia, sepsis, or organ failure occurs. When stress is present, mucosal ischemia is thought to be the main factor responsible for the breakdown of these normal defense mechanisms. While increased gastric acid secretion rarely occurs in this situation, the presence of luminal acid appears to be a prerequisite for this form of gastritis to evolve. 

Presentation and Diagnosis Stress gastritis develops within 1 to 2 days after a traumatic event in more than 50% to 75% of patients, although the majority of patients have minimal or no related symptoms. The only clinical sign may be painless upper GI bleeding. The bleeding is usually slow and intermittent and may be detected by only a few flecks of blood in the NG tube or an unexplained decrease in hemoglobin level. Occasionally, there may be profound upper GI hemorrhage accompanied by hypotension and hematemesis. The stool is frequently guaiac-positive, although melena or hematochezia is rare. Endoscopy is required to confirm the diagnosis and differentiate stress gastritis from other sources of GI hemorrhage. 

CHAPTER 49  Stomach Prophylaxis Because of the high mortality rate in patients with acute stress gastritis who develop hemodynamically significant upper GI hemorrhage, high-risk patients should be treated prophylactically, although the definition of what constitutes high risk is still debated. Because mucosal ischemia may alter many mucosal defense mechanisms that enable the stomach to withstand luminal irritants and protect itself from injury, every effort should be made to correct any perfusion deficits secondary to shock. The two strongest risk factors for developing clinically significant bleeding from gastric stress ulcers are coagulopathy and respiratory failure requiring prolonged mechanical ventilation (>48 hours). Other significant risk factors include a history of PUD or GI bleeding in the past year, central nervous system injury, significant burn injury, and sepsis. Enteral nutrition reduces the risk of stress ulcer formation and should be initiated as soon as possible. If prophylaxis is indicated, a PPI, rather than H2-receptor antagonists or sucralfate, should be used, although the evidence supporting this is weak. Prophylaxis should be limited only to high-risk patients, as gastric acid suppression has been associated with increased rates of nosocomial pneumonia and C. difficile infection. Of note, a recent meta analysis showed that while prophylaxis did reduce the incidence of bleeding, the mortality rates were unaffected.15 Larger randomized trials are still needed to determine which patients may benefit most from stress ulcer prophylaxis in the critical care setting. 

Treatment Any patient with significant upper GI bleeding requires fluid resuscitation with correction of any coagulation or platelet abnormalities. An NG tube should be placed if not already present and IV PPI therapy started promptly. Urgent endoscopy should be performed for diagnosis and treatment; however, the bleeding from stress ulcers is usually diffuse and the rebleeding rate is high. In experienced centers, vasopressin can be administered into the left gastric artery and can be embolized as well to help control bleeding. If the patient has underlying cardiac or liver disease, vasopressin should not be used. Bleeding that results in hemodynamic instability or requires persistent transfusions is an indication for surgery. Because most lesions are in the proximal stomach or fundus, a long anterior gastrotomy should be made in this area. The gastric lumen is cleared of blood, and the mucosal surface is inspected for bleeding points. All bleeding areas are oversewn with figure-of-eight stitches taken deep within the gastric wall. Most superficial erosions are not actively bleeding and do not require ligation unless a blood vessel is seen at its base. In stable patients, the operation is completed by closing the anterior gastrotomy and performing a truncal vagotomy and pyloroplasty to reduce acid secretion. Less commonly, a partial gastrectomy combined with vagotomy is performed. Total gastrectomy should be performed rarely and only in patients with life-threatening hemorrhage refractory to other forms of therapy. 

POSTGASTRECTOMY SYNDROMES Gastric surgery can result in numerous physiologic derangements caused by loss of reservoir function, interruption of the pyloric sphincter mechanism, and vagal nerve transection. The GI and cardiovascular symptoms may result in disorders collectively referred to as postgastrectomy syndromes. Approximately 20% to 25% of patients who undergo surgery for PUD subsequently develop some degree of postgastrectomy syndrome, although this frequency is much lower in patients who undergo highly selective

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vagotomy. The physiologic changes are not specific to PUD and can occur after gastrectomy for resection of neoplasm or Rouxen-Y gastric bypass for treatment of severe obesity. Approximately 1% to 5% of patients become permanently disabled from their postgastrectomy symptoms.

Dumping Syndrome Dumping syndrome is a combination of both GI and vasomotor symptoms due to rapid postprandial gastric emptying. GI symptoms include abdominal pain, early satiety, nausea/vomiting, diarrhea, and bloating. Vasomotor systemic symptoms include diaphoresis, tachycardia, palpitations, headache, and syncope. This symptom complex can develop after any operation on the stomach but is more common after partial gastrectomy with the Billroth II reconstruction. It is much less commonly observed after the Billroth I gastrectomy or after vagotomy and drainage procedures. Dumping syndrome can be divided into two categories: early and late. Early dumping occurs within 30 minutes of a meal and is a result of rapid passage of high osmolarity food from the stomach into the small intestine. This occurs because gastrectomy, or any interruption of the pyloric sphincter mechanism, prevents the stomach from preparing its contents and delivering them to the proximal bowel in the form of small particles in isotonic solution. The resultant hypertonic food bolus passes into the small intestine, which induces a rapid shift of extracellular fluid into the intestinal lumen to achieve isotonicity. After this shift of extracellular fluid, luminal distention occurs and induces the resultant symptoms. Late dumping occurs 1 to 3 hours after a meal and is less common. The basic defect of late dumping is also rapid gastric emptying; however, it is related specifically to carbohydrates being delivered rapidly into the proximal intestine. When carbohydrates are delivered to the small intestine, they are quickly absorbed, resulting in hyperglycemia, which triggers the release of large amounts of insulin to control the increasing blood sugar level. An overcompensation results so that profound hypoglycemia occurs in response to the insulin. This hypoglycemia activates the adrenal gland to release catecholamines, which results in diaphoresis, tremulousness, light-headedness, tachycardia, and confusion. The symptoms associated with early dumping syndrome appear to be secondary to the release of several humoral agents, such as serotonin, bradykinin-like substances, neurotensin, and enteroglucagon. Dietary measures are usually sufficient to treat most patients. These include avoiding foods containing large amounts of sugar, frequent feeding of small meals rich in protein, fats, and fiber, and separating liquids from solids during a meal. In some patients without a response to dietary measures, pharmacologic treatments directed at specific symptoms can be effective, such as tincture of opium or imodium for diarrhea and meclizine for nausea. Anticholinergics can slow gastric emptying and treat spasms. Octreotide can be given in either short-acting form immediately before a meal or via an intramuscular longacting formulation. These peptides not only inhibit gastric emptying but also affect small bowel motility so that intestinal transit of the ingested meal is prolonged. Octreotide is the best studied medication for dumping syndrome and can be very effective. However, the peptides are expensive and are thus not considered first-line treatment typically. Patients with severe symptoms may require a reoperation if conservative management is unsuccessful. The choice of operation depends on the original gastric surgery. Pyloric reconstruction can sometimes be performed. For patients with a gastrojejunostomy without a gastrectomy, takedown of the gastrojejunostomy can be performed if the pylorus function is

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SECTION X   Abdomen

maintained. In patients with a prior distal gastrectomy, converting a loop gastrojejunostomy to a Roux-en-Y reconstruction is recommended. 

Metabolic Disturbances The most common metabolic defect appearing after gastrectomy is anemia. Anemia is related to iron deficiency (more common) or impairment in vitamin B12 metabolism. More than 30% of patients undergoing gastrectomy have iron deficiency anemia. The exact cause is not fully understood but appears to be related to a combination of decreased iron intake, impaired iron absorption, and chronic blood loss. In general, the addition of iron supplements to the patient’s diet corrects this problem. Megaloblastic anemia from vitamin B12 deficiency only rarely develops after partial gastrectomy but is dependent on the amount of stomach removed. Vitamin deficiency occurs secondary to poor absorption of dietary vitamin B12 because of the lack of intrinsic factor. Patients undergoing subtotal gastrectomy should be placed on lifelong vitamin B12 supplementation. If a patient develops a macrocytic anemia, serum vitamin B12 levels should be obtained and, if abnormal, treated with long-term vitamin B12 therapy. Osteoporosis and osteomalacia have also been observed after gastric resection and appear to be caused by deficiencies in calcium. If fat malabsorption is also present, the calcium malabsorption is aggravated further because fatty acids bind calcium. The incidence of this problem also increases with the extent of gastric resection and is usually associated with a Billroth II gastrectomy. Bone disease generally develops approximately 4 to 5 years after surgery. Treatment of this disorder usually requires calcium supplements in conjunction with vitamin D. Patients with Billroth II or Roux-en-Y reconstruction that bypasses the duodenum should also receive supplementation of the fat-soluble vitamins (vitamins A, D, E, and K). 

Afferent Loop Syndrome The afferent loop is the duodenojejunal loop proximal to the gastrojejunal anastomosis after either a Billroth II reconstruction or gastrojejunostomy. Afferent loop syndrome occurs as a result of partial obstruction of the afferent limb, which is then unable to empty its contents. After obstruction of the afferent limb, pancreatic and hepatobiliary secretions accumulate within the limb, resulting in its distention, which causes epigastric discomfort and cramping. The intraluminal pressure eventually increases enough to empty the contents of the afferent loop forcefully into the stomach, resulting in projectile bilious vomiting that offers immediate relief of symptoms. If the obstruction has been present for a long time, it can also be aggravated by the development of blind loop syndrome. In this situation, bacterial overgrowth occurs in the static loop, and the bacteria bind with vitamin B12 and deconjugated bile acids; this results in a systemic deficiency of vitamin B12 (with the development of megaloblastic anemia), fat malabsorption, and deficiency in fat-soluble vitamins. In contrast to the diagnosis of an acute bowel obstruction, the diagnosis of chronic afferent loop obstruction can be problematic. Failure to visualize the afferent limb on upper endoscopy is suggestive of the diagnosis. Radionuclide studies imaging the hepatobiliary tree have also been used with some success in diagnosing this syndrome. Normally, the radionuclides should pass into the stomach or distal small bowel after being excreted into the afferent limb. If this does not occur, the possibility of an afferent loop obstruction should be considered.

Surgical correction is indicated for this mechanical problem to prevent bowel necrosis or duodenal stump blowout. A long afferent limb is usually the underlying problem, so treatment involves the elimination of this loop. Remedies include conversion of the Billroth II construction into a Billroth I anastomosis, enteroenterostomy below the afferent and efferent loops, and conversion to a Roux-en-Y reconstruction. 

Efferent Loop Obstruction Obstruction of the efferent limb is rare. Efferent loop obstruction may occur at any time; however, more than 50% of cases do so within the first postoperative month. Establishing a diagnosis is difficult. Initial complaints may include left upper quadrant abdominal pain that is colicky in nature, bilious vomiting, and abdominal distention. The diagnosis is usually established by an upper GI series or CT with oral contrast, with failure of contrast to enter the efferent limb. Operative intervention is almost always necessary and consists of reducing the retroanastomotic hernia if this is the cause of the obstruction and closing the retroanastomotic space to prevent recurrence of this condition. 

Alkaline Reflux Gastritis After gastrectomy, reflux of bile is common. In a small percentage of patients, this reflux is associated with severe epigastric abdominal pain accompanied by bilious vomiting and weight loss. The diagnosis is typically made by careful history. A technetium biliary scan can be used to demonstrate reflux of bile into the stomach. Upper endoscopy demonstrates friable, beefy red mucosa. Most patients with alkaline reflux gastritis have had gastric resection performed with a Billroth II anastomosis. Although bile reflux appears to be the inciting event, numerous issues remain unanswered with respect to the role of bile in its pathogenesis. For example, many patients have reflux of bile into the stomach after gastrectomy without any symptoms. Moreover, there is no clear correlation between the volume or composition of bile and the subsequent development of alkaline reflux gastritis. After a definitive diagnosis is made, therapy is directed at relief of symptoms. Most medical therapies that have been tried to treat alkaline reflux gastritis have not shown any consistent benefit. For patients with intractable symptoms, the surgical procedure of choice is conversion of the Billroth II anastomosis into a Roux-en-Y gastrojejunostomy, in which the Roux limb has been lengthened to more than 40 cm. In general, a Roux-en-Y procedure should be preferred over a Billroth II for reconstruction at the time of partial or subtotal distal gastrectomy to decrease the likelihood of alkaline reflux II.16 

Gastric Atony Gastric emptying is delayed after truncal and selective vagotomies but not after a highly selective vagotomy. With selective or truncal vagotomy, patients lose their antral pump function and have a reduction in the ability to empty solids. In contrast, emptying of liquids is accelerated due to the loss of receptive relaxation in the proximal stomach. Although most patients undergoing vagotomy and a drainage procedure manage to empty their stomach adequately, some patients have persistent gastric stasis that results in retention of food within the stomach for several hours. This condition may be accompanied by a feeling of fullness and, occasionally, abdominal pain. In still rarer cases, it may be associated with a functional gastric outlet obstruction. The diagnosis of gastric atony is confirmed by scintigraphic assessment of gastric emptying. However, other causes of delayed

CHAPTER 49  Stomach gastric emptying, such as diabetes mellitus, electrolyte imbalance, drug toxicity, and neuromuscular disorders, must also be excluded. In addition, a mechanical cause of gastric outlet obstruction, such as postoperative adhesions, afferent or efferent loop obstruction, and internal herniation, must be ruled out. Endoscopic examination of the stomach also needs to be performed to rule out an anastomotic obstruction. In patients with a functional gastric outlet obstruction and documented gastroparesis, pharmacotherapy is generally utilized. The agents most commonly used are prokinetic agents such as metoclopramide and erythromycin. Metoclopramide exerts its prokinetic effects by acting as a dopamine antagonist and has cholinergic-enhancing effects because of facilitation of acetylcholine release from enteric cholinergic neurons. In contrast, erythromycin markedly accelerates gastric emptying by binding to motilin receptors on GI smooth muscle cells, where it acts as a motilin agonist. In rare cases of persistent gastric atony refractory to medical management, gastrectomy may be required. 

GASTRIC CANCER Epidemiology

Incidence Gastric cancer has the fourteenth highest cancer incidence and is the thirteenth highest cause of cancer death in the United States, with an estimated 26,240 new cases and more than 10,800 deaths in 2018.17 The disease affects men disproportionately, with more than 60% of new cases and deaths occurring in men. It is a disease of older individuals, with peak incidence in the seventh decade of life. Among racial groups, the disease is more common and has a higher mortality in African Americans, Asian Americans, and Hispanics compared with whites. Worldwide in 2018, gastric cancer is more prevalent; it is the fifth most common cancer and the second leading cause of cancer death.18 Over half of new cases occur in developing countries. It is especially prevalent in East Asia, Eastern Europe, and Central and South America. Higher geographic latitudes are associated with higher gastric cancer risk. Among developed countries, Japan and Korea have the highest rates of the disease. Gastric cancer is the most common cancer in Japan. As a result, gastric cancer screening in Japan was started in the 1970s, with significant improvements in mortality. 

Risk Factors The major risk factors for gastric cancer are discussed here; they include both environmental and genetic factors (Box 49.3). Helicobacter pylori Infection In 1994, the International Agency for Research on Cancer (IARC) labeled H. pylori a definite carcinogen; it is the most common cause of infection-related cancers.19 Numerous longitudinal prospective studies have demonstrated its association with the development of gastric cancer. In epidemiological studies, H. pylori seropositivity has been associated with an approximately sixfold increased risk of developing gastric cancer. The primary mechanism is thought to be the presence of chronic inflammation. Long-term infection with the bacteria can lead to atrophic gastritis or chronic active gastritis. In some patients, gastritis progresses to intestinal metaplasia, dysplasia, and ultimately intestinal-type adenocarcinoma. A wide range of molecular alterations in intestinal metaplasia have been described and may affect the transformation into gastric cancer. These include

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BOX 49.3  Factors associated with

increased risk for developing stomach cancer. Nutritional Low fat or protein consumption Salted meat or fish High nitrate consumption Obesity High complex carbohydrate consumption  Environmental Poor food preparation (smoked, salted) Lack of refrigeration Poor drinking water (e.g., contaminated well water) Smoking and alcohol  Social Low socioeconomic class  Medical Prior gastric surgery Helicobacter pylori and Epstein-Barr virus infection Hereditary predisposition Prior abdominal irradiation Atrophic gastritis Adenomatous polyps  Other Male sex

overexpression of cyclooxygenase-2 and cyclin D2, p53 mutations, microsatellite instability, decreased p27 expression, and alterations in transcription factors such as CDX1 and CDX2.19 Intestinal metaplasia is a risk factor for the development of gastric carcinoma; however, not every patient with intestinal metaplasia develops invasive cancer. Host inflammatory responses also play an important role in this process. Specifically, higher levels of interleukin-1β and tumor necrosis factor-α expression lead to an increased risk of gastric cancer development. Some regional variances in the development of cancer may be attributed to the prevalence and virulence of H. pylori. It is more common in areas with less sanitation, and infection rates remain high in developing countries, with a concomitant increase in gastric cancer incidence. In contrast, the prevalence in more developed countries has been decreasing. The presence of the cytotoxinassociated gene A upregulates proinflammatory response, cellular migration, and elongation, leading to increased virulence and risk of gastric cancer. Countries with high levels of gastric cancer, such as Japan, have a much higher rate of cytotoxin-associated gene A–positive H. pylori infection than countries with lower rates of gastric cancer, such as the United States.  Dietary Factors High-salt foods, particularly salted or smoked meats that contain high levels of nitrate, along with low intake of fruits and vegetables, are linked to an increased risk of gastric cancer. The mechanism is postulated to involve salt damaging the stomach mucosa. N-nitroso compounds are generated after nitrate ingestion. Nnitroso compounds are also found in tobacco smoke, another known risk factor for gastric cancer. Fresh fruits and vegetables

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SECTION X   Abdomen

FIG. 49.19  Computed tomography scan of fundic gland polyps. (Courtesy Dr. David Bentrem, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL.)

contain ascorbic acid, which can remove the carcinogenic N-nitroso compounds and oxygen free radicals. Synergy between a high-salt diet and H. pylori infection has been shown, with the bacteria increasing carcinogen production and inhibiting its removal. H. pylori has been shown to promote the growth of the bacteria that generate the carcinogenic N-nitroso compounds. At the same time, H. pylori can inhibit the secretion of ascorbic acid, preventing effective scavenging of oxygen free radicals and N-nitroso compounds. The increase in refrigeration over the past 70 years has likely contributed to the decrease in gastric cancer by reducing the amount of meat preserved by salting alone and allowing the increased storage and consumption of fresh fruits and vegetables. In 2015, the WHO IARC classified processed meats as a group 1 carcinogen.  Hereditary Risk Factors and Cancer Genetics Gastric cancer is associated with several rare inherited disorders. Patients with hereditary diffuse gastric cancer, resulting from a gene mutation for the cell adhesion molecule E-cadherin (CDH1), have 60% to 70% lifetime incidence of developing gastric cancer. Prophylactic total gastrectomy should be considered for patients with this mutation prior to age 30. Notably, these patients are also at higher risk of lobular breast cancer and screening should begin by age 30, with consideration of prophylactic risk-reducing bilateral mastectomy. Two newer autosomal dominant disorders have been identified, gastric adenocarcinoma and proximal polyposis of the stomach and familial intestinal gastric cancer; the genetic causes of these have yet to be identified. A number of hereditary cancer syndromes are associated with gastric cancer. In familial adenomatous polyposis, most patients have fundic or body sessile polyps, with 40% of these polyps having some degree of dysplasia. These polyps, combined with the much higher frequency of potentially malignant duodenal polyps, warrant upper GI surveillance. Li-Fraumeni syndrome is an autosomal dominant disorder caused by a mutation in the tumor suppressor gene p53, which puts patients at risk for gastric cancer as well as sarcoma, breast cancer, brain tumors, and adrenocortical carcinomas. Hereditary nonpolyposis colorectal cancer, or Lynch syndrome, is associated with microsatellite instability and increases risk of gastric and endometrial cancers. Several genetic alterations have been identified that are associated with gastric adenocarcinoma. These changes can be classified as the activation of oncogenes, inactivation of tumor suppressor genes, reduction of cellular adhesion, reactivation of telomerase,

and presence of microsatellite instability. The c-met proto-oncogene is the receptor for the hepatocyte growth factor and is frequently overexpressed in gastric cancer, as are the K-ras and HER2 oncogenes. Inactivation of the tumor suppressor genes p53 has been reported in diffuse and intestinal-type cancers, whereas adenomatous polyposis coli gene mutations tend to be more frequent in intestinal-type gastric cancers. Also, a reduction or loss in the cell adhesion molecule E-cadherin can be found in approximately 50% of diffuse-type gastric cancers. Microsatellite instability can be found in approximately 20% to 30% of intestinal-type gastric cancers. Aberrant epigenetic methylation can also play a role in carcinogenesis.  Polyps Gastric polyps are a common incidental finding during upper endoscopy (seen in about 5% of procedures) and are usually asymptomatic. The malignancy risk and subsequent management largely are dependent on the polyp histopathology. Patients with an isolated polyp greater than 1 cm in size should have a complete polypectomy. For those with multiple polyps, the largest should be removed endoscopically, if possible, and remaining polyps should be biopsied. Biopsies of normal mucosa should be performed as well to assess for underlying dysplasia and H. pylori infection.20 Adenomatous polyps carry a distinct risk for the development of malignancy in the polyp and are felt to fall on the classic adenoma-carcinoma sequence. They are typically solitary lesions. Mucosal atypia is frequent, and progression from dysplasia to carcinoma in situ has been observed. The risk for the development of carcinoma is greater than 30% and increases with increasing size of the polyp.20 Endoscopic removal is indicated for pedunculated lesions and is sufficient if the polyp is completely removed and there are no foci of invasive cancer on histologic examination. If the polyp is larger than 2 cm, is sessile, or has a proven focus of invasive carcinoma, operative excision is warranted. Fundic gland polyps (Fig. 49.19) are benign lesions that are thought to result from glandular hyperplasia and decreased luminal flow. They are strongly associated with PPI use and occur in one third of patients by 1 year. Dysplasia, although common in patients whose polyps result from familial adenomatous polyposis, has been described only as individual case reports for patients whose polyps result from PPI therapy. Such cases do not require excision, regular surveillance, or cessation of therapy. Hyperplastic polyps are associated with H. pylori infection and chronic gastritis, with an associated malignancy rate of under 2%. Peutz-Jeghers syndrome also results in gastric polyps and has a 2% to 3% malignancy rate.20 

CHAPTER 49  Stomach Proton pump inhibitors The use of PPIs has increased dramatically because they have been proven to be an effective treatment for patients with GE reflux disease and PUD. They are often prescribed empirically as first-line treatment for dyspepsia. The impact of prolonged PPI use on the incidence of gastric cancer is being actively explored. Physiologically, PPIs, as their name suggests, block the hydrogen-potassium pump within the parietal cells, effectively blocking all acid secretion in the stomach. The potential for cancer is at the intersection between H. pylori, already considered a carcinogen for gastric cancer, and the physiologic changes that are a consequence of PPI use. In patients with H. pylori taking long-term PPIs, the low-acid environment allows the bacteria to colonize the gastric body, leading to corpus gastritis. One third of these patients develop atrophic gastritis, which is significantly more common in patients with H. pylori who are taking PPIs. While this atrophic gastritis quickly resolves after eradication of the H. pylori, atrophic gastritis is considered a major risk factor for the development of gastric cancer. Meta analyses of randomized trials have not shown clear evidence of elevated gastric cancer risk associated with PPI use. However, a recent study of over 63,000 patients in Hong Kong demonstrated an excess of 4.29 gastric cancers per 10,000 person-years and that long-term PPI use increased gastric cancer risk even after H. pylori eradication.21 Other large observational studies have demonstrated increased risk of gastric cancer with prolonged PPI use, however, these studies are all prone to selection bias. Nonetheless, while PPIs are an effective first-line treatment for dyspepsia and remain an effective long-term therapy for patients with GE reflux disease, in patients with persistent symptoms after initiation of therapy or who require long-term therapy, surveillance for and eradication of H. pylori is warranted. Further research into potential gastric cancer risks is needed in order to make clinical guidelines for physicians considering long-term PPI therapy.  Other Risk Factors Patients with pernicious anemia are at increased risk for developing gastric cancer. Achlorhydria is the defining feature of this condition; it occurs when chief and parietal cells are destroyed by an autoimmune reaction. Obesity was determined by the IARC to be a risk factor for gastric cardia cancers. Epstein-Barr virus infection is also associated with gastric cardia cancers. Smoking is associated with an approximately 1.5-fold increase in gastric cancer risk. Prior abdominal irradiation, most commonly after testicular cancer or Hodgkin lymphoma, increases gastric cancer risk. 

Pathology Numerous pathologic classification schemes of gastric cancer have been proposed. The Borrmann classification system was developed in 1926; it remains useful today for the description of gross appearance of endoscopic findings. This system divides gastric carcinoma into four types, type I for polypoid, type II for fungating, type III for ulcerating, and type IV for diffusely infiltrating growths (also referred to as linitis plastica in signet ring cell carcinoma) (Fig. 49.20). Other classification systems have been proposed, but the most useful and widely used system is the one proposed by Lauren in 1965. This system separates gastric adenocarcinoma into intestinal or diffuse types based on histology, with both types having distinct pathology, epidemiology, and prognosis (Table 49.5). Newer Japanese and Paris classification systems further subdivide lesions based on their level of elevation or depression.

1221

Borrmann classification Protruded type

Type 1

Type 2

Type 3

Depressed type

Type 4 FIG. 49.20  Borrmann pathologic classification of gastric cancer based on gross appearance. (From Iriyama K, Asakawa T, Koike H, et al. Is extensive lymphadenectomy necessary for surgical treatment of intramucosal carcinoma of the stomach? Arch Surg. 1989;124:309–311.)

TABLE 49.5  Lauren classification system

for gastric cancer. INTESTINAL

DIFFUSE

Environmental Gastric atrophy, intestinal metaplasia Men > women Increasing incidence with age Gland formation Hematogenous spread Microsatellite instability APC gene mutations p53, p16 inactivation

Familial Blood type A Women > men Younger age group Poorly differentiated, signet ring cells Transmural, lymphatic spread Decreased E-cadherin p53, p16 inactivation

APC, Adenomatous polyposis coli.

The intestinal variant is more well- differentiated and typically arises in the setting of a recognizable precancerous condition, such as gastric atrophy or intestinal metaplasia. Men are more commonly affected than women, and the incidence of intestinal-type gastric adenocarcinoma increases with age. These cancers have a tendency to form glands. The intestinal type is also the dominant histology in areas in which gastric cancer is epidemic, suggesting an environmental cause. Local rates of H. pylori prevalence likely play a large part in this increased environmental risk, as infection has been linked to the development of intestinal variant gastric cancer specifically. The diffuse form of gastric adenocarcinoma consists of tiny clusters of small, uniform signet ring cells, is poorly differentiated, and lacks glands. It tends to spread submucosally, with early metastatic spread via transmural extension and lymphatic invasion. It is generally not associated with chronic gastritis, is equally frequent in both sexes, and affects a slightly younger age group. The diffuse form also has an association with blood type A and familial occurrence, suggesting an underlying genetic cause. Intraperitoneal metastases are frequent, and, in general, the prognosis is less favorable than for patients with intestinal-type cancers. In 2010, the World Health Organization (WHO) revised their alternative classification system for gastric cancers based on morphologic features. In the WHO system, gastric adenocarcinoma is divided into five main categories—papillary, tubular, mucinous, poorly cohesive (including signet ring cell

1222

SECTION X   Abdomen

carcinoma), and uncommon histologic variants. Although widely used, the WHO classification system offers little in terms of patient management, although a new revision is expected soon that may be of greater clinical utility. There is little evidence that any of the above-mentioned classification systems can add to the prognostic information provided by the American Joint Cancer Commission (AJCC) tumor, node, metastasis (TNM) staging system (see later). 

Diagnosis and Workup Signs and Symptoms The symptoms of gastric cancer are generally vague and nonspecific, contributing to its frequently advanced stage at the time of diagnosis. Symptoms include epigastric pain, early satiety, and weight loss. These symptoms are frequently mistaken for more common benign causes of dyspepsia including PUD and gastritis. The epigastric pain associated with gastric cancer tends to be constant and nonradiating and is generally not relieved by eating. More advanced lesions may manifest with either gastric outlet obstruction or dysphagia depending on the location of the tumor. Some degree of GI bleeding is common, with 40% of patients having some form of anemia. A complete history and physical examination should be performed, with special attention to any evidence of advanced disease, including metastatic nodal disease. Presence of supraclavicular (Virchow node), axillary (Irish node), or periumbilical (Sister Mary Joseph node) adenopathy should be assessed, as well as any evidence of intra abdominal metastases such as hepatomegaly, jaundice, or ascites. Drop metastases to the ovaries (Krukenberg tumor) may be detectable on pelvic examination, and peritoneal metastases can be felt as a firm shelf (Blumer shelf ) on rectal examination. Complete blood count, chemistry panel including liver function tests, and coagulation studies should be performed as well.  Screening Gastric cancer screening has been implemented in some regions with high incidence, such as Japan, Korea, and Chile. The two primary modalities for screening are upper endoscopy and barium radiography, with upper endoscopy having better sensitivity. While there is evidence suggesting that screening in high-incidence populations improves oncologic outcomes, this has not been evaluated in a randomized trial. The optimal screening modality and interval have not been universally established and varies by region. Selective screening of patients with specific risk factors (see above) can be considered, including gastric polyps/adenomas, pernicious anemia, and certain genetic disorders. Of note, this should not include patients with hereditary diffuse gastric cancer as these tumors often arise beneath an intact mucosa and would be missed by routine screening. 

Staging The most widely used staging system is the AJCC TNM staging system. This system is based on the depth of tumor invasion (T), number of involved lymph nodes (N), and presence or absence of metastatic disease (M), with the 8th edition published in 2017 (Table 49.6). Before 1997, N stage was determined by the anatomic location of the nodes with respect to the primary tumor, rather than the absolute number of nodes. This staging, based on anatomy, was intimately related to the D1 versus D2 anatomic lymphadenectomy debate (see later). The revised system does not differentiate among the locations of positive nodes. In the current

staging system, a minimum of 16 nodes must be evaluated for accurate staging. Some experts have suggested that other factors be included in the T and N assessment, such as the location of the primary (cardia compared with distal tumors) because this may independently predict survival and emphasis on the percentage of positive nodes (lymph node ratio) rather than the number of positive nodes. However, the current AJCC staging system does not reflect these factors. The most recent edition of TNM staging also includes a separate staging section for patients who received neoadjuvant therapy. The Siewert classification system is used for adenocarcinomas that are in close proximity to the GE junction. This is an important distinction because such gastric cancers are more aggressive in nature and are treated in a similar manner to esophageal adenocarcinomas. There are three Siewert types: Type I tumors are tumors of the distal esophagus, within 1 to 5 cm above the GE junction; type II tumors have a tumor center located from 1 cm above the GE junction to 2 cm below; type III tumors are located between 2 and 5 cm caudad to the GE junction. In general, Siewert types I and II tumors are treated similar to esophageal adenocarcinoma, whereas type III tumors can be treated according to the guidelines for gastric adenocarcinoma described here, as long as the tumor does not extend into the GE junction; these distinctions are now reflected in the current AJCC TNM staging guidelines as well. Although not part of the formal AJCC staging system, the term R status, first described by Hermanek in 1994, is used to describe tumor status after resection and is important for determining the adequacy of surgery. R0 describes a microscopically margin-negative resection, in which no gross or microscopic tumor remains in the tumor bed. R1 indicates removal of all macroscopic disease, but microscopic margins are positive for tumor. R2 indicates gross residual disease. Because the extent of resection can influence survival, some include this R designation to complement the TNM system. Long-term survival can be expected only after an R0 resection for patients with gastric cancer. Staging Workup The goals of preoperative staging are to gain information on prognosis, to counsel the patient effectively, and to determine the extent of disease to decide the most appropriate course of therapy. The three main treatment pathways are upfront resection (with or without subsequent adjuvant therapy), neoadjuvant therapy followed by resection, or treatment of systemic disease without resection (Fig. 49.21). The main modalities for staging gastric adenocarcinoma are upper endoscopy; EUS; cross-sectional imaging such as CT, MRI, and/or positron emission tomography (PET); and diagnostic laparoscopy. Their roles are discussed here. Endoscopy and endoscopic ultrasound. Flexible endoscopy is an essential tool for the diagnosis of gastric cancer. It allows visualization of the tumor, provides tissue for pathologic diagnosis, and can help treat patients with obstruction or bleeding (Fig. 49.22). On initial diagnostic endoscopy, if a suspicious mass or ulcer is encountered in the stomach, it is essential to obtain adequate tissue to confirm the correct diagnosis histologically. Current National Comprehensive Cancer Network (NCCN) guidelines recommend harvesting six to eight biopsy specimens from different areas of the lesion in order to maximize the diagnostic yield.22 Small lesions (≤2 cm in diameter) can be resected at the time of initial diagnostic endoscopy using endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD,

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CHAPTER 49  Stomach TABLE 49.6  Tumor, node, metastasis classification of carcinoma of the stomach. Primary Tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ; intraepithelial tumor without invasion of the lamina propria, high-grade dysplasia T1 Tumor invades lamina propria, muscularis mucosae, or submucosa T1a Tumor invades lamina propria or muscularis mucosae T1b Tumor invades submucosa T2 Tumor invades muscularis propria* T3 Tumor penetrates subserosal connective tissue without invasion of visceral peritoneum or adjacent structures† T4 Tumor invades serosa (visceral peritoneum) or adjacent structures† T4a Tumor invades serosa (visceral peritoneum) T4b Tumor invades adjacent structures

PATHOLOGIC STAGE 0 IA IB IIA

IIB

IIIA

Regional Lymph Nodes (N) NX Regional lymph node(s) cannot be assessed N0 No regional lymph node metastasis‡ N1 Metastasis in 1–2 regional lymph nodes N2 Metastasis in 3–6 regional lymph nodes N3 Metastasis in 7 or more regional lymph nodes N3a Metastasis in 7–15 regional lymph nodes N3b Metastasis in 16 or more regional lymph nodes

IIIB

IIIC

Distant Metastasis (M) M0 No distant metastasis M1 Distant metastasis

IV

PROGNOSTIC GROUP Tis T1 T1 T2 T1 T2 T3 T1 T2 T3 T4a T2 T3 T4a T4a T4b T1 T2 T3 T4a T4b T4b T3 T4a T4b T4b Any T

N0 N0 N1 N0 N2 N1 N0 N3a N2 N1 N0 N3a N2 N1 N2 N0 N3b N3b N3a N3a N1 N2 N3b N3b N3a N3b Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

From Amin MB, Edge SB, Greene FL, et al. AJCC Cancer Staging Manual. 8th ed. New York: Springer International Publishing; 2017. *A tumor may penetrate the muscularis propria with extension into the gastrocolic or gastrohepatic ligaments, or into the greater or lesser omentum, without perforation of the visceral peritoneum covering these structures. In this case, the tumor is classified T3. If there is perforation of the visceral peritoneum covering the gastric ligaments or the omentum, the tumor should be classified T4. †The adjacent structures of the stomach include the spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum. ‡A designation of pN0 should be used if all examined lymph nodes are negative, regardless of the total number removed and examined.

Adenocarcinoma

STAGE (CT, endoscopy with EUS)

Metastatic disease

No metastatic disease

Symptomatic (bleeding, obstruction)

Asymptomatic

Laparoscopy

Consider palliative resection

Refer to medical oncology

No metastatic disease

Resection with nodal harvest

FIG. 49.21  General staging and treatment strategy for gastric adenocarcinoma. CT, Computed tomography; EUS, endoscopic ultrasound.

1224

SECTION X   Abdomen

described in further detail later). This resection can provide a more complete specimen to aid the pathologist in obtaining an accurate diagnosis and can potentially be curative for early-stage cancers, obviating the need for invasive surgical intervention.

FIG. 49.22  Endoscopic view of intestinal-type adenocarcinoma of the gastric cardia. (Courtesy Dr. David Bentrem, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL.)

SM

EUS is recommended by NCCN guidelines as part of the staging workup for gastric cancer if there is no evidence of metastatic disease.22 EUS provides the most accurate evaluation of the depth of tumor invasion, assessment of perigastric lymph node involvement, and can sometimes identify involvement of surrounding organs or the presence of ascites. EUS is performed using a flexible endoscope with a 7.5- to 12-MHz ultrasound transducer. The stomach is filled with water to provide an acoustic window, and the stomach wall is visualized as five alternating hypoechoic and hyperechoic layers (Fig. 49.23A). The mucosa and submucosa represent the first three layers (T1) (Fig. 49.23B). The fourth layer is the muscularis propria, invasion of which signifies a T2 tumor. Expansion of the tumor beyond the muscularis propria causing an irregular border correlates with expansion into the subserosa, or a T3 tumor (Fig. 49.23C). The serosa is the fifth layer, and loss of this bright line correlates with penetration through it, indicating a T4a tumor. Direct invasion of surrounding structures, including named vessels, indicates a T4b tumor. Nodes are evaluated based on their size and ultrasound appearance and can additionally be sampled using fine-needle aspiration (FNA) under EUS guidance. FNA can also be performed if ascites is present to evaluate for peritoneal spread. The overall accuracy of EUS is operator dependent and ranges from 57% to 88% for T stage and 30% to 90% for N stage.22 There is improved accuracy when T and N stages are grouped together to differentiate high-risk versus low-risk disease, defined by the presence of any subserosal or serosal (T3/T4) involvement or any nodal disease (>N0). From a prognostic and treatment standpoint, this classification may be more clinically relevant because an EUS finding indicative of advanced disease strongly correlates with decreased resectability and poorer disease-specific survival. A Cochrane meta analysis found that the summary sensitivity and specificity of EUS for discriminating T1/T2 versus T3/T4 disease were 86% and 90%, respectively.23 The sensitivity and specificity for nodal involvement were 83% and 67%, respectively. EUS is becoming increasingly important in the workup of gastric cancer

L. node

MM

Mass

MP

MP

A T3N1

Mass

B

SM MP

C

FIG. 49.23  Endoscopic ultrasound views of normal stomach (A), T1N0 gastric cancer (B), and T3N1 gastric cancer (C). (Courtesy Dr. Rajesh Keswani, Division of Gastroenterology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.) MM, Mucosa; MP, muscularis propria; SM, submucosa.

CHAPTER 49  Stomach to guide treatment decisions regarding neoadjuvant therapy and consideration for EMR (see below).  Computed tomography. CT of the chest, abdomen, and pelvis with oral and IV contrast agents is a mandatory component of the assessment of patients with gastric cancer to evaluate for metastatic disease. CT has also been used in locoregional staging but is less accurate than EUS. The overall accuracy of CT for T staging in 43% to 82%,22 with tumors more often being understaged. Although improved technology may increase the role for CT in locoregional evaluation and for neoadjuvant therapy, its primary role remains the evaluation of metastatic disease.  Positron emission tomography. Combined PET/CT is more accurate in preoperative staging (68%) than either PET (47%) or CT (53%) alone.22 The utility of PET/CT for initial staging of diffuse and mucinous cancers is limited due to low tracer accumulation. However, in patients with locally advanced disease and patients being considered for neoadjuvant therapy, there may be a role for PET/CT. PET/CT is slightly better than CT alone for detection of occult metastases. Further, patients with PET-avid tumors can be monitored for a response to neoadjuvant therapy, which strongly correlates with survival. Based on these data, the NCCN guidelines recommend considering PET/CT as part of staging for patients with greater than T1 disease without evidence of metastatic disease on initial CT.  Staging laparoscopy. Staging laparoscopy is an integral part of the standard workup for gastric cancer. The high rate of occult peritoneal metastatic disease makes laparoscopy an attractive staging modality given the low sensitivity of CT and PET/CT for detecting peritoneal metastases. Approximately 20% to 30% of patients undergoing staging laparoscopy for T2 or greater gastric cancer and no prior evidence of metastases will be found to have peritoneal disease; the NCCN recommends staging laparoscopic in this setting.22 The overall sensitivity of laparoscopy for detecting metastatic disease is greater than 95%. Laparoscopy alters management in 9% to 60% of cases, depending on the series and patient population, and specifically allows patients to avoid an unnecessary laparotomy by detecting metastatic disease that was missed on preoperative staging. Positive peritoneal washing cytology without overt macroscopic evidence of metastatic disease is used by some as an indication for neoadjuvant therapy. Staging laparoscopy is a safe, low-risk procedure that can be planned as a single-stage procedure with resection. Meanwhile, there are many benefits of avoiding laparotomy, which include avoiding a delay in starting chemotherapy for patients with metastatic disease. Given the persistence of high rates of metastatic disease not detected by preoperative workup in many centers, even with improved imaging modalities, we believe that these benefits far outweigh the risk and that staging laparoscopy should be part of the workup for most patients with gastric cancer. An evolving research question is whether patients should undergo a repeat staging laparoscopy following neoadjuvant therapy for advanced disease. Retrospective series have shown a 5% to 15% rate of finding occult metastatic disease in this setting, even in those who had a negative staging laparoscopy prior to initiation of neoadjuvant therapy. While not currently standard of care, repeat staging laparoscopy after neoadjuvant therapy detects a nontrivial amount of occult metastatic disease and should be strongly considered prior to undergoing a laparotomy for curative intent. 

Treatment

Surgical Therapy Complete resection of a gastric tumor with a wide margin of normal stomach remains the standard of care for resection with

1225

curative intent. Patients without metastatic disease or invasion of unresectable vascular structures such as the aorta, celiac trunk, proximal common hepatic, or proximal splenic arteries are candidates for curative resection. The extent of resection depends on the location of the tumor in the stomach and size of the tumor. For T4 tumors, any organ with invasion needs to be removed en bloc with the gastrectomy specimen to achieve a curative resection. While worldwide the standard technique is via a laparotomy, minimally invasive techniques, including endoscopic resection for very early tumors and laparoscopy, have proven effective. For cancers of the distal stomach, including the body and antrum, a distal gastrectomy is the appropriate operation. Because of propensity for intramural spread, the proximal stomach is transected at the level of the incisura at a margin of at least 2 to 3 cm for early cancers and at least 4 to 6 cm for advanced cancers. The distal margin is the proximal duodenum just distal to the pylorus. Frozen section analysis should be performed before reconstruction, and if positive, a wider excision should be performed when possible. The choice of reconstruction depends on the remnant anatomy with consideration of postgastrectomy physiology, although a Roux-en-Y reconstruction has been shown to result in less alkaline reflux gastritis and improved quality of life at 1 year compared to Billroth reconstruction. In East Asian countries, where early gastric cancer is more common, a pylorus-preserving segmental gastrectomy can be performed for cT1N0M0 disease for cancers in the middle third of the stomach. The antral cuff length can range from 1.5 to 3 cm. A recent review showed that for early gastric cancers, the oncologic outcomes were similar between pylorus-preserving segmental gastrectomy and distal gastrectomy, with the former having lower rates of dumping syndrome, bile reflux, and malnutrition.24 A randomized controlled trial in Korea (KLASS-04) is currently recruiting that will provide stronger evidence regarding the safety and oncologic equivalence of this newer technique. For proximal lesions of the fundus or cardia that do not invade the GE junction, a total gastrectomy with a Roux-en-Y esophagojejunostomy and proximal gastrectomy are equivalent from an oncologic perspective. However, rates of anastomotic stenosis and reflux esophagitis are much higher after proximal gastrectomy and the lymph node harvest may be inadequate; thus, most surgeons prefer a total gastrectomy for these patients. Minimally invasive techniques have been used for many GI malignancies, and gastric cancer is no exception. There is a learning curve to these procedures and a surgeon should be able to perform an equivalent oncologic resection and reconstruction. In systematic reviews, laparoscopic gastrectomy is associated with faster return of bowel function, shorter length of stay, and comparable lymph node retrieval, morbidity, and oncologic outcomes for early gastric cancers. The Japanese LOC-1 study propensity matched 1848 patients with stage I disease who underwent open and laparoscopic gastrectomy (n = 924 for both groups). They found that the 5-year overall survival and recurrence rates were similar between the two groups.25 Smaller series have shown that laparoscopic gastrectomy is feasible for locally advanced gastric cancer (T2 or above); however, long-term oncologic data are currently lacking. Japanese and Korean trials are presently ongoing to address this issue. Similarly, multiple groups have reported on laparoscopic total gastrectomy, although this procedure is more technically demanding given the need for an esophagojejunostomy and most series are from highvolume centers with extensive laparoscopic experience. Robotic gastrectomy is also being explored and while there is currently no high-quality long-term oncologic data, there is a phase III trial

1226

SECTION X   Abdomen

BOX 49.4  Standard criteria for endoscopic

resection of gastric adenocarcinoma. • Intestinal-type adenocarcinoma • Tumor confined to the mucosa • Absence of lymphovascular invasion • Nonulcerated tumor • Less than 2 cm in diameter

recruiting in Japan that randomizes patients between laparoscopic and robotic gastrectomy. Similar to other GI surgeries, enhanced recovery after surgery (ERAS) protocols have been developed for perioperative care after gastrectomy. Specific recommendations from the ERAS society include no routine use of NG/nasojejunal decompression, avoiding perianastomotic drains, and using minimally invasive approaches when possible. A weak recommendation was also made for offering oral diet to patients undergoing a total gastrectomy starting on postoperative day 1. A recent updated meta analysis found that ERAS protocols resulted in similar rates of total complications, perioperative mortality, and reoperation. The incidence of pulmonary infections, length of stay, medical costs, and time to first flatus were all significantly lower and the quality of life was superior. However, the readmission rate was nearly tripled in the ERAS group.26 ERAS and other fast-track protocols after gastrectomy are an area of active research interest and further optimization should elucidate ideal patient selection and balancing decreased length of stay with readmission rates.  Endoscopic Resection For select patients with early gastric cancer, endoscopic tumor resection can be performed for curative intent with adequate oncologic outcomes. The two primary modalities are EMR and ESD. The most significant advantage of endoscopic resection is avoiding the need for gastrectomy, whether by laparotomy or laparoscopy. The major disadvantages are risk of incomplete resection and unrecognized lymph node metastases. The standard criteria for endoscopic resection consideration are intestinal type adenocarcinoma, tumor confined to the mucosa, absence of lymphovascular invasion, nonulcerated, and less than 2 cm in diameter (Box 49.4). A recent systematic review and meta analysis found that in 9800 patients, those who met these standard criteria had only a 0.2% rate of lymph node metastases.27 Some centers in East Asia have proposed expanding criteria to include any differentiated mucosal tumor without ulceration, mucosal tumors up to 3 cm with ulceration, undifferentiated mucosal tumors up to 2 cm, and slight submucosal invasion. Risk of lymph node involvement in patients meeting this expanded criteria is higher at 0.7%, with undifferentiated histology and slight submucosal invasion having statistically significantly higher rates of lymph node metastases. Given that all these patients had early gastric cancer and were potentially curable with gastrectomy and lymphadenectomy, undertreatment in this group is not warranted unless part of a clinical trial or for patients with significant medical comorbidities who wish to avoid surgery. The basic principle for EMR involves elevating the tumor using a saline injection, encircling the affected mucosa using a snare device, and then excising it with electrocautery. Perforation rates are low, and bleeding rates are approximately 15%;

1

2

3

4

FIG. 49.24  Endoscopic mucosal resection by strip biopsy: Saline is injected into the submucosal layer, and the area is elevated (1). The top of the mound is pulled upward with forceps, and the snare is placed at the base of the lesion (2 and 3). Electrosurgical current is applied through the snare to resect the mucosa, and the lesion is removed (4). (From Tanabe S, Koizumi W, Kokutou M, et al. Usefulness of endoscopic aspiration mucosectomy as compared with strip biopsy for the treatment of gastric mucosal cancer. Gastrointest Endosc. 1999;50:819–822.)

these can generally be controlled endoscopically without the need for further intervention (Fig. 49.24). En bloc resection is preferred, as piecemeal resection is associated with an increased risk of recurrence. Patients with positive lateral margins can be considered for repeat endoscopic therapy or close surveillance. Patients with positive vertical margins, lymphovascular invasion, or submucosal invasion should be referred for gastrectomy with lymphadenectomy. ESD is mostly utilized in East Asia and allows for resection of larger tumors and those with limited submucosal involvement. This technique begins by marking the borders of the lesion using electrocautery. A submucosal injection of epinephrine with indigo carmine hydrodissects the lesion, and an insulation-tipped knife is used to remove the lesion by dissecting a submucosal plane deep to the tumor and removing it en bloc. Any bleeding is controlled with electrocautery (Fig. 49.25). There is a higher risk of perforation with ESD compared to EMR. Endoscopic resection leads to similar survival outcomes in appropriately selected patients. A meta analysis comparing endoscopic resection to radical gastrectomy for early gastric cancer with standard endoscopic resection criteria found that endoscopic resection had higher rates of recurrence and metachronous lesions, but that 3-year and 5-year survival was similar. Further, the morbidity rate was significantly lower with endoscopic resection.28  Extent of Lymph Node Dissection The stomach has a rich supply of lymphatics (Fig. 49.26). Number of positive lymph nodes correlates with survival in gastric cancer (Table 49.7). The extent of lymphadenectomy for gastric adenocarcinoma is a continuing area of ongoing debate. Historically, lymphadenectomy for gastric adenocarcinoma was defined by, and is still often discussed in terms of, the location of the nodes relative to the primary tumor. The extent of dissection ranges from the more local D1 lymphadenectomy involving only perigastric nodes

CHAPTER 49  Stomach

A

D

G

B

E

1227

C

F

H FIG. 49.25  Procedure of endoscopic submucosal dissection. (A) A type Iia + Iic early gastric cancer was located at the lesser curvature side of the antrum. (B) Indigo carmine dye was sprayed around the lesion to define the margin accurately. (C) Marking dots were made circumferentially at approximately 5 mm lateral to the margin of the lesion. (D) After a submucosal injection of saline with epinephrine mixed with indigo carmine, a circumferential mucosal incision was performed outside the marking dots to separate the lesion from the surrounding non neoplastic mucosa. (E and F) After an additional submucosal injection, the submucosal connective tissue just beneath the lesion was directly dissected using an electrosurgical knife instead of using a snare. (G) The lesion was completely resected, and the consequent artificial ulcer was seen. (H) The resected specimen with a central early gastric cancer. (From Min B-H, Lee JH, Kim JJ, et al. Clinical outcomes of endoscopic submucosal dissection (ESD) for treating early gastric cancer: comparison with endoscopic mucosal resection after circumferential precutting (EMR-P). Dig Liver Dis. 2009;41:201–209.)

(stations 1 to 7) to clearance of the celiac axis, with or without splenectomy, in an extended D2 dissection (stations 1 to 12a) to complete clearance of the celiac axis and periaortic nodes in a superextended D3 lymphadenectomy (stations 1 to 16) (Table 49.8).

Several randomized trials compared the outcomes of patients undergoing D1 versus D2 dissection, with conflicting results based on a combination of different patient populations, tumor biology, and surgical techniques. Earlier randomized trials showed

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SECTION X   Abdomen 110 111 20 1 7 12a

12p 12b 5 13 6 17

4d

9

8a 9 9 8p 16 15 14a 16 16

2 19

4sa 11d

3 11p

10 10

4sb 4sb

18 4d 4d

14v

13 15

FIG. 49.26  Lymph node station numbers as defined by the Japanese Gastric Cancer Association. (From Japanese Gastric Cancer Association. Japanese Classification of Gastric Carcinoma, 2nd English edition. Gastric Cancer. 1998;1:10–24.)

TABLE 49.7  Median survival according to

location of positive nodes versus number of positive nodes. MEDIAN SURVIVAL (MONTHS) SIZE

1–6 PNS

7–15 PNS

>15 PNS

3 cm (n = 233)

38.8 (n = 311) 35.5 (n = 81)

20.8 (n = 82) 19.7 (n = 96)

9.5 (n = 9) 12.5 (n = 56)

Adapted from Karpeh MS, Leon L, Klimstra D, et al. Lymph node staging in gastric cancer: Is location more important than number? An analysis of 1038 patients. Ann Surg. 2000;232:362–371. PN, Positive nodes.

either no survival benefit for D2 dissection or that while there was a significant disease-specific survival advantage that this was tempered by the increased perioperative mortality. More recently, it has been shown that the majority of this excess mortality was due to the routine use of splenectomy and distal pancreatectomy during D2 dissection, which is no longer standardly performed. A Cochrane review of five randomized trials comparing D2 to D1 dissection found a significantly improved hazard ratio of 0.81 in favor of D2 for disease-specific survival.29 Given the improving perioperative mortality, the NCCN and European Society for Medical Oncology have recommended D2 dissection in patients undergoing surgery for curative intent. While there has been some study into the potential for sentinel lymph node mapping in cases of early gastric cancers, these results have been inconsistent and should be considered investigational at this time. On the other hand, a D3 dissection for more advanced disease has not been shown to offer a survival benefit but does increase morbidity and should not be considered standard.29

TABLE 49.8  Regional lymph nodes

classification.

LYMPH NODE STATION (NO.) 1 2 3 4sa 4sb 4d 5 6 7 8a 8p 9 10 11p 11d 12a 12b, p 13 14v 14a 15 16al 16a2, b1 16b2

DESCRIPTION Right paracardial Left paracardial Lesser curvature Short gastric Left gastroepiploic Right gastroepiploic Suprapyloric Infrapyloric Left gastric artery Anterior common hepatic Posterior common hepatic Celiac artery Splenic hilum Proximal splenic Distal splenic Left hepatoduodenal Posterior hepatoduodenal Retropancreatic Superior mesenteric vein Superior mesenteric artery Middle colic Aortic hiatus Paraaortic, middle Paraaortic, caudal

From the Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma. 2 English ed. Gastric Cancer. 1998;1:10–24.

CHAPTER 49  Stomach The improvement in survival rates may be caused by stage migration. Patients who were previously understaged are now classified as having node-positive disease status, improving the prognosis of both groups. Regardless, better stage homogeneity and reducing understaging are critical to clinical decisions on potential treatments and prognosis. Recently, improved laparoscopic techniques have shown that laparoscopic lymph node dissection can achieve an adequate number of lymph nodes in experienced hands, and robotic-assisted surgery is also being actively explored to ensure oncologic equivalence.30  Locally Advanced Gastric Cancer Patients with advanced disease that is deemed unresectable because of adjacent organ involvement, generally the pancreas or spleen, or extensive nodal disease, including the para-aortic nodes, are particularly challenging. Multiple studies have indicated that, unsurprisingly, multiorgan resection significantly increases morbidity and perioperative mortality. Underlying all these studies, and the objective of performing multiorgan resection in general, is the desire to achieve an R0 resection. Patients with proven T4 disease who achieve an R0 resection have a clinically and statistically significant survival benefit over patients undergoing palliative resection only, with the palliative resection group having survival rates similar to patients receiving chemotherapy alone. In an effort to increase the number of patients for whom an R0 resection can be achieved, several investigators explored the role of neoadjuvant therapy in otherwise unresectable disease. A phase II trial treated 49 patients with clinically unresectable gastric cancer with cisplatin, docetaxel, and capecitabine and found an overall R0 resection rate of 63% compared with historical rates of 30% to 60%.31 These patients were prospectively stratified according to which criteria made them unresectable—adjacent organ involvement, bulky para-aortic nodal disease, or limited peritoneal disease. For patients without peritoneal disease, the R0 resection rate was greater than 70%. Of all patients who achieved R0 resection, patients with only adjacent organ involvement had significantly better outcomes. At a median follow-up of 51 months, median progression-free and overall survival have yet to be reached, with a predicted 5-year overall survival of 54%. A separate Japanese phase II study of 55 patients with extensive lymph node metastases studied neoadjuvant irinotecan and cisplatin followed by gastrectomy with D3 lymphadenectomy.32 The R0 resection rate was 65% and median OS was 14.6 months and 3-year survival was 27%, but with two chemotherapy-related deaths and one postoperative death. All these data suggest that multiorgan resection is beneficial in a highly selected patient population and that neoadjuvant therapy followed by more extensive surgery may provide a chance for long-term survival, although with worse outcomes than patients with less advanced disease and higher treatmentassociated morbidity and mortality. The difficulty is how to select these patients properly. As preoperative staging modalities improve in accuracy, so will the ability to select patients properly for various treatment modalities, including multiorgan resection. However, in patients who at the time of laparoscopy or laparotomy have clearly unresectable disease and who have no symptoms that would warrant resection, palliative resection should be avoided. Furthermore, any aggressive surgical intervention in these patients with locally advanced disease should be done within a multidisciplinary setting and preferably within the context of a clinical trial. 

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Adjuvant and Neoadjuvant Therapy Gastric cancer remains a biologically aggressive cancer, with high recurrence and subsequent mortality rates. Recurrences are most commonly distant or peritoneal, but a large number of patients also have locoregional recurrence, with a subset of 10% to 20% having only a local recurrence. For patients who recur, the prognosis is dismal and there has been much focus on how to prevent recurrent disease with neoadjuvant and/or adjuvant therapies. The Southwest Oncology Group (9008/INT-0116) reported a randomized controlled trial of 556 patients who underwent curative gastrectomy alone or gastrectomy combined with adjuvant 5-fluorouracil (5-FU) and radiotherapy.33 This study demonstrated a significant benefit for adjuvant therapy for overall survival (41% vs. 50%) and recurrence-free survival (41% vs. 64%). However, several authors have criticized these results, noting a high rate of inadequate lymphadenectomy (54% of patients underwent a D0 resection). Given these findings, it is possible that some of the benefit from radiation was clearance of residual disease in the perigastric nodal basin. Also, treatment with a single-agent 5-FU does not perform as well as multiagent therapy. Furthermore, only 64% of patients randomly assigned to the treatment arm were able to complete therapy; 17% had to stop treatment because of toxic effects, and 5% progressed while on treatment. Some of these study design deficiencies were addressed in the CLASSIC trial, which randomly assigned 1035 patients undergoing gastrectomy with D2 lymph node dissection to either surgery alone or surgery followed by eight 3-week cycles of capecitabine plus oxaliplatin. In the chemotherapy group, 67% of patients received all eight cycles as planned per protocol. At 5 years, the disease-free survival (68% vs. 53%) and overall survival (78% vs. 69%) were both significantly improved with adjuvant chemotherapy.34 Numerous other studies have been done and multiple metaanalyses support the survival benefit of adjuvant chemotherapy after complete oncologic resection for patients with greater than pathologic T2N0 disease. The optimal regimen has not been established. Common first-line regimens include ECF (epirubicin, cisplatin, and 5-FU), CAPOX (capecitabine and oxaliplatin), and FOLFOX (5-FU, leucovorin, and oxaliplatin). The benefit of adjuvant radiotherapy is less clear and often debated but has theoretical benefits given the high rates of local recurrence and nodal disease. The previously mentioned INT-0116 trial did show a benefit to chemoradiation; however, this is at least in part due to inadequate lymphadenectomy. The ARTIST trial evaluated whether the addition of adjuvant radiotherapy would be beneficial by randomizing 458 patients undergoing gastrectomy with D2 dissection to adjuvant chemotherapy with capecitabine and cisplatin alone or with radiotherapy.35 There was no difference in outcomes found between the adjuvant chemotherapy and adjuvant chemotherapy plus radiotherapy groups with 7-year followup. However, an initially unplanned subgroup analysis did show radiotherapy improved disease-free survival in patients who had lymph node metastases. A follow-up study (ARTIST 2) is ongoing to examine the benefit of radiotherapy in this patient subgroup alone. Based on presently available studies, adjuvant radiotherapy should be considered for patients with less than D2 lymphadenectomy and with positive nodal disease as part of multidisciplinary management. Given the relatively high rate of failure to complete adjuvant treatment in these trials, there has been increased focus on neoadjuvant therapy for gastric cancer, rather than postoperative

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SECTION X   Abdomen

adjuvant therapy. The most significant results are those of the MAGIC trial, a randomized study of 503 patients with stage II or higher GE cancer (372 stomach, 58 GE junction, 73 lower esophagus) that compared perioperative chemotherapy with surgery alone.36 The treatment group received three 3-week cycles of ECF preoperatively and three additional cycles postoperatively. More than 90% of patients who started the preoperative chemotherapy were able to complete it; however, only 65% of these patients went on to receive postoperative chemotherapy, and only 50% successfully completed both. The treatment group had significantly better pathologic results and long-term outcomes. The chemotherapy group had a higher percentage of T1 and T2 tumors in the final specimens, along with a higher proportion of limited (N0 and N1) nodal disease compared with the surgery alone arm. The rates of local recurrence, distant metastases, and 5-year overall survival were significantly improved in the chemotherapy group compared with the surgery-only group (14.4% vs. 20.6%, 24.4% vs. 36.8%, and 36.3% vs. 23%, respectively). Smaller trials and meta analyses have shown similar benefits with tumor downstaging and higher rates of R0 resection without significantly increased perioperative morbidity. Recently, the FLOT4 study compared the regimen used in the MAGIC trial to four preoperative and four postoperative cycles of FLOT (docetaxel, oxaliplatin, leucovorin, and 5-FU). A total of 716 patients were randomized. They found that both median overall survival (50 vs. 35 months, P = 0.012) and progression-free survival (30 vs. 18 months, P = 0.004) significantly favored the FLOT regimen.37 The optimal chemotherapy regimen, timing of therapy, and addition of radiotherapy for patients with operable gastric cancer is an active and evolving area of research with numerous trials ongoing. Neoadjuvant and adjuvant therapy options and patientspecific recommendations are likely to change in the coming years based on further study and improved granularity. Furthermore, as discussed below, targeted treatments and immunotherapy have shown promise in advanced and systemic disease and may become a part of therapeutic regimens for patients with resectable gastric cancer as well.  Palliative Therapy and Systemic Therapy Patients with unresectable or metastatic gastric cancer account almost 50% of patients presenting with the disease and have only a 3- to 5-month median survival with the best supportive therapy. While many patients with advanced disease are asymptomatic, a significant subset of patients with unresectable gastric cancer have debilitating symptoms and should be considered for palliative surgical therapy even in the setting of metastatic disease. Common complications of locally advanced gastric cancer include bleeding, obstruction, pain, and nausea. Acute bleeding can be treatment related or a result of the tumor itself. Patients presenting with bleeding should undergo prompt endoscopic assessment with attempt at endoscopic control. However, the initial success rate and rate of recurrent bleeding are both suboptimal and patients should be considered for other potential interventions as well, such as angiographic embolization or external beam radiation therapy. Nausea and vomiting are common and should be treated with appropriate antiemetic therapy, but these patients should also be assessed for luminal obstruction. Obstructing gastric cancers can sometimes be symptomatically improved with the placement of an endoscopic enteral stent. Radiation therapy and systemic chemotherapy can be considered in an attempt to shrink

the obstructing tumor. Surgical intervention can also be offered to patients fit to undergo surgery. The most common procedure in this setting is a gastrojejunostomy; however, a palliative gastrectomy can be considered in select patients. If the obstruction is unable to be alleviated, a venting gastrostomy tube can be placed either endoscopically, percutaneously, or surgically. Perforation of gastric cancer requires surgical intervention. Primary closure of perforated, frequently necrotic, tumor is not generally possible. Given the relatively poor functional status and prognosis for many of these patients, closure with healthy omentum is a reasonable approach. If it can be done without excess morbidity, gastrectomy can also be performed. Chemotherapy improves survival in patients with unresectable tumors, although prognosis is still poor with a median survival of less than a year. Standard doublet regimens include 5-FU and a platinum agent (either cisplatin or oxaliplatin). There is a debate about the utility of adding a third agent (usually either a taxane or anthracycline), with possibly improved outcomes at the expense of increased toxicity.38 NCCN guidelines recommend doublet regimens, with triplet regimens reserved for patients who are medically fit, have good performance status, and have access to frequent toxicity evaluation.22 Although better than supportive care alone, results of systemic treatments remain relatively poor. Investigators continue to evaluate for newer targeted therapeutic options. These include the epidermal growth factor receptor inhibitor cetuximab, vascular endothelial growth factor inhibitors ramucirumab and bevacizumab, and the human epidermal growth factor receptor 2 (HER2) antagonist trastuzumab. HER2 positivity has been reported about 20% of gastric cancers. Results of a phase III trial (ToGA trial) were first presented in 2009, evaluating 594 patients with HER2-overexpressing advanced gastric cancers. These patients were randomly assigned to receive capecitabine or 5-FU with cisplatin and trastuzumab or cisplatin alone. The trastuzumab group had a better median survival (13.8 vs. 11.1 months, P = 0.0046), and rates of severe complications did not differ between the groups.39 HER2 testing is now recommended by the NCCN guidelines for all patients with metastatic disease at time of initial diagnosis.22 More recently, immunotherapy has been investigated as a potential adjunctive therapy for advanced gastric cancer. Approximately 40% of gastric tumors have the upregulated programmed death ligand.38 Nivolumab and pembrolizumab have undergone trials, both with modest survival improvements in advanced disease. 

Outcomes The overall mortality rate and incidence of gastric cancer have been declining since 1930, likely because of changes in diet such as decreased sodium intake, changes in food storage and preparation, decreased smoking, and improved treatment options. Nonetheless, the overall 5-year survival remains poor, at approximately 30%. More than 63% of patients present with locally advanced or distant disease and are not candidates for surgery. For patients who undergo a potentially curative resection, overall 5-year survival rates range from of 25% to 75%; for the subset with early gastric cancer, cure rates are greater than 80%. For patients who present with distant disease, long-term survival is only 5% (Fig. 49.27). Recurrence Recurrence rates after gastrectomy are high, from 30% to 90%, depending on the series. Most recurrences occur within the first 2

CHAPTER 49  Stomach years. Locoregional recurrence is seen in about 40% of these patients. The most common sites of locoregional recurrence are the gastric remnant at the anastomosis, in the gastric bed, and in the regional nodal basins. The predominant sites of systemic recurrence are the liver and peritoneum. Surveillance. Although all patients should be followed systematically, the evidence for how this should occur is unclear and there is currently no evidence that follow-up improves long-term survival.40 The NCCN recommends a complete history and physical examination every 3 to 6 months for 1 to 2 years, every 6 to 12 months for 3 to 5 years, and annually thereafter. Laboratory tests, including complete blood count and liver function tests, should be performed as clinically indicated. CT or PET/CT scans can be obtained if there is clinical suspicion of recurrence, although some perform these routinely in high-risk patients. Sensitivity for detecting peritoneal recurrence is low. Annual endoscopy can be considered for patients who have undergone a subtotal gastrectomy or endoscopic resection.  100 90

All races White African American

80

Survival (%)

70 60

61

58

56

50 40 30

25 23 26

25 23 24

20 10

4

3 3

0 Localized

Regional

Distant

All stages

FIG. 49.27  The 5-year relative survival rates in patients with stomach cancers by race and stage at diagnosis, United States, 1996–2004. (From Jemal A, Siegel R, Ward E, et al. Cancer statistics. CA Cancer J Clin. 2009;59:225–249.)

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Gastric Lymphoma Epidemiology The stomach is the most common site of extranodal lymphoma. However, primary gastric lymphoma is still relatively uncommon, accounting for approximately 3% of gastric cancers. Patients often present with vague symptoms, such as epigastric pain, early satiety, and fatigue. Constitutional B symptoms (i.e., fever, night sweats) occur in only about 10% of patients. Lymphomas occur in older patients, with the peak incidence in the sixth and seventh decades, and there is a slight male predominance. Gastric lymphomas usually occur in the gastric antrum, but can arise from any part of the stomach. Patients are considered to have primary gastric lymphoma if the stomach is the exclusive or predominant site of disease. Several conditions have been shown to be associated with gastric lymphoma, including H. pylori infection, certain autoimmune diseases (i.e., rheumatoid arthritis, systemic lupus erythematous), immunosuppression, and celiac disease.  Pathology In the management of gastric lymphomas, as in the management of nodal lymphomas, it is important to determine not only the stage of disease but also the subtype of lymphoma. There are many classification systems for lymphomas (Table 49.9). The most common gastric lymphoma is diffuse large B cell lymphoma (DLBCL; 45%–60%), followed by gastric MALT lymphoma (40%–50%). Less commonly, peripheral T-cell lymphoma (1%–4%) and mantle cell and follicular lymphomas (both 5 mitoses/50 HPF  Low to Moderate Malignant Potential (12%–15% Tumor-Related Mortality) • >10 cm; no more than 5 mitoses/HPF • >2 cm but ≤5 cm; >5 mitoses/50 HPF  High Malignant Potential (49%-86% Tumor-Related Mortality) • >5 cm but ≤10 cm; >5 mitoses/50 HPF • >10 cm; >5 mitoses/50 HPF From Miettinen M, Sobin L, Lasota J. Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol. 2005;29:52–58. HPF, High-power field.

involved in performing EUS-directed FNA, in addition to the fact that most submucosal GI tumors require surgical resection regardless of histology, some experts have argued that routine preoperative pathologic diagnosis is not needed for such tumors. Presently, preoperative biopsy is not recommended if there is a high suspicion for GIST and the patient is otherwise operable, but is preferred to confirm presence of metastatic disease or if the patient is being considered for neoadjuvant imatinib therapy. CT of the abdomen and pelvis with oral and IV contrast is used to assess for metastatic disease. MRI is preferred in patients who cannot receive IV contrast or for rectal GISTs. Pathologically, GISTs can either have a spindle cell or epithelioid appearance. Immunohistochemical staining for CD117, CD34, and PDGFRA are used to confirm the diagnosis. The mainstay of treatment is complete surgical resection. Tumors that are symptomatic or greater than 2 cm in diameter should be resected, but the treatment for smaller tumors is controversial. Tumors that are less than 2 cm but which have highrisk features on endoscopy and EUS, such as irregular borders, ulceration, echogenic foci, and heterogeneity, should be resected, whereas tumors without such features can be observed with repeat endoscopy and EUS at 6- to 12-month intervals. Depending on tumor size and location, resection can include wide local excision, enucleation, sleeve gastrectomy, or total gastrectomy, with or without en bloc resection of adjacent organs. No specific surgical margin other than an R0 resection is required, and an anatomic resection according to lymph node basins is not required, as lymph node metastases are rare. The tumor should be handled carefully intraoperatively to avoid rupture or spillage. The two primary prognostic factors for gastric GISTs are tumor size and mitotic rate. Based on a long-term follow-up study of 1700 patients with gastric GISTs, malignant potential based on the combination of these two factors has been established (Box 49.5).45 Most patients who experience recurrence demonstrate

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metastasis to the liver, with one-third having only isolated local recurrence. Recurrence can occur over 20 years after resection; thus, long-term follow-up is warranted. Patients presenting with recurrent or metastatic disease are primarily treated with imatinib or a second-line tyrosine kinase inhibitor (see below), but a subset of patients may benefit from surgical intervention. A recent series of 323 patients found that response to neoadjuvant imatinib predicted clinical response after metastasectomy. Patients with responsive or stable disease had a median progression-free survival of 30 to 36 months, whereas those with unifocal or multifocal progressive disease had median progression-free survival of only 6 to 11 months.46 The timing of surgery in this setting is typically 6 to 9 months after neoadjuvant therapy initiation. Patients who are not surgical candidates due to isolated liver metastases can be considered for radiofrequency ablation or hepatic arterial embolization, both of which have shown some benefit in nonrandomized series. Adjuvant Therapy Adjuvant therapy for GIST changed dramatically with the discovery of the tyrosine kinase inhibitor imatinib (Gleevec). Originally designed to treat chronic myelogenous leukemia, it has proven in randomized controlled trials to be an effective treatment modality for patients with GIST. The ACOSOG Z9001 phase III, placebo-controlled, randomized trial of 713 patients with c-kit– positive tumors 3 cm or larger who underwent complete resection found that patients treated with imatinib for 1 year had a significantly improved 1-year recurrence-free survival (98% vs. 83%, P < 0.0001).47 This difference was even more pronounced for patients with larger tumors. The Scandinavian Sarcoma Group XVIII trial compared an extended 36-month course of adjuvant imatinib to a 12-month course after resection for 400 patients with high-risk GISTs (defined as >10 cm tumor, mitotic count >10/50 HPF, both tumor >5 cm and mitotic count >5 per 50 HPF, or tumor rupture). In the second planned analysis of the trial, patients in the extended treatment arm had higher 5-year recurrence-free survival (71.1% vs. 52.3%, P < 0.001) and overall survival (91.9% vs. 85.3%, P = 0.036).48 The results of this trial have established a 3-year course as the standard of care after surgical resection of high-risk GIST, though longer duration of therapy is being explored. Imatinib has also been reported to be successful in the neoadjuvant treatment of patients with nonmetastatic but unresectable disease, although the exact indications are not yet fully defined. Currently, patients with locally advanced, borderline resectable disease or in whom tumor shrinkage would increase the likelihood of organ preservation should be considered for neoadjuvant therapy. As stated previously, patients with limited metastatic disease can be offered neoadjuvant imatinib followed by possible metastatectomy based on clinical response. Fig. 49.28 is an algorithm for using imatinib in the treatment of GISTs in the neoadjuvant, adjuvant, and palliative settings. Patients who progress on imatinib or are intolerant to the drug are typically offered second-line tyrosine kinase inhibitors such as sunitinib or regorafenib. 

Other Neoplasms Gastric Neuroendocrine Tumors Gastric NETs, also referred to as carcinoid tumors, are a rare malignancy that arise from neuroendocrine precursor cells and can

1234

SECTION X   Abdomen

GIST

Resectable

Unresectable

Metastatic

Resect

Gleevec

Gleevec

Low risk of recurrence or metastases 5 mitoses/50 hpf

Surveillance

Adjuvant Gleevec

Reimage

Resect

Unresectable

Adjuvant Gleevec

Gleevec

FIG. 49.28  Algorithm for the workup and treatment of gastrointestinal stromal tumors (GISTs). hpf, High-power field.

TABLE 49.11  Gastric carcinoid types. TYPE 1

TYPE 2

Percentage of gastric 70%–80% 5%–10% NETs Associated pathology Pernicious anemia ZES, MEN1 Location Fundus or body Fundus, body, antrum Acid level Low High Gastrin level High High Prognosis Excellent Good

TYPE 3 10%–15% n/a Fundus or antrum Normal Normal Poor

MEN, Multiple endocrine neoplasia; n/a, not applicable; NETs, neuroendocrine tumors; ZES, Zollinger-Ellison syndrome.

manifest at any site in the body. The most common sites in the GI tract are the small intestine, rectum, and appendix. The stomach is becoming an increasing common site of NETs, now representing 8% of tumors. This increasing incidence is thought to be due to a combination of improved surveillance and the widespread use of PPIs.49 Unlike other GI tract NETs, gastric NETs are typically nonfunctioning and rarely cause carcinoid syndrome. There are three distinct subtypes of gastric NETs (Table 49.11). Type I gastric NETs are the most common, accounting for 70%– 80% of cases. They are associated with chronic achlorhydria from atrophic gastritis, pernicious anemia, or possibly prolonged PPI use.49 Type 1 gastric NETs are typically seen as multiple small tumors confined to the mucosa and submucosa with a relatively benign course and favorable prognosis. Type II gastric NETs are associated with hypergastrinemia in the setting of gastrinomas and ZES. Similar to Type I, patients will have multiple small tumors. While the prognosis is still good, with long-term survival of 70% to 90%, Type II has a slightly higher risk of metastasis (5%–35% of patients have spread to regional lymph nodes). Type III tumors are sporadic lesions with no associated conditions and without hypergastrinemia. They typically present as a large solitary lesion and account for 15% to 20% of gastric NETs. Type III portends a more aggressive course, with higher rates of metastases resulting

in a 5-year survival of 25% to 30%. The combined 5-year overall survival for all localized gastric NETs is 63%. While not universally adopted, neuroendocrine carcinoma has been referred to as Type IV gastric NET. These tumors are very aggressive, with most patients presenting with widespread metastatic disease. These patients are rarely candidates for curative resection but occasionally may require surgery to address bleeding, perforation, or obstruction.49 Diagnosis of gastric NET is established on esophagogastroduodenoscopy (EGD) with biopsy of the lesion. EUS can be performed to assess for depth of invasion subsequently. Either CT or MRI can be useful to evaluate for metastatic disease. Chromogranin A is often elevated and can serve as a biomarker for these tumors. The treatment for localized NETs is complete removal. For small pedunculated lesions that do not invade beyond the submucosa, complete removal can be accomplished endoscopically. Larger (>1 cm) lesions may require wedge resection or partial gastrectomy. Some clinicians will perform an antrectomy for Type I NETs to remove the source of gastrin secretion. Patients with numerous gastric NETs may require total gastrectomy. In patients with type II NETs, gastrinoma resection should be performed as well, if possible. Patients with localized type III NETs should undergo oncologic resection with lymphadenectomy. For patients with recurrent or metastatic disease, somatostatin analogues or chemotherapy can be used to decrease the burden of disease and treat carcinoid syndrome.  Heterotopic Pancreas Heterotopic pancreas (i.e., functioning pancreatic tissue is found in an abnormal anatomic location) is found in 0.5% to 14% of autopsy specimens. The most common location is within the stomach, typically along the antral greater curvature. Symptomatic patients generally present with vague abdominal pain. There have been reports of pancreatitis, islet cell tumors, and pancreatic adenocarcinoma within these lesions. On endoscopy and CT, they are frequently small submucosal masses and may be confused with a GIST or some other gastric neoplasm. The treatment is surgical excision, and the diagnosis is confirmed pathologically. 

CHAPTER 49  Stomach

OTHER GASTRIC LESIONS Hypertrophic Gastritis (Ménétrier Disease) Ménétrier disease (hypoproteinemic hypertrophic gastropathy) is a rare disease characterized by massive gastric folds in the fundus and body of the stomach, giving the mucosa a cobblestone or cerebriform appearance. The antrum is typically spared. Histologic examination reveals foveolar hyperplasia (expansion of surface mucus cells), with decreased or absent parietal cells. The condition is also associated with protein loss from the stomach, excessive mucus production, and hypochlorhydria or achlorhydria. The cause of Ménétrier disease is unknown, but it has been associated with cytomegalovirus infection in children and H. pylori infection in adults. Also, increased levels of transforming growth factor-α have been noted in the gastric mucosa of patients with the disease, which can stimulate epithelial cell growth and inhibit gastric acid secretion. Patients often present with epigastric pain, vomiting, weight loss, decreased appetite, and peripheral edema. Typical gastric mucosal changes can be detected by radiographic or endoscopic examination. Biopsy should be performed to establish the diagnosis and to rule out gastric carcinoma or lymphoma. Medical treatment yields inconsistent results; however, some benefit has been shown with the use of acid suppression, octreotide, and cytomegalovirus or H. pylori eradication. Total gastrectomy should be performed in patients who continue to have massive protein loss despite optimal medical therapy and high-protein diet or if dysplasia or carcinoma develops. Given the increased risk of gastric neoplasms in patients with Ménétrier disease, patients should undergo endoscopic surveillance every 1 to 2 years. 

Mallory-Weiss Tear Mallory-Weiss tears are mucosal lacerations related to forceful vomiting, retching, coughing, or straining that cause disruption of the gastric mucosa high on the lesser curve at the GE junction. They account for 10% to 15% of acute upper GI hemorrhages and are rarely associated with massive bleeding. The overall mortality rate for the lesion is 3% to 5%, with the greatest risk for massive hemorrhage in alcoholic patients with preexisting portal hypertension. Most patients with active bleeding can be managed by endoscopic methods, such as multipolar electrocoagulation, epinephrine injection, endoscopic band ligation, or endoscopic hemoclipping. Angiographic transarterial embolization may be useful in patients who have persistent or recurrent bleeding after endoscopy. Operative intervention is rarely needed. If surgery is required, the lesion at the GE junction is approached through an anterior gastrotomy, and the bleeding site is oversewn with several deep 2-0 silk ligatures to reapproximate the gastric mucosa in an anatomic fashion. Dieulafoy Gastric Lesion Dieulafoy lesions account for 0.3% to 7% of nonvariceal upper GI hemorrhages. Bleeding from a gastric Dieulafoy lesion is caused by an abnormally large (1–3 mm), tortuous artery coursing through the submucosa without a primary ulcer. Erosion of the superficial mucosa overlying the artery occurs secondary to the pulsations of the large submucosal vessel. The artery is then exposed to the gastric contents, and further erosion and bleeding occur. Generally, the mucosal defect is 2 to 5 mm and is surrounded by normal-appearing gastric mucosa. The lesions generally occur near the GE junction along the lesser curvature. Dieulafoy lesions are more common in men

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(2:1), with associated comorbidities including cardiovascular disease, chronic kidney disease, and diabetes. Most patients present with hematemesis. The classic presentation of a patient with a Dieulafoy lesion is sudden onset of massive, painless hematemesis. Detection and identification of the Dieulafoy lesion can be difficult. The diagnostic modality of choice is upper endoscopy, which correctly identifies the lesion in 80% of patients. Because of the intermittent nature of the bleeding, repeat endoscopies may be needed. If the lesion can be identified endoscopically and is actively bleeding, endoscopic modalities such as bipolar electrocoagulation, heater probe thermocoagulation, injection sclerotherapy, or endoscopic hemoclipping can be applied. Angiography can be useful in cases in which endoscopy is unable to definitely identify the source of bleeding. Angiographic findings may include a tortuous ectatic artery in the distribution of the left gastric artery, with accompanying contrast extravasation in the setting of acute bleeding. Embolization has been reported to control bleeding successfully in patients with Dieulafoy lesion, although the reported experience is limited. Surgical therapy was once the only available treatment for Dieulafoy lesion, but it is now reserved for patients in whom other modalities have failed. Surgical management consists of gastric wedge resection to include the offending vessel. The difficulty at the time of exploration is locating the lesion, unless it is actively bleeding. The surgical procedure can be greatly facilitated by asking the endoscopist to tattoo the stomach when the lesion is identified or with intraoperative endoscopic localization. A wedge resection is performed with a linear stapling device using endoscopic transillumination to determine the resection margin. 

Gastric Varices Gastric varices are dilated submucosal veins commonly seen in patients with portal hypertension and cirrhosis. Gastric varices account for 10% to 30% of variceal hemorrhages. They are broadly classified into two types: isolated gastric varices and GE varices. Isolated gastric varices are subclassified into type 1 varices, located in the fundus of the stomach, and type 2, isolated ectopic varices located anywhere in the stomach. While GE varices are more common overall, isolated gastric varices are more prone to bleeding. Gastric varices can develop secondary to portal hypertension, in conjunction with esophageal varices, or secondary to sinistral hypertension from splenic vein thrombosis. In generalized portal hypertension, the increased portal pressure is transmitted by the left gastric vein to esophageal varices and by the short and posterior gastric veins to the fundic plexus and cardia veins. Isolated gastric varices tend to occur secondary to splenic vein thrombosis, which is most commonly the result of pancreatitis. Splenic blood flows retrograde through the short and posterior gastric veins into the varices and then through the coronary vein into the portal vein. Left-to-right retrograde flow through the gastroepiploic vein to the superior mesenteric vein can explain the development of ectopic varices in the stomach. The incidence of bleeding from gastric varices has been reported to be between 3% and 30%. However, the incidence of bleeding can be much higher in patients with splenic vein thrombosis and fundic varices. There are limited data on risk factors associated with hemorrhage in patients with gastric varices, although increasing size of the varices or decompensated cirrhosis increases the risk for bleeding.

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Gastric varices in the setting of splenic vein thrombosis are readily treated by splenectomy. Patients with bleeding gastric varices should have an imaging study to document splenic vein thrombosis before a splenectomy is performed as gastric varices are more often associated with generalized portal hypertension. Acutely bleeding gastric varices in the setting of portal hypertension should be managed similarly to esophageal varices. The patient should be volume-resuscitated, with attention paid to the correction of abnormal coagulation profiles. Temporary tamponade can be attempted with a Sengstaken-Blakemore tube. Endoscopy serves as the primary diagnostic and therapeutic tool. Endoscopic treatment options for gastric variceal bleeding include sclerotherapy, band ligation, glue, or thrombin injection. A major problem with gastric varices after endoscopic treatment is rebleeding, occurring in 10% to 35% of cases.50 An emerging treatment modality is EUS-guided cyanoacrylate-lipiodol injection or coil embolization of perforating veins. Transjugular intrahepatic portosystemic shunting can be effective in controlling gastric variceal hemorrhage that does not respond to endoscopic treatments, with initial hemostasis rates over 90% and rebleeding rates of approximately 10% to 30%.50 A gastrorenal shunt between gastric varices and the left renal vein is present in 60% to 85% of patients with gastric varices. This spontaneous shunt decompresses the portal system and lessens the efficacy of transjugular intrahepatic portosystemic shunting. A balloon catheter can be inserted into the gastrorenal shunt through the left renal vein, and the shunt can be occluded by inflating the balloon. A sclerosant (e.g., ethanolamine oleate iopamidol) is injected and left to remain until clots have formed within the varices. Balloon-occluded retrograde transvenous obliteration has a high success rate (75%–100%) with a low recurrence rate (0%–15%).50 The major complication of this procedure is aggravation of esophageal varices secondary to an increase in portal pressure as a consequence of occluding the gastrorenal shunt. 

Gastric Volvulus Gastric volvulus is an uncommon condition. Torsion occurs along the stomach’s long longitudinal axis (organoaxial) in approximately two-thirds of cases and along the short vertical axis (mesenteroaxial) in one-third of cases (Fig. 49.29). Rotation more than 180 degrees causes gastric outlet obstruction and can lead to ischemia, necrosis, and potentially perforation if left uncorrected. Usually, organoaxial gastric volvulus occurs acutely and is associated with a diaphragmatic defect, whereas mesenteroaxial volvulus is partial (3 mm), mesenteric edema, fluid trapped in between loops, decreased bowel wall enhancement, pneumatosis intestinalis, and mesenteric or portovenous gas.6 Serum levels, including lactate dehydrogenase, amylase, alkaline phosphatase, and ammonia

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levels, have been assessed with no real benefit. Previous reports described limited success in discriminating strangulation by measuring serum d-lactate, creatine kinase isoenzyme (particularly the BB isoenzyme), or intestinal fatty acid–binding protein; however, these studies were ultimately abandoned as they showed no significant diagnostic benefits. Finally, noninvasive determinations of mesenteric ischemia have been described using a superconducting quantum interference device (SQUID) magnetometer to detect mesenteric ischemia noninvasively. Intestinal ischemia is associated with changes in the basic electrical rhythm of the small intestine. This technique remains investigational and is not in widespread clinical use. Thus, it is important to remember that bowel ischemia and strangulation cannot be reliably diagnosed or excluded preoperatively in all cases by any known clinical parameter, combination of parameters, or current laboratory and radiographic examinations. 

Treatment Patients with symptoms of a bowel obstruction usually present to the emergency department for evaluation and often require a surgical consultation. Patients identified to have small bowel obstruction should be primarily managed by a surgical service. A large population-based study demonstrated significantly shorter length of stay, lower cost, readmission rate, and mortality rate when adhesive bowel obstruction was managed by a surgical service compared to being managed by a medicine service.7 Fluid Resuscitation and Antibiotics Patients with intestinal obstruction are usually dehydrated and depleted of sodium, chloride, and potassium, requiring aggressive intravenous (IV) replacement with an isotonic saline solution such as lactated Ringer solution. Urine output should be monitored by the placement of a Foley catheter. After the patient has formed adequate urine, potassium chloride can be added to the infusion, if needed. Serial electrolyte level measurements as well as hematocrit and white blood cell count are performed to assess the adequacy of fluid repletion. Broad-spectrum antibiotics are given prophylactically by some surgeons on the basis of the reported findings of bacterial translocation occurring even in simple mechanical obstructions; however, there is no substantial evidence to support the use of antimicrobial therapy in nontoxic-appearing patients or those without suspected bacterial overgrowth of the small intestine. Antibiotics should only be administered preoperatively in the event that the patient requires surgery.  Tube Decompression In addition to IV fluid resuscitation, another important adjunct to the supportive care of patients with intestinal obstruction is nasogastric suction. Suction with a nasogastric tube empties the stomach, reducing the hazard of pulmonary aspiration of vomitus and minimizing further intestinal distention from swallowed air. Nasogastric decompression in a patient with small bowel obstruction is still considered standard of care. The use of long intestinal tubes (e.g., Cantor or Baker tube) has been advocated by some. However, prospective randomized trials have demonstrated no significant difference regarding the decompression achieved, success of nonoperative treatment, or incidence of postoperative morbidities compared with the use of nasogastric tubes. Furthermore, the use of these long tubes has been associated with a significantly longer hospital stay, duration of postoperative ileus, and postoperative complications in some

series. Therefore, it appears that long intestinal tubes offer no benefit in the preoperative setting over nasogastric tubes. Patients with a partial intestinal obstruction may be treated conservatively with resuscitation and tube decompression alone. Resolution of symptoms and discharge without the need for surgery have been reported in up to 85% of patients with a partial obstruction. Enteroclysis can assist in determining the degree of obstruction, with higher-grade partial obstructions requiring earlier operative intervention. Although an initial trial of nonoperative management of most patients with partial small bowel obstruction is warranted, clinical deterioration of the patient or increasing small bowel distention on abdominal radiographs during tube decompression warrants prompt operative intervention. The decision to continue to treat a patient nonoperatively with a presumed bowel obstruction is based on clinical judgment and requires constant vigilance to ensure that the clinical course has not changed.  Contrast Challenge The use of a water-soluble contrast challenge in lower-grade obstructions (i.e., those that have not resolved from nasogastric suction management after 48 hours) has become a more common practice. The challenge requires 100 mL of water-soluble contrast given through the nasogastric tube and follow-up radiographs obtained after 8 and 24 hours. If contrast material still has not passed into the colon after 24 hours, conservative management will probably fail and surgical intervention is likely needed.6  Operative Management As the management of intestinal obstruction has shifted more to conservative care with nasogastric tube decompression and rehydration, operative intervention is reserved for those who fail conservative management and have evidence of vascular compromise, strangulation, or perforation.6 A nonoperative approach for selected patients with complete small intestinal obstruction has been proposed by some surgeons who argue that prolonged gastrointestinal decompression is safe in these patients, provided no fever, tachycardia, tenderness, or leukocytosis is noted. Nevertheless, one must weigh the risks and benefits of nonoperative management in overlooking an underlying strangulated obstruction. Retrospective studies report that a 12- to 24-hour delay is safe but that the incidence of strangulation and other complications increases significantly after this time period. The nature of the problem dictates the approach for the obstructed patient. Patients with intestinal obstruction secondary to an adhesive band may be treated with lysis of adhesions. Great care should be used in the gentle handling of the bowel to reduce serosal trauma and to avoid unnecessary dissection and inadvertent enterotomies. Incarcerated hernias can be managed by manual reduction of the herniated segment of bowel and closure of the defect. The treatment of patients with an obstruction and history of malignant tumors can be particularly challenging. In the terminal patient with widespread metastasis, nonoperative management, if successful, is usually the best course; however, only a small percentage of cases with complete obstruction can be successfully managed nonoperatively. In this case, an intestinal bypass of the obstructing lesion, by whatever means, may offer the best option rather than a long and complicated operation that might entail bowel resection. An obstruction secondary to Crohn disease will often resolve with conservative management if the obstruction is acute. If a

CHAPTER 50  Small Intestine chronic fibrotic stricture is the cause of the obstruction, a bowel resection or strictureplasty may be required. Patients with an intraabdominal abscess can present in a manner indistinguishable from those with mechanical bowel obstruction. CT is particularly useful in diagnosing the cause of the obstruction in these patients. Percutaneous drainage of the abscess may be sufficient to relieve the obstruction, but laparotomy and abdominal washout may be required for large and established abscesses. Laparoscopic drainage is also an option in cases not amenable to image-guided percutaneous drainage or for patients who would not otherwise tolerate a laparotomy; this procedure is associated with reduced wound morbidity and is also useful in multiloculated collections and allows a washout of the peritoneal cavity at the same time. Radiation enteropathy, as a complication of radiation therapy for pelvic malignant neoplasms, may cause bowel obstruction. Most cases can be treated nonoperatively with tube decompression and the potential addition of corticosteroids, particularly during the acute setting. In the chronic setting, nonoperative management is rarely effective; laparotomy will be required with possible resection of the irradiated bowel or bypass of the affected area. At the time of exploration, it can sometimes be difficult to evaluate bowel viability after the release of a strangulation. If intestinal viability is questionable, the bowel segment should be completely released and placed in a warm, saline-moistened sponge for 15 to 20 minutes and then reexamined. If normal color has returned and peristalsis is evident, it is safe to retain the bowel. A prospective controlled trial comparing clinical judgment with the use of a Doppler probe or the administration of fluorescein for intraoperative discrimination of viability found that the Doppler flow probe added little to the conventional clinical judgment of the surgeon. In difficult borderline cases, fluorescein fluorescence may supplement clinical judgment. Intraoperative near-infrared angiography to determine the presence of ischemic bowel has shown promising results, but this technique is currently not in wide clinical use. Another approach to the assessment of bowel viability is the so-called second-look laparotomy 18 to 24 hours after the initial procedure. This decision should be made at the time of the initial operation. A second-look laparotomy is clearly indicated for a patient whose condition deteriorates after the initial operation. Multiple studies have evaluated the efficacy of laparoscopic management of acute small bowel obstruction. Laparoscopic treatment of small bowel obstruction appears to be effective and leads to a lower morbidity and mortality, shorter length of stay, shorter operating time, lower reoperation rate, and reduced overall complications in a select group of patients.8 The patient profile appropriate for consideration of laparoscopic management include those with the following clinical presentation: mild abdominal distention proximal or partial obstruction; anticipated single-band obstruction, and those with low risk of strangulation or perforation. In particular, laparoscopic treatment has been found to be of greatest benefit in patients who have undergone fewer than three previous operations, were seen early after the onset of symptoms, and were thought to have adhesive bands as the cause. Currently, patients with advanced, complete, or distal small bowel obstructions are not candidates for laparoscopic treatment. Similarly, patients with matted adhesions or carcinomatosis or those who remain distended after nasogastric intubation should be managed with conventional laparotomy. Therefore, the role of laparoscopic surgery in small bowel obstruction depends on clinical judgment and individualized treatment.8 

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Management of Specific Problems Recurrent Intestinal Obstruction All surgeons can readily remember the complicated patient with multiple previous abdominal operations and a frozen abdomen who presents with yet another bowel obstruction. An initial nonoperative trial is usually desirable and often safe. In those patients who do not respond conservatively, reoperation is required. This can often be a long and arduous procedure, with great care taken to prevent enterotomies or adjacent organ injury. In these difficult patients, various surgical procedures and pharmacologic agents have been tried in an effort to prevent recurrent adhesions and obstruction. External plication procedures have been described in which the small intestine or its mesentery is sutured in large, gently curving loops. Common complications include the development of fistulas, gross leakage, peritonitis, and death. Because of frequent complications and low overall success rate, these procedures have largely been abandoned. Several series have reported moderate success with internal fixation or stenting procedures using a long intestinal tube inserted through the nose, a gastrostomy, or even a jejunostomy that is left in place for 2 weeks or longer. Complications associated with these tubes include prolonged drainage of bowel contents from the tube insertion site, intussusception, and difficult removal of the tube, which may require surgical reexploration. Pharmacologic agents, including corticosteroids and other antiinflammatory agents, cytotoxic drugs, and antihistamines, have been used with limited success. The use of anticoagulants, such as heparin, dextran solutions, dicumarol, and sodium citrate, has modified the extent of adhesion formation, but their side effects far outweigh their efficacy. Intraperitoneal instillation of various proteinases (e.g., trypsin, papain, pepsin), which cause enzymatic digestion of the extracellular protein matrix, has been unsuccessful. Hyaluronidase has been of questionable value, and conflicting results were obtained with fibrinolytic agents such as streptokinase, urokinase, and fibrinolytic snake venoms. In a prospective multicenter trial, the use of a hyaluronate-based, bioresorbable membrane reduced the incidence and severity of postoperative adhesion formation. One study found that placement of this membrane reduced the severity but not the incidence of postoperative adhesions, and another study found that a multilayer approach has maximum effectiveness.9 Longer term, prospective randomized studies are required to determine the efficacy of this material in preventing adhesions and ultimately preventing bowel obstructions. To date, the most effective means of limiting the number of adhesions is a good surgical technique. This includes the gentle handling of the bowel to reduce serosal trauma, avoidance of unnecessary dissection, exclusion of foreign material from the peritoneal cavity (the use of absorbable suture material when possible, avoidance of excessive gauze sponge use, and the removal of starch from gloves), adequate irrigation and removal of infectious and ischemic debris, and preservation and use of the omentum around the site of surgery or in the denuded pelvis.  Acute Postoperative Obstruction Small bowel obstruction that occurs in the immediate postoperative period presents a challenge with regard to diagnosis and treatment. Diagnosis is often difficult because the primary symptoms of abdominal pain and nausea or emesis may be attributed to a postoperative ileus. Electrolyte deficiencies, particularly

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hypokalemia, can be a cause of ileus and should be corrected. Plain abdominal films are usually not helpful to distinguish an ileus from obstruction. CT may be useful in this regard, and in particular, enteroclysis studies may be helpful in determining whether an obstruction exists and, if so, the level of the obstruction.6 More than 90% of early postoperative obstructions are partial and will resolve spontaneously, given ample time. Conservative management in the form of bowel rest, fluid resuscitation, electrolyte replacement, and parenteral nutrition, if necessary, is routinely successful. However, the development of complete obstruction or signs of strangulation mandates reoperative intervention. Postoperative bowel obstruction after laparoscopic surgery is more commonly associated with a definitive obstruction point, such as a port site, hernia, or an internal hernia, and should prompt a high index of suspicion for the need for operative intervention.  Ileus An ileus is defined as intestinal distention and the slowing or absence of passage of luminal contents without a demonstrable mechanical obstruction. An ileus can result from a number of causes, including those that are drug induced, or from metabolic, neurogenic, and infectious factors (Box 50.3). Pharmacologic agents that can produce an ileus include anticholinergic drugs, autonomic blockers, antihistamines, and various psychotropic agents, such as haloperidol and tricyclic antidepressants. One of the more common causes of drug-induced ileus in the operative patient is the use of opiates, such as morphine or meperidine. Metabolic causes of ileus are common and include hypokalemia, hyponatremia, and hypomagnesemia. Other metabolic causes include uremia, diabetic coma, and hypoparathyroidism. Neurogenic causes of an ileus include postoperative ileus, which occurs after abdominal operations. Spinal injury, retroperitoneal irritation, and orthopedic procedures on the spine or pelvis can result in an ileus. Finally, infections can result in an ileus; common infectious causes include pneumonia, peritonitis, and generalized sepsis from a nonabdominal source. Patients often present in a manner similar to those with a mechanical small bowel obstruction. Abdominal distention, usually without the colicky abdominal pain, is the typical and most notable finding. Nausea and vomiting may occur but may also be absent. Patients with an ileus may continue to pass flatus and diarrhea, which may help distinguish these patients from those with a mechanical small bowel obstruction. BOX 50.3  Causes of ileus. • After laparotomy • Metabolic and electrolyte derangements (e.g., hypokalemia, hyponatremia, hypomagnesemia, uremia, diabetic coma) • Drugs (e.g., opiates, psychotropic agents, anticholinergic agents) • Intraabdominal inflammation • Retroperitoneal hemorrhage or inflammation • Intestinal ischemia • Systemic sepsis Adapted from Turnage RH, Bergen PC. Intestinal obstruction and ileus. In Feldman M, Scharschmidt FG, Sleisenger MH, eds. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. Philadelphia: WB Saunders; 1998:1799–1810.

Radiologic studies may help distinguish ileus from small bowel obstruction. Plain abdominal radiographs may reveal distended small bowel as well as large bowel loops. In cases that are difficult to differentiate from obstruction, barium studies may be beneficial. The treatment of an ileus is entirely supportive, with nasogastric decompression and IV fluids. The most effective treatment to correct the underlying condition may be aggressive treatment of the sepsis, correction of any metabolic or electrolyte abnormalities, and discontinuation of medications that may produce an ileus. Pharmacologic agents have been used but for the most part have been ineffective. Drugs that block sympathetic input (e.g., guanethidine) or stimulate parasympathetic activity (e.g., bethanechol, neostigmine) have been tried. Hormonal manipulation, using cholecystokinin or motilin, has been evaluated, but the results have been inconsistent. Erythromycin has been ineffective, and cisapride, although apparently beneficial in stimulating gastric motility, does not appear to alter intestinal ileus. Chewing gum has been suggested as an easy and inexpensive method to stimulate the cephalic phase of digestion (e.g., vagal cholinergic stimulation and the release of gastrointestinal hormones) and therefore a potential adjunct to prevent and to treat ileus. A more recent randomized trial demonstrated that chewing gum provides no benefit regarding return of bowel function or length of stay and even suggested that postoperative ileus may be further exacerbated by the use of sugared gum. 

INFLAMMATORY AND INFECTIOUS DISEASES Crohn Disease Crohn disease is a chronic, transmural inflammatory disease of the gastrointestinal tract for which the definitive cause is unknown, although a combination of genetic and environmental factors has been implicated. Crohn disease can involve any part of the alimentary tract from the mouth to the anus but most commonly affects the small intestine and colon. The most common clinical manifestations are abdominal pain, diarrhea, and weight loss. Crohn disease can be complicated by intestinal obstruction or localized perforation with fistula formation. Medical and surgical treatments are palliative; however, operative therapy can provide effective symptomatic relief for patients with complications from Crohn disease and produces a reasonable long-term benefit. History The first documented case of Crohn disease was described by Morgagni in 1761. In 1913, the Scottish surgeon Dalziel described nine cases of intestinal inflammatory disease. However, it is the landmark paper by Crohn and colleagues in 1932 that provided, in eloquent detail, the pathologic and clinical findings of this inflammatory disease in young adults.10 This classic paper crystallized the description of this inflammatory condition. Although many different (and sometimes misleading) terms have been used to describe this disease process, Crohn disease has been universally accepted as its name.  Incidence and Epidemiology Crohn disease is the most common primary surgical disease of the small bowel. The annual incidence of Crohn disease, which is rising in the United States, is 3 to 20 cases per 100,000 individuals.11 The total direct and indirect costs for Crohn disease in the United States have been estimated at more than $800 million

CHAPTER 50  Small Intestine when factoring both inpatient stays and outpatient visits. Crohn disease primarily attacks young adults in the second and third decades of life. However, a bimodal distribution is apparent, with a second smaller peak occurring in the sixth decade of life. Crohn disease is more common in urban dwellers, and although earlier reports suggested a somewhat higher female predominance, the two genders are affected equally. The risk for development of Crohn disease is about twice as high in smokers as in nonsmokers. Several studies indicate an increased incidence of Crohn disease in women using oral contraceptives; however, more recent studies have shown no differences. Worldwide, Crohn disease is relatively uncommon in African Americans; however, in the United States, the rates of Crohn disease in African Americans is similar to that seen in Caucasians. Certain ethnic groups, particularly Ashkenazi Jews, have a two- to four fold higher incidence of Crohn disease than age- and gender-matched control subjects. Individuals born during the spring months (e.g., April to June) are more likely to develop Crohn disease; there also appears to be a north-south gradient worldwide, and populations in higher latitudes have higher incidence rates than populations in lower latitudes. Of note, within one generation, migrants moving from a low-risk region to a high-risk region develop Crohn disease at similar rates to those in the high-risk region. There is a strong familial association, with the risk for development of Crohn disease increased about 30-fold in siblings and 14- to 15-fold for all first-degree relatives. Other analyses that support a genetic role for Crohn disease have shown a concordance rate of only 4% in dizygotic twins but a 20% to 50% rate in monozygotic twins. More recent studies evaluating twins with and without Crohn disease have used advanced genomic and proteomic techniques to show that intestinal microflora and epigenetic changes induced by environmental factors play an important role in disease development and progression in genetically susceptible individuals.12  Etiology The cause(s) of Crohn disease remain unknown. A number of potential causes have been proposed, with the most likely possibilities being infectious, immunologic, and genetic. Other possibilities that have met with various levels of enthusiasm include environmental and dietary factors, smoking, and psychosocial factors. Although these factors may contribute to the overall disease process, it is unlikely that they represent the primary etiology for Crohn disease. Infectious agents. Although a number of infectious agents have been proposed as potential causes of Crohn disease, the two that have received the most attention are mycobacterial infections, particularly Mycobacterium paratuberculosis and enteroadherent E. coli. The existence of atypical mycobacteria as a cause for Crohn disease was proposed by Dalziel in 1913. Subsequent studies using polymerase chain reaction (PCR) techniques have confirmed the presence of mycobacteria in intestinal samples of patients with Crohn disease. Transplantation of tissue from patients with Crohn disease has resulted in ileitis, but antimicrobial therapy directed against mycobacteria has not been effective in ameliorating the established disease process. Strains of enteroadherent E. coli are in higher abundance in patients with Crohn disease compared with the general population based on PCR analysis. More recent studies have used fluorescent in situ hybridization to demonstrate increased numbers of E. coli in the lamina propria of patients with active Crohn disease compared with those with inactive disease. Furthermore, an increased number of E. coli has been associated with a shorter time before relapse of the disease. 

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Immunologic factors. Humoral and cell-mediated immune reactions directed against intestinal cells in Crohn disease suggest an autoimmune phenomenon. Attention has focused on the role of cytokines, such as interleukin (IL)-1, IL-2, IL-8, and TNF-α, as contributing factors in the intestinal inflammatory response. The role of the immune response remains controversial in Crohn disease and may represent an effect of the disease process rather than an actual cause.  Genetic factors. Genetic factors play an important role in the pathogenesis of Crohn disease because the single strongest risk factor for development of disease is having a first-degree relative with Crohn disease. Several genome-wide association sequencing studies have been performed and have identified more than 200 alleles associated with Crohn disease (Table 50.5). The genes with the strongest and most frequently replicated associations with Crohn disease are NOD2, MHC, and MST1 3p21. Putative inflammatory bowel disease loci have been identified on chromosomes 16q, 5q, 19p, 7q, and 3p. The most important gene in Crohn disease development is NOD2. The NOD2 gene is associated with a decreased expression of antimicrobial peptides by Paneth cells. Heterozygosity of one NOD2 variant confers a 2- to 4-fold increase in risk of Crohn disease, while homozygosity confers a 17- to 40-fold increase in risk. In addition, NOD2 has been identified as a genetic predictor of ileal disease, ileal stenosis, fistula, and Crohn-related surgery.12 Another gene, CARD15, leads to impaired activation of the transcription factor nuclear factor kappa B (NF-κB) and also specifically codes for a protein expressed in monocytes, macrophages, dendritic cells, epithelial cells, and Paneth cells. CARD15 is also helpful in distinguishing Crohn disease from ulcerative colitis as it is more strongly associated with Crohn disease, especially in patients of northern European descent. The FHIT gene located on 3p14.2 has been identified as a tumor suppressor gene and is suggested to play a role in the pathogenesis of Crohn disease as well as in the development and progression of Crohn disease–related cancers. A complex cellular and molecular crosstalk occurs between the genes NOD2/CARD15 and the autophagy gene ATG16L1, which is associated with a synergistic increase in earlier onset and disease severity. Genetic profiling may be helpful in selecting patients who will benefit from intensified treatment with immunomodulators and anti-TNF therapy, thus decreasing medical nonresponse. More recent genome-wide association sequencing studies in monozygotic twins have shown no reproducible differences within twin pairs in comparing whole genome sequences and tissue-specific variants in the intestinal mucosa directly affected by the inflammation of Crohn disease. These findings suggest that it is unlikely that somatic mutations have a substantial impact on the development of the disease, and simple Mendelian inheritance cannot account for the pattern of occurrence. Therefore, it is likely that multiple causes (e.g., environmental factors) contribute to the cause and pathogenesis of this disease.  Environmental factors. Low-risk countries in Asia that have adopted a more Western lifestyle have noted a significant rise in the incidence of Crohn disease. Smoking is the single largest environment factor, with a two fold increase in risk of Crohn disease. Single nucleotide polymorphisms associated with smoking increase the risk of Crohn disease in smokers, identifying a genetic disposition for an environmental risk factor.13 In addition, other factors that increase the risk of Crohn disease include medications (oral contraceptives, aspirin, nonsteroidal antiinflammatory drugs

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TABLE 50.5  Genetic polymorphisms

related to Crohn disease.

Genes and the Diagnosis of Crohn Disease Genes related to innate pattern NOD2/CARD15, OCTN, TLR recognition receptors Genes related to epithelial barrier IBD5, DLG5 homeostasis Genes related to molecular mimicry ATG16L1, IRGM, LRRK2 and autophagy Genes related to lymphocyte IL23R, STAT3 differentiation Genes related to secondary immune MHC, HLA response and apoptosis Genes and the Prognosis of Crohn Disease Genes related to age at Crohn disease TNFRSF6B, CXCL9, IL23R, NOD2, onset ATG16L1, CNR1, IL10, MDR1, DLG5, IRGM Genes Related to Crohn Disease Behavior Stenotic/structuring behavior NOD2, TLR4, IL12B, CX3CR1, IL10, IL6 Penetrating/fistulizing behavior NOD2, IRGM, TNF, HLADRB1, CDKAL1 Inflammatory behavior HLA Granulomatous disease TLR4/CARD15 Genes Related to Crohn Disease Location Upper gastrointestinal NOD2, MIF Ileal IL10, CRP, NOD2, ZNF365, STAT3 Ileocolonic ATG16L1, TCF4 (TCF7L2) Colonic HLA, TLR4, TLR1, TLR2, TLR6 Other Genes Related to Crohn Disease Genes related to Crohn disease activity HSP702, NOD2, PAI1, CNR1 Genes related to surgery NOD2, HLAG Genes related to dysplasia and cancer FHIT Genes related to extraintestinal CARD15, FcRL3, HLADRB103, HLAB27, manifestations HLA-B44, HLA-B35, TNFa-308A, TNF-1031C, STAT3 Pharmacogenetics in Crohn CARD15, NAT, TPMT, MDR1, MIF, DLG5, TNF, LTA Disease Adapted from Tsianos EV, Katsanos KH, Tsianos VE. Role of genetics in the diagnosis and prognosis of Crohn’s disease. World J Gastroenterol. 2012;18:105–118.

multi-institutional study proposed a three-category model to better characterize inflammatory bowel disease into ileal Crohn disease, colonic Crohn disease, and ulcerative colitis. These categories provide risk stratification for surgical complications and genetic risk score based on location.15 Ileal involvement has been shown with mutations of IL10, CRP, NOD2, ZNF365, and STAT3; ileocolonic involvement has been shown with mutations of ATG16L1, TCF4, and TCF7L2; and colonic involvement has been associated with mutations of HLA, TLR4, TLR1, TLR2, and TLR6. The involvement of the large and small intestine has been noted in about 55% of patients. Thirty percent of patients present with small bowel disease alone, and in 15%, the disease appears limited to the large intestine. The disease process is discontinuous and segmental. In patients with colonic disease, rectal sparing is characteristic of Crohn disease and helps distinguish it from ulcerative colitis. Perirectal and perianal involvement occurs in about one third of patients with Crohn disease, particularly those with colonic involvement. Crohn disease can also involve the mouth, esophagus, stomach, duodenum, and appendix. Involvement of these sites can accompany disease in the small or large intestine, but in only rare cases have these locations been the only apparent sites of involvement. Gross pathologic features. At exploration, thickened graypink or dull purple-red loops of bowel are noted, with areas of thick gray-white exudate or fibrosis of the serosa. Areas of diseased bowel separated by areas of grossly appearing normal bowel, called skip areas, are commonly encountered. A striking finding of Crohn disease is the presence of extensive fat wrapping caused by the circumferential growth of the mesenteric fat around the bowel wall, also known as creeping fat (Fig. 50.16). As the disease progresses, the bowel wall becomes increasingly thickened, firm, rubbery, and almost incompressible (Fig. 50.17). The uninvolved proximal bowel may be dilated secondary to obstruction of the diseased segment. Involved segments often are adherent to adjacent intestinal loops or other viscera, with internal fistulas common in these areas. The mesentery of the involved segment is usually thickened, with enlarged lymph nodes often noted. On opening of the bowel, the earliest gross pathologic lesion is a superficial aphthous ulcer noted in the mucosa. With increasing disease progression, the ulceration becomes pronounced, and complete transmural inflammation results. The ulcers are characteristically linear and may coalesce to produce transverse sinuses

[NSAIDs]), decreased dietary fiber, and increase fat intake. In addition, dysbiosis with a decrease in intraluminal Bacteroides and Firmicutes and an increase in Gammaproteobacteria and Actinobacteria are associated with higher risk. Specifically, an increase of mucosal—adherent—invasive E. coli survive within macrophages and induce higher TNF-α production.14 There are numerous studies evaluating the therapeutic benefits of microbiota manipulation.  Pathology The most common sites of Crohn disease are the small intestine and colon. The location of disease involvement is biologically defined by the genetic variation. As such, a large

FIG. 50.16  Crohn disease with evidence of creeping fat. Laparoscopic evaluation of extensive fat wrapping caused by the circumferential growth of the mesenteric fat around the bowel wall. (Courtesy Dr. John Draus, University of Kentucky Medical Center, Lexington, KY.)

CHAPTER 50  Small Intestine

A

B

FIG. 50.17  Gross pathologic features of Crohn disease. (A) Serosal surface demonstrates extensive fat wrapping and inflammation. (B) Resected specimen demonstrates marked fibrosis of the intestinal wall, stricture, and segmental mucosal inflammation. (Courtesy Dr. Mary R. Schwartz, Baylor College of Medicine, Houston, TX.)

with islands of normal mucosa in between, thus giving the characteristic cobblestone appearance.  Microscopic features. Mucosal and submucosal edema may be noted microscopically before any gross changes. A chronic inflammatory infiltrate appears in the mucosa and submucosa and extends transmurally. This inflammatory reaction is characterized by extensive edema, hyperemia, lymphangiectasia, intense infiltration of mononuclear cells, and lymphoid hyperplasia. Characteristic histologic lesions of Crohn disease are noncaseating granulomas with Langerhans giant cells. Granulomas appear later in the course and are found in the wall of the bowel or in regional lymph nodes in 60% to 70% of patients (Fig. 50.18).  Clinical Manifestations Crohn disease can occur at any age, but the typical patient is a young adult in the second or third decade of life. The onset of disease is often insidious, with a slow and protracted course. Characteristically, there are symptomatic periods of abdominal pain and diarrhea interspersed with asymptomatic periods of varying lengths. With time, the symptomatic periods gradually become more frequent, more severe, and longer lasting. The most common symptom of Crohn disease is chronic diarrhea, followed by intermittent and colicky abdominal pain, most commonly noted in the lower abdomen. The pain, however, may be more severe and localized in the right lower quadrant and may mimic the signs and symptoms of acute appendicitis.16 In contrast to ulcerative colitis, patients with Crohn disease typically have fewer bowel movements, and the stools rarely contain mucus, pus, or blood. Systemic nonspecific symptoms include a low-grade fever present in about one third of the patients, weight loss, loss of strength, and malaise. Clinically, Crohn disease is often classified on the basis of age at onset, behavior, and site of origin. The Montreal Classification (Table 50.6) divides all patients into distinct categories based on

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symptom onset (before or after the age of 40 years), disease behavior (nonstricturing/nonpenetrating, stricturing, or penetrating), and disease site (terminal ileum, colon, ileocolonic, upper gastrointestinal tract). This classification was developed to provide a reproducible staging of the disease, to help predict remission and relapse, and to direct therapy. The main intestinal complications of Crohn disease include obstruction and perforation. Obstruction can occur as a manifestation of an acute exacerbation of active disease or as the result of chronic fibrosing lesions, which eventually narrow the lumen of the bowel, producing partial or near-complete obstruction. Free perforations into the peritoneal cavity leading to a generalized peritonitis can occur in patients with Crohn disease, but this presentation is rare. More commonly, fistulas occur between the sites of perforation and adjacent organs, such as loops of small and large intestine, urinary bladder, vagina, stomach, and sometimes the skin, usually at the site of a previous laparotomy. Localized abscesses can occur near the sites of perforation. Patients with Crohn colitis may develop toxic megacolon and present with a marked colonic dilation, abdominal tenderness, fever, and leukocytosis. Bleeding is typically indolent and chronic, but massive gastrointestinal bleeding can occasionally occur, particularly in duodenal Crohn disease associated with chronic ulcer formation. Long-standing Crohn disease predisposes to cancer of the small intestine and colon. These carcinomas typically arise at sites of chronic disease and more commonly occur in the ileum as a result of the chronic inflammation of the mucosa. Most are not detected until in advanced stages, and the prognosis is poor. Although the relative risk for small bowel cancer in Crohn disease is approximately 100-fold, the absolute risk is still small. Of greater concern is the development of colorectal cancer in patients with colonic involvement and a long duration of disease. Dysplasia is the putative precursor lesion for Crohn disease–associated cancer. Patients with long-standing Crohn disease should have an equally aggressive colonoscopic surveillance regimen as patients with extensive ulcerative colitis.17 Small bowel adenocarcinoma associated with Crohn disease has an aggressive behavior and a strong probability of extracellular mucin. In surgical specimens from patients with Crohn disease, mucinous-appearing anal fistulas and ileal areas of adhesion/retraction should always be closely examined by a pathologist to evaluate for dysplasia or malignancy. Extraintestinal cancer, such as squamous cell carcinoma of the vulva and anal canal and Hodgkin and non-Hodgkin lymphomas, may be more frequent in patients with Crohn disease, especially those treated with immunomodulators. Perianal disease (fissure, fistula, stricture, or abscess) is common and occurs in 25% of patients with Crohn disease limited to the small intestine, 41% of patients with ileocolitis, and 48% of patients with colonic involvement alone. Perianal disease may be the sole presenting feature in 5% of patients and may precede the onset of intestinal disease by months or even years. Crohn disease should be suspected in any patient with multiple, chronic perianal fistulas. Extraintestinal manifestations of Crohn disease may be present in 30% of patients. The most common symptoms are skin lesions (Fig. 50.19), which include erythema nodosum and pyoderma gangrenosum, arthritis and arthralgias, uveitis and iritis, hepatitis, pericholangitis, and aphthous stomatitis. In addition, amyloidosis, pancreatitis, and nephrotic syndrome may occur in these patients. These symptoms may precede, accompany, or appear independently of the underlying bowel disease. 

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SECTION X  Abdomen

A

B

C FIG. 50.18  Microscopic features of Crohn disease. (A) Transmural inflammation. (B) Fissure ulcer (arrows). (C) Noncaseating granuloma located in the muscular layer of the small bowel (arrow). (Courtesy Dr. Mary R. Schwartz, Baylor College of Medicine, Houston, TX.)

Diagnosis A diagnosis of Crohn disease should be considered in patients with chronic recurring episodes of abdominal pain, diarrhea, and weight loss. However, there is not a single diagnostic test for Crohn disease; a multimodal approach of laboratory testing, endoscopy, radiology, and pathology is required. Laboratory. Serologic markers may useful in the diagnosis of Crohn disease. In particular, perinuclear antineutrophil cytoplasmic antibody (and its target proteins bactericidal/permeability increasing protein [BPI], lactoferrin, cathepsin G and elastase), anti–Saccharomyces cerevisiae antibody (ASCA), outer membrane porin of flagellin (anti-CBir1), and outer membrane porin of E. coli (OmpC-IgG) can predict the development of inflammatory bowel disease even in patients thought to be at low risk for

development of disease.18 ASCA is also useful in differentiating Crohn disease from ulcerative colitis as well as playing a role in determining patients who will require surgery in the future. Noninvasive inflammatory markers, historically C-reactive protein and erythrocyte sedimentation rate, were used to aid in the initial diagnosis, to rule out exacerbations, to monitor response to systemic therapy, and to predict relapse; however, these markers were generally nonspecific and have largely been abandoned. Stool lactoferrin, an iron-binding protein in the secretory granules of neutrophils, and fecal calprotectin, a protein with antimicrobial properties released by squamous cells in response to inflammation, are inflammatory markers specific to the intestine that have shown promising results for the detection and surveillance of Crohn disease. A prospective study showed that both calprotectin

CHAPTER 50  Small Intestine TABLE 50.6  Montreal classification of

Crohn disease. Age at diagnosis (years)

Behavior

Location

A1: ≤16 A2: 17–40 A3: >40 B1: Nonstricturing/nonpenetrating B2: Stricturing B3: Penetrating P: Perianal disease modifier (can add to B1-3) L1: Ileal L2: Colonic L3: Ileocolonic L4: Isolated upper gastrointestinal tract (can add to L1-3)

Adapted from Spekhorst LM, Visschedijk MC, Alberts R, et al. Performance of the Montreal classification for inflammatory bowel diseases. World J Gastroenterol. 2014;20:15374–15381.

and lactoferrin levels correlate well with CT enterography (CTE) images of small bowel inflammation (mucosal irregularity, hyperdensity, stenosis, prestenotic dilation and mesenteric hypervascularity [i.e., comb sign]). Fecal calprotectin levels greater than 140 ng/mL, predicted small bowel inflammation with a sensitivity of 69% and a specificity of 82%. Similarly, fecal lactoferrin (>6 ng/ mL) predicted small bowel inflammation with a sensitivity of 69% and a specificity of 79%. Fecal calprotectin is associated with elevated C-reactive protein and erythrocyte sedimentation rate levels, whereas fecal lactoferrin is only associated with elevated C-reactive protein levels. Together, these findings identify fecal calprotectin and lactoferrin as helpful screening tools for detecting early small bowel Crohn disease.19  Radiology. CTE or magnetic resonance enterography (MRE) are often used as the initial assessment of Crohn disease to complement

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direct ileocolonoscopy. Imaging studies can provide information regarding severity of inflammation, length, and focality and identify complications (e.g., obstruction or fistula). In addition, these studies support surgical planning and the evaluation of response to medical therapy.20 Previously, barium enema was commonly used to identify features of Crohn disease. For example, long lengths of narrowed terminal ileum (Kantor string sign) may be present with long-standing disease (Fig. 50.20). Segmental and irregular patterns of bowel involvement may be noted. Fistulas between adjacent bowel loops and organs may be apparent (Fig. 50.21). CTE may be useful in demonstrating the marked transmural thickening; it can also greatly aid in diagnosing extramural complications of Crohn disease, especially in the acute setting (Fig. 50.22). Both MRE and CTE are equally accurate in assessing disease activity and bowel damage; however, MRE may be superior to CTE in detecting intestinal strictures and ileal wall enhancement.20 Recent studies suggest limiting the use of CTE in patients with long-standing Crohn disease because of its significant radiation exposure and need for numerous studies during the course of the disease. MRE is a useful adjunct to determine intestinal strictures as well as fistulas and sinus tracks; however, the relatively high cost, prolonged examination time, and limited availability may preclude many patients from receiving this procedure. Ultrasonography has limited value in the evaluation of patients with Crohn disease and has an especially lower accuracy for detecting the disease proximal to the terminal ileum. One study determined that this modality failed to identify disease proximal to the terminal ileum in up to 67% of patients; however, ultrasound may be helpful in the assessment of undiagnosed right lower quadrant pain. 

FIG. 50.20  Small bowel obstruction secondary to Crohn disease. Small FIG. 50.19  Crohn disease patient with erythema nodosum. The most common extraintestinal presentations of Crohn disease are skin lesions, which include erythema nodosum and pyoderma gangrenosum.

bowel series in a patient with Crohn disease demonstrates a narrowed distal ileum (arrows) secondary to chronic inflammation and fibrosis. (Courtesy Dr. Melvyn H. Schreiber, The University of Texas Medical Branch, Galveston, TX.)

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SECTION X  Abdomen

FIG. 50.21  Intraabdominal fistulas in Crohn disease. Multiple short fistulous tracts communicating between the distal loops of ileum and the proximal colon in a patient with Crohn disease (arrows). (Courtesy Dr. Melvyn H. Schreiber, The University of Texas Medical Branch, Galveston, TX. Adapted from Evers BM, Townsend CM Jr, Thompson JC. Small intestine. In: Schwartz SI, ed. Principles of Surgery. 7th ed. New York: McGraw-Hill; 1999:1233.)

small intestine. With more progressive and severe disease, the ulcerations involve progressively more of the bowel lumen, and it may be difficult to distinguish Crohn disease from ulcerative colitis. However, the presence of discrete ulcers and cobblestoning as well as the discontinuous segments of involved bowel favors a diagnosis of Crohn disease. Endoscopic advances that allow better evaluation of the small intestine include singleballoon enteroscopy, double-balloon enteroscopy, and spiral enteroscopy; the most well-established technique is doubleballoon enteroscopy, which allows increased enteral intubation (240–360 cm) compared with push enteroscopy (90–150 cm) or ileocolonoscopy (50–80 cm). Limitations include specialized examiner skills and equipment, prolonged procedure times, and a 1% risk of complications (e.g., pancreatitis, perforation, or bleeding). After the diagnosis is confirmed, the Crohn Disease Endoscopic Index of Severity (CDEIS) or the Simple Endoscopic Score for Crohn Disease (SES-CD) is used to define extent of disease and severity. Recently, capsule endoscopy was approved by the U.S. Food and Drug Administration (FDA) in 2001 and is helpful in the diagnosis of superficial mucosal abnormalities. The most commonly used criterion for an abnormal finding is the presence of three or more ulcers in the absence of NSAID use. The use of this modality is limited because of concern for capsule retention, defined as the presence of the capsule in the gastrointestinal tract for more than 2 weeks, which is of greater concern to patients with Crohn disease due to a significantly higher risk of retention (13%) compared with the general population (1%–2.5%). However, capsule endoscopy has been found to be superior to any other modality in the identification of intestinal ulceration. Severity is measured utilizing the Capsule Endoscopy Crohn Disease Activity Index (CECDAI or Niv score).21 Further studies are needed to provide a more comprehensive evaluation of Crohn disease in the entire intestinal tract since new generations of capsule endoscopy devices will also provide visualization of colonic mucosa.  Histology

R

L

FIG. 50.22  Mechanical small bowel obstruction secondary to chronic structuring disease. Computed tomography enterography of a patient with Crohn disease demonstrates marked thickening of the bowel (arrows) with a high-grade partial small bowel obstruction and dilated proximal intestine. (Courtesy Dr. Melvyn H. Schreiber, The University of Texas Medical Branch, Galveston, TX. Adapted from Evers BM, Townsend CM Jr, Thompson JC. Small intestine. In: Schwartz SI, ed. Principles of Surgery. 7th ed. New York: McGraw-Hill; 1999:1233.)

Endoscopy. Ileocolonoscopy with biopsies of the terminal ileum are the gold standard for the diagnosis of Crohn disease. When the colon is involved, sigmoidoscopy or colonoscopy may reveal characteristic aphthous ulcers with granularity and a normal-appearing surrounding mucosa. Intubation of the ileocecal valve during colonoscopy allows examination and biopsy of the terminal ileum but fails to evaluate other segments of the

Differential diagnosis. The differential diagnosis of Crohn disease includes specific and nonspecific causes of intestinal inflammation. Bacterial inflammation (such as that caused by Salmonella and Shigella), intestinal tuberculosis, and protozoan infections (such as amebiasis) may manifest as an ileitis. In the immunocompromised host, rare infections, particularly mycobacterial and cytomegalovirus (CMV) infections, have become more common and may cause ileitis. Acute distal ileitis may be a manifestation of early Crohn disease, but it also may be unrelated, such as when it is caused by a bacteriologic agent (e.g., Campylobacter, Yersinia). Patients usually present in a similar fashion to those presenting with acute appendicitis, with a sudden onset of right lower quadrant pain, nausea, vomiting, and fever. These entities normally resolve spontaneously, and when they are noted during surgery, no biopsy or resection should be performed. In most cases, Crohn disease of the colon can be readily distinguished from ulcerative colitis; however, in 5% to 10% of patients, the delineation between Crohn disease and ulcerative colitis may be difficult if not impossible to make (Table 50.7). Ulcerative colitis almost always involves the rectum most severely, with lessening inflammation from the rectum to the ileocolic area. In contrast, Crohn disease may be worse on the right side of the colon than on the left side, and sometimes the rectum is spared. Ulcerative colitis also demonstrates continuous involvement from

CHAPTER 50  Small Intestine

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TABLE 50.7  Diagnosis of Crohn colitis versus ulcerative colitis. PARAMETER

CROHN COLITIS

ULCERATIVE COLITIS

Symptoms and Signs Diarrhea Rectal bleeding Abdominal pain (cramps) Palpable mass Anal complaints

Common Less common Moderate to severe At times Frequent (>50%)

Common Almost always Mild to moderate No (unless large cancer) Infrequent (47%, or females >42%) Body weight (1 - weight/standard weight) × 100 (add or subtract according to sign) Adapted from Sandborn WJ, Feagan BG, Hanauer SB, et al. A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn’s disease. Gastroenterology. 2002;122:512–530.

Clinical remission is achieved when CDAI is below 150, and clinical response to therapy occurs with a drop of 100 points.22 A score between 150 and 220 is considered mild to moderate disease and can be followed by outpatient visits; a score between 220 and 450 is considered moderate to severe disease and occurs after failure to first line therapy; a score greater than 450 is considered severe fulminant disease with failed medical therapy and complications of obstruction, peritonitis, and abscess. Other innovative therapies such as MadCAM-1 ([mucosal addressin cell adhesion molecule 1] inhibitor), tofacitinib (JAK3 pathway inhibitor), mongersen (SMAD7 inhibitor), and ozanimod (S1P1 inhibitor) are all currently under phase II/III clinical trials.

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SECTION X  Abdomen

Aminosalicylates. Sulfasalazine (azulfidine) is an aminosalicylate with 5-aminosalicylic acid as the active moiety. Although a clear benefit has been noted in patients with colonic involvement, the effectiveness of sulfasalazine alone in the treatment of small bowel Crohn disease is controversial, and its use in maintenance therapy has fallen out of favor. Mesalamine, which is also an aminosalicylate, provides a slow release of 5-aminosalicylic acid with passage through the small bowel and colon. Clinical trials have demonstrated efficacy of mesalamine at a dosage of 4 g/day without an increase in side effects. However, 1% of patients will develop interstitial nephritis and renal function evaluation is needed periodically. If remission is achieved with mesalamine induction, then the medicine should be continued for maintenance.11 Studies are currently being conducted to evaluate the efficacy of higher dosages of mesalamine to determine its continued utility as an appropriate first-line therapy.  Corticosteroids. Steroids are fast acting and effective at inducing remission but are not ideal as maintenance therapy. Budesonide, a corticosteroid, has a high first-pass hepatic metabolism, which allows targeted delivery to the intestine while mitigating the systemic effects of steroid therapy. Controlled ileal release budesonide (9 mg/day) is effective when active disease is confined to the ileum or right colon and has been shown to be more effective than either placebo or mesalamine.23 Given a relatively good response and its relative safety, budesonide is recommended as the preferred primary treatment to mesalamine for patients with mild to moderately active Crohn disease with localized ileal disease. An alternative corticosteroid, prednisone, can be beneficial in moderate to severe Crohn disease. Prednisone is not ideal for maintenance therapy as more than 50% of patients, particularly smokers, treated with corticosteroids become “steroid dependent,” and chronic treatment is associated with osteoporosis and increased rates of Crohn disease relapse.11 Patients with moderate to severe disease should be treated with high-dose (40–60 mg daily) prednisone until resolution of symptoms and resumption of weight gain. Parenteral corticosteroids are indicated for patients with severe disease once the presence of an abscess has been excluded. Steroids should be tapered once the patient experiences clinical improvement. Currently, there are no standards for corticosteroid taper, but doses are generally tapered by 5 to 10 mg/ week until 20 mg, and then by 2.5 to 5 mg weekly until cessation. Dual-energy x-ray absorptiometry scan, calcium and vitamin D supplementation, and consideration of bisphosphonate therapy are warranted once corticosteroid therapy is initiated to identify baseline bone density and to prevent steroid-induced loss of bone mineral density.  Antibiotics. Certain antibiotics were found to be effective as a primary therapy for Crohn disease. Promising results were initially reported for metronidazole, but later studies determined that it was no more effective than placebo for inducing remission. Other antibiotics that have been used with varying success include ciprofloxacin, rifaximin, clofazimine, ethambutol, isoniazid, and rifabutin. Antibiotic therapy has a clear role in the septic complications associated with Crohn disease and is beneficial in perianal disease.11 The mechanism of action of antibiotics in Crohn disease is unclear, and side effects of these antibiotics preclude their longterm use. Therefore, antibiotics may play an adjunctive role in the treatment of Crohn disease and, in selected patients, may be useful in treating perianal disease, enterocutaneous fistulas, or active colonic disease but should not be used in maintenance therapy or to induce remission. 

Immunosuppressive agents. The immunosuppressive agents AZT, 6-MP, and MTX are effective in maintenance therapy and for the treatment of moderate to severe Crohn disease. AZT and 6-MP are effective for maintaining steroid-induced remission, and weekly IV MTX is effective for both induction and maintenance therapy.11 Because of the slow onset of action of immunosuppressive agents and to prevent flares, steroids are needed for induction and continued until the transition to immunosuppressive agents is complete. Despite their potential toxicity, these drugs have proved to be relatively safe in patients with Crohn disease; the most common side effects are pancreatitis, hepatitis, fever, and rash. The more disconcerting complications of immunosuppressants include chronic liver disease, bone marrow suppression, and the potential for malignant transformation. No prospective controlled trial has evaluated dose escalation or initiation of therapy using these drugs. Genetic polymorphisms for thiopurine methyltransferase (TPMT), which is the primary enzyme that metabolizes AZT and 6-MP, have been identified and suggested for use to regulate therapy according to the measurement of their metabolites (6-thioguanine nucleotides). Patients with decreased TPMT activity have a significantly increased risk of fatal bone marrow suppression. Previous studies reported severe myelosuppression in patients who are wild-type or heterozygous carriers for TPMT variant alleles; these findings suggest that TPMT genotype testing may be a safe screening tool to determine which patients may have a genetic predisposition to adverse outcomes. MTX also has side effects of hepatotoxicity and can cause myelosuppression and should not be used in pregnant women. Other immunosuppressive agents that have been used with some efficacy include cyclosporine and FK-506. FK-506 inhibits the production of IL-2 by helper T cells and was found to be effective for fistula improvement, but not fistula remission, in patients with perianal Crohn disease. Both of these agents have been used in patients with severe disease who do not respond to IV steroids. Low-dose cyclosporine was not found to be efficacious; however, in uncontrolled studies, FK-506 demonstrated some benefit in patients with steroid-refractory disease.  Anti-TNF therapy. The introduction of anti-TNF therapy for Crohn disease was considered a breakthrough in medical management. The first anti-TNF agent introduced was infliximab, a chimeric monoclonal antibody to TNF-α. Infliximab is efficacious and safe as a monotherapy in the treatment of moderate to severe Crohn disease and effective both an induction and maintenance agent. Multiple studies demonstrated that treatment with infliximab results in perineal fistula closure in approximately twothirds of patients. Although it is highly effective in certain Crohn disease patients with penetrating and extraintestinal disease, not every patient responds to infliximab. Other FDA-approved TNF antagonists include adalimumab (humanized IgG1 monoclonal antibody), which is an effective maintenance agent that can be self-administered, and certolizumab (humanized antibody fragment), which is ideal in pregnant and nursing women as it is linked to a polyethylene glycol moiety and does not cross the placenta and is not excreted in breast milk. Safety profiles for these three anti-TNF medications are similar. There is an increased risk for tuberculosis reactivation, invasive fungal and other opportunistic infections, demyelinating central nervous system lesions, activation of latent multiple sclerosis, exacerbation of congestive heart failure, and concerns for increased risk of melanoma. Patients who develop a flare while on anti-TNF agents require measurement of serum drug concentrations and antidrug antibodies (antibodies binding to competitive and noncompetitive sites to inhibit drug function). Measured levels would indicate the need

CHAPTER 50  Small Intestine to increase dosage (if low drug concentration and low antibodies), switch to another anti-TNF agent (high antidrug antibodies), or switch to another drug class (normal drug concentration). Due to the potential for immunogenicity of monoclonal antibodies, the combination of an anti-TNF agent and an immunosuppressive provides optimal drug levels and low antidrug antibodies.11  Novel therapies. Other therapeutic agents for Crohn disease include leukocyte trafficking inhibitors, interleukin inhibitors, and antibodies to antiadhesion molecule. These agents are often used if the patient has failed or is unable to tolerate anti-TNF therapy. Natalizumab, a recombinant humanized monoclonal antibody against α4 integrin, showed effectiveness in the induction and maintenance of remission in patients with active Crohn disease. It was removed from the market after several patients developed progressive multifocal leukoencephalopathy but was later reinstated for refractory Crohn disease and approved for use in 2008. Similarly, vedolizumab is a humanized monoclonal antibody that specifically binds to α4β7 integrin and blocks its interaction with MadCAM-1; this action inhibits the translocation of memory T lymphocytes into inflamed gastrointestinal parenchymal tissues. Vedolizumab can be used for induction of remission, but it has a very slow onset of action. Because MadCAM-1 is preferentially expressed on blood vessels in the gastrointestinal tract, vedolizumab is more gut specific and therefore a more targeted form of immunosuppression. Also, vedolizumab prevents the gastrointestinal mucosal or transmural inflammation without the nonspecific neurologic side effects seen in less selective α4 integrin inhibitors, such as natalizumab. Vedolizumab was approved for use in 2014 in those with a poor response to anti-TNF or immunosuppressants.14 Ustekinumab is a humanized IgG1 monoclonal antibody that inhibits IL-12/23 through targeting of a shared p40 subunit. In two large trials, it was shown to be effective in severe Crohn disease that is refractory to anti-TNF therapies with similar efficacy. Ustekinumab was approved for use in 2016.11 Compounds are also being evaluated that block certain signaling pathways (e.g., NF-κB, mitogen-activated protein kinases, and peroxisome proliferator-activated receptor-γ) in limited studies. Some compounds have shown clinical improvement, but results have varied, and these agents are still under development.  Nutritional therapy. Nutritional therapy in patients with Crohn disease has been used with varying success. The use of chemically defined elemental diets has been shown in some studies to reduce disease activity, particularly in patients with disease localized to the small bowel, and they can reduce corticosteroid-induced toxicities. Liquid polymeric diets may be as effective as elemental feedings and are more acceptable to patients. With few exceptions, standard elemental diets have not been effective to prevent relapse of Crohn disease. Total parenteral nutrition (TPN) was also useful in patients with active Crohn disease; however, complication rates exceed those for enteral nutrition. Although the primary role of nutritional therapy is questionable in patients with inflammatory bowel disease, there is definitely a secondary role for nutritional supplementation to replenish depleted nutrient stores, allowing intestinal protein synthesis and healing, and to prepare patients for surgery.  Smoking cessation. Although the implication of tobacco abuse as a causative factor in the development of Crohn disease has been difficult to prove, smoking clearly affects the disease course. Smoking is associated with the late bimodal onset of disease and has been shown to increase the incidence of relapse and failure of maintenance therapy. It also appears to be associated with the severity of disease in a linear dose-response relationship. Tobacco

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exposure is an independent predictor of the need for maintenance treatment, specifically biologic therapy. Therefore, smoking cessation therapy is an important component of medical therapy.  Surgical treatment. Although medical management is indicated during acute exacerbations of disease, most patients with chronic Crohn disease will require surgery at some time during the course of their illness. The goals are to preserve bowel length while minimizing postoperative complications and disease recurrence. Approximately 70% of patients will require surgical resection within 15 years after diagnosis. Indications for surgery include failure of medical treatment, bowel obstruction, fistula or abscess formation, steroid dependence, dysplasia or malignancy. Most patients can be treated with elective surgery, especially with the improvement of medical management in the past decade. However, patients with intestinal perforation, peritonitis, excessive bleeding, or toxic megacolon require urgent surgery.24 Children with Crohn disease and resulting systemic symptoms, such as growth retardation, may benefit from resection. The extraintestinal complications of Crohn disease, although not primary indications for operation, often subside after resection of the involved bowel; exceptions are that problems may continue with ankylosing spondylitis and hepatic complications. The aim of surgery for Crohn disease has shifted from a radical operation to one that achieves inflammation-free margins with minimal surgery, intended to remove just grossly inflamed tissue or to increase the luminal diameter of the bowel (i.e., dilation or strictureplasty). Even if adjacent areas of bowel are clearly diseased, they should be ignored. Fistulizing disease rarely requires operative intervention unless the fistula involves the bladder, vagina or skin. A bowel resection with fistulotomy may be needed. Early in the history of surgical therapy for Crohn disease, surgeons tended to perform wider resections with the hope of cure or significant remission. However, recurring wide resections resulted in neither cure nor a greater incidence of remissions and led to short bowel syndrome, a devastating surgical complication. Frozen sections to determine microscopic disease are unreliable and should be performed only when malignant disease is suspected. It must be emphasized that operative treatment of a complication must be limited to that segment of bowel involved with the complication, and no attempt should be made to resect more bowel, even though grossly evident disease may be apparent. However, often after removal of a diseased segment, endoscopic recurrence can occur up to 70% to 90% within 1 year after surgery in patients with Crohn disease.24 Laparoscopic surgery for patients with Crohn disease has been determined to be safe and feasible in appropriately selected patients, for example, those with localized abscesses, simple intraabdominal fistulas, perianastomotic recurrent disease, and disease limited to the distal ileum. A large comparative study evaluating laparoscopic colectomy for Crohn colitis determined that the laparoscopic group had a significantly shorter median operative time, earlier return of bowel function, and shorter hospital stay.25 Multiple randomized clinical trials verified that laparoscopic surgery is associated with a more rapid recovery of bowel function and shorter hospital stay; importantly, the rate of disease recurrence is similar when compared with open procedures. Randomized controlled trials with long-term follow-up have demonstrated that patients undergoing laparoscopic ileocolonic resection for Crohn disease had improved body image and satisfaction with cosmesis of surgery and less incidence of incisional hernia compared with the open surgery group. The potential for earlier recovery after laparoscopic resection has stimulated interest in extending the role of surgical resection to induce remission; the LIR!C trial

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SECTION X  Abdomen

is a randomized multicenter trial that found laparoscopic resection of uncomplicated ileocecal disease (terminal ileum 10 cm), the strictureplasty can be performed similar to a Finney pyloroplasty (Fig. 50.24B) or a side-to-side isoperistaltic strictureplasty.24 Strictureplasty is best used in those patients with multiple short areas of narrowing present over long segments of intestine, in those who have already had several previous resections of the small intestine, and in those with chronic fibrous obstruction. This procedure preserves intestine and is associated with complication and recurrence rates comparable to those of resection and reanastomosis. Given the concerns for development of carcinoma at chronically strictured segments, full-thickness biopsy with frozen section of the stricture site has been advocated at the time of surgery to rule out malignant disease before strictureplasty is performed (Box 50.5). In the past, bypass procedures were commonly used. There are two types of bypass operations: exclusion bypass and simple (continuity) bypass. For certain types of ileocecal disease associated with an abscess or phlegmon densely adherent to the retroperitoneum, the proximal transected end of the ileum is anastomosed to the transverse colon in an end-to-side fashion with or without construction of a mucous fistula using the distal transected end of the ileum (exclusion bypass), or an ileotransverse colonic anastomosis is made in a side-to-side fashion (continuity bypass). Currently, bypass with exclusion is used only in patients with severe gastroduodenal Crohn disease not amenable to strictureplasty, older poor-risk patients, patients who have had several prior resections and cannot afford to lose any more bowel, and those in whom

CHAPTER 50  Small Intestine

A

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B

FIG. 50.24  Types of strictureplasty. (A) Technique of short strictureplasty in the manner of a Heineke-Mikulicz pyloroplasty. (B) For longer diseased segments, strictureplasty may be performed in a manner similar to Finney pyloroplasty. (Adapted from Alexander-Williams J, Haynes IG. Up-to-date management of small-bowel Crohn’s disease. In: Mannick JA, ed. Advances in Surgery. St. Louis: Mosby; 1987:245–264.)

BOX 50.5  Contraindications to

strictureplasty.

• Excessive tension due to rigid and thickened bowel segments • Perforation of the intestine • Fistula or abscess formation at the intended strictureplasty site • Hemorrhagic strictures • Multiple strictures within a short segment • Malnutrition or hypoalbuminemia (90%) than traditional microscopic examinations. Symptoms are most commonly related to diarrhea, which may be at times intractable. Current treatment regimens have not been entirely effective, but drugs such as prophylactic cotrimoxazole and a highly active antiretroviral therapy appear to elicit a response to human immunodeficiency virus (HIV)–related diarrheal illnesses.29  Bacteria Infections by enteric bacteria are more frequent and more virulent in individuals infected with HIV than in healthy hosts. Salmonella, Shigella, and Campylobacter are associated with higher rates of bacteremia and antibiotic resistance in the immunocompromised patient. The diagnosis of Shigella or Salmonella infection may be established by stool cultures. The diagnosis of Campylobacter infection is not as easily established because stool cultures are often negative, but PCR techniques evaluating stool and serum have shown promising diagnostic results in patients with negative cultures. These enteric infections are manifested clinically with high fever, abdominal pain, and diarrhea that may be bloody. Abdominal pain may mimic an acute abdomen. Bacteremia and serious infections should be treated by IV administration of imipenem antibiotics; ciprofloxacin is an attractive choice if the organisms are multiply resistant; the pregnant patient may be safely treated with erythromycin. The incidence of Campylobacter infection among patients with AIDS who were treated with rifabutin prophylaxis was reported to be decreased compared with untreated controls. Diarrhea caused by Clostridium difficile is more common in patients with AIDS because of the increased antibiotic use in this population compared with healthy hosts. Diagnosis is by standard

assays of stool for C. difficile enterotoxin. Treatment with metronidazole or vancomycin is usually effective.  Mycobacteria Mycobacterial infection is a frequent cause of intestinal disease in immunocompromised hosts. This can be secondary to Mycobacterium tuberculosis or Mycobacterium avium complex (MAC), which is an atypical mycobacterium related to the type that causes cervical adenitis (scrofula). The usual route of infection is by swallowed organisms that directly penetrate the intestinal mucosa. The luminal gastrointestinal tract is affected by MAC infection, with massive thickening of the proximal small intestine often noted (Fig. 50.26). Clinically, patients with MAC present with diarrhea, fever, anorexia, and progressive wasting. The most frequent site of intestinal involvement of M. tuberculosis is the distal ileum and cecum, with approximately 90% of patients demonstrating disease at this site. The gross appearance can be ulcerative, hypertrophic, or ulcerohypertrophic. The bowel wall appears thickened, and an inflammatory mass often surrounds the ileocecal region. Acute inflammation is apparent, as are strictures and even fistula formation. The serosal surface is normally covered with multiple tubercles, and mesenteric lymph nodes are frequently enlarged and thickened; on sectioning, caseous necrosis is noted. The mucosa is hyperemic, edematous, and, in some cases, ulcerated. On histologic evaluation, the distinguishing lesion is a granuloma, with caseating granulomas found most commonly in the lymph nodes. Most patients complain of chronic abdominal pain that may be nonspecific, weight loss, fever, and diarrhea. The diagnosis of mycobacterial infection is made by identification of the organism in tissue by direct visualization with an

FIG. 50.26  Contrasted radiograph of thickened intestinal folds secondary to bacterial infection. A patient with acquired immunodeficiency syndrome shows thickened intestinal folds consistent with enteritis secondary to atypical mycobacterium. (Courtesy Dr. Melvyn H. Schreiber, The University of Texas Medical Branch, Galveston, TX.)

CHAPTER 50  Small Intestine acid-fast stain, culture of the excised tissue, or PCR assay. Radiographic examinations usually reveal a thickened mucosa with distorted mucosal folds and ulcerations. CT may be useful and shows a thickening of the ileocecal valve and cecum. The treatment of M. tuberculosis is similar in the immunocompromised or nonimmunocompromised host. The organism is usually responsive to multidrug antimicrobial therapy. The therapy for MAC infection is evolving; drugs that have been successfully used invivo and invitro include amikacin, ciprofloxacin, cycloserine, and ethionamide. Clarithromycin has also been successfully used in combination with other agents. Surgical intervention may be required for intestinal tuberculosis, particularly M. tuberculosis. Obstruction and fistula formation are the leading indications for surgery; however, with current treatment, most fistulas now respond to medical management. Surgery may be necessary for ulcerative complications when free perforation, perforation with abscess, or massive hemorrhage occurs. The treatment is usually resection with anastomosis.  Viruses CMV is the most common viral cause of diarrhea in immunocompromised patients. Clinical manifestations include intermittent diarrhea accompanied by fever, weight loss, and abdominal pain. The manifestations of enteric CMV infection result from mucosal ischemic ulcerations, which account for the high rate of perforations noted with CMV. As a result of the diffuse ulcerating involvement of the intestine, patients may present with abdominal pain, peritonitis, or hematochezia. Diagnosis of CMV is made by demonstrating viral inclusions. The most characteristic form is an intranuclear inclusion, which is often surrounded by a halo, producing a so-called owl’s eye appearance. There may also be cytoplasmic inclusions (Fig. 50.27). Cultures for CMV are usually positive when inclusion bodies are present, but these cultures are less sensitive and specific than histopathologic identification. Once CMV infection is diagnosed, treatment is usually effective with ganciclovir. An alternative to ganciclovir is foscarnet, a pyrophosphate analogue that inhibits viral replication. Infections with other less common viruses, including adenovirus, rotavirus, and novel enteric viruses such as astrovirus and picornavirus, have been reported. 

FIG. 50.27  Intestinal cytomegalovirus infection inclusions. Microscopic section of small bowel in a patient with acquired immunodeficiency syndrome who has cytomegalovirus enteritis. Multiple large cells with intranuclear and intracytoplasmic inclusions typical of cytomegalovirus are demonstrated (arrows). (Courtesy Dr. Mary R. Schwartz, Baylor College of Medicine, Houston, TX.)

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Fungi Fungal infections of the intestinal tract have been recognized in patients with AIDS. Gastrointestinal histoplasmosis occurs in the setting of systemic infection, often in association with pulmonary and hepatic disease. Diagnosis is made by fungal smear and culture of infected tissue or blood. The infection is most commonly treated by the administration of amphotericin B. Coccidioidomycosis of the intestinal tract is rare and, like histoplasmosis, occurs in the context of systemic infection. 

NEOPLASMS General Considerations Despite composing 75% of the length and 90% of the surface area of the gastrointestinal tract, the small bowel develops relatively few primary neoplasms and less than 2% of gastrointestinal malignant neoplasms. However, the incidence of small bowel cancer has increased an average of approximately 2% each year during the past 10 years. In 2018, an estimated 10,470 adults in the United States will be diagnosed with small bowel cancer, and approximately 1450 individuals will die of this disease. The 5-year survival for localized small bowel cancer is approximately 85%. Unfortunately, only 32% of patients are diagnosed with local disease; therefore, patients with regional and distant disease have 5-year survival rates of approximately 75% and 42%, respectively. This trend may be a reflection of the increase in incidence of small bowel carcinoids in the past decade. The mean age at presentation is 62 years in the setting of benign tumors and approximately 57 years for malignant tumors. Similar to other cancers, there appears to be a geographic distribution, with the highest cancer rates found among the Maori of New Zealand and ethnic Hawaiians. The incidence of small bowel cancer is particularly low in India, Romania, and other parts of Eastern Europe. The incidence of small bowel neoplasia varies considerably, with benign lesions identified more often at autopsy. In contrast, malignant neoplasms account for 75% of symptomatic lesions that lead to surgery. This reflects the fact that most benign neoplasms are asymptomatic and often identified as an incidental finding. Stromal tumors and adenomas are the most frequent of the benign tumors and appear to be more common in the distal small bowel but may be somewhat misleading because of the relatively short length of the duodenum. Adenocarcinoma is the most common malignant neoplasm, accounting for 30% to 50% of malignant neoplasms of the small intestine; neuroendocrine tumors (NETs) account for 25% to 30% of small intestine malignant neoplasms. Adenocarcinomas are more prevalent in the proximal small bowel, whereas the other malignant lesions are more common in the distal small bowel. The risk factors and associated conditions related to small bowel neoplasms have been described. These include patients with familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer, Peutz-Jeghers syndrome, Crohn disease, gluten-sensitive enteropathy (i.e., celiac sprue), prior peptic ulcer disease, cystic fibrosis, and biliary diversion (i.e., previous cholecystectomy). Controversial factors that may contribute to small bowel neoplasms include smoking, heavy alcohol consumption (>80 g/day of ethanol), and consumption of red meat or saltcured foods. Although the molecular genetics of small bowel neoplasms have not been entirely characterized, similar to colorectal cancers, mutations of the KRAS gene are commonly identified. Allelic losses, particularly involving tumor suppressor genes at chromosome locations

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SECTION X  Abdomen

5q (APC gene), 17q (p53 gene), and 18q (DCC [deleted in colon cancer] and DPC4 [SMAD4] genes), have been noted in some small bowel cancers. Recent findings demonstrate that in approximately 15% of small intestinal adenocarcinomas, DNA mismatch gene repair is inactivated and displays a high level of microsatellite instability (MSI-H). Interestingly, MSI-H is typical of small bowel carcinomas associated with celiac disease, which is potentially linked by an aberrant CpG island methylation. Furthermore, microarray analyses demonstrate a high percentage of small bowel tumors expressing both epidermal growth factor receptor and vascular endothelial growth factor (VEGF), which may contribute to carcinogenesis. Clinical Manifestations Symptoms associated with small bowel neoplasms are often vague and nonspecific and may include dyspepsia, anorexia, malaise, and dull abdominal pain, often intermittent and colicky. These symptoms may be present for months or years before diagnosis. Most patients with benign neoplasms remain asymptomatic, and the neoplasms are only discovered at autopsy or as incidental findings at laparotomy or upper gastrointestinal radiologic studies. Of the remainder, pain, most often related to obstruction, is the most frequent complaint. Usually, obstruction is the result of intussusception, and benign small tumors are the most common cause of this condition in adults. Hemorrhage is the next most common symptom. Bleeding is usually occult; hematochezia or hematemesis may occur, although life-threatening hemorrhage is uncommon.  Diagnosis Because of the insidious nature of many small bowel neoplasms, a high index of suspicion must be present for these neoplasms to be diagnosed. In most series, a correct preoperative diagnosis is made in only 50% of symptomatic patients. Plain films may confirm the presence of an obstruction; however, for the most part, plain films are not helpful in making a diagnosis of small bowel neoplasms. An upper gastrointestinal tract series with small bowel follow-through yields an accurate diagnosis in 53% to 83% of patients with malignant neoplasms of the small intestine (Fig. 50.28). Ultrasonography has not proved effective for preoperative diagnosis of small bowel neoplasms. CT of the abdomen can prove particularly useful in detecting extraluminal tumors, such as malignant gastrointestinal stromal tumors (GISTs), and can provide helpful information about the staging of malignant cancers (Fig. 50.29). CT enteroclysis appears to be a more sensitive technique, with a diagnostic accuracy of approximately 95%, while MRI enteroclysis has a sensitivity and specificity of 98% and 97%, respectively. Flexible endoscopy may be useful, particularly in diagnosing duodenal lesions, and the colonoscope can be advanced into the terminal ileum for visualization and biopsy of ileal neoplasms. Push enteroscopy has not been used routinely to evaluate lesions in the small bowel because this test may take up to 8 hours to perform and may not visualize the entire small bowel. Doubleballoon enteroscopy can be a helpful adjunct; however, it should be reserved for cases in which biopsy or preoperative tattoo is required, as it carries a risk of perforation, and for cases where less invasive and more accurate diagnostic tools are unavailable. Lastly, more advanced capsule endoscopy may have a role in the diagnosis of intestinal lesions. The sensitivity and specificity for diagnosis of a small bowel tumor by capsule endoscopy in the setting of obscure bleeding are between 89% and 95% and between 75% and 95%, respectively. Angiography is of value in diagnosing and localizing tumors of vascular origin. Despite these sophisticated

FIG. 50.28  Contrasted radiograph demonstrating a small bowel adenocarcinoma. Barium radiograph demonstrates a typical apple core lesion (arrows) caused by adenocarcinoma of the small bowel, producing a partial obstruction with dilated proximal bowel. (Courtesy Dr. Melvyn H. Schreiber, The University of Texas Medical Branch, Galveston, TX.)

R

L

FIG. 50.29  Small bowel neoplasm. Computed tomography scan of the abdomen demonstrates a small bowel neoplasm (arrow). (Courtesy Dr. Melvyn H. Schreiber, The University of Texas Medical Branch, Galveston, TX.)

imaging and diagnostic modalities, diagnosis of a small bowel tumor is often achieved only at the time of surgical exploration. 

Benign Neoplasms The most common benign neoplasms include benign stromal tumors, adenomas, and lipomas. Adenomas are the most common benign tumors reported in autopsy series, but stromal tumors are

CHAPTER 50  Small Intestine the most common benign small bowel lesions that produce symptoms. In general, when a benign tumor is identified at operation, resection is indicated because symptoms are likely to develop over time. At operation, a thorough search of the remainder of the small bowel is warranted because multiple tumors are not uncommon. Stromal Tumors GIST make up 20% of all soft tissue sarcomas occurring throughout the gastrointestinal tract, are most prevalent in the stomach (60%) and jejunum and ileum (30%), and rarely in duodenum (5%). Stromal tumors arise from the interstitial cell of Cajal, an intestinal pacemaker cell of mesodermal descent. Median age of diagnosis is 65 years of age, with similar rates in males and females. GISTs are often large, with a median size of 6 cm at diagnosis; some GISTs can even be larger than 20 cm.30 GISTs can be malignant tumors and nearly 20% of patients are found to have metastatic disease, most commonly in the liver. Symptoms of GIST include abdominal pain, fullness, bowel obstruction, or tumor hemorrhage resulting in anemia, melena, or hematemesis. The workup of GIST is often initiated with a CT scan. MRI may provide more information for tumors in the rectum or duodenum. Next, an endoscopic core biopsy with immunohistochemical staining for KIT (95%) and anoctamin-1 (98%) confirms the diagnosis. More than 95% of stromal tumors express CD117, the KIT proto-oncogene protein that is a transmembrane receptor for the stem cell growth factor, and 70% to 90% express CD34, the human progenitor cell antigen. These tumors infrequently stain positive for actin (20%–30%), S100 (2%–4%), and desmin (2%–4%). In gross appearance, stromal tumors are firm, gray-white lesions with a whorled appearance noted on cut surface; microscopic examination demonstrates well-differentiated smooth muscle cells. These tumors may grow intramurally and cause obstruction. Alternatively, the tumors demonstrate intramural and extramural growth, sometimes achieving considerable size and eventually outgrowing their blood supply, resulting in bleeding manifestations. Surgical resection is necessary for appropriate treatment. GIST malignancy risk and prognosis is stratified based on the number of mitoses per high-power field (hpf ) and tumor size. The mitotic index is classified as low (5 mitoses/50 hpf ). While benign tumors generally show a low mitotic index (5 cm) in diameter. They are usually noted secondary to abdominal pain or

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bleeding; obstruction may also occur. The malignant potential of these lesions is reportedly between 35% and 55%. Treatment is determined by location and adenoma type. The options for treatment are endoscopic and surgical. In the jejunum and ileum, the treatment of choice is segmental resection. Although only 5% of adenomas occur in the duodenum, they frequently cause symptoms, and decisions about surgical management must be carefully planned because of the potential morbidity (20%–30%) associated with duodenal resection by pancreaticoduodenectomy or pancreas-preserving duodenectomy. Endoscopic ultrasound has recently emerged as a useful modality in the preintervention evaluation and may help guide management planning. Endoscopic resection of these neoplasms is a safe alternative and may delay a more aggressive and potentially morbid surgical procedure; however, some series showed that the lifelong risk of recurrence is approximately 50% after endoscopic treatment (i.e., snare excision, thermal ablation, argon plasma coagulation, or photodynamic therapy). Endoscopic mucosal resection is gaining acceptance as a useful technique for the treatment of duodenal adenomas and Brunner gland tumors. A single-center study found that endoscopic mucosal resection, even in the setting of large (>2 cm) sessile duodenal adenomas, had a high success rate for complete removal; however, the risk of delayed bleeding is significant. Other studies have shown that endoscopic mucosal resection is associated with an approximate 17% risk of other complications, including perforation, hemorrhage, and pancreatitis. Invasive changes or a recurrence after polypectomy necessitates a more definitive approach (e.g., pancreaticoduodenectomy). Familial adenomas typically occur in the presence of FAP syndrome and require a different algorithm. Extracolonic manifestations of FAP have significant consequences. Numerous studies have shown that adenomas in the duodenum can be found in 50% to 90% of cases, and increasing age was identified as an independent risk factor for adenoma development. Although these neoplasms grow slowly, FAP patients carry a 5% lifetime risk for development of duodenal adenocarcinoma, which represents the leading cause of cancer-related mortality in these patients; therefore, routine lifelong surveillance is a priority. To direct surveillance and treatment, patients are classified by the Spigelman classification (Table 50.8). Screening endoscopy with a forward- and side-viewing endoscope is performed at regular intervals with biopsy of all suspicious, villous, or large (>3 cm) adenomas in addition to random duodenal biopsy specimens. The frequency of endoscopic screening ranges from 1 to 5 years, depending on the Spigelman classification (Box 50.6).31 Endoscopic mucosal resection or surgical polypectomy can be performed for large adenomas. Ablative therapy in the form of argon beam coagulation or photodynamic therapy has been attempted for these patients but with disappointing results. The presence of high-grade dysplasia, carcinoma in situ, or a Spigelman stage IV classification necessitates pancreaticoduodenectomy or pancreas-preserving duodenectomy. Adenomas of the remaining small bowel also occur more frequently in patients with FAP but are not as prevalent as duodenal disease in this population of patients. Brunner gland adenomas represent benign hyperplastic lesions arising from the Brunner glands of the proximal duodenum. These adenomas may produce symptoms mimicking those of peptic ulcer disease. Diagnosis can usually be accomplished by endoscopy and biopsy, and symptomatic lesions in an accessible region can be resected by simple excision, either endoscopically or surgically. There is no malignant potential for Brunner gland adenomas, and a radical resection should not be used. 

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TABLE 50.8  Spigelman classification for duodenal adenomatosis. POINTS PARAMETER

1

2

3

No. of polyps Polyp size (mm) Histology Degree of dysplasia

1–4 1–4 Tubular Mild

5–20 5–10 Tubulovillous Moderate

>20 >10 Villous Severe

From Johnson MD, Mackey R, Brown N, et al. Outcome based on management for duodenal adenomas: sporadic versus familial disease. J Gastrointest Surg. 2010;14:229–235. Stage 0, 0 points; stage I, 1–4 points; stage II, 5–6 points; stage III, 7–8 points; stage IV, 9–12 points.

BOX 50.6  Recommended surveillance

interval for upper gastrointestinal endoscopic examination in relation to the Spigelman classification. Spigelman Classification (Surveillance Interval in Years) 0 (4) I (5) II (2–3) III (0.5–1) IV (consider surgery) Adapted from Campos FG, Sulbaran M, Safatle-Ribeiro AV, et al. Duodenal adenoma surveillance in patients with familial adenomatous polyposis. World J Gastrointest Endosc. 2015;7:950–959.

Lipomas. Lipomas, which are also included in the category of stromal tumors, are most common in the ileum and are manifested as single intramural lesions located in the submucosa. They usually occur in the sixth and seventh decades of life and are more frequent in men. Less than one third of these tumors are symptomatic, and of these, the most common manifestations are obstruction and bleeding from superficial ulcerations. The treatment of choice for symptomatic lesions is excision. Lipomas do not have malignant potential and, therefore, if found incidentally, should be removed only if the resection is simple.  Peutz-Jeghers syndrome. Hamartomas of the small bowel occur as part of the Peutz-Jeghers syndrome, an inherited syndrome of mucocutaneous melanotic pigmentation and gastrointestinal polyps. The pattern of inheritance is autosomal dominant, with a high degree of penetrance. The classic pigmented lesions are small, 1 to 2 mm, as brown or black spots located in the circumoral region of the face, buccal mucosa, forearms, palms, soles, digits, and perianal area. Hamartomas are most commonly found in the jejunum and ileum. However, 50% of patients may also have rectal and colonic lesions, and 25% of patients have gastric lesions. The most common symptom is recurrent colicky abdominal pain, usually the result of intermittent intussusception. Lower abdominal pain associated with a palpable mass has been reported in one third of patients. Hemorrhage as a result of autoamputation of the polyps occurs, but infrequently, and is most commonly manifested by anemia. Acute life-threatening hemorrhage is uncommon but may occur. Although once considered a purely benign disease, adenomatous changes have been reported in 3% to 6% of hamartomas. Extracolonic cancers are common, occurring in 50% to 90% of patients (small intestine, stomach, pancreas, ovary, lung, uterus, and breast). The small intestine represents the most frequent site for these cancers compared to other sites. The

treatment for complications of Peutz-Jeghers syndrome is directed at bowel obstruction or persistent gastrointestinal bleeding. Resection should be limited to the segment of bowel that is producing complications. Because of the widespread nature of intestinal involvement, cure is not possible; therefore, extensive resection is not indicated.  Hemangiomas. Hemangiomas are developmental malformations consisting of submucosal proliferation of blood vessels. They can occur at any level of the gastrointestinal tract; the jejunum is the most commonly affected small bowel segment. Hemangiomas account for 3% to 4% of all benign tumors of the small bowel and are multifocal in 60% of patients. In addition, hemangiomas of the small bowel may occur as part of an inherited disorder known as Osler-Weber-Rendu disease. Hemangiomas may also occur in the lung, liver, and mucous membranes. Patients with Turner syndrome are likely also to have cavernous hemangiomas of the intestine. The most common symptom of small bowel hemangiomas is intestinal bleeding. Angiography and technetium Tc-99m red blood cell scanning are the most useful diagnostic studies. If a hemangioma is localized preoperatively, resection of the involved intestinal segment is warranted. Intraoperative transillumination and palpation may help to identify a nonlocalized hemangioma. 

Malignant Neoplasms Population-based analyses have shown that the incidence of malignant neoplasms of the small intestine has increased steadily during the past three decades. This increase has mirrored the increase in diagnosis of small bowel neuroendocrine neoplasms (NENs), which have increased more than fourfold (from 2.1–9.3 new cases per million population) during the past three decades, whereas changes in the frequency of adenocarcinomas, stromal tumors, and lymphomas were less pronounced. A large retrospective study evaluating the Surveillance, Epidemiology, and End Results (SEER) and Medicare database from 1992 to 2010 identified small bowel carcinoma 5-year survival rate of 34.9% compared to 51.5% survival rate for colorectal cancer over the same time period. Unlike colorectal cancer, chemotherapy for small bowel adenocarcinoma has not improved overall survival when matching for stage. In fact, chemotherapy with surgery has not resulted in an appreciable survival benefit compared to surgery alone, indicating, perhaps, an overuse of adjuvant chemotherapy in this population.32 These findings highlight the need for more novel and effective treatment strategies. In contrast to benign lesions, malignant neoplasms almost always produce symptoms, the most common of which are pain and weight loss. Obstruction develops in 15% to 35% of patients and, unlike the intussusception produced by benign lesions, is usually the result of tumor infiltration and adhesions. Diarrhea with tenesmus and passage of large amounts of mucus may occur.

CHAPTER 50  Small Intestine Gastrointestinal bleeding, manifested by anemia and guaiac-positive stools or occasionally by melena or hematochezia, occurs to varying degrees with malignant lesions and is more common with GISTs. A palpable mass may be felt in 10% to 20% of patients, and perforations develop in approximately 10%, usually secondary to lymphomas and sarcomas. Although presentation may be similar, each tumor type has a distinct biology that dictates management and prognosis. Neuroendocrine Neoplasms Intestinal NENs arise from enterochromaffin cells (Kulchitsky cells), which are considered neural crest cells situated at the base of the crypts of Lieberkühn. These cells are also known as argentaffin cells because of their staining by silver compounds. These tumors were first described by Lubarsch in 1888; in 1907, Oberndorfer coined the term Karzinoide to indicate the carcinoma-like appearance and the presumed lack of malignant potential. However, the term “carcinoid” has become a misnomer, as all NENs have malignant potential. These tumors have been reported in a number of organs, including lungs, bronchi, and the gastrointestinal tract. Most patients with small bowel NENs are in their seventh decade of life, with a median age for gastroenteric NEN of 63 years. The classification of NENs is based predominately on tumor grade and differentiation. NENs are divided into NETs and neuroendocrine carcinomas. NETs may be benign or of the well-differentiated malignant type and are further subdivided into three groups, lowgrade (grade 1, G1), intermediate-grade (grade 2, G2), or highgrade (grade 3, G3) tumors, based on the appearance, mitotic rates, behavior (invasion of other organs, angioinvasion), and Ki67 proliferative index. On the other hand, neuroendocrine carcinomas are all G3, poorly differentiated malignant tumors. The distinction between a G3 well-differentiated NET and a G3 poorly differentiated NEC can be difficult and may require additional pathologic confirmation or immunohistochemical staining.33 NETs are also categorized based on the embryologic site of origin and secretory product. These tumors may derive from the foregut (respiratory tract, thymus), midgut (jejunum, ileum and right colon, stomach, proximal duodenum), and hindgut (distal colon, rectum). Foregut NETs characteristically produce low levels of serotonin (5-hydroxytryptamine) but may secrete 5-hydroxytryptophan or adrenocorticotropic hormone. Midgut NETs are characterized by having high serotonin production. Hindgut NETs rarely produce serotonin but may produce other hormones, such as somatostatin and peptide YY. The gastrointestinal tract is the most common site for NETs. After the appendix, the small intestine is the second most frequently affected site in the gastrointestinal tract. In the small intestine, NETs almost always occur within the last 2 feet of the

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ileum. NETs have a variable malignant potential and are composed of multipotential cells with the ability to secrete numerous humoral agents, the most prominent of which are serotonin and substance P (Table 50.9). In addition to these substances, NETs have been found to secrete corticotropin, histamine, dopamine, neurotensin, prostaglandins, kinins, gastrin, somatostatin, pancreatic polypeptide, calcitonin, and neuron-specific enolase. The primary importance of NETs is the malignant potential of the tumors themselves. Additionally, carcinoid syndrome, secondary to serotonin or tachykinin production, is characterized by episodic attacks of cutaneous flushing, bronchospasm, diarrhea, and vasomotor collapse, is present mostly in those patients with hepatic metastases. Primary tumors that secrete directly into the venous system, bypassing the portal system (e.g., ovary, lung), give rise to carcinoid syndrome without metastasis. Pathology. Seventy percent to 80% of NETs are asymptomatic and found incidentally at the time of surgery. In the gastrointestinal tract, more than 90% of NETs are found in five typical sites: small intestine (38%), rectum (34%), colon (16%), stomach (11%), and unknown sites (1%). The recent increase in incidence of NETs in the United States is due to improved diagnostic detection of both the rectal and gastric tumors. Interestingly, in Korea, the most common site for NETs is the rectum.34 The malignant potential (ability to metastasize) is related to location, size, depth of invasion, and growth pattern. Only approximately 3% of appendiceal NETs metastasize, but about 35% of ileal NETs are associated with metastasis. Most (approximately 75%) gastrointestinal NETs are smaller than 1 cm in diameter, and about 2% of these are associated with metastasis. In contrast, NETs 1 to 2 cm in diameter and larger than 2 cm are associated with metastasis in 50% and 80% to 90% of cases, respectively. In gross appearance, these tumors are small, firm, submucosal nodules that are usually yellow on the cut surface (Fig. 50.30A). They may be as subtle as a small whitish plaque seen on the antimesenteric border of the small intestine (Fig. 50.30B). Typically, they are associated with a larger mesenteric mass caused by nodal disease and desmoplastic invasion of the mesentery, which is often mistaken for the primary tumor. They tend to grow very slowly, but after invasion of the serosa, the intense desmoplastic reaction produces mesenteric fibrosis, intestinal kinking, and intermittent obstruction. Small bowel NETs are multicentric in 20% to 30% of patients. This tendency to multicentricity exceeds that of any other malignant neoplasm of the gastrointestinal tract. Another unusual observation is the frequent coexistence of a second primary malignant neoplasm of a different histologic type. This is usually a synchronous adenocarcinoma (most commonly in the large intestine) that can occur in 10% to 20% of patients with NETs.

TABLE 50.9  Secretory products of neuroendocrine tumors.* AMINES

TACHYKININS

PEPTIDES

OTHER

5-HT 5-HIAA (88%) 5-HTP Histamine Dopamine

Kallikrein Substance P (32%) Neuropeptide K (67%)

Pancreatic polypeptide (40%) Chromogranins (100%) Neurotensin (19%) HCG-α (28%) HCG-β Motilin (14%)

Prostaglandins

Compiled with the help of Zandee WT, Kamp K, van Adrichem RC, et al. Effect of hormone secretory syndromes on neuroendocrine tumor prognosis. Endocr Relat Cancer. 2017;24:R261–R274. HCG, Human chorionic gonadotropin; 5-HIAA, 5-hydroxyindoleacetic acid; 5-HT, 5-hydroxytryptamine; 5-HTP, 5-hydroxytryptophan. *Values in parentheses represent percentage frequency.

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SECTION X  Abdomen

A

B FIG. 50.30  Gross pathologic characteristics of neuroendocrine tumor (NET). (A) NET of the distal ileum demonstrates the intense desmoplastic reaction and fibrosis of the bowel wall. (B) Mesenteric metastases from a NET of the small bowel. (Adapted from Evers BM, Townsend CM Jr, Thompson JC. Small intestine. In: Schwartz SI, ed. Principles of Surgery. 7th ed. New York: McGraw-Hill; 1999:1245.)

Multiple endocrine neoplasia type 1 is associated with NETs in approximately 10% of cases.  Clinical manifestations. In the absence of carcinoid syndrome, symptoms of patients with NETs of the small bowel are similar to those of patients with small bowel tumors of other histologic types. The most common symptom is abdominal pain, which is variably associated with partial or complete small intestinal obstruction. Obstructive symptoms can be caused by intussusception but usually occur secondary to a local desmoplastic reaction, apparently produced by humoral agents elaborated by the tumor. Diarrhea and weight loss may also occur. The diarrhea is a result of a partial bowel obstruction rather than the secretory diarrhea noted in patients with the malignant carcinoid syndrome. As mesenteric and nodal extension progresses, local venous engorgement and, ultimately, ischemia of the affected segment of intestine contribute to most symptoms and complications related to the tumor. Malignant carcinoid syndrome. Malignant carcinoid syndrome is a relatively rare disease, occurring in less than 10% of patients with NETs. The syndrome is usually associated with NETs of the gastrointestinal tract, particularly from the small bowel, but NETs in other locations, such as the bronchus, pancreas, ovary, and testes, have also been described in association with the syndrome. Because of the first-pass metabolism of the vasoactive peptides responsible for carcinoid syndrome, hepatic metastasis or extraabdominal disease is necessary to elicit the syndrome. The classic description of the carcinoid syndrome includes vasomotor, cardiac, and gastrointestinal manifestations. A number of humoral factors are produced by NETs, but those considered to contribute to the carcinoid syndrome include serotonin, 5-hydroxytryptophan (a precursor of serotonin synthesis), histamine, dopamine, tachykinin, kallikrein, substance P, prostaglandin, and neuropeptide K. Most patients who exhibit malignant carcinoid syndrome have massive hepatic replacement by metastatic disease. However, tumors that bypass the liver, specifically ovarian and retroperitoneal NETs, may produce the syndrome in the absence of liver metastasis. Common symptoms and signs include cutaneous flushing (80%); diarrhea (76%); hepatomegaly (71%); cardiac lesions,

most commonly right-sided heart valvular disease (41%–70%); and asthma (25%). Cutaneous flushing in the carcinoid syndrome may be of four varieties: 1. diffuse erythematous, which is short-lived and normally affects the face, neck, and upper chest; 2. violaceous, which is similar to a diffuse erythematous flush except that the attacks may be longer and patients may develop a permanent cyanotic flush, with watery eyes and injected conjunctivae; 3. prolonged flushes, which may last up to 2 or 3 days and involve the entire body and may be associated with profuse lacrimation, hypotension, and facial edema; and 4. bright-red patchy flushing, typically seen with gastric NETs. The diarrhea associated with carcinoid syndrome is episodic (usually occurring after meals), watery, and often explosive. Increased circulating serotonin levels are thought to be the cause of the diarrhea because the serotonin antagonist, methysergide, effectively controls the symptom. Cardiac lesions usually involve the right side of the heart, but left-sided lesions are present in 15% of patients and can lead to congestive heart disease and symptomatic left-sided heart failure. The three most common cardiac lesions are pulmonary stenosis (90%), tricuspid insufficiency (47%), and tricuspid stenosis (42%). Asthmatic attacks are usually observed during the flushing symptom, and serotonin and bradykinin have been implicated in this symptom. Malabsorption and pellagra (dementia, dermatitis, and diarrhea) are occasionally present and are thought to be caused by excessive diversion of dietary tryptophan.  Diagnosis. The elevation of various humoral factors forms the basis for diagnostic tests in patients with NETs and the carcinoid syndrome. NETs produce serotonin, which is then metabolized in the liver and the lung to the pharmacologically inactive 5-hydroxyindoleacetic acid (5-HIAA). Elevated urinary levels of 5-HIAA measured during 24 hours with high-performance liquid chromatography are highly specific although not sensitive. For the last decade, chromogranin A (CgA) has been a well-established marker for carcinoid disease; it is elevated in more than 80% of patients with NETs. CgA alone may be used for the diagnosis of

CHAPTER 50  Small Intestine NETs, given its specificity of 95%, but some investigators suggest that other tests should be used in conjunction with CgA for diagnostic purposes because its sensitivity is only 55%. A combination of serum CgA measurement with 24-hour urine 5-HIAA is an acceptable diagnostic combination with increased sensitivity. Studies suggest that serum CgA and N-terminal pro-brain natriuretic peptide may also be used in combination for both diagnosis and surveillance because patients with increased N-terminal pro-brain natriuretic peptide and CgA levels showed worse overall survival than patients with elevated CgA alone. In terms of surveillance after resection or as a prognostic marker to monitor response to therapy, CgA levels have proven efficacy over urine 5-HIAA levels. Plasma serotonin, substance P, neurotensin, neurokinin A, and neuropeptide K levels can be measured, but these peptides may not be elevated in all patients. Provocative tests using pentagastrin, calcium, or epinephrine may be used to reproduce the symptoms of NETs. More recently, pentagastrin has been used to differentiate between NETs and chronic atrophic gastritis but is generally not used for the diagnosis of NETs, given the diagnostic reliability of 5-HIAA, CgA, and N-terminal pro-brain natriuretic peptide. NETs of the small intestine are rarely diagnosed preoperatively. Barium radiographic studies of the small bowel may exhibit multiple filling defects as a result of kinking and fibrosis of the bowel (Fig. 50.31). A combination of anatomic and functional imaging techniques is routinely performed to optimize sensitivity and specificity. Traditionally, CT scanning was the imaging modality of choice for identifying the site of disease and the presence of lymphatic or hematogenous metastases. CT scan findings depend on the size, the degree of mesenteric invasion and desmoplastic reaction, and the presence of regional lymph node invasion. If these entities are not well defined, CT has limited diagnostic capabilities in this disease. However, when CT scanning reveals a solid mass with spiculated borders and radiating surrounding strands that is associated with linear strands within the mesenteric fat and kinking of the bowel, a diagnosis of gastrointestinal NET can be made fairly confidently. CT angiography may be useful in cases associated with a large mesenteric process to identify encasement and pseudoaneurysm formation, typical of a malignant process in the mesentery. In general, MRI is not used in the diagnosis of gastrointestinal NETs but can be helpful in diagnosing metastatic disease, especially in the liver. Liver metastases are well demonstrated with MRI and usually have low signal intensity on T1-weighted images and high signal intensity on T2-weighted images. After the administration of a gadolinium-based contrast agent, liver metastases enhance peripherally in the hepatic arterial phase and appear as hypointense defects in the portal venous phase. Diffusion-weighted MRI and dynamic contrast-enhanced techniques represent promising advances in radiologic imaging, although these imaging techniques have not yet been validated for monitoring therapy of NETs. Octreotide is a synthetic analogue of somatostatin, and indium (111In)-labeled pentetreotide specifically binds to somatostatin receptor subtypes 2 and 5. Functional nuclear imaging studies capitalize on the concept of somatostatin receptor positivity and these techniques are used to image many NETs, including those with somatostatin-binding sites. Scintigraphic localization has a higher sensitivity than CT for delineating and localizing NETs and is particularly useful in the identification of extraabdominal metastatic disease or in cases in which the primary tumor cannot be identified by CT scan. An area of great interest is functional imaging by 18F-fluorodeoxyglucose positron emission tomography

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FIG. 50.31  Contrasted radiograph demonstrating a neuroendocrine tumor (NET). Barium radiograph of a NET of the terminal ileum demonstrates fibrosis with multiple filling defects and high-grade partial obstruction (arrows). (Courtesy Dr. Melvyn H. Schreiber, The University of Texas Medical Branch, Galveston, TX.)

(18FDG PET) scanning. However, this imaging modality alone has limited capabilities because 18FDG is taken up only in highgrade NETs (e.g., high Ki-67 expression), whereas most NETs have low Ki-67 expression and are not apparent with this imaging modality. However, the addition of newer isotopes, such as 18F-ldihydroxyphenylalanine (18F-DOPA), has dramatically improved the sensitivity of PET for the diagnosis and surveillance of neuroendocrine malignant neoplasms. Somatostatin receptor imaging with gadolinium 68Ga–DOTATATE PET/CT is increasingly used for the preoperative staging for patients with NETs. DOTATATE is an amide of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and the octreotide derived radionuclide, tyrosine-3-octreotate (TATE). The latter binds to somatostatin receptors and thus directs the radioactivity into the tumor. 68Ga-DOTATATE PET/CT is a clinically useful imaging technique to localize primary tumors in patients with neuroendocrine metastases of unknown origin as well as to define the existence and extent of metastatic disease. Combining the two modalities may be even more helpful in diagnosing and

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managing NETs. In a study designed to investigate the relationship between PET/CT results and histopathologic findings in 27 patients with NETs, the sensitivity of 68Ga-DOTATATE and 18FDG PET/CT was 95% and 37%, respectively. The sensitivity in detecting liver, lymph node, and bone metastases and the primary lesion was 95%, 95%, 90%, and 93% for 68Ga-DOTATATE and 40%, 28%, 28%, and 75% for 18FDG, respectively. Recently, a new radionuclide, 64Cu-DOTATATE, was FDA approved for diagnostic use in NETs. The benefits of 64Cu-DOTATATE imaging include better true positive lesion detection, longer shelf life and scanning window when compared with 68Ga-DOTATATE, making it an ideal diagnostic tool.35 Lastly, the peptide receptor radionuclide therapy agent lutetium-177 (177Lu) is both diagnostic and therapeutic and belongs to a new class of drugs known as theranostics. The reason for developing compounds with high affinity for somatostatin receptors 2, 3, and 5 is to improve diagnostic sensitivity. Because resection is the only curative treatment in patients with small intestinal NETs, accurate preoperative imaging is critical to guide surgical management.  Treatment

Surgical therapy. The treatment of patients with small bowel NETs is based on tumor size, location, and presence of metastatic disease. For primary tumors smaller than 1 cm in diameter without evidence of regional lymph node metastasis, a segmental intestinal resection is adequate. For patients with lesions larger than 1 cm, with multiple tumors, or with regional lymph node metastasis, regardless of the size of the primary tumor, wide excision of bowel and mesentery is required. Lesions of the terminal ileum are best treated by right hemicolectomy. Small duodenal tumors can be excised locally; however, more extensive lesions may require pancreaticoduodenectomy. A single-center, prospective, longitudinal study showed that a laparoscopic approach is safe and feasible in selected patients. Laparoscopy was associated with similar R0 (i.e., without residual microscopic tumor) resection and morbidity rates but a shorter hospital stay compared with laparotomy. Median follow-up was 39 months, and progression-free survival at 1, 3, and 5 years was as follows: 95%, 83%, and 75%, respectively, for R0 patients without liver metastasis; 92%, 83%, and 57%, respectively, for R0 patients with resected liver metastasis; and 82%, 58%, and 30%, respectively, for patients with R2 resection (i.e., evidence of residual tumor on visual examination). Overall survival and progression-free survival did not show any difference in comparing the laparoscopic and open groups.36 Caution should be exerted in the anesthetic management of patients with NETs because anesthesia may precipitate a carcinoid crisis characterized by hypotension, bronchospasm, flushing, and tachyarrhythmias. Carcinoid crisis is treated with IV octreotide given as a bolus of 50 to 100 μg, which may be continued as an infusion at 50 μg/hr. In addition to treatment of the primary tumor, it is important that the abdomen be thoroughly explored for multicentric lesions. There often is a large desmoplastic reaction causing shortening, folding and pleating of the small bowel mesentery resulting in intestinal angina and obstruction. In cases in which the mesenteric disease appears to involve a large portion of the mesentery, dissection of the tumor off the mesenteric vessels, with preservation of the blood supply to unaffected bowel, is appropriate, albeit technically demanding. Extensive mobilization of the small bowel mesentery is required to perform a difficult resection. Not only does removal of the mesenteric disease provide a significant survival advantage, but also mesenteric debulking ensures the most

durable palliation for the patient. Aggressive surgical resection and debulking achieve relief of 93% of obstruction and 83% of mesenteric vessel encasement.37 In patients with NETs and widespread metastatic disease, surgery may still be indicated. In contrast to metastases from other tumors, there is a definite role for surgical debulking, which often provides beneficial symptomatic relief. In patients with limited hepatic involvement, metastasectomy provides the most durable survival benefit compared with other treatment modalities. For patients with liver metastases, surgical resection is an option as long as there are no extrahepatic metastases, liver function is not compromised, and there is no diffuse bilobar involvement. Unfortunately, most patients are not candidates for liver resection because of extensive disease at diagnosis. Even with liver metastasectomy, there is still a high recurrence rate of 75%. In these cases, transarterial chemoembolization or radioembolization has been shown to provide liver-directed control of disease. Furthermore, resection of the primary tumor, with or without mesenteric resection, has been shown to improve survival and to slow progression of hepatic metastases in patients with unresectable disease. Although there have been some small studies that evaluate hepatic transplantation for extensive liver metastases from NETs, unacceptably high recurrence rates limit this approach. Overall, due to the complexity of treatment regimens, all surgical resections should be performed at a high volume center.  Medical therapy. Medical therapy for patients with malignant carcinoid syndrome is primarily directed toward the relief of symptoms caused by the excess production of humoral factors. Table 50.10 summarizes medical therapies for NET treatment. Somatostatin analogs (SSAs) are the standard of care for controlling symptoms of patients with functional gastrointestinal NETs, and they control symptoms in more than 70% of patients with carcinoid syndrome.38 SSAs such as octreotide (Sandostatin) and lanreotide and their depot formulations (Sandostatin LAR and Somatuline, respectively) relieve symptoms of the carcinoid syndrome (e.g., diarrhea, flushing, antisecretory effect) in most patients and delay cancer progression (antiproliferative effect). The antiproliferative effect was demonstrated in two randomized phase 3 trials. First, the PROMID trial of 85 patients confirmed that tumor burden is an important predictor of survival and octreotide LAR provided delayed tumor progression compared to placebo.39 Octreotide LAR is recommended for Grade 1 and 2 NETs and not recommended in grade 3 disease. Second, the landmark controlled study of Lanreotide Antiproliferative Response In NeuroEndocrine Tumors (CLARINET) trial found that lanreotide, an SSA, was associated with prolonged progression-free survival among patients with metastatic grade 1 or 2 enteropancreatic NETs.40 Currently, there is no guideline regarding the selection of Octreotide LAR versus lanreotide as a first-line therapy. The treatment of asymptomatic patients with low volume and unresectable disease requires a personalized decision on observation or initiation of SSAs. However, observation requires close monitoring with diagnostic imaging every 3 to 6 months.41 For patients who have disease progression on SSA therapy, several emerging treatment options remain. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, initially developed as immunosuppressant therapy, is approved for the treatment of nonfunctional gastrointestinal NETs with unresectable, locally advanced or metastatic disease. A randomized controlled trial (RADIANT-4) demonstrated that, with everolimus treatment, progression-free survival improved from 3.9 months to 11 months. Although everolimus can slow tumor progression, significant

CHAPTER 50  Small Intestine TABLE 50.10  Medical therapies for

neuroendocrine tumor treatment. Approved Therapeutics Somatostatin analogs Cytotoxic therapies mTOR inhibitor Tyrosine kinase inhibitors Peptide receptor radionuclide therapy Serotonin synthesis inhibitors Used Off-Label Pan-receptor somatostatin agonists Interferons Cytotoxic therapies

Investigational Peptide receptor radiotherapy

Octreotide (Sandostatin; Sandostatin LAR) Lanreotide (Somatuline depot) Streptozotocin (pancreatic NET only) Everolimus (Afinitor; gastrointestinal, pancreatic, lung NET) Sunitinib (Sutent; pancreatic NET only) 177Lu isotopes conjugated with somatostatin analogs (Lutathera) Telotristat etiprate (Xermelo)

Pasireotide (Signifor); approved indication for Cushing disease only Interferon alfa-2b (Intron A) 5-Fluorouracil (5-FU) Capecitabine (Xeloda); oral 5-FU Temozolomide (Temodar)

177Lu-OPS

201 JR11 Dopastatins JS001 PEN-221 177Lu-DOTA

Dopamine agonists Checkpoint inhibitor Somatostatin drug conjugate

Compiled with the assistance of Lowell B. Anthony, MD, University of Kentucky. NET, Neuroendocrine tumor.

tumor reduction is rarely obtained. Targeting multiple signaling pathways is a treatment strategy that may provide better tumor control and overcome resistance mechanisms involved with simply targeting a single pathway. Results of ongoing and future studies will provide important information about the added benefit of combining mTOR inhibitors with other targeted agents, such as VEGF pathway inhibitors, and cytotoxic chemotherapy in the treatment of advanced NETs.41 Peptide receptor radionuclides are another class of therapy used in progressive disease. The NETTER-1 randomized control trial demonstrated that treatment with radionuclide 177LuDOTATATE had a 79% improvement in progression-free survival when compared to high-dose octreotide. 177Lu-DOTATATE can be used for PET imaging as well as to determine the distribution and the dosimetry of the tumor. There is also an interest in targeting incretin receptor family members, particularly glucagon-like peptide (GLP) 1, which are overexpressed in NETs. The GLP-1 inhibitor Lys40(Ahx-DTPA/DOTA111In) NH2-exendin-4 is highly sensitive and can be detected up to 14 days after IV injection using a probe to facilitate surgical excision. Second-generation SSAs have been developed to address the limitations of the current regimens. Studies are ongoing using pan-receptor agonists (e.g., pasireotide) as well as chimeric dimers, which possess features of somatostatin and dopamine agonists (dopastatins). These promising biologic therapies are thought to enhance symptom control by binding multiple receptors (somatostatin and dopamine receptors). Somatostatin receptor antagonists are also currently being developed for clinical use.

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Other treatment options include interferon alpha, which was used as monotherapy for NET in 1983. Interferon binds to two different receptors to elicit effects that include cell cycle inhibition at G1/S, antiangiogenesis effects through downregulation of VEGF, and upregulation of somatostatin receptors. Although some series showed tumor regression in 10% of patients and tumor stabilization in 65%, side effects, which included chronic fatigue, pancytopenia, thyroiditis, and systemic lupus erythematosus, were not tolerable, and thus, interferon alpha is no longer used. Pegylated interferon alpha-2b showed comparable survival rates to interferon alpha, but with more tolerable side effects. Some series showed that given the upregulation of somatostatin receptors by interferon alpha, its combination with SSAs may be efficacious. Prospective randomized controlled trials demonstrated variable findings, but one retrospective study determined that combined treatment resulted in a longer progression-free survival (58 vs. 55 months). Interferon is less expensive than the SSAs, but the increased incidence of side effects and variable outcomes preclude the widespread use of this drug.41 Patients with carcinoid syndrome that are resistant to SSAs have limited treatment options, which include increasing the dose of SSA or adding a short acting octreotide and starting antidiarrheals. An extensive workup is needed to rule out other causes of diarrhea, but few treatment options remain. Currently, the serotonin synthesis inhibitor, telotristat etiprate, is indicated for somatostatin refractory diarrhea in the setting of carcinoid syndrome. In the TELESTAR trial, telotristat treatment reduced daily bowel movements by 35%.41 Serotonin receptor antagonists have been used with limited success. Methysergide is no longer used because of the increased incidence of retroperitoneal fibrosis. Ketanserin and cyproheptadine have been shown to provide some control of symptoms, and other antagonists, such as ondansetron, also have a role. Historically, the only available treatment for metastatic NETs was cytotoxic chemotherapy, most frequently combinations that included streptozotocin, 5-fluorouracil (5-FU), and cyclophosphamide. These treatments resulted in a median survival of around 2 years. Currently, the role of chemotherapy is confined predominantly to patients with G2 metastatic disease who are symptomatic, are unresponsive to other therapies, or have high tumor proliferation rates. The duration of response, however, is short-lived. Temozolomide as monotherapy has acceptable toxicity and provides antitumoral effects in a small series of patients with advanced NETs, and in combination with capecitabine, it was shown to prolong survival in patients with well-differentiated, metastatic NETs who experienced progression with previous therapies. The use of cisplatin and etoposide has shown some promise, but only in patients with poorly differentiated neuroendocrine carcinomas. The treatment of metastatic NENs requires a multidisciplinary approach; combined modalities may be the best option, including surgical debulking, hepatic artery embolization, chemoembolization, or radioembolization and medical therapy. In addition, newer and more targeted therapies are being developed that may be useful in the future. Sunitinib, which is a multitargeted or selective tyrosine kinase inhibitor that is active against alpha-type and beta-type platelet-derived growth factor receptor (PDGFR) and VEGF receptor (VEGFR), has been noted to decrease angiogenesis and to prolong progression-free survival in pancreatic NETs in multiple clinical trials, most notably those with mutations associated with exons 9 and 11. 

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Prognosis. NETs have the best prognosis of all small bowel tumors, whether the disease is localized or metastatic. Resection of a NET localized to its primary site approaches a 100% survival rate. Five-year survival rates are approximately 65% in patients with regional disease and 25% to 35% in those with distant metastasis. Metastatic disease at the time of diagnosis is approximately 20% to 50%, and tumors recur in 40% to 60% of patients. When widespread metastatic disease precludes cure, extensive resection for palliation may be indicated. In fact, long-term palliation often can be obtained because these tumors are relatively slow growing. A number of factors have been evaluated in an attempt to identify patients with NETs who have a poor prognosis. An elevated level of CgA, which is an independent predictor of an adverse prognosis, is probably the most useful factor identified. 

Adenocarcinomas Adenocarcinomas constitute approximately 40% of the malignant tumors of the small bowel. The median age at diagnosis is in the sixth decade of life, and most series show a slight male predominance. Most of these tumors are located in the duodenum and proximal jejunum (Fig. 50.32). Those arising in association with Crohn disease tend to occur at a somewhat younger age, and more than 70% arise in the ileum. Small bowel adenocarcinoma may have important gene mutations (APC, β-CATENIN, EGFR, VEGF-A, KRAS, HER2, TP53).42 The most common familial causes include FAP, Lynch syndrome, and Peutz Jeghers syndrome. Tumors of the duodenum tend to manifest somewhat earlier than those in the jejunum and ileum because of the earlier presentation of symptoms, which are usually jaundice and chronic bleeding. Adenocarcinomas of the jejunum and ileum usually produce more nonspecific symptoms that include vague abdominal pain and weight loss. Intestinal obstruction and chronic bleeding may also occur. Perforation is uncommon. As with adenocarcinomas in other organs, survival of patients with small bowel adenocarcinomas is related to the stage of disease at the time of diagnosis. Unfortunately, diagnosis is often delayed, and the disease is advanced at the time of surgery secondary to a variety of factors (e.g., vagueness of symptoms, absence of physical findings, lack of clinical suspicion because of the rarity of these lesions). A variety of radiologic and endoscopic techniques such as CT of the abdomen and pelvis with enteroclysis, video capsule endoscopy, and double balloon enteroscopy (for biopsy

and diagnosis) may be very useful in establishing the diagnosis prior to surgery. Treatment of small bowel adenocarcinoma is determined by location and stage. An R0 resection of the primary tumor with locoregional lymph node resection is the only curative treatment. Neoadjuvant chemotherapy is appropriate to consider if there is tumor invasion into adjacent structures. Patients are then reevaluated for surgery after 2 to 3 months of treatment. Duodenal resection can be performed for a noninfiltrating tumor if it is located in the first, third, or fourth portion of the duodenum, but this is not recommended if an expected R0 resection (no microscopic tumor at margin) is not possible. Residual microscopic tumor (R1 status) or grossly visible tumor after resection (R2 status) are associated with poor prognosis. Resectable adenocarcinomas in the second portion of the duodenum are treated with pancreaticoduodenectomy. In addition, regional lymphadenectomy of the periduodenal, peripancreatic, and hepatic lymph nodes as well as involved vascular structures is necessary. Jejunal and ileal adenocarcinomas require surgical resection with regional lymphadenectomy and jejunojejunal or ileoileal anastomosis (Fig. 50.33). If the terminal ileum is involved, an ileocecectomy with right hemicolectomy should be performed with ligation of the ileocolic artery and subsequent regional lymphadenectomy. There is currently no standard adjuvant protocol for small bowel adenocarcinoma. Despite this, most guidelines suggest that patients with poorly differentiated cancers or those who had incomplete lymph node resections (200 mg/dL No evidence of bowel obstruction, discontinuity, infection, inflammation

Ileal, jejunal, nonsurgical etiology Inflammatory bowel disease, cancer, radiation Transferrin 2 cm, end fistula Output 25 g/L Period of convalescence >6 weeks  Surgical Strategy One-stage procedure Careful adhesiolysis Wedge excision of intestinal resection Limit number of anastomoses to minimum Cover sutures with healthy, viable tissue Keep away from compromised area Adapted from Visschers RG, van Gemert WG, Winkens B, et al. Guided treatment improves outcome of patients with enterocutaneous fistulas. World J Surg. 2012;36:2341–2348. ECF, Enterocutaneous fistula.

wound around the associated fistula. Care should be given to avoid direct contact with visceral contents as this can cause new fistulas. Skin grafting up to the fistula has also been used in cases associated with an open abdomen, with a graft success rate of up to 80% in some series. Importantly, patients who could not be discharged before definitive repair also have higher mortality risk.  Definitive management. If the fistula persists despite adequately addressing the patient’s nutritional, fluid, and wound care needs, reoperative intervention will ultimately be necessary for some patients. Surgery is most easily accomplished by entering the previous abdominal wound, with great care taken to avoid further damage to adherent bowel. The preferred operation is fistula tract excision and segmental resection of the involved segment of intestine and

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reanastomosis. Simple closure of the fistula after removal of the fistula tract almost always results in fistula recurrence. If an unexpected abscess is encountered or if the bowel wall is rigid and distended over a long distance, thus making primary anastomosis unsafe, exteriorization of both ends of the intestine should be accomplished. Various bypass procedures have also been described as part of a staged approach in which exclusion of the segment containing the fistula is accomplished in the first reoperation, and then another operation is required for resection of the involved segment and fistula tract. Although this may be necessary in extreme circumstances, this is certainly not the preferred surgical management. Basic surgical considerations include attempting a one-stage procedure, careful adhesiolysis, addressing compromised tissues with wedge excision or intestinal resection, covering sutures with viable tissues, and avoiding friable areas that are not directly involved with the fistula. In summary, enterocutaneous fistulas occur most commonly as a result of a previous operative procedure. Once identified, a three-phase approach of stabilization, staging, and supportive care, and, in some cases, definitive surgical intervention is necessary. Most of these fistulas heal spontaneously within 6 weeks. If closure is not achieved after 6 weeks, surgery is indicated. 

Pneumatosis Intestinalis Pneumatosis intestinalis is an uncommon condition manifesting as multiple gas-filled cysts of the gastrointestinal tract. The cysts may be located in the subserosa, submucosa, and, rarely, muscularis layer and vary in size from microscopic to several centimeters in diameter. They can occur anywhere along the gastrointestinal tract, from the esophagus to the rectum; however, they are most common in the jejunum, followed by the ileocecal region and colon. Extraintestinal structures such as mesentery, peritoneum, and the falciform ligament may also be involved. There is an equal incidence in men and women, and the condition usually occurs in the fourth to seventh decades of life. Pneumatosis in neonates is usually associated with necrotizing enterocolitis. The cause of pneumatosis intestinalis has not been completely delineated. A number of theories have been proposed; mechanical, mucosal damage, bacterial, and pulmonary hypotheses seem to be most plausible. There are two forms of pneumatosis intestinalis. Primary pneumatosis (15%) is a benign idiopathic condition that is not associated with any other conditions or symptoms and is found incidentally. The majority of pneumatosis intestinalis (85%) are associated with chronic obstructive pulmonary disease or an immunocompromised state (e.g., in AIDS; after transplantation; in association with leukemia, lymphoma, vasculitis, or collagen vascular disease; and in patients undergoing chemotherapy or taking corticosteroids). Other associated conditions include inflammatory, obstructive, or infectious conditions of the intestine; iatrogenic conditions, such as endoscopy and jejunostomy placement; small bowel ischemia; and extraintestinal diseases, such as diabetes. Upon gross inspection, the cysts resemble cystic lymphangiomas or hydatid cysts. On histologic section, the involved portion has a honeycomb appearance. The cysts are thin walled and break easily. Spontaneous rupture gives rise to pneumoperitoneum. Symptoms are nonspecific, and in pneumatosis associated with other disorders, the symptoms may be those of the associated disease. Symptoms in primary pneumatosis intestinalis, when present, usually include diarrhea, abdominal pain, abdominal distention, nausea, vomiting, weight loss, and mucus in stools. Hematochezia and constipation have also been described. Complications associated

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with pneumatosis intestinalis occur in about 3% of cases and include volvulus, intestinal obstruction, hemorrhage, and intestinal perforation. Usually, pneumoperitoneum occurs in these patients, generally in association with small bowel rather than large bowel pneumatosis. Peritonitis is unusual. In fact, pneumatosis intestinalis represents one of the few cases of sterile pneumoperitoneum and should be considered in the patient with free abdominal air but no evidence of peritonitis. Pneumatosis intestinalis is an ominous sign when associated with peritonitis, mesenteric gas, or portovenous gas, as this is most concerning for life threatening small bowel ischemia. The diagnosis is usually made radiographically by plain abdominal or barium studies. On plain films, pneumatosis intestinalis appears as radiolucent areas within the bowel wall, which must be differentiated from luminal intestinal gas (Fig. 50.48A). The radiolucency may be linear or curvilinear or appear as grapelike clusters or tiny bubbles. Alternatively, barium contrast or CT studies can be used to confirm the diagnosis (Fig. 50.48B). Visualization of intestinal cysts has also been described by ultrasound. No treatment is necessary unless one of the very rare complications supervenes, such as small bowel ischemia, rectal bleeding, cyst-induced volvulus, or tension pneumoperitoneum. Prognosis in most patients is that of the underlying disease. The important point is to recognize that pneumatosis intestinalis is a radiographic finding and not a diagnosis. Treatment should be directed at the underlying cause of the pneumatosis, and surgical intervention should be predicated on the clinical course of the patient. 

aerobes and facultative anaerobes. However, with stasis, the number of bacteria increases, with excessive proliferation of aerobic and anaerobic bacteria; bacteroides, anaerobic lactobacilli, coliforms, and enterococci are likely to be present in varying numbers. The bacteria compete for dietary vitamin B12, producing a systemic deficiency of vitamin B12 and megaloblastic anemia. The syndrome can be confirmed by a series of laboratory investigations. Bacterial overgrowth can be diagnosed with cultures obtained through an intestinal tube or by indirect tests such as the 14C-xylose or 14C-cholylglycine breath tests. Excessive bacterial use of 14C substrate leads to an increase in 14C-labeled CO2. After bacterial overgrowth and steatorrhea are confirmed, the Schilling test (57Co-labeled vitamin B12 absorption) may be performed, which should reveal a pattern of urinary excretion of vitamin B12 resembling that of pernicious anemia (a urinary loss of 0% to 6% of vitamin B12 compared with the normal of 7%–25%). In patients with blind loop syndrome, vitamin B12 excretion is not altered by the addition of intrinsic factor, but a course of a broadspectrum antibiotic (e.g., tetracycline) should return vitamin B12 absorption to normal. Treatment of patients with blind loop syndrome includes parenteral vitamin B12 therapy and broad-spectrum antibiotics. Tetracyclines have been the mainstay of treatment, but studies have shown that rifaximin and metronidazole demonstrate less resistance and are also effective. For most patients, a single course of therapy (7–10 days) is sufficient, and the patient may remain symptom free for months. Prokinetic agents have been used without real success. Surgical correction of the condition causing stagnation and blind loop syndrome produces a permanent cure and is indicated for patients who require multiple rounds of antibiotics or are receiving continuous therapy. 

Blind Loop Syndrome Blind loop syndrome is a rare condition manifested by diarrhea, steatorrhea, megaloblastic anemia, weight loss, abdominal pain, and deficiencies of the fat-soluble vitamins as well as neurologic disorders. The underlying cause of this syndrome is bacterial overgrowth in stagnant areas of the small bowel produced by stricture, stenosis, fistulas, or diverticula (e.g., jejunoileal or Meckel diverticulum). Under normal circumstances, the upper gastrointestinal tract contains fewer than 105 bacteria/mL, mostly gram-positive

Radiation Enteritis Radiation therapy is generally used as adjuvant therapy for various abdominal and pelvic cancers. In addition to tumor cells, however, other rapidly dividing cells in normal tissues may be affected by radiation. Surrounding normal tissue, such as the small

120 mm

A

B

FIG. 50.48  Pneumatosis intestinalis. (A) Plain abdominal film demonstrates pneumatosis intestinalis (arrows). (B) Computed tomography findings consistent with curvilinear radiolucency appearing as tiny bubbles in the antimesenteric border of the bowel consistent with pneumatosis intestinalis. (A, Courtesy Dr. Melvyn H. Schreiber, The University of Texas Medical Branch, Galveston, TX. B, Courtesy Dr. Kristin Long, University of Kentucky Medical Center, Lexington, KY.)

CHAPTER 50  Small Intestine intestinal epithelium, may sustain severe, acute, and chronic deleterious effects. Radiation injury to the small bowel can be subdivided into acute and chronic forms. Acute radiation-induced small bowel disease usually is manifested with colicky abdominal pain, bloating, loss of appetite, nausea, diarrhea, and fecal urgency during or shortly after a course of radiotherapy. Most patients notice symptoms during the third week of treatment and these resolve 2 to 6 weeks after completion of radiation. Symptoms consistent with chronic radiation injury typically develop between 18 months and 6 years after a completed course of radiotherapy, but symptoms can be manifested up to 30 years after the treatment course. The amount of radiation appears to correlate with the probability for the development of radiation enteritis. Serious late complications are unusual if the total radiation dosage is less than 4000 cGy; morbidity risk increases with dosages exceeding 5000 cGy. Other factors, including previous abdominal surgeries, preexisting vascular disease, hypertension, diabetes, and adjuvant treatment with certain chemotherapeutic agents (such as 5-FU, doxorubicin, dactinomycin, and MTX), contribute to the development of enteritis after radiation treatments. A previous history of laparotomy increases the risk for enteritis, presumably because of adhesions that fix portions of the small bowel into the irradiated field. Radiation damage leads to symptoms of diarrhea, abdominal pain, and malabsorption. The late effects of radiation injury are the result of damage to small submucosal blood vessels, with a progressive obliterative arteritis and submucosal fibrosis; these events eventually result in thrombosis and vascular insufficiency. This injury may produce necrosis and perforation of the involved intestine but, more commonly, leads to stricture formation with symptoms of obstruction or small bowel fistulas. Multiple strategies are used to reduce radiation injury to the small bowel (Box 50.8). Radiation enteritis may be minimized by adjusting ports and dosages of radiation to deliver optimal treatment specifically to the tumor and not to surrounding tissues. Placement of radiopaque markers, such as titanium clips, at the time of the original operation facilitates better targeting of the radiation treatment. A reduction in field size, multiple field arrangements, conformal radiotherapy techniques, and intensitymodulated radiotherapy can reduce toxicity related to radiotherapy. Methods designed to exclude the small bowel from the irradiated field include reperitonealization, omental transposition, and placement of absorbable mesh slings. A number of pharmacologic interventions have also been described to reduce the side effects of radiation enteritis. Angiotensin-converting enzyme inhibitors and statins significantly reduce acute gastrointestinal symptoms during radical pelvic radiotherapy. Sucralfate, a highly sulfated polyanionic disaccharide thought to stimulate epithelial healing and thereby form a protective barrier over damaged mucosal surfaces, may help in the treatment of bleeding from radiation proctitis, but no evidence exists supporting its use in the prevention of radiation-induced small bowel disease. Superoxide dismutase, a free radical scavenger, has been used successfully to reduce complications. Other compounds that have been evaluated include glutathione, antioxidants (e.g., vitamin A, vitamin E, beta-carotene), histamine antagonists, and the combination of pentoxifylline and tocopherols, a class of chemical compounds with vitamin E activity. In addition, early studies support the use of probiotics as having a radioprotective effect in the gut; however, further studies are required before a final assessment can be made. The most effective radioprotectant agent appears to be amifostine (WR-2721), a sulfhydryl compound that

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is converted intracellularly to an active metabolite, WR-1065, which in turn binds to free radicals and protects the cell from radiation injury.48 A randomized controlled trial determined that glutamine offers little benefit, even when it is used before or during radiation therapy. Agents that may prove useful in the prevention of the acute symptoms of radiation enteritis include the hormones bombesin, growth hormone, GLP-2, and IGF-I, which, in experimental studies, demonstrated effectiveness in preventing or reducing symptoms associated with radiation enteritis. The treatment of acute radiation enteritis is directed at controlling symptoms. Antispasmodics and analgesics may alleviate abdominal pain and cramping, and diarrhea usually responds to opiates or other antidiarrheal agents. The use of corticosteroids for acute radiation enteritis is of uncertain value. Dietary manipulation, including oral elemental diets, has also been advocated to ameliorate the acute effects of radiation enteritis; however, results are conflicting. Antibiotics are frequently used in the setting of bacterial overgrowth. Bile acid malabsorption, thought to be responsible for diarrheal symptoms in 35% to 72% of patients with radiation-induced small bowel disease, responds well to cholestyramine, but it is not well tolerated and many patients voluntarily discontinue use. Operative intervention may be required for a subgroup of patients with the chronic effects of radiation enteritis. This is a small (1%–2%) subgroup of the total number of patients who received abdominal or pelvic irradiation. Indications for operation include obstruction, fistula formation, perforation, and bleeding, with obstruction being the most common presentation. Operative procedures include a bypass or resection with reanastomosis. Advocates for bypass procedures contend that this procedure is safer and controls the symptoms better than resection. Advocates of resection contend that the high morbidity and mortality rates previously reported with resection and reanastomosis reflect inadequate resection and anastomosis of diseased intestine. In patients presenting with obstruction, extensive lysis of adhesions should be avoided. Obstruction caused by rigid, fixed intestinal loops in the pelvis is best bypassed. If resection and reanastomosis are planned, at least one end of the anastomosis should be from intestine outside the irradiated field. Macroscopic inspection may not be accurate in evaluating the full extent of radiation damage. Frozen section and laser Doppler flowmetry techniques have been used to assist resection and BOX 50.8  Prevention of radiation-induced

small bowel disease.

Clinical Guidance Use of modern imaging and radiotherapy techniques to minimize radiation exposure to normal tissues Consideration of circadian rhythm effects and use of evening radiotherapy sessions Continuation of angiotensin-converting enzyme inhibitors and statins and consideration of their introduction if appropriate Consideration of the use of probiotics Consideration of surgical techniques to minimize radiation exposure to the small bowel if appropriate and surgical team is experienced and competent at the procedure involved Adapted from Stacey R, Green JT. Radiation-induced small bowel disease: latest developments and clinical guidance. Ther Adv Chronic Dis. 2014;5:15–29.

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anastomosis. However, reports of their clinical usefulness are conflicting. Perforation of the intestine should be treated with resection and anastomosis. When reanastomosis is thought to be unsafe, the ends should be exteriorized. 

Short Bowel Syndrome The short bowel syndrome results from a total small bowel length that is inadequate to support nutrition. Of these cases of short bowel syndrome, 75% occur from massive intestinal resection. In the adult, mesenteric occlusion, midgut volvulus, and traumatic disruption of the superior mesenteric vessels are the most frequent causes. Multiple sequential resections, usually associated with recurrent Crohn disease, account for 25% of patients. In neonates, the most common cause of short bowel syndrome is bowel resection secondary to necrotizing enterocolitis. The clinical hallmarks of short bowel syndrome include diarrhea, fluid and electrolyte deficiency, and malnutrition. Other complications include an increased incidence of gallstones caused by disruption of the enterohepatic circulation and of nephrolithiasis from hyperoxaluria. Specific nutrient deficiencies must be prevented, and levels must be monitored closely; these nutrients include iron, magnesium, zinc, copper, and vitamins. The likelihood that a patient with short bowel syndrome will be permanently dependent on TPN is thought to be primarily influenced by the length, location, and health of the remaining intestine. In patients with short bowel syndrome, postabsorptive levels of plasma citrulline, a nonprotein amino acid produced by intestinal mucosa, may provide an indicator to differentiate transient from permanent intestinal failure. The bowel has a remarkable capacity to adapt after small bowel resection; in many cases, this process of intestinal adaptation, termed adaptive hyperplasia, effectively prevents severe complications that result from the markedly decreased surface area available for absorption and digestion. However, any adaptive mechanism can be overwhelmed, and adaptation can be inadequate if too much small bowel is lost. Although there is considerable individual variation, resection of up to 70% of the small bowel usually can be tolerated if the terminal ileum and ileocecal valve are preserved. Length alone, however, is not the only determining factor of complications related to small bowel resection. For example, if the distal two thirds of the ileum, including the ileocecal valve, is resected, significant abnormalities of absorption of bile salts and vitamin B12 may occur, resulting in diarrhea and anemia, although only 25% of the total length of the small bowel has been removed. Proximal bowel resection is tolerated better than distal resection because the ileum can adapt and increase its absorptive capacity more efficiently than the jejunum. Treatment The most important issue to remember about short bowel syndrome is prevention. In patients with Crohn disease, limiting bowel resections to only segments with a particular complication should be performed. In addition, during surgery for problems related to intestinal ischemia, the smallest possible resection should be performed, and if necessary, second-look operations should be carried out to allow the ischemic bowel to demarcate, thus potentially preventing unnecessary extensive resection of the bowel. After massive small bowel resection, the treatment course may be divided into early and late phases. In its early phase, treatment is primarily directed at the control of diarrhea, replacement of fluid and electrolytes, and prompt institution of TPN in patients

who cannot safely tolerate enteral feedings. Volume losses may exceed 5 L/day, and vigorous monitoring of intake and output with adequate replacement must be carried out. Diarrhea in this early phase can be caused by a multitude of sources. For example, hypergastrinemia and gastric hypersecretion occur after massive small bowel resection and can significantly contribute to diarrhea after a massive small bowel resection. Acid hypersecretion can be managed by H2 receptor antagonists or proton pump blockers, such as omeprazole. Diarrhea may also be caused by ileal resection, resulting in disruption of the enterohepatic circulation and excessive amounts of bile salts entering the colon. Cholestyramine may be beneficial when diarrhea is related to the cathartic effects of unabsorbed bile salts in the colon. In addition, the judicious use of agents that inhibit gut motility (e.g., codeine, diphenoxylate) may be helpful. The long-acting SSA octreotide also appears to reduce the amount of diarrhea during the early phase of short bowel syndrome. Some studies suggest that octreotide may inhibit gut adaptation; other studies, however, have not confirmed this deleterious effect of octreotide. As soon as the patient has recovered from the acute phase, enteral nutrition should be started. The most common types of enteral diets are elemental (e.g., Vivonex, Flexical) and polymeric (e.g., Isocal, Ensure). Controversy exists about the optimal diet for these patients. Initially, a high-carbohydrate, high-protein diet is appropriate to maximize absorption. Milk products should be avoided, and the diet should begin at iso-osmolar concentrations and with small amounts. As the gut adapts, the osmolality, volume, and calorie content can be increased. The provision of nutrients in their simplest forms is an important part of the treatment. Simple sugars, dipeptides, and tripeptides are rapidly absorbed from the intestinal tract. Reduction in dietary fat has long been considered important in the treatment of patients with short bowel syndrome. Supplementation of the diet with 100 g or more of fat, however, should be carried out, often requiring the use of medium-chain triglycerides, which are absorbed in the proximal bowel. Vitamins, especially fat-soluble vitamins, as well as calcium, magnesium, and zinc supplementation should be provided. The roles of hormones administered systemically and glutamine administered enterally have been evaluated. The hormones neurotensin, growth hormone, bombesin, and GLP-2 have demonstrated marked mucosal growth in a variety of experimental studies and have been shown to prevent gut atrophy associated with TPN in experimental studies; combination therapy appears more efficacious than single-agent administration. Randomized controlled trials showed that teduglutide, a GLP-2 analogue that is resistant to degradation by the proteolytic enzyme dipeptidyl peptidase 4 and therefore has a longer half-life than natural GLP-2, is well tolerated and led to the restoration of intestinal functional and structural integrity through significant intestinotrophic and proabsorptive effects. It is the first targeted therapeutic agent to gain approval for use in pediatric and adult short bowel syndrome with intestinal failure.49 Two other hormones, not derived from the gut, that have been evaluated extensively in various experimental and limited clinical trials include growth hormone and IGF-I. A meta analysis of randomized controlled trials using growth hormone in short bowel syndrome suggests a possible short-term benefit in terms of body weight, lean body mass, and absorptive capacity; however, long-term efficacy was not noted. Somatropin, a recombinant human growth hormone that elicits anabolic and anticatabolic influence on various cells, either as a direct effect or indirectly through IGF-I, is currently indicated to treat short

CHAPTER 50  Small Intestine bowel syndrome in conjunction with nutritional support. The combination of various trophic hormones with glutamine and a modified diet may prove more efficacious in the treatment of this difficult group of patients. The first step in terms of surgical intervention is to restore digestive continuity, which can be accomplished by the reversal of a proximal stoma to reduce rates of dehydration. A number of surgical strategies have been attempted in patients who are chronically TPN dependent, with limited success; these include procedures to delay intestinal transit time, methods to increase absorptive area, and small bowel transplantation. Methods to delay intestinal transit time include the construction of various valves and sphincters, with inconsistent results reported. Antiperistaltic segments of small intestine have been constructed to slow the transit, thus allowing additional contact time for nutrient and fluid absorption. Moderate successes have been described with this technique. Other procedures, including colonic interposition, recirculating loops of small bowel, and retrograde electrical pacing, have been tried but were found to be unsuccessful in humans and were largely abandoned. Surgical procedures to increase absorptive area include the intestinal tapering and lengthening procedure (e.g., Bianchi procedure), which improves intestinal function by correcting the dilation and ineffective peristalsis of the remaining intestine and by doubling the intestinal length while preserving the mucosal surface area. Serial transverse enteroplasty creates staple lines parallel to the mesenteric blood supply on alternating sides to create a channel of intestine that is both longer and smaller in diameter. This technique also increases the surface area of bowel for nutritional absorption.50 Although beneficial in selected patients, potential complications can include necrosis of divided segments due to poor vasculature, stenosis from smaller caliber of bowel, and anastomotic leaks. Intestinal transplantation remains the standard of care for patients for whom intestinal rehabilitation attempts have failed and who are at risk of life-threatening complications of TPN; these include impending liver failure, thrombosis of more than two major access veins, frequent severe line infections, and dehydration. Patient survival after intestinal transplantation has significantly improved with the use of the immunosuppressive agents alemtuzumab and tacrolimus and transplantation at a high volume center (≥10 grafts per year). The 1- and 5-year survival rates for isolated intestinal transplantation are 77% and 58%, respectively. Combined intestinal-liver transplants have comparable 1- and 5-year survival rates of approximately 66% and 54%, respectively. The challenges of small bowel transplantation continue to require better immunosuppression and earlier detection of rejection.50 

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Predisposing factors for vascular compression of the duodenum, aside from weight loss, include supine immobilization, scoliosis, and placement of a body cast, sometimes called the cast syndrome. An association between vascular compression of the duodenum and peptic ulcer has been observed. Vascular compression of the duodenum has been reported in association with anorexia nervosa and after proctocolectomy and J-pouch anal anastomosis, resection of an arteriovenous malformation of the cervical cord, abdominal aortic aneurysm repair, and orthopedic procedures, usually spinal surgery. One report in the literature described a family with a preponderance of vascular compression of the duodenum. Diagnosis of this condition is made by a barium upper gastrointestinal series (Fig. 50.49) or hypotonic duodenography, which demonstrates abrupt or near-total cessation of flow of barium from the duodenum to the jejunum. CT is useful in certain cases. Treatment for this syndrome varies. Conservative measures should be tried initially and have been increasingly successful as definitive treatment. Operative management may include duodenojejunostomy, gastrojejunostomy to bypass the obstructing segment, or duodenal derotation (Strong procedure).

Vascular Compression of the Duodenum Vascular compression of the duodenum, also known as superior mesenteric artery syndrome or Wilkie syndrome, is a rare condition characterized by compression of the third portion of the duodenum by the superior mesenteric artery as it passes over this portion of the duodenum. Symptoms include profound nausea and vomiting, abdominal distention, weight loss, and postprandial epigastric pain, which varies from intermittent to constant, depending on the severity of the duodenal obstruction. Weight loss usually occurs before the onset of symptoms and contributes to the syndrome. This syndrome is most commonly seen in young asthenic individuals, with women more commonly affected than men.

FIG. 50.49  Superior mesenteric artery (SMA) syndrome. Barium radiograph demonstrates obstruction of the third portion of the duodenum secondary to superior mesenteric artery compression as a consequence of burn injury. (Adapted from Reckler JM, Bruck HM, Munster AM, et al. Superior mesenteric artery syndrome as a consequence of burn injury. J Trauma. 1972;12:979–985.)

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SELECTED REFERENCES Caplin ME, Pavel M, Cwikla JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371:224–233. The landmark CLARINET trial (Lanreotide Antiproliferative Response in patients with GEP-NET) is the largest phase 3, randomized, double-blind, placebo-controlled, multinational study that evaluated the antiproliferative effect of the SSA lanreotide in patients with GEP-NETs. Lanreotide was associated with significantly prolonged progression-free survival among patients with grade 1 or 2 metastatic enteropancreatic NETs.

Crohn BB, Ginzburg L, Oppenheimer GD. Regional ileitis: a pathologic and clinical entity. JAMA. 1932;99:1323–1329. This landmark paper succinctly crystallizes the clinical course, differential diagnosis, and pathologic findings of regional ileitis in young adults. Although other terms have been applied to this disease process, based on the descriptions in this classic paper, Crohn disease has been universally accepted as the name.

Feuerstein JD, Cheifetz AS. Crohn disease: epidemiology, diagnosis, and management. Mayo Clin Proc. 2017;92:1088–1103. This paper provides an extensive review for current diagnostic and therapeutic options for Crohn disease, with a focus on medical and surgical management.

Paulson EK, Thompson WM. Review of small-bowel obstruction: the diagnosis and when to worry. Radiology. 2015;275:332–342. This review identifies the important radiologic findings in bowel obstruction that are commonly used to make clinical decisions for operative intervention.

Shi HY, Ng SC. The state of the art on treatment of Crohn’s disease. J Gastroenterol. 2018;53:989–998. This represents a clear and concise review article highlighting critical issues in the medical management of Crohn disease, new evidence from clinical trials, and prospective studies.

Strosberg JR, Halfdanarson TR, Bellizzi AM, et al. The North American Neuroendocrine Tumor Society consensus guidelines for surveillance and medical management of midgut neuroendocrine tumors. Pancreas. 2017;46:707–714. This paper provides an extensive review of current medical treatment guidelines for neuroendocrine tumors as agreed upon by the North American Neuroendocrine Tumor Society.

Thirunavukarasu P, Sathaiah M, Sukumar S, et al. Meckel’s diverticulum—a high-risk region for malignancy in the ileum. Insights from a population-based epidemiological study and implications in surgical management. Ann Surg. 2011;253:223–230. A national database study during 33 years that suggests Meckel diverticulum is a high-risk area for ileal cancer and supports the resection of incidental Meckel diverticulum.

Torres J, Mehandru S, Colombel JF, et al. Crohn’s disease. Lancet. 2017;389:1741–1755. A recent comprehensive review of Crohn disease from the etiology to diagnosis and medical/surgical treatment.

Young JI, Mongoue-Tchokote S, Wieghard N, et al. Treatment and survival of small-bowel adenocarcinoma in the United States: a comparison with colon cancer. Dis Colon Rectum. 2016;59:306–315. This study represents a large, national database analysis of the outcomes of small intestine malignant neoplasms during the past two decades and its comparisons to colorectal cancer outcomes.

REFERENCES 1. Moore KL, Persaud TVN, Torchia MG. Alimentary system. In: Moore KL, Persaud TVN, eds. The Developing Human: Clinically Oriented Embryology. 10th ed. Philadelphia: Elsevier; 2016:209–240. 2. Bykov VL. [Paneth cells: history of discovery, structural and functional characteristics and the role in the maintenance of homeostasis in the small intestine]. Morfologiia. 2014;145:67–80. 3. Chung DH, Evers BM. The digestive system. In: O’Leary JP, ed. The Physiologic Basis of Surgery. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2007:475–507. 4. Li J, Song J, Zaytseva YY, et al. An obligatory role for neurotensin in high-fat-diet-induced obesity. Nature. 2016;533:411–415. 5. Allaire JM, Crowley SM, Law HT, et al. The intestinal epithelium: central coordinator of mucosal immunity. Trends Immunol. 2018;39:677–696. 6. Paulson EK, Thompson WM. Review of small-bowel obstruction: the diagnosis and when to worry. Radiology. 2015;275:332–342. 7. Aquina CT, Becerra AZ, Probst CP, et al. Patients with adhesive small bowel obstruction should be primarily managed by a surgical team. Ann Surg. 2016;264:437–447. 8. Quah GS, Eslick GD, Cox MR. Laparoscopic versus open surgery for adhesional small bowel obstruction: a systematic review and meta-analysis of case-control studies. Surg Endosc. 2019;33:3209–3217. 9. Tsuruta A, Itoh T, Hirai T, et al. Multi-layered intra-abdominal adhesion prophylaxis following laparoscopic colorectal surgery. Surg Endosc. 2015;29:1400–1405.

CHAPTER 50  Small Intestine 10. Crohn BB, Ginzburg L, Oppenheimer GD. Regional ileitis: a pathologic and clinical entity. JAMA. 1932;99: 1323–1329. 11. Feuerstein JD, Cheifetz AS. Crohn disease: epidemiology, diagnosis, and management. Mayo Clin Proc. 2017;92:1088–1103. 12. Wang MH, Picco MF. Crohn’s disease: genetics update. Gastroenterol Clin North Am. 2017;46:449–461. 13. Lang BM, Biedermann L, van Haaften WT, et al. Genetic polymorphisms associated with smoking behaviour predict the risk of surgery in patients with Crohn’s disease. Aliment Pharmacol Ther. 2018;47:55–66. 14. Torres J, Mehandru S, Colombel JF, et al. Crohn’s disease. Lancet. 2017;389:1741–1755. 15. Cleynen I, Boucher G, Jostins L, et al. Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study. Lancet. 2016;387:156–167. 16. Lichtenstein GR, Loftus EV, Isaacs KL, et al. ACG clinical guideline: management of Crohn’s disease in adults. Am J Gastroenterol. 2018;113:481–517. 17. Adami HO, Bretthauer M, Emilsson L, et al. The continuing uncertainty about cancer risk in inflammatory bowel disease. Gut. 2016;65:889–893. 18. Kyriakidi KS, Tsianos VE, Karvounis E, et al. Neutrophil anti-neutrophil cytoplasmic autoantibody proteins: bactericidal increasing protein, lactoferrin, cathepsin, and elastase as serological markers of inflammatory bowel and other diseases. Ann Gastroenterol. 2016;29:258–267. 19. Shimoyama T, Yamamoto T, Umegae S, et al. Faecal biomarkers for screening small bowel inflammation in patients with Crohn’s disease: a prospective study. Therap Adv Gastroenterol. 2017;10:577–587. 20. Deepak P, Park SH, Ehman EC, et al. Crohn’s disease diagnosis, treatment approach, and management paradigm: what the radiologist needs to know. Abdom Radiol (NY). 2017;42:1068–1086. 21. Niv Y, Gal E, Gabovitz V, et al. Capsule endoscopy Crohn’s disease activity index (CECDAIic or Niv Score) for the small bowel and colon. J Clin Gastroenterol. 2018;52:45–49. 22. Shi HY, Ng SC. The state of the art on treatment of Crohn’s disease. J Gastroenterol. 2018;53:989–998. 23. Rezaie A, Kuenzig ME, Benchimol EI, et al. Budesonide for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2015:CD000296. 24. Schlussel AT, Steele SR, Alavi K. Current challenges in the surgical management of Crohn’s disease: a systematic review. Am J Surg. 2016;212:345–351. 25. Sevim Y, Akyol C, Aytac E, et al. Laparoscopic surgery for complex and recurrent Crohn’s disease. World J Gastrointest Endosc. 2017;9:149–152. 26. Ponsioen CY, de Groof EJ, Eshuis EJ, et al. Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn’s disease: a randomised controlled, open-label, multicentre trial. Lancet Gastroenterol Hepatol. 2017;2:785–792. 27. Shimada N, Ohge H, Kono T, et al. Surgical recurrence at anastomotic site after bowel resection in Crohn’s disease: comparison of Kono-S and end-to-end anastomosis. J Gastrointest Surg. 2019;23:312–319. 28. Schlussel AT, Cherng NB, Alavi K. Current trends and challenges in the postoperative medical management of Crohn’s disease: a systematic review. Am J Surg. 2017;214:931–937.

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29. Pavlinac PB, Tickell KD, Walson JL. Management of diarrhea in HIV-affected infants and children. Expert Rev Anti Infect Ther. 2015;13:5–8. 30. von Mehren M, Joensuu H. Gastrointestinal stromal tumors. J Clin Oncol. 2018;36:136–143. 31. Campos FG, Sulbaran M, Safatle-Ribeiro AV, et al. Duodenal adenoma surveillance in patients with familial adenomatous polyposis. World J Gastrointest Endosc. 2015;7:950–959. 32. Young JI, Mongoue-Tchokote S, Wieghard N, et al. Treatment and survival of small-bowel adenocarcinoma in the United States: a comparison with colon cancer. Dis Colon Rectum. 2016;59:306–315. 33. Tsoli M, Chatzellis E, Koumarianou A, et al. Current best practice in the management of neuroendocrine tumors. Ther Adv Endocrinol Metab. 2019;10:2042018818804698. 34. Kim JY, Hong SM. Recent updates on neuroendocrine tumors from the gastrointestinal and pancreatobiliary tracts. Arch Pathol Lab Med. 2016;140:437–448. 35. Johnbeck CB, Knigge U, Loft A, et al. Head-to-head comparison of (64)Cu-DOTATATE and (68)Ga-DOTATOC PET/ CT: a prospective study of 59 patients with neuroendocrine tumors. J Nucl Med. 2017;58:451–457. 36. Figueiredo MN, Maggiori L, Gaujoux S, et al. Surgery for small-bowel neuroendocrine tumors: is there any benefit of the laparoscopic approach? Surg Endosc. 2014;28:1720–1726. 37. Farley HA, Pommier RF. Surgical treatment of small bowel neuroendocrine tumors. Hematol Oncol Clin North Am. 2016;30:49–61. 38. Paul D, Ostwal V, Bose S, et al. Personalized treatment approach to gastroenteropancreatic neuroendocrine tumors: a medical oncologist’s perspective. Eur J Gastroenterol Hepatol. 2016;28:985–990. 39. Herrera-Martinez AD, Hofland J, Hofland LJ, et al. Targeted systemic treatment of neuroendocrine tumors: current options and future perspectives. Drugs. 2019;79:21–42. 40. Caplin ME, Pavel M, Cwikla JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371:224–233. 41. Strosberg JR, Halfdanarson TR, Bellizzi AM, et al. The North American Neuroendocrine Tumor Society consensus guidelines for surveillance and medical management of midgut neuroendocrine tumors. Pancreas. 2017;46:707–714. 42. Aparicio T, Zaanan A, Mary F, et al. Small bowel adenocarcinoma. Gastroenterol Clin North Am. 2016;45:447–457. 43. Thirunavukarasu P, Sathaiah M, Sukumar S, et al. Meckel’s diverticulum—a high-risk region for malignancy in the ileum. Insights from a population-based epidemiological study and implications in surgical management. Ann Surg. 2011;253:223–230. 44. Soltero MJ, Bill AH. The natural history of Meckel’s diverticulum and its relation to incidental removal. A study of 202 cases of diseased Meckel’s diverticulum found in King County, Washington, over a fifteen year period. Am J Surg. 1976;132:168–173. 45. Zani A, Eaton S, Rees CM, et al. Incidentally detected Meckel diverticulum: to resect or not to resect? Ann Surg. 2008;247:276–281. 46. Blouhos K, Boulas KA, Tsalis K, et al. Meckel’s diverticulum in adults: surgical concerns. Front Surg. 2018;5:55. 47. Quinn M, Falconer S, McKee RF. Management of enterocutaneous fistula: outcomes in 276 patients. World J Surg. 2017;41:2502–2511.

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48. Teo MT, Sebag-Montefiore D, Donnellan CF. Prevention and management of radiation-induced late gastrointestinal toxicity. Clin Oncol (R Coll Radiol). 2015;27:656–667. 49. Kim ES, Keam SJ. Teduglutide: a review in short bowel syndrome. Drugs. 2017;77:345–352.

50. Billiauws L, Maggiori L, Joly F, et al. Medical and surgical management of short bowel syndrome. J Visc Surg. 2018;155:283–291.

CHAPTER

51

The Appendix Bryan Richmond

OUTLINE Anatomy and Embryology Appendicitis History Pathophysiology and Bacteriology Differential Diagnosis Presentation Treatment of Appendicitis Acute Uncomplicated Appendicitis Perforated Appendicitis Laparoscopic Versus Open Appendectomy

Delayed Presentation of Appendicitis The Normal-Appearing Appendix at Operation Nonoperative Treatment of Uncomplicated Appendicitis “Chronic” Appendicitis as a Cause of Abdominal Pain Incidental Appendectomy Appendicitis in Special Populations Appendicitis in the Pregnant Patient Appendicitis in the Elderly Appendicitis in the Immunocompromised Patient Neoplasms of the Appendix

 lease access Elsevier eBooks for Practicing Clinicians to view P the videos for this chapter https://expertconsult.inkling.com/.

some to hypothesize that the appendix may play a role in the immune system. In addition, evidence suggests that the appendix may serve as a reservoir of “good” intestinal bacteria and may aid in recolonization and maintenance of the normal colonic flora.4 Although historically removal of the appendix was not felt to result in any adverse sequelae, this has recently been challenged. For example, patients who have had previous appendectomy have been demonstrated to have a more difficult clinical course and overall poorer outcomes in recurrent cases of Clostridium difficile infection when compared with patients who have not undergone appendectomy. The theory is that the microbiome of the appendix has a protective function and that the loss of this eliminates an element of beneficial immunologic redundancy.5 In addition, a recently published epidemiological study found a significant link between appendectomy prior to age twenty and the development of prostate cancer, although a precise causative mechanism could not be elucidated.6 As a midgut organ, the blood supply of the appendix is derived from the superior mesenteric artery. The ileocolic artery, one of the major named branches of the superior mesenteric artery, gives rise to the appendiceal artery, which courses through the mesoappendix. The mesoappendix also contains lymphatics of the appendix, which drain to the ileocecal nodes, along with the blood supply from the superior mesenteric artery.3,7 The appendix is of variable size (5–35 cm in length) but averages 8 to 9 cm in length in adults. Its base can be reliably identified by defining the area of convergence of the taeniae at the tip of the cecum and then elevating the appendiceal base to define the course and position of the tip of the appendix, which is variable in location. The appendiceal tip may be found in a variety of locations, with the most common being retrocecal (but intraperitoneal) in approximately 60% of individuals, pelvic in 30%, and retroperitoneal in 7% to 10%. Agenesis of the appendix has been

Appendicitis remains one of the most common diseases faced by the surgeon in practice. It is the most common urgent or emergent general surgical operation performed in the United States and is responsible for as many as 300,000 hospitalizations annually.1 Although appendectomy is frequently the first “major” case performed by the surgeon in training, the impact of a timely diagnosis and prompt treatment is as impressive as that of any other major surgical intervention. It is estimated that as much as 6% to 7% of the general population will develop appendicitis during their lifetime, with the incidence peaking in the second decade of life.2 Despite its high prevalence in Western countries, the diagnosis of acute appendicitis can be challenging and requires a high index of suspicion on the part of the examining surgeon to facilitate prompt treatment of this condition, thereby avoiding the substantial morbidity (and even mortality) associated with delayed diagnosis and subsequent perforation. Appendicitis is much less common in underdeveloped countries, suggesting that elements of the Western diet, specifically a low-fiber, high-fat intake, may play a role in the development of the disease process.3 

ANATOMY AND EMBRYOLOGY The appendix is a midgut organ and is first identified at 8 weeks of gestation as a small outpouching of the cecum. As gestation progresses, the appendix becomes more elongated and tubular as the cecum rotates medially and becomes fixed in the right lower quadrant of the abdomen. The appendiceal mucosa is of the colonic type, with columnar epithelium, neuroendocrine cells, and mucin-producing goblet cells lining its tubular structure.3 Lymphoid tissue is found in the submucosa of the appendix, leading

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VIDEOS Video 51.1 Laparoscopic Appendectomy Video 51.2 Laparoscopic Appendectomy in Pregnant Patients Video 51.3 SILS Appendectomy Across a Spectrum of Disease Severity

1301.e1

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reported, as has duplication and even triplication.3,7 Knowledge of these anatomic variations is important to the surgeon because the variable position of the appendiceal tip may account for differences in clinical presentation and in the location of the associated abdominal discomfort. For example, patients with a retroperitoneal appendix may present with back or flank pain, just as patients with the appendiceal tip in the midline pelvis may present with suprapubic pain. Both of these presentations may result in a delayed diagnosis, as the symptoms are distinctly different from the classically described anterior right lower quadrant abdominal pain associated with appendiceal disease. 

APPENDICITIS History The first appendectomy was reported in 1735 by a French surgeon, Claudius Amyand, who identified and successfully removed the appendix of an 11-year-old boy that was found within an inguinal hernia sac and that had been perforated by a pin. Although autopsy findings consistent with perforated appendicitis appeared sporadically thereafter in the literature, the first formal description of the disease process, including the common clinical features and a recommendation for prompt surgical removal, was in 1886 by Reginald Heber Fitz of Harvard University.3 Notable advances in surgery for appendicitis include McBurney’s description of his classic muscle-splitting incision and technique for removal of the appendix in 1894 and the description of the first laparoscopic appendectomy by Kurt Semm in 1982.3 Laparoscopic appendectomy has become the preferred method for management of acute appendicitis among surgeons in the United States and may be accomplished using several (typically three) trocar sites or through single-incision laparoscopic surgical techniques. Finally, but of no less significance, was the development of broad-spectrum antibiotics, interventional radiologic techniques, and better surgical critical care strategies, all of which have resulted in substantial improvements in the care of patients with appendiceal perforation and its subsequent complications. 

Pathophysiology and Bacteriology Appendicitis is caused by luminal obstruction.3 The appendix is vulnerable to this phenomenon because of its small luminal diameter in relation to its length. Obstruction of the proximal lumen of the appendix leads to elevated pressure in the distal portion because of ongoing mucus secretion and production of gas by bacteria within the lumen. With progressive distention of the appendix, the venous drainage becomes impaired, resulting in mucosal ischemia. With continued obstruction, full-thickness ischemia ensues, which ultimately leads to perforation. Bacterial overgrowth within the appendix results from bacterial stasis distal to the obstruction.3 This is significant because this overgrowth results in the release of a larger bacterial inoculum in cases of perforated appendicitis. The time from onset of obstruction to perforation is variable and may range anywhere from a few hours to a few days. The presentation after perforation is also variable. The most common sequela is the formation of an abscess in the periappendiceal region or pelvis. On occasion, however, free perforation occurs that results in diffuse peritonitis.3 Because the appendix is an outpouching of the cecum, the flora within the appendix is similar to that found within the colon. Infections associated with appendicitis should be considered polymicrobial, and antibiotic coverage should include agents that

TABLE 51.1  Bacteria commonly isolated in

perforated appendicitis. TYPE OF BACTERIA

ISOLATES (N = 694)

Gram-Negative Bacteria Escherichia coli Pseudomonas aeruginosa Klebsiella pneumoniae Citrobacter species Enterobacter species Serratia marcescens Raoultella planticola Comamomas testosteroni Aeromonas species Proteus species Acinetobacter species Yersinia species Morganella species

448 (64.6%) 114 (16.4%) 37 (5.3%) 18 (2.6%) 10 (1.4%) 3 (0.4%) 3 (0.4%) 2 (0.3%) 2 (0.3%) 2 (0.3%) 1 (0.1%) 1 (0.1%) 1 (0.1%)

Gram-Positive Bacteria Enterococcus species Streptococcus species Staphylococcus species

27 (3.9%) 20 (2.9%) 5 (0.7%)

Adapted from Song DW, Park BK, Suh SW, et al. Bacterial culture and antibiotic susceptibility in patients with acute appendicitis. Int J Colorectal Dis. 2018;33:441–447.

address the presence of both gram-negative bacteria and anaerobes. Common isolates include Escherichia coli, Bacteroides fragilis, enterococci, Pseudomonas aeruginosa, Klebsiella pneumoniae, and others (Table 51.1).8 The choice and duration of antibiotic coverage and the controversies surrounding the need for cultures are discussed later in the chapter. The causes of the luminal obstruction are many and varied. These most commonly include fecal stasis and fecaliths but may also include lymphoid hyperplasia, neoplasms, fruit and vegetable material, ingested barium, and parasites such as ascaris or pinworm infestation. Pain associated with appendicitis has both visceral and somatic components. Distention of the appendix is responsible for the initial vague abdominal pain (visceral) often experienced by the affected patient. The pain typically does not localize to the right lower quadrant until the tip becomes inflamed and irritates the adjacent parietal peritoneum (somatic) or perforation occurs, resulting in localized peritonitis.3,9 

Differential Diagnosis Appendicitis must be considered in every patient (who has not had an appendectomy) who presents with acute abdominal pain.9 Knowledge of disease processes that may have similar presenting symptoms and signs is essential to avoid an unnecessary or incorrect operation. Consideration of the patient’s age and gender may help narrow the list of possible diagnoses. In children, other considerations include but are not limited to mesenteric adenitis (often seen after a recent viral illness), acute gastroenteritis, intussusception, Meckel diverticulitis, inflammatory bowel disease, and (in males) testicular torsion. Nephrolithiasis and urinary tract infection may be manifested with right lower quadrant pain in either gender.3,9 In women of childbearing age, the differential diagnosis is expanded even further. Gynecologic pathology may be mistaken for appendicitis and result in a higher negative appendectomy rate

CHAPTER 51  The Appendix than in male patients of comparable age. These processes include ruptured ovarian cysts, mittelschmerz (midcycle abdominal pain occurring with ovulation), endometriosis, ovarian torsion, ectopic pregnancy, and pelvic inflammatory disease.3,9 Two other patient populations deserve mention. In the elderly, consideration must be given to acute diverticulitis and malignant disease as possible causes of lower abdominal pain. In the neutropenic patient, typhlitis (also known as neutropenic enterocolitis) should also be considered within the differential diagnosis. Appendicitis in these special populations is discussed in greater detail later in the chapter. 

Presentation History Patients presenting with acute appendicitis typically complain of vague abdominal pain that is most commonly periumbilical in origin and reflects the stimulation of visceral afferent pathways through the progressive distention of the appendix. Anorexia is often present, as is nausea with or without associated vomiting. Either diarrhea or constipation may be present as well. As the condition progresses and the appendiceal tip becomes inflamed, resulting in peritoneal irritation, the pain localizes to its classic location in the right lower quadrant. This phenomenon remains a reliable symptom of appendicitis3,9 and should serve to further increase the clinician’s index of suspicion for appendicitis (Fig. 51.1). Whereas these symptoms represent the “classic” presentation of appendicitis, the clinician must be aware that the disease may be manifested in an atypical fashion. For example, patients with a retroperitoneal appendix may present in a more subacute manner, with flank or back pain, whereas patients with an appendiceal tip in the pelvis may have suprapubic pain suggestive of urinary tract infection.3,9 Although cases such as these are less common than the typical presentation, knowledge of these variations is essential to maintain the necessary index of suspicion to permit a prompt and accurate diagnosis.  Physical Examination Patients with appendicitis typically appear ill. They frequently lie still because of the presence of localized peritonitis, which makes any movement painful. Tachycardia and mild dehydration are often present to varying degrees. Fever is frequently present, ranging from low-grade temperature elevations (3%), as a high proliferative index portends a worse prognosis and also warrants right hemicolectomy for proper staging and treatment. The same is true for Grade 2 or greater tumors, or those showing lymphovascular or perineural invasion.45 After definitive treatment, measurement of serum chromogranin A serves as a useful tumor marker.45 Five-year survival rates based on Surveillance Epidemiology and End Results (SEER) data are 94% for confined disease, 84.6% for locoregional disease, and 33.7% when distant metastases are present.45,46 Adenocarcinoma of the appendix is rare and occurs at a frequency of 0.08% to 0.1% of all appendectomies.1 Treatment is identical to that of cecal adenocarcinoma and consists of right hemicolectomy with regional lymphadenectomy. In addition, recently published literature utilizing SEER data suggests that, as in staging of adenocarcinoma of the colon, retrieval of more than 12 lymph nodes may be associated with improved staging and subsequently improved survival.47

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Chemotherapy is also identical to that of adenocarcinoma of the colon with adjuvant administration of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) to selected patients. FOLFOX has also been used in the neoadjuvant setting in patients with mucinous adenocarcinoma before the implementation of cytoreductive (debulking) surgery. Mucinous tumors of the appendix, which account for less than 0.4% to 1% of gastrointestinal malignancies overall, are a rare and heterogeneous disease for which clinical management is changing.48 Low-grade appendiceal mucinous neoplasms (AMNs) are often diagnosed incidentally at appendectomy, where advancedstage AMNs may present with advanced-stage disease and associated pseudomyxoma peritonei (PMP).48,49 Early classification schemes considered AMN a benign disease, with different terminologies including appendiceal mucocele, cystadenoma, and cystadenocarcinoma.48 Criteria for simple mucoceles were developed and distinguished from those of malignant histologies; however, intermediate-grade lesions were also identified that were more difficult to accurately characterize. Mucinous appendiceal tumors, if ruptured, can result in intraperitoneal spread and the development of PMP. Of note, it is now recommended that PMP be a term used to describe the existence of mucinous ascites and not be considered a histologic diagnosis itself.48,49 Classification and nomenclature of these lesions have been confusing and not universally agreed upon.1,48 The most important distinction is between that of lesions that behave in a benign manner and those that have a more malignant course. Of note, it is thought that these tumors represent a spectrum of disease and that more aggressive malignant tumors likely evolved from lower grade tumors that were previously present (much like the polypcancer sequence seen in carcinoma of the colon), rather than arising de novo. It is also important to note that all AMNs may result in PMP regardless of their malignant potential.48 A number of changes in nomenclature and classification have emerged recently. First of all, the term “low-grade AMN” has replaced the term “benign mucocele.” Also of note is the widely accepted Ronnet classification, which bases the nomenclature of AMNs primarily on cellularity, differentiation, and likelihood of malignant behavior.48 The Ronnet scheme divides more clinically advanced AMNs into three major variants: disseminated peritoneal adenomucinosis (DPAM), peritoneal mucinous carcinomatosis (PMCA), and PMCA of indeterminant or discordant features.48 The clinical course is highly variable among the three variants. Patients with DPAM have an indolent course without distant extraperitoneal spread, whereas patients with PMCA are far more likely to develop metastasis to lymph nodes and extraperitoneal organs, thus suffering a worse prognosis. The behavior of the intermediate category has a more unpredictable course, with authors reporting clinical courses similar to both DPAM and PMCA in individual

patients, suggesting that other factors yet to be identified may be present which affect the prognosis and outcome.47 Treatment of AMNs varies according to histology and presentation. Low-grade AMNs less than 2 cm are treated adequately with appendectomy alone (with excision of the mesoappendix), with right hemicolectomy reserved for cases in which a positive margin is present, involvement of the appendiceal base, those exhibiting extra appendiceal extension, or those with invasive histology (adenocarcinoma) on final pathologic examination.48 If PMP or peritoneal metastases are present or subsequently develop, additional therapeutic measures are warranted. First of all, because PMP results as a consequence of perforation and direct peritoneal seeding from the appendiceal contents, the surgeon should use great caution to avoid rupturing an intact appendix if a mucocele or mucinous neoplasm is suspected on preoperative imaging or diagnosed intraoperatively. If PMP or peritoneal metastases occur, treatment by extensive cytoreductive surgery combined with heated intraperitoneal chemotherapy (CRS-HIPEC) is typically employed and is associated with improved, often long-term survival.48,49 Systemic chemotherapy may also be used in combination with HIPEC at the discretion of the treating oncologist, with 5-fluorouracil–based therapies as the mainstay of adjuvant treatment.48 Although the complexity of CRS-HIPEC precludes its complete discussion in this chapter, a brief description is provided for completeness. The goal of the operation is first to physically remove all tumor burden that can be possibly removed at operation, with the goal being to remove all macroscopic tumor via peritoneal stripping and excision of involved organs. This may involve omental excision, hysterectomy, colectomy, splenectomy, cholecystectomy, liver capsulectomy, and peritonectomy of the parietal, diaphragmatic, and pelvic surfaces. Heated chemotherapy (40.0°C) is then instilled into the peritoneal space and allowed to dwell. Mitomycin C is the most commonly used agent, although cisplatin and oxaliplatin are also sometimes administered.48 The goal is to achieve maximum eradication of residual tumor burden while limiting systemic toxicity by administering the chemotherapy locally. These are extremely complex and difficult operations; operative times of 10 hours are not unusual.49 Long-term survival with this approach is not unusual and is dependent on the presence of other metastases, histologic grade of the primary tumor, adequacy of cytoreduction, and response to chemotherapy.48 An excellent algorithm for the management of the incidentally identified appendiceal mass was proposed by Wray and colleagues, and a modified version is provided for review (Fig. 51.12).1 This algorithm is useful both in cases of appendicitis and in cases in which an appendiceal tumor is identified incidentally. The availability of frozen-section diagnosis may provide additional help with intraoperative decision making.

CHAPTER 51  The Appendix

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APPROACH TO PATIENT WITH APPENDICEAL NEOPLASM

Tumor detected at operation

Yes

No

Tumor >2 cm

Tumor found after appendectomy

Yes

Adenocarcinoma

No

R hemicolectomy

Is base or mesoappendix involved?

Yes

Appendiceal neuroendocrine neoplasm (ANEN)

R hemicolectomy

Tumor 2 cm

Observation

R hemicolectomy

Low-grade AMN (LAMN)

Aggressive behavior (DPAM/PMCA)

Margin +, involves base, >2 cm, involves mesoappendix

R colectomy consider CRS-HIPEC +/adjuvant chemotherapy

Tumor 1–2 cm

No

R hemicolectomy

Perforation? Lymphovascular invasion or involvement of mesoappendix

Yes

No

Evidence of mucin spillage or mucinous ascites

Yes

Appendiceal mucinous neoplasm (AMN)

Appendectomy

Yes

No

R hemicolectomy

Appendectomy

Yes

No

R hemicolectomy

Observation

No

Appendectomy Appendectomy Peritoneal lavage Consider referral for cytoreductive surgery/intraperitoneal chemotherapy (CRS-HIPEC) Note: All patients with appendiceal neoplasm should undergo routine colonoscopy.

FIG. 51.12  Suggested algorithm for managing the patient with an appendiceal neoplasm. DPAM, Disseminated peritoneal adenomucinosis; PMCA, peritoneal mucinous carcinomatosis.

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SELECTED REFERENCES

REFERENCES

Di Saverio S, Birindelli A, Kelly MD, et  al. WSES Jerusalem guidelines for diagnosis and treatment of acute appendicitis. World J Emerg Surg. 2016;11:34. Gorter RR, Eker HH, Gorter-Stam MA, et al. Diagnosis and management of acute appendicitis. EAES Consensus Development Conference 2015. Surg Endosc. 2016;30:4668–4690.

1. Wray CJ, Kao LS, Millas SG, et al. Acute appendicitis: controversies in diagnosis and management. Curr Probl Surg. 2013;50:54–86. 2. Addiss DG, Shaffer N, Fowler BS, et al. The epidemiology of appendicitis and appendectomy in the United States. Am J Epidemiol. 1990;132:910–925. 3. Prystowsky JB, Pugh CM, Nagle AP. Current problems in surgery. Appendicitis. Curr Probl Surg. 2005;42:688–742. 4. Randal Bollinger R, Barbas AS, Bush EL, et  al. Biofilms in the large bowel suggest an apparent function of the human vermiform appendix. J Theor Biol. 2007;249:826–831. 5. Girard-Madoux MJH, Gomez de Aguero M, Ganal-Vonarburg SC, et al. The immunological functions of the appendix: an example of redundancy? Semin Immunol. 2018;36:31–44. 6. Ugge H, Udumyan R, Carlsson J, et al. Appendicitis before age 20 years is associated with an increased risk of later prostate cancer. Cancer Epidemiol Biomarkers Prev. 2018;27: 660–664. 7. Deshmukh S, Verde F, Johnson PT, et  al. Anatomical variants and pathologies of the vermix. Emerg Radiol. 2014;21:543–552. 8. Song DW, Park BK, Suh SW, et al. Bacterial culture and antibiotic susceptibility in patients with acute appendicitis. Int J Colorectal Dis. 2018;33:441–447. 9. Silen W. Cope’s Early Diagnosis of the Acute Abdomen. 22nd ed. New York: Oxford University Press; 2010. 10. Andersson RE. Meta-analysis of the clinical and laboratory diagnosis of appendicitis. Br J Surg. 2004;91:28–37. 11. Di Saverio S, Birindelli A, Kelly MD, et al. WSES Jerusalem guidelines for diagnosis and treatment of acute appendicitis. World J Emerg Surg. 2016;11:34. 12. Gorter RR, Eker HH, Gorter-Stam MA, et  al. Diagnosis and management of acute appendicitis. EAES Consensus Development Conference 2015. Surg Endosc. 2016;30:4668–4690. 13. Alvarado A. A practical score for the early diagnosis of acute appendicitis. Ann Emerg Med. 1986;15:557–564. 14. Parks NA, Schroeppel TJ. Update on imaging for acute appendicitis. Surg Clin North Am. 2011;91:141–154. 15. Partain KN, Patel A, Travers C, et  al. Secondary signs may improve the diagnostic accuracy of equivocal ultrasounds for suspected appendicitis in children. J Pediatr Surg. 2016;51:1655–1660. 16. Sola R Jr, Theut SB, Sinclair KA, et al. Standardized reporting of appendicitis-related findings improves reliability of ultrasound in diagnosing appendicitis in children. J Pediatr Surg. 53:984–987. 17. Barger Jr RL, Nandalur KR. Diagnostic performance of magnetic resonance imaging in the detection of appendicitis in adults: a meta-analysis. Acad Radiol. 2010;17:1211–1216. 18. Solomkin JS, Mazuski JE, Bradley JS, et  al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis. 2010;50:133–164. 19. Sartelli M, Chichom-Mefire A, Labricciosa FM, et  al. The management of intra-abdominal infections from a global perspective: 2017 WSES guidelines for management of intraabdominal infections. World J Emerg Surg. 2017;12:29.

These two recently published consensus statements provide a comprehensive review of the current literature and expert opinion relating to all aspects of the diagnosis and treatment of appendicitis.

Findlay JM, Kafsi JE, Hammer C, et al. Nonoperative management of appendicitis in adults: a systematic review and metaanalysis of randomized controlled trials. J Am Coll Surg. 2016;223:814–824 e812. This meta analysis provides a comprehensive review of one of the most interesting and controversial topics relating to the treatment of appendicitis today: the concept of nonoperative management. The highest quality trials to date are analyzed in detail via statistical methods that define the strengths and weaknesses of a nonoperative treatment strategy and accentuate the need for largescale randomized controlled trials to further investigate this evolving topic.

Moris D, Tsilimigras DI, Vagios S, et  al. Neuroendocrine neoplasms of the appendix: A review of the literature. Anticancer Res. 2018;38:601–611. This comprehensive and authoritative review details the newest classification of neuroendocrine neoplasms of the appendix. In addition, the most current information regarding treatment, follow-up, and prognosis is provided in detail.

Shaib WL, Assi R, Shamseddine A, et  al. Appendiceal mucinous neoplasms: diagnosis and management. Oncologist. 2017;22:1107–1116. This recently published authoritative review details the current literature on the diagnosis, classification, treatment, and prognosis of mucinous neoplasms of the appendix, including the role of initial surgical therapy and subsequent adjuvant strategies, and the role of adjuvant chemotherapy and heated intraperitoneal chemotherapy (HIPEC).

Silen W. Cope’s Early Diagnosis of the Acute Abdomen. 22nd ed. New York: Oxford University Press; 2010. This classic text, now in its 22nd edition, provides a masterful overview of the differential diagnoses and subtle historical findings of appendicitis and related disease. It is a timeless source of wisdom and is considered a “must read” by many surgeons.

CHAPTER 51  The Appendix 20. Ingraham AM, Cohen ME, Bilimoria KY, et al. Comparison of outcomes after laparoscopic versus open appendectomy for acute appendicitis at 222 ACS NSQIP hospitals. Surgery. 2010;148:625–635; discussion 635–627. 21. Deelder JD, Richir MC, Schoorl T, et  al. How to treat an appendiceal inflammatory mass: operatively or nonoperatively? J Gastrointest Surg. 2014;18:641–645. 22. Puapong D, Lee SL, Haigh PI, et  al. Routine interval appendectomy in children is not indicated. J Pediatr Surg. 2007;42:1500–1503. 23. Al-Kurd A, Mizrahi I, Siam B, et  al. Outcomes of interval appendectomy in comparison with appendectomy for acute appendicitis. J Surg Res. 2018;225:90–94. 24. Raval MV, Lautz T, Reynolds M, et al. Dollars and sense of interval appendectomy in children: a cost analysis. J Pediatr Surg. 2010;45:1817–1825. 25. Schwartz JA, Forleiter C, Lee D, et  al. Occult appendiceal neoplasms in acute and chronic appendicitis: a singleinstitution experience of 1793 appendectomies. Am Surg. 2017;83:1381–1385. 26. Furman MJ, Cahan M, Cohen P, et al. Increased risk of mucinous neoplasm of the appendix in adults undergoing interval appendectomy. JAMA Surg. 2013;148:703–706. 27. Garlipp B, Arlt G. Laparoscopy for suspected appendicitis. Should an appendix that appears normal be removed? Chirurg. 2009;80:615–621. 28. Lee M, Paavana T, Mazari F, et al. The morbidity of negative appendicectomy. Ann R Coll Surg Engl. 2014;96:517–520. 29. Varadhan KK, Neal KR, Lobo DN. Safety and efficacy of antibiotics compared with appendicectomy for treatment of uncomplicated acute appendicitis: meta-analysis of randomised controlled trials. BMJ. 2012;344:e2156. 30. Mason RJ, Moazzez A, Sohn H, et al. Meta-analysis of randomized trials comparing antibiotic therapy with appendectomy for acute uncomplicated (no abscess or phlegmon) appendicitis. Surg Infect (Larchmt). 2012;13:74–84. 31. Di Saverio S, Sibilio A, Giorgini E, et  al. The NOTA Study (Non Operative Treatment for Acute Appendicitis): prospective study on the efficacy and safety of antibiotics (amoxicillin and clavulanic acid) for treating patients with right lower quadrant abdominal pain and long-term follow-up of conservatively treated suspected appendicitis. Ann Surg. 2014;260:109–117. 32. Svensson JF, Patkova B, Almstrom M, et  al. Nonoperative treatment with antibiotics versus surgery for acute nonperforated appendicitis in children: a pilot randomized controlled trial. Ann Surg. 2015;261:67–71. 33. Salminen P, Paajanen H, Rautio T, et  al. Antibiotic therapy vs appendectomy for treatment of uncomplicated acute

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appendicitis: the APPAC Randomized Clinical Trial. JAMA. 2015;313:2340–2348. 34. Findlay JM, Kafsi JE, Hammer C, et al. Nonoperative management of appendicitis in adults: a systematic review and meta-analysis of randomized controlled trials. J Am Coll Surg. 2016;223:814–824.e812. 35. Giuliano V, Giuliano C, Pinto F, et al. Chronic appendicitis “syndrome” manifested by an appendicolith and thickened appendix presenting as chronic right lower abdominal pain in adults. Emerg Radiol. 2006;12:96–98. 36. Teli B, Ravishankar N, Harish S, et al. Role of elective laparoscopic appendicectomy for chronic right lower quadrant pain. Indian J Surg. 2013;75:352–355. 37. Teixeira PG, Demetriades D. Appendicitis: changing perspectives. Adv Surg. 2013;47:119–140. 38. Wen SW, Hernandez R, Naylor CD. Pitfalls in nonrandomized outcomes studies. The case of incidental appendectomy with open cholecystectomy. JAMA. 1995;274:1687–1691. 39. Wang HT, Sax HC. Incidental appendectomy in the era of managed care and laparoscopy. J Am Coll Surg. 2001;192:182–188. 40. Brown JJ, Wilson C, Coleman S, et  al. Appendicitis in pregnancy: an ongoing diagnostic dilemma. Colorectal Dis. 2009;11:116–122. 41. McGory ML, Zingmond DS, Tillou A, et al. Negative appendectomy in pregnant women is associated with a substantial risk of fetal loss. J Am Coll Surg. 2007;205:534–540. 42. Khandelwal A, Fasih N, Kielar A. Imaging of acute abdomen in pregnancy. Radiol Clin North Am. 2013;51:1005–1022. 43. Pearl JP, Price RR, Tonkin AE, et  al. SAGES guidelines for the use of laparoscopy during pregnancy. Surg Endosc. 2017;31:3767–3782. 44. Rodrigues FG, Dasilva G, Wexner SD. Neutropenic enterocolitis. World J Gastroenterol. 2017;23:42–47. 45. Moris D, Tsilimigras DI, Vagios S, et al. Neuroendocrine neoplasms of the appendix: a review of the literature. Anticancer Res. 2018;38:601–611. 46. Modlin IM, Sandor A. An analysis of 8305 cases of carcinoid tumors. Cancer. 1997;79:813–829. 47. Fleischmann I, Warschkow R, Beutner U, et al. Improved survival after retrieval of 12 or more regional lymph nodes in appendiceal cancer. Eur J Surg Oncol. 2017;43:1876–1885. 48. Shaib WL, Assi R, Shamseddine A, et al. Appendiceal mucinous neoplasms: diagnosis and management. Oncologist. 2017;22:1107–1116. 49. Mittal R, Chandramohan A, Moran B. Pseudomyxoma peritonei: natural history and treatment. Int J Hyperthermia. 2017;33:511–519.

52

CHAPTER

Colon and Rectum Susan Galandiuk, Uri Netz, Emilio Morpurgo, Sara Maria Tosato, Naim Abu-Freha, C. Tyler Ellis

OUTLINE Embryology of the Colon and Rectum Anatomy of the Colon, Rectum, and Pelvic Floor Colon Anatomy Rectal Anatomy Physiology of the Colon Absorption of Fluid and Electrolytes Secretion Urea Recycling Recycling Bile Salts Colonic Flora, Fermentation, and Short-Chain Fatty Acids Probiotics and Prebiotics Colonic Motility Defecation Preoperative Evaluation Nutritional and Risk Assessment Preoperative Bowel Preparation Planning Intestinal Stomas Colostomy Ileostomy Enhanced Recovery Protocols Preoperative Interventions Preadmission Nutrition and Bowel Preparation Perioperative Interventions Postoperative Interventions Diverticular Disease Background Pathophysiology and Epidemiology Clinical Evaluation Management Special Populations Large Bowel Obstruction Diagnosis and Assessment Treatment Colonic Pseudo-Obstruction Diagnosis Management Inflammatory Bowel Disease Epidemiology and Etiology Disease Distribution and Classification Clinical Presentation and Disease Diagnosis Biologics in the Treatment of Inflammatory Bowel Disease Assessment of Symptom Severity Indications for Surgery for Ulcerative Colitis Indications for Surgery for Crohn Disease Surgical Options for Ulcerative Colitis Surgery for Crohn Disease

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Cancer Risk Postoperative Complications Postoperative Recurrence Infectious Colitis Clostridium difficile Infection Epidemiology Microbiology and Transmission Risk Factors Clinical Presentation Diagnosis Treatment Other Colonic Infections Ischemic Colitis Anatomic Considerations Risk Factors Presentation and Diagnosis Treatment Neoplasia Colorectal Cancer Genetics Epithelial-Mesenchymal Transition Consensus Molecular Subtypes Colorectal Polyps Nonneoplastic Polyps Serrated Polyps Neoplastic Polyps Malignant Polyps Postpolypectomy Surveillance Hereditary Cancer Syndromes Familial Adenomatous Polyposis MUTYH-Associated Polyposis Peutz-Jeghers Syndrome Juvenile Polyposis Syndrome Lynch Syndrome Staging Rules for Classification Clinical Staging Pathologic Staging Additional Prognostic Factors Surgical Treatment of Colorectal Cancer General Rules and Principles Surgical Technique Obstructing Colon Cancers Management of Left-Sided Obstructions Management of Right-Sided Obstructions Rectal Cancer Preoperative Evaluation of Patients With Rectal Cancer Local Excision

CHAPTER 52  Colon and Rectum Resections for Rectal Cancers Low Anterior Resection Sphincter-Sparing Surgery Procedures for Low Rectal Cancers Transanal Total Mesorectal Excision Abdominoperineal Resection Special Circumstances Complications Please access Elsevier eBooks for Practicing Clinicians to view the videos for this chapter https://expertconsult.inkling.com/. Acknowledgments: Josè Adolfo Navarro, MD; Silvia Neri, MD; and Alberto Morabito, MD.

EMBRYOLOGY OF THE COLON AND RECTUM A sound knowledge base of the gastrointestinal (GI) tract embryologic development is important in understanding colon and rectal anatomy and pathophysiology. The primitive gut tube is formed from the endodermal roof of the yolk sac. Early in the development process, beginning in the third week of gestation, the gut tube divides into three sections: the foregut, midgut, and hindgut (Fig. 52.1). The foregut forms the oral (buccopharyngeal) membrane, esophagus, stomach, and proximal duodenum (to the duodenal ampulla) and is supplied by the celiac artery. The midgut, including the distal part of the duodenum, small intestine, right colon, and the proximal two thirds of the transverse colon, receives it blood supply from the superior mesenteric artery (SMA). The midgut temporarily herniates ventrally out of the abdomen, a key step in the physiologic development progress for acquiring length and correct positioning of its structures (Fig. 52.2). The hindgut develops into the distal third of the transverse colon, descending colon, sigmoid, and rectum all the way to the upper anal canal. It is supplied by the inferior mesenteric artery (IMA). The venous

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Postoperative Treatment and Follow-up Pelvic Floor Disorders and Constipation Diagnosis: Testing and Evaluation Rectal Prolapse (Procidentia) Solitary Rectal Ulcer Rectocele Constipation and lymphatic networks develop parallel to their corresponding sectional arteries. The embryologic development of the rectum is complex and prone to developmental complications (see Chapter 67, Pediatric Surgery). The proximal rectum develops similar to the colon. The distal regions develop from the terminal hindgut that enters into the cloaca (an endoderm-lined cavity in contact with the surface ectoderm at the cloacal membrane). Prior to 5 weeks, the intestinal and urogenital tracts terminate at a common cavity in the cloaca. During the next few weeks, the urorectal septum migrates caudally and divides the cloaca into an anterior urogenital sinus and posterior distal rectum and anal sinus (Fig. 52.3). The urorectal septum fusion with the cloacal membrane is represented in the adult by the perineal body. The external anal sphincter is formed by the posterior part of the cloacal sphincter, whereas the internal anal sphincter is formed from enlarging circular fibers of the rectum. The upper two thirds of the anal canal are derived from the hindgut and the lower third from the proctodeum. The dentate line marks the fusion of endodermal (hindgut) and ectodermal depression (proctodeum). The anal transition zone is formed from the cloacal part of the anal canal. The hindgut part of the anal canal is supplied by the IMA, while the lower third, by the internal pudendal artery. 

ANATOMY OF THE COLON, RECTUM, AND PELVIC FLOOR The large bowel including the colon and rectum is a tube of variable diameter, approximately 150 cm in length (Fig. 52.4).

Colon Anatomy Heart

Pharynx Aorta

Stomodeum

Esophageal region Gastric and duodenal regions

Septum transversum

Celiac trunk

Omphaloenteric duct and vitelline artery

Primordium of liver

Allantois

Superior mesenteric artery to midgut

Anal pit

Inferior mesenteric artery

Cloacal membrane Cloaca

Hindgut

FIG. 52.1  Median section of the embryo showing the early alimentary system and its blood supply (week 4). (From Moore KL, Persaud TVN, Torchia MG. Alimentary system. In: The Developing Human. 11th ed. Philadelphia: Elsevier; 2020:193–221.)

The cecum is the saccular beginning of the colon, with an average diameter of 7.5 cm and a length of 10 cm. It has no mesentery and is completely covered with peritoneum and is therefore considered an intraperitoneal structure. The cecum is variably connected to the posterior abdominal wall by a peritoneal reflection. Patients with an abnormally mobile cecum and ascending colon, found in a small proportion of patients, can be predisposed to volvulus (torsion) or cecal bascule (intermittent anterior and superior folding of the cecum associated with obstructive symptoms). The cecum has a thin wall compared to the rest of the colon, and considering its large diameter, in accordance with the law of Laplace, it is the site most likely to perforate in the presence of large bowel obstructions. Although it is distensible, acute dilation of the cecum to a diameter of more than 12 cm, which can be measured on a plain abdominal radiograph, is associated with risk of ischemic necrosis and perforation of the bowel wall and should be treated promptly, usually with surgery. The terminal ileum empties into the cecum along its medial border through the ileocecal valve, a thickened, nipple-shaped invagination containing circular muscle. In cases of large bowel obstruction, the ileocecal valve is clinically important. An ileocecal valve that does not allow reflux of colonic contents into the ileum (competent ileocecal valve) can result in a closed-loop

1322

SECTION X  Abdomen

obstruction, a surgical emergency, whereas a valve that allows retrograde flow into the ileum (incompetent ileocecal valve) will result in less colonic distension and a less acute clinical scenario. The vermiform appendix extends from the cecum approximately 3 cm below the ileocecal valve as a blind-ending elongated tube, 8 to 10 cm in length (Fig. 52.5). It is most commonly found in a retrocecal position (65%), followed by pelvic (31%), subcecal (2.3%), preileal (1.0%), and retroileal (0.4%) locations. In the setting of inflammation and adhesions, locating the appendix can Amniotic cavity

be difficult. One can reliably reach its base by following the anterior taenia of the cecum to the convergence with the other two taeniae. The bloodless fold of Treves extends from the antimesenteric border of the terminal ileum to the base of the appendix or the anterior surface of the mesoappendix, or to both areas. This fold contains no sizable blood vessels. Since it is the only part of the ileum that has a fold on the antimesenteric side of the bowel, it can help in the recognition of the ileocecal region and the base of the appendix.

Proctodeum Body stalk

F

A

M

H

Allantois

B

C

D

FIG. 52.2  At the third week of development, the primitive tube can be divided into three regions (A): the foregut (F) in the head fold, the hindgut (H) with its ventral allantoic outgrowth in the smaller tail fold, and the midgut (M) between these two portions. Stages of development of the midgut are physiologic herniation (B), return to the abdomen (C), and fixation (D). (From Corman ML, ed. Colon and Rectal Surgery. 4th ed. Philadelphia: Lippincott-Raven; 1998:2.)

Allantois

Urorectal septum Urogenital sinus Genital tubercle

Urogenital sinus

Perineum

Cloaca Cloacal membrane

A

D

Urorectal septum

Cloacal membrane

B

Coronal fold of forming urorectal septum

Anorectal canal

C

Urorectal septum

Rupturing cloacal membrane

FIG. 52.3  Development of the distal rectum and anus. Progressive steps between 4 and 6 weeks in subdivision of the cloaca into a ventral primitive urogenital sinus and a dorsal anorectal canal (A–D). The urorectal septum is formed by the fusion of yolk sac extraembryonic mesoderm and allantois mesoderm, which produces a tissue wedge between the hindgut and urogenital sinus during craniocaudal folding of the embryo. As the tip of the urorectal septum approaches the cloacal membrane dividing the cloaca into the urogenital sinus and anorectal canal, the cloacal membrane ruptures, thereby opening the urogenital sinus and dorsal anorectal canal to the exterior. The tip of urorectal septum forms the perineum. A, B, and D, Sections through the cloacal and related endoderm-derived structures. C, Surface view of the caudal endoderm to better depict its three-dimensional shape. Curved arrows indicate the direction of growth of the developing urorectal septum. (From Schoenwolf GC, Bleyl SB, Brauer PR, et al. Larsen’s Human Embryology. 5th ed. Philadelphia, PA: Churchill Livingstone, an imprint of Elsevier; 2015.)

CHAPTER 52  Colon and Rectum

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First part of the duodenum Spleen Right lobe of the liver

Tail of pancreas

Hepatic flexure

Splenic flexure

Transverse colon

Superior taenia

Third part of the duodenum Right kidney

Left kidney Descending colon

Ascending colon Anterior taenia (libera) Anterior taenia (libera) Left iliac crest Caecum

Vermiform appendix

Sigmoid colon Rectum

FIG. 52.4  The large bowel includes the colon, consisting of ascending, transverse, descending, and sigmoid colon and the rectum, shown here in relation to neighboring anatomic structures. (From Standring S, Anand N, Rolfe B, et al. Gray’s Anatomy. 41st ed. Philadelphia: Elsevier; 2016.)

The ascending colon begins at the ileocecal junction and extends upward toward the hepatic flexure on the right side and is approximately 15 cm in length. The anterior and lateral surfaces are covered with peritoneum and are considered intraperitoneal, whereas the posterior surface is fixed against the retroperitoneum by the fascia of Toldt. The ascending colon is best mobilized along the lateral peritoneal reflection by incising the “white line of Toldt,” which represents the fusion of the peritoneum with the posterior fascia of the same name. When releasing the hepatic flexure and lifting the colon medially, one must be aware of the proximity of the second part of the duodenum, which can be inadvertently injured. The transverse colon, which is approximately 45 cm in length, is suspended between the hepatic and splenic flexures, which are fixed structures. It is completely covered by visceral peritoneum and connected to the posterior abdominal wall by the transverse mesocolon. It has a “U”-shaped curve, which can even reach down to the pelvis in some patients. Recognizing its variability in position is very important when attempting to exteriorize a loop of colon with a “target incision” for a transverse or sigmoid colostomy. The greater omentum is attached to the superior aspect of the transverse colon. It has two parts, the superior gastrocolic ligament composed of two serous layers, and the inferior portion, which is composed of four serous layers draping over the anterior abdominal cavity like an apron. Its size and volume are highly variable, although in most cases correlated with body weight. Lifting the greater omentum upward with downward traction of the transverse colon will reveal an avascular plane adjacent to the colon most easily identified close to the midline. This plane is useful when separating these two structures. The greater omentum

is commonly used to cover the intraperitoneal contents when closing abdominal incisions and also used to fill cavities after surgery helping to control infection. It also provides a good patch, or reinforcement, in cases when closure of inflamed and friable tissues is not possible or likely to fail, such as in the treatment of perforated duodenal ulcer. The omentum can be mobilized to create an omental pedicle that reaches the pelvis, by ligating and detaching either the right- or left-sided omental vessels, achieving extra omental length while the blood supply is adequately maintained by the distal arcade from the other side. Such an omental pedicle can be positioned between the rectum and vagina to buttress a colo- or rectovaginal fistula repair or used to fill the pelvic and perineal spaces after rectal excision. The splenic flexure, where the transverse colon flexes downward, is found adjacent and inferior to the spleen. It is usually situated higher and deeper than the right colic or hepatic flexure. The splenic flexure is suspended by four mainly avascular ligaments: by the phrenicocolic ligament to the diaphragm, by the splenocolic ligament to the lower pole of the spleen, by the renocolic ligament to the Gerota fascia, which surrounds the left kidney, and by the pancreaticocolic ligament to the tail of the pancreas. The splenic flexure can be released or mobilized without dividing any major blood vessels if one is separating the correct plane (Fig. 52.6). Surgeons commonly dissect the descending colon along the line of Toldt from below and then enter the lesser sac by lifting the omentum above the transverse colon. This maneuver allows mobilization of the flexure to be achieved, with minimal traction. Bleeding is most commonly encountered from excessive downward traction resulting in avulsion of a portion of the splenic capsule.

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SECTION X  Abdomen

Ileocolic artery Colic branch Ileal branch Superior mesenteric artery Posterior cecal artery Appendicular artery Anterior cecal artery Vascular fold of cecum Superior ileocecal recess Ileocecal fold (bloodless fold of Treves) Terminal part of ileum Inferior ileocecal recess Mesoappendix Appendicular artery Vermiform appendix Freetaenia (taenia libera)

Cecum

External iliac vessels (retroperitoneal) Retrocecal recess

Cecal folds Appendicular artery

Right paracolic gutter

Mesocolic taenia

Omental taenia Posterior cecal artery Cecal folds Retrocecal recess

Some variations in posterior peritoneal attachment of cecum Attached area

Lines of posterior peritoneal reflection

Attached area

Lines of posterior peritoneal reflection

Attached area

Lines of posterior peritoneal reflection

Attached area

FIG. 52.5  The appendix and mesoappendix in relation to the cecum and surrounding structures. (From Netter FH. Atlas of Human Anatomy. Philadelphia: Elsevier; 2019.)

Lines of posterior peritoneal reflection

CHAPTER 52  Colon and Rectum

Pancreas Pancreaticocolic ligament

Greater omentum Parietal peritoneum Descending colon Splenocolic ligament Spleen Kidney Vertebra

FIG. 52.6  Ligaments of the splenic flexure; the arrow indicates potential plane of dissection. (From Netz U, Galandiuk S. Clinical anatomy for procedures involving the small bowel, colon, rectum and anus. In: Fischer JE, Ellison EC, Upchurgh Jr. GR, et al., eds. Fischer’s Mastery of Surgery. 7th ed. Philadelphia: Wolter Kluwer; 2019.)

Sigmoid colon

Intersigmoid recess

Ureter

Descending colon

External iliac artery

FIG. 52.7  The intersigmoid recess, the sigmoid colon being retracted upward and to the right. (From Hollinshead WH. Anatomy for Surgeons. Vol 2, 2nd ed. New York: Harper and Row; 1971.)

The descending colon begins at the splenic flexure where the intestine loses its mesentery and extends downward on the left side of the abdomen approximately 25 cm until it transitions into the sigmoid colon. It is smaller in diameter than the ascending

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colon. The descending colon is similar to the ascending colon with regard to its peritoneal coverage and approach to dissection. The sigmoid colon begins at or below the level of the iliac crest, where the colon becomes completely intraperitoneal again, acquiring a mesentery covered on both sides with peritoneum. The sigmoid is thicker and more mobile compared to the descending colon varying in length from 15 to 50 cm (average, 38 cm). The mobile portion of the sigmoid colon is attached by the sigmoid mesocolon to the posterior abdominal wall and pelvis in the pattern of an inverted V creating the intersigmoid fossa (Fig. 52.7). When mobilizing the sigmoid colon, this mesenteric fold is a surgical landmark for the underlying left ureter. The sigmoid colon ends at the rectosigmoid junction, which is recognized as the point where the colonic taeniae confluence to form a complete longitudinal muscle layer, and the colon loses its mesentery, usually between the level of the sacral promontory and the S3 vertebra. Blood Supply, Lymphatic Drainage, and Innervation of the Colon Arterial blood supply. The anatomy of the blood supply is in accordance with the embryologic development of the GI tract. The celiac artery supplies the foregut, the SMA the midgut, and the IMA the hindgut. The colon receives its blood supply from the SMA and the IMA, both anterior branches of the abdominal aorta (Fig. 52.8). The SMA is the second unpaired anterior branch of the aorta, arising at the level of the lower border of the L1 vertebra, it descends posterior to the pancreas and then crosses anteriorly to the uncinate process of the pancreas and the third part of the duodenum and enters the mesentery of the bowel. On the left side, it provides up to 20 branches to the small intestine. On the right, it gives off three major branches to the colon. The first branch is the middle colic artery, arising near the inferior border of the pancreas, followed by the right colic and ileocolic arteries. The ileocolic artery is the most constant of these arteries. It runs toward the ileocecal junction within the mesentery giving off the anterior and posterior cecal arteries and the appendicular artery, supplying the terminal ileum, cecum, and appendix. The avascular space between the SMA and the ileocolic artery is a safe region to begin vascular dissection in a minimally invasive right colectomy and can also be used as a space through which one can pull the transverse or right colon through in cases of “retroileal” colorectal anastomoses to gain bowel length. The right colic artery, absent in up to 20%, usually arises from the SMA but may be a branch of the ileocolic or left colic vessels. The middle colic artery enters the transverse mesocolon and divides into right and left branches, which supply the proximal and distal transverse colon, respectively. When lifting the transverse colon, the middle colic artery can be tracked to the base of the mesentery just to the right of the ligament of Treitz, and into the proximal SMA. The middle colic artery is the main blood supply to the splenic flexure in about a third of the cases. The IMA is the third unpaired anterior artery arising from the aorta at the level of the L2–3 vertebrae approximately 3 cm above the aortic bifurcation. The IMA descends inferiorly and to the left giving off the left colic artery, followed by several sigmoid branches, and culminating in the superior rectal (hemorrhoidal) artery. The left colic artery divides into an ascending branch to the splenic flexure and a descending branch to the descending colon. The marginal artery of Drummond runs along the mesenteric margin of the colon from the cecocolic junction to the

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SECTION X  Abdomen

Ascending branch of left colic artery

Middle colic artery Superior mesenteric artery

Marginal artery

Right colic artery

Inferior mesenteric artery

Ileocolic artery Left colic artery

Ileal branch Anterior cecal branch

Sigmoid arteries

Median sacral artery Posterior cecal branch Left common iliac artery

Appendicular artery Internal iliac artery

Bifurcation of superior rectal artery

Accessory middle rectal artery Middle rectal artery Inferior rectal artery

FIG. 52.8  The arterial blood supply to the colon is from the superior and inferior mesenteric arteries. (From Gordon PH, Nivatvongs S, eds. Principles and Practice of Surgery for the Colon, Rectum and Anus. 2nd ed. St. Louis: Quality Medical Publishing; 1999:23.)

rectosigmoid junction. Vasa recta from this artery branch off at short intervals and supply the bowel wall directly. The marginal artery is important clinically for when one of the larger arteries is obstructed (emboli, atherosclerosis, surgical ligation, etc.). The colon can receive collateral blood supply through this artery. The meandering mesenteric artery, or “arc of Riolan,” is an uncommon finding described as a thick tortuous collateral vessel that runs close to the base of the mesentery and connects the SMA or middle colic artery to the IMA or left colic artery. It can have an important role in blood delivery in cases of SMA or IMA occlusion. Flow can be forward (IMA stenosis) or retrograde (SMA stenosis), depending on the site of obstruction. The presence of a large arc of Riolan suggests occlusion of one of the major mesenteric arteries.  Venous drainage. Venous drainage somewhat follows the arterial supply through the superior mesenteric and inferior mesenteric veins (IMVs), which contribute to the formation of the portal vein. It is important to note that the IMV continues beyond the IMA along the base of the mesentery to the left of the ligament

of Treitz and into the portal vein (Fig. 52.9). The IMV can be divided to achieve extra colonic length for low pelvic anastomoses.  Lymphatic system. Lymphatic drainage generally follows the vascular supply. The wall of the large bowel is supplied with a rich network of lymphatic capillaries that drain to groups of lymph nodes paralleling the arterial supply. Most of the lymphatic drainage goes in this direction, but communications are found between groups of lymph nodes, especially at the level of the paracolic groups at the level of the marginal arteries. There is also some dual drainage from the distal transverse and splenic flexure into both the superior and inferior mesenteric lymph nodes.  Innervation. The innervation of the large intestine has both sympathetic and parasympathetic components, which generally follow the blood supply. 

Rectal Anatomy The rectum begins at the rectosigmoid junction and ends at the level of the anus. Anatomists define the distal border as the dentate (pectinate) line based on the mucosal surface, whereas surgeons

CHAPTER 52  Colon and Rectum

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Superior pancreaticoduodenal vein Portal vein

Splenic vein

Superior mesenteric vein

Inferior mesenteric vein

Right colic vein

Left colic vein Ileocolic vein Testicular/ovarian veins

Superior mesenteric vein

Inferior vena cava

Sigmoid veins

Right common iliac vein Right internal iliac vein Right external iliac vein

Middle sacral vein Superior rectal vein

Middle rectal vein Internal pudendal vein

Inferior rectal vein

Internal hemorrhoidal plexus External hemorrhoidal plexus

FIG. 52.9  Venous anatomy of the colon and rectum. (From Gordon PH, Nivatvongs S, ed. Principles and Practice of Surgery for the Colon, Rectum and Anus. 2nd ed. St. Louis: Quality Medical Publishing; 1999:30.)

define it as the proximal border of the anal sphincter complex at the level of the levator ani (about 2 cm above the dentate line). The rectum with a total length of around 15 to 20 cm is divided into thirds based on its peritoneal relationships. The upper rectum is covered by peritoneum anteriorly and laterally and its lower limit extends to approximately 10 cm above the dentate line. The middle third is covered by peritoneum only anteriorly and extends from 5 to 10 cm above the dentate line. The lower third of the rectum is totally extraperitoneal, extending from 1 to 5 cm above the dentate line. The rectum has three lateral curves or valves of Houston, the proximal and distal valves fold to the right and the middle to the left. They are lost after full surgical mobilization of the rectum, providing approximately 5 cm of additional length assisting the surgeon’s ability to fashion an anastomosis deep in the pelvis. Structurally, the rectum lacks taeniae coli, epiploic appendices, and haustra. The anterior peritoneal reflection between the rectum and anterior structures, the rectovesicular pouch in males and rectouterine or Douglas pouch in females, is 7 to 9 cm from the anal verge in men and 5 to 7.5 cm in women (Fig. 52.10). The anterior peritoneal reflection is the lowest dependent part of the

peritoneal cavity. It is clinically important as a common location of fluid and pus accumulation and may serve as a site of peritoneal metastases from visceral tumors. These “drop” metastases can form a mass in the cul-de-sac (Blumer shelf ) that can be recognized on digital rectal examination. “Mesorectum” refers to the visceral mesentery of the rectum. Recognition of mesorectal planes during rectal surgery is extremely important as it allows for a relatively bloodless dissection with consistent excision of relevant lymphatic tissues, adhering to the basic surgical oncologic principle of removing the cancer in continuity with its blood and lymphatic supply. Total mesorectal excision (TME), based on a detailed understanding of anatomy, has been shown to reduce the incidence of local recurrence of rectal cancer and increase the preservation of urinary and sexual function. The mesorectum is relatively thick posteriorly, thinner along the sides, and very thin anteriorly. Anatomic structures adjacent to the rectum are clinically important with regard to dissection planes and to direct extension of tumors and/or fistulas. In males, the rectum is adjacent anteriorly and extraperitoneally to the urinary bladder, ureters, vas deferens, seminal vesicles, and prostate. In women, intraperitoneally, it is

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SECTION X  Abdomen

Peritoneum

Investing fascia of rectum

Presacral fascia

Rectosacral fascia

Denonvilliers fascia

FIG. 52.10  Fascial relationships of the rectum. (From Gordon PH, Nivatvongs S, ed. Principles and Practice of Surgery for the Colon, Rectum and Anus. 2nd ed. St. Louis: Quality Medical Publishing; 1999:10.)

adjacent to the uterus, tubes, ovaries, and to the upper part of the posterior vaginal wall. Extraperitoneally, the rectum is adjacent to the uterine cervix and posterior vaginal wall. In both genders, the intraperitoneal cul-de-sac is commonly filled with small bowel and colon. The sacrum, sacral vessels, and sacral nerve roots are located posterior to the rectum. The posterior aspect of the rectum is invested with a thick, closely applied mesorectum (Fig. 52.11). A thin layer of investing fascia (fascia propria) coats the mesorectum and represents a distinct layer from the presacral fascia against which it lies. During proctectomy for rectal cancer, mobilization and dissection of the rectum proceed between the presacral fascia and fascia propria. The presacral fascia covers the anterior sacrum and coccyx. A group of veins, on the presacral periosteum, the presacral veins, drain into the sacral foramina. Dissection deep to the presacral fascia can cause severe bleeding from the underlying presacral venous plexus. Such bleeding can be very difficult to control, as the torn vessels tend to withdraw into the sacral foramina. The rectosacral fascia, or Waldeyer fascia, is a thick condensation of endopelvic fascia connecting the presacral fascia to the fascia propria at the level of S4 that extends to the posterior-inferior rectum. Dividing Waldeyer fascia during dissection from an abdominal approach provides access to the deep retrorectal pelvis. Laterally, the rectum is connected to the pelvic sidewall by the “lateral stalks” or ligaments. These are found in the low pelvis at the level of the prostate or mid-vagina. It is important to remember that in about a quarter of the cases, a branch of the middle rectal artery traverses them and may cause bleeding when cutting through them.

Denonvilliers fascia, located anterior to the rectum, is a membranous layer that is an extension of the inferior peritoneal reflection and extends to the perineal body. This fascial layer separates the rectum from the previously mentioned anterior structures and is considered as the anterior border of a TME. Blood Supply, Lymphatic Drainage, and Innervation of the Rectum The blood supply to the rectum is derived from the superior, middle, and inferior rectal (hemorrhoidal) arteries. All three rectal arteries are connected with a strong anastomotic network, which helps avoid rectal ischemia after dividing the superior rectal arteries during anterior resections (Fig. 52.12). The superior rectal artery is the end branch of the IMA. It usually divides into left and right branches that run posteriorly downward. The middle rectal arteries are paired vessels derived from the internal iliac arteries to the lower rectum through the lateral columns. They are not considered a major blood supply to the rectum and are found inconstantly. They can be inadvertently injured when dissecting the lateral ligaments. The inferior rectal arteries are branches of the internal pudendal arteries and generally supply the anus distal to the dentate line. The superior rectal vein drains the upper two thirds of the rectum, draining into the IMV and portal system. The lower rectum and anus drain into the middle and inferior rectal veins, which are connected to the internal iliac and systemic circulation. This drainage pattern explains the higher rate of lung metastases observed with low rectal cancers as compared to mid and

CHAPTER 52  Colon and Rectum

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Seminal vesicles Bladder

Lateral ligaments Denonvillier fascia

Left middle rectal artery

Inferior hypogastric (pelvic) plexus Rectum

Mesorectum Right middle rectal artery Left and right branches of superior rectal artery Parasympathetic nervi erigentes

Right hypogastric nerve Presacral fascia

Presacral veins

FIG. 52.11  Cross-section of mesorectum and surrounding structures. (From Netz U, Galandiuk S. Clinical anatomy for procedures involving the small bowel, colon, rectum and anus. In: Fischer JE, Ellison EC, Upchurgh Jr. GR, et al., eds. Fischer’s Mastery of Surgery. 7th ed. Philadelphia: Wolter Kluwer; 2019.)

upper rectal cancers, which are much more likely to metastasize to the liver. The lymph from the upper two thirds of the rectum drains upward toward the inferior mesenteric and paraaortic nodes. The lower part of the rectum drains in two directions, cephalad toward the inferior mesenteric nodes and laterally and inferiorly toward the internal iliac nodes. Below the dentate line, lymph drains toward the inguinal lymph nodes. The sympathetic innervation of the rectum is derived from sympathetic nerves exiting at the level of L1–3, forming the superior hypogastric plexus (Fig. 52.13). At the level of the sacral promontory, they divide into left and right hypogastric nerves, traveling on both sides of the pelvis. These nerves supply the rectum and send branches to supply the genitourinary system anteriorly. When performing pelvic operations, it is important to be aware of these nerves and avoid injuring them if possible. A high IMA ligation injuring the superior hypogastric plexus or severing the hypogastric nerves near the sacral promontory may result in sympathetic dysfunction characterized by retrograde ejaculation in men. Division of the lateral stalks too close to the pelvic sidewall may injure the pelvic plexus and nervi erigentes and cause erectile dysfunction, impotence, and atonic bladder. Injury to the periprostatic plexus when dissecting anteriorly can also cause sexual and bladder dysfunction. 

Pelvic Floor Anatomy The pelvic floor or diaphragm supports the pelvic organs and, together with the anal sphincter, regulates defecation. The pelvic diaphragm resides between the sacrum, obturator fascia, ischial spines, and pubis. The levator ani muscle, which makes up the floor, consists of three subdivisions: the pubococcygeus, iliococcygeus, and the puborectalis (Fig. 52.14). The pubococcygeus forms the levator hiatus, which ellipses the top of the anal canal, urethra, and vagina in women and the dorsal vein in men. The puborectalis originates in the lower part of the symphysis pubis and courses

parallel to the anorectal junction, forming a U-shaped sling of striated muscle posterior to the rectum. The puborectalis is in a state of constant contraction, increasing the anorectal angle, a factor critical to the maintenance of fecal continence. Relaxation of the puborectalis straightens the anorectal angle and permits defecation. Puborectalis dysfunction is an important cause of defecation disorders. 

PHYSIOLOGY OF THE COLON Absorption of Fluid and Electrolytes The major functions of the colon are water absorption and electrolyte exchange. This process converts succus from the terminal ileus into formed stool that is stored in the rectal reservoir until it can be excreted at a convenient time. The body has the ability to adapt and sustain life without a colon, making it uniquely different to small bowel. The problems associated with colonic patients provide a simplistic view of colonic function—individuals with a diverting ileostomy are at particular risk for dehydration and electrolyte derangement. By surface area, the colon is the most efficient site of absorption in the GI tract. It has the ability to absorb up to 5 L of fluid per day; however, only 1 to 2 L are generally excreted from the ileum. By the time succus reaches the terminal ileum, most of the nutrients have been absorbed, leaving a mix of electrolyte-rich fluid, bile salts, and some proteins and starches that have resisted digestion. Approximately 90% of the fluid in succus is reabsorbed in the colon, and the total volume of water in stool is only ∼150 mL/day. The colon’s ability to absorb sodium is equally impressive. Succus in the ileum has a sodium concentration of 200 mEq/L that is reduced to approximately 30 mEq/L in rectal stool. Sodium and chloride are actively absorbed via Na+/H+, Na+/ K+, and Cl−/HCO3− exchange. Water is passively absorbed and follows sodium along an osmotic gradient. Potassium chloride and bicarbonate are actively secreted into the lumen. 

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SECTION X  Abdomen Median sacral artery and vein (from aorta and inferior vena cava)

Superior rectal artery and vein (from inferior mesenteric vessels)

Internal iliac vein

Left internal iliac artery

Common iliac vein Left common iliac artery Peritoneum

Obturator vein

Obturator artery

Superior vesical vein Umbilical artery

Communication between internal and external rectal plexus

Middle rectal artery Bladder

Middle rectal vein

Iliococcygeus (part of levator ani)

Inferior vesical vein Perimuscular rectal venous plexus Internal pudendal vein in pudendal canal

Obturator internus Internal pudendal artery and vein in pudendal canal Pubococcygeus (part of levator ani)

Inferior rectal vein

Inferior rectal artery and vein Ischioanal fossa Inferior pubic ramus

External anal sphincter

Internal rectal plexus

Subcutaneous part of external anal sphincter Internal anal sphincter

Pectinate line

External rectal plexus

Vasculature of the rectum (posterior view) FIG. 52.12  Vasculature of the rectum, posterior view. (From Drake RL, Vogl AW, Mitchell AWM, et al. Gray’s Atlas of Anatomy. 2nd ed. Philadelphia: Churchill Livingstone, an imprint of Elsevier; 2015.)

Secretion The physiologic role of colon secretion is demonstrated in patients with chronic renal failure. Uremic patients can remain normokalemic while ingesting a normal amount of potassium before requiring dialysis. This phenomenon is associated with a compensatory increase in colonic secretion and fecal excretion of potassium. Aldosterone promotes colonic potassium secretion, and this effect is blocked by spironolactone. Many forms of colitis are associated with increased potassium secretion, such as inflammatory bowel disease (IBD), cholera, and shigellosis. In addition, some forms of colitis impair colonic absorption or produce secretion of chloride, such as collagenous and microscopic colitis and congenital chloridorrhea. Chloride is secreted by colonic epithelium at a basal rate, which is increased in pathologic conditions such as cystic fibrosis and secretory diarrhea. Colonic secretion of H+ and bicarbonate is coupled to the absorption of Na+ and Cl−, respectively. It is through these exchangers that the colon is linked to systemic acid-base metabolism. The supply of H+ and bicarbonate for these exchangers is catalyzed

by colonic carbonic anhydrase. Changes in systemic pH induce changes in the activity of carbonic anhydrase, eliciting elimination of H+ or bicarbonate as needed to bring the systemic pH back to normal. 

Urea Recycling Colonic bacteria are rich in urease, which is important for urea recycling. Since mammalian cells do not produce urease, this process relies on the symbiotic relationship found in a healthy colonic lumen. Ammonia is the by-product of urea metabolism, and its absorption depends on the concentration of bacteria present and the intraluminal pH. Antibiotics and lactulose decrease the amount of ammonia absorbed by lowering the concentration of bacteria and reducing the pH, respectively. Absorbed ammonia is transported to the liver. Urea recycling is not beneficial in cases of liver failure. When the liver cannot reuse the urea nitrogen absorbed by the colon, ammonia crosses the blood-brain barrier and produces “false” neurotransmitters, which results in hepatic coma. 

CHAPTER 52  Colon and Rectum

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Prevertebral plexus Abdominal aorta Left lumbar sympathetic trunk

Right lumbar sympathetic trunk

Right common iliac artery Left common iliac artery Superior hypogastric plexus Gray ramus communicans

Right hypogastric nerve

Lumbosacral trunk

Sacral splanchnic nerves to inferior hypogastric plexus (postganglionic sympathetic)

Left hypogastric nerve Superior gluteal nerve Greater sciatic foramen

Superior gluteal nerve

Sacral splanchnic nerves to inferior hypogastric plexus (postganglionic sympathetic)

Pelvic splanchnic nerves (preganglionic parasympathetics from S2 to S4)

Pelvic splanchnic nerves (preganglionic parasympathetics from S2 to S4)

Inferior hypogastric plexus

Coccygeal plexus

Piriformis

Pudendal nerve Coccygeus (ischiococcygeus) Ganglion impar Iliococcygeus (part of levator ani) Pubococcygeus (part of levator ani)

Pelvic extensions of the prevertebral nerve plexus (anterior view) FIG. 52.13  Pelvic nerve plexus. (From Drake RL, Vogl AW, Mitchell AWM, et al. Gray’s Atlas of Anatomy. 2nd ed. Philadelphia: Churchill Livingstone, an imprint of Elsevier; 2015.)

Recycling Bile Salts The colon absorbs bile acids that escape absorption by the terminal ileum. Bile acids are passively transported across the colonic epithelium by nonionic diffusion. When the colonic ­absorptive capacity is exceeded, colonic bacteria deconjugate bile acids. Deconjugated bile acids can then interfere with

sodium and water absorption, leading to secretory, or choleretic, diarrhea. Choleretic diarrhea is seen early after right hemicolectomy as a transient phenomenon and more permanently after extensive ileal resection. This diarrhea can often be effectively treated by administration of cholestyramine, which binds to bile acids. 

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External anal sphincter

SECTION X  Abdomen

Subcutaneous Superficial Muscle fibers over central tendon of perineum Puborectalis

Levator ani

Pubococcygeus Ileococcygeus

Anococcygeal ligament Gluteus maximus

FIG. 52.14  The pelvic musculature and innervation from below. The deep anal sphincter muscles are hidden under the superficial part. (From Netz U, Galandiuk S. Clinical anatomy for procedures involving the small bowel, colon, rectum and anus. In: Fischer JE, Ellison EC, Upchurgh Jr. GR, et al., eds. Fischer’s Mastery of Surgery. 7th ed. Philadelphia: Wolter Kluwer; 2019.)

Colonic Flora, Fermentation, and Short-Chain Fatty Acids Large bowel contents have a concentration of 1011 to 1012 bacterial cells per gram, contributing approximately 50% of fecal mass. Over 400 bacterial species, mostly anaerobic, are present in the colon. Bacteroides species are obligate anaerobes that comprise two thirds of the total colonic bacteria. Other species commonly found in the colonic flora are the following facultative anaerobes: Escherichia, Klebsiella, Proteus, Lactobacillus, and Enterococci. These bacteria feed on proteins sloughed from the bowel wall and undigested complex carbohydrates. In turn, colonocytes and gutassociated lymphoid tissue rely on the colonic flora for nutrients. The main source of energy for intestinal bacteria is dietary fiber, composed of complex carbohydrates (i.e., starches and nonstarch polysaccharides). However, not all complex carbohydrates are fermented in the same manner. Dietary recommendations (i.e., “adding fiber”) generally refer to bulking agents, such as lignin and psyllium, which are nonabsorbable and nonfermentable by colonic bacteria. Bulking agents decrease intracolonic pressures and increase colonic transit time, which help prevent the formation of colonic diverticula and minimize colonic exposure to toxins. For the fermentable complex carbohydrates available, colonic flora produce short-chain fatty acids (SCFAs). Butyrate, an SCFA, is the principal source of nutrition for the colonocyte. Because mammalian cells do not produce butyrate, the colonic epithelium and luminal bacteria form an essential and elegant symbiotic relationship. Antibiotics disrupt this cohabitation—decreased bacteria leads to less butyrate, which, in turn, negatively affects colonocyte function leading to diarrhea. Likewise, mucosal atrophy is seen after fecal diversion (i.e., diversion colitis). The other

physiologic effects of SCFAs on the colon include stimulation of blood flow, mucosal cell renewal, and regulation of intraluminal pH for homeostasis of the bacterial flora. The role of SCFAs on homeostasis extends beyond the colon. Besides butyrate, two other SCFAs, acetate and propionate, are produced in the colon, with acetate being the most common of all three. Over 90% of the SCFAs produced are absorbed. Hepatocytes metabolize SCFAs for use in gluconeogenesis, and muscle cells oxidize acetate to generate energy. Additionally, acetate is the primary substrate for cholesterol synthesis. The production of acetate is reduced by nonabsorbable, nonfermentable dietary fiber, such as psyllium, which in turn has a beneficial effect on cholesterol levels. Similarly, propionate, which has a glycolytic role in the liver, may also lower serum lipid levels by inhibiting cholesterol synthesis. Butyrate may also play an important role in maintaining cellular health by arresting the proliferation of neoplastic colonocytes while paradoxically being trophic for normal colonocytes. The end products of fermentation are SCFAs and gas—carbon dioxide, methane, and hydrogen. In addition to nonstarch polysaccharides, colonic bacteria ferment poorly absorbed starches and proteins from the upper GI tract. Although highly variable from person to person, the gases produced by bacterial fermentation compose approximately 50% of flatus, with the remainder consisting of swallowed air. Protein fermentation (i.e., putrefaction) results in the formation of potentially toxic metabolites, including phenols, indoles, and amines. The production of these toxins is inhibited in intestinal bacteria by the presence of carbohydrate energy sources. This process becomes accentuated more distally in the colon as

CHAPTER 52  Colon and Rectum carbohydrate sources become scarcer. These end products of bacterial metabolism can lead to mucosal injury and reactive hyperproliferation, which have been hypothesized to promote carcinogenesis. 

Probiotics and Prebiotics Probiotics can be defined as dietary supplements that contain live cultures of bacteria and/or yeast that are beneficial to colonic and host function. The two most widely used agents are Lactobacillus and Bifidobacterium. Studies have indicated that probiotics may have widespread health benefits, including stimulation of immune function, anti-inflammatory effects, and suppression of enteropathogenic colonization.1 In addition, they may increase the digestibility of dietary proteins and enhance absorption of amino acids. Probiotics have been shown to prevent Clostridium difficile– associated diarrhea, but there are insufficient data to recommend probiotics for the primary prevention of C. difficile infection (CDI).1 Indications for probiotics use are evolving. Currently, there are a small number of studies to support the role of probiotics for the following colorectal conditions: necrotizing enterocolitis in neonates, ulcerative colitis (UC), pouchitis, and constipation. Further research is needed, but the evidence for probiotic use in various settings is encouraging. Prebiotics are nutrients that support the growth of probiotic bacteria. Prebiotics are nondigestible oligosaccharides (e.g., inulin) that help the host by stimulating the growth of certain species of beneficial intestinal bacteria. There is a growing body of data suggesting health benefits; however, there is currently little evidence to guide recommendations for their use. 

Colonic Motility In the colon, there is extrinsic and intrinsic innervation made up by the autonomic nervous system and enteric nervous system, respectively. The autonomic nervous system is comprised of parasympathetic and sympathetic innervation. Parasympathetic innervation is excitatory, and it reaches the colon via the vagus nerve and the rectum via the sacral nerves (S2–S4) through the pelvic plexus. Sympathetic innervation is, conversely, inhibitory. Sympathetic fibers originate from lumber ventral roots (L2–L5), postganglionic hypogastric nerves, and the splanchnic nerves (T5–T12), which reach the colon and rectum through perivascular plexuses (see also the section on Colon Anatomy). The intrinsic colonic nervous system consists of the myenteric (Auerbach) plexus and the submucosal (Meissner) plexus. These plexus regulate colonic motility, as well as colonic blood flow, a­ bsorption, and secretion. The interstitial cells of Cajal are the p ­ rimary pacemaker cells governing the function of the enteric nervous system and are important for colonic motility. Most motility is involuntary and is divided into two primary patterns: (1) low-amplitude propagated contractions (LAPCs) and (2) high-­amplitude propagated contractions (HAPCs). LAPCs allow mixing, which promotes optimal absorption and are bursts of short-duration contractions. HAPCs propagate colonic contents distally in a coordinated fashion, and their role lies in shifting large quantities of contents through the colon one to three times per day. Other factors affecting motility are circadian rhythms and food ingestion. 

Defecation Normal defecation requires adequate colonic transit time, stool consistency, and fecal continence. The frequency of defecation is just as variable among individuals as is their perception of abnormal stool frequency. The definitions of diarrhea and constipation

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differ by individual patients and providers; therefore, reporting stool frequency and consistency provides a clearer understanding of defecation patterns. Many factors influence colonic transit rate. Colonic transit is longer in women than in men and longer in premenopausal than in postmenopausal women. Supplementation with nonstarch polysaccharides shortens colonic transit time in individuals with idiopathic constipation. 

PREOPERATIVE EVALUATION Nutritional and Risk Assessment Over the last 20 years since the original work on the National Veterans’ Administration Surgical Risk Study, few parameters have been as reliable at predicting postoperative complications as the preoperative serum albumin level. Unfortunately, this laboratory value is seldom obtained preoperatively in elective surgery patients and therefore needs to be explicitly ordered. There are numerous preoperative indices such as POSSUM, CR-POSSUM, and the ACS-NSQIP calculators and others that have been used to predict operative risk. If operating on a patient with a condition such as diverticulitis, or IBD, the addition of an inflammatory marker such as C-reactive protein (CRP) may be beneficial. In general, patients with an albumin less than 3 are considered higher risk. Some studies suggest that preoperative correction of risk factors may result in improved postoperative outcomes. There is a growing field of immunonutrition suggesting that consumption of nutritional supplements rich in arginine may, in fact, boost the immune system and lead to a reduction in postoperative infectious complications, such as surgical site infection (SSI).2 Patients who are at particularly high risk are those who have chronic partial bowel obstruction and cancer and those who have lost a significant amount of weight (greater than 10% of body weight) in unintentional weight loss. 

Preoperative Bowel Preparation As human feces can have as much as 1012 bacteria/gram, colon surgery has been associated with a higher rate of SSI than small bowel and upper GI surgery. Issues of antibiotic prophylaxis have focused upon the choice of an antibiotic with an appropriate spectrum, administration prior to making the surgical incision, and discontinuation of the antibiotic postoperatively. Over the last 20 years, performing or omitting preoperative bowel preparation has been a cyclical phenomenon. The reader is referred to the American Society of Colon & Rectal Surgeons’ Clinical Practice Guidelines for the Use of Bowel Preparation in Elective Colon and Rectal Surgery for a more in-depth coverage of this issue. Studies suggest that mechanical bowel preparation alone is not beneficial prior to colon resection. These recommendations were based upon findings that bowel preparation generally led to fluid and electrolyte abnormalities that, in turn, led to large volumes of fluid administration during surgery and subsequent bowel edema and ileus. In addition, bowel preparation is poorly tolerated in the elderly and in those with multiple medical comorbidities. Lower volume bowel preparations generally have higher patient compliance. Higher rates of spillage of liquid as opposed to more formed stool at the time of surgery following mechanical bowel preparation was thought to be the cause of the higher observed rates of SSI. However, for many surgeons performing rectal resection, either with minimally invasive or open techniques, particularly when inserting intraluminal staplers for the purpose of creating intestinal anastomoses, it was felt to be more convenient and safer

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SECTION X  Abdomen

to have the large bowel free of solid particulate matter. Recently, large administrative database studies have demonstrated that the combination of a mechanical and an oral antibiotic bowel preparation is associated with a very low rate of postoperative infectious complications in patients undergoing colorectal surgery. Generally, many surgeons believe that a formal mechanical bowel preparation is not required for patients undergoing surgery for IBD since these patients are already having numerous liquid bowel movements. Bowel preparation is also not used for patients with partial obstruction. 

Planning Intestinal Stomas When operating on a patient in whom there may be a need for a diverting stoma (e.g., patients with Crohn disease, diverticular ­disease, intestinal obstruction, and low rectal cancer), it is always wise to mark the patient for a preoperative stoma site. Most ­patients do not have an ideal abdomen. The area of the abdomen that usually is chosen for a stoma, the infraumbilical fat mound (Fig. 52.15), may not look the same in a patient who is sitting up as it does when they are recumbent. In many patients, there are skin folds that may prevent a stoma bag from sealing properly. It is essential to mark the patients in a sitting position and to avoid old scars and any skin folds that may interfere with adherence of a stoma appliance. Fig. 52.16 shows how important it is to avoid skin folds that would interfere with a normal adherence of a stoma appliance and how this can be underestimated if the patient is supine. Stoma Types Many different types of stoma configurations can be chosen at the time of surgery. Stomas can be differentiated by whether they: • are small bowel stomas or colostomies • drain stool or urine • are temporary or permanent • are end, loop, or end-loop stomas. Temporary stomas are often chosen to aid in anastomotic healing or in the presence of sepsis or other conditions, when it is not considered not safe to perform an unprotected anastomosis. Loop ileostomies are often chosen for temporary diversion due to their lack of odor, ease of care, and ease of closing. Loop descending or sigmoid colostomies can similarly easily be closed. Transverse loop

A

colostomies should seldom be used, as they are large, very prone to prolapse, and can be difficult to maintain pouch adherence, frequently being located in an area around the patient’s belt line or mid-upper abdomen. Temporary diversion can be performed for a number of situations. Most often, temporary diversion is used to aid in healing of distal anastomosis. Alternatively, diversion of the fecal stream is sometimes recommended in patients undergoing treatment of distal pathology, such as anal squamous cell carcinoma, in order to make the treatment (e.g., chemoradiation) more tolerable. In these scenarios, a diverting stoma is anticipated to be closed after healing of the anastomosis or after conclusion of treatment. Each of the three different types of stomas (end, loop, and end loop) has advantages and disadvantages. The consistency and amount of stoma effluent can differ significantly depending on: • whether the small bowel or the colon is selected for stoma construction

FIG. 52.15  Demonstration of the infraumbilical fat mound that is the ideal stoma site in many patients, here showing marking for a descending colostomy.

B FIG. 52.16  Patient referred following surgery for ischemic colitis without preoperative stoma marking. (A) Patient in supine position. (B) Patient sitting up. Note the colostomy “disappears” within folds of her abdominal wall making pouching extremely difficult.

CHAPTER 52  Colon and Rectum

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• if the colon is selected, upon which site of the colon is selected for stoma construction • what types of treatment (radiation) the patient has undergone • previous bowel resection(s) the patient may have had. 

Colostomy Ascending colostomies tend to have a higher amount of liquid effluent, while descending and left-sided colostomies are usually preferable, as most of the colon is in circuit, allowing for more colonic water absorption, with a more formed effluent, while still providing proximal diversion. With the increasing body mass index of patients in the United States today, creating a well-functioning stoma can be a challenge. Both early and late complications can occur with stoma construction. Remember, a stoma should look good at the end of an ­operation! This is your best opportunity to address issues of stoma construction. One should not make the error of hoping that a suboptimal-appearing stoma will improve postoperatively. While edema secondary to obstruction may improve, ischemia does not and will only worsen over time. If there is doubt about stoma viability, construct the stoma prior to closing the abdomen, when revision is easy. A key aspect to creating a good stoma is to create a large enough aperture in the abdominal wall to allow the stoma to reach to the skin without tension, but not to create such a wide opening that the patient will develop a hernia at the site. Typically, creating an aperture that will admit two fingers is adequate (Fig. 52.17). In addition, one should ensure that the patient is marked for a stoma site preoperatively, as was discussed earlier. It is important to create a muscle-splitting stoma aperture within the rectus muscle and sharply divide the rectus sheath (Fig. 52.18). In creating a colostomy in an obese patient, especially with the left side of the colon, one frequently has to perform the same central vascular ligation as one does for a cancer resection merely to achieve the same degree of mobilization and mobility to enable the colon to reach to the ­abdominal wall in a tension-free manner. This can particularly be true with patients who have a very rigid abdominal wall and those with a very thick layer of subcutaneous tissue. In constructing an end colostomy, typically this does not need to protrude more than 0.5 to 1 cm above the level of the abdominal skin. However, there are some circumstances where the patient may be expected to have a more liquid effluent (e.g., due to receiving chemotherapy), and one may wish to have the stoma protrude more to permit easier pouch placement and adherence. In the presence of a liquid effluent, a protruding “spout-like” stoma is always easier to maintain pouch adherence compared with a flatter stoma. In the obese patient, it is sometimes easier to construct an end-loop colostomy than an end colostomy if complete fecal diversion is required. This is constructed in a similar fashion as a loop-end ileostomy (see later), whereby a loop of mesentery is brought up, rather than an end of mesentery. Remember, traditional loop colostomies are not always completely diverting. If one wishes total diversion, an endloop stoma, with tacking of the distal limb in close proximity of the stoma site, may be a preferable option. Also remember that, in obese individuals, the thinnest part of the abdominal wall is often in the upper abdomen. 

Ileostomy As with colostomy, an ileostomy can be constructed as an end ileostomy, loop, or end-loop ileostomy (Fig. 52.19). Ileostomies are generally favored by colorectal surgeons for fecal diversion as they are easier to construct, especially in obese individuals, usually easier to close, and do not risk compromising the marginal vessels

FIG. 52.17  A stoma aperture that admits two fingers is typically of adequate size to allow the bowel and mesentery to pass without tension. In cases of obstruction or an obese mesentery, a larger aperture will be needed.

FIG. 52.18  In making the stoma aperture in the abdominal wall, the rectus muscle is split and the rectus sheath is divided sharply. In laparoscopic cases, one can cut down directly on the trocar inserted through this site.

of the colon that are so important to the viability of low and ultralow colorectal and coloanal anastomoses. Ileostomy effluent usually has no odor, in contrast to colostomy effluent, which usually has odor associated with colonic flora. However, in contrast to a colostomy, an ileostomy will empty continuously and has a high rate of associated chemical dermatitis due to the more alkaline pH associated with small bowel effluent as opposed to the stool of the colon. There is also a much higher risk of dehydration with an ileostomy, which is a frequent reason for hospital readmission following elective colorectal surgery. Prior to hospital discharge, one should ensure that the 24-hour stoma output is less than 1000 mL.

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SECTION X  Abdomen Preoperative Interventions Counseling before surgery to set expectations on milestones and discharge criteria is considered a cornerstone of successful ERPs. If an ostomy is a part of the planned operation, marking, education, and counseling on dehydration should be started in the preoperative period. Ostomy creation is an independent risk factor for increased postoperative length of stay, and structured education has been shown to mitigate this risk. Additionally, dehydration is the most common reason for readmission after an ileostomy creation. Prehabilitation or increasing the patient’s physical conditioning before elective surgery may be considered for patients with ­deconditioning or multiple comorbidities. The evidence to support prehabilitation is in evolution but appears promising. 

Preadmission Nutrition and Bowel Preparation

FIG. 52.19  The Intraoperative photo showing the “matured” loop i­leostomy protruding 2 to 3 cm above the abdominal wall. The distal limb at skin level is located inferiorly.

If the output is greater than this amount, the patient is at high risk of hospital readmission. In patients in whom temporary ileostomy diversion is contemplated, wrapping the segment of diverted bowel in hyaluronatecarboxymethylcellulose membrane (Seprafilm) at the time of stoma creation facilitates stoma closure. Loop ileostomy is often performed at the time of ileal pouch–anal anastomosis (IPAA) in patients who are immunosuppressed and in those in whom there is tension on the anastomosis. It is also performed in cases of low colorectal and coloanal anastomosis following neoadjuvant chemoradiation, in some patients in whom complex pelvic reconstructions are performed (e.g., redo rectovaginal fistula repairs, repair of cloacal defects) and in other cases when temporary fecal diversion is desired. Laparoscopic-assisted diversion is particularly convenient for these cases. 

ENHANCED RECOVERY PROTOCOLS The last edition of this textbook reported that protocols for enhanced recovery after surgery had not been widely implemented. Since that time, there has been much attention to enhanced recovery protocols (ERPs) in colorectal surgery with widespread dissemination and implementation in the community. These protocols, also called fast-track or enhanced recovery after surgery protocols, have been shown to reduce complications, length of stay, and cost of care without increasing readmission rates. Protocols include a bundle of components affecting the preoperative, intraoperative, and postoperative phases of care. The factors that comprise a single protocol are numerous and heterogeneous between centers, thus making it difficult to identify the most beneficial components in a bundled protocol. In 2017, the American Society of Colon and Rectal Surgeons (ASCRS) and the Society of American Gastrointestinal and Endoscopic Surgeons published evidence-based guidelines for the components of ERPs.3

There is strong evidence to support the recommendation of a clear liquid diet up until 2 hours before the induction of anesthesia. However, there is weaker evidence to support the use of per os carbohydrate loading prior to surgery. Mechanical bowel preparation alone has not shown to be beneficial (strong recommendation based on high-quality evidence, 1A). In the United States, mechanical bowel preparation plus oral antibiotics preparation has become the preferred preparation to reduce complications, including SSIs, especially when left-sided and rectal resections are anticipated. In the American Society of Colon & Rectal Surgeons Clinical Practice Guidelines for the Use of Bowel Preparation in Elective Colon and Rectal Surgery, this practice was given a strong recommendation based on moderate-quality evidence, 1B. Interestingly, a recent randomized controlled trial found no evidence to support this practice for elective colon resection compared to no bowel preparation as a mechanism to reduce SSIs or postoperative morbidity.4 It is important to note that the majority of reported studies, including this one, were performed in patients undergoing colon as opposed to rectal resections. 

Perioperative Interventions ERPs commonly involve preset orders for the preoperative, intraoperative, and postoperative care for all patients. Standardization requires collaborative buy-in from different stakeholders, which helps avoid confusion and promotes timely adherence to care. Colorectal surgery patients have up to a 20% risk of developing a SSI postoperatively. Bundles of care aimed at SSI reduction have shown SSI rates to be significantly reduced. These bundles include some, if not all, of the following measures: preoperative chlorhexidine shower, mechanical bowel preparation with oral antibiotics, prophylactic antibiotic administration within 1 hour of incision, the use of wound protectors during surgery, changing gown, gloves, and instruments before fascial closure, euglycemia, and normothermia. The degree to which each element impacts the reduction of SSIs is unclear. There is strong evidence to support the use of multimodal, opioid-sparing, pain management plans starting before the induction of anesthesia. Minimizing opioids is associated with earlier return of bowel function and shorter length of stay. Acetaminophen, nonsteroidal antiinflammatory drugs (NSAIDs), and gabapentin have all been incorporated into various ERPs. Transverse abdominis plane block with local anesthetic, including liposomal bupivacaine, have shown promising results. Epidural analgesia is generally recommended for open, but not laparoscopic, colorectal surgery.

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CHAPTER 52  Colon and Rectum The use of goal-directed fluid therapy in the intraoperative and postoperative phases of care is associated with a reduction in time to return of bowel function and length of stay. Lastly, minimally invasive surgical (MIS) approaches should be used, when possible, with avoidance of routine use of intraabdominal drains and nasogastric tubes. 

Peritoneum Taenia coli

Mucosa Diverticulum

Postoperative Interventions Early patient mobilization with early feeding has good evidence to support its role in an ERP. Alvimopan use has been shown to hasten return of bowel function after open surgery, but not with MIS. In addition, intravenous (IV) fluids and urinary catheters should be discontinued early in the postoperative period. In summary, ERPs are evidence-based protocols that benefit colorectal surgery patients. Local implementation involves buy-in for a range of stakeholders that may be in opposition to the preferences of individual healthcare professionals. Adherence to the constellation of ERP components and the outcomes of interest should be continually monitored and evaluated. 

DIVERTICULAR DISEASE

Epiploic appendix

Concentration in diverticulum

Circular muscle Blood vessel piercing musculature

FIG. 52.20  Pathogenesis of diverticulosis. (From Netter FH. Netter Collection of Medical Illustrations. Vol 9. Philadelphia: Elsevier Saunders; 2016:145.)

Background Diverticular disease is used to describe a spectrum of manifestations associated with colonic diverticulosis. Diverticula are saccular outpouchings of the bowel wall. They are described as “true” diverticula when they contain all layers of the bowel wall; these are rare and usually congenital. The vast majority of diverticula in the colon are “false” diverticula (pulsion, pseudodiverticula), containing only the mucosa and muscularis mucosa. Diverticulitis is thought to be mainly a disease of the modern world, coinciding with dietary changes following the industrial revolution. 

Pathophysiology and Epidemiology Hypertrophy of the muscular layers of the colon wall, combined with a narrowed lumen and disordered colonic motility, causes localized high-pressure zones in which the mucosa herniates through areas of relative weakness. Diverticula are classically formed on the mesenteric side of the colonic wall in regions where vasa recta traverse through the muscular layer to provide blood to the mucosa (Fig. 52.20). The sigmoid and descending colon are typically affected, whereas the rectum, having an extra layer of muscle, is generally not affected (Fig. 52.21). This has implications for surgery and is why the distal anastomosis margin in operations for diverticulitis should always be within the rectum. Diverticulosis increases with age and is relatively rare in young adults. Colonic diverticula are noted in approximately 40% of individuals between the ages of 50 and 60 years and in over 60% of individuals over the age of 80 years (Fig. 52.22). The mechanism for developing diverticulitis is thought to be a result of obstruction of the orifice of a diverticulum, with stasis leading to bacterial overgrowth, inflammation, and increased pressure within the diverticulum, causing ischemia and microperforation. Interestingly, only a small proportion of patients with diverticulosis develop diverticulitis. Modern estimates indicate that fewer than 5% of patients with diverticulosis will develop diverticulitis; however, due to the high prevalence of diverticulosis, it has become a significant clinical and financial burden, accounting for more than 2.7 million outpatient visits in the United States annually and more than 200,000 inpatient admissions for diverticulitis at an estimated cost of more than $2 billion.

FIG. 52.21  Computed tomography scan of the pelvis showing extensive sigmoid diverticulosis.

Diet and lifestyle factors play an important role in diverticular disease. Western dietary patterns high in red meat, fat, and refined grains are associated with an increased risk of the disease, whereas increased fiber intake, with abundant fruit, vegetables, and whole grains, reduces the risk of diverticulitis. Intake of nuts, seeds, and popcorn does not appear to increase the risk. Central obesity and smoking increase the risk, whereas physical activity such as running has been correlated with a decreased risk. A study examining the joint contribution of multiple lifestyle risk factors, defined as fewer than four servings of red meat per week, at least 23 g of fiber per day, 2 hours of vigorous activity per week, a body mass index 18.5 to 24.9 kg/m2, and no history of smoking on the risk of incident diverticulitis, found that adherence to a low-risk lifestyle could prevent 50% of incident diverticulitis.5 

Clinical Evaluation Diverticular disease can manifest as diverticulitis, but it is also the most common reason for severe lower GI bleeding (discussed

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SECTION X  Abdomen TABLE 52.1  Modified Hinchey

classification system. Stage 0 Stage Ia Stage Ib Stage II Stage III Stage IV

Mild clinical diverticulitis Confined pericolic inflammation—phlegmon Confined pericolic abscess (within sigmoid mesocolon) Pelvic, distant intraabdominal or intraperitoneal abscess Generalized purulent peritonitis Fecal peritonitis

From Klarenbeek BR, de Korte N, van der Peet DL, et al. Review of current classifications for diverticular disease and a translation into clinical practice. Int J Colorectal Dis. 2012;27:207–214.

FIG. 52.22  Endoscopic view of diverticulosis.

elsewhere). Since diverticulitis is caused by inflammation and perforation of a colonic diverticulum, signs and symptoms will generally result from the pericolonic inflammation. Patients will commonly present with abdominal pain localized to the left lower quadrant (following the location of the inflamed sigmoid colon). Additionally, fever, change in bowel habits, anorexia, and urinary urgency (in cases where the bladder is secondarily inflamed) are frequent. On physical examination, localized tenderness is noted, commonly with moderate abdominal distension. A tender mass can be palpable if there is a significant phlegmon. Rectal bleeding is rare in the presentation of acute diverticulitis and should raise suspicion of another diagnosis such as ischemic colitis or IBD. Leukocytosis is a common laboratory finding. Several imaging modalities have been used to evaluate patients with suspected diverticular disease. Flat and upright plain films can be used to diagnose obstruction or free intraperitoneal air but are generally nonspecific. Contrast studies, ultrasound, and magnetic resonance imaging (MRI) have also been used, but currently, computed tomography (CT) has become the most useful examination to confirm the diagnosis, exclude other diagnoses, and classify the severity of the disease. Signs of diverticulitis on CT include the presence of diverticula, colonic wall thickening, pericolic fat stranding, and abscess formation. CT studies have the capacity to localize abscesses and fistulas and define the extent of the disease. The modified Hinchey classification6 is the most ­commonly used tool to describe the severity of diverticulitis (Table 52.1). Grade 0, not included in the original publication, is commonly used to describe mild clinical diverticulitis. If CT is performed, colonic wall thickening without pericolonic fat stranding can be seen. Grade 1a presents with a phlegmon with colonic wall thickening and pericolonic fat stranding, while grade 1b also includes a pericolonic or mesocolic abscess (Fig. 52.23). Patients with grade 2 disease have distant intraabdominal or pelvic abscesses. Patients with grade 3 disease have generalized purulent peritonitis, and grade 4 disease, fecal peritonitis. The ability of a CT scan to distinguish between grade 3 and grade 4 is limited, and in these cases, accurate diagnosis is usually made in the operating room. Flexible endoscopy during the acute setting should be approached with caution because distention of the colon may result in worsening perforation. 

FIG. 52.23  Computed tomography of the pelvis demonstrating sigmoid diverticulitis with a thickened bowel wall, fat stranding a pericolonic abscess (arrow), modified Hinchey grade 1b. 333

Management Complicated Diverticulitis Patients with complicated diverticulitis are characterized by the presence of an abscess, fistula, obstruction, or free perforation. Abscess. Signs and symptoms will depend on the size and location of the abscess, with diagnosis usually provided on imaging. Smaller abscesses can often be treated successfully with antibiotics alone. Larger abscesses will require drainage. Following recovery, elective surgery is generally recommended; however, some of these patients, especially those with smaller abscesses that were treated without drainage, can probably be managed nonoperatively. Patients with abscesses not amenable to percutaneous drainage and unresponsive to treatment require urgent surgery.  Fistula. Fistulas are abnormal connections to surrounding epithelial lined organs and are a relatively common complication of diverticulitis. They are a result of the local inflammation and development of an abscess that decompresses into a neighboring organ. The most common type, especially in men, is a colovesical fistula to the dome of the bladder. Patients will present with recurrent urinary tract infections, which are in many cases polymicrobial. Pneumaturia and fecaluria may also be present. CT

CHAPTER 52  Colon and Rectum can reveal air or contrast in the bladder in the absence of prior instrumentation. Cystoscopy will usually disclose inflammation at the site of the fistula. Colovaginal fistulas occur almost exclusively in women who have undergone previous hysterectomy and present with vaginal discharge and passing of air per vagina. Colocutaneous fistulas usually present at a previous drain site in patients who have undergone percutaneous drainage. Patients with fistulas usually do not need emergency surgery as the abscess has usually decompressed. Initial management includes broad spectrum antibiotics to decrease the inflammation. Patients are then investigated with colonoscopy and appropriate imaging (i.e., cystoscopy) to exclude malignancy and Crohn disease. Surgical principles then encompass resection of the involved colon and fistula tract with primary anastomosis. If possible, the fistula opening into the secondarily involved organ is primarily suture repaired; however, in many cases, the opening is small and difficult to recognize. In the case of the bladder, with small fistula openings, drainage of the bladder with a Foley catheter for 7 to 10 days will usually allow for healing. A cystogram can be done to confirm fistula healing prior to Foley removal. Fistulas to the small bowel will characteristically require resection and primary anastomosis.  Obstruction. Patients with recurrent and chronic diverticulitis can develop fibrosis of the colonic wall, leading to stricture formation. In most cases, these patients will present with insidious symptoms and a partial obstruction. Small bowel obstruction may also be seen as a result of a small bowel loop adhering to an area of inflamed colonic tissue or abscess. Management depends on the degree and type of obstruction. Patients with a partial obstruction can usually be initially treated with a nasogastric tube for decompression, antibiotics, fluids, and bowel rest. If the obstruction resolves, elective resection can be planned. It is usually important, prior to resection, to perform a colonoscopy to rule out malignancy. In cases where the stricture is impossible to pass using a colonoscope, virtual colonoscopy or a retrograde contrast study can be helpful to visualize the remainder of the bowel. Patients with a complete obstruction unresponsive to therapy will require emergency surgery.  Perforation. Patients with a free intraabdominal perforation with widespread contamination will present with diffuse peritonitis with rebound tenderness and guarding. Signs of sepsis including fever, tachycardia, and hemodynamic instability are frequently seen. Imaging can demonstrate free abdominal fluid, signs of peritonitis, and free intraabdominal air. The ability to distinguish between purulent and fecal diverticulitis prior to surgery is limited. Hinchey grades 3 and 4 are considered a surgical emergency. Following initial resuscitation, patients are taken to the operating room with a goal of controlling the source of infection by resection and washing out the abdominal contamination. The mainstay of treatment in these cases has traditionally been the Hartmann procedure, which removes the involved colon and exteriorizes an end colostomy. Reversing the colostomy, however, requires a second major surgical procedure with its own significant morbidity and mortality. Practically, up to 50% of patients will never be reversed, with even higher rates in the elderly. Given these implications, several studies have investigated alternatives to the Hartmann procedure. One option has been laparoscopic lavage, which entails laparoscopic irrigation of the abdominal cavity to reduce the abdominal contamination and placement of drains without resection (mainly for Hinchey grade 3 diverticulitis). Although this approach results in lower stoma rates, it has

1339

been associated with significantly higher rates of ongoing and recurrent sepsis and emergency reoperations.7 This approach is still controversial and should probably only be used in highly selected individuals. Another option is performing a resection with a primary anastomosis and diverting ileostomy. Although lengthening the initial surgery, this technique has been found to be safe and significantly simplifies and shortens the second operation. Overall morbidity and mortality are similar; however, a much higher proportion of patients will have their stomas reversed (94%–96% for primary anastomosis vs. 65%–72% for Hartmann).8 This has become an attractive option for patients who are stable enough to withstand the additional time of the initial surgery.  Uncomplicated Diverticulitis The treatment for uncomplicated diverticulitis depends on the severity of symptoms, and the approach is subsequently individualized. The majority of these patients can be managed as outpatients. The mainstay of treatment is based on pain medications, short-term alteration of diet, and antibiotics. Commonly, patients are initially prescribed clear liquids, followed by a low-residue diet until the inflammation subsides. Antibiotics have traditionally been prescribed to cover colonic bacteria. A systematic review and metaanalysis assessing the effect of antibiotic administration in patients with uncomplicated diverticulitis has not shown the usage of antibiotics to accelerate recovery or prevent complications or subsequent surgery.9 As a result, some physicians have stopped prescribing antibiotics for uncomplicated diverticulitis. A small proportion of patients diagnosed with diverticulitis will actually have a colonic neoplasm mimicking diverticulitis. Overall, this is currently estimated at around 1% to 3%, with significantly higher rates observed in complicated disease.10 Upon recovery, it is recommended that patients undergo a colonoscopy after 4 to 8 weeks to exclude malignancy. Following the initial episode of acute, uncomplicated diverticulitis, only 10% to 35% of individuals will have another episode.11 After more episodes, the chances of recurrence increase significantly. In an attempt to avoid severe complicated diverticulitis, elective surgery was previously suggested following uncomplicated diverticulitis, depending on the number of episodes, with the thought that more episodes would lead to more chances of recurrence and a higher chance of severe complicated diverticulitis. However, recurrences in general tend to follow the severity of the initial episode. As a result, the number of attacks of uncomplicated diverticulitis has fallen out of favor as an indication for surgery. Currently, an individual assessment is performed on the frequency of attacks, ongoing symptoms, and their effect on quality of life versus the age and medical condition of the patient and their surgical risk. The aim of elective surgery is to remove the affected segment of the colon (usually the sigmoid colon) and to perform a primary anastomosis of the healthy remaining bowel. When removing the sigmoid colon, the proximal margin should be in soft pliable bowel, but it is not necessary to include all proximal diverticula. The distal anastomosis, however, should be to the upper rectum, since leaving a section of distal sigmoid colon is associated with a higher risk of recurrent diverticulitis. Surgery can be performed by either an open, laparoscopic, hand-assisted, or robotic approach. MIS for diverticular disease has been shown to be safe, with advantages of more rapid recovery of bowel function, less pain, and shorter hospitalization. 

1340

SECTION X  Abdomen

Special Populations Right-Sided Diverticulitis This is common in Asian countries but rare in the west. This typically affects younger patients and may be challenging to diagnose as signs and symptoms are very similar to those of acute appendicitis. Other differential diagnoses to be considered include Meckel’s diverticulitis, cholecystitis, ischemic colitis, mesenteric adenitis, pyelonephritis, and pelvic inflammatory disease. The recommended approach should generally be similar to that for diverticulitis in other sites. Patients who have recurrent episodes or complicated disease and patients with an uncertain diagnosis should be considered for resection with a right hemicolectomy.  Immunocompromised Patients Immunocompromised patients include transplant patients; patients with diabetes mellitus, renal failure, or cirrhosis; and patients being treated with systemic steroids and/or chemotherapy. While the prevalence of diverticulitis in these patients is similar to the general population, they are more likely to present with free perforation and complicated disease because of their impaired ability to mount an inflammatory response. Because of this risk, there should be a lower threshold for resection after a single attack of diverticulitis. Immunocompromised patients who require emergency surgery and resection should probably not undergo primary anastomosis at the initial surgery because of their impaired immune system and healing.  Young Patients Historically, patients younger than 50 were considered to have a more virulent form of diverticulitis and were recommended to undergo resection after one episode of uncomplicated disease. Although current evidence does demonstrate higher rates of recurrence, young patients do not have a higher rate of emergency surgical intervention. Current guidelines do not support treating young patients differently than others. 

LARGE BOWEL OBSTRUCTION Large bowel obstruction, defined as bowel obstruction distal to the ileocecal valve, can occur as a result of a variety of etiologies. Broadly, it is classified into mechanical (dynamic) obstruction and functional (adynamic or pseudoobstruction). Mechanical obstruction can be further characterized into endoluminal, mural, and extraluminal causes (Box 52.1). The most common etiology of mechanical obstruction in the United States is colorectal cancer (CRC), whereas colonic volvulus is more common in Russia, Eastern Europe, Africa, the Middle East, and India. Presentation and symptoms depend on whether it is an acute obstruction or a more chronic progressive change, as well as partial, in which some gas/fecal contents are able to pass versus complete obstruction in which nothing passes distally. It is thought that worldwide, volvulus is responsible for roughly one third of the cases of large bowel obstruction. The most common site of volvulus is the sigmoid colon; however, cecal volvulus can also occur. Any portion of the colon that is not fixed to the retroperitoneum and that has an elongated mesentery has the potential for volvulus. In these cases, there is an axial twisting of the colon around the mesentery resulting in an obstruction.

BOX 52.1  Large bowel obstruction

common etiologies. Mechanical Intraluminal Intrinsic mass—neoplasm Foreign body Bezoar Fecal impaction 

Mural Diverticular stricture Crohn disease stricture Ischemic stricture Radiation stricture Infectious (i.e., lymphogranuloma venereum, tuberculosis, schistosomiasis) Hirschsprung disease  Extraluminal Sigmoid volvulus Cecal volvulus Hernia (inguinal, ventral, internal) Metastatic/intraabdominal tumor Abdominal abscess Retroperitoneal fibrosis Adhesions (rare in large bowel)  Functional Colonic pseudo-obstruction (Ogilvie) Toxic megacolon Paralytic ileus

Mechanical obstruction will generally present with increased peristalsis and low-grade colicky pain, but late, long-lasting obstruction may have decreased bowel sounds. In addition, patients will fail to pass stool and flatus and demonstrate increasing abdominal distention. Acute obstructions tend to present more dramatically with rapid onset of pain, distension, and abdominal tenderness, whereas patients with progressive obstruction may present with increasing constipation, pencil-thin stools, and intermittent abdominal pain. Functional obstruction usually presents with distension, vague abdominal pain, and weak or absent bowel sounds. Patients with a closed-loop obstruction in which both the proximal and distal parts of a segment of bowel are blocked must be promptly recognized and treated, as they have the potential for ischemia and perforation with rapid deterioration. Closed-loop obstruction is commonly encountered in cases such as volvulus and strangulated hernias. Fig. 52.24 shows a plain film of a patient with a sigmoid volvulus. Note the bent, inner-tube appearance of the colon. The volvulus has resulted in a closed-loop obstruction. In these situations, the colon becomes progressively distended with pressure increasing to the point of ischemic necrosis and perforation. Fig. 52.25 shows a CT scan illustrating the characteristic mesenteric whorl seen in patients with a volvulus. Another common circumstance of closed-loop obstruction is patients with obstructing colon cancers that have a competent ileocecal valve, which does not allow backflow of intestinal contents. Obstructing cancers with an incompetent ileocecal valve will usually present less acutely, with a much lower chance of

CHAPTER 52  Colon and Rectum

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FIG. 52.25  Computed tomography scan of the abdomen in a patient with sigmoid volvulus. Note characteristic whorl in mesentery.

FIG. 52.24  Plain film of sigmoid volvulus. Note bent inner tube appearance.

perforation as the valve allows backflow of intestinal contents into the small bowel, resulting in a progressively distended abdomen with nausea and vomiting of a feculent nature. Distention of the colon occurs as a result of gas and stool that gather proximal to the obstruction. The gas originates both from swallowed air (around two thirds) and bacterial fermentation. In segments that undergo increasing distension, the pressure within the bowel wall can rise above the capillary pressure, diminishing adequate oxygenation, leading to ischemic necrosis and perforation. Although most malignant obstructions occur in the distal parts of the colon, the necrosis and perforation usually occur in the cecum as it has the largest diameter, and in accordance with the law of Laplace will distend more under lower pressures and develop higher wall stress. In cases such as incarcerated hernias and volvulus, pressure on the mesentery can compromise the blood supply initially obstructing venous return, and with increasing edema and inflammation, eventually occluding the arterial blood supply. The resultant ischemia can also lead to early necrosis and perforation. In closed-loop obstructions, distention initially involves the trapped or incarcerated segment, but with time, the proximal bowel will also distend as a result of ongoing accumulation of gas and stool.

Diagnosis and Assessment A good history and physical examination are critical in the diagnosis of large bowel obstruction. The onset and progression of symptoms, background illnesses, and medications can provide important clues. The abdomen should be palpated for masses, tenderness, and previous incisions; the groins should be examined for hernias; and a digital rectal examination should be performed to inspect for neoplasms and for the presence of fecal impaction (Fig. 52.26).

Plain films of the abdomen can help in localizing the obstruction, demonstrating the degree of distension as well as the status of the ileocecal valve (competent vs. incompetent), and, in some cases, provide the diagnosis. Water-soluble and IV contrast-enhanced CT scans provide significant information revealing the location and etiology of the obstruction such as diverticulitis, IBD, and extraluminal causes (e.g., abscesses and inflammation) (Fig. 52.27). CT can also provide clues regarding tissue ischemia and impending perforation. Flexible endoscopy can assist in the diagnosis of the obstruction and permit biopsies to be collected for further investigation. Endoscopy can also allow for treatment such as detorsion of a sigmoid volvulus and insertion of stents in cases of malignant or benign obstruction. Basic blood analyses are also important in the initial workup. Electrolyte abnormalities can be diagnosed, which are important both as a cause for adynamic nonfunction and being in the operative and perioperative care. Increased white blood cell counts and CRP, as well as increased lactate, base excess, and decreased pH, are all generally associated with a more severe state and can help guide the aggressiveness of treatment. 

Treatment The treatment of large bowel obstruction is tailored to the etiology of the obstruction, several of which are discussed in detail later in the chapter. Treatment options vary considerably depending on the cause of obstruction, suspicion of bowel ischemia, and impending perforation, as well as the patient’s general condition and comorbidities. Patients who present with peritonitis, signs of perforation, or ischemic bowel should be taken immediately to surgery. It is imperative to promptly relieve mechanical obstructions, particularly those with complete and closed-loop obstructions before compromise of the blood supply results in necrosis and perforation. Patients who do not present with immediate, ominous signs can be managed according to the cause of obstruction. In patients with sigmoid volvulus, endoscopic decompression is often successful using either a rigid or flexible sigmoidoscope with placement of a rectal tube proximal to the point of torsion. If this is unsuccessful, patients require surgery with resection, colostomy, and a Hartmann procedure. If decompression is successful, elective sigmoid resection with primary anastomosis should be performed due to the high rate of recurrence. With cecal volvulus, primary resection and anastomosis

1342

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can typically be performed unless the patient is at increased risk of anastomotic leak (e.g., nonviable bowel, sepsis, hypotension, etc.). Patients with obstruction as a result of active IBD will commonly respond initially to steroids. Paracolic abscesses can be drained percutaneously. Foreign bodies can usually be removed endoscopically. Fecal impaction is commonly relieved with a combination of stool softeners and laxatives from above and manual disimpaction at the bedside or in the operating room under anesthesia. Hernias causing mechanical large bowel obstruction usually require surgery. Adult

100 mm

colonic intussusceptions, in contrast to pediatric intussusceptions, are almost always associated with a pathologic lead point, such as a polyp, cancer, Meckel, or colonic diverticulum. A recent metaanalysis found malignancy as the causative factor in 36.9% of ileocolonic and 46.5% of colonic intussusceptions.12 Most authors recommend surgical resection adhering to oncologic principles without reduction. Patients with malignant obstruction of the low and mid rectum usually require an initial diverting stoma to allow for neoadjuvant chemoradiation prior to definitive surgery. Malignant obstructions of the sigmoid and left colon without signs of impending perforation can be treated with initial endoscopic stenting as a bridge to surgery, or initial surgery. Surgical options include segmental resection with Hartmann operation (end colostomy with internal closure of the rectal stump) or primary anastomosis with or without a diverting stoma. If the cecum is ischemic or nonviable, a subtotal colectomy is performed. In cases of right-sided obstruction, a right hemicolectomy is typically performed with primary anastomosis. Patients who are unstable with a high risk for anastomotic failure should undergo creation of a temporary diverting stoma or exteriorization of the anastomosis as a loop ileostomy. 

COLONIC PSEUDO-OBSTRUCTION

Lossy P

FIG. 52.26  Computed tomography scan of the pelvis showing a sizable barium impaction following a barium enema resulting in a large bowel obstruction. This patient required disimpaction in the operating room.

Acute colonic pseudo-obstruction, also termed Ogilvie syndrome, was initially described by Sir William Heneage Ogilvie in 1948. It is characterized by acute colonic dilatation in the absence of a mechanical obstruction. Ogilvie syndrome is rare, with an estimated incidence of 100/100,000 admissions.13 Dysregulation of the colonic autonomic innervation is hypothesized to play an important part. Several mechanisms have been implicated including autonomic imbalance with a relative excess of sympathetic over

120 mm

A

Loosy

B

FIG. 52.27  (A) Gastrografin enema in a patient presenting with obstructing symptoms revealing an “applecore” type lesion in the vicinity of the hepatic flexure (arrow). (B) Computed tomography scan of the abdomen and pelvis in the same patient showing a large hepatic flexure carcinoma with perforation into the mesentery and associated mesenteric abscess (arrow). Computed tomography–guided abscess drainage was not possible. This patient underwent extended right hemicolectomy with exteriorization of his ileocolic anastomosis as a loop ileostomy.

CHAPTER 52  Colon and Rectum TABLE 52.2  Conditions associated with

pseudo-obstruction. CATEGORY

RISK FACTORS

Postsurgical

Following major orthopedic and/or spinal surgery, solid organ transplants, cardiac procedures Parkinson disease, Alzheimer disease, stroke, spinal cord injury Congestive heart failure, myocardial infarction Chronic obstructive pulmonary disease Major trauma, shock, burns Diabetes mellitus, renal failure, electrolyte disturbances Cytomegalovirus, varicella-zoster virus Caesarean section, normal and instrumental delivery Lupus, scleroderma Opiates, chemotherapy, anti-Parkinson drugs, anticholinergics, antipsychotic drugs, clonidine

Neurologic disease Cardiac Pulmonary Trauma Metabolic Infectious Obstetric/gynecologic Miscellaneous Drugs

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S AP SUPINE PORTABLE

100 mm

Lossy I

FIG. 52.28  Massive transverse colon distension due to Ogilvie s­ yndrome in a woman with multiple comorbidities including a body mass index of 69, severe pulmonary hypertension, and cardiac disease.

parasympathetic activity, disrupted colonic reflex arcs, chronic disease, and medications.13 It is most commonly encountered among elderly and comorbid patients, classically following an acute illness on a background of neurologic, cardiac, or respiratory diseases. Common associated conditions are depicted in Table 52.2.

A

Diagnosis The typical patient is elderly with multiple comorbidities who is hospitalized for an acute medical event or has undergone surgery (abdominal or nonabdominal). The presenting symptoms of the condition commonly include abdominal distension, pain, nausea, and vomiting. Obstipation is common, but some patients will have diarrhea due to hypersecretion of water. Lack of intestinal contractility is often associated with decreased or absent bowel sounds, but high-pitched, tinkling bowel sounds may also be encountered. Systemic toxicity and peritoneal signs are uncommon and should raise suspicion of ischemia and perforation. Initial evaluation should include a complete blood count, serum electrolytes, renal function assessment, and diagnostic imaging. Plain abdominal radiographs typically demonstrate a distended colon, with the largest diameter usually encountered in the cecum and right colon, which can reach 10 to 12 cm in diameter (Fig. 52.28). Dilation and gas continuing all the way down to the distal rectum support the suspicion of pseudo-obstruction in contrast to a mechanical obstruction in which a paucity of gas is commonly encountered distal to the obstruction. A water-soluble contrast enema can reliably distinguish between a mechanical obstruction and pseudo-obstruction. Currently, however, abdominal CT is typically utilized as the standard confirmatory test with the ability to commonly ­distinguish the type of obstruction as well as to assess for signs of ischemia and impending perforation (Fig. 52.29). Abdominal tenderness, leukocytosis, fever, and cecal dilation more than 12 cm are signs that may be indicative of colon ischemia, perforation, or impending ­perforation. The differential diagnosis includes mechanical obstruction, toxic megacolon due to C. difficile, or toxic megacolon due to other causes. 

160 mm

Lossy P

FIG. 52.29  Computed tomography scan showing massively distended colon without sign of ischemic change.

Management The treatment of colonic pseudo-obstruction comprises a series of escalating interventions contingent on the degree of distension, risk for perforation, and the patient’s response. Treatment options include supportive care, pharmacologic therapy (neostigmine), endoscopic decompression (colonoscopy), and surgery. Readers are referred to the American Society of Colon & Rectal Surgeons’ Clinical Practice Guidelines. Nonoperative, supportive care is initiated for patients with a cecal diameter that is less than 12 cm without evidence of ischemia

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SECTION X  Abdomen

or perforation. This includes nothing by mouth (NPO), correction of electrolyte disturbances, and discontinuation of medications that may be contributing such as opiates, anticholinergics, anti-­Parkinson agents, antidepressants, neuroleptics, clonidine, atropines, and antihypertensives. Insertion of a nasogastric tube and rectal tube for decompression may be of help. Osmotic and stimulant laxatives should be avoided as they can worsen colonic dilation. Ambulation, prone positioning, and knee-chest position to encourage passage of flatus can assist. Patients should be monitored with serial physical exams and abdominal x-rays to assess for response or deterioration. Ischemia or perforation of the colon is the most feared complication and has been reported in the range of 3% to 15% of cases, leading to an associated mortality rate of close to 50%. In cases that do not improve with supportive care or with a cecal diameter of more than 12 cm, but without systemic toxicity and abdominal tenderness, colonic decompression is indicated. Neostigmine is the keystone of pharmacologic decompression therapy. It is an acetylcholinesterase inhibitor that stimulates the muscarinic receptors and enhances colonic motor activity. Neostigmine is given as a 2 to 2.5 mg IV bolus injected over 3 to 5 minutes and results in significant parasympathetic stimulation causing strong colonic peristalsis that usually leads to subsequent flatus and bowel movements. It has been found to be a safe and effective option for patients with acute colonic pseudo-obstruction who have failed conservative management. Success rates for neostigmine treatment range from 60% to 94%, with recurrences observed in up to 31% of patients, with some patients requiring multiple drug administrations. Neostigmine is contraindicated in mechanical bowel obstruction and in patients with signs of ischemia or perforation. It should be used with caution among patients with asthma, chronic obstructive lung disease, bradycardia, and recent acute coronary syndrome and in those with renal failure. Neostigmine should be given in a monitored setting with atropine immediately available. Common side effects include vomiting, crampy abdominal pain, excessive salivation, and bradycardia. Colonoscopic decompression should be considered in patients with contraindications to neostigmine or for those who are unresponsive to it. The aim of endoscopic decompression is to advance the scope to the right colon with minimal insufflation and use of narcotics and place a colonic decompression tube while removing as much gas as possible from the colon. Endoscopic decompression has a high success rate of 61% to 95% for initial decompression and 70% to 90% for sustained decompression. Colonoscopic perforation rates following decompression for pseudo-obstruction are in the range of 1% to 3%. Patients who do not respond to other lines of treatment or those who demonstrate signs of systemic toxicity, ischemia, or perforation require surgery. Surgical options are determined according to the condition of the colon and the patient. If the colon is viable, tube cecostomy or cecostomy can be performed, with high rates of success. For patients with signs of ischemia or perforation, a resection, usually with a diverting stoma, is recommended. 

INFLAMMATORY BOWEL DISEASE Epidemiology and Etiology IBD, which includes both UC and Crohn disease, are largely diseases of the Western world. As Asian countries are adopting a more Western diet, the incidence of these disorders is increasing in these countries as well. The prevalence of IBD in Western countries is approximately 0.5% of the general population.14 In the United States, over 1 million individuals are estimated to have IBD, with

over 200,000 Canadians affected, and 2.5 to 3 million individuals in Europe having these disorders.14 The highest incidence of UC has been reported in Europe, followed by the United States, whereas for Crohn disease, the highest incidence was observed in the United States, followed by Europe. Europe was noted to have the highest prevalence of IBD. Over time, the incidence of both disorders appears to be increasing. Both disorders appear to have a genetic predisposition with many contributing environmental factors. Over 10% of patients with IBD have a family history of IBD. To date, genome-wide association studies have linked to over 230 IBD susceptibility loci.15 Cigarette smoking is the most studied environmental factor, having opposite effects in UC and Crohn disease. In UC, smoking tends to suppress symptoms, whereas in Crohn disease, smoking tends to exacerbate symptoms. Antibiotic use in early life has also been thought to predispose to IBD, as has NSAID use. 

Disease Distribution and Classification The extent of UC can also be graded with respect to the extent of inflammation within the colon. It can be limited only to the rectum and sigmoid colon (proctitis or proctosigmoiditis), restricted to the left side of the colon, or extended to involve the entire colon (pancolitis). There are many classification schemes of Crohn disease. However, one of the most popular was initially the Vienna Classification, which was later updated to the Montreal Classification. With these classification schemes, patients are classified according to age of onset of disease, bowel location of their Crohn disease, as well as type of disease behavior. In addition to the different ages of onset, the Vienna Classification divided patients into whether or not they develop inflammatory Crohn disease at age of 40 or later. The Montreal Classification subdivides this into less than 20 or greater than 20 years old. In addition, the Montreal Classification adds a further subdivision of whether the patients have perianal Crohn disease. The three different types of behavior classifications for Crohn disease that are possible include inflammatory Crohn disease, fibrostenotic Crohn disease, and fistulizing Crohn disease. Many people feel that these three types of disease behaviors represent different time points in the progression of disease. In other words, a patient is initially diagnosed with inflammatory Crohn disease, which over time progresses to fibrostenotic Crohn disease. This, in turn, will frequently progress to an obstruction, with perforation proximal to the obstruction and abscess formation. When this abscess spontaneously drains into an adjacent structure or organ, fistula formation ensues. In this manner, there is a progression from inflammatory to fibrostenosing to fistulizing Crohn disease. It is with this thought in mind that the progression to “top-down” medical therapy has evolved (see later discussion on medical therapy). The goal is to interrupt this natural progression or cycle in the course of Crohn disease to prevent the progressive fibrosis that results in many of the complications leading to surgery. 

Clinical Presentation and Disease Diagnosis Clinical Presentation Clinical presentation of both diseases can be similar. Diarrhea can be a presenting symptom in both diseases; however, this is typically more prevalent and severe in UC, where the diarrhea is characteristically bloody. Significant hemorrhage is much more common with UC than with Crohn disease. Typical UC symptoms also include tenesmus and urgency as well as associated anemia. In Crohn disease, symptoms of abdominal pain may predominate.

CHAPTER 52  Colon and Rectum

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FIG. 52.30  Large anal Crohn tags. Note the bluish coloring and waxy

FIG. 52.31  A woman with significant fistulizing perianal Crohn disease.

appearance of the perianal skin

Note the multiple external fistula openings shown by the white arrows. These all had a common internal opening in the anterior midline, which was also associated with a rectovaginal fistula. This patient ultimately elected to undergo ileostomy diversion.

In any patient initially presenting with diarrhea, stool cultures should first be obtained to exclude the presence of infectious causes of diarrhea, such as Salmonella, Giardia, or communityacquired C. difficile that is now increasingly seen. Patients with Crohn disease may present with a palpable abdominal mass due to an intraabdominal abscess or have an external fistula. Roughly 25% of patients with Crohn disease will have associated perianal disease. This can include a variety of problems, including anal fissure, which in contrast to patients without Crohn, is often not painful and may be multiple. In addition, these patients can present with large anal skin tags (Fig. 52.30), which are not true external hemorrhoids. As a rule, these should not be excised, as they may lead to very delayed wound healing. These patients may also present with anorectal abscesses, fistula(s) (Fig. 52.31), and anal stenosis. Digital rectal examination should always be performed. Extraintestinal manifestations. Extraintestinal manifestations can occur in many IBD patients, and it is estimated that up to half of IBD patients will have one or more extraintestinal manifestations. There is a slightly higher prevalence of extraintestinal manifestations in patients with Crohn disease as compared with those with UC and can be divided into those affecting the joints, eyes, and skin. Arthritis is by far the most common extraintestinal manifestation. One of the most common manifestations is sacroiliitis. One of the most serious joint manifestations is ankylosing spondylitis which runs a course independent of the bowel disease. These patients are HLA-B27 positive and may present in advanced cases with decreased cervical flexion, which has important anesthetic implications for intubation. These patients may require fiber optic intubation and will require specific preoperative anesthesia evaluation. Cutaneous extraintestinal manifestations include erythema nodosum and pyoderma gangrenosum. From long experience of treating surgical patients with IBD, pyoderma is much more frequent than erythema nodosum. Erythema nodosum (Fig. 52.32) is characterized by red painful swollen nodules that can occur and

FIG. 52.32  A patient with a Crohn disease flare and active erythema nodosum. Note the red purplish nodule on the dorsum of the foot.

usually will respond to systemic steroid administration, whereas pyoderma gangrenosum is characterized by typically extremely painful ulcerating lesions that frequently occur at sites of repeated trauma such as in the vicinity of surgical incisions or more frequently around intestinal stomas (Fig. 52.33). There is a phenomenon called “pathergy,” which refers to a worsening of the

1346

SECTION X  Abdomen

FIG. 52.33  Pyoderma gangrenosum adjacent to an end ileostomy in a patient with Crohn disease. Here, the lesions have started to heal with granulation tissue.

pyoderma with any type of surgical manipulation or debridement. These lesions are therefore best treated by nonoperative means and can include intralesional steroid injections (i.e., triamcinalone), topical (tacrolimus 0.1%), or systemic biologic therapy (antitumor necrosis factor [TNF] antibodies or similar agents). Such treatment will typically result in symptom resolution. Ocular manifestations of UC can include uveitis, iritis, and episcleritis. Some of these can lead to significant irritation and require referral to an ophthalmologist. Sclerosing cholangitis is estimated to affect approximately 5% of patients with IBD. It has a course that is curiously independent of the IBD. At its worst, it can progress to cirrhosis, result in liver failure, and require hepatic transplantation. Patients with sclerosing cholangitis are at higher risk for developing colorectal neoplasia, as will be discussed later, and are also at higher risk of developing pouchitis, as will be discussed in the section on IPAA and surgical treatment.  Disease Diagnosis Endoscopy. The diagnosis of IBD is frequently made by endoscopy. This can be accomplished by either rigid proctoscopy, flexible sigmoidoscopy, or colonoscopy. Generally, a complete evaluation of the colon with colonoscopy is performed both to evaluate the extent of the disease as well as to examine the terminal ileum. With UC, inflammation begins at the level of the dentate line and extends proximally, whereas in Crohn disease, in many cases, the inflammation is more patchy and there can be discontinuous inflammation (i.e., skip areas), with areas of intervening normalappearing mucosa. In some cases, differentiation between the two diseases can be difficult, both endoscopically as well as histologically. A typical endoscopic view of UC is shown in Fig. 52.34. Note the more roughened or granular appearance of the colonic mucosa. One of the most common scoring systems for endoscopic assessment of UC is the Mayo Clinic Scoring System, which grades the

endoscopic findings based upon the severity of the mucosal ulceration or the absence thereof. Grade 1 refers to a normal endoscopic appearance, grade 2 refers to slightly more erythematous, grade 3 refers to even more erythematous area with touch bleeding, and grade 4 refers to significant bleeding and friability. As the disease becomes more severe, there is an increasingly erythematous appearance of the mucosa with progressive mucosal ulceration. With respect to endoscopy, Crohn disease is more characterized by deeper punched-out appearing ulcerations. In these cases, there are often longer serpiginous ulcerations covered with fibrin. These can oftentimes extend longitudinally along the lumen of the bowel, in which case they are sometimes referred to as “bear claw” ulcerations (Fig. 52.35). In many cases, Crohn disease ulcers are worse on the mesenteric side of the bowel. Regarding the distribution of Crohn disease, the most common site of involvement in nearly half of patients is ileocolic, followed by colonic involvement. Crohn disease can also affect the small bowel or upper GI tract.  Histologic evaluation. In UC, colonic mucosal biopsies will typically show significant inflammation with the presence of multiple polymorphonuclear leukocytes within the lamina propria. There may be depletion of mucin in goblet cells. One can also identify crypt abscesses, although this is somewhat of a nonspecific finding. As a rule, inflammation in UC is restricted to the surface epithelium (Fig. 52.36). The disease process is limited to the large intestine. Proximal colonic disease occurs in continuity with an involved rectum (i.e., no gross or histologic skip lesions). The inflammation is characterized by the absence of mural sinus tracts, deep fissural ulcers, and granulomas, as well as by the absence of transmural lymphoid aggregates in an area not deeply ulcerated. In contrast, in patients with Crohn disease, there is often transmural inflammation, which is seen in histologic evaluation of resected specimens. In approximately one third of patients, there are noncaseating granulomas (Fig. 52.37). In biopsy specimens, the diagnosis of Crohn disease is made in the presence of non-necrotizing granulomas or the presence of transmural lymphoid aggregates in an area not deeply ulcerated. In patients with Crohn disease, just as one can macroscopically see “skip” disease with patchy inflammation, the same is true on microscopic evaluation. The term “focal active enteritis” is used. The differential diagnosis frequently includes infectious colitis or drug-induced colitis, and pathology reports often include this differential diagnosis when areas are biopsied during GI endoscopy. In patients who are suspected of having Crohn disease, it is important to make an effort to intubate the terminal ileum, as this is a common site of disease involvement. IBD undetermined refers to a subset of patients who have overlapping characteristics of both Crohn disease as well as UC on endoscopic biopsy. It is thought that up to 10% to 15% of patients fall into this category. The diagnosis of indeterminate colitis is made in patients in whom there is uncertainty of the diagnosis on evaluation of the colectomy specimen, since histologic features of both Crohn and UC are seen. Overall, this diagnosis is more likely in patients with fulminant disease where the significant amount of inflammation interferes with precise disease diagnosis.  Medical Treatment Changing medical treatment philosophy. The last two decades has seen a tremendous change in medical treatment for IBD. There has been a gradual evolution from a “bottom-up” approach to what is termed “top-down” approach. These terms refer to the

CHAPTER 52  Colon and Rectum

A

B FIG. 52.34  (A) Endoscopic view of moderately severe ulcerative colitis. Note the bleeding and ulceration. (B) Macroscopic view of right colon following total proctocolectomy for fulminant ulcerative colitis.

A

B FIG. 52.35  Bear claw ulcers in Crohn colitis. (A) Endoscopic view. (B) Macroscopic view.

FIG. 52.36  Histologic section of active ulcerative colitis. There is gland­ ular architectural distortion manifested by irregular branching and orientation of glands relative to the surface. The lamina propria is expanded with inflammatory cells, and intraepithelial neutrophils are present. A crypt abscess is noted (lower left). (Courtesy Dr. Jeffrey P. Baliff, Thomas Jefferson University, Philadelphia.)

FIG. 52.37  Crohn colitis with noncaseating granuloma.

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SECTION X  Abdomen

TABLE 52.3  Different types of medical treatment used for inflammatory bowel disease. DRUG CLASS

EXAMPLES

INDICATION

ADMINISTRATION

Biologics

Infliximab Adalimumab Golimumab Natalizumab Vedolizumab Ustekinumab Sulfasalazine Mesalamine Conventional steroids Budesonide Antimetabolites Tofacitinib Lactobacillus Bifidobacterium Ciprofloxacin Metronidazole Rifaximin

UC, CD UC, CD UC CD UC, CD UC, CD UC, CD UC, CD UC, CD UC, CD UC, CD UC UC, CD

IV SC IV IV IV IV, SC PO PO, enema, suppository PO, IV, suppository PO, rectal foam PO PO Food, tablets, capsules, powders

UC, CD UC, CD Off-label

PO, IV PO, IV PO

Antiinflammatory Immunosuppressives

Probiotics Antibiotics

CD, Crohn disease; IV, intravenous; PO, per os; SC, subcutaneous; UC, ulcerative colitis.

“bottom-up approach,” beginning with the safest, least expensive medications first and only proceeding to the more potent, more expensive medications with a higher side effect profile once these have failed. This treatment approach has been largely replaced by the top-down approach, whereby patients are initially treated with the stronger, more potent medications which may, in turn, have a greater side effect profile and are associated with higher costs. Many of these drugs have been implicated with a higher rate of postoperative complications in patients undergoing surgery, and their use also has been associated with reactivation of certain remote infections. It is important for the surgeon to be aware of these medications and knowledgeable about their mechanism of action. Table 52.3 lists some of the more commonly utilized medications used in the treatment of IBD. The surgeon will find that these medications are being used increasingly not only in patients with IBD but also in patients with rheumatoid arthritis and psoriasis. Medical therapy formerly was based largely on medications such as sulfasalazine and steroids. However, the last 25 years has seen a revolution with the introduction of “biologic therapy,” based largely on treatment with antibodies directed against TNF-α (anti-TNF-α). This began with the Food and Drug Administration (FDA) approval for infliximab (chimeric anti-TNF antibody) for Crohn disease in 1998, followed by adalimumab (humanized antiTNF antibody) in 2007, certolizumab pegol (a PEGylated Fab’ fragment of a humanized TNF antibody) and natalizumab (humanized monoclonal antibody to α4-integrin) both in 2008, golimumab (human monoclonal anti-TNF) approval for UC in 2013, vedolizumab (monoclonal antibody to integrin α4β7) in 2014, ustekinumab (human monoclonal antibody to p40 protein subunit used by interleukin [IL]-12 and IL-23) in 2016, and tofacitinib (janus kinase inhibitor) approval for UC in 2018. Currently, there is a wide assortment of drugs to choose from. There has also been a change in the philosophy of treatment with respect to IBD.  Medications for treatment of IBD

Aminosalicylates. Sulfasalazine has long been used for the treatment of colonic IBD. Originally used as a treatment for

arthritis, it was noted that many arthritis patients with coexisting IBD noted an improvement in the latter when taking this medication. Use of this drug was limited by its sulfapyridine ring, which excludes use in patients with sulfa allergies. When this medication is used, patients require folic acid supplementation. Eventually, the sulfapyridine ring is cleaved, leaving the active 5-aminosalicylate (5-ASA) moiety. Pharmacologists rapidly realized that, depending upon how this drug was formulated, its delivery could be targeted to different portions of the GI tract. For example, mesalmine (­ Pentasa) begins to dissolve in the stomach and releases drug throughout the GI tract, whereas Asacol begins to be released in the terminal ileum by means of a pH-dependent mechanism and coats the entire colon. Drugs manufactured with an “MMX technology” are designed as once-a-day preparations and formulated so that they slowly dissolve, thus releasing medication throughout the colon. For this reason, they are thought to have greater patient compliance. There are also topical formulations of these medications for distal disease. Suppository formulations are administered at bedtime. While the patient sleeps, the suppositories melt and coat the rectum with mesalamine, which has a very potent antiinflammatory effect. The most popular brand of suppository is Canasa. The same medication in small-volume enema form (Rowasa enemas) can be administered also at bedtime. The patient is advised to lie on their left side, allowing the small volume of fluid to be delivered not only to the rectum but also sigmoid and, in some cases, the left colon. These medications are most effective for mild to moderate disease.  Corticosteroids. If the patient has severe disease, steroids still play a prominent role in the treatment of IBD. Although they have numerous side effects, they are inexpensive, act quickly, and are readily available, not requiring lengthy insurance preauthorizations as with the more expensive biologic medication alternatives. The recognized side effects of steroids include the following: • Cushingoid appearance that is very unpopular, particularly among young patients • Feared complication of aseptic necrosis of the hips

CHAPTER 52  Colon and Rectum • H  ypertension • Mood changes that can escalate up to actual psychiatric conditions • Hyperglycemia • Increased risk of infectious complications after surgery • Cataract formation • Striae and others Because of these complications, as well as the growth retardation seen when these drugs are used for prolonged periods in children, these medications should be used sparingly for as short a period as possible. Steroids are usually started at a high dose and then tapered quickly. Their main uses are either in the outpatient setting in the form of pulse therapy, as high doses that are tapered quickly, or intravenously in patients who are hospitalized with flares of their disease. In the outpatient setting, pulse therapy is usually given in the form of prednisone at doses starting at 40 to 60 mg/day, tapering by 5 to 10 mg at 2-week intervals until 10 mg/day is reached and then tapering by 5 mg every 2 weeks, at which time the drug is discontinued. In the hospital setting, 100 mg of hydrocortisone can be given intravenously every 6 to 8 hours depending on disease severity.  Immunomodulators Thiopurines. Thiopurines are a “steroid-sparing” class of medication that are usually begun once patients are placed on steroids and perhaps have been unsuccessful in weaning off steroids after one or two attempts at pulse therapy. Thiopurines have been used for many decades in the treatment of Crohn disease and have long been used in the organ transplant population. Two drugs fall into this category: azathioprine and its metabolite 6-mercaptopurine. The side effects of this therapy include leukopenia and pancreatitis. These side effects are largely seen in individuals who are homozygous for a variant of the enzyme thiopurine methyltransferase responsible for metabolizing these drugs poorly. For this reason, many physicians now routinely perform thiopurine methyltransferase genotyping of patients to see whether they will be able to metabolize these drugs properly prior to initiating thiopurine treatment. These drugs have several advantages in that they are readily available and are an oral medication taken once a day, and dosing is based on body weight. On the downside, once a patient begins therapy, there is usually a 3- to 4-month lag time until these medications exert their therapeutic effect. For this reason, these medications cannot be used to treat a flare. Long-term thiopurine use is also associated with a higher risk of developing non-Hodgkin lymphoma than the general population.  Methotrexate. Methotrexate is another commonly used immunosuppressive for the treatment of IBD. This medication, which has long been used particularly in the treatment of patients with arthritis, can be dosed either orally or intramuscularly. Intramuscular dosing is particularly convenient in patients who have problems with significant diarrhea or absorption issues (e.g., short bowel syndrome). The side effects of methotrexate include elevations in liver function tests, as well as pulmonary fibrosis. When methotrexate is given, patients require folic acid supplementation. 

Biologics in the Treatment of Inflammatory Bowel Disease The term “biologics” as it pertains to drugs used for IBD initially referred to monoclonal antibodies directed against TNF-α. The first such agent, infliximab, was approved by the FDA for use in 1998. Since then, there has been a continued increase in both the

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number and type (based upon mechanism of action) of medications that have been approved (see Table 52.3). The side effects of these drugs include reactivation of infections including tuberculosis, histoplasmosis, actinomycosis, and hepatitis. For this reason, a careful patient history regarding these infections should be taken prior to consideration of treatment. In addition, before starting these drugs, the patient should have either a tuberculin skin test or undergo testing with QuantiFERON gold assay as well as obtain a hepatitis profile. There is currently no accurate test for past exposure for histoplasmosis. In addition, these types of agents, similar to the thiopurines, can be associated with a higher risk of developing non-Hodgkin lymphoma compared to the general population. In addition, anti-TNF-α antibody has been associated with a low risk of hepatosplenic T-cell lymphomas, particularly in young men who have been taking anti-TNF antibody therapy in combination with other immunosuppressive therapy such as a thiopurine. 

Assessment of Symptom Severity Truelove and Witts is a popular classification scheme that characterizes patients by the severity of their diarrhea, the presence of blood in stool, the presence of fever, tachycardia, anemia, or an elevated erythrocyte sedimentation rate. Many similar classification schemes are used, in addition to analyzing stool samples for either fecal calprotectin or lactoferrin that can be used as an inflammatory marker to assess disease activity. With Crohn disease, both the Crohn disease activity index (CDAI) and the Harvey Bradshaw index have been used to quantitate symptoms.16 The CDAI is made up of eight clinical and laboratory variables, including the number of bowel movements/day, the presence of abdominal pain, hematocrit, and weight loss. A score of less than 150 indicates clinical remission, and a score of more than 450 denotes severe disease. Since the CDAI requires a 7-day patient symptom diary, the Harvey-Bradshaw Index was proposed as a modification of this scheme that only used clinical data. 

Indications for Surgery for Ulcerative Colitis There are several indications for surgery for UC, the foremost of which is failure to respond to maximum medical therapy. The frequency of surgery for UC has actually decreased over the last several decades with the improvement in efficacy and the number of new and more effective medical options such as the entire class of biologic therapies. However, despite these new therapies, patients still present with a failure to respond. Patients falling into this category range from those patients who have severe disease, namely, those patients with multiple bowel movements, poor nutritional status, “failure to thrive,” and a need for surgery in order to regain their good physical health. These patients have a very poor quality of life with urgency, tenesmus, and low body weight; surgery represents a significant improvement in the quality of life. The second group of patients failing to respond to maximum medical therapy refers to patients with fulminant colitis. These patients have such severe disease that they need to be hospitalized and placed on IV steroids. In some cases, they have received in-hospital biologic therapy; in rare cases, these patients may be receiving intravenous cyclosporine as an attempt to avert colectomy. In these patients with fulminant colitis, toxic megacolon may be present (Fig. 52.38). This has arbitrarily been defined as having three or more of the following criteria present: tachycardia greater than 100, leukocytosis greater than 12,000/dL3, hypoalbuminemia less than 3 g/dL3, a temperature greater than 38°C, or a diameter of the transverse colon on a

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SECTION X  Abdomen

73 mm

120 mm

FIG. 52.38  Toxic megacolon. Abdominal film shows significant distension of the transverse colon in a 20-year-old man with toxic megacolon. (From Rojas-Khalil Y, Galandiuk S. Management of chronic ulcerative colitis. In: Cameron JL, Cameron A, eds. Current Surgical Therapy. 13th ed. Philadelphia: Elsevier; in press.)

plain abdominal radiograph greater than 5 cm. Three or more of these criteria meet the definition of toxic megacolon; note that a “megacolon” does not need to be present in order to meet this definition. Thus, the definition of toxic megacolon merely refers to a patient who is septic due to very severe colitis. Toxic megacolon can be present not only from severe UC but also due to severe Crohn colitis or severe infectious or ischemic colitis. When the colitis is severe enough, it is associated with a significant colonic ileus, and, in these cases, the colon becomes dilated and there is a significant risk of colonic perforation. The next category of indication for surgery occurs in patients in whom there is significant GI bleeding. Recalling basic anatomy, the vessels located underneath the colonic vessels are located underneath the mucosa. If the mucosa sloughs, this will, in effect, expose the underlying blood vessels of the colon and can result in massive GI hemorrhage if an ulcer erodes into these vessels. Significant hemorrhage can be one of the reasons for urgent surgery with UC, although the frequency of this complication has decreased over time. Another indication for surgery in children with UC is failure to grow, which is also an indication for surgery in patients with Crohn disease. The presence of a dysplasia or cancer is an indication for surgery, as well. Patients with longstanding UC (>8 years) have a high risk of developing dysplasia or cancer, as do those who have sclerosing cholangitis. Once the disease has been present longer than 8 years, patients are advised to undergo regular (yearly) colonoscopic surveillance with or without chromoendoscopy. If multiple areas of low-grade dysplasia or areas of high-grade dysplasia (Fig. 52.39) are found, a colectomy is recommended to prevent the development of invasive adenocarcinoma. The finding of colonic dysplasia in patients with

longstanding UC is an indication for surgery that has undergone significant change over the last 20 years. There is currently somewhat of a controversy as to exactly who requires surgery and who requires continued observation with close surveillance. Much of this has arisen due to the development of high-definition colonoscopy, as well as the development of techniques of surveillance such as chromoendoscopy. Chromoendoscopy involves the performance of colonoscopy with the spraying of dyes such as methylene blue or indigo carmine onto the colonic mucosa at the time of colonoscopy to highlight areas suspicious for dysplasia to permit targeted biopsies rather than just performing the random biopsies that were previously standard of care. In addition to this, there has been recognition that there are different types of dysplasia. The flat dysplasia that is difficult to detect and blends in with the surrounding mucosa is very different from the “polypoid” dysplasia that is apparent and can be treated in many cases like a polyp and removed using techniques similar to that used for removal of a conventional polyp during colonoscopy. In some studies, patients with UC have undergone “polypectomy” removal of dysplastic lesions and have been followed long-term without interval development of cancer.17 What is important to stress is that patients must have very close follow-up colonoscopy and that meticulous colonoscopy and pathology expertise are vital to this process, as is excellent patient compliance. If any one of these three factors is lacking, this is clearly not a viable treatment alternative. There is, however, still agreement that if there are multiple areas of flat dysplasia within the colon, colectomy is indicated. There is still much to be learned regarding the actual risk of cancer in patients with IBD. Overall, it is felt that approximately one fifth of the world’s cancers arise in the setting of chronic inflammation. This mirrors t nhe problem with hepatitis, anal cancer, gastric cancer, and many others. With the advent of better medications and interruption in this chronic cycle of inflammation, it will be interesting to see whether the incidence of cancer and IBD begins to decline compared to historical data. The same is true regarding the indication for failure to grow in children. As more effective medications are identified and are able to be instituted at earlier ages, it is anticipated that there will be less of an indication to operate in these young patients. Similarly, if an adenocarcinoma is identified, colectomy is indicated. In certain patients, the presence of severe extraintestinal disease is also an indication for surgery. In some cases, severe extraintestinal disease will respond to surgery; however, there are some cases in which the extraintestinal disease has a course relatively independent of the colon. 

Indications for Surgery for Crohn Disease Unlike indications for surgery for UC, indications for surgery for Crohn disease are generally reserved for complications of the disease. Similar to UC, surgery is also performed in children with Crohn disease when they show failure to grow. In addition, surgery is frequently performed for symptoms of obstruction secondary to fibrostenosing Crohn disease (Fig. 52.40). Also, if patients have a perforating Crohn disease associated with abscess or fistula, surgery may be indicated. The presence of many types of fistulas is also a relative indication for surgery. For example, the presence of a symptomatic ileal sigmoid fistula resulting in significant diarrhea bypassing the entire colon can be an indication for surgery. The occurrence of enterocutaneous fistulas is an indication for surgery. Enteroenteric fistulae are not an indication for surgery unless they are associated with significant symptoms of obstruction or discomfort. The

CHAPTER 52  Colon and Rectum

A

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B FIG. 52.39  (A) A dysplasia-associated lesion or mass (DALM) in a patient with long-standing ulcerative colitis and sclerosing cholangitis. (B) High-grade dysplasia within a DALM in a patient with long-standing ulcerative colitis and sclerosing cholangitis.

A

B FIG. 52.40  (A) Gastrografin enema showing significant stricture (arrow) of sigmoid colon secondary to Crohn disease. (B) Segmental colonic resection for fibrostenotic disease. Note the significant wall thickening and narrowed lumen (arrow) and its size compared to the tip of the scissors.

presence of significant abdominal pain associated with obstruction is considered an indication for surgery. Patients with Crohn disease who have associated cancer or dysplasia, as with patients with UC, are an indication for surgery. In patients with Crohn disease, as with UC, areas of dysplasia in the colon can be multifocal, and for this reason, if this occurs in the colon, a total proctocolectomy is considered preferable to a segmental resection. 

Surgical Options for Ulcerative Colitis There are several operations that are currently performed for UC. These include subtotal colectomy, ileostomy, and Hartmann procedure, frequently performed for fulminant disease. Total proctocolectomy with end ileostomy and proctocolectomy with either

stapled or hand-sewn IPAA are commonly performed in the elective setting. Subtotal colectomy and ileal rectal anastomosis and total proctocolectomy with continent ileostomy are less commonly performed procedures. We discuss these in order next. Total Proctocolectomy With End Ileostomy Subtotal colectomy and ileostomy and Hartmann procedure is the treatment for patients with fulminant colitis not responding to maximal medical therapy. The term “toxic megacolon” has long been used to refer to a condition arising when patients become toxic from colitis irrespective of its etiology (e.g., whether this be UC, Crohn colitis, infectious, or ischemic). In any of these conditions, as the mucosa sloughs, the endotoxins within the bowel

1352

SECTION X  Abdomen

lumen are absorbed leading to a septic state characterized by leukocytosis, tachycardia, fever, and in severe cases, hemodynamic instability. Many of these patients have protein-losing enteropathy and have associated hypoalbuminemia. If the colitis is severe enough to have an associated colonic ileus, this is apparent on an abdominal film with an increased diameter of the transverse colon (>5 cm). The definition of toxic megacolon is made when any three of these five factors are present. It is important to realize that a patient can have toxic megacolon without having a “megacolon” (i.e., they can just be “toxic” or septic from their colitis). When patients begin exhibiting symptoms of toxic megacolon, prompt surgery is indicated in order to prevent colonic perforation. With the improved medical therapy, this clinical scenario is becoming less common. In performing this operation, whether performed open or in a minimally invasive fashion, it is important to be gentle with the colon, as ordinary manipulation can result in perforation. If the colon is very dilated and there is loss of domain, the procedure may not be able to be safely performed in a minimally invasive fashion. One of the common complications of this procedure postoperatively is a “blow out” of the Hartmann stump, resulting in a pelvic abscess. This complication many times can be avoided simply by leaving a very long Hartmann stump and incorporating this into the fascial closure of the midline abdominal laparotomy wound or the specimen extraction site, depending on whether it is an open or minimally invasive procedure, and closing the incision over this. In this manner, if the stump dehisces and a wound infection develops, the wound is opened and there is a controlled mucous fistula rather than a deep pelvic infection. Once the patient has stabilized and weaned off immunosuppressant medications, usually after a period of 3 months, another procedure for restoration of intestinal continuity can be performed.  Subtotal Colectomy and Ileorectal Anastomosis The option of ileal rectal anastomosis for the treatment of UC avoids complications of pelvic dissection such as disturbances of sexual function in men and reduced fertility seen in women, since there is no pelvic dissection. The key to good function following this operation is proper patient selection. Patients with limited rectal involvement do best, however, that is uncommon in UC, where the worst disease is usually located distally. In addition, since the patient retains the rectum with this procedure, these patients need to undergo continued surveillance for dysplasia because they are at in an increased risk of cancer in the retained rectum over time.  Ileal Pouch–Anal Anastomosis IPAA has become the most popular procedure for UC not responding to medical therapy as well as for patients requiring colectomy for the presence of dysplasia. It has several advantages over ileal-rectal anastomosis in that it removes the entire colon as well as the majority of the at-risk mucosa, depending on how the operation is performed (i.e., stapled or hand-sewn anastomosis). IPAA was described in the mid to late 1970s and involves removing the entire colon and the majority of the rectum. It has two essential components: proctocolectomy and creation of a small bowel reservoir using the terminal ileum. This reservoir is then either sewn or sutured to the anal canal or lower rectum. There have been many different configurations of pouches or reservoirs that have been proposed in the past, including S Pouches, W Pouches, and H Pouches, all with relative advantages and disadvantages. However, by far, the simplest and easiest pouch and the one with the least complications is the J Pouch, which has withstood the test of time.

FIG. 52.41  Creation of an ileal J pouch using a cutting linear stapler. For replacement of the rectum, a reservoir is created from the distal ileum. The stapler joins two limbs of intestine with staples while dividing the intervening wall. The diameter of the pouch is created twice as large as the original diameter of the ileum. The limbs of the J pouch should be 15 cm in length. Two fires of a linear stapler are required; either a 75- or 100-mm stapler can be used.

This is created using 15-cm limbs of terminal ileum and two firings of a GIA stapler (Fig. 52.41). The apex of this J Pouch is then either stapled to the distal rectum, leaving a very short rectal cuff (Fig. 52.42), or hand-sewn to the distal rectum after a 2-cm mucosectomy is performed (Fig. 52.43). Currently, the stapled approach is preferred simply because it provides superior continence and it is much quicker to perform. However, in cases of dysplasia or cancer, hand-sewn approaches still may be warranted. IPAA generally yields good functional results in patients with UC. Since many patients who are undergoing this operation are on immunosuppressives at the time of surgery or in poor nutritional state, this operation is commonly performed with temporary fecal diversion (temporary loop ileostomy). This is in place for 2 to 3 months, during which these immunosuppressant medications are weaned and the patient regains their normal nutritional state. The temporary ileostomy can then be closed, typically without requiring a laparotomy. In patients who are not on immune suppression and in good nutritional state (this usually refers to patients undergoing surgery for the findings of colonic dysplasia), the operation can safely be done in one stage without fecal diversion provided that there is no tension on the IPAA. Several technical maneuvers can be performed to lessen the tension on the IPAA. These include mobilization of the small bowel mesentery to the level of the pancreas (Fig. 52.44). When dividing the right colon mesentery, the ileocolic vessels should be preserved in their entirety. If distal traction is placed on the apex of the J pouch, it should easily reach just below the symphysis pubis (Fig. 52.45). When this maneuver is performed, one can either feel or visualize which small bowel mesenteric vessel is under more tension, the superior mesentery vessels or the ileocolic vessels. The vessel with the greater amount of tension can be divided, allowing greater length on the small bowel mesentery. “Peritoneal windowing” can

CHAPTER 52  Colon and Rectum

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FIG. 52.42  Fashioning of stapled ileal pouch–anal anastomosis. A circular stapler is used; typically a 29-mm stapler is selected. A common error is to leave too long a segment of rectum, resulting in the persistent symptoms due to this retained segment of mucosa affected with inflammatory bowel disease (cuffitis).

FIG. 52.44  Mobilization of the small bowel mesentery to the third portion of the duodenum. Here the small bowel mesentery has been retracted cephalad exposing the third portion of the duodenum (arrow).

FIG. 52.43  Hand-sewn ileal pouch–anal anastomosis after anorectal mucosectomy.

also provide mesenteric length. This is a maneuver whereby small slits are created in the anterior and posterior peritoneum covering the mesenteric vessels. These horizontal slits in the peritoneum, in

most cases, provide for one or two extra centimeters of mesenteric length (Fig. 52.46). Needless to say, the more obese an individual is, the more difficult it can be to obtain sufficient mesenteric length for the small bowel to reach tension-free to the pelvis. In addition to this, with very tall individuals and those with a long torso, tension can be an issue as well. Common early complications of IPAA include those associated with nonhealing of the IPAA: pelvic sepsis, ileal pouch–anal anastomotic fistulae, ileal pouch–vaginal fistulae, ileal pouch–anal anastomotic sinuses, and ileal pouch–anal

1354

SECTION X  Abdomen

anastomotic strictures (often a reflection of anastomotic tension). Late complications include the diagnosis of Crohn disease, which is more common in patients who undergo emergent colectomy and in those patients who have a diagnosis of indeterminate colitis. With a “good” result, patients with IPAA will have up to six bowel movements within a 24-hour period, usually including one nocturnal bowel movement. In the majority of patients, at about 6 months, there will be significant enlargement of the ileal pouch, allowing patients to reduce the amount of antidiarrheal medication they take to control their output. 

choice for young patients with UC. This operation involved construction of a reservoir, similar to that used with the IPAA. Here, instead of continence being maintained by the anal sphincter, continence was maintained by an intussuscepted segment of ileum positioned between this reservoir and the end ileostomy. A continent ileostomy is air and water tight; however, the intussuscepted segment is very prone to dessusception, rendering the stoma incontinent and requiring revisional surgery. This procedure works best in individuals with a thin body habitus as with heavier individuals the thicker mesentery also predisposes to dessusception. 

Continent Ileostomy Continent ileostomy was first described in the late 1960s and remained very popular until IPAA surpassed it as the procedure of

Surgery for Crohn Disease Ileocolic Resection Ileocolic resection is one of the most common operations performed for patients with Crohn disease as it is estimated that the ileocecal area is the site of involvement in nearly half of patients. Indications for surgery in these patients are usually either due to fibrostenosing disease with obstruction or associated fistulizing disease/mass/abscess or phlegmon. As the terminal ileum lies in the pelvis in close proximity to a number of pelvic structures, if there is a significant obstruction and a proximal perforation occurs, the resulting abscess can perforate into the sigmoid colon or bladder. The sigmoid colon is by far the more common, and the resulting ileosigmoid fistula fairly frequently occurs in these patients. When performing an ileocolic resection, one must always be alert to any “adhesions” and make sure these are not enteroenteric fistulas. Ileocolic resection lends itself well to the laparoscopic approach. Exceptions are cases in which there is extensive fistulizing disease or a significant phlegmon in which there is difficulty separating the right colon mesentery/terminal ileum away from the retroperitoneal structures. In deciding margins of resection, one should select areas of bowel that feel normal and are not thickened and have a normal thickness of the bowel-mesenteric junction. The ability to palpate a discrete small bowel-mesenteric junction is usually a good indicator that the lumen is free of significant Crohn inflammation. While there are many ways to construct the ileocolic anastomosis, the authors prefer a hand-sewn

FIG. 52.45 Estimation of J-pouch length. The apex of the J pouch should be able to be brought down below the level of the symphysis pubis. This is a good estimate of a tension-free reach to the anal canal.

A

B FIG. 52.46  Peritoneal windowing. (A) The mesenteric peritoneum is lifted away from the superior mesenteric artery by lifting it up with a hemostat and then divided using the electrocautery. (B) The mesenteric peritoneum has been divided perpendicular to the axis of the superior mesenteric artery. Note that at each area where the peritoneum has been divided, an additional 1 cm of mesenteric length has been obtained.

CHAPTER 52  Colon and Rectum end-to-end anastomosis. Postoperatively, these anastomoses are very easy to evaluate endoscopically and to dilate in the event of recurrent disease, which is not true of side-to-side stapled anastomoses. It is paramount that however the anastomosis is constructed, it is made very wide.  Segmental Colon Resection Segmental colonic resection has increasingly been used in the treatment of Crohn disease over the last two decades. This has been performed for two reasons: (1) recognition of the important role of water absorption (see section on colonic physiology) performed by the colon, and recognition that many of these patients will undergo repeated operations, and (2) availability of newer and more potent medications for Crohn disease allowing more effective suppression of recurrent disease. The idea of segmental resection for colonic Crohn disease can be performed in patients who have isolated areas of colonic stricture with relatively normal areas of “skipped” normal-appearing colon with normal colonic distensibility. In these patients, performing a segmental resection is associated with a much higher risk of recurrence, so this should always be accompanied by some type of postoperative chemoprophylaxis to reduce the risk of recurrence of the disease.  Subtotal Colectomy and Ileorectal Anastomosis This is an operation that is well suited to patients with Crohn disease if they have a relative rectal-sparing and an otherwise diseased colon. Segmental resection is preferable if there are areas of normal intervening colon. However, this operation also, as with segmental colectomy, is associated with a much higher rate of recurrence. Options for this, if there is a smaller amount of retained rectum, are to perform an ileal pouch–rectal anastomosis in order to lessen the number of bowel movements that the patient has after surgery. Depending on the height of the anastomosis and the circumstances of the surgery (redo, associated immunosuppression, patients’ nutritional state), this may require temporary fecal diversion (temporary loop ileostomy) to facilitate healing.  Proctocolectomy and Ileal-Pouch–Anal Anastomosis In previous editions of the Sabiston textbook, there perhaps was only a passing mention of this procedure; however, every year, this is more frequently considered a possibility for patients with Crohn disease, providing that they do not have obvious perianal disease. With the advent of newer and more potent immunosuppressive drugs, this procedure is considered an option in an educated patient who is aware of the increased risk of morbidity and the less favorable functional results (i.e., greater number of bowel movements) as compared to when this operation is performed for patients with UC. In addition, there is, of course, a higher risk of fistulizing disease and the need to convert to an end ileostomy. However, in the motivated patient who recognizes and accepts these risks, this procedure can be performed. See the section on IPAA for UC for technical details regarding this procedure. 

Cancer Risk As with UC, there is an increased risk of colon cancer in patients with longstanding Crohn disease, although it is thought to be somewhat less than with UC. However, in patients in whom there has been a cancer identified, total colectomy should be performed,

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as there have been studies showing colonic procarcinogenic mutations tracking along the colon and the risk of a subsequent cancer in other areas of the colon is high.18 

Postoperative Complications Many patients with IBD who undergo surgery are on immunosuppressive medications, and in addition, many of these patients are hypoalbuminemic, since they have protein-losing enteropathy from their disease. Because of this, they are at increased risk for infectious postoperative complications. There are differing opinions as to the relative risk of complications with these different medications. However, overall, it is thought that steroids pose an increased risk for infectious complications, as do the administration of biologic medications, within several months before surgery.19 Because of this, there should be a discussion with patients regarding the possibility of a temporary fecal diversion if an operation is undertaken in which an anastomosis is considered so that, if in the clinical judgment of the surgeon a temporary ileostomy is considered prudent, this can be performed. 

Postoperative Recurrence Recurrence rate following surgery for Crohn disease varies depending on the site of surgery as well as other factors such as environmental factors. It has been reported that Crohn patients who smoke are at higher risk of early disease recurrence, as are patients younger than 30 years old and those who have already had two or more operations for fistulizing disease.20 There has been an increasing recognition that early intensive medical treatment beginning very soon postoperatively may successfully reduce the risk of recurrence. Regular endoscopic monitoring of the lower GI tract for signs of recurrent disease is important to allow therapeutic intervention prior to the development of therapy-resistant fibrosis. 

INFECTIOUS COLITIS Infectious colitis may be diagnosed among patients with acute diarrhea and colonic inflammation. Their importance for the surgeon arises in their capacity to mimic surgical conditions such as an acute abdomen or IBD and in some cases to deteriorate to the point where they require surgical treatment.

Clostridium difficile Infection C. difficile is a common inhabitant of the GI tract that can manifest in a spectrum of symptoms ranging from that of an asymptomatic carrier to fulminant colitis. 

Epidemiology C. difficile is the most common cause of healthcare-associated diarrhea and is considered to be a major source of healthcare-associated morbidity occurring in 2% of all hospital discharges for all diseases. The prevalence of asymptomatic colonization of C. difficile among adult hospitalized patients ranges from 3% to 26% in different studies. Around 453,000 new cases of CDI are diagnosed annually in the United States, of which 83,000 are recurrent cases, with 29,300 attributed deaths.21 Interestingly, after plateauing at historical high rates, some regions have begun to show a decline in incidence attributed to specific prevention and treatment programs. In participating Canadian hospitals, for example, the incidence of CDI has decreased from 7.9/10,000 patient-days in 2011 to 4.3/10,000 patient-days in 2015.22 

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SECTION X  Abdomen

Microbiology and Transmission C. difficile is an anaerobic, spore-forming, gram-positive bacillus. Transmission routes include person-to-person spread through the fecal-oral route or through exposure to a contaminated environment by ingestion of spores from other patients and transmission via healthcare personnel’s hands. Toxicogenic C. difficile pathogens can produce A and B toxins, both of which have been associated with colitis. Binding of toxin A or B to colonocyte glycoprotein receptors leads to colonocyte death and release of inflammatory mediators. The emergence of the C. difficile Ribotype 027 strain in the mid-2000s resulted in significant outbreaks across the Western world associated with more severe disease outcomes and deaths. 

Risk Factors The most important risk factor for the development of a clinical infection is recent exposure to antibiotics. Antibiotics affect the natural bowel flora, decreasing the natural ability to suppress the growth and spread of C. difficile. Virtually all antibiotics have been associated with C. difficile, but particularly third and fourth generation cephalosporins, fluoroquinolones, clindamycin, and carbapenems have been linked to a higher risk of CDI. Other risk factors include immunodeficiency (including human immunodeficiency virus infection), chemotherapy treatment, use of acid suppressing medications such as proton pump inhibitors, GI surgery or manipulation of GI tract including tube feeding, and prolonged hospitalization or lengthy stay in nursing homes or rehabilitation units. Patients with IBD have increased rates of CDI, along with worse outcomes [HIV] and higher rates of colectomy. These patients are more likely to receive immunosuppressants and antibiotics and have a different intestinal flora compared to healthy subjects. Differentiating between an IBD exacerbation and CDI can be difficult as the symptoms overlap, and a high index of suspicion must be maintained. Patients with an increased risk for death from CDI include those with advanced age, multiple comorbidities, hypoalbuminemia, leukocytosis, acute renal failure, and those infected with Ribotype 027. 

Clinical Presentation Symptoms of CDI commonly begin 4 to 9 days after initiation of antibiotics but can commence 10 weeks or more after antibiotic treatment. Patients presenting with new-onset, unexplained, watery diarrhea (with three or more unformed stools in 24 hours) should be suspected of having CDI. Patients may also have abdominal pain, fever, and an associated ileus. Patients with CDI can be categorized into asymptomatic colonization, nonsevere disease, severe disease, and fulminant disease. A variety of scores have been utilized to assess clinical severity and treatment response. Leukocytes of at least 15,000 cells/μL and/or serum creatinine of at least 1.5 cells/μL are predictors of severe disease according to the Infectious Disease Society of America. Fulminant or severe CDI is diagnosed in patients demonstrating hypotension or shock, ileus, or megacolon. The ATLAS criteria is a simple clinical bedside score, which includes age, temperature, leukocytosis, albumin, and systemic antibiotic treatment and has been used to assess response to treatment.23 

Diagnosis The diagnosis of CDI is based on typical symptoms in combination with stool testing. Laboratory testing is based on detection of C. difficile toxins, C. difficile antigen, or the bacteria itself. A variety of commercial tests are utilized, including enzyme-linked immunosorbent assay for toxin detection, glutamate dehydrogenase

immunoassay for C. difficile antigen detection, nucleic acid amplification test, polymerase chain reaction testing, and stool cultures. Flexible sigmoidoscopy may be helpful as a diagnostic modality for CDI. Although it is not a first-line modality for diagnosis, it can be helpful in cases of inconclusive stool testing or to help exclude other etiologies. Classically raised, yellowish-white small (2–10 mm) plaques (pseudomembranes) can be observed in approximately half of patients with CDI (Fig. 52.47). Nonspecific colitis can be found in an additional 25%. Histologic findings from the plaques reveal an inflammatory exudate with mucinous debris, fibrin, necrotic epithelial cells, and polymorphonuclear cells. In fulminant colitis, colonoscopy may increase the risk of perforation and should be considered only when the benefit is higher than the risk of complications. Imaging is not very useful for diagnosis as it is not specific but can assist in assessing disease severity and response to treatment. Typical CT findings include significant colonic wall thickening, bowel dilation, pericolonic fat stranding, high attenuation oral contrast in the colonic lumen alternating with low-attenuation inflamed mucosa (accordion sign), and ascites. Ultrasound may also be useful, especially among critically ill patients who cannot be transported to the CT scanner in radiology. Ultrasonography may show bowel wall thickening, narrowing of the lumen, as well as pseudomembranes, which are seen as hyperechoic lines covering the mucosa. 

Treatment Initial treatment includes stopping or minimizing previous antibiotics, parenteral fluids, and correction of electrolytes. The use of antiperistaltic agents for the treatment of CDI should be avoided. Antibiotic treatment of CDI is determined according to the clinical setting and can be divided into the initial episode, recurrent episode, severe, and fulminant disease. Table 52.4 summarizes current antibiotic treatment recommendations for initial episodes and for severe and fulminant disease. Treatment options for recurrent episodes generally include changing antibiotics (from metronidazole to vancomycin or fidaxomicin from vancomycin). In addition, tapered and pulsed regimens are used. Fecal Microbiota Transplant Fecal microbiota transplant (FMT) for patients with recurrent episodes of CDI is a relatively new treatment. Patients with CDI lack protective colonic microbiota to resist replication and colonization of C. difficile. Reimplantation of normal gut bacteria, particularly bacteria resistant to C. difficile from healthy donors can help restore normal gut biodiversity and correct the imbalance. Different routes of administration have been described in the literature including nasogastric, oral (frozen fecal microbial capsules), rectal enema, and colonic per colonoscopy. A recent comparison between upper and lower methods of delivery demonstrated the lower approaches being more effective.24 The efficacy of FMT ranges from 77% to 100%, with multiple FMTs needed to achieve a good clinical response. Current guidelines recommend FMT for patients with multiple recurrences of CDI, in whom antibiotic treatment has failed.  Monoclonal Antibodies Bezlotoxumab and actoxumab are monoclonal antibodies directed against C. difficile toxins B and A, respectively. These antibodies limit colonic damage by neutralization of the toxin and block the binding to host cells.25 They can be used as coadjuvant treatment

CHAPTER 52  Colon and Rectum

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1

B

A

FIG. 52.47  (A) Endoscopic view of pseudomembranes associated with Clostridium difficile. (B) Pseudomembranes overlying the colon mucosa at the time of colectomy. The patient had active Clostridium difficile colitis with coexisting Crohn colitis.

TABLE 52.4  Antibiotic treatment of Clostridium difficile infection. CLINICAL CONDITIONS

TREATMENT

First episode

1. Oral vancomycin 125 mg 4 times daily OR 10 days 2. Fidaxomicin 200t mg twice Daily If vancomycin and fidaxomicin are not available: metronidazole 500 mg 3 times daily can be given for nonsevere disease. Vancomycin, 500 mg 4 times daily (oral or by nasogastric tube). At least 10 days, duration should be individualized In case of ileus: 1. Consider adding rectal instillation of vancomycin. 2. Intravenously administered metronidazole (500 mg every 8 hours) should be administered together with oral or rectal vancomycin.

First episode—fulminant (hypotension, shock, ileus, megacolon)

TREATMENT DURATION

Adopted from McDonald LC, Gerding DN, Johnson S, et al, Clinical Practice Guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66:987–994.

with antimicrobial therapy to help prevent recurrence, especially among patients infected by Ribotype 027, in severe CDI, and in immunocompromised patients.  Surgery Patients with fulminant CDI who develop signs of systemic toxicity, toxic megacolon, or perforation should be operated upon emergently. Emergency colectomy for patients with fulminant colitis provides a survival advantage compared with continuing antibiotics. Among severely ill patients, a total or subtotal abdominal colectomy with preservation of the rectum has traditionally been performed. A newer option with similar results for patients without necrosis or perforation is exteriorization of a diverting loop ileostomy with on-table colonic lavage followed by antegrade vancomycin flushes.26 

OTHER COLONIC INFECTIONS Diarrhea and colitis can be caused by other pathogens. Most of these will not require surgery. A careful history can discover the source in many cases, such as polluted drinking or recreational

water, consumption of contaminated fruits and vegetables, unpasteurized milk, undercooked meat and fish, shellfish, and eggs. International travel, as well as contact with animals and their feces should also be queried. Table 52.5 summarizes the important characteristics of common bacteria causing diarrhea and colitis. The initial approach includes a careful history, evaluation for dehydration and electrolyte disturbances, and stool testing for ova and parasites and for culture and sensitivity. Patients with signs of sepsis or those who have traveled from enteric fever–endemic regions and immunocompromised patients should also have blood cultures obtained. Initial treatment includes rehydration and correction of electrolyte disturbances. Oral rehydration solution is recommended for mild to moderate disease. Nasogastric administration of oral rehydration solution may be considered for patients who do not tolerate oral intake. Patients with signs of severe dehydration or ileus should be treated with isotonic IV fluids (normal saline or lactated Ringer’s solution). The majority of patients who present with acute watery diarrhea and those without recent international travel do not require antimicrobial therapy. Immunocompromised

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SECTION X  Abdomen

TABLE 52.5  Clinical characteristics of common enteric infections. PATHOGEN

CHARACTERISTICS AND CLINCAL PRESENTATION

Campylobacter jejuni

Spiral, microaerophilic gram-positive rod. Exposure to improperly prepared chicken or beef. Fever, watery diarrhea, and abdominal pain. Commonly involves the cecum and terminal ileum. May mimic appendicitis or Crohn disease. Gram-negative coccobacillus. Exposure to contaminated water or food. Abdominal pain and bloody diarrhea, may mimic appendicitis or Crohn disease. Gram-negative, facultative anaerobe. Common cause for dysentery in developing countries. Often affects rectum and sigmoid colon. Fever, abdominal pain, watery diarrhea that can progress to bloody diarrhea. Gram-negative, facultatively anaerobic bacilli Recent travel to an endemic area, consumption of foods prepared by a traveler to an endemic area. Fever with or without diarrhea, abdominal pain, cramping and vomiting.

Yersinia enterocolitica

Shigella

Salmonella typhi or Salmonella enterica serotypes Paratyphi

Adapted from Shane AL, Mody RK, Crump JA, et al. 2017 Infectious Diseases Society of America Clinical Practice Guidelines for the diagnosis and management of infectious diarrhea. Clin Infect Dis. 2017;65:1963–1973.

or septic patients, as well as those suspected of enteric fever, should be treated with empirical, broad-spectrum antimicrobial therapy, usually with fluoroquinolones, such as ciprofloxacin, or macrolides, such as azithromycin, depending on local susceptibility patterns. Surgical intervention is rarely required apart from those cases developing severe fulminant disease that lead to perforation or toxic megacolon. Viruses can also cause acute diarrhea and colitis. Cytomegalovirus (CMV) is an important etiology to consider in immunocompromised hosts, particularly in advanced HIV infection, transplant patients, patients with IBD, and in those receiving chemotherapy. CMV colitis commonly presents with watery or bloody diarrhea, fever, and abdominal pain. Diagnosis is established by serology and by determining viral load in the blood. Endoscopy demonstrates patchy mucosal erythema in the colon. Inclusion bodies seen on biopsy are pathognomonic for CMV. CMV colitis can progress to sepsis, toxic megacolon and colon perforation. Treatment is usually supportive with the addition of ganciclovir. Patients with severe, complicated disease may require surgery. 

ISCHEMIC COLITIS Ischemic colitis is a common disorder that develops when the arterial blood supply to the colon is insufficient to support cellular metabolic demands. It is the most common form of GI ischemia, with rates of 7.1 to 22.9/100,000 person-years.27 Severity varies within a wide spectrum, from mild self-limiting disease to severe life-threatening colonic ischemia. Considering the wide range of clinical findings with most patients presenting with mild nonspecific symptoms, the true incidence is likely much higher. It is important to differentiate ischemic colitis from situations of acute mesenteric ischemia, in which a major vessel of the bowel is obstructed, wherein patients commonly present with severe pain out of proportion to physical findings and require immediate vascular intervention. Ischemic colitis is considered a disease of small blood vessels and typically presents less dramatically, seldom requiring vascular intervention. Most cases, when recognized and managed promptly, do not require surgery. Delays in diagnosis

and treatment, however, can result in the need for emergency colectomy with high morbidity and mortality.

Anatomic Considerations The arterial blood supply to the colon is derived from the SMA and the IMA. The SMA gives off the ileocolic, right colic, and middle colic arteries. The IMA gives rise to the left colic and sigmoid arteries and ends as the superior rectal (hemorrhoidal) artery (Fig. 52.8). There are two well-described collateral networks that aid in preventing colonic ischemia by providing “backup” both within the territories of the two major arteries and between them. The main collateral vessel is the marginal artery of Drummond, which runs parallel and close to the mesenteric margin of the colon from the cecocolic junction to the rectosigmoid junction. The colon can receive collateral blood supply through this artery when one of the larger arteries is obstructed. It is important when resecting a section of colon to preserve this artery since only the vasa recta are located between it and the colon. When it is compromised, ischemia of that section of colon may result. The second collateral circulation can be found in the proximal region of the large arteries. The “arc of Riolan” (meandering mesenteric artery) is an infrequent finding, traversing close to the mesenteric root and connecting the SMA or middle colic artery to the IMA or left colic artery (Fig. 52.48). It can have a critical role in situations of SMA or IMA occlusion. The presence of a large arc of Riolan commonly indicates an obstruction of one of the major mesenteric arteries. Watershed areas of the colon are potentially found at the edge of the region supplied by the two main arteries, the SMA and the IMA, zones that are frequently dependent upon collateral circulation (Fig. 52.49). There are two well-described watershed areas where the collateral circulation is classically inconsistent and vulnerable to ischemia. The first is the area of the splenic flexure (Griffiths point). In some studies, up to 50% of specimens were found to lack a marginal artery in the region where the SMA and IMA circulations meet. Commonly, surgeons avoid making anastomoses in this area for fear that the impaired blood supply will not be sufficient to permit anastomotic healing, leading to anastomotic leaks. A second potential watershed area is the

CHAPTER 52  Colon and Rectum Arc of Riolan

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can affect thrombogenesis, and illicit drugs such as cocaine and methamphetamines cause ischemia through vasoconstriction, hypercoagulation, and direct endothelial injury. 

Presentation and Diagnosis Middle colic artery Superior mesenteric artery

FIG. 52.48  The Arc of Riolan. (From Gordon PH, Nivatvongs S, ed. Principles and Practice of Surgery for the Colon, Rectum and Anus. 2nd ed. St. Louis: Quality Medical Publishing; 1999:27.)

rectosigmoid junction (Sudeck’s point). This region receives it blood supply from the superior hemorrhoidal artery and distal sigmoid branches, both terminal branches of the IMA and prone to atherosclerotic changes. The right colon, although not classically considered a watershed area, it is also vulnerable to ischemia from embolic occlusion because the ileocolic artery is the terminal branch of the SMA. For this reason, the right colon is also particularly prone to low-flow conditions such as heart failure, hemorrhage, and sepsis. The rectum, which has a good blood supply from both the IMA and the iliac circulation, as well as a strong collateral network, is rarely the victim of ischemic injury. 

Risk Factors Ischemic colitis may occur in all ages but is significantly more common in elderly patients, in women, and in patients with multiple comorbidities. Several medical conditions and medications have been associated with ischemic colitis (Box 52.2)28 Patients with low-flow states, as a result of heart failure or sepsis, are especially prone to develop ischemic colitis. Diabetes mellitus, hypertension, chronic obstructive pulmonary disease, peripheral vascular disease, and renal disease have also been associated with this disorder. Patients undergoing aortic reconstructive surgery or abdominal surgery in which the IMA is ligated are also especially predisposed to colonic ischemia. In these patients, if the collateral circulation is not sufficient, acute occlusion of the IMA can result in sigmoid and left colon ischemia. Several medications have been implicated in ischemic colitis. Constipation-inducing drugs can cause ischemic colitis, most likely as a result of reduced blood flow and increased intraluminal pressure. Immunomodulator drugs such as anti-TNF-α inhibitors

The majority of patients with partial-thickness ischemia of a localized section of colon present with relatively nonspecific signs and symptoms. A high index of suspicion is needed to make an early diagnosis. Presenting symptoms usually include sudden abdominal pain and cramping, tenesmus, and bloody diarrhea or hematochezia. The combination of these symptoms is present in close to 50% of the patients, with the pain usually beginning prior to the bleeding. Bleeding associated with ischemic colitis is usually minor and seldom requires blood transfusions. Patients may also experience nausea, vomiting, and a low-grade fever. On physical exam, abdominal distension may be noted, as well as tenderness overlying the involved region. A good medical history is important in establishing the diagnosis, with a focus on associated diseases and medications. The most common affected region is the left colon (including the splenic flexure), followed by the sigmoid colon based on the affected blood supply. Pancolitis due to ischemia is associated with a worse prognosis. About a quarter of the patients present with isolated right-sided ischemic colitis. These patients are more likely to present with abdominal pain without bleeding and more commonly have atrial fibrillation, coronary artery disease, and/or chronic renal failure. Patients with isolated right-sided ischemic colitis have a higher chance of requiring surgery and have a poorer prognosis. A minority of patients will present with full-thickness ischemia. These patients are sicker and commonly present with high fever, leukocytosis, acidosis, and peritonitis. Basic laboratory testing is nonspecific but can assist in predicting severity. Severe disease has been associated with an increased white blood cell count, blood urea nitrogen, lactate dehydrogenase, and decreased hemoglobin and albumin levels. Acidosis, decreased bicarbonate, and increased lactate levels are also associated with severe ischemic colitis. It is also recommended to test stool for C. difficile toxin, ova and parasites, and culture and sensitivity in order to exclude an infectious etiology. Abdominal plain films may show bowel distension and “thumbprinting,” which are rounded densities along the sides of a gas-filled colon indicative of submucosal edema. These are nonspecific to ischemic colitis since thumbprinting can be found with other situations of colonic inflammation. Free intraperitoneal air suggests bowel perforation and should lead to immediate operative management. Water-soluble contrast enemas have generally become obsolete in the diagnosis of ischemic colitis but may still be used for the evaluation of chronic ischemic strictures. CT scans of the abdomen have become the primary noninvasive modality for the initial diagnosis of colonic pathology. CT scans, performed using both IV and oral contrast, can assist in determining the location of involved areas, to assess the severity, identify complications, and exclude the presence of other diseases. Findings suggestive of ischemic colitis, although relatively nonspecific, include segmental bowel thickening, pericolonic fat stranding, and thumb printing. Pneumatosis intestinalis (the presence of gas in the colonic wall), portal venous gas, and the absence of large bowel enhancement on contrast-enhanced CT usually indicate severe transmural disease favoring immediate surgical intervention. Vascular imaging is usually not indicated in cases of ischemic colitis, as this is usually a disease of small vessels; however, in cases of pain of sudden onset

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SECTION X  Abdomen Arch of Riolan

Superior mesenteric artery Middle colic artery

Marginal artery of Drummond Left colic artery

Right colic artery

Sigmoidal arteries

Inferior mesenteric artery Ileocolic artery

Superior hemorrhoidal artery

FIG. 52.49  Lightly shaded colonic regions especially vulnerable to ischemia. (From Netz U, Galandiuk S. Management of ischemic colitis. In: Cameron JL, Cameron A, eds. Current Surgical Therapy. 12th ed. Philadelphia: Elsevier; 2017:171–176.)

that is out of proportion to physical and laboratory findings and in isolated right colon ischemic colitis, multiphasic CT angiography should be performed to exclude acute proximal mesenteric ischemia. The gold standard for the diagnosis of ischemic colitis is flexible endoscopy. Early colonoscopy should be performed (within 48 hours), except in cases of acute peritonitis or in cases of suspected severe transmural ischemia. In contrast to the expected increased risk of perforation due to endoscopy in the evaluation of ischemic colitis, current published literature does not demonstrate a higher rate of perforation compared to other patients. It is recommended, however, to refrain from overinsufflation and avoid advancing the scope beyond the most distal extent of disease. Common endoscopic findings characteristic of ischemic colitis include edematous and friable mucosa, erythema, petechial hemorrhage, and mucosal ulceration. The “single-stripe sign,” a single linear ulcer running along the longitudinal axis of the colon is rare but considered specific for ischemic colitis. Segmental distribution, with abrupt transition between injured and noninjured mucosa, and sparing of the rectum support ischemia over IBD. It is important to note that diagnostic endoscopy usually cannot distinguish between partial-thickness and full-thickness ischemia. Fig. 52.50 depicts a recommended algorithm for diagnosis and treatment of ischemic colitis. 

Treatment The majority of patients, nearly 80%, will respond to conservative nonoperative treatment, with significant improvement within a few days. The mainstay of treatment includes bowel rest, IV fluids, and broad-spectrum antibiotics. A nasogastric tube should be inserted if ileus is present. Efforts should be made to correct low-flow states and hypotension with aggressive fluid resuscitation and optimal treatment of associated conditions such as heart failure and sepsis. Colonic ischemia can result in failure of the intestinal epithelial barrier with bacterial translocation leading to overt sepsis. For this reason, empiric broad-spectrum antibiotics against both anaerobic and aerobic coliform bacteria are prescribed in ischemic colitis to cover the normal colonic bacterial flora. Cathartics are not recommended as they may lead to colon perforation. Glucocorticoids should be avoided unless treating a preexisting disorder such as lupus or rheumatoid arthritis. Most episodes of ischemic colitis are mild and self-limiting. Patients who fail to improve or have worsening symptoms within a few days should raise the concern for the development of fullthickness ischemia and should have repeat imaging or endoscopy to help guide treatment. A small proportion of patients with mild to moderate symptoms will develop a chronic colitis, with ongoing or recurrent bouts of

CHAPTER 52  Colon and Rectum BOX 52.2  Conditions and drugs

associated with ischemic colitis. Low Flow State • Septic shock • Congestive heart failure • Hemorrhagic shock • Hypotension  Atherosclerosis • Ischemic heart disease • Cerebrovascular disease • Peripheral vascular disease  Gastrointestinal • Constipation • Diarrhea • Irritable bowel syndrome 

Surgery and Invasive Interventions • Abdominal surgery • Aortic surgery (especially abdominal aortic aneurysm repair) • Cardiovascular surgery • Following endovascular abdominal manipulations (i.e., chemoembolization) • Postcolonoscopy  Cardiovascular/Pulmonary • Chronic obstructive pulmonary disease • Atrial fibrillation • Hypertension  Metabolic/Rheumatoid • Diabetes mellitus • Dyslipidemia • Systemic lupus erythematosus • Rheumatoid arthritis  Miscellaneous • Hypercoagulable states • Sickle cell disease • Long-distance running  Drugs • Constipation inducing drugs (opioids and nonopioids) • Cocaine and methamphetamines • Immunomodulatory drugs (anti-tumor necrosis factor-α, type 1 ­interferon-α, type 1 interferon-β) • Chemotherapeutic drugs (i.e., taxanes) • Female hormones and oral contraceptives • Decongestants (pseudoephedrine) • Serotoninergic (i.e., alosetron, sumatriptan)

symptoms of abdominal pain, bloody diarrhea, and sepsis. These patients have a higher rate of complications and commonly require surgical resection of the involved segment. Some patients who initially recover from partial-thickness ischemic colitis will eventually develop a chronic stricture at the involved segment. These patients may complain of constipation, narrowed stools, and abdominal pain. Diagnosis can be confirmed with a contrast enema, CT, or endoscopy. Symptomatic patients or those in which malignancy cannot be excluded should undergo elective resection.

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Patients who present with, or develop signs of transmural ischemia and perforation, including peritonitis, hemodynamic instability, free peritoneal air, and ominous signs on CT as mentioned earlier, such as portal venous gas, require emergent surgical exploration. A recent large database study identified a 25% 30-day postoperative mortality rate for ischemic colitis29 with other studies ranging up to 47% mortality following acute surgical intervention. Risk factors independently identified as associated with perioperative mortality after colectomy for ischemic colitis include the elderly, poor functional status, multiple ­comorbidities, preoperative septic shock, preoperative blood transfusions, preoperative acute renal failure, and delay from hospital admission to surgery. During surgery, it is important to visualize and assess the entire small and large intestine for signs of ischemia and gangrene. Ischemia commonly affects a recognizable segment of the colon, frequently in watershed areas. In these cases, an anatomic resection should be performed to allow sufficient blood supply to the remaining colon with minimal reliance on stressed collaterals. Deciding how much to resect or whether a specific segment is likely to survive can be difficult. Visual examination tends to be inaccurate, especially when the bowel is ischemic but still viable. Intraoperative infrared angiography is a relatively new technique that has been gaining popularity as an adjunct for determining bowel viability and for determining the integrity of intestinal anastomoses. In this technique, indocyanine green is injected intravenously and distributes throughout the circulation. Then, using a variety of commercially available imaging systems, the indocyanine green undergoes laser excitation, demonstrating realtime tissue perfusion (Fig. 52.51). Creation of an anastomosis is usually not recommended in the acute setting, due to the concern for evolving ischemia and the existence of hemodynamic instability and sepsis commonly encountered in these situations. A temporary abdominal closure with a planned second-look after 24 hours may be prudent to determine the need for further resection. Staple the ends and leave them in the abdomen, avoiding complications of a stoma as in very obese patients. Pancolic ischemia is rare, but such cases require total colectomy with ileostomy. In contrast to mesenteric ischemia of the small intestine, there is usually no indication for revascularizing the large bowel in primary colonic ischemia, which is not generally related to large artery obstruction. 

NEOPLASIA Colorectal Cancer Genetics As CRC is one of the most common cancers worldwide, much research has been directed into the genetics of CRC. It has long been appreciated that genetics play a role in the disorder and there has been an appreciation and recognition of specific inherited cancer syndromes that has greatly aided in our understanding of sporadic CRC. Before the reader passes on the next section, this section explains why some patients will develop a CRC very quickly and others, more slowly. Chromosomal Instability Pathway Much of our initial understanding of the genetic basis of CRC comes from the work of Vogelstein and colleagues, who evaluated nearly 200 samples of colorectal neoplasia ranging from polyps to invasive cancers. By checking for alterations in specific genes, they were able to propose a step-wise model of CRC carcinogenesis, involving the activation of an oncogene (a gene

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SECTION X  Abdomen

Symptoms: Abdominal pain, tenesmus, bright red blood per rectum, diarrhea

History: Comorbid conditions, surgical and recent procedural history, medications Physical exam and initial laboratory evaluation: Complete blood count, blood chemistry, arterial blood gases, serum lactate, coagulation studies

Initial treatment: Broad-spectrum antibiotics, hydration, analgesics

Peritonitis

Localized tenderness

CT Oral and IV contrast

Surgery Consider resection, determine margins using visual inspection, indocyanine green, or fluoroscein; anastomosis vs. Hartmann and diversion

Pneumoperitoneum pneumatosis, portal air

Segmental colon thickening, pericolonic inflammation

Apparent transmural necrosis

Endoscopy

Segmental edema, erythema and petechial hemorrhages, ulceration

Repear endoscopy/CT

Continued symptoms

Observation, IV fluids, bowel rest, antibiotics

Late complications (e.g., stricture)

Resolution

FIG. 52.50 Algorithm for investigation and treatment for ischemic colitis. (From Netz U, Galandiuk S. Management of ischemic colitis. In: Cameron JL, Cameron A, eds. Current Surgical Therapy. 12th ed. Philadelphia: Elsevier; 2017:171–176.) CT, Computed tomography; IV, intravenous.

that can induce cancer formation) and loss of several genes that act as tumor suppressors. Currently, it is thought that the majority of sporadic CRC arise in this fashion over the course of approximately 10 years from a precursor dysplastic adenoma. The molecular events involved include early APC (adenomatous polyposis coli) gene mutations, subsequent activating mutations in the oncogene KRAS, as well as mutations resulting in inactivation of the tumor suppressor gene TP53. Chromosomal instability refers to changes (gains or losses) in the numbers of chromosomes (aneuploidy) as well as subchromosomal genomic

amplifications and loss of heterozygosity seen with this pathway of carcinogenesis. It is currently thought that this pathway accounts for approximately 60% of patients with CRC. The second major pathway accounting for approximately 35% of patients is the CpG island methylator phenotype cancer, and then the mutator phenotype associated with Lynch syndrome, accounting for 5%. Fig. 52.52 shows the different genetic pathways or mechanisms for development of CRC and their overlap. This is a complex topic, and a detailed discussion is beyond the scope of this chapter. The surgeon does, however, need to know the basics

CHAPTER 52  Colon and Rectum

A

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B FIG. 52.51  Indocyanine green–based infrared angiography. (A) Colon before injection. (B) Colon after injection: ischemia of resection margin (blue arrow); normal perfusion of colon (yellow arrow). (From Netz U, Galandiuk S. Management of ischemic colitis. In: Cameron JL, Cameron A, eds. Current Surgical Therapy. 12th ed. Philadelphia: Elsevier; 2017:171–176.) FAP-associated carcinoma CIMP-MSS –1%

Suppressor (chromosomal instability) pathway

Familial adenomatous polyposis

CIMP+MSS carcinoma –20%

CIMP+MSS pathway

TSA pathway Conventional adenomacarcinoma sequence Sporadic CIMP-MSS carcinoma –60%

Mutator (microsatellite instability) pathway

Serrated (CIMP+) pathway TSA-associated carcinoma (?CIMP+ MSI-L) –1% MYH pathway

Lynch syndrome carcinoma CIMP-MSI-H –5% Sporadic CIMP+MSI-H carcinoma –13%

FIG. 52.52  Schematic represents several overlapping ways to describe the development of colorectal carcinoma. The red circles represent mechanisms based on suppressor and mutator pathways. The blue circles represent mechanisms based on the precursor lesion (the conventional adenoma-carcinoma sequence and serrated pathways). The yellow circles represent poorly characterized pathways. (From Snover DC. Update on the serrated pathway to colorectal carcinoma. Hum Pathol. 2011;42:1–10.) CIMP-, CpG island methylator phenotype negative; CIMP+, CpG island methylator phenotype positive; FAP, familial adenomatous polyposis; MSI-H, high degree of microsatellite instability; MSI-L, low degree of microsatellite instability; MSS, microsatellite stable; TSA, traditional serrated adenoma.

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SECTION X  Abdomen Oncogene mutations

15%

MSI-H

Colorectal cancer

3%

Lynch syndrome

12%

Sporadic

84%

Sporadic

1%

FAP

CIMP BRAF KRAS

MSS or 85% MSI-L

FIG. 52.53  Most colorectal cancers (85%, light blue and dark blue) show the MSS or MSI-L phenotype but are characterized by chromosomal changes. Most of these cancers develop through the classic adenomacarcinoma pathway, but about 1% develop with an inherited syndrome FAP (dark blue). About 15% of colorectal cancers (red and pink) have the MSI-H phenotype as a result of DNA mismatch repair deficiency. About 3% of colorectal cancers have MSI-H in context of the inherited Lynch syndrome (red), whereas 12% develop as sporadic tumors (pink), with sessile serrated adenomas as a typical precursor lesion. The distribution of typical molecular changes including the CIMP and mutations of the BRAF or KRAS oncogenes are sketched in green. Dark green is the proportion of positive or mutant changes and light green is the proportion of negative or wild-type changes. (From Brenner H, Kloor M, Pox CP. Colorectal cancer. Lancet. 2014;383:1490–1502.) CIMP, CpG island methylator phenotype; FAP, familial adenomatous polyposis; MSI-H, high-level microsatellite instability in relation to the phenotypes in the first bar; MSI-L, low-level microsatellite instability; MSS, microsatellite-stable.

regarding these pathways. Fig. 52.53 provides a summary of the different molecular subtypes of cancer, their frequency, and common genetic mutations.  CpG Island Methylator Phenotype The most common initiating mutation in this CpG island methylator phenotype pathway involves a mutation of the BRAF gene resulting in inhibition of normal colon cell apoptosis. This in turn leads to the development of hyperplastic or sessile serrated adenomas or polyps, which are prone to epigenetic silencing of genes within “CpG islands” in promoter regions by hypermethylation. A CpG island merely refers to a short segment of DNA with a cytosine and guanine content. The hMLH1 gene (one of the DNA repair genes involved in Lynch syndrome) is one of the best characterized genes that undergoes this type of epigenetic silencing by CpG hypermethylation. This will, in turn, result in a microsatellite instable-high (MSI-H) cancer if there is further gene mutation or methylation. As a consequence of this, most cancers arising from sessile serrated adenomas will have a MSI-H phenotype and are often located in the right colon.  Microsatellite Instability Mutator Pathway The microsatellite instability (MSI) pathway is thought to be involved in up to 15% of early-stage CRCs. This is due to a mutation in genes that are responsible for repairing base mismatches in DNA. These genes include mutL homologue 1 (MLH1), MLH3, mutS homologue 2 (MSH2), MSH3, MSH6, or PMS1 homologue 2 (PMS2).30 When mutations in these genes are present, mistakes that occur during DNA replication lead to mismatches

between DNA base pairs that are not repaired and accumulate further, leading to a progressive accumulation of mutations (microsatellites). Microsatellites refer to normally occurring repeated sequences of one to six DNA base pairs. These associated cancers will be MSI-H and are often characterized by location in the proximal colon, large local tumor, typical absence of metastatic disease, and poor tumor differentiation. When this occurs in patients with sporadic cancer, they are often elderly; when this occurs in the hereditary form (i.e., Lynch syndrome), patients are often younger (30 mm) adenomas), or a severe familial phenotype (>1000 synchronous adenomas) should undergo IPAA. This operation is also the treatment of choice for patients with a large number of rectal adenomas, but the optimal timing of surgery should be individualized. IPAA should be performed with removal of the anal transitional zone by mucosectomy and a handsewn anastomosis or retaining some of the anal transitional zone with a stapled anastomosis. The choice of which is best to perform has been debated. The benefits of a stapled anastomosis include better function (less risk of incontinence) and fewer complications. A stapled IPAA is also easier to survey, and anal transitional zone adenomas may possibly be treated endoscopically or transanally. The benefit of a handsewn IPAA is a reduced incidence of anal transitional zone adenomas, but this is achieved at a potential cost of worse function. This procedure can be performed with or without a diverting ileostomy. A temporary diverting ileostomy proximal to the pouch has been classically performed in order to mitigate the effects of anastomotic leakage and to prevent pelvic sepsis (reported in as low as 6% and as high as 37%, respectively), fistulization, and thus compromised pouch function. Consequently, it should also prevent the need for relaparotomy. Ileostomy omission has been advocated in selected cases. The benefits of laparoscopy can be applied in this surgery, but in the literature, there is no evidence that this approach is better than the open approach. IPAA should be performed only in specialized centers and by skilled and experienced surgical teams. • Subtotal colectomy and IRA provide good surgical and functional outcomes but require long-term follow-up of the retained rectum. The risk of metachronous rectal cancer is on the order of 30%. IRA is generally recommended for patients with few rectal polyps, AFAP, and a family history of a mild phenotype and for those young women with desire to become pregnant after recommendations of genetic counseling. IRA should not be performed in patients with a severely diseased rectum (adenomas >3 cm diameter, adenomas with severe dysplasia, cancer, sphincter dysfunction, or a rectum containing more than 20 rectal adenomas) or in the presence of colon cancer. IRA may provide good results in AFAP, MAP, and mild FAP

patients who agree to undergo close follow-up, and proctocolectomy and IPAA should be reserved for those with profuse polyposis. • Proctocolectomy with end ileostomy is currently rarely performed as a permanent stoma and is usually unacceptable to young patients. However, this option still has a role in the treatment of very low rectal cancer, when sphincter preservation is not possible, in cases of malignant transformation after IPAA or ileal pouch failure or in cases in which there is poor sphincter function. Most patients are eligible for chemoprevention after surgery because proctocolectomy with IPAA or a colectomy with IRA can retain “at-risk” rectal mucosa, and the duodenal mucosa remains “at risk” in all these patients. Chemoprevention (i.e., taking medications that slow polyp growth such as sulindac or celecoxib) should not replace routine endoscopic surveillance. Regular follow-up is mandatory after any procedure. Standard care includes perianal digital and flexible endoscopic examination at yearly intervals. 

MUTYH-Associated Polyposis MAP is an autosomal recessively inherited syndrome caused by germline mutation of both alleles of the MUTYH gene, located on chromosome 1. Because the autosomal recessive inheritance pattern requires that affected individuals have a biallelic mutation, both parents of affected individuals must be at least monoallelic carriers. If so, siblings of affected individuals have a 25% chance of biallelic mutations. Monoallelic MUTYH mutations are found in 0.7% to 1% of unselected individuals in population-based cohorts, with biallelic mutations identified in 1.7% of unselected individuals with CRC. CRC risk is increased twenty-eight fold for individuals with biallelic ­MUTYH mutations, while the risk for monoallelic carriers ­appears to be only moderately increased.36 The colonic phenotype mimics that of AFAP. The diagnosis of MAP should be considered in patients presenting with colorectal polyposis (>20 lifetime adenomas). Although most polyps in MAP are adenomas, patients can present with serrated polyps or a mixture of adenomas and serrated polyps. Bleeding or obstruction may occur, but the disease is suspected on findings from a screening colonoscopy. The syndrome is primarily characterized by multiple colorectal adenomas and an increased risk for CRC at a younger age (40–50 years of age). The colorectal polyp phenotype

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SECTION X  Abdomen

is highly variable usually with moderate polyposis (3.5 mg/dL), encephalopathy, hypoalbuminemia (80%) and necessary for a successful long-term outcome. Unfortunately, stone recurrence is common and is mostly related to the presence of biliary strictures. The goal of operative approaches is to clear the biliary tree of stones and to bypass, resect, or enlarge strictures. Many cases require only exploration of the common bile duct with or without hepaticojejunostomy. In complicated cases, providing permanent access to the biliary tree for interventional radiologic procedures

by extending the end of the Roux-en-Y hepaticojejunostomy to the skin or subcutaneous space has been a successful approach (Fig. 54.33). Other potentially necessary procedures include stricturoplasty and partial hepatectomy. Partial hepatectomy is advocated for patients with intrahepatic strictures, hepatic atrophy, liver abscess, or suspicion of cholangiocarcinoma. In a large series from Asia, where surgery and hepatectomy are liberally applied, surgical mortality rates are 1%. Moreover, with aggressive treatment, there is almost a 100% stone clearance rate. Long-term outcome is excellent, with a less than 5% stone recurrence rate. Long-term survival is mostly related to the presence of cholangiocarcinoma, which is found in approximately 10% of patients. Particularly complicated cases can have a higher rate of recurrent symptoms. 

NEOPLASMS Solid Benign Neoplasms It is estimated that benign focal liver masses are present in approximately 10% to 20% of the population in developed countries. With the increasing use of rapidly improving radiologic examinations, these entities have been encountered more frequently. Familiarity with the clinical characteristics, natural history, imaging characteristics, and indications for surgery in these tumors is essential. Many benign lesions can be adequately characterized by modern imaging studies, such as CT, ultrasound, and MRI. In unclear cases, serum tumor markers (e.g., AFP, CEA) and a search for a primary tumor in the case of suspected metastases should be carried out. A resection might be necessary to make a definitive diagnosis. Laparoscopy for assessment, biopsy, or resection has become an important diagnostic technique as well.

CHAPTER 54  The Liver Liver Cell Adenoma Liver cell adenoma (LCA) is a relatively rare benign proliferation of hepatocytes in the context of a normal liver. It is predominantly found in young women (aged 20–40 years) and is often associated with steroid hormone use, such as long-term oral contraceptive pill (OCP) use. Increased prevalence of LCA was observed in the 1970s, following the introduction of oral contraceptives. Male anabolic hormone use can also predispose to development of LCA. The female-to-male ratio is approximately 11:1. Other risk factors for LCA include vascular liver diseases, glycogenosis type 1A, and familial adenomatous polyposis. LCAs are usually singular, but multiple lesions have been reported in 12% to 30% of cases. Liver adenomatosis is defined by the presence of more than 10 LCAs in the liver. Interestingly, cases with multiple adenomas are not associated with OCP use and do not have as dramatic a female preponderance. On histologic evaluation, LCAs are composed of cords of benign hepatocytes containing increased glycogen and fat. Bile ductules are not observed histologically, and the normal architecture of the liver is absent in these lesions. Hemorrhage and necrosis are commonly seen. On the basis of detailed molecular pathology correlation studies, a French collaborative group has recently proposed a molecular-pathologic classification whereby the adenomas are classified as β-catenin mutated adenoma, HNF1A mutated adenoma, inflammatory adenoma, and not otherwise specified adenoma.11 Molecular studies have also identified genetic signatures associated with a higher risk of malignant transformation. Specifically, highest risk of malignant transformation is observed in LCA with β-catenin activation.11 With further research, new pathways driving the formation of adenomas are being identified and the “not otherwise specified adenoma” group is becoming smaller. For example, recently, sonic hedgehog activation has been observed in 5% of LCAs. Interestingly, these LCAs with sonic hedgehog activation are associated with obesity and bleeding. Furthermore, LCA with β-catenin mutations can be further classified by the nature of the mutation. For example, those with exon-3 mutation have increased risk of hepatocellular carcinoma (HCC) degeneration, whereas mutation in exon 7/8 leads to only weak activation of β-catenin and no risk of malignant transformation. Patients with LCA present with symptoms approximately 50% to 75% of the time. Upper abdominal pain is common and may be related to hemorrhage into the tumor or local compressive symptoms. The physical examination is usually unrevealing, and tumor markers are normal. Dramatic presentations with free intraperitoneal rupture and bleeding can occur. Imaging tends to be characteristic and obviates the need for tissue diagnosis most of the time Because of intratumoral hemorrhage, the necrosis and fat component of LCA tends to be heterogeneous on CT. On contrast-enhanced CT, LCA tends to have peripheral enhancement with centripetal progression. MRI scans of LCA also have specific imaging characteristics, including a well-demarcated heterogeneous mass containing fat or hemorrhage. Despite highquality imaging, resection may sometimes be necessary to secure a diagnosis in difficult cases. Intriguingly, studies are elucidating a correlation between the molecular subtypes described and imaging characteristics. The two major risks of LCA are rupture, with potentially lifethreatening intraperitoneal hemorrhage, and malignant transformation. Quantifying the risk of rupture is difficult, but it has been estimated to be as high as 30% to 50%, with all instances of spontaneous rupture occurring in lesions 5 cm and larger. Although there are numerous reports of transformation of LCA into HCC,

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the true risk of transformation is probably low. Hepatic adenomas with β-catenin activation should be considered for early surgical intervention as malignant transformation most commonly occurs in this subtype. Patients who present with acute hemorrhage need emergent attention. If possible, hepatic artery embolization is a helpful and usually effective temporizing maneuver. Once the patient is stabilized and appropriately resuscitated, a laparotomy and resection of the mass are required. Symptomatic masses should be similarly resected. Patients with asymptomatic LCAs taking OCPs can be watched for regression after stopping of the OCPs, although progression and rupture have been observed in this setting. Behavior of LCAs during pregnancy has been unpredictable, and resection before a planned pregnancy is usually recommended. Overall, the surgeon must compare the risks of expectant management with serial imaging studies and AFP measurements against those of resection. Resection is usually recommended because of low mortality in experienced hands and the risks of observation. Margin status is not important in these resections, and limited resections can be performed. The management of adenomatosis is controversial, but large lesions should probably be resected because of the risk of rupture, whereas the risk of malignancy is low in lesions smaller than 5 cm. On occasion, liver transplantation is necessary for aggressive forms of adenomatosis.  Focal Nodular Hyperplasia Focal nodular hyperplasia (FNH) is the second most common benign tumor of the liver after hemangioma and is predominantly discovered in young women.12 FNH is characterized by a central fibrous scar with radiating septa, although no central scar is seen in approximately 15% of cases. On microscopic examination, FNH contains cords of benign-appearing hepatocytes divided by multiple fibrous septa originating from a central scar. Typical hepatic vascularity is not seen, but atypical biliary epithelium is found scattered throughout the lesion. The central scar often contains a large artery that branches out into multiple smaller arteries in a spoke wheel pattern. The cause of FNH is not known, but the most common theory is that FNH is related to a developmental vascular malformation. Female hormones and OCPs have been implicated in the development and growth of FNH, but the association is weak and difficult to prove. In most patients, FNH is an incidental finding at laparotomy or, more commonly, on imaging studies. If symptoms are noted, vague abdominal pain is most often present, but a variety of nonspecific symptoms have been described. It is often difficult to ascribe these reported symptoms to the presence of FNH, and therefore, other possible causes must be sought. Physical examination is usually unrevealing, and mild abnormalities of liver function may be found. Serum AFP levels are normal. With advances in hepatobiliary imaging, most cases of FNH can be diagnosed radiologically with reasonable certainty. Contrast-enhanced CT and MRI have become accurate methods of diagnosing FNH. FNH typically shows strong hypervascularity in the arterial phase of CT or MRI with central nonenhancing scar. The enhancement fades over time, and the lesion becomes isointense to the liver parenchyma in the portal and delayed phases. When no central scar is seen, however, radiologic diagnosis is difficult, and differentiation from LCA or a malignant mass, especially fibrolamellar HCC, can sometimes be impossible. On occasion, histologic confirmation is necessary, and resection is recommended for definitive diagnosis. Fine-needle aspiration for the diagnosis of FNH has been recommended but is often unrevealing.

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SECTION X  Abdomen

A

B FIG. 54.34  (A and B) Computed tomography scans of a large cavernous hemangioma showing displacement of left and middle hepatic veins and abutment of the left portal vein. The mass was symptomatic and required an extended right hepatectomy for removal.

Most FNH tumors are benign and indolent. Rupture, bleeding, and infarction are exceedingly rare, and malignant degeneration of FNH has never been reported. The treatment of FNH therefore depends on diagnostic certainty and symptoms. Asymptomatic patients with typical radiologic features do not require treatment.12 If diagnostic uncertainty exists, resection may be necessary for histologic confirmation. Symptomatic patients should be thoroughly investigated to look for other pathologic processes to explain the symptoms. Careful observation of symptomatic FNH with serial imaging is reasonable because symptoms may resolve in a significant number of cases. Patients with persistent symptomatic FNH or an enlarging mass should be considered for resection. Because FNH is a benign diagnosis, resection must be performed, with minimal morbidity and mortality.  Hemangioma Hemangioma is the most common benign tumor of the liver.12 It occurs in women more than in men (3:1 ratio) and at a mean age of approximately 45 years. Small capillary hemangiomas are of no clinical significance, whereas larger cavernous hemangiomas more often come to the attention of the liver surgeon (Fig. 54.34). Cavernous hemangiomas have been associated with FNH and are also theorized to be congenital vascular malformations. The enlargement of hemangiomas is by ectasia rather than by neoplasia. They are usually solitary and less than 5 cm in diameter, and they

occur with equal incidence in the right and left hemilivers. Lesions larger than 5 cm are arbitrarily called giant hemangiomas. Involution or thrombosis of hemangiomas can result in dense fibrotic masses that may be difficult to differentiate from malignant tumors. On microscopic examination, they are endothelium-lined, blood-filled spaces separated by thin fibrous septa. Hemangiomas are usually asymptomatic and found incidentally on imaging studies. Large compressive masses may cause vague upper abdominal symptoms. Symptoms ascribed to a liver hemangioma, however, mandate a search for other disease because an alternative cause of symptoms will be found in approximately 50% of cases. Rapid expansion or acute thrombosis can occasionally cause symptoms. Spontaneous rupture of liver hemangiomas is exceedingly rare. An associated syndrome of thrombocytopenia and consumptive coagulopathy known as Kasabach-Merritt syndrome is rare but well described. LFT results and tumor markers are usually normal in liver hemangiomas. Radiologic investigation can make the diagnosis reliably in most cases. CT and MRI are usually sufficient if a typical peripheral nodular enhancement pattern is seen. Isotope-labeled red blood cell scans are an accurate test but are rarely necessary if high-quality CT and MRI are available. Percutaneous biopsy of a suspected hemangioma is potentially dangerous and inaccurate. Therefore, biopsy is not recommended. The natural history of liver hemangioma is generally benign; it appears that most remain stable for a long time, with a low risk of rupture or hemorrhage.12 Growth and development of symptoms do occur, however, occasionally requiring resection. There has never been a report of malignant degeneration of a liver hemangioma. An asymptomatic patient with a secure diagnosis can therefore be simply observed.12 Symptomatic patients should undergo a thorough evaluation looking for alternative explanations for the symptoms but are candidates for resection if no other cause is found. Rupture, significant change in size, and development of the Kasabach-Merritt syndrome are indications for resection. In rare cases of diagnostic uncertainty, resection may be necessary for a definitive diagnosis to be made. Resection of liver hemangiomas should be performed, with minimal morbidity and mortality. The preferred approach to resection is enucleation with arterial inflow control, but anatomic resections may be necessary in some cases. Surgery on large central hemangiomas can be associated with significant morbidity. Liver hemangiomas in children are common, accounting for approximately 12% of all childhood hepatic tumors. They are usually multifocal and can involve other organs. Large hemangiomas in children can result in congestive heart failure secondary to arteriovenous shunting. Untreated symptomatic childhood hemangiomas are associated with high mortality. On the other hand, almost all small capillary hemangiomas resolve. Symptomatic childhood hemangiomas may be treated with therapeutic embolization; medical therapy should be initiated for congestive heart failure. Radiation and chemotherapeutic agents have been used, but experience has been limited. Resection may be necessary for symptomatic lesions or rupture.  Other Benign Tumors Most benign solid liver tumors are LCAs, FNHs, or hemangiomas, but there are other benign hepatic tumors. However, these are rare and can be difficult to differentiate from malignant neoplasms. Macroregenerative nodules, previously known as adenomatous hyperplasia, are single or multiple, well-circumscribed, bilestained, bulging surface nodules that occur primarily in cirrhotics

CHAPTER 54  The Liver and result from the hyperplastic response to chronic liver injury. These lesions have malignant potential and can be difficult to distinguish from HCC. Nodular regenerative hyperplasia is a benign diffuse micronodular (usually 10–20 cases/100,000). The lowest incidence (1–3 cases/100,000) is found in Australia, North America, and Europe. Epidemiologic evidence strongly suggests that HCC is largely related to environmental factors; the incidence of HCC in immigrants eventually approaches that of the local population after several generations. An exception to this is that whites living in high-prevalence areas tend to have a low incidence of HCC. This is likely related to the continuation of the lifestyle and environment of their home country. It is probable that the variation in incidence rates among immigrants is related to hepatitis B virus (HBV) carrier rates. A significant rise in the incidence of HCC in the United States and other Western countries has been noted during the last 35 years. However, recent data suggest

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that at least in the United States, the epidemic may have peaked as the incidence rates have stabilized in the last few years. The explanation for the observed increase during the last few decades is not understood, but the emergence of hepatitis C virus (HCV) infection and immigration patterns have been suggested. In the United States, HCC incidence is highest in Asians, Pacific Islanders, and Native Americans and lowest among Caucasians. HCV is the most common cause of HCC, accounting for more than half of all cases in the United States and with HBV only present in up to 20% of cases. A third of HCC cases are not infected by either virus. Risk of HCC is further increased in obese patients and in those with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Given that obesity and its ensuing complications are increasing at epidemic proportion in the Western world, obesity as the cause of HCC is becoming more important. Recent data also suggest that addressing the environmental factors can lead to reduction in incidence of HCC. In Taiwan, treatment of chronic hepatitis B and C under the auspices of a national viral hepatitis therapy program has met with a reduction in incidence and mortality due to HCC. HCC is two to eight times more common in men than in women in low- and high-incidence areas. Although sex hormones may play a minor role in the development of HCC, the higher incidence in men is probably related to higher rates of associated risk factors, such as HBV infection, cirrhosis, smoking, alcohol abuse, and higher hepatic DNA synthesis in cirrhosis. In general, the incidence of HCC increases with age, but a tendency to development of HCC earlier in high-incidence areas has been noted. For example, in Mozambique, 50% of patients with HCC were found to be younger than 30 years. This may be related to differing ages at infection and the natural histories of hepatitis B and C.  Causative factors. A large number of associations between hepatic viral infections, environmental exposure, alcohol use, smoking, genetic metabolic diseases, cirrhosis, and OCP use and the development of HCC have been recognized. Overall, 75% to 80% of HCC cases are related to HBV (50%–55%) or HCV (25%–30%) infections. It is also clear from research that the development of HCC is a complex and multistep process that involves any number of these risk factors. Many years of research have documented a clear association between persistent HBV infection and the development of HCC. Up to 5% of the world population is chronically infected with HBV. Chronic HBV infection accounts for up to 50% of the world’s cases of HCC and most of the cases of childhood HCC. Studies have estimated relative risks of 5 to 100 for the development of HCC in HBV-infected individuals compared with noninfected individuals. The risk of developing HCC is also affected by the presence of other factors including, age, Asian or African ancestry, family history, viral factors (genotype, duration of infection, coinfection with HCV, HIV or hepatitis D), and environmental factors (exposure to aflatoxin, alcohol, and tobacco). Other evidence includes the following observations: geographic areas high in HBV infection have high rates of HCC; HBV infection precedes the development of HCC; the sequence of HBV infection to cirrhosis to HCC is well documented; and the HBV genome is found in the HCC genome. The HBV has no known oncogenes, but insertional mutagenesis into hepatocytes may be a contributing factor to the development of HCC. Another proposed mechanism is related to cirrhosis and chronic hepatic inflammation, which is present in 60% to 90% of patients with HBV infection and HCC. Cirrhosis, however, is not a prerequisite for the development of HBV-related HCC. The risk of HCC is not simply related to HBV exposure but

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SECTION X  Abdomen

requires chronic infection (i.e., chronically positive HBV surface antigen). There is a higher risk of persistent infection (carrier state) when the infection is acquired at birth or during early childhood. Familial clustering of HCC is probably related to early vertical transmission of the virus and establishment of the chronic carrier state. Individuals with greater HBV replication, evident from the presence of hepatitis B e antigen (HBeAg) and higher levels of HBV DNA, have higher risk of HCC development. HBV genotypes (A–H) also affect the clinical outcomes. Hepatitis C has been discovered to be a major cause of chronic liver disease in Japan, Europe, and the United States, where there is a relatively low rate of HBV infection. 2% of the world’s population is infected with HCV. Antibodies to the HCV are found in 76% of patients with HCC in Japan and Europe and in 36% of patients in the United States. HBV and HCV infections are both independent risk factors for the development of HCC but probably act synergistically when an individual is infected with both viruses. Although the natural history of HCV infection is not completely understood, it appears to be one of chronic infection, with a benign early course. However, the ultimate development of cirrhosis with increased risk of HCC may ensue. The rate of HCC among HCV-infected persons ranges from 1% to 3% over 30 years, and in individuals with HCVrelated cirrhosis, HCC develops at an annual rate of 1%–4%. Studies on the rates of progression to cirrhosis estimate a median time of 30 years, but differing progression rates yield a range of less than 20 years to more than 50 years. Factors associated with a more rapid progression include male gender, chronic alcohol use, and older age at the time of infection. HCV is an RNA virus that does not integrate into the host genome, and therefore, the pathogenesis of HCV-related HCC may be related more to chronic inflammation and cirrhosis than to direct carcinogenesis. Data from era of interferon-based therapy suggests that the patients who achieved a sustained viral response had up to 75% reduction in their risk of HCC. This is exciting and has immense global health significance, especially now as there are many effective HCV treatments available. However, future studies will determine if these new treatments will change the incidence and course of HCC. The true relationship of cirrhosis and HCC is difficult to ascertain, and suggestions of causation remain speculative. Cirrhosis is not required for the development of HCC, and hepatocarcinogenesis is not an inevitable result of cirrhosis. The relationship of cirrhosis and HCC is further complicated by the fact that they share common associations. Furthermore, some associations (e.g., HBV infection, hemochromatosis) are associated with higher risk of HCC, whereas others (e.g., alcohol, primary biliary cirrhosis) are associated with a lower risk of HCC. Research has demonstrated that cirrhotic livers with higher DNA replication rates are associated with the development of HCC. Chronic alcohol abuse has been associated with an increased risk of HCC, and there may be a synergistic effect with HBV and HCV infection. Alcohol causes cirrhosis but has never been shown to be directly carcinogenic in hepatocytes. Thus, alcohol likely acts as a cocarcinogen. Cigarette smoking has been linked to the development of HCC, but the evidence is not consistent, and the contributing risk independent of viral hepatitis is likely to be small. Aflatoxin, produced by Aspergillus spp., is a powerful hepatotoxin. With chronic exposure, aflatoxin acts as a carcinogen and increases the risk of HCC. The offending fungi grow on grains, peanuts, and food products in tropical and subtropical regions. Ingestion of contaminated foods results in aflatoxin exposure.

Levels of aflatoxin in these implicated foods are regulated in the United States. Other chemicals have also been implicated as carcinogens related to HCC. These include nitrites, hydrocarbons, solvents, pesticide, and vinyl chloride. Thorotrast (colloidal thorium dioxide) is an angiographic medium that was used in the 1930s. It emits high levels of long-lasting radiation and has been associated with hepatic fibrosis, angiosarcoma, cholangiosarcoma, and HCC. Associations with inherited metabolic liver diseases, such as hereditary hemochromatosis, α1-antitrypsin deficiency, and Wilson disease, have also been implicated as risk factors for HCC. Associations with hormonal manipulations, such as the use of OCPs and anabolic steroids, have been suggested but are weak and are probably better linked specifically to adenoma and well-differentiated HCC. Research has been focusing on relationships of HCC with diabetes, obesity, and metabolic syndrome.  Clinical presentation. Most commonly, patients presenting with HCC are men 50 to 60 years of age who complain of right upper quadrant abdominal pain and weight loss and have a palpable mass. In countries endemic for HBV, presentation at a younger age is common and probably related to childhood infection. Unfortunately, in unscreened populations, HCC tends to be manifested at a later stage because of the lack of symptoms in early stages. Presentation at an advanced stage is often with vague right upper quadrant abdominal pain that sometimes radiates to the right shoulder. Nonspecific symptoms of advanced malignant disease, such as anorexia, nausea, lethargy, and weight loss, are also common. Another common presentation of HCC is hepatic decompensation in a patient with known mild cirrhosis or even in patients with unrecognized cirrhosis. HCC can rarely be manifested as a rupture, with the sudden onset of abdominal pain followed by hypovolemic shock secondary to intraperitoneal bleeding. Other rare presentations include hepatic vein occlusion (Budd-Chiari syndrome), obstructive jaundice, hemobilia, and fever of unknown origin. Less than 1% of cases of HCC are manifested with a paraneoplastic syndrome, usually hypercalcemia, hypoglycemia, and erythrocytosis. Small, incidentally noted tumors have become a more common presentation because of the knowledge of specific risk factors, screening programs for diagnosed HBV or HCV infection, and increasing use of high-quality abdominal imaging.  Diagnosis. Radiologic investigation is a critical part of the diagnosis of HCC. In the past, liver radioisotope scans and angiography were common methods of diagnosis, but ultrasound, CT, and MRI have replaced these studies. Ultrasound plays a significant role in screening and early detection of HCC, but definitive diagnosis and treatment planning rely on CT or MRI. Contrastenhanced CT and MRI protocols aimed at diagnosing HCC take advantage of the hypervascularity of these tumors, and arterialphase images are critical to assess the extent of disease adequately. Unlike many other cancers, the diagnosis of HCC can be established based on imaging findings alone. Typical imaging criteria for HCC include rapid arterial enhancement followed by washout in the delayed phase. An enhancing capsule supports the diagnosis of HCC. CT and MRI also evaluate the extent of disease in terms of peritoneal metastases, nodal metastases, and extent of vascular and biliary involvement. Detection of bland or tumor thrombus in the portal or hepatic venous system is also important and can be diagnosed with any of these modalities (Fig. 54.35). AFP measurements can be helpful in the diagnosis of HCC. However, AFP measurement is associated with multiple problems. First, AFP measurements have low sensitivity and specificity. The

CHAPTER 54  The Liver

FIG. 54.35  Contrast-enhanced computed tomography scan demonstrating multifocal hepatocellular carcinoma. The left portal vein is invaded and expanded by tumor (arrows). (From Roddie ME, Adam A. Computed tomography of the liver and biliary tree. In: Blumgart LH, Fong Y, eds. Surgery of the Liver and Biliary Tract. London: WB Saunders; 2000:309–340.)

specificity and positive predictive values of AFP improve with higher cutoff levels (e.g., 400 ng/mL) but at the cost of sensitivity. False-positive elevations of serum AFP levels can be seen in inflammatory disorders of the liver, such as chronic active viral hepatitis. Furthermore, AFP is not specific to HCC and can be elevated with intrahepatic cholangiocarcinoma (IHC) and colorectal metastases. With improvements in imaging technology and the ability to detect smaller tumors, AFP is largely used as an adjunctive test in patients with liver masses. AFP levels are particularly useful in monitoring treated patients for recurrence after normalization of levels. Since the proposal of guidelines for the diagnosis of HCC by the Barcelona-2000 European Association for the Study of the Liver conference13 and the American Association for the Study of Liver Disease,14 new data have accumulated and the recommendations have evolved.15,16 AFP used to play a major role in the diagnosis of HCC larger than 2 cm.14 However, given the excellent performance of contrast-enhanced imaging modalities, AFP does not play a critical role in the diagnosis of HCC anymore.15,16 For hepatic nodules 1 to 2 cm on a background of cirrhosis, a contrast-enhanced triple-phase CT and MRI scan is now recommended.15,16 If typical features of HCC on imaging (arterially enhancing mass with washout of contrast material in delayed phases) are observed, diagnosis of HCC is presumed. For lesions larger than 2 cm, a single study may suffice. However, for lesions 1 to 2 cm, contrast-enhanced CT and MRI have a sensitivity of 53% to 62%, specificity of approximately 100%, positive predictive value of 95% to 100%, and negative predictive value of 80% to 84%. The performance of both MRI and CT in a sequential fashion can increase the sensitivity and may be required for difficult cases. Patients with appropriate risk factors and suggestive radiologic features, with or without an elevated AFP level, who are candidates for potentially curative surgical therapy do not require preoperative biopsy unless the diagnosis is in question. Percutaneous fine-needle aspiration of HCC does run a small risk of tumor cell spillage (estimated to be ∼1%) and rupture or bleeding, especially in cirrhotic livers and subcapsular tumors. Once the diagnosis of HCC has been made, the disease must be staged to develop an appropriate treatment plan. Most patients with HCC have two

1467

diseases, and survival is as much related to the tumor as it is to cirrhosis. Staging includes an extent of disease and extent of cirrhosis workup. In assessing the extent of disease, the common sites of metastases must be considered. HCC largely metastasizes to the lung, bone, and peritoneum. Preoperative history should focus on symptoms referable to these areas. Extent of disease in the liver, including macrovascular invasion and the presence of multiple liver masses, must also be considered. Cross-sectional abdominal imaging, including arterial-phase images (see earlier), yields information on the extent of disease in the liver as well as peritoneal disease. Preoperative chest CT is mandatory because lung metastases are usually asymptomatic. Routine bone scans are not performed unless there are suggestive symptoms or signs. Assessment of liver function is absolutely critical in considering treatment options for a patient with HCC. Liver resection is considered the treatment of choice for HCC, and the risk of postoperative liver failure and death must be considered. This risk is related to the degree of cirrhosis, portal hypertension, amount of liver resected (functional liver reserve), and regenerative potential response. Other successful treatments are available for HCC, such as ablative techniques, embolization techniques, and liver transplantation. Therefore, a complete assessment of tumor and liver function must be carried out. A number of tests of liver function are available, generally divided into clinical assessment and functional tests, and there are many clinical assessment schemes (see earlier). However, Child-Pugh status is used most often. ChildPugh class C patients are not candidates for resectional therapy, whereas Child-Pugh class A patients can usually tolerate some extent of liver resection. Many consider Child-Pugh class B patients to be candidates for operation, but they are generally borderline, and therapy must be individualized. Outside of scoring systems, it has been demonstrated that significant portal hypertension, regardless of biochemical assessments, is highly predictive of postoperative liver failure and death. Portal hypertension can be assessed directly through hepatic vein wedge pressures, but it is usually obvious on high-quality imaging in the form of splenomegaly, a cirrhotic-appearing liver, and intraabdominal varices. Blood work usually demonstrates marked cytopenias. Most typically, patients have thrombocytopenia. Functional tests of liver function have been well described but are not routinely used in most Western centers because the results of studies evaluating their predictive value have been mixed. Staging laparoscopy has been used as a staging tool in HCC and spares about one in five patients a nontherapeutic laparotomy. Laparoscopy yields additional information about the extent of disease in the liver, extrahepatic disease, and cirrhosis. The yield of laparoscopy is dictated by the extent of disease and is only selectively used. The presence of clinically apparent cirrhosis, radiologic evidence of vascular invasion, or bilobar tumors increases the yield to 30%, whereas without these factors, the yield is 5%.17 There are a number of staging systems for HCC, but none have been shown to be particularly superior; they probably depend on the specific population in which the disease is being staged as well as the cause of HCC in that particular population of patients. The tumor, node, metastasis (TNM) staging system is not routinely used for HCC because it does not accurately predict survival; it does not take liver function into account. Moreover, the TNM staging system relies on pathology that is frequently unavailable preoperatively. The Okuda staging system is an older but simple and effective system that takes liver function and tumor-related factors into account. It adds up a single point for the presence of

1468

SECTION X  Abdomen

TABLE 54.7  Cancer of the Liver Italian

Program score.* CLINICAL PARAMETERS Child-Pugh class

Tumor morphology

AFP level Portal vein thrombosis

CUTOFF VALUES A B C Uninodular, 90%) and specific (>99%) in identifying CBD stones (Fig. 55.26). But as a noninvasive test, it will stay at diagnostic level, and a treatment procedure, such as ERCP or CBD exploration, still has to be done after diagnosis. Some surgeons resorted to preoperative MRCP to determine the need for preoperative ERCP.10 ERCP is also highly sensitive and specific for choledocholithiasis (Fig. 55.27) and often is the therapeutic procedure by clearing the duct in more than 75% of patients during first procedure and in 90% with repeated ERCP. A sphincterotomy with a balloon sweep is done and stones are extracted, with a less than 5% to 8% complication rate. Indications for preoperative ERCP include cholangitis, biliary pancreatitis, and patients with multiple comorbidities. However, some studies have suggested higher risk of surgical site infection in patients who receive preoperative ERCP before cholecystectomy.11 Finding of choledocholithiasis via intraoperative cholangiogram during cholecystectomy may be managed by either CBD exploration or postoperative ERCP. The experience of the surgeon with open biliary exploration may be a factor determining which route is chosen. PTC can also be used to treat choledocholithiasis in case of unsuccessful ERCP, or anatomical difficulty for ERCP such as the patients’ post-Roux-en-Y procedures. PTC is as effective as ERCP in patients with dilated biliary system with similar complication rate, but less effective in a nondilated biliary tree patient. In short, in patients with likelihood of CBD stones, other modalities such as ERCP or MRCP must be considered on top of ultrasound. Choledocholithiasis identified but not removed during cholecystectomy mandates ERCP for stone extraction. 

1502

SECTION X  Abdomen

FIG. 55.29  Computed tomography scan of the cholecystoduodenal fistula (arrow).

FIG. 55.28  Computed tomography scan of stone (arrow) obstructing the distal ileum.

Treatment Treatment for choledocholithiasis is generally ERCP or CBD exploration, which can be performed via laparoscopic or open technique. Endoscopic sphincterotomy with stone extraction is effective for the treatment of choledocholithiasis. In the preoperative setting, it can clear the duct of stones, and when it is unsuccessful at removal of all stones, it will alter intraoperative decision-making. More than half of patients managed by ERCP without cholecystectomy will have recurrent symptoms of biliary tract disease.12 Large stones (usually more than 2.5 cm), altered gastric or duodenal anatomy such as Roux-en-Y, impacted stones, intrahepatic stones, or multiple stones, are the most common causes of failure of ERCP. 

Gallstone Pancreatitis When a stone passes from the bile duct through the ampulla into the duodenum, this may cause secondary injury to the pancreas. Temporary elevation of the pancreatic duct pressure causes inflammation and may result in severe pancreatic injury. Symptoms usually persist even after passage of stone. Ultrasound usually shows gallstones, choledocholithiasis, or a dilated CBD. The offending stone usually passes spontaneously but the injury still can be severe. In most cases of gallstone pancreatitis, the pancreatitis is self-limited. Early ERCP to remove a stone that may not have passed is indicated and has been shown to reduce the morbidity of the episode of pancreatitis.13 To prevent a future episode of gallstone pancreatitis, a cholecystectomy is warranted; this is generally recommended during the same hospitalization, just before discharge.14 Given the suspicion of choledocholithiasis, intraoperative cholangiography should be performed if no other imaging has been performed to confirm the passage of the gallstone. 

Gallstone Ileus A misnomer, gallstone ileus is in fact a mechanical intestinal obstruction secondary to a gallstone. A large stone in the dependent portion of the gallbladder fistulizes into the adjacent duodenum, passing directly into the intestine. This usually happens in older patients and can be caused by inflammation or simply pressure necrosis. The most common site for obstruction is in the terminal ileum before entering the cecum (Fig. 55.28). The common

presentation is an elderly patient with some history of biliary tree disorder, with no past surgical history or hernia, with a sudden mechanical small intestine obstruction. Although most patients will have constant pain from the obstruction, others can present with only episodic discomfort because the gallstone only intermittently obstructs the intestinal tract. Plain radiographs usually demonstrate air-fluid levels consistent with a small bowel obstruction, although the offending stone may or may not be identified. Pneumobilia, which may sometimes be identified only by CT scan, is a ubiquitous finding because the fistula that permitted a stone to pass into the duodenum allows air to enter the biliary tree (Fig. 55.29). Treatment Gallstone ileus is a surgical disorder. During an exploration, a longitudinal incision on the antimesenteric border of the ileum is made a few centimeters proximal to the stone. This site of impaction is at risk of perforation, so signs of ischemia may mandate resection. The stone is milked back through the enterotomy. Approximately 10% of patients have multiple large stones, so the remainder of the small intestine should be inspected. Although some surgeons advocate surgical treatment of the biliary-enteric fistula at the same setting, the intense inflammatory process in the right upper quadrant may complicate the cholecystectomy and duodenal repair. In addition, because most of these patients are older, their overall physiologic status may not permit fistula repair in the emergent setting. One-stage repair should generally be performed in healthy patients without severe inflammatory changes in the right upper quadrant. Enterotomy with removal of the offending stone should suffice for patients with multiple comorbidities. Palpation of the remaining small intestine should be performed to exclude a second stone that could cause recurrent obstruction. A second operation for the cholecystectomy can be considered to avoid the possibility of future biliary complications. 

Noncalculous Biliary Disease Acute Acalculous Cholecystitis Blockage of the cystic duct in the absence of stones is called acalculous cholecystitis. The exact mechanism and pathophysiology are poorly understood, but there is a role for bile stasis and gallbladder ischemia. Risk factors include old age, burns and trauma, prolonged

CHAPTER 55  Biliary System

1503

FR 33Hz RS 2D 45% C 55 P Low Res

LONG GB LLD

FIG. 55.30  Ultrasound image of a gallbladder with acute acalculous cholecystitis. The diffusely thickened gallbladder wall (arrows) is highly suggestive of cholecystitis.

use of total parenteral nutrition, critical illness, immunosuppression, and diabetes, and the presentation can be similar or more fulminant than calculous cholecystitis and may progress to gangrenous gallbladder. Critically ill patients with acalculous cholecystitis may not have right upper quadrant pain and any fever with unknown origin in critically ill patients, especially with pericholecystic fluid and gallbladder wall thickening on imaging should raise suspicion for this disorder (Fig. 55.30). HIDA scan is diagnostic for acalculous cholecystitis but can have false-positive result. Treatment of acalculous cholecystitis is similar to that of calculous cholecystitis, with cholecystectomy being therapeutic. However, many of these patients are critically ill, raising the mortality and morbidity of this procedure. Therefore, percutaneous cholecystostomy tube placement under imaging to drain the gallbladder is a much more attractive and feasible treatment. More than 90% of these patients improve with a cholecystostomy tube, and interval cholecystectomy is necessary only if follow-up imaging continues to demonstrate the positive findings.  Biliary Dyskinesia Biliary dyskinesia is a functional disorder of the biliary tree, generally defined by gallbladder dysmotility, and it is usually a diagnosis of exclusion. Patients may present with classic symptoms of calculous biliary disease but have no ultrasonographic evidence of stones or sludge. In some of these cases, the dysfunction of the gallbladder creates pain, even in the absence of stones. Rome criteria, which was defined in the late 1980s and has been updated multiple times,15 helps in defining and diagnosing this functional disorder. Other diagnosis must be excluded first using different modalities such as CT and endoscopy. CCK-stimulated HIDA scan is helpful in confirming diagnosis. An ejection fraction of less than one third at 20 minutes after CCK administration in a patient without stone is considered diagnostic. More than 85% of patients show improvement in symptoms after cholecystectomy. In nonresponders, ERCP with sphincterotomy may prove useful.  Sphincter of Oddi Dysfunction Similar to dyskinesia, sphincter of Oddi dysfunction is a functional disorder of the biliary tree; however, Rome IV criteria15 recommends not using the term functional. It is caused by a structurally or physiologically abnormal sphincter with higher tone and failing to relax, manifested by pain, and recurrent pancreatitis with a usually normal liver function panel. Risk factors include chronic pancreatitis

FIG. 55.31  Magnetic resonance cholangiopancreatography showing primary sclerosing cholangitis. Note the multilevel strictures (arrows).

or calculous disease, which can cause fibrosis due to inflammation, and, subsequently, failure of the sphincter to relax. The diagnosis of sphincter of Oddi dysfunction should be suspected in patients with biliary pain and a common duct diameter of more than 12 mm. The bile duct in these patients tends to increase in diameter in response to CCK, as does the pancreatic duct after secretin administration. Sphincter manometry has also been used to make the diagnosis, with sphincter pressure higher than 40 mm Hg predicting good response to therapy. Therapy consists of endoscopic sphincterotomy or transduodenal sphincteroplasty with approximately equivalent results from the two approaches. In patients with objective evidence of sphincter of Oddi dysfunction, division of the sphincter will improve or resolve the pain in 60% to 80% of patients.  Primary Sclerosing Cholangitis Primary sclerosing cholangitis (PSC) is an idiopathic disorder and considered an autoimmune process affecting the biliary tree. PSC is associated with other autoimmune disorders such as ulcerative colitis (in almost 70% of patients)16 and Riedel thyroiditis.17 PSC can be categorized into four anatomical subtypes depending on the level of biliary tree it involves, including intrahepatic, extrahepatic, combined, or small ducts disease. The course of PSC is characterized by progressive chronic cholestasis and advances at an unpredictable rate to biliary cirrhosis and eventually death from liver failure. With improved understanding of the disease and early diagnosis, PSC outcomes have improved.17 Clinical presentation. Most patients present with general symptoms such as fatigue and pruritus, but abnormal liver function studies are usually what prompts biliary imaging. Approximately 80% of patients have elevated perinuclear antineutrophil cytoplasmic antibodies, but the severity of disease does not correlate to titer levels. Abnormal liver function tests in a patient observed for inflammatory bowel disease should suggest PSC. Imaging with cholangiography demonstrates a multifocal diffuse dilation and stricturing of the intrahepatic and/or extrahepatic biliary trees. This pattern is called “beading” or “chain of lakes” and is characteristic of PSC. MRCP is useful in the diagnosis and surveillance of PSC patients, while ERCP is reserved for the treatment of dominant strictures and to exclude malignancy, namely, cholangiocarcinoma (Fig. 55.31).

1504

SECTION X  Abdomen

Liver biopsy tends to show an onionskin concentric periductal fibrosis. With disease progression, periportal fibrosis occurs, progressing to bridging necrosis and, eventually, biliary cirrhosis. Unfortunately, PSC is associated with cholangiocarcinoma, and distinguishing the strictures of PSC fibrosis from those of cholangiocarcinoma can be challenging.  Treatment. Ursodeoxycholic acid is commonly used as medical therapy for PSC and has demonstrated some improvement in liver function tests; however, it is controversial whether this alters the progression of disease. Ongoing trials in PSC include ursodeoxycholic acid homologs, antibiotics to alter the microbiome, and interruption of the enterohepatic bile circulation.17 However, none of these agents has shown a consistent clinical benefit. In the symptomatic patient, endoscopic therapy, consisting of balloon dilation of the dominant strictures, has been shown to alleviate pruritus, to reduce likelihood of cholangitis, and even to prolong survival. Surgical treatment options include biliary reconstruction in symptomatic patients with focal extrahepatic disease in some cases. Such patients are rare, and repeated operations for drainage have been shown to complicate definitive treatment by liver transplantation. Therefore, the use of biliary reconstructive procedures has decreased for this indication. Although it is associated with ulcerative colitis, a proctocolectomy does not appear to affect biliary disease progression or survival in patients with both ulcerative colitis and PSC. Orthotopic liver transplantation appears to be the only lifesaving option for patients with progressive hepatic dysfunction from PSC. The survival rate for patients undergoing liver transplantation for PSC is approximately equivalent to that of those undergoing transplantation for other causes of end-stage liver disease, with 5-year survival rates ranging from 75% to 85%.18 Although the development of cholangiocarcinoma in a PSC liver is generally considered a contraindication to transplantation, some centers have shown excellent survival rates, up to 70% at 5 years, for patients with limited hilar disease who undergo a neoadjuvant protocol of chemotherapy and radiation followed by transplantation.19 Because these results have not been reproduced universally, the use of liver transplantation for the treatment of cholangiocarcinoma occurring in the setting of PSC is limited to experimental protocols. After liver transplantation, 10% to 30% of PSC patients develop recurrent biliary strictures, suggestive of recurrence of disease in the donor liver. Even with the development of strictures, disease progression does not usually follow the aggressive course for which PSC is known. In cases where retransplantation is required, the morbidity and mortality are higher than for primary transplantation.  Biliary Strictures Benign strictures can occur anywhere along the intrahepatic or extrahepatic portions of the biliary tree. Intrahepatic strictures are usually a result of cholangiohepatitis and/or ischemic events. Any inflammatory of ischemic process along the length of the CBD may cause an extrahepatic stricture. Chronic pancreatitis can cause strictures in the intrapancreatic portion of CBD and are usually long (2–4 cm) with gradually tapered narrowing. Stricturing at the middle portion of CBD is usually associated with a gallbladder process. The most common reason is iatrogenic and postcholecystectomy, reported in 0.1% to 1% of postcholecystectomy patients.20 Alternatively, Mirizzi syndrome is a large stone in Hartmann pouch of the gallbladder, compressing the adjacent bile duct and leading to biliary obstruction (Fig. 55.32). These

FIG. 55.32  Mirizzi syndrome. Obstruction of the bile duct from an inflammatory process is the hallmark of this syndrome; the cholecystocholedochal fistula may or may not be apparent.

patients often have a cystic duct parallel to common hepatic duct and an impacted gallstone in the neck or cystic duct. The resultant inflammation can cause a cholecystocholedochal fistula. The treatment of Mirizzi syndrome is cholecystectomy, which may require repair of the common duct; when a large fistula exists, a choledochojejunostomy may be necessary. Long-standing choledocholithiasis also can cause fibrosis and stricture. ERCP with sphincterotomy, balloon dilation, and stent placement is generally regarded as primary treatment for benign bile duct strictures to make the diagnosis and potentially to treat the process. Endoscopic and percutaneous therapy can provide long-term success in more than 50% of patients. When this is unsuccessful, surgical management with anastomosis of the biliary tree to a Roux-en-Y jejunal limb has success rates of up to 90%.  Biliary Cysts Choledochal cysts, or biliary cysts, are congenital intrahepatic and/or extrahepatic dilation anomalies. Due to new insights into epithelial markers, and different pathophysiology in different etiologic subtypes, now they are called biliary malformations rather than cysts. They are rare disorders, occurring in less than 1/100,000 patients. They occur more frequently in female patients and in Asian populations. These are considered premalignant conditions and are sometimes diagnosed in infancy; however, they can present in adulthood (Fig. 55.33).21 Type I choledochal cyst is the most common form and involves only the extrahepatic biliary tree with a fusiform dilation. Type II cysts appear as a saccular diverticulum off the CBD and may be mistaken for an accessory gallbladder. Type III cysts appear as a cystic dilation of the intramural CBD, within the wall of the duodenum, and are also known as choledochoceles. Cysts involving the intrahepatic and extrahepatic biliary tree are known as type IVa, with type IVb being multiple cysts limited to the extrahepatic biliary tree. Type V cysts, also known as Caroli disease, involve the intrahepatic ducts only. Type V cysts may be solitary but usually occur diffusely in all segments. Although classified as a single disease, there are multiple theories for etiology, but mostly accepted, especially for types I and IV, is the anomalous pancreatobiliary junction (APBJ; Figs. 55.34 and 55.35).22 With APBJ, the pancreatic duct and biliary tree fuse to form a common channel before passage through the duodenal wall; APBJ is seen in up to 90% of patients with choledochal cysts, but almost exclusively in types I and IV. The fused duct forms a long common channel, which allows pancreatic

CHAPTER 55  Biliary System

Type I

Type II

1505

Type III

FIG. 55.35  Magnetic resonance cholangiopancreatography showing anomalous pancreaticobiliary junction with long common channel. The pancreatic duct fuses with the common bile duct (slender arrow), and the common channel enters the duodenum (bold arrow). Also noted in this illustration is the fusiform dilation of only the extrahepatic bile duct, as seen in a type I choledochal cyst. Type IV

Type V

FIG. 55.33  Choledochal cyst classification.

FIG. 55.34  Anomalous pancreaticobiliary junction. With fusion of the common bile duct and pancreatic duct long before they pass through the duodenal wall, the pancreatic secretions can reflux into the common bile duct and may cause damage to the common duct through pressure or chemical injury.

secretions to reflux into the biliary tree. Because the pancreatic duct has higher secretory pressures than the biliary tree, exocrine pancreatic secretions reflux up into the bile duct and can inflame and damage the biliary epithelium, leading to cystic degeneration. Types II and III almost never present with APBJ and are associated with minimal risk of malignancy. Presentation. Jaundice is the most consistent symptom, sometimes accompanied with right upper quadrant pain and rarely a palpable mass. Patients may also suffer from nonspecific problems such as weight loss, nausea, and vomiting. Rarely, a long-standing

malformation can cause liver injury and even cirrhosis. Diagnostic imaging is the only diagnostic confirmation test. With the current liberal use of CT, the diagnosis of a choledochal cyst is usually suspected in CT but it is further classified by MRCP or ERCP. Sometimes the distal bile duct is difficult to evaluate by MRCP, so ERCP is more useful for defining the distal biliary tree and pancreaticobiliary junction. Laboratory studies may identify cholestasis and jaundice. In late stages of disease, secondary hepatic injury and evidence of cirrhosis may be seen. Rarely, first presentation is cholangiocarcinoma. The incident of malignancy ranges between 5% and 30% over a lifetime, most commonly occurring in the seventh decade and almost exclusively occurring in types I and IV. Interestingly, malignancy has been seen in the nondilated intrahepatic biliary tree in type I choledochal cysts.22  Treatment. Historically, enteric drainage of the cyst was performed without resection, but this approach is complicated by the development of malignancy, recurrent biliary stasis, and infection. Surgical management of choledochal cysts consists of resection of the entire cyst and appropriate surgical reconstruction. Type I cysts are treated by complete surgical excision, cholecystectomy, and Roux-en-Y hepaticojejunostomy. The proximal extent of resection should continue to the nondilated biliary tree and may require anastomosis to the left and right hepatic ducts.22 The distal duct is oversewn, with care taken not to injure the pancreatic duct. Type II cysts should be excised entirely. Type III cysts are uncommon and may be approached transduodenally. Because the pathogenesis of type III cysts is not clear and almost always does not involve APBJ, endoscopic drainage may suffice. In the setting of duodenal or biliary obstruction, transduodenal excision or sphincteroplasty can be performed. Surgical treatment of type IV cysts must be carefully individualized to the affected anatomy. Type IV cysts affecting only the extrahepatic bile ducts are managed similarly to type I cysts, with excision and hepaticojejunostomy. Those with intrahepatic extension involving only one lobe can be treated with partial hepatectomy and reconstruction. Surgical treatment of Caroli disease ranges from resection if the disease is unilobar to liver transplantation when diffuse disease is detected. 

1506

SECTION X  Abdomen biliary tree, the mass-like stricture may be the result of ischemia to the duct, with subsequent inflammation and fibrosis. Alternatively, pseudotumors may occur de novo; these commonly affect the extrahepatic biliary tree above the bifurcation. 

Map 3 170dB/C 2 Persist Off 2D Opt: FSCT Fr Rate: Surv SonoCT XRes

Surgery for Calculous Biliary Disease

GB

FIG. 55.36  Ultrasound image of adenomyomatosis. Seen in the fundus of the gallbladder is a sessile thickening (arrow) with smaller microcysts within it, consistent with adenomyomatosis.

Polypoid Lesions of the Gallbladder Benign masses of the gallbladder are common. The estimated prevalence is between 3% and 12.3% of the population.23 They can be divided into pseudopolyps and true polyps. Pseudopolyps are further divided into cholesterol polyps, focal adenomyomatosis, hyperplastic polyps, and inflammatory polyps. Cholesterol polyps appear as pedunculated echogenic lesions of the gallbladder, are usually smaller than 1 cm, and are frequently multiple. Alternatively, adenomyomatosis is seen as a sessile lesion, commonly in the fundus, with characteristic microcysts within the lesion, and is frequently larger than 1 cm (Fig. 55.36). True polyps are benign growths in the wall of the gallbladder and consist of only 5% of all polypoid disorders of gallbladder. True polyps may be difficult to differentiate from adenocarcinoma preoperatively due to imaging limitations in detecting mural invasion. This is discussed further in the malignancy section of this chapter. Asymptomatic lesions smaller than 10 mm with no other risk factors and no ultrasonographic features suggesting malignant disease can be observed with serial ultrasonography.  Benign Biliary Masses Benign intraluminal lesions of the biliary tract have been a constant evolving field. The most accepted categorization of benign biliary lesions currently includes intraepithelial and intraductal types. Intraepithelial lesions are described in different grading system of “biliary intraepithelial neoplasms.” These are considered precursors of epithelial malignancies of bile ducts. The intraductal lesions are described as “intraductal papillary neoplasms.” These lesions include mucin producing neoplasms, adenomas, papillomas, and papillomatosis. Some of these lesions are premalignant, including mucin producing and papillomatosis. The presentation is that of biliary obstruction with jaundice and sometimes right upper quadrant pain. Treatment consists of complete resection with a small rim of normal epithelium because incomplete excision of affected epithelium carries a high risk of recurrence. These lesions occur in the periampullary duct, so a transduodenal approach can be used. Rarely, intraductal papillary or mucin-producing lesions may be found in intrahepatic biliary radicles. Inflammatory lesions of the biliary tree, known as pseudotumors or benign fibrosing disease, may be mistaken for cholangiocarcinoma. When this process follows surgical intervention on the

Laparoscopic Cholecystectomy Laparoscopic cholecystectomy, first done by Muhe in 1985 (using a direct scope) and later in 1987 by Mouret, is one of the most commonly performed general surgery procedures in the United States. Laparoscopic cholecystectomy has a 0.1% to 0.5% mortality and 2% to 3% morbidity.7 Laparoscopic surgery results in smaller incisions, less pain, and shorter hospitalization when compared to traditional open cholecystectomy, which has significantly increased the number of these procedures done worldwide. Most cholecystectomies are performed for biliary colic, but the operation can be performed safely in the setting of acute inflammation. Studies have shown that laparoscopic cholecystectomy for acute cholecystitis may carry longer operative times and a higher conversion rate to the open procedure than when it is performed in the elective setting, with possibly a higher risk of common duct injury.24 General anesthesia with muscle relaxation is required when a laparoscopic cholecystectomy is performed. Therefore, one contraindication to the procedure is the inability to tolerate general anesthesia. Others include end-stage liver disease with portal hypertension, precluding safe portal dissection, and coagulopathy. Because most pneumoperitoneum laparoscopies are performed using CO2 and has a number of adverse physiologic effects, severe chronic obstructive pulmonary disease, with poor ability for gas exchange, and congestive heart failure are considered relative contraindications. Preparation of the patient, induction of anesthesia, and sterile draping are performed as for an open cholecystectomy. Although use of a urinary catheter depends on the clinical setting, an orogastric tube is helpful with decompressing the stomach and exposure of the upper abdomen. The standard way is the four-port technique, usually one large port that will be used as extraction site, typically placed around umbilicus, and three 5-mm or even smaller ports for dissection. After the establishment of a CO2 pneumoperitoneum, a brief exploration is performed, and additional 5-mm ports are placed in the right anterior axillary line, right midclavicular line, and subxiphoid location (Fig. 55.37). The lateral port at the anterior axillary line is used to elevate the fundus of the gallbladder toward the right shoulder. This retraction provides exposure to the infundibulum and porta hepatis. The midclavicular trocar is used to grasp the gallbladder infundibulum, retracting it inferolaterally to open the triangle of Calot (Figs. 55.38 to 55.40). By distraction of Hartmann pouch laterally, the cystic duct no longer lies almost parallel to the common hepatic duct and is an extremely important maneuver to avoid injuring the CBD during this procedure. The dissection is then carried along the infundibulum on the anterior and posterior surfaces to expose the base of the gallbladder to clear all fibrofatty tissue from the triangle of Calot. Then the cystic duct and artery are identified by inferolateral traction of the infundibulum. A useful landmark for the cystic artery is the overlying lymph node, known as Calot node. To minimize bile duct injury, a strategy known as the critical view of safety can be employed. Rotating the gallbladder infundibulum laterally and then medially, there should be only two structures entering the gallbladder, and the liver on the opposite side of the gallbladder

1507

CHAPTER 55  Biliary System Laparoscopic tower

Accessory monitor

CA

CBD

CD

Surgeon 5 mm 12 mm

FIG. 55.39  Laparoscopic view of the same patient as in Fig. 55.38 but Camera assistant

Nurse

with inferolateral traction on the infundibulum. Note the angular change to the cystic duct (CD) compared with the common bile duct (CBD). The dissecting tool indicates the location of the right hepatic artery. The key element to this view in minimizing CBD injury is the identification of the cystic artery (CA) and duct entering the gallbladder with the inferior aspect of segment V of the liver identified in the space on either side of the artery and duct.

FIG. 55.37  Laparoscopic cholecystectomy ports. The assistant uses the periumbilical port to provide access for the camera and the most lateral port to elevate the fundus and to expose the neck. The surgeon can then provide inferolateral traction on the infundibulum and open the critical view of safety.

CA

CD

CBD

G CBD

FIG. 55.40  An artist’s representation of Fig. 55.39, showing hidden anatomy. CA, Cystic artery; CBD, common bile duct; CD, cystic duct.

FIG. 55.38  Laparoscopic view of the porta and gallbladder infundibulum without inferolateral traction on the infundibulum. Note that the gallbladder infundibulum (G) lies immediately adjacent to the common bile duct (CBD).

should be visible through the open spaces around each structure (Fig. 55.41).24 Clips are then placed on the cystic artery and duct. If cholangiography is performed, the cystic duct is clipped only adjacent to the gallbladder, the cystic duct is incised but not transected so that the cholangiogram catheter can be passed into it, and fluoroscopic images are obtained (Fig. 55.42). On obtaining a normal cholangiogram or when cholangiography is not performed, the cystic duct is doubly clipped on the common duct side and transected. The previously clipped artery is also transected, and the gallbladder is dissected off the liver bed using electrocautery. Because the venous drainage of the gallbladder is directly into the liver bed through venules, excellent hemostasis must be achieved during

FIG. 55.41  Wide critical view.

this dissection. The cystic duct and cystic artery clips are inspected just before completion of the dissection of the fundic attachments because the superior traction of the fundus has provided exposure to the porta and triangle of Calot. The gallbladder is then brought out of the abdominal cavity through the umbilical port. In the setting of acute cholecystitis or if the gallbladder was entered during

1508

SECTION X  Abdomen

FIG. 55.42  Normal cholangiogram.

dissection, a plastic bag should be used for retrieval. Any stones that are spilled during a cholecystectomy also should be retrieved. Opinion is sharply divided regarding the performance of selective versus routine cholangiography, with supportive data for each approach. Routine cholangiography will identify unsuspected stones in less than 10% of patients, does not decrease the incidence of biliary injury, and can be misinterpreted.25 However, cholangiogram may capture a CBD injury at the time of surgery, as opposed to a later diagnosis. Indications for cholangiography in the selective setting include any questionable anatomy and difficulty identifying the structures, suspicion of intraoperative CBD injury, unexplained pain at the time of cholecystectomy, any suspicion of current or previous choledocholithiasis without preoperative duct clearance, elevated preoperative liver enzyme levels, dilated CBD in preoperative imaging, and suspicion of intraoperative biliary injury. The Tokyo Guidelines7 does not encourage the routine use of cholangiography; however, many authors advocate its use in the academic setting to ensure that trainees are facile in its performance.10 Although it is just as accurate as cholangiography for the identification of choledocholithiasis, laparoscopic ultrasonography is highly operator dependent, requires additional instrumentation, and is not widely available.  Bailout Procedures As the grade of cholecystitis increases from I to II or III, a laparoscopic procedure becomes increasingly difficult to complete safely. The Tokyo Guidelines on recommendations for surgical management of cholecystitis recommend a few bailout options, and a surgeon must be prepared to perform these, especially with a higher-grade cholecystitis. The common bailout procedures include subtotal cholecystectomy, fundus first procedure (retrograde), and conversion to open. Subtotal cholecystectomy is removing as much gallbladder as possible, from fundus to infundibulum, and is “reconstituting” (closed gallbladder remnant) or “fenestrated” (open gallbladder remnant, with or without closure of the internal opening of the cystic duct).7 Fundus first procedure refers to separation of the gallbladder from the liver surface starting from the fundus without visualizing the cystic duct and artery. This procedure can end with subtotal cholecystectomy or completion of cholecystectomy.7 

FIG. 55.43  Laparoscopic choledochotomy for common bile duct exploration.

Open Cholecystectomy Although open cholecystectomy is considered a safe alternative or bailout procedure for the difficult laparoscopic cholecystectomy, experience with it has drastically declined, making this procedure not necessarily the safer technique.7 Open cholecystectomy is generally performed after conversion from the laparoscopic approach, for patients who have a contraindication to the laparoscopic approach, or as a step during another operation, such as a pancreaticoduodenectomy. Open cholecystectomy can be performed through a midline or right subcostal incision. Early identification and ligation of the cystic artery limit the blood loss during the procedure but may prove difficult because of inflammation. This approach must be used with caution as the extension of the dissection continues inferiorly, putting portal vein and other portal structures at risk.26 When it is performed for severe cholecystitis, the dissection of the gallbladder of the liver bed may be associated with substantial blood loss, but with removal of the infected gallbladder and packing of the area, the bleeding is usually well controlled.  Open CBD Exploration Clearance of choledocholithiasis or any other reason for CBD exploration is typically performed by open technique. Most surgeons prefer right upper quadrant incision; however, an upper midline incision can be used as well. Gentle palpation of the distal bile duct will frequently find the offending stone, which may be milked backward. Stay sutures are then placed and a choledochotomy is performed in the supraduodenal bile duct. Flushing of the duct with a soft rubber catheter will frequently remove the offending stones. Balloon catheters and, with fluoroscopic guidance, wire baskets may be useful to withdraw the stone. Flexible choledochoscopes are used to visualize the distal bile duct (Fig. 55.43). With complete removal of stones, a T tube is placed, and a cholangiogram obtained before closure to document clearance.

CHAPTER 55  Biliary System

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2 to 2.5 cm

A

B

C

D

FIG. 55.44  Choledochoduodenostomy. In the setting of a dilated common bile duct (CBD) with inability to clear all the stones from the distal duct, an anastomosis can be performed between the CBD and adjacent duodenum. Although maintaining the possibility of future endoscopic therapy, this arrangement risks sump syndrome in the undrained distal duct. (A) Vertical incision on CBD and horizontal incision on duodenum. (B) Stay sutures on corners, creating open anastomosis. (C) Suturing posterior wall. (D) Suturing anterior wall.

With dilated bile ducts, multiple distal impacted stones, a distal duct stricture with stones, intrahepatic stones, or primary bile duct stones drainage procedures provide more successful long-term outcomes. Options in this setting include choledochoduodenostomy (Fig. 55.44), or Roux-en-Y hepaticojejunostomy (Fig. 55.45). A side-to-side or end-to-side choledochoduodenostomy allows future endoscopic intervention of the upper biliary tree, if necessary. An alternative to duodenostomy is a Roux-en-Y choledochojejunostomy. Transduodenal sphincteroplasty must be the procedure of choice when impacted stones at the ampulla cannot be removed through choledochotomy or several stones are impacted in a nondilated tree (Figs. 55.46 and 55.47). After completion of the Kocher maneuver, a longitudinal duodenotomy is made on the lateral wall. Compression of the lateral wall against the medial wall will allow palpation of the ampulla to plan placement of the duodenotomy appropriately. With identification of the ampulla, an incision is made at the 11 o’clock position, and each wall is elevated with stay sutures. The pancreatic duct usually enters at the 5 o’clock position on the ampulla and must

be avoided. It is also imperative to remember that the inferior pancreaticoduodenal arcade is adjacent to the distal part of the ampulla and can be injured during sphincterotomy. Sequential straight clamps are placed along the planned incision of the ampulla to guide visualization through hemostasis. With each step, the duodenal mucosa is sewn to the bile duct mucosa with absorbable 4-0 or 5-0 sutures. A 1.5-cm sphincterotomy is usually sufficient to allow stone removal and subsequent drainage. Closure of the longitudinal duodenotomy in transverse fashion avoids a future duodenal stricture. Open exploration carries a low morbidity (8%–15%) and mortality (1%–2%), with a low rate of retained stones (2 cm

E1

10 mg/dL) and those with a prolonged time interval between presentation and resection. For patients with hilar cholangiocarcinoma, hepatic resection remains an important feature of the operative strategy. In the setting of complete biliary obstruction, hepatic resection carries an additional risk of bleeding, sepsis, and hepatic failure. Drainage of the obstructed but unaffected segments can enhance the postresection hypertrophy of the remaining liver but may increase perioperative infectious complications.  Treatment Operative management. With the clinical suspicion of cholangiocarcinoma in adequate operative candidates without contraindications to resection, exploration should proceed, even in the absence of a confirmed tissue diagnosis. Between 7% and 15%

CHAPTER 55  Biliary System

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TABLE 55.2  Staging for intrahepatic bile duct cancer. Definition of Primary Tumor (T) T Category TX T0 Tis T1 T1a T1b T2 T3 T4

T Criteria Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ (intraductal tumor) Solitary tumor without vascular invasion, ≤5 cm or >5 cm Solitary tumor ≤5 cm without vascular invasion Solitary tumor >5 cm without vascular invasion Solitary tumor with intrahepatic vascular invasion or multiple tumors, with or without vascular invasion Tumor perforating the visceral peritoneum Tumor involving local extrahepatic structures by direct invasion

Definition of Regional Lymph Node (N) N Category NX N0 N1

N Criteria Regional lymph nodes cannot be assessed No regional lymph node metastasis Regional lymph node metastasis present

Definition of Distant Metastasis (M) M Category M0 M1

M Criteria No distant metastasis Distant metastasis

AJCC Prognostic Stage Groups When T is… And N is… Tis N0 T1a N0 T1b N0 T2 N0 T3 N0 T4 N0 Any T N1 Any T Any N

And M is… M0 M0 M0 M0 M0 M0 M0 M1

Then the stage group is… 0 IA IB II IIIA IIIB IIIB IV

From Amin MB,1 Greene FL,2 Edge SB,3,4 Compton CC,5,6 Gershenwald JE,7 Brookland RK,8 Meyer L,9 Gress DM,10 Byrd DR,11 Winchester DP.12 AJCC Cancer Staging Manual. 8th ed. New York: Springer; 2017:295–302. AJCC, American Joint Committee on Cancer. 1Professor and Chairman, UTHSC Gerwin Chair for Cancer Research, Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN. 2Medical Director, Cancer Data Services, Levine Cancer Institute, Charlotte, NC. 3Vice President, Healthcare Outcomes and Policy, Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY. 4Professor of Oncology, Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY. 5Chief Medical Officer, Complex Adaptive Systems Initiative, Arizona State University, Scottsdale, AZ. 6Professor of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN. 7Professor of Surgery and Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX. 8Radiation Oncologist, Greater Baltimore Medical Center, Baltimore, MD. 9Eighth Edition Project Manager and Managing Editor, American Joint Committee on Cancer, Chicago, IL. 10Technical Specialist and Technical Editor, American Joint Committee on Cancer, Chicago, IL. 11Section Chief of Surgical Oncology and Professor of Surgery, University of Washington, Seattle, WA. 12Medical Director, American Joint Committee on Cancer, Chicago, IL.

of patients undergoing resection for suspected biliary malignant disease will prove to have benign disease. Alternatively, more than 50% of patients undergoing exploration have historically had findings precluding resection, such as peritoneal metastases, hepatic metastases, or locally advanced lesions. With experienced judgment and advances in the quality of preoperative imaging, this rate is decreasing. Staging laparoscopy can also be an important initial step at the time of resection to reduce the incidence of nontherapeutic laparotomy.  Distal cholangiocarcinoma. Distal cholangiocarcinoma is managed by pancreaticoduodenectomy. Because these lesions tend

to grow in a submucosal plane, a frozen section of the proximal bile duct margin helps ensure an R0 resection. An R0 resection remains one of the most important prognostic factors for this disease, with 5-year survival rates of up to 50% in node-negative patients with an R0 resection.  Proximal cholangiocarcinoma. Surgical management of proximal cholangiocarcinoma involves resection of regional nodal tissue and en bloc resection of the CBD with hepatic parenchyma as necessary to achieve negative margins. The Bismuth-Corlette classification of the tumor by assessment of the involvement of biliary radicals helps with operative planning (Fig. 55.61).51

1522

SECTION X  Abdomen

TABLE 55.3  Staging for perihilar bile duct cancer. Definition of Primary Tumor (T) T Category T Criteria TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ/high-grade dysplasia T1 Tumor confined to the bile duct, with extension up to the muscle layer or fibrous tissue T2 Tumor invades beyond the wall of the bile duct to surrounding adipose tissue, or tumor invades adjacent hepatic parenchyma T2a Tumor invades beyond the wall of the bile duct to surrounding adipose tissue T2b Tumor invades adjacent hepatic parenchyma T3 Tumor invades unilateral branches of the portal vein or hepatic artery T4 Tumor invades the main portal vein or its branches bilaterally, or the common hepatic artery; or unilateral second-order biliary radicals with contralateral portal vein or hepatic artery involvement Definition of Regional Lymph Node (N) N Category N Criteria NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 One to three positive lymph nodes typically involving the hilar, cystic duct, common bile duct, hepatic artery, posterior pancreatoduodenal, and portal vein lymph nodes N2 Four or more positive lymph nodes from the sites described for N1 Definition of Distant Metastasis (M) M Category M Criteria M0 No distant metastasis M1 Distant metastasis AJCC Prognostic Stage Groups When T is… And N is… Tis N0 T1 N0 T2a–b N0 T3 N0 T4 N0 Any T N1 Any T N2 Any T Any N

And M is… M0 M0 M0 M0 M0 M0 M0 M1

Then the stage group is… 0 I II IIIA IIIB IIIC IVA IVB

From Amin MB,1 Greene FL,2 Edge SB,3,4 Compton CC,5,6 Gershenwald JE,7 Brookland RK,8 Meyer L,9 Gress DM,10 Byrd DR,11 Winchester DP.12 AJCC Cancer Staging Manual. 8th ed. New York: Springer; 2017:311–316. AJCC, American Joint Committee on Cancer. 1Professor and Chairman, UTHSC Gerwin Chair for Cancer Research, Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN. 2Medical Director, Cancer Data Services, Levine Cancer Institute, Charlotte, NC. 3Vice President, Healthcare Outcomes and Policy, Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY. 4Professor of Oncology, Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY. 5Chief Medical Officer, Complex Adaptive Systems Initiative, Arizona State University, Scottsdale, AZ. 6Professor of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN. 7Professor of Surgery and Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX. 8Radiation Oncologist, Greater Baltimore Medical Center, Baltimore, MD. 9Eighth Edition Project Manager and Managing Editor, American Joint Committee on Cancer, Chicago, IL. 10Technical Specialist and Technical Editor, American Joint Committee on Cancer, Chicago, IL. 11Section Chief of Surgical Oncology and Professor of Surgery, University of Washington, Seattle, WA. 12Medical Director, American Joint Committee on Cancer, Chicago, IL.

Types I and II lesions are treated with common duct resection, cholecystectomy, and a 5- to 10-mm margin of resection. Type II lesions may also require partial hepatic resection, which commonly includes resection of the caudate lobe. Resection of the bile duct and nodal tissue requires skeletonization of the hepatic artery and portal vein. Reconstruction is performed using a Roux limb of jejunum. Types III and IV lesions may involve complex resection

and reconstruction of the portal vein, hepatic artery, or both. With resection to secondary biliary radicals, transanastomotic stenting is used liberally to allow healing and even confirmation of anastomotic integrity. A substantial improvement in long-term survival has correlated with the increasing use of hepatic resection to achieve negative margins. Negative margin status is the most important variable associated with outcome.52

CHAPTER 55  Biliary System

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TABLE 55.4  Staging for distal bile duct cancer. Definition of Primary Tumor (T) T Category TX Tis T1 T2 T3 T4

T Criteria Primary tumor cannot be assessed Carcinoma in situ/high-grade dysplasia Tumor invades the bile duct wall with a depth less than 5 mm Tumor invades the bile duct wall with a depth of 5–12 mm Tumor invades the bile duct wall with a depth greater than 12 mm Tumor involves the celiac axis, superior mesenteric artery, and/or common hepatic artery

Definition of Regional Lymph Node (N) N Category NX N0 N1 N2

N Criteria Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastasis in one to three regional lymph nodes Metastasis in four or more regional lymph nodes

Definition of Distant Metastasis (M) M Category M0 M1

M Criteria No distant metastasis Distant metastasis

AJCC Prognostic Stage Groups When T is… Tis T1 T1 T1 T2 T2 T2 T3 T3 T3 T4 T4 T4 Any T

And N is… N0 N0 N1 N2 N0 N1 N2 N0 N1 N2 N0 N1 N2 Any N

And M is… M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

Then the stage group is… 0 I IIA IIIA IIA IIB IIIA IIB IIB IIIA IIIB IIIB IIIB IV

From Amin MB,1 Greene FL,2 Edge SB,3,4 Compton CC,5,6 Gershenwald JE,7 Brookland RK,8 Meyer L,9 Gress DM,10 Byrd DR,11 Winchester DP.12 AJCC Cancer Staging Manual. 8th ed. New York: Springer; 2017:317–326. AJCC, American Joint Committee on Cancer. 1Professor and Chairman, UTHSC Gerwin Chair for Cancer Research, Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN. 2Medical Director, Cancer Data Services, Levine Cancer Institute, Charlotte, NC. 3Vice President, Healthcare Outcomes and Policy, Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY. 4Professor of Oncology, Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY. 5Chief Medical Officer, Complex Adaptive Systems Initiative, Arizona State University, Scottsdale, AZ. 6Professor of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN. 7Professor of Surgery and Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX. 8Radiation Oncologist, Greater Baltimore Medical Center, Baltimore, MD. 9Eighth Edition Project Manager and Managing Editor, American Joint Committee on Cancer, Chicago, IL. 10Technical Specialist and Technical Editor, American Joint Committee on Cancer, Chicago, IL. 11Section Chief of Surgical Oncology and Professor of Surgery, University of Washington, Seattle, WA. 12Medical Director, American Joint Committee on Cancer, Chicago, IL.

Five-year survival rates as high as 59% have been reported in selected series, and with vascular resection and reconstruction techniques, resectability rates have also increased. Increases in the magnitude of the operation have also correlated with an expected increase in surgical mortality, from 2% to 4% in limited resection up to 3% to 11% when more complex.

Although the importance of achieving an R0 resection is clear, the role of routine lymph node dissection is debated. There has been no demonstrable benefit of routine lymph node dissection; however, lymph nodes are one of the most important prognostic factors in cholangiocarcinoma and may help direct adjuvant therapy.

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SECTION X  Abdomen

As noted previously, an extensive neoadjuvant therapy protocol followed by transplantation has shown promising results in tightly controlled trials where hilar cholangiocarcinoma occurs in the setting of underlying liver disease. In spite of these findings, the role of transplantation in the management of cholangiocarcinoma remains experimental, and substantial debate remains about the routine use of an extremely limited resource in this disease process. Many patients entering such a

FIG. 55.59  Computed tomography scan of cholangiocarcinoma with left lobar atrophy caused by obstruction of the left duct. Noted in the atrophied left lobe are dilated biliary radicals (arrows).

FIG. 55.60  Computed tomography scan of Klatskin tumor (arrow) encasing the main portal vein, consistent with unresectable disease.

protocol develop disseminated disease prior to achieving transplantation.  Palliation. In patients found to have unresectable or incurable disease preoperatively, all attempts to palliate their symptoms nonoperatively should be used. The goals of palliation should include relief of jaundice, alleviation of pain, and relief of duodenal obstruction, if necessary. Surgical palliation has not been shown to prolong survival or to reduce complication rates and thus should be reserved for candidates found to be unresectable or metastatic at time of operation. Depending on the location of the biliary obstruction, endoscopic or percutaneous routes of drainage can be used, and placement of a selfexpandable metallic stent provides a durable solution. When plastic stents are used, additional manipulation or placement of subsequent stents may be required. For distal cholangiocarcinomas, ERCP is the preferred route of nonoperative biliary drainage, whereas PTC is more useful for proximal lesions. Drainage of atrophic lobes with stents does not improve palliation of disease. Pain can be treated with oral narcotics. IV narcotics and even percutaneous destruction of the celiac plexus have demonstrated some benefit. For distal cholangiocarcinomas, in which duodenal obstruction may occur, endoscopic duodenal stenting can relieve obstruction in this preterminal condition.  Medical treatment. Chemotherapy has not been shown to improve survival in patients with cholangiocarcinoma. In addition, radiation therapy has not been proven in a prospective fashion to affect survival. Therefore, neither chemotherapy nor radiation therapy is used routinely in the adjuvant or neoadjuvant setting. Although some retrospective studies have shown a small survival advantage with adjuvant radiation, prospective studies of adjuvant radiotherapy have shown no benefit in completely resected patients. Radiation therapy may provide a small survival advantage as an adjunct to resection when microscopic residual disease remains. Most studies have reported a clinical response rate of less than 10%. Even in the absence of supportive data, adjuvant chemoradiation is used routinely at many centers but should be limited to patients with nodal disease, those with R1 resections, and those undergoing a clinical trial.  Outcomes Long-term survival is highly dependent on stage at presentation and complete surgical resection to negative margins. With the use of common duct resection with partial hepatectomy, negative margin rates have increased to more than 75%. This has resulted in 5-year survival rates of 20% to 45% in most series. The principal reason for the variability in survival appears to be the presence of lymph node metastases. Although

Bismuth, Nakache, and Diamond Type I

Type II

Type IIIa

Type IIIb

Type IV

FIG. 55.61  Bismuth-Corlette classification of tumor involvement.

CHAPTER 55  Biliary System morbidity rates of 35% to 50% are common, mortality rates are generally low (100 g/day for at least 5 years), smoking, and genetic

Gallstones Ethanol

ERCP

Idiopathic

Drugs

Autoimmune pancreatitis

Anatomic obstruction

Pancreatic injury

TNF-α and IL-1

Inflammatory cascade (IL-2, IL-6, IL-8, IL-10, bradykinin, PAF)

Systemic inflammatory response syndrome

Multiorgan dysfunction syndrome

Death

FIG. 56.7  Pathophysiology of severe acute pancreatitis. The local injury induces the release of tumor necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1). Both cytokines produce further pancreatic injury and amplify the inflammatory response by inducing the release of other inflammatory mediators, which cause distant organ injury. This abnormal inflammatory response is responsible for the mortality seen during the early phase of acute pancreatitis. ERCP, Endoscopic retrograde cholangiopancreatography; PAF, XXX.

predisposition. Compared with nonsmokers, the relative risk of alcohol-induced pancreatitis in smokers is 4.9.7 Alcohol has a number of deleterious effects in the pancreas and its mechanism of injury is likely multifaceted. It has been shown to: 1) trigger proinflammatory pathways via upregulation of nuclear factor κB (NF-κB), TNF-α, and IL-1, 2) cause inappropriate basolateral exocytosis of pancreatic zymogens, 3) increased autophagy possibly due to dysregulation of cathepsin L and B, 4) increased oxidative stress leading to mitochondrial dysfunction, 5) activation of pancreatic stellate cells (PSCs) leading to increased secretion of matrix metalloproteases, 6) impaired pancreatic cell repair due to dysregulation in developmental factors PDX1, PTF1a, and Notch, and 7) a shift in cell death caused by apoptosis to necrosis by decreasing caspase 3/8 activity and loss of adenosine triphosphate (ATP) production via mitochondrial depolarization.  Anatomic Obstruction Abnormal flow of pancreatic juice into the duodenum can result in pancreatic injury. AP has been described in patients with pancreatic tumors, parasites, and congenital defects. Pancreas divisum is an anatomic variation present in 10% of the population. Its association with AP is controversial. Patients with this variation have a 5% to 10% lifetime risk for development of AP caused by relative outflow obstruction through the

CHAPTER 56  Exocrine Pancreas minor papilla. Endoscopic retrograde cholangiopancreatography (ERCP) with minor papillotomy and stenting may be beneficial for such patients. Infrequent anatomic obstructions that have been associated with AP include Ascaris lumbricoides infection and annular pancreas. Although pancreatic cancer is not uncommon, patients with pancreatic cancer usually do not develop AP.  Endoscopic Retrograde Cholangiopancreatography–Induced Pancreatitis AP is the most common complication after ERCP, occurring in up to 5% of patients. However, the incidence of this complication after ERCP could be as high as 15% in high-risk patients. PostERCP pancreatitis is more common in female patients, young individuals, and in patients with prior history of ERCP induced pancreatitis. AP occurs more frequently in patients who have undergone therapeutic procedures compared with diagnostic procedures. It is also more common in patients who have had multiple attempts of cannulation, sphincter of Oddi dysfunction, and abnormal visualization of the secondary pancreatic ducts after injection of contrast material. The clinical course is mild in 90% to 95% of patients. ERCP-induced pancreatitis is one of the rare opportunities where primary prevention of development of AP may be possible. First, ERCP should only be performed when absolutely necessary. With improvement in other diagnostic modalities including magnetic resonance cholangiopancreatography (MRCP), the use of diagnostic ERCP with its associated complications including ERCP-induced pancreatitis has decreased. Among pharmacologic agents to prevent ERCP-induced pancreatitis, use of indomethacin has gained the most traction. Technique related and interventional strategies, which have been shown to reduce the risk of postERCP pancreatitis, include use of pancreatic stents and using minimal pressure while performing ERCP.  Drug-Induced Pancreatitis Up to 2% of AP cases are caused by medications. The most common agents include sulfonamides, metronidazole, erythromycin, tetracyclines, didanosine, thiazides, furosemide, 3-hydroxy3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins), azathioprine, 6-mercaptopurine, 5-aminosalicylic acid, sulfasalazine, valproic acid, and human immunodeficiency virus antiretroviral agents.  Metabolic Factors Hypertriglyceridemia and hypercalcemia can also lead to pancreatic damage. Direct pancreatic injury can be induced by triglyceride metabolites. It is more common in patients with type I, II, or V hyperlipidemia. It should be suspected in patients with a triglyceride level higher than 1000 mg/dL. A triglyceride level higher than 2000 mg/dL confirms the diagnosis. Hypertriglyceridemia secondary to hypothyroidism, diabetes mellitus, and alcohol does not typically induce AP. Hypercalcemia is postulated to induce pancreatic injury through the activation of trypsinogen to trypsin and intraductal precipitation of calcium, leading to ductal obstruction and subsequent attacks of pancreatitis. Approximately 1.5% to 13% of patients with primary hyperparathyroidism develop AP.  Miscellaneous Conditions Blunt and penetrating abdominal trauma can be associated with AP in 0.2% and 1% of cases, respectively. Prolonged intraoperative hypotension and excessive pancreatic manipulation during abdominal surgery can also result in AP. Pancreatic ischemia in

1535

association with acute pancreatic inflammation can develop after splenic artery embolization. Other rare causes include scorpion venom stings and perforated duodenal ulcers. 

Clinical Manifestations The cardinal symptom of AP is epigastric or periumbilical pain that radiates to the back. Up to 90% of patients have nausea or vomiting that typically does not relieve the pain. The nature of the pain is constant; therefore, if the pain disappears or decreases, another diagnosis should be considered. Dehydration, poor skin turgor, tachycardia, hypotension, and dry mucous membranes are commonly seen in patients with AP. Severely dehydrated and older patients may also develop mental status changes. The physical examination findings of the abdomen vary according to the severity of the disease. With mild pancreatitis, the physical examination findings of the abdomen may be normal or reveal only mild epigastric tenderness. Significant abdominal distention associated with generalized rebound and abdominal rigidity is present in severe pancreatitis. The nature of the pain described by the patient may not correlate with the physical examination findings or the degree of pancreatic inflammation. Rare findings include flank and periumbilical ecchymosis (Grey Turner and Cullen signs, respectively). Both are indicative of retroperitoneal bleeding associated with severe pancreatitis. Patients with concomitant choledocholithiasis or significant edema in the head of the pancreas that compresses the intrapancreatic portion of the common bile duct can present with jaundice. Dullness to percussion and decreased breathing sounds in the left or, less commonly, in the right hemithorax suggest pleural effusion secondary to AP. 

Diagnosis The diagnosis of AP requires two of the following three features to be present according to international consensus: 1) abdominal pain consistent with AP (acute onset of a persistent, severe, epigastric pain often radiating to the back), 2) a threefold or higher elevation of serum amylase or lipase levels above the upper laboratory limit of normal, or 3) characteristics findings of pancreatitis by imaging. The serum half-life of amylase (10 hours) is shorter than that of lipase (6.9–13.7 hours) and therefore normalizes faster (3–5 vs. 8–14 days, respectively). In patients who do not present to the emergency department within the first 24 to 48 hours after the onset of symptoms, determination of lipase levels is a more sensitive indicator to establish the diagnosis. Lipase is also a more specific marker of AP because serum amylase levels can be elevated in a number of conditions, such as peptic ulcer disease, mesenteric ischemia, salpingitis, and macroamylasemia. Patients with AP are typically hyperglycemic; they can also have leukocytosis and abnormal elevation of liver enzyme levels. The elevation of alanine aminotransferase levels in the serum in the context of AP confirmed by high pancreatic enzyme levels has a positive predictive value of 95% in the diagnosis of acute biliary pancreatitis.5 Imaging Studies Imaging studies are not required for diagnosis, but may be helpful in determining need for intervention in severe AP or elucidating an elusive etiology. Although simple abdominal radiographs are not useful for diagnosis of pancreatitis, they can help rule out other conditions, such as perforated ulcer disease. Nonspecific findings in patients with AP include air-fluid levels suggestive of ileus,

1536

SECTION X  Abdomen

cutoff colon sign as a result of colonic spasm at the splenic flexure and widening of the duodenal C loop caused by severe pancreatic head edema. The usefulness of ultrasound for diagnosis of pancreatitis is limited by intraabdominal fat and increased intestinal gas as a result of the ileus. Nevertheless, this test should always be ordered in patients with AP because of its high sensitivity (95%) in diagnosing gallstones. Combined elevations of liver transaminase and pancreatic enzyme levels and the presence of gallstones on ultrasound have an even higher sensitivity (97%) and specificity (100%) for diagnosing acute biliary pancreatitis. Contrast-enhanced computed tomography (CT) is currently the best modality for evaluation of the pancreas, especially if the study is performed with a multidetector CT scanner. Indications for CT include diagnostic uncertainty, confirmation of severity based on clinical predictors, failure to respond to conservative treatment, or clinical deterioration. The most valuable contrast phase in which to evaluate the pancreatic parenchyma is the portal venous phase (65–70 seconds after injection of contrast material), which allows evaluation of the viability of the pancreatic parenchyma, amount of peripancreatic inflammation, and presence of intraabdominal free air or fluid collections. Noncontrast CT scanning may also be of value in the setting of renal failure by identifying fluid collections or extraluminal air. Abdominal magnetic resonance imaging (MRI) is also useful to evaluate the extent of necrosis, inflammation, and presence of free fluid. However, its cost and availability and the fact that patients requiring imaging are critically ill and need to be in intensive care units limit its applicability in the acute phase. Although MRCP is not indicated in the acute setting of AP, it has an important role in the evaluation of patients with unexplained or recurrent pancreatitis because it allows noninvasive complete visualization of the biliary and pancreatic duct anatomy. For difficult to view pancreatic ducts, intravenous (IV) administration of secretin can be injected prior to imaging to stimulate pancreatic juice secretion, thereby causing a transient distention of the pancreatic duct. Any pain associated with the timing of secretin stimulation should be noted as it may help in confirming an uncertain etiology of epigastric pain. For example, secretin stimulated MRCP is useful in patients with AP and no evidence of a predisposing condition to rule out pancreas divisum, intraductal papillary mucinous neoplasm (IPMN), or a small tumor in the pancreatic duct. In the setting of gallstone pancreatitis, endoscopic ultrasound (EUS) may play an important role in the evaluation of persistent choledocholithiasis. Several studies have shown that routine ERCP for suspected gallstone pancreatitis reveals no evidence of persistent obstruction in most cases and may actually worsen symptoms because of manipulation of the gland. EUS has been proven to be sensitive for identifying choledocholithiasis; it allows examination of the biliary tree and pancreas with no risk of worsening of the pancreatitis. In patients in whom persistent choledocholithiasis is confirmed by EUS, ERCP can be used selectively as a therapeutic measure. 

Assessment of Severity of Disease The earliest scoring system designed to evaluate the severity of AP was introduced by Ranson and colleagues in 1974. It predicts the severity of the disease on the basis of 11 parameters obtained at the time of admission or 48 hours later. The mortality rate of AP directly correlates with the number of parameters that are positive. Severe pancreatitis is diagnosed if three or more of the Ranson criteria are fulfilled. The main disadvantage is that it does not

BOX 56.1  Ranson Prognostic Criteria for

Nongallstone Pancreatitis

At presentation • Age >55 years • Blood glucose level >200 mg/dL • White blood cell count >16,000 cells/mm3 • Lactate dehydrogenase level >350 IU/L • Aspartate aminotransferase level >250 IU/L After 48 hours of admission • Hematocrit*: decrease >10% • Serum calcium level 4 mEq/L • Blood urea nitrogen level: increase >5 mg/dL • Fluid requirement >6 L • Pao2 70 years • Blood glucose level >220 mg/dL • White blood cell count >18,000 cells/mm3 • Lactate dehydrogenase level >400 IU/L • Aspartate aminotransferase level >250 IU/L After 48 hours of admission • Hematocrit*: decrease >10% • Serum calcium level 5 mEq/L • Blood urea nitrogen level: increase >2 mg/dL • Fluid requirement >4 L • Pao2: Not available Ranson score ≥3 defines severe pancreatitis. *Compared with admission value.

predict the severity of disease at the time of the admission because six parameters are assessed only after 48 hours of admission. The Ranson score has a low positive predictive value (50%) and high negative predictive value (90%). Therefore, it is mainly used to rule out severe pancreatitis or to predict the risk of mortality. The original scoring symptom designed to predict the severity of the disease and its modification for acute biliary pancreatitis are shown in Boxes 56.1 and 56.2. AP severity can also be addressed by the Acute Physiology and Chronic Health Evaluation (APACHE II) score. Based on the patient’s age, previous health status, and 12 routine physiologic measurements, APACHE II provides a general measure of the severity of disease. An APACHE II score of eight or higher defines severe pancreatitis. The main advantage is that it can be used on admission and repeated at any time. However, it is complex, not specific for AP, and based on the patient’s age, which easily upgrades the AP severity score. APACHE II has a positive predictive value of 43% and a negative predictive value of 89%. Using imaging characteristics, Balthazar and associates have established the CT severity index. This index correlates CT findings

CHAPTER 56  Exocrine Pancreas TABLE 56.2  Computed Tomography

Severity Index (CTSI) for acute pancreatitis. FEATURE Pancreatic Inflammation Normal pancreas Focal or diffuse pancreatic enlargement Intrinsic pancreatic alterations with peripancreatic fat inflammatory changes Single fluid collection or phlegmon Two or more fluid collections or gas, in or adjacent to the pancreas Pancreatic Necrosis None ≤30% 30%–50% >50%

POINTS 0 1 2 3 4

0 2 4 6

CTSI 0–3, mortality 3%, morbidity 8%; CTSI 4–6, mortality 6%, morbidity 35%; CTSI 7–10, mortality 17%, morbidity 92%.

BOX 56.3  Definition of systemic

inflammatory response syndrome (SIRS). Two or more of the following conditions must be met: • Temperature >38.3°C or 90 beats/minute • Respiratory rate of >20 breaths/minute or PaCO2 of 12,000 cells/mL, 10% immature (band) forms From Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet. 2005;365:63–78.

with the patient’s outcome. The CT severity index is shown in Table 56.2. While many prognostic indices have been developed to predict severity of disease, most are hindered by complexity, need for imaging, or inability to be calculated at admission. This has led to multiple professional societies recommending the use of the systemic inflammatory response syndrome (SIRS) scoring system (Box 56.3) as a fast, inexpensive, and reliable replacement.8,9 Having a persistent SIRS throughout hospital admission, having a transient SIRS, or never meeting SIRS criteria has been associated with mortality rates of 25%, 8%, and 0%, respectively. In 1992, the International Symposium on Acute Pancreatitis defined severe pancreatitis as the presence of local pancreatic complications (necrosis, abscess, or pseudocyst) or any evidence of organ failure. Severe pancreatitis is diagnosed if there is any evidence of organ failure or a local pancreatic complication (Box 56.4). In 2012, the International Symposium on Acute Pancreatitis updated their three-tiered grading schema of pancreatitis severity. Mild pancreatitis has no organ dysfunction or local/systemic complications, moderate pancreatitis can have organ failure lasting less than 48 hours and/or local/systemic complications, while severe pancreatitis is characterized by organ failure lasting beyond 48 hours. With increasing severity comes increased rates of morbidity and mortality. C-reactive protein (CRP) is an inflammatory marker that peaks 48 to 72 hours after the onset of pancreatitis and correlates

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BOX 56.4  Atlanta criteria for acute

pancreatitis.

Organ Failure, as Defined by Shock (systolic blood pressure 500 mL/24 hour)  Systemic Complications Disseminated intravascular coagulation (platelet count ≤100,000) Fibrinogen 80 μg/dL Metabolic disturbance (calcium level ≤7.5 mg/dL)  Local Complications Necrosis Abscess Pseudocyst Severe pancreatitis is defined by the presence of any evidence of organ failure or a local complication.

with the severity of the disease. A CRP level of 150 mg/mL or higher defines severe pancreatitis. The major limitation is that it cannot be used on admission; the sensitivity of the assay decreases if CRP levels are measured within 48 hours after the onset of symptoms. In addition to CRP, a number of studies have shown other biochemical markers (e.g., serum levels of procalcitonin, IL-6, IL-1, elastase) that correlate with the severity of the disease. However, their main limitation is their cost, and they are not widely available. 

Treatment Regardless of the cause or the severity of the disease, the cornerstones of treating AP are aggressive fluid resuscitation with isotonic crystalloid solution, pain control, and early nutrition. The rate of fluid administration should be individualized and adjusted on the basis of age, comorbidities, vital signs, mental status, skin turgor, and urine output. Patients who do not respond to initial fluid resuscitation or have significant renal, cardiac, or respiratory comorbidities often require invasive monitoring with central venous access and a Foley catheter. While the nature of fluid which should be used for initial resuscitation is still being debated, some evidence suggest that Ringer’s lactate may be the best fluid for initial resuscitation.10 In addition to fluid resuscitation, patients with AP require continuous pulse oximetry because one of the most common systemic complications of AP is hypoxemia caused by the acute lung injury associated with this disease. Patients should receive supplementary oxygen to maintain arterial saturation above 95%. It is also essential to provide effective analgesia. Narcotics are usually preferred, especially morphine. One of the physiologic effects described after systemic administration of morphine is an increase in tone in the sphincter of Oddi; however, there is no evidence that narcotics exert a negative impact on the outcome of patients with AP. Nutritional support is vital in the treatment of AP. Oral feeding may be impossible because of persistent ileus, pain, or intubation. In addition, 20% of patients with severe AP develop recurrent pain shortly after the oral route has been restarted.

1538

SECTION X  Abdomen

The main options to provide this nutritional support are enteral feeding and total parenteral nutrition (TPN). Although there is no difference in the mortality rate between both types of nutrition, enteral nutrition is associated with fewer infectious complications and reduces the need for pancreatic surgery. Although TPN provides most nutritional requirements, it is associated with mucosal atrophy, decreased intestinal blood flow, increased risk of bacterial overgrowth in the small bowel, antegrade colonization with colonic bacteria, and increased bacterial translocation. In addition, patients with TPN have more central line infections and metabolic complications (e.g., hyperglycemia, electrolyte imbalance). Whenever possible, enteral nutrition should be used rather than TPN and TPN should be used only if there is intolerance to enteral feeding. Nasojejunal feeding tube placement is currently favored, but there is some low-level evidence suggesting that nasogastric feeding can safely be considered as an alternative if significant gastric outlet obstruction is not present. Given the significant increase in mortality associated with septic complications in severe pancreatitis, a number of physicians advocated the use of prophylactic antibiotics in the 1970s. Recent meta-analyses and systematic reviews that have evaluated multiple randomized controlled trials have proved that prophylactic antibiotics do not decrease the frequency of surgical intervention, infected necrosis, or mortality in patients with severe pancreatitis. In addition, they are associated with gram-positive cocci infection, such as by Staphylococcus aureus, and Candida infection, which is seen in 5% to 15% of patients. Current recommendations are to only administer antibiotics if a preexisting infection is present on presentation or radiographic imaging suggests infected peripancreatic fluid collections (e.g., air within collection or rim enhancement). Special Considerations Endoscopic retrograde cholangiopancreatography. Early ERCP, with or without sphincterotomy, was initially advocated to reduce the severity of pancreatitis because the obstructive theory of AP states that pancreatic injury is the result of pancreatic duct obstruction. However, multiple randomized trials have evaluated the use and efficacy of early ERCP in the management of acute biliary pancreatitis. The results of these trials do not support the use of ERCP in the management of acute biliary pancreatitis regardless of the severity. Routine use of ERCP is not indicated for patients with mild pancreatitis because the bile duct obstruction is usually transient and resolves within 48 hours after the onset of symptoms. Based on a meta-analysis of these clinical trials11 as well as two major society guidelines based on these clinical trials,8 ERCP is only indicated for patients who develop cholangitis and those with persistent bile duct obstruction demonstrated by other imaging modalities, such as EUS. Finally, in older patients with poor performance status or severe comorbidities that preclude surgery, ERCP with sphincterotomy is a safe alternative to prevent recurrent biliary pancreatitis.  Laparoscopic cholecystectomy. In the absence of definitive treatment, 30% of patients with acute biliary pancreatitis will have recurrent disease. With the exception of older patients and those with poor performance status, laparoscopic cholecystectomy is indicated for all patients with mild acute biliary pancreatitis. Studies have shown that early laparoscopic cholecystectomy, defined as laparoscopic cholecystectomy during the initial admission to the hospital, is a safe procedure that decreases recurrence of the disease.5 Choledocholithiasis can be excluded by intraoperative cholangiography, EUS, or MRCP. For patients with severe

pancreatitis, early surgery may increase the morbidity and length of stay. Current recommendations suggest conservative treatment for at least 6 weeks before laparoscopic cholecystectomy is attempted in this setting. This approach has significantly decreased morbidity.5 

Complications

Sterile and Infected Peripancreatic Fluid Collections Discussion regarding appropriate management of pancreatic and peripancreatic fluid collections requires an understanding of the current classification of these entities as defined in Table 56.3. Fluid collections are divided into acute (present for less than four weeks) and chronic (lasting past four weeks) and either being simple or complex in nature. Acute peripancreatic fluids collections are simple in nature and after four weeks are referred to as a pseudocyst. Fluid collections associated with necrotizing pancreatitis are referred to as an acute necrotic collection (ANC) before four weeks and as walled off necrosis after that period. The presence of acute peripancreatic fluids collection during an episode of AP has been described in 30% to 57% of patients. In contrast to pseudocysts and cystic neoplasias of the pancreas, fluid collections are not surrounded or encased by epithelium or fibrotic capsule. Treatment is supportive because most fluid collections will be spontaneously reabsorbed by the peritoneum. All of these fluid collections may become infected. The usual signs and symptoms of infection (e.g., fever, elevated white blood cell count, and abdominal pain) may also be present without an infection in AP due to a robust SIRS response in many of these patients, making diagnosis of infection difficult. Evidence of gas within a fluid collection on imaging is highly suggestive. Acute decompensation or failure to improve after 10 to 14 days may suggest infection and consideration should be given to CT-guided fluid sampling. Drainage (percutaneous or endoscopic) and IV administration of antibiotics should be instituted if infection is present. Antibiotics known to penetrate pancreatic necrosis include carbapenems, quinolones, metronidazole, and high-dose cephalosporins.  Pancreatic Necrosis and Infected Necrosis Necrosis is the presence of nonviable pancreatic parenchyma or peripancreatic fat and can manifest as a focal area or diffuse involvement of the gland. Contrast-enhanced CT is the most reliable technique to diagnose ANC and are typically seen as areas of low attenuation (4 Weeks • Well circumscribed, usually round or oval • Homogeneous fluid density • No nonliquid component • Well-defined wall; that is, completely encapsulated • Heterogeneous with liquid and nonliquid density with varying degrees of loculations (some may appear homogeneous) • Well-defined wall; that is, completely encapsulated • Location—intrapancreatic and/or extrapancreatic

Adapted from: Banks,P, Bollen, T, Dervenis C. Classification of acute pancreatitis—2012: revision of the Atlanta classification and definitions by internationa1. Banks PA, Bollen TL, Dervenis C, et al: Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013;62:102–111. *Acute inflammation of the pancreatic parenchyma and peripancreatic tissues but without recognizable tissue necrosis. †Inflammation associated with pancreatic parenchymal necrosis and/or peripancreatic necrosis.

develops sepsis, SIRS, and/or organ failure later in the course of the disease (>7 days after the onset of the AP). Evidence of air within the pancreatic necrosis seen on a CT scan confirms the diagnosis but is a rare finding. If infected necrosis is suspected, fine-needle aspiration (FNA) may be performed if the diagnosis is equivocal; from the aspirate, a positive Gram stain or culture establishes the diagnosis. Although positive cultures are confirmatory, a review has demonstrated that despite negative preoperative cultures, 42% of patients with so-called persistent unwellness will have infected necrosis.12 Fig. 56.8 illustrates the pathophysiologic process of pancreatic necrosis infection. With decades of experience with treatment of pancreatic necrosis, few general concepts have emerged. First, all sterile necrotic collections do not need to be intervened upon. Indications for intervening in sterile necrotizing pancreatitis include: persistent pain, failure to improve clinically with conservative management, and/or symptomatic biliary or enteric obstruction. Intervention for these indications should be delayed as much as possible to allow development of walled off necrosis. Second, clinical suspicion of or documented infected necrotic collection with clinical deterioration is a clear indication for intervention. Even in this situation, the intervention should be delayed as much as possible to allow the collection to become walled off. Once infection has been demonstrated, IV antibiotics should be given. Because of their penetration into the pancreas and spectrum coverage, carbapenems are the first option of treatment. Alternative therapy includes quinolones, metronidazole, third-generation cephalosporins, and piperacillin. Historically, the definitive treatment of infected pancreatic necrosis is surgical

Mucosal ischemia/ reperfusion injury

Impaired local immunity/ bacterial overgrowth

↑ Intestinal permeability

Bacterial translocation Bloodborne dissemination (distant infection)

Necrosis infection

Direct contamination (interventional procedure/ surgery)

FIG. 56.8  Pathophysiology of pancreatic necrosis infection. The acute inflammatory injury that occurs during the first 48 to 72 hours causes mucosal ischemia and reperfusion injury. Both effects favor bacterial overgrowth because they alter local immunity. Mucosal ischemia also produces an increase in the permeability of intestinal cells, which is initiated 72 hours after the acute episode but typically peaks one week later. These transient episodes of bacteremia are associated with pancreatic necrosis infection. Less frequently, distant sources of infection, such as pneumonia and vascular or urinary tract infection associated with central lines and catheters, are associated with bacteremia and pancreatic necrosis. Finally, local contamination after surgery or interventional procedures such as endoscopic retrograde cholangiopancreatography is responsible for necrosis infection.

1540

SECTION X  Abdomen

FIG. 56.9  Infected pancreatic necrosis. This 45-year-old man had severe ethanol-induced pancreatitis. Four weeks after the initial episode, the patient developed fever (39.5°C [103°F]), hypotension, and leukocytosis (19,000 cells/mm3). The computed tomography (CT) scan documented pancreatic necrosis involving 35% of the gland. After fine-needle aspiration (FNA), Gram staining documented the presence of gramnegative rods. The exploratory laparotomy indicated pancreatic necrosis involving mainly the body of the gland (arrow). The patient was treated with necrosectomy, closed drainage, and intravenous meropenem. Final culture documented the presence of Escherichia coli. The patient was discharged home 56 days after the initial episode.

debridement with necrosectomy, closed continuous irrigation, or open packaging (Fig. 56.9). The overall mortality rate after open necrosectomy has been as high as 25% to 30%12 because of the severe nature of the disease as well as the high complication rate of an open debridement. Outcomes are time dependent; patients who undergo surgery in the first 14 days have a mortality rate of 75%, and those who undergo surgery between 15 and 29 days and after 30 days have mortality rates of 45% and 8%, respectively.13 As a result of the elevated morbidity and mortality rates with open debridement, percutaneous, endoscopic, and laparoscopic techniques have been employed as alternatives. In 2010, the Dutch Pancreatitis Study Group performed a randomized trial evaluating open necrosectomy versus a “step-up approach” consisting of percutaneous drainage followed by minimally invasive video-assisted retroperitoneal debridement for necrotizing and infected necrotizing pancreatitis. The results showed that long-term end-point complications (e.g., exocrine and endocrine insufficiency) and mortality rates were better in the “step-up approach” group compared with the open necrosectomy group.14 A companion study to this was published in 2018 wherein endoscopic management was compared to the “step-up approach”. While the endoscopic approach was nonsuperior to the minimally invasive surgical approach regarding mortality and most secondary endpoints, it was associated with fewer pancreatic fistulae, reduced cumulative hospital length of stay, and lower cost.15 Currently, an endoscopic drainage with a large-bore stent and possible endoscopic debridement with or without percutaneous drainage can avoid an operation in most patients. If the endoscopic and/or percutaneous management fails, a minimally invasive operation will usually be more straightforward and the results improved. Regardless of which route is taken, physiologic and nutritional support of the patient will have a large impact on outcome.  Pancreatic Pseudocysts Pancreatic pseudocysts occur in 5% to 15% of patients who have peripancreatic fluid collections after AP. By definition, the capsule

of a pseudocyst is composed of collagen and granulation tissue, and it is not lined by epithelium. The fibrotic reaction typically requires at least four to eight weeks to develop. Fig. 56.10 shows CT scans of a large pseudocyst arising in the tail of the pancreas. Up to 50% of patients with pancreatic pseudocysts will develop symptoms. Persistent pain, early satiety, nausea, weight loss, and elevated pancreatic enzyme levels in plasma suggest this diagnosis. The diagnosis is corroborated by CT or MRI. EUS with FNA is indicated for patients in whom the diagnosis of pancreatic pseudocyst is not clear. Characteristic features of pancreatic pseudocysts include high amylase levels associated with the absence of mucin and low carcinoembryonic antigen (CEA) levels. Observation is indicated for asymptomatic patients because spontaneous regression has been documented in up to 70% of cases; this is particularly true for patients with pseudocysts smaller than 4 cm in diameter, located in the tail, and no evidence of pancreatic duct obstruction or communication with the main pancreatic duct. Invasive therapies are indicated for symptomatic patients or when the differentiation between a cystic neoplasm and pseudocyst is not possible. Because most patients are treated with decompressive procedures and not with resection, it is imperative to have a pathologic diagnosis. Surgical drainage had been the traditional approach for pancreatic pseudocysts. However, modern evidence suggests that transgastric and transduodenal endoscopic drainage are safe and effective approaches for patients with pancreatic pseudocysts in close contact (defined as 50% of the main pancreatic duct in the body and tail*  Diagnosis of Chronic Pancreatitis Consistent With Chronic Pancreatitis • 1 major A criterion + ≥3 or more minor criteria • 1 major A criterion + major B criterion • 2 major A criteria  Suggestive of Chronic Pancreatitis¶ • 1 major A criterion + 192 ng/mL; log scale), and low amylase. Fig. 56.18 illustrates the sensitivity and specificity of CEA in identifying mucinous neoplasms on the basis of fine-needle fluid aspiration. These fluid analyses provide accurate diagnosis in up to 80% of cases.24 Table 56.4 summarizes the distinguishing features of cystic neoplasms of the pancreas. Pancreatic resection is the standard treatment for MCNs, given the potential for malignant transformation. In the absence of invasive malignant disease, resection is curative and no further surveillance is required. The prognosis of patients who undergo pancreatectomy for invasive MCNs is poor although more favorable than that of patients with ductal adenocarcinoma of the pancreas. Invasive MCNs exhibit slower growth, less frequent nodal involvement, and less aggressive clinical behavior compared with ductal adenocarcinoma; a 5-year survival of 50% to 60% can be expected after resection. Despite limited experience with invasive MCNs, most centers offer adjuvant systemic chemotherapy after surgical resection, especially when node-positive disease is present. 

onic antigen (CEA) concentrations (ng/mL; log scale) for differentiating between mucinous and nonmucinous cystic lesions. An optimal cutoff value of 192 ng/mL correlated with the crossover of the sensitivity and specificity curves. (From Brugge WR, Lewandrowski K, Lee-Lewandrowski E, et al. Diagnosis of pancreatic cystic neoplasms: A report of the cooperative pancreatic cyst study. Gastroenterology. 2004;126:1330– 1336.)

Intraductal Papillary Mucinous Neoplasm IPMNs of the pancreas are mucinous epithelial neoplasms, which arise from the main pancreatic ducts or branch ducts or both. IPMNs were first described by Ohashi and typically manifest in the sixth to seventh decade of life. Due to increasing use of crosssectional imaging (CT and MRI), this entity is being increasingly diagnosed. IPMNs encompass a wide spectrum of epithelial changes. Recent efforts to standardize nomenclature for IPMN has been critical to allow for better study of diagnosis, management, and outcomes for IPMN. The terms “adenoma” and “carcinoma in situ” have been abandoned in order to standardize reporting. Current histopathologic grading includes low, moderate, or highgrade dysplasia, and presence or absence of invasive malignancy. There are three subtypes of IPMN which are defined by the pattern of ductal involvement that is present. IPMNs are further characterized by the extent to which they involve the pancreatic ducts. Neoplasia that affects only the small side branches is termed side branch or branch duct IPMN (BD-IPMN), whereas involvement of the main pancreatic duct is termed main duct IPMN (MDIPMN). Side branch IPMNs that extend into the main duct, often leading to upstream dilation, are termed mixed-type IPMNs.  Management Strategies for Intraductal Papillary Mucinous Neoplasm Risk of malignant transformation has been described in IPMN and is related to multiple factors that have been stratified as worrisome and high risk. These factors have been identified through international consensus and are reported in the international consensus guidelines for the management of IPMN of the pancreas, most recently updated in 2017.25 Worrisome features of IPMN based on imaging include ­BD-IPMN cyst size larger than 3 cm, enhancing mural nodule smaller than mm, thickened enhancing cyst wall, main pancreatic duct size of 5 to 9 mm, abrupt change in caliber of main pancreatic duct with distal pancreatic atrophy, and lymphadenopathy. In addition, patients who present with clinical signs of pancreatitis, an elevated CA19-9 level or cyst growth of more than 5 mm over two years should be considered to have worrisome features. These features are summarized in Table 56.5.

CHAPTER 56  Exocrine Pancreas

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TABLE 56.4  Defining characteristics of pseudocysts and pancreatic cystic neoplasms. CHARACTERISTICS

PSEUDOCYST

SCN

MCN

IPMN

Epidemiology Gender Age (years)

F=M 40–60

F ≫ M (4 : 1) 60–70

F ≫> M (10 : 1) 50–60

F=M 60–70

Imaging Findings Location Appearance

Communication with ducts

Evenly distributed Evenly distributed Head ≪ body/tail Round, thick-walled large cyst; Multiple small cysts separated Thick-walled, septated gland atrophy ± calcification by internal septations with macrocyst with smooth central starburst calcifications contour; ± solid component, eggshell calcifications Yes No Very rare

Cyst Fluid Analysis Cytology

Inflammatory cells

Mucin stain Amylase CEA

Negative Very high Low

Scant glycogen-rich cells, with positive periodic acid–Schiff stain Negative Low Low

Head > diffuse > body/tail Poorly demarcated, lobulated, polycystic mass with dilation of main or branch ducts Yes

Sheets and clusters of columnar, Tall, columnar, mucin-containing mucin-containing cells cells Positive Low High

Positive High High

CEA, Carcinoembryonic antigen; F, female; M, male; IPMN, intraductal papillary mucinous neoplasm; MCN, mucinous cystic neoplasm; SCN, serous cystic neoplasm. From Tran Cao HS, Kellogg B, Lowy AM, et al. Cystic neoplasms of the pancreas. Surg Oncol Clin N Am. 2010;19:267–295.

High-risk features of IPMN include the presence of an enhancing nodule larger than 5 mm within the cyst and main pancreatic duct dilation of more than 1 cm. Patients who present with clinical signs of jaundice should also be considered at high risk. Numerous genetic mutations which may lead to malignant transformation of IPMN have been evaluated, including KRAS, p53, MUC and others. To date, genetic analysis of cyst fluid has failed to improve our ability to predict malignancy or select patients for surgical resection over existing clinical guidelines. Branch duct intraductal papillary mucinous neoplasm. As the name implies, BD-IPMN involves dilation of the pancreatic duct side branches that communicate with but do not involve the main pancreatic duct. BD-IPMNs may be focal, involving a single side branch, or multifocal, with multiple cystic lesions throughout the length of the pancreas. Multiplicity of cysts favors a diagnosis of BD-IPMN. All cysts with worrisome features on CT or MRI should undergo EUS; all cysts with high-risk features should be resected. Recommendations for management of suspected BD-IPMN are summarized in Fig. 56.19. 25 For asymptomatic patients with BD-IPMN who have no worrisome or high-risk features, surveillance may be a reasonable initial strategy; however, multiple variables including patient age and comorbidities also play a role in decision making.25 Based on size alone, asymptomatic patients with cysts larger than 3 cm (worrisome feature) should be strongly considered for surgical resection, while those with 2- to 3-cm cysts may be considered for resection or observation depending on age and physical condition. Cysts smaller than 2 cm generally have a low risk for malignancy and therefor are most appropriate for surveillance. Any patient with symptoms or high-risk features related to BD-IPMNs (e.g., jaundice, enhancing mural nodule, and dilated main pancreatic duct) should undergo surgical resection because the risk of malignant disease in symptomatic patients is heightened. Overall, the risk of invasive malignant disease in the setting of BD-IPMN is approximately 10% to 15%; however, it is

TABLE 56.5  A summary of worrisome and

high-risk features of intraductal papillary mucinous neoplasm. WORRISOME FEATURES

HIGH-RISK FEATURES

Main duct 5–9 mm Enhancing mural nodule 3 cm Abrupt caliber change in main duct with upstream atrophy Lymphadenopathy Pancreatitis Increased serum 19–9 Cyst growth >5 mm over 2 years

Main duct >1 cm Enhancing mural nodule >5 mm Jaundice

BD-IPMN; Branch-duct intraductal papillary mucinous neoplasm.

increasingly clear that not all patients with IPMNs require surgery. Overall, for BD-IPMN, the risk of invasive malignant disease is approximately 2% to 3% per year. A plan for watchful surveillance with delayed intervention in these patients is reasonable because the risk for malignant transformation with small, asymptomatic branch duct tumors is low, most patients are older, and the time required for development of invasive malignant disease may be longer than the patient’s life expectancy.  Main duct intraductal papillary mucinous neoplasm. In contrast to BD-IPMN, MD-IPMN indicates abnormal cystic dilation of the main pancreatic duct with columnar metaplasia and thick mucinous secretions, which can be seen oozing from a patulous papilla on endoscopic evaluation (Fig. 56.20). Involvement of the main pancreatic duct may be focal or diffuse; it is most relevant because of the significantly increased risk of malignant degeneration. Individuals with MD-IPMN have a 30% to 50% risk of harboring invasive pancreatic cancer at the time of presentation.

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SECTION X  Abdomen Are any of the following “high-risk stigmata” of malignancy present? i) obstructive jaundice in a patient with cystic lesion of the head of the pancreas, ii) enhancing mural nodule ≥5 mm, iii) main pancreatic duct ≥10 mm

Yes

No

Consider surgery, if clinically appropriate

Are any of the following “worrisome features” present? Clinical: Pancreatitisa Imaging: i) cyst ≥3 cm, ii) enhancing mural nodule 192 ng/mL; log scale). This elevation of the CEA level is not predictive of invasive malignant disease, only the presence of mucinous metaplasia.  Mixed-type intraductal papillary mucinous neoplasm. Mixedtype IPMN denotes a side branch IPMN that has extended to involve the main pancreatic duct to a varying degree. Concern for mixed-type IPMNs should be raised in individuals with side branch cysts who exhibit upstream dilation of the pancreatic duct because this is an indication of main duct involvement. The biologic behavior of mixed-type IPMNs most closely resembles that of MD-IPMNs, with a significant risk of invasive malignant disease at the time of presentation (30% to 50%). As for MD-IPMN, surgical resection is indicated for the treatment of mixed-type IPMN. 

Treatment: Surgical Resection for Intraductal Papillary Mucinous Neoplasm Partial pancreatectomy is the primary treatment for high-risk lesions; however, the optimal extent of pancreatic resection for some patients remains unknown. For BD-IPMN, resection should target the lesion of concern, and therefore surgical decision making is usually straightforward. For MD-IPMN, however, it is not always possible to determine the extent of microscopic abnormality within the duct. In the absence of diffuse polyps or enhancing nodules in the main duct, a right-sided pancreatectomy is preferred. Intraoperative frozen section of the pancreas neck margin is obtained, and total pancreatectomy is reserved for those cases

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with high-grade dysplasia or invasive carcinoma identified at the margin. Although some investigators continue to advocate total pancreatectomy for the treatment of any IPMN, the evidence supporting this approach is decreasing with longer follow-up of patients treated by R0 and R1 partial pancreatectomy. It is appropriate to recommend partial pancreatectomy and to discuss management of the pancreatic margin preoperatively, advising the patient that approximately 15% of patients will require conversion to total pancreatectomy to achieve negative parenchymal resection margins. Survival outcomes are significantly better in patients with IPMNs than in patients with PDACs. Sohn and associates26 have analyzed a series of 136 patients with IPMNs; survival rates for patients with noninvasive IPMNs are 97% at 1 year, 94% at 2 years, and 77% at 5 years. When the group of patients with noninvasive IPMNs was analyzed further, no survival differences were found between patients with IPMNs and those with borderline IPMNs. On the contrary, there was a significant difference in survival rate between patients with noninvasive IPMNs and those with invasive IPMNs. The 1-, 3-, and 5-year survival rates for patients with invasive IPMNs were 72%, 58%, and 43%, respectively. Therefore, survival is clearly dependent on the invasive component of the lesion. Following resection, surveillance of the remnant pancreas is advocated due to risk of recurrence of IPMN or invasive malignancy, which has been reported to range between 5% and 22%. The decision to terminate surveillance should depend on the age and condition of the patient. Reoperation should be considered for patients who present with recurrence or progression of disease in the pancreas remnant. 

ADENOCARCINOMA OF THE EXOCRINE PANCREAS Epidemiology In 2018, it is estimated that PDAC will affect approximately 55,440 individuals in the United States and 44, 330 will die of the disease. In comparison, two decades ago in 1995, there were 24,000 new cases of pancreatic cancer. While the increasing and aging population is the most likely cause of this increase, whether factors other than population size and age have contributed to this increase is not known. Although it is the ninth most common cancer diagnosis, pancreatic cancer has recently out ranked breast cancer and has become the third most common cause of cancer deaths in United States. Despite significant advances in the treatment of other cancers, the prognosis of pancreatic cancer remains dismal. Overall, less than 8% of individuals will survive 5 years beyond their diagnosis. One of the reasons for these dismal outcomes is that most patients with pancreatic cancer have locally advanced or distant metastatic disease at presentation. Efforts at early detection of pancreatic cancer may change these outcomes by detecting pancreatic cancer at an early and curable stage. In a recent study, the authors performed a quantitative analysis of the timing of evolution of metastatic clones in pancreatic cancer. This elegant study suggested that on average, 5 years are required for the acquisition of metastatic ability in pancreatic cancer, thus suggesting that a window of opportunity does exist when the cancer is a locoregional disease and potentially curable.27 Men are affected slightly more commonly than women, with a 1.3 : 1 incidence ratio. African Americans have a slightly higher risk for development of pancreatic cancer and dying of their disease compared with whites. The risk of pancreatic cancer increases with age beyond the sixth decade; the mean age at diagnosis is 72 years. 

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SECTION X  Abdomen

TABLE 56.6  Hereditary risk factors associated with development of pancreatic cancer. GENE

ASSOCIATED SYNDROME

CLINICAL SIGNIFICANCE

PRSS1 STK11 CDKN2A

Mutation results in chronic pancreatitis and 40% lifetime risk of PDAC Mutation results in >100-fold increase in risk of PDAC Mutation leads to increased risk of melanoma and >40-fold increase in risk of PDAC

CFTR BRCA2

Familial pancreatitis Peutz-Jeghers syndrome Familial atypical mole and multiple melanoma syndrome Cystic fibrosis Hereditary breast and ovarian cancer

MLH1

Lynch syndrome

APC

Familial adenomatous polyposis

Thick secretions result in chronic pancreatitis and 30-fold increase in risk of PDAC Mutation results in elevated risk of breast and ovarian cancer and 10-fold increase in risk of PDAC Mismatch repair gene mutation leads to increased risk of colon cancer and eightfold increase in risk of PDAC Mutation results in polyposis coli and colon cancer with fourfold increase in risk of PDAC

PDAC; Pancreatic ductal adenocarcinoma.

Risk Factors Environmental Risk Factors and Causes Although the cause of pancreatic cancer remains unclear, several environmental risks have been associated with its increased incidence. The most notable risk factor is related to smoking. Several epidemiologic studies have shown an association of the amount and duration of smoking history with an elevated risk of pancreatic cancer. On average, smokers face a onefold to threefold increase in risk for development of pancreatic cancer compared with nonsmokers. This risk seems to be a linear association, with pancreatic cancer incidence directly related to the number of packyears smoked (packs per day × number of years smoking). As with other cancers, the risk of pancreatic cancer persists many years beyond smoking cessation. Over the years, there have been several other factors, including chronic pancreatitis and occupational exposure, that were thought to contribute to an elevated risk of pancreatic cancer; however, population data have been somewhat controversial. It is likely that these factors are associated with an elevated risk, but the magnitude of the risk is uncertain. Obesity has recently become the focus of investigation; several authors have found that obese patients may be up to three times more likely to develop pancreatic cancer than nonobese individuals. It remains unclear whether obesity itself or one of the comorbidities related to obesity is associated with the higher incidence of pancreatic cancer seen in this population. The relationship between diabetes and pancreatic cancer is a complicated one. Studies suggest that patients with new-onset diabetes have higher incidence of pancreatic cancer.28 The association with pancreatic cancer is especially strong if the new diagnosis of diabetes is made in those who are elderly, have a lower body mass index, or have weight loss and in those who do not have family history of diabetes. In these patients with new-onset diabetes, diabetes may be caused by pancreatic cancer. The diagnosis of diabetes may precede the diagnosis of pancreatic cancer by up to 36 months, suggesting that there may be a window of opportunity for early diagnosis. Thus, patients with new onset diabetes constitute a high-risk group at which the pancreatic cancer early diagnosis effort may be focused. The mechanism of pancreatic cancer–induced diabetes is unclear at this time. Other studies have suggested that long-term diabetes may increase the risk of pancreatic cancer. However, these observations may be confounded by the fact that factors like obesity are associated with both diabetes and pancreatic cancer. It is clear, though, that in elderly patients with new-onset diabetes in the presence of unusual symptoms

like weight loss and abdominal symptoms, diagnosis of pancreatic cancer should be considered and may lead to early diagnosis of pancreatic cancer.  Hereditary Risk Factors An inherited predisposition to pancreatic cancer is seen in a range of clinical settings. Several hereditary cancer syndromes (e.g., Peutz-Jeghers syndrome, familial atypical mole and multiple melanoma syndrome, hereditary breast and ovarian cancer syndrome) are known to be associated with increased risk of pancreatic cancer. Increased risk of pancreatic cancer is present in patients with inheritable inflammatory disease of the pancreas, namely, hereditary pancreatitis and cystic fibrosis. These patients with known genetic syndromes are responsible for about 20% of hereditary cases of pancreatic cancer. The term familial pancreatic cancer (FPC) applies to the remaining 80% of patients with an inherited predisposition but who do not have an identifiable genetic syndrome. Table 56.6 summarizes several known gene mutations and their clinical significance. Hereditary pancreatitis (PRSS1 and SPINK1 gene mutation).

It has long been noted that individuals with familial pancreatitis have an elevated risk of pancreatic cancer. Mutations in the cationic trypsinogen gene (PRSS1) are responsible for 80% of the cases of hereditary pancreatitis and lead to increased trypsin activity and chronic inflammation in the pancreas. The SPINK1 gene codes for a serine protease inhibitor that inhibits active protein, and mutations in this gene have been associated with hereditary pancreatitis. Individuals with hereditary pancreatitis have a greater than 50-fold increase in their risk for development of pancreatic cancer compared with unaffected individuals.29  Peutz-Jeghers syndrome (STK11 gene mutation). Individuals with Peutz-Jeghers syndrome are distinguished by the development of gastrointestinal hamartomatous polyps and pigmented mucocutaneous lesions. The specific role of STK11 is not defined, although it is thought to act as a tumor suppressor gene, with loss of heterozygosity leading to the development of gastrointestinal tumors. In addition to gastrointestinal cancers, individuals with Peutz-Jeghers syndrome are at a higher risk of lung, ovarian, breast, uterine, and testicular cancers. The risk of pancreatic cancer in the setting of Peutz-Jeghers syndrome is more than 100 times greater than that in unaffected individuals.29  Cystic fibrosis (CFTR gene mutation). Although the cause remains unclear, those with cystic fibrosis (CFTR gene mutation) are up to 30 times more likely to develop pancreatic cancer than

CHAPTER 56  Exocrine Pancreas the general population. It is postulated that this elevated risk is caused by the chronic inflammatory condition of the pancreas resulting from a lifetime of thickened secretions and partial ductal obstruction.29  Familial atypical mole and multiple melanoma syndrome (CDKN2A gene mutation). CDKN2A encodes protein p16, which nor-

mally inhibits cell proliferation by binding to cyclin-dependent kinases (CDKs). Mutations of CDKN2A lead to uninhibited cell cycle activation and proliferation. Although CDKN2A is most noted for its associated increased risk of melanoma, individuals with CDKN2A mutations have up to a 20-fold increase in risk for the development of pancreas cancer.29  Hereditary breast and ovarian cancer (BRCA2 gene mutation).

Although germline BRCA mutations are most recognized because of their association with breast cancer, 10% of individuals from high-risk pancreatic cancer families (at least two first-degree relatives with pancreas cancer) have been found to have BRCA2 mutations. Germline mutations of the BRCA2 gene lead to an elevated risk for pancreatic cancer, which is up to 10 times that of the general population.29  Lynch syndrome (mismatch repair gene mutations). Although most strongly associated with colon cancers caused by mutations in mismatch repair genes (MLH1, MSH2, MSH6), Lynch syndrome also leads to an increased risk of pancreatic cancer. The microsatellite instability noted in colon cancer cells has also been seen in pancreatic cancer cells from individuals with Lynch syndrome, indicative of a common genetic cause. It is estimated that the risk of pancreatic cancer is increased eightfold in individuals with Lynch syndrome.29  Familial adenomatous polyposis (APC gene mutation). Familial adenomatous polyposis results from mutation of the adenomatous polyposis coli (APC) gene, leading to the development of thousands of colonic polyps. It has been found that individuals affected by familial adenomatous polyposis are also significantly more likely to develop pancreas cancer, with a fourfold increase above that in the general population. These data remain observational because the cause of pancreatic cancer in this setting has not been defined.29  Familial pancreatic cancer (unknown gene). FPC is defined by families with two or more first-degree relatives with pancreatic adenocarcinoma that do not fulfill the criteria of other inherited tumor syndromes with an increased risk for the development of pancreatic adenocarcinoma. Compared with relatives of patients with sporadic pancreatic cancer, the risk for development of pancreatic cancer is markedly elevated in FPC kindreds. Family members of FPC kindreds are at an 18-fold increased risk for development of pancreatic cancer compared with the general population. Furthermore, this risk increases with increasing numbers of first-degree relatives with pancreatic cancer in FPC kindreds and if one of the affected individuals is diagnosed before 50 years of age. Segregation analysis suggests that the aggregation of pancreatic cancer in these families is due to unidentified, autosomal dominantly inherited genes with reduced penetrance. This entity is being increasingly appreciated, and guidelines for pancreatic cancer screening and management of identified suspicious lesions in this population are under evolution. 

Pathogenesis of Sporadic Pancreatic Cancer Although there are several inherited forms of PDAC, most cases are sporadic. As for many other cancers, a sequential pathway has been observed in the development of PDAC from pancreatic intraepithelial neoplasia (PanIN) to invasive cancer. A number of tumor suppressor genes and oncogenes have been identified that play

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a significant role in the pathogenesis of PDAC, including PDX1, KRAS2, CDKN2A/p16, P53, and SMAD4. Novel techniques like sleeping beauty transposon-mediated insertional mutagenesis has helped identify tumor suppressor genes like deubiquitinase USP9X which is mutated in as many as 50% of the tumors. It must be noted that up to 5% of patients who, due to lack of any family history, are believed to have sporadic pancreatic cancer, harbor germline mutation in pancreatic cancer susceptibility genes. This has led to National Comprehensive Cancer Network (NCCN) recommendation to consider offering germline gene testing in all patients with a personal history of pancreatic cancer, regardless of family history or age at diagnosis Genetic Progression of Pancreatic Intraepithelial Neoplasia to Invasive Pancreatic Ductal Adenocarcinoma PanIN is defined histologically by progressive abnormality of the ductal epithelium from columnar metaplasia (PanIN-1A) through carcinoma in situ (PanIN-3). PanIN-1A is histologically characterized by the presence of columnar, mucin-producing ductal epithelium that maintains basally located homogeneous nuclei without atypia. The development of papillary architecture defines PanIN-1B, but it is otherwise identical to PanIN-1A. PanIN-2 denotes the progression from simple papillary growth to evidence of nuclear atypia not seen in PanIN-1B. Enlarged nuclei with nuclear crowding and loss of polarity are present. Prominent nuclear abnormalities with complete loss of polarity and marked cytologic atypia are characteristic of PanIN-3 (carcinoma in situ). Clusters of abnormal cells can usually be seen within the duct lumen. The KRAS2 oncogene is activated in more than 95% of pancreatic cancers and is thought to be the initiating event in tumorigenesis. KRAS2 is activated by point mutation (codon 12, 13, or 61), which causes constitutive activation and loss of regulation of mitogen-activated protein kinase cell signal transduction. Mutation of the KRAS2 oncogene is one of the earliest genetic abnormalities identified in the progression of PanIN to PDAC and has been noted in 36% of PanIN-1 cases, 44% of PanIN-2 cases, and 87% of PanIN-3 cases. CDKN2A/p16, P53, and SMAD4 are tumor suppressor genes that also appear to play critical roles in the development of PDAC. CDKN2A encodes a protein, p16, that binds to CDK4 and CDK6, resulting in cell cycle arrest. Mutation of CDKN2A and loss of p16 lead to a loss of cell cycle regulation. Like mutation of KRAS, mutation of CDKN2A (loss of p16 expression) has been identified in 30% of PanIN-1 cases, 55% of PanIN-2 cases, and 71% of PanIN-3 cases. Approximately 90% of PDACs demonstrate loss of p16 function. Also, P53 encodes the protein p53, which regulates cell proliferation through cell cycle arrest and proapoptotic mechanisms. Although it is rare in PanIN, 79% of invasive PDACs demonstrate P53 mutations, indicating its potential importance in the transition from noninvasive to invasive tumors. Similarly, SMAD4 mutations occur late in the pathway from PanIN to PDAC. Loss of SMAD4, which normally functions as a downstream mediator related to TGF-β, leads to decreased inhibition of cell growth and proliferation. Loss of SMAD4 function has been observed in 20% to 30% of PanIN-3 and localized cancers, whereas 78% of widely metastatic tumors show loss of SMAD4. Fig. 56.22 demonstrates the molecular genetic alterations involved in the PanIN-PDAC pathway. 

Clinical Presentation The defining presenting symptom of patients with PDACs in the periampullary region is jaundice. Although painless jaundice has

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SECTION X  Abdomen

Normal

PanIN-1A

PanIN-1B

K-ras

PanIN-2 CDKN2A

PanIN-3 p53 SMAD4

FIG. 56.22  Molecular genetic progression from pancreatic intraepithelial neuroplasia (PanIN) to invasive ductal adenocarcinoma. (Adapted from Wilentz RE, Iacobuzio-Donahoe CA, Argani P, et al. Loss of expression of SMAD4 in pancreatic intraepithelial neoplasia: Evidence that SMAD4 inactivation occurs late in neoplastic progression. Cancer Res. 2000;60:2002–2006.)

frequently been described, a significant number of patients present with pain in addition to jaundice, typically arising in the epigastrium and radiating to the back. Weight loss is also common at the time of presentation, affecting more than 50% of individuals. For tumors of the body and tail of the pancreas, pain and weight loss become more common at presentation. Table 56.7 lists the most common presenting symptoms and their frequency. As mentioned before, new-onset diabetes in an elderly patient with weight loss may be an early presenting symptom of pancreatic cancer. Except for jaundice, the physical examination findings are otherwise unremarkable for most patients with PDAC. A palpable distended gallbladder can be identified in approximately one third of patients with periampullary PDAC, an association first described by Courvoisier, a Swiss surgeon, in 1890. He noted that choledocholithiasis was commonly associated with a shrunken fibrotic gallbladder, whereas the slow progressive occlusion by other causes, including tumors, was more likely to result in ectasia of the organ. Although not diagnostic in itself, Courvoisier sign is familiar to medical students as a defining characteristic of PDACs. With widespread disease, a left supraclavicular node (Virchow node) may be palpable. Similarly, periumbilical lymphadenopathy may be palpable (Sister Mary Joseph node). In cases of peritoneal dissemination, perirectal tumor involvement may be palpable through digital rectal examination, referred to as Blumer shelf. 

Diagnosis Laboratory Evaluation Laboratory evaluation of patients presenting with suspected PDAC should include hepatic function evaluation, including a coagulation profile and nutritional assessment. An elevated bilirubin level is expected, but careful attention should be paid to nutritional values, including prealbumin and albumin levels if surgical intervention is to be considered. Individuals with malnutrition should be given preoperative nutritional supplementation. Several tumor markers may be appropriate at the initial evaluation, including CEA, carbohydrate antigen 19-9 (CA 19-9), and α-fetoprotein. Of these, CA 19-9 is most sensitive for pancreatic adenocarcinoma, with a sensitivity of approximately 79% and a specificity of 82%. A notable limitation of CA 19-9 testing in the setting of periampullary tumors is the false elevation caused by biliary obstruction, which can be misleading. In addition, 10% to 15% of individuals do not have elevation of the CA 19-9 level, a finding that has been associated with blood Lewis antigen–negative status and is caused by a lack of the fucosyltransferase gene. Accepting these limitations, CA 19-9 continues to be the most

TABLE 56.7  Presenting symptoms for

periampullary tumors of the pancreas. PRESENTING SYMPTOM Jaundice Weight loss Abdominal pain Nausea/vomiting Pruritus Fever Gastrointestinal bleeding

FREQUENCY (%) 75 51 39 13 11 3 1

reliable tumor marker for pretreatment evaluation and posttreatment surveillance for pancreatic adenocarcinoma. Besides being used in the diagnosis of pancreatic cancer, CA 19-9 is also used as a predictive and prognostic marker. For instance, some studies have suggested its use for identifying patients who will benefit from staging laparoscopy.30 Similarly, normalization of CA 19-9 after neoadjuvant therapy has been suggested as an important prognostic factor.31  Imaging Studies Multidetector CT is the imaging study of choice for the evaluation of lesions arising in the pancreas. CT allows an accurate determination of the level of biliary obstruction, the relationship of the tumor to critical vascular anatomy, and the presence of regional or metastatic disease. For suspected periampullary disease, a three-phase (noncontrast, arterial, and portal venous) CT scan with 3-mm slices and coronal and three-dimensional reconstruction should be routine. Because of its widespread availability and excellent sensitivity (85%), CT has become the imaging modality of choice for the evaluation of suspected pancreatic cancer. Pancreatic adenocarcinoma is typically seen as a hypoattenuating lesion during the portal venous phase of the imaging. ERCP is frequently used in the assessment of the jaundiced patient because of its ability to perform a biopsy and to palliate jaundice, if necessary. Although palliative biliary stenting remains routine for PDAC tumors resulting in jaundice, its usefulness is questionable for patients who are candidates for surgical resection. Preoperative biliary decompression may increase the rate of wound infection caused by bactibilia, although overall morbidity and mortality are unchanged. In modern medical practice, ERCP should be reserved for cases requiring therapeutic or palliative intervention because other imaging modalities provide superior

CHAPTER 56  Exocrine Pancreas diagnostic abilities without the invasiveness of ERCP. The use of ERCP for biliary decompression is bound to increase, given the increased use of neoadjuvant chemotherapy approach. In such cases, use of short metal stent rather than plastic stents is recommended, given the propensity of plastic stents to get blocked thus requiring repeat procedures. EUS is becoming widely used for the evaluation of suspected pancreatic disease. Perhaps its most important ability is to provide tissue diagnosis of suspected tumors through the use of FNA before initiation of systemic therapy. FNA has a sensitivity and specificity that are far superior to those of brush cytology, with a diagnostic accuracy of 92% to 95%. It may also play a crucial role in the molecular evaluation of tumor samples from patients undergoing neoadjuvant therapy. Although the use of EUS is increasing for the evaluation of peritumoral vasculature and regional lymph nodes, it has not been shown to provide any significant benefit over CT alone in the absence of a need for tissue diagnosis. EUS may be beneficial for the identification of small tumors that do not appear on CT scans and for the delineation of more clearly suspicious lesions smaller than 2 cm; it therefore plays an important complementary role. For cases that require detailed assessment of luminal pancreatobiliary anatomy, MRCP should be considered. MRCP has become useful for the investigation of cystic lesions of the pancreas, with sensitivity and specificity slightly superior to CT alone. MRCP also provides several advantages over ERCP; it is noninvasive, has no risk of inciting pancreatitis, and provides three-dimensional reconstruction of the ductal system. Biologic imaging. 18F-fluorodeoxyglucose positron emission tomography (FDG PET) in combination with CT scanning has been increasingly used in the evaluation of pancreatic cancer. The ability of FDG PET to detect cancers is based on the principle that cells that are actively metabolizing will preferentially take up 18F-labeled glucose compared with surrounding normal tissues. Several studies have noted the potential benefits of FDG PET with CT, including the ability to differentiate between benign and malignant pancreas tumors (autoimmune pancreatitis vs. adenocarcinoma) and also to identify unsuspected disease, which alters clinical planning in more than 10% of cases. False-positive findings are also possible, most notably because of inflammatory conditions, and the risk-benefit ratio of FDG PET with CT has not yet been determined. Further studies will be necessary to clarify the role of FDG PET with CT in the evaluation of pancreatic cancer before its routine use should be advocated. 

Staging Pancreatic cancer staging is based on the American Joint Committee on Cancer (AGCC) tumor, node, metastasis (TNM) system.31a After biopsy confirmation, typically by EUS-FNA, accurate staging is accomplished by multidetector CT scanning of the abdomen and pelvis with three-phase administration of contrast material and three-dimensional reconstruction. Chest radiography is sufficient for the evaluation of potential pulmonary metastasis and should be followed by CT of the chest if any suspicious lesions are noted. In the 8th edition of AJCC staging, the T category is revised from descriptive to size-based definitions, as tumor size is the best surrogate of pancreatic cancer biology. After CT imaging, tumors are classified into resectable, borderline resectable, or unresectable. Resectable tumors are defined as localized to the pancreas, with no evidence of SMV or portal vein involvement (i.e., no abutment, distortion, thrombus, or encasement) and a preserved fat plane surrounding the SMA and

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celiac artery branches, including the hepatic artery. Traditionally patients with imaging consistent with resectable disease used to proceed with operative resection. Currently, given the success of neoadjuvant strategy in the treatment of borderline resectable pancreatic cancer, there is increased use of preoperative chemotherapy for the treatment of even resectable disease. However, use of neoadjuvant therapy for the treatment of resectable pancreatic cancer is highly variable amongst various institutes. The appropriate definition of borderline resectable tumors continues to evolve. The NCCN defines borderline resectable as tumors that exhibit one or more of the following characteristics: 1. Venous involvement: solid tumor contact with SMV or portal vein of more than 180 degrees or contact of less than or equal to 180 degrees with contour irregularity of the vein or thrombosis of the vein but with suitable vessel proximal and distal to the site of involvement allowing for safe and complete resection and vein reconstruction. 2. Arterial involvement: a. Hepatic artery involvement: solid tumor contact with common hepatic artery (abutment or encasement) without extension to the celiac axis or hepatic artery bifurcation allowing for safe and complete resection and reconstruction. b. SMA involvement: solid tumor contact with the SMA of less than or equal to 180 degrees. Currently, these patients are started for surgical resection only after neoadjuvant therapy. There is limited evidence with respect to the type and duration of neoadjuvant therapy and this varies widely at various institutions (see below). Unresectable tumors are those that exhibit metastasis (including lymph node metastasis outside the field of resection), ascites, or vascular involvement beyond what has been detailed here. Laparoscopy Staging laparoscopy has been advocated by several authors as a means to reduce the frequency of nontherapeutic laparotomy for patients with unsuspected metastatic or locally advanced unresectable disease identified at the time of surgery. For patients who appear to have resectable disease on imaging studies alone, laparoscopy identifies additional unresectable disease in up to 30% of cases. Others have argued that with current imaging used properly, the benefit of additional laparoscopy only rarely alters surgical planning. Recently, there has been some consensus on a more selective use of laparoscopy for those at particularly high risk for occult disease, including those with large tumors (>3 cm), significantly elevated CA 19-9 level (>100 U/mL), uncertain findings on CT, or body or tail tumors. It may be clinically prudent also to consider laparoscopy for patients with clinical indicators of widespread disease, including significant weight loss, malnutrition, and pain. There are no level I data available to define the role of staging laparoscopy, and therefore its use remains at the discretion of the surgeon. Furthermore, the role and place of peritoneal cytology are unclear at this time. However, patients with positive findings on peritoneal cytology have very poor prognosis and behave like patients with metastatic disease. 

Treatment Surgical resection remains the only potentially curative treatment of pancreas cancer. Surgery for Tumors of the Head of the Pancreas For tumors involving the head of the pancreas, pancreaticoduodenectomy is the procedure of choice. Although first described

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SECTION X  Abdomen

in 1909 by Kausch, the technique became widely known after the first successful surgical resection was performed by Whipple and Parsons and presented to the American Surgical Association by Parsons in 1935. The first two attempts, in 1934, resulted in operative mortality; but in 1935, a two-stage procedure, which included biliary decompression followed by pancreaticoduodenectomy, was successful. The initial operative description included ligation of the pancreas remnant without reanastomosis. The first one-stage Whipple procedure was reported by Trimble and colleagues at Johns Hopkins University in 1941.32 The modern Whipple procedure maintained a perioperative mortality of 25% and morbidity of well above 50% up until the late 1970s. The advent of improved outcomes for this complex procedure can be attributed to many surgeons and institutions. Most notable on this list of early and seminal leaders in regard to improved mortality and outcome are Cameron (Johns Hopkins Hospital, Baltimore), Tredi (Mannheim Clinic, Mannheim, Germany), Warshaw (Massachusetts General Hospital, Boston), and Brennan (Memorial Sloan Kettering Cancer Center, New York). Each surgeon and center performed more than 100 procedures without any deaths in the 1980s and 1990s. Surgical technique. The modern pancreaticoduodenectomy begins with exploration of the peritoneal surfaces for evidence of metastatic disease, which would deem the patient inoperable. A Kocher maneuver is performed to the level of the left lateral border of the aorta. The transverse mesocolon is separated off the head of the pancreas, exposing the infrapancreatic SMV. Fig. 56.23 shows complete mobilization of the head of the pancreas and gallbladder. The lesser sac is entered through the gastrocolic ligament, sparing the gastroepiploic vessels. The right gastroepiploic vein is ligated at its confluence with the SMV, allowing the SMV to be dissected from the inferior border and posterior neck of the pancreas. The middle colic vein may also be sacrificed, if necessary, to allow adequate dissection at this level. Once the infrapancreatic SMV is dissected and the head of the pancreas is fully mobilized, the gallbladder is removed and the common hepatic duct is circumferentially dissected. Division of

Porta hepatis Vena cava

Duodenum Head of pancreas Gallbladder

FIG. 56.23  Complete mobilization of the head of the pancreas is shown. The vena cava is visible posteriorly. The gallbladder has been freed from the gallbladder fossa.

the common hepatic duct allows visualization of the suprapancreatic portal vein. In pylorus preserving pancreaticoduodenectomy, the duodenum is divided at least 2 cm distal to the pylorus. The hepatic artery is exposed proximally and distally and assessed for replacement or aberrant anatomy. The GDA and right gastric artery are visualized. Before division of the GDA, the vessel is temporarily occluded, and blood flow through the distal common hepatic artery is ensured using a Doppler device. This maneuver is vital in patients with atherosclerosis of celiac origin to ensure that the hepatic blood supply is not dependent on collateral retrograde arterial flow from the SMA through the GDA. Once hepatic arterial flow is confirmed, the right gastric artery and GDA are ligated and divided. If flow in the hepatic artery is interrupted by occlusion of the GDA, resection may proceed only with preservation of the GDA or arterial resection and bypass, typically as an aortohepatic conduit. The pancreas is then divided after four-point ligation of the inferior and superior pancreaticoduodenal arteries. The jejunum is divided approximately 10 cm distal to the ligament of Treitz, and the short mesenteric vessels are divided to allow retromesenteric rotation of the jejunum and third and fourth portions of the duodenum. The head of the pancreas and attached small bowel are then retracted to the patient’s right, and the remaining portal vein and uncinate dissection is completed. With the portal vein completely free, the gland is retracted farther to the right to allow complete visualization of the uncinate process and SMA. The retroperitoneal tissue is dissected from the SMA, allowing complete removal of the periarterial lymphatic tissue. Fig. 56.24A shows the anatomy after removal of the head of the pancreas, and Fig. 56.24B highlights complete clearance of periarterial tissue from the SMA. If portal venous or SMV tumor involvement is encountered, as shown in Fig. 56.25A and B, venous resection should be performed. Resections that compromise less than 50% of the venous diameter can be closed primarily (Fig. 56.25C); otherwise, segmental resection with primary anastomosis or interposition graft using internal jugular or femoral vein should be performed.  Reconstruction. Before reconstruction, some surgeons will obtain a frozen section evaluation of the pancreatic neck margin. Once negative margins are ensured, the proximal jejunum is brought through the transverse mesocolon or the retromesenteric defect in preparation for pancreaticojejunostomy and hepaticojejunostomy. The pancreaticojejunostomy is created in two layers, anterior and posterior, with a duct-to-mucosa anastomosis (Fig. 56.26). An internal or external33,34 pancreatic stent can be left in place for ducts smaller than 5 mm. The hepaticojejunostomy anastomosis is then created downstream from the pancreaticojejunostomy in an end-to-side fashion. If the duct is smaller than 5 mm, it can be spatulated to improve patency. After this, a duodeno- or gastrojejunostomy is completed. External drains are selectively placed adjacent to the pancreaticojejunostomy and hepaticojejunostomy. A feeding jejunostomy can be considered in selected patients with significant preoperative malnutrition (albumin level 3 times normal serum value,” is a frequent complication after pancreaticoduodenectomy, occurring after 5% to 22% of surgeries. Perhaps the most predictive factor is the texture of the gland, with soft fatty glands at significantly higher risk of leak. Most fistulas are controlled by drainage catheters placed at the time of surgery and require no additional intervention. Rarely, uncontrolled fistulas require additional drain placement or operative exploration, sometimes mandating completion pancreatectomy to eliminate further abdominal contamination. The classification of pancreatic fistulas is given in Table 56.9. Anastomotic leaks from the hepaticojejunostomy and duodenojejunostomy are rare and occur after less than 5% of procedures. Infectious complications (e.g., intraabdominal abscess, wound infection) are slightly more common and may require intervention with percutaneous drainage or open wound dressing changes.

CHAPTER 56  Exocrine Pancreas TABLE 56.9  International Study Group on

Pancreatic Fistula Classification of Pancreatic Fistulas. GRADE PARAMETER

A

B

C

Clinical conditions Specific treatment US/CT (if obtained)

Well No Negative

Ill-appearing, bad Yes Positive

Persistent drainage (after 3 weeks) Reoperation Death related to POPF Signs of infections Sepsis Readmission

No

Often well Yes/no Negative/ positive Usually yes

No No

No No

Yes Possibly yes

No No No

Yes No Yes/no

Yes Yes Yes/no

Yes

From Bassi C, Dervenis C, Butturini G, et al: Postoperative pancreatic fistula: An international study group (ISGPF) definition. Surgery 138:8–13, 2005. CT, Computed tomography; POPF, postoperative pancreatic fistula; US, ultrasound.

Pancreatic endocrine and exocrine insufficiency can occur after pancreaticoduodenectomy, but the risk of these events is unpredictable. For individuals with a normal gland, pancreatic insufficiency is rare. However, for those with preexisting chronic pancreatitis, fibrosis of the gland, or insulin resistance, exogenous enzyme and insulin replacement is usually needed. 

Controversies Palliative Bypass in the Case of Unresectable/Metastatic Disease Despite availability of high quality thin cut cross-sectional imaging, up to 10% of patients are still found to have locally advanced or metastatic disease at the time of operation. Metastatic disease may be observed during laparoscopy. Given that palliation of gastrointestinal obstruction as well as biliary obstruction can be achieved by endoscopic (duodenal stents, ERCP with metallic stents for biliary system) means, proceeding with laparotomy and palliative bypass when metastatic disease is observed on staging laparoscopy is usually not indicated. If metastases or unresectable disease is observed once laparotomy has been performed, decision to proceed with biliary and/or gastrointestinal bypass needs to be individualized. Options include proceeding with operative palliation or closing the abdomen and pursuing endoscopic interventions if the patient did not already undergo preoperative biliary drainage. Unfortunately, there are no definitive data describing survival and quality of life of patients undergoing surgical bypass versus closure and rapid placement of endoscopic stents. To make this decision, the surgeon needs to assimilate data on patient’s symptoms, performance status, and projected survival. In the setting of carcinomatosis or multifocal metastatic disease, regardless of performance status, endoscopic intervention should be favored due to the short median survival. However, these should be obvious on staging laparoscopy. If patient has had obstructive gastrointestinal symptoms or a need for placement of duodenal stent previously, it may be prudent to do gastrointestinal bypass. Similarly, in those patients with good functional

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status and low-volume metastatic disease or locally advanced disease, operative biliary bypass is a reasonable option.  Pylorus-Preserving versus Non–Pylorus-Preserving Whipple Procedure We have described the pylorus-preserving Whipple procedure, which is the operation of choice for a growing number of pancreatobiliary surgeons. It was initially proposed as a means to reduce postpancreatectomy dumping and bile reflux, which is common after a non–pylorus-preserving Whipple procedure. Although initial results were encouraging, none of the randomized controlled trials have suggested superiority of a pylorus-preserving over a non–pylorus-preserving Whipple procedure.  Pancreaticojejunostomy Versus Pancreatogastrostomy The pancreaticojejunostomy remains the Achilles heel of the Whipple procedure because of the frequency of pancreatic fistula. Several studies have reported successful outcomes with pancreatogastrostomy and reduced leak rates compared with pancreaticojejunostomy, but this finding has not been reproducible in several randomized trials, and most surgeons continue to prefer pancreaticojejunostomy.40 In cases in which the pancreatic duct is not identified, invagination of the gland into the jejunal stump or pancreatogastrostomy may be performed.  Use of Somatostatin Analogues to Reduce Pancreatic Fistula Although the mortality of pancreaticoduodenectomy has gone down, postoperative morbidity continues to be a significant problem. Pancreatic fistula is the major source of morbidity after the Whipple operation. Because pancreatic exocrine secretion is the proposed mechanism by which postoperative fistula occurs, inhibition of this secretion by means of somatostatin and its analogues has been evaluated in multiple trials with mixed results. Whereas European studies have shown that use of octreotide perioperatively leads to a decreased incidence of postoperative pancreatic fistula, North American trials have not confirmed these results. A recent trial from Memorial Sloan Kettering Cancer Center evaluated the efficacy of pasireotide, a somatostatin analogue with a longer half-life (11 hours for pasireotide vs. 2 hours for octreotide) and a broader binding profile (pasireotide binds to somatostatin-receptor subtypes 1, 2, 3, and 5, whereas octreotide binds only to receptor subtypes 2 and 5), in reducing pancreatic fistula, leak, or abscess of grade 3 or higher after pancreatic surgery (both pancreaticoduodenectomy and distal pancreatectomy). In this trial, pasireotide treatment significantly lowered the rate of grade 3 or higher postoperative pancreatic fistula, leak, or abscess (9% vs. 21%; relative risk, 0.44; 95% confidence interval, 0.24–0.78; P = 0.006). This finding was seen consistently in patients who underwent pancreaticoduodenectomy or distal pancreatectomy as well as in patients with dilated duct versus nondilated pancreatic duct.41 A follow-up prospective observational study from Memorial Sloan Kettering Cancer Center confirmed the findings of the clinical trial.42 Unfortunately, these results have not been reproduced outside this institute.43  Extent of Lymphadenectomy Given the fact that 75% to 80% of patients are found to have lymph node involvement at the time of the Whipple procedure and, overall, 80% to 85% of patients will experience tumor recurrence and cancer-related death, some have proposed that radical lymphadenectomy may improve outcomes. Regional pancreatectomy was first proposed by Fortner in 1973 and has been used widely in Japan, where significant improvements in survival of patients undergoing extended lymphadenectomy have been reported. In addition to

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peripancreatic, portal, and pyloric lymph nodes, extended lymphadenectomy includes retrieval of hilar and retroperitoneal lymph nodes, extending from the celiac origin to the level of the inferior mesenteric artery and including all tissue between the renal hilum laterally. Several randomized controlled trials have since been completed, with no evidence to suggest improved survival after extended lymphadenectomy. In fact, more than one trial has shown increased morbidity associated with extended lymphadenectomy, including delayed gastric emptying, pancreatic fistula, and dumping. In view of the current evidence, standard pancreaticoduodenectomy is the operation of choice for localized pancreatic adenocarcinoma.  Laparoscopic and Robotic Pancreaticoduodenectomy The first laparoscopic pancreaticoduodenectomy was performed in 1994 by Gagner and Pomp. Since then, several case reports and small series have demonstrated the feasibility of the minimally invasive approach. In the largest U.S. series to date, Kendrick and Cusati44 have reported outcomes of 65 laparoscopic pancreaticoduodenectomies, with an overall morbidity rate of 42%: pancreatic fistula, 18%; delayed gastric emptying, 15%; bleeding, 8%; wound infection, 6%; reoperation, 5%; and mortality, 1.5%. These results indicate that laparoscopic pancreaticoduodenectomy has similar short-term outcomes to the open approach. Recently, the authors have presented the updated experience with 108 laparoscopic pancreaticoduodenectomies. Their data suggested that the median length of hospital stay was shorter with the laparoscopic approach. Furthermore, the authors observed that compared with the laparoscopic approach, a significantly higher proportion of patients had delay in delivery of adjuvant therapy with the open approach.45 Pancreaticoduodenectomy is one of the most complex intraabdominal operations, and to perform it laparoscopically, the operator needs advanced training in both hepatopancreatobiliary and laparoscopic approaches, not to mention years of high-volume experience. Given the complexity of the procedure and the fact that the major morbidities that follow pancreaticoduodenectomy are not related to the size of the incision, the laparoscopic Whipple procedure has not become widely adopted. Robotics has emerged as both an alternative and an adjunct to laparoscopy. Given the limitations of current laparoscopic technology and the need for meticulous vascular control and complex reconstruction in pancreatic surgery, robotic pancreaticoduodenectomy has been proposed as an alternative to laparoscopic pancreaticoduodenectomy. There are only a few centers in the United States that are pursuing robotics as an approach to pancreaticoduodenectomy. The largest series on robotic pancreaticoduodenectomy is from the University of Pittsburgh. Zureikat and colleagues published their experience with 132 robotic pancreaticoduodenectomies.46 However, as mentioned before, the major morbidity of pancreaticoduodenectomy does not emanate from the incision, and it is too early to predict whether robotic pancreaticoduodenectomy will ever be widely adopted. At this time, open pancreaticoduodenectomy remains the standard of care.  Antecolic versus Retrocolic Duodenojejunostomy Delayed gastric emptying is a common occurrence after pancreaticoduodenectomy with an elusive cause. Emerging data suggest that creation of an antecolic duodenojejunostomy may improve gastric emptying compared with the retrocolic technique.  Drain Versus No Drain Given the high frequency of pancreatic fistula after pancreatic resection and morbidity associated with uncontrolled pancreatic

leak, drains are routinely used after pancreatic resections. However, surgical drains are not without untoward effects, and their use has been associated with increased rates of intraabdominal and wound infection, increased pain, and prolonged hospital stay. Use of surgical drains after pancreatic resection has been evaluated in randomized controlled trials. In a randomized controlled trial from Memorial Sloan Kettering Cancer Center comparing outcomes in patients undergoing pancreatic resection with and without placement of surgical drains, no difference in complication rate was observed between the two groups. Furthermore, presence of a drain failed to reduce the need for radiologic intervention or surgical exploration. However, a multiinstitution randomized controlled trial comparing drain versus no drain in patients undergoing pancreaticoduodenectomy had to be terminated early as a result of increased morbidity as well as a fourfold increase in mortality in the no-drain group. In this trial, the use of a drain decreased the adverse clinical impact of pancreatic fistula. Good results without use of surgical drains have been achieved only at high-volume specialized centers that have vast experience in dealing with intraabdominal complications after pancreaticoduodenectomy. These centers have access to advanced interventional radiology techniques as well as experienced endoscopists who can drain many of the intraabdominal collections internally through the stomach. At this time, use of a surgical drain should be considered standard of care.  Irreversible Electroporation The use of irreversible electroporation for treatment of locally advanced nonresectable pancreas cancers, or as “margin accentuation” to treat grossly positive margins is being investigated at many specialty centers. Irreversible electroporation preserves collagen rich structures such as blood vessels and ducts, while killing tumor cells, and therefore is proposed to provide improved local control or overall survival for patients with pancreas cancer. Currently, however, its utility in the management of locally advanced pancreas cancer remains to be determined. 

Adjuvant Therapy for Pancreatic Cancer Chemotherapy and Radiation Therapy During the last 30 years, there have been conflicting reports about the survival benefit of adjuvant therapy after surgical resection of localized pancreatic cancer, particularly with regard to radiation therapy. Although the use of chemotherapy is widely accepted, the usefulness of radiation therapy has been increasingly questioned. In the United States, chemotherapy and radiation therapy are still widely used, whereas European centers have stopped using radiation therapy as part of standard adjuvant therapy because of lack of evidence to support a survival benefit. Several randomized trials have attempted to clarify the roles of chemotherapy and radiation therapy for adjuvant treatment of pancreatic cancer after surgical resection. Table 56.10 summarizes the findings of several important trials. In 1974, the Gastrointestinal Tumor Study Group (GITSG) began a prospective randomized trial comparing adjuvant 5-fluorouracil (5-FU) and 40-Gy radiation with observation after curative resection.47 The trial was terminated prematurely because of low accrual and the observation that the chemoradiation arm had a significant survival advantage. During an 8-year period, only 49 patients were accrued and randomized (43 patients were included in the final analysis because of withdrawal of 5 individuals and misdiagnosis of 1). Median survival was 20 months for the chemoradiation group compared

CHAPTER 56  Exocrine Pancreas TABLE 56.10  Summary of Clinical Trials

Defining Role of Adjuvant Therapy After Resection of Pancreatic Cancer. TRIAL

CONCLUSIONS

GITSG

Adjuvant chemoradiation with 5-FU and 40-Gy radiation therapy improves survival compared with observation alone. Adjuvant chemotherapy improves survival; chemoradiation is deleterious. Adjuvant gemcitabine improves disease-free survival compared with observation. Gemcitabine before and after 5-FU–based chemoradiation provides similar overall survival compared with 5-FU but with significantly less toxicity. Adjuvant chemotherapy alone with gemcitabine provides similar overall survival compared with 5-FU but with significantly less toxicity. Adjuvant combination of gemcitabine and capecitabine is superior to gemcitabine alone.

ESPAC-1 CONKO-001 RTOG 97-04

ESPAC-3

ESPAC-4

with 11 months for the observation group. Despite its limitations, this was the first randomized controlled trial that demonstrated an overall survival benefit after chemoradiation. The European Study Group for Pancreatic Cancer-1 (ESPAC-1) trial was a 2 × 2 factorial design that compared chemoradiotherapy alone (5-FU, 20 Gy during 2 weeks) versus chemotherapy alone (5-FU) versus chemoradiotherapy and chemotherapy versus observation.48 At a median follow-up of 47 months, it was noted that the estimated 5-year survival for those who underwent chemoradiotherapy was significantly less than that for those who did not (10% vs. 20%; P = 0.05). At the same time, those who received chemotherapy had a 5-year survival of 21% versus 8% for those who did not (P < 0.009). These findings led to the conclusion that although chemotherapy provided significant improvement in overall survival, the routine use of chemoradiation may be detrimental. In 2007, the Charité Onkologie (CONKO-001) trial of 368 individuals enrolled during a 6-year period evaluated whether chemotherapy with gemcitabine (without radiation) could extend disease-free survival compared with observation.49 Trial patients received six cycles of gemcitabine (days 1, 8, and 15 every 4 weeks for 6 months), and outcomes were compared with observation alone. Median disease-free survival was significantly improved in the gemcitabine group compared with the observation group (13.4 vs. 6.9 months). There was a trend toward improved overall survival, but this did not meet statistical significance (median, 22.1 vs. 20.2 months). This trial established the use of adjuvant gemcitabine for the treatment of pancreatic cancer. The Radiation Therapy Oncology Group (RTOG 97-04) trial compared 5-FU versus gemcitabine chemotherapy before and after 5-FU–based chemoradiation.50 The purpose of the study was to determine whether gemcitabine provided a survival benefit over 5-FU in combination with 5-FU–based chemoradiation. It was noted that although overall survival was similar (20.5 months for gemcitabine vs. 16.9 months for 5-FU; P = NS), the treatmentrelated toxicity was significantly higher in the 5-FU group. These data have led to the use of gemcitabine as the first-line agent for adjuvant chemotherapy, with or without radiation therapy. ESPAC-3 trial was designed to evaluate overall survival comparing 5-FU (425 mg/m2 IV bolus injection, given on days 1–5 every 28 days) versus gemcitabine (1000 mg/m2 IV infusion, days

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1, 8, and 15 every 4 weeks) after curative surgery. No observation arm was included because it was thought to be unethical, given the existing data suggesting a survival benefit of chemotherapy over observation alone. More than 1000 participants from 16 countries were randomized. Overall survival was similar between the groups (23.0 months for 5-FU, 23.6 months for gemcitabine), but gemcitabine was found to have less treatment-related toxicity, with fewer severe adverse events and better compliance. The current NCCN guidelines recommend gemcitabine or 5-FU alone or in combination with 5-FU–based chemoradiation as adjuvant treatment after resection for PDAC. Given the overall poor prognosis, enrollment into clinical trials is encouraged. ESPAC-4 trial is the most recent international randomized controlled trial to finish.51 ESPAC-4 was aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer. In this two-group, open-label, multicenter randomized clinical trial, patients who had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection) were randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m2 gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m2 oral capecitabine administered for 21 days followed by 7 days rest (one cycle). The median overall survival for patients in the gemcitabine plus capecitabine group was 28.0 months (95% CI, 23.5–31.5) compared with 25.5 months (22.7–27.9) in the gemcitabine group (hazard ratio 0.82 [95% CI, 0.68–0.98], P = 0.032). This trial has established gemcitabine and capecitabine as the new standard for adjuvant therapy following resection for PDAC. In the America Society of Clinical Oncology (ASCO) 2018 results of a randomized, multicenter phase III PRODIGE 24 trial was reported. In this trial, patients with surgical resected pancreatic cancer were randomized to receive either modified regimen of 5-FU, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) or gemcitabine for 6 months. The median disease-free survival was nearly 9 months longer in the mFOLFIRINOX arm compared to the gemcitabine arm. Median overall survival was 54 months for the mFOLFIRNOX arm and 35 months for gemcitabine arm. While promising, FOLFIRINOX is associated with higher rate of toxicity and may be difficult to administer in a community setting, especially in postoperative setting.  Role of Neoadjuvant Therapy It is clear that for the optimal outcome, patients with pancreatic cancer require multimodal treatment that includes a combination of surgery and chemotherapy with or without radiation treatment. The administration of chemotherapy, with or without radiation therapy, before planned surgical resection for pancreatic cancer is becoming increasingly common. The rationale for the neoadjuvant approach is multifaceted. After surgical resection, approximately 25% of patients do not receive adjuvant therapy because of refusal, surgical complications, or an inability to recover physiologically. Giving therapy before surgery ensures that all patients will receive multimodality therapy, and by delivery of therapy to an intact gland with an established blood supply, the efficacy of therapy may be maximized. In addition, by treatment of patients with measurable disease, response to therapy can be assessed more readily. Progression of disease during neoadjuvant treatment is indicative of aggressive tumor biology and may prevent these patients from undergoing extensive surgery, which is unlikely to provide any survival benefit. Finally, the

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administration of chemotherapy and radiation therapy before surgery has been viewed as a physiologic stress test and helps select patients who would be unlikely to tolerate the major stress of surgical resection. Neoadjuvant therapy may provide improved selection of patients, avoiding surgery for those who progress, but also improved negative margin rates and reduced lymph node metastasis. Both retrospective data and recently emerging level 1 data support use of neoadjuvant approaches. In a study from MD Anderson Cancer Center, the authors retrospectively reviewed and compared the outcomes of patients with resectable pancreatic adenocarcinoma who underwent neoadjuvant therapy followed by surgery with the outcomes of patients who were treated with the surgery first approach. In this study, 83% of patients with neoadjuvant therapy completed all components of therapy, including surgery with chemotherapy or radiotherapy, compared with 58% of patients treated with the surgery first approach. In this study, patients who completed all components of multimodal therapy had better outcomes compared with those who received only one component, whether surgery or chemotherapy. Although the rate of complications in both groups was similar, patients who received neoadjuvant therapy and suffered postoperative major complication had longer survival compared with patients with the surgery first approach who had a major postoperative complication. This may suggest that neoadjuvant therapy protects patients with pancreatic cancer who undergo pancreatectomy for pancreatic cancer from early recurrence and death. Alternatively, these results may just be a reflection of the fact that the patients who underwent surgery first and developed a complication were unable to receive adjuvant therapy, which is an equally critical component of treatment. In select patients, the role of neoadjuvant therapy is clearer, particularly for those with significant venous or limited arterial involvement whose disease is classified as borderline resectable. In these patients, for whom upfront surgical exploration has a significant risk of exposing them to nontherapeutic laparotomy, the argument for neoadjuvant therapy is strengthened and is now supported by level 1 evidence. The results of PREOPANC-1 randomized controlled multicenter trial, which randomized patients with borderline resectable pancreatic cancer into immediate surgery versus preoperative chemoradiotherapy, were recently released.52 Both groups received adjuvant therapy. The study demonstrated that the patients undergoing neoadjuvant approach had significantly better overall survival (median 17.1 months vs. 13.5 months in surgery first approach), better disease-free survival (median 11.2 months vs. 7.9 months in surgery first approach). No significant difference was observed in grade ≥3 adverse events between both groups. Another small-randomized controlled trial from South Korea53 demonstrated that neoadjuvant treatment of borderline resectable pancreatic cancer patients led to improvement in overall survival and R0 resection rate when compared with upfront surgery. Furthermore, for individuals with significant SMV–portal vein involvement (>180 degrees or short-segment encasement) or hepatic arterial or SMA abutment (120 days) become trapped and destroyed in the spleen. Abnormal erythrocytes that result from hemoglobinopathies such as sickle cell anemia, hereditary spherocytosis, thalassemia, or pyruvate kinase deficiency (PKD) are also trapped and destroyed by the spleen. The overall effect is worsening anemia, splenomegaly, and sometimes autoinfarction of the spleen.

Similarly, the spleen is involved in platelet destruction in immune thrombocytopenia (ITP), formerly known as idiopathic thrombocytopenia purpura. 

Immunity It functions by antibody synthesis and phagocytosis. Asplenic patients have been found to express subnormal immunoglobulin M

CHAPTER 57  The Spleen

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Hilum Capsule

Red pulp: Venous sinus Reticular spaces Trabecular artery White pulp

Trabecula

White pulp follicles

Red pulp

A

Trabecular vein

RP

Closed theory

Lymphatic nodule

Open theory Venous sinuses

FIG. 57.4  Structure of the sinusoidal spleen showing the open and closed blood flow routes. (From Bellanti JA. Immunology: Basic processes. Philadelphia, PA: WB Saunders ,1979.)

levels, and their peripheral blood mononuclear cells exhibit a suppressed immunoglobulin response. Other factors involved in the immune response are opsonins, such as properdin and tuftsin. Opsonins, produced in the spleen, exhibit reduced serum levels after splenectomy. Properdin, a globulin protein also known as factor P, initiates the alternate pathway of complement activation; this increases the destruction of bacteria and abnormal cells. Tuftsin, a tetrapeptide, enhances the phagocytic activity of mononuclear phagocytes and polymorphonuclear leukocytes. Absence of a circulating mediator appears to result in suppressed neutrophil function. The spleen also plays a key role in cleaving tuftsin from the heavy chain of immunoglobulin G; thus, circulating levels of tuftsin are subnormal in asplenic patients. Additionally, splenic filtration may be particularly important for removal of microorganisms for which the host does not have a specific antibody (Box 57.1). The immune functions of the spleen become evident after splenectomy, when patients are noted to be at risk for specific infections related to encapsulated bacteria Streptococcus pneumoniae, Haemophilus influenza, and Neisseria meningitidis. Asplenia and hyposplenism could be a result of surgical absence of spleen or lack of functioning of an anatomically present spleen. The most serious sequela is overwhelming postsplenectomy infection (OPSI). OPSI is discussed in detail at the end of this chapter. 

SPLENECTOMY Splenectomy may be indicated for conditions other than trauma. These indications encompass mainly hematologic disorders in addition to other mass lesions and splenic vascular lesions that are discussed elsewhere in this textbook.

WP

B

Mantle zone

Marginal zone Germinal center

C FIG. 57.5  Normal human spleen on hematoxylin-eosin staining. (A) Low-power photomicrograph showing relationship and relative proportions of red and white pulp. (B) Medium-power photomicrograph (arrow indicates periarterial lymphoid sheath). (C) High-power photomicrograph showing detailed secondary follicle architecture. (From Pernar LIM, Tavakkoli A. Anatomy and physiology of the spleen. In: Yeo CJ, eds. Shackelford’s surgery of the alimentary tract. 8th ed. Philadelphia, PA: Elsevier; 2019:1595.). RP, Red pulp; WP, white pulp (secondary follicle).

Benign Hematologic Conditions Immune Thrombocytopenia ITP is the most common hematologic indication for splenectomy and is discussed here in detail. ITP was previously known as

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FIG. 57.6  The presence of Howell-Jolly bodies (arrow) on the peripheral blood smear is suggestive of asplenia or hyposplenism. (From Hashimoto N. Management of overwhelming postsplenectomy infection syndrome. Clin Surg. 2016;1:1148.)

BOX 57.1  Biologic substances removed by

the spleen.

Normal Subjects Red blood cell membrane Red blood cell surface pits and craters Howell-Jolly bodies Heinz bodies Pappenheimer bodies Acanthocytes Senescent red blood cells Particulate antigen  Patients With Disease Spherocytes (hereditary spherocytosis) Sickle cells, hemoglobin C cells Antibody-coated red blood cells Antibody-coated platelets Antibody-coated white blood cells Adapted from Eichner ER. Splenic function: Normal, too much and too little. Am J Med. 1979;66:311–320.

idiopathic thrombocytopenic purpura. In 2009, the ITP workgroup (IWG) published guidelines and defined the abbreviation to be ITP and dropped idiopathic and purpura as pathophysiology is better understood and the majority do not present with purpura.1 ITP is characterized by a low platelet count below 100 × 109/L despite normal bone marrow and the absence of other causes of thrombocytopenia that could be responsible for the finding.2 The pathogenesis is not fully understood. However, immunoglobulin G autoantibodies directed towards the platelet membranes are believed to be responsible for platelet destruction within the reticuloendothelial system by macrophages and cytotoxic T cells. In addition to the destruction, there is dysfunction of megakaryocytes with low level of thrombopoietin. It is classified as primary ITP when there is no clear etiology.1 Primary ITP is further classified into three subtypes based on disease chronicity: newly diagnosed (within 3 months), persistent ( 3–12 months), and chronic (greater than 12 months). Secondary ITP is due to a known cause such as medication-induced, infectious, or rheumatologic conditions (i.e., systemic lupus erythromatosis). The typical presentation of ITP is characterized by purpura, epistaxis,

and gingival bleeding. Less commonly, gastrointestinal bleeding and hematuria are noted. Intracerebral hemorrhage is a rare but sometimes fatal presentation. The diagnosis of primary ITP involves the exclusion of other relatively common causes of thrombocytopenia—pregnancy, drug-induced thrombocytopenia (e.g., heparin, quinidine, quinine, sulfonamides), viral infections, and hypersplenism (Box 57.2). Mild thrombocytopenia may be seen in approximately 6% to 8% of otherwise normal pregnancies and in up to 25% of women with preeclampsia. Drug-induced thrombocytopenia is thought to occur rarely, in approximately 20 to 40 cases/million users of common medications, such as trimethoprim-sulfonamide and quinine. Other medications, such as gold salts, have a higher incidence, almost 1% of users. Viral infection (e.g., hepatitis C, human immunodeficiency virus (HIV) infection, rarely EpsteinBarr virus infection) can be responsible for thrombocytopenia independent of splenic sequestration. Once again, other processes must be ruled out, but healthcare providers can be confident of these causative factors if platelet counts improve with successful treatment of the responsible infection. Bacterial infection, specifically Helicobacter pylori, has also been linked to infection-related thrombocytopenia that improves with eradication. Other causes are listed in Box 57.2; spurious laboratory values caused by platelet clumping or the presence of giant platelets should not be ignored. ITP is predominantly a disease of young women; 72% of patients older than 10 years are women, and 70% of affected women are younger than 40 years. ITP is manifested somewhat differently in children; both genders are affected equally, onset is sudden, thrombocytopenia is severe, and complete spontaneous remissions are seen in approximately 80% of affected children. Girls older than 10 years with more chronic purpura are those in whom the disease seems to persist. Management of ITP depends primarily on the severity of the thrombocytopenia. Asymptomatic patients with platelet counts higher than 50,000/mm3 may be observed without further intervention. Platelet counts of 50,000/mm3 and higher are rarely associated with clinical sequelae, even with invasive procedures. Patients with slightly lower platelet counts, between 30,000 and 50,000/mm3, may be observed but with more routine follow-up because they are at increased risk for progressing to severe thrombocytopenia. Initial medical treatment of patients with platelet counts below 50,000/mm3 and symptoms such as mucous membrane bleeding, high-risk conditions (e.g., active lifestyle, hypertension, peptic ulcer disease), or platelet counts below 20,000 to 30,000/mm3, even without symptoms, is glucocorticoid administration (typically, prednisone, 1 mg/kg body weight per day). Clinical response with increases in platelet levels to higher than 50,000/mm3 is seen in up to two thirds of patients within 1 to 3 weeks of initiating treatment. Of patients treated with steroids, 25% will experience a complete response. Patients with platelet counts higher than 20,000/mm3 who remain symptom free or who experience minor purpura as their only symptom do not require hospitalization. Hospitalization may be required for patients whose platelets counts remain below 20,000/mm3 with significant mucous membrane bleeding and is required for those who have life-threatening hemorrhage. Platelet transfusion is indicated only for those who experience severe hemorrhage. Intravenous immune globulin is important for the treatment of acute bleeding, in pregnancy, or for patients being prepared for operation, including splenectomy. The usual dose is 1 g/kg body weight per day for 2 days. This dose usually increases the platelet count within 3 days; it also increases the efficacy of platelet transfusions.

CHAPTER 57  The Spleen BOX 57.2  Differential diagnosis of immune

thrombocyopenia (ITP).

Falsely Low Platelet Count In vitro platelet clumping caused by ethylenediaminetetraacetic acid (EDTA)– dependent or cold-dependent agglutinins, insufficiently anticoagulated specimen, glycoprotein IIb/IIIa inhibitors (e.g., abciximab) Giant platelets that are miscounted as WBC by automated counters rather than platelets  Common Causes of Thrombocytopenia Pregnancy (gestational thrombocytopenia, preeclampsia, HELLP syndrome) Drug-induced thrombocytopenia (common drugs include heparin, quinidine, quinine, sulfonamides, acetaminophen, cimetidine, ibuprofen, naproxen, ampicillin, piperacillin, vancomycin, linezolid, glycoprotein IIb/IIIa inhibitors Viral infections, such as HIV, HCV, EBV (infectious mononucleosis), rubella Helicobacter pylori Malaria Hypersplenism caused by chronic liver disease Alcohol Nutrient deficiencies (e.g., vitamin B12, folate, copper) Rheumatologic/autoimmune disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis)  Other Causes of Thrombocytopenia Mistaken for Immune Thrombocytopenia (ITP) Myelodysplasia Congenital thrombocytopenias Thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome Chronic disseminated intravascular coagulation  Thrombocytopenia Associated With Other Disorders Autoimmune diseases, such as systemic lupus erythematosus Lymphoproliferative disorders (chronic lymphocytic leukemia, non-Hodgkin lymphoma) Adapted from George JN, El-Harake MA, Raskob GE. Chronic idiopathic thrombocytopenic purpura. N Engl J Med. 1994;331:1207–1211. HELLP, Hemolysis, elevated liver enzymes, and a low platelet count; EBV, Epstein-Barr virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus.

Should initial therapy for ITP fail, medical options for refractory ITP include oral prednisone, oral dexamethasone (40 mg/ day for 4 days), rituximab (375 mg/m2/week intravenously for 4 weeks), and thrombopoietin receptor antagonists (eltrombopag, romiplostim). Successful response for months is observed in 28% to 44% of patients using rituximab; more transient responses are observed from thrombopoietin receptor antagonists.3 Before the establishment of glucocorticoids for treatment of ITP in 1950, splenectomy was the treatment of choice. For those two thirds of patients in whom glucocorticoids result in the normalization of platelet counts, no further treatment is necessary. For patients with severe thrombocytopenia with counts below 10,000/ mm3 for 6 weeks or longer, with thrombocytopenia refractory to glucocorticoid treatment, and who require toxic doses of steroid to achieve remission, the treatment of choice is to proceed to splenectomy. Splenectomy is also the treatment of choice for patients with incomplete response to glucocorticoid treatment and for pregnant women in the second trimester of pregnancy who have also failed

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to respond to steroid treatment or intravenous immune globulin therapy with platelet counts below 10,000/mm3 without symptoms or below 30,000/mm3 with bleeding problems. It is not necessary to proceed to splenectomy for patients who have platelet counts higher than 50,000/mm3, who have had ITP for longer than six months, who are not experiencing bleeding symptoms, and who are not engaged in high-risk activities. A review of short-term and long-term failure of laparoscopic splenectomy has reported an overall approximate failure rate of 28% at five years after splenectomy.4 A systematic review of 436 published articles from 1966 to 2004 has reported that 72% of patients with ITP had a complete response to splenectomy. Relapse occurred in a median of 15% of patients (range, 1%–51%), with a median follow-up of 33 months.5 In addition to relapse rates, predictors of successful splenectomy were examined. Of the variables in the multivariate model, age at the time of splenectomy was an independent variable that was most correlated with response.5 Most patients will exhibit improved platelet counts within 10 days postoperatively, and durable platelet responses are associated with patients who have platelet counts of 150,000/mm3 by postoperative day 3 or more than 500,000/mm3 by postoperative day 10. Even with splenectomy, however, some patients may relapse (12%, range 4%–25%). A review of 1223 ITP patients has estimated the long-term failure rate of laparoscopic splenectomy at approximately 8% and approximately 44/1000 patient-years of follow-up.4 Another study has estimated the complete response of ITP patients after splenectomy to be 66%.5 Although a thorough search for accessory spleens is completed during the initial surgery, evaluation for a missed accessory spleen must be undertaken in patients who experience a relapse. In their evaluation of 394 patients treated with laparoscopic splenectomy, Katkhouda and colleagues noted 15% of patients with accessory spleens. In those with accessory spleens, examination of a peripheral blood smear will lack the characteristic RBC morphology resulting from excision of the spleen. Radionuclide imaging may also be helpful in locating the presence and location of any accessory splenic tissue. Patients with chronic ITP in whom an accessory spleen is identified should have this removed, as long as the patient can withstand the surgical risk. Other treatment options for these patients include observation of stable nonbleeding patients with platelet counts higher than 30,000/mm3, long-term glucocorticoid therapy, and treatment with azathioprine or cyclophosphamide. Recent evidence indicates that thrombopoietin receptor agonists can be used as a novel medical therapy for patients with chronic ITP with no response to steroids, intravenous immune globulin therapy, or splenectomy.6 Approximately 10% to 20% of otherwise asymptomatic patients with HIV infection will develop ITP. Splenectomy is a safe treatment option for this cohort of patients and may actually delay HIV disease progression.7  Hereditary Anemia This is usually classified into: 1) defects of the RBC membrane (e.g., hereditary spherocytosis); 2) defect in erythrocyte enzyme (e.g., glucose-6-phosphate dehydrogenase deficiency [G6PD]); and 3) defect in hemoglobin synthesis (e.g., thalassemia, sickle cell anemias [hemoglobin S]).  Hereditary Spherocytosis Hereditary spherocytosis is the most common anemia and results from a defect in the erythrocyte cell membrane. Hereditary spherocytosis is usually transmitted as an autosomal dominant disease;

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SECTION X  Abdomen

however, albeit rare autosomal recessive transmission also occurs. Hereditary spherocytosis is thought to be most commonly caused by mutation of genes affecting the production of the RBC cytoskeleton proteins such as spectrin, ankryin, band 3 (anion exchanger AE1), and band 4.2. Mutations of spectrin and band 3 proteins are the most frequently associated with hereditary spherocytosis.8 Loss of function of those proteins causes RBCs to lack their characteristic biconcave shape. This affects the deformability of RBCs because lack of this protein results in rigid erythrocytes that are small and sphere shaped. Also, these cells have increased osmotic fragility and are more susceptible to trapping and destruction by the spleen. The most common resulting clinical features are moderate hemolytic anemia, occasionally with jaundice, folate deficiency, and splenomegaly. Diagnosis is made by hematologic workup: complete blood count with indices, increased reticulocyte count on peripheral blood smear with spherocytes, elevated lactate dehydrogenase, increased indirect bilirubin, absence of decreased haptoglobin, increased osmotic fragility, and negative Coombs test result. The resultant anemia can be successfully treated with splenectomy, but normalization of the erythrocyte morphology does not occur. Splenectomy should be delayed until the age of five years to preserve immunologic function of the spleen and to reduce the risk of OPSI. If patient requires splenectomy before that age, partial splenectomy is an option. Just as with other hemolytic anemias, the presence of pigmented gallstones is common. The preoperative workup should include ultrasound evaluation; if gallstones are present, cholecystectomy may be performed at the same time as splenectomy. Hereditary elliptocytosis, hereditary pyropoikilocytosis, hereditary xerocytosis, and hereditary hydrocytosis also result in anemia secondary to RBC membrane abnormalities. Splenectomy is indicated in cases of severe anemia with these conditions, except hereditary xerocytosis, which results in only mild anemia of limited clinical significance.  Hemolytic Anemia Caused by Erythrocyte Enzyme Deficiency PKD and G6PD deficiency are the predominant hereditary conditions associated with hemolytic anemia. Although PKD is the second most common enzymopathy after G6PD deficiency, it is the most common cause for hemolytic anemia compared to G6PD deficiency. PKD is an autosomal recessive disease caused by a mutation to the pyruvate kinase L/R (PKLR gene). The gene is expressed as liver (L) and RBC (R) isoforms of pyruvate kinase. Mature RBC lack mitochondria and rely on anaerobic glycolysis as their sole source of energy. Pyruvate kinase is involved in glycolysis and adenosine triphosphate (ATP) production, therefore a PKLR mutation causes reduced pyruvate kinase production leading to reduced levels of ATP in red cells and increased production of other byproducts of glycolysis. This results in the rapid depletion of ATP and the inability of the RBC to maintain its membrane integrity. They are subsequently destroyed by the spleen via phagocytosis. In G6PD deficiency, however, splenectomy is rarely indicated. This X-linked condition is typically seen in people of African, Middle Eastern, or Mediterranean ancestry. G6PD catalyzes the first step in the oxidative part of the pentose phosphate pathway leading to the production of NDPH. NDPH is a crucial enzyme in combatting oxidative stress in cells. Therefore, cells with G6PD deficiency are especially susceptible to oxidative stress. RBCs with G6PD deficiency are unable to protect themselves from reactive oxygen species, which is precipitated by infection

or exposure to certain foods, medications, or chemicals. Primary treatment, therefore, is avoidance of exacerbation of the condition. Thus, PKD causes chronic hemolysis compared to G6PD deficiency, which is more episodic. As a result, there is a role for splenectomy in PKD.9 Splenectomy has been shown to eliminate or decrease transfusion requirements through elevating the hemoglobin and reticulocyte count.9  Hemoglobinopathies In addition to cellular membranes or enzyme gene mutation, hereditary anemias may also result from globin chain of the hemoglobin molecule mutations. Almost 1000 different globin mutations have been discovered. Out of all these hemoglobin mutations, sickle cell disease and thalassemia are the two most clinically important disorders. Sickle cell disease is a point mutation in the beta globin gene resulting a single amino acid substitution (valine for glutamic acid) in the sixth position of the β chain of hemoglobin A). Sickle cell disease results from homozygous inheritance of the defective hemoglobin (hemoglobin S), although sickling can also be seen when hemoglobin S is inherited along with other hemoglobin variants, such as hemoglobin C or sickle cell β-thalassemia. In African Americans, 8% are heterozygous for hemoglobin S (sickle cell trait), and approximately 0.5% are homozygous for hemoglobin S. The affected hemoglobin chains become rigid, sickle shaped, and unable to deform under reduced oxygen conditions. These misshapen cells are unable to pass through the microvasculature, which results in capillary occlusion, thrombosis, and ultimately microinfarction. This cascade of events frequently occurs in the spleen. These episodes of vasoocclusion and progressive infarction result in autosplenectomy. The spleen, which is usually hypertrophied early in life, typically atrophies by adulthood, although splenomegaly may occasionally persist. Other causes of hemolytic anemia are the thalassemias. The thalassemias are a group of disorders with disproportional alpha to beta chain ratio, this results in precipitation of the unpaired chain and subsequent RBC destruction.10 These abnormal cells are destroyed either in the bone marrow (ineffective erythropoiesis) or in the blood stream (hemolysis). Thalassemia is classified into two main types depending on which globin chain is defective: alpha thalassemia and beta thalassemia. The mode of inheritance is autosomal recessive. Splenomegaly, hypersplenism, and splenic infarction, common in sickle cell disease, are also commonly seen in patients with thalassemia. Acute splenic sequestration crises are life-threatening disorders in children with sickle cell disease or sickle-Beta thalassemia. In this condition, there is rapid drop in hemoglobin level due to vasoocclusion and RBC sequestration in the spleen. This could lead to life-threatening hypovolemic shock and require multiple blood transfusions. Patients with acute splenic sequestration crisis present with severe anemia, splenomegaly, and an acute bone marrow response, with reticulocytosis. There may be a concurrent decrease in hemoglobin levels, abdominal pain, and circulatory collapse. Resuscitation with hydration and transfusion may be followed by splenectomy in these patients. Splenectomy is usually indicated after the first attack to prevent subsequent attacks. Hypersplenism related to sickle cell disease is characterized by anemia, leukopenia, and thrombocytopenia requiring transfusions; transfusions may be reduced by performing splenectomy. Symptomatic massive splenomegaly that interferes with daily activities may also be improved by splenectomy. Finally, in children with sickle cell disease who exhibit growth delay or even weight loss because of increased metabolic rate

CHAPTER 57  The Spleen and whole body total protein turnover, splenectomy may relieve these symptoms. Splenic abscesses may also be seen in patients with sickle cell anemia. These patients present with fever, abdominal pain, and a tender enlarged spleen. Most patients with splenic abscesses will have a leukocytosis as well as thrombocytosis and Howell-Jolly bodies, indicating a functional asplenia. Salmonella and Enterobacter spp. and other enteric organisms are common pathogens. These patients require resuscitation, antibiotics, and may require urgent splenectomy after stabilization. 

Malignant Disease Hematopoietic Neoplasm Lymphomas

Hodgkin lymphoma. Hodgkin lymphoma, formerly known as Hodgkin disease, is a group of malignant conditions that are characterized by the presence of Reed-Sternberg cells on histology. Hodgkin lymphoma usually affects young adults in their 20s and 30s with a second peak in adults over the age of 50. Rarely, patients present with constitutional symptoms such as night sweats, weight loss, and pruritus; but more typically, asymptomatic lymphadenopathy usually involves the cervical nodes. Hodgkin lymphoma histologic subtypes are lymphocyte predominant, nodular sclerosing, mixed cellularity, or lymphocyte depleted. The disease staging is based on the Ann Arbor staging with Cotswold modifications.11 Stage I is disease in a single lymphatic site. Stage II is disease in two or more lymphatic sites on the same side of the diaphragm. Stage III indicates disease on both sides of the diaphragm and includes splenic involvement. Stage IV disease is disease with additional noncontiguous extralymphatic implication with or without associated lymphatic involvement. The addition of a subscript E to stage I, II, or III indicates single or contiguous extralymphatic spread; subscript S indicates splenic involvement. Patients who exhibit constitutional symptoms are denoted with a B (presence), and those without symptoms are denoted with an A (absence). Historically, patients with Hodgkin lymphoma underwent a staging laparotomy that included splenectomy to provide pathologic staging information required to determine appropriate therapy. Staging methods have evolved to include imaging techniques. The recommended imaging modality is computed tomography (CT) and 18F-fluorodeoxyglucose positron emission tomography (PET). Hodgkin lymphoma is a fluorodeoxyglucose-avid lymphoma. In the absence of a PET scan, CT with intravenous contrast is recommended. Early-stage Hodgkin lymphoma is now often treated with the combination of radiation and chemotherapy. Advanced stage is usually managed with chemotherapy with or without radiation. Splenectomy for Hodgkin lymphoma is currently rarely indicated. However, it may be performed for symptomatic splenomegaly.12  Non-Hodgkin lymphoma. Non-Hodgkin lymphoma is a group of malignant neoplasms derived from progenerates of B cell, T cell, mature B cells, and mature T cells. Staging relies mostly on integrated PET/CT, this also helps with targeting fluorodeoxyglucose-avid lymph nodes with biopsy. Surgeons are frequently involved with obtaining a lymph node or tissue biopsy. Ideally, biopsy is obtained before initiation of steroid therapy as steroids would lyse lymphoid tissue and might obscure the diagnosis. Splenomegaly or hypersplenism is a common occurrence during the course of non-Hodgkin lymphoma. Splenectomy is indicated for non-Hodgkin lymphoma patients with massive splenomegaly

1573

leading to abdominal pain, early satiety, and fullness. It may also be indicated for patients who develop anemia, neutropenia, and thrombocytopenia associated with hypersplenism. Splenectomy may also be instrumental in the diagnosis and treatment of a rare subtype of non-Hodgkin lymphoma currently known as splenic marginal zone lymphoma (previously termed splenic lymphoma).13 Most of these patients present with splenomegaly, lymphocytosis with anemia, and thrombocytopenia. Diagnosis of splenic marginal zone lymphoma is based on clinical feature of unexplained lymphocytosis and splenomegaly, triggering splenectomy and/or immunophenotypic findings on bone marrow biopsy. PET/CT is also indicated as part of the workup. Splenectomy is indicated for symptomatic splenomegaly and with those suspected large cell transformations on PET/CT scan. In patients with spleen-predominant features, survival is significantly improved after splenectomy and could be considered as a mainstay therapy for those that are surgical candidates.  Leukemia Hairy cell leukemia. Hairy cell leukemia, a rare disease that accounts for approximately 2% of adult leukemias, is characterized by splenomegaly, pancytopenia, and neoplastic mononuclear cells in the peripheral blood and bone marrow. The cells that give the disease its name are B lymphocytes that have a ruffling of the cell membrane. This ruffling causes the cells to appear to have cytoplasmic projections under the light microscope. The maleto-female ratio is approximately 4:5. They usually present with palpable splenomegaly. Approximately 10% of patients require no treatment because of the indolent course of the disease. Treatment for cytopenias or splenomegaly typically begins with first line therapy with purine analogue chemotherapy.14 For more refractory cancers, a second-line immunotherapy may be instituted. In others, however, the extent of splenomegaly or symptoms from hypersplenism can lead to splenectomy. Most patients show improvement after the procedure, with a response lasting approximately 10 years after splenectomy, and some patients (∼40%–60%) show normalization of blood counts after splenectomy. Patients with diffusely involved bone marrow without massive splenomegaly are less responsive to splenectomy. Patients with hairy cell leukemia are also at a twofold to threefold risk for development of other malignant neoplasms after their diagnosis of hairy cell leukemia. Most of these second malignant neoplasms are solid tumors, such as skin cancers, lung cancer, prostate cancer, and gastrointestinal adenocarcinomas. Hairy cell leukemia behaves like a chronic leukemia; many patients can achieve a clinical remission, with a normal or near-normal life span.15  Chronic lymphocytic leukemia. Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world. It is a clinically heterogeneous disease of B lymphocytes characterized by the progressive accumulation of relatively morphologically normal, mature but functionally incompetent lymphocytes. CLL is seen with a slight predominance in men, mainly after the age of 50 years. CLL is staged according to the Rai system and correlates fairly well with survival. Low-risk CLL (formerly stage 0) involves bone marrow and blood lymphocytosis only; intermediate-risk CLL (formerly stages I and II) involves lymphocytosis and lymphadenopathy in any site or splenomegaly, hepatomegaly, or hepatosplenomegaly; and high-risk CLL (formerly stages III and IV) involves lymphocytosis and anemia or thrombocytopenia. The Rai system helps clinicians determine when therapy should be started. Other genetic and biologic markers are also used for prognostication. An International prognostication score (CLL-IPI) integrates

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SECTION X  Abdomen

clinical, genetic, and biologic variables. Medical treatment is reserved for fit patients with symptomatic disease and advanced Rai stages.16 Treatment involves chemotherapy with fludarabine, rituximab, and cyclophosphamide. Conversely, unfit patients have two options: anti-CD20 antibody combined with chlorambucil or ibrutinib. The indication for splenectomy in CLL has declined dramatically in the past decade and is rarely performed.  Chronic myelogenous leukemia. Chronic myelogenous leukemia (CML) is a myeloproliferative disorder that develops as a result of a neoplastic transformation of myeloid elements. CML is characterized by the progressive replacement of normal diploid elements of the bone marrow with mature-appearing neoplastic myeloid cells. Although CML can be asymptomatic at presentation, patients commonly present with fever, fatigue, malaise, effects of pancytopenia (e.g., infections, anemia, easy bruising), and occasionally splenomegaly. Peripheral blood smear analysis shows leukocytosis of white blood cell count up to 100,000/µL with white blood cell count from myeloblasts to mature neutrophils. The gold standard for the diagnosis of CML is a chromosomal marker, the Philadelphia chromosome, is caused by the fusion of fragments of chromosomes Abelson gene (ABL1) 9q34 and breakpoint cluster region gene (BCR) on chromosome 22q11.2. This fusion results in expression of the BCR-ABL1 fusion oncogene and trannslates to BCR-ABL1 oncoprotein which then accelerates cell division and inhibits DNA repair.17 CML may occur in patients from childhood to old age. It usually is manifested with an asymptomatic chronic phase but may progress to an accelerated phase associated with fever, night sweats, and progressive splenomegaly. The accelerated phase may be asymptomatic and may be detectable only by changes in peripheral blood or bone marrow. The accelerated phase may then progress to the blastic phase. This phase is also characterized by fever, night sweats, and splenomegaly but is also associated with anemia, infections, and bleeding. The BCR-ABL gene product is the target for therapy with tyrosine kinase inhibitors (imatinib, dasatinib, and nilotinib) and other chemotherapeutic modalities. Bone marrow transplantation is an option, but prognosis has improved dramatically with the advent of recent therapies, making transplantation less common. Studies evaluating the efficacy of newer therapies and combination therapies are ongoing. Symptomatic splenomegaly and hypersplenism in CML can be effectively treated with splenectomy, but there does not appear to be a survival benefit when it is performed during the early chronic phase. Surgery is therefore reserved for patients with significant symptoms attributable to splenomegaly or hypersplenism.  Nonhematologic Tumors of the Spleen Lymphoma is the most common tumor involving the spleen. Other primary and secondary neoplasms are rare. Primary tumors of the spleen are commonly vascular neoplasms and include benign and malignant variants. Splenic hamartomas are rare and are usually composed of malformed disorganized red pulp elements. Hemangiomas are frequent findings in spleens removed for other reasons. Angiosarcomas (or hemangiosarcomas) of the spleen usually occur spontaneously but have been linked to environmental exposures, such as to thorium dioxide and monomeric vinyl chloride. Patients with angiosarcomas may present with splenomegaly, hemolytic anemia, ascites, pleural effusions, or even spontaneous splenic rupture. These tumors are aggressive and have a poor prognosis. Lymphangiomas, by contrast, are endothelium-lined cysts that come to attention because of splenomegaly

secondary to cyst enlargement. These are usually benign tumors; however, lymphangiosarcoma has been found within lymphangiomas. Splenectomy is appropriate for the diagnosis, treatment, and palliation of these conditions. Secondary metastatic splenic neoplasms are rare and thought to be due to lack of afferent lymphatics.18 They are seen in up to 7% of autopsies of cancer patients. The solid tumors that most frequently spread to the spleen are carcinomas of the breast, lung, and melanoma. Any primary malignant neoplasm, however, can metastasize to the spleen. Metastases are often asymptomatic but may be associated with splenomegaly and even splenic rupture; thus, splenectomy may provide palliation for carefully chosen patients with symptomatic splenic metastases. 

Miscellaneous Benign Conditions Splenic Cysts Splenic cysts have been seen with increasing frequency since the advent of CT and ultrasound scanning. They are classified as parasitic and nonparasitic cysts. The nonparastic cysts are further divided into true cysts and pseudocysts. True cysts are lined with epithelium and may be considered congenital. They account for 10% of all splenic cysts. Tumors of the spleen may also appear to be cystic; these include lymphangiomas and cavernous hemangiomas (see earlier). Parasitic cysts occur in areas of endemic hydatid disease (Echinococcus spp.). Radiographic imaging, usually with ultrasound, reveals cyst wall calcifications or daughter cysts, and although hydatid disease is uncommon in North America, this diagnosis must be excluded before invasive procedures are undertaken that might result in spillage of the cyst contents. Rupture of the cyst and expulsion of contents into the abdomen may precipitate anaphylactic shock and can also lead to intraperitoneal dissemination of the infection. Serologic testing is helpful for verifying the presence of these parasites. Splenectomy is the treatment of choice. As with hydatid cysts of the liver, the cysts may be sterilized by injection of a 3% sodium chloride solution, alcohol, or 0.5% silver nitrate. Even so, great care should be taken to avoid intraoperative rupture of the cyst. Nonparasitic true cysts of the spleen account for approximately 10% of all splenic cysts. These epithelial cells are often positive for carbohydrate antigen 19-9 and carcinoembryonic antigen by immunohistochemistry. Patients with splenic epidermoid cysts may have elevated serum levels of one or both of these tumor markers. These cysts, however, are benign and apparently do not have malignant potential beyond that of the surrounding native tissue. True splenic cysts are often asymptomatic and discovered incidentally. Patients may complain of abdominal fullness, early satiety, pleuritic chest pain, shortness of breath, and left shoulder or back pain. They may also experience renal symptoms from compression of the left kidney. On physical examination, an abdominal mass may be palpable. Rarely, splenic cysts are manifested with acute symptoms related to rupture, hemorrhage, or infection. Diagnosis is best made by CT, and operative intervention is indicated for those with symptomatic or large cysts. Total or partial splenectomy may provide appropriate treatment. Partial splenectomy has the advantage of preserving splenic function; 25% of the spleen appears to be sufficient to protect against pneumococcal pneumonia. Open and laparoscopic procedures allow total or partial splenectomy, cyst wall resection, or partial decapsulation.19 Nonparasitic pseudocysts represent the remaining 70% to 80% of nonparasitic splenic cysts. A history of prior trauma can typically be elicited. Pseudocysts of the spleen are not lined with epithelium.

CHAPTER 57  The Spleen Radiologic imaging usually reveals a smooth, unilocular, thickwalled lesion, sometimes with focal calcifications. Asymptomatic, small (3 cm but ≤4 cm in greatest dimension T2b Tumor >4 cm but ≤5 cm in greatest dimension T3 Tumor >5 cm but ≤7 cm in greatest dimension or associated with separate tumor nodule(s) in the same lobe as the primary tumor or directly invades any of the following structures: chest wall (including the parietal pleura and superior sulcus tumors), phrenic nerve, parietal pericardium T4 Tumor >7 cm in greatest dimension or associated with separate tumor nodule(s) in a different ipsilateral lobe than that of the primary tumor or invades any of the following structures: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, and carina N: Regional Lymph Nodes Involvement 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) M (Distant Metastasis) M0 No distant metastasis M1 Distant metastasis present • M  1a Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodule(s) or malignant pleural or pericardial effusion d • M1b Single extrathoracic metastasise • M  1c Multiple extrathoracic metastases in one or more organs From Goldstraw P, Chansky K, Crowley J, et al. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2016;11:39–51. Note: Changes to the seventh edition are in bold. aThe uncommon superficial spreading tumor of any size with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus, is also classified as T1a. bSolitary adenocarcinoma, ≤3cm with a predominately lepidic pattern and ≤5mm invasion in any one focus. cT2 tumors with these features are classified as T2a if ≤4 cm in greatest dimension or if size cannot be determined, and T2b if >4 cm but ≤5 cm in greatest dimension. dMost pleural (pericardial) effusions with lung cancer are due to tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor and the fluid is nonbloody and not an exudate. When these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor. eThis includes involvement of a single distant (nonregional) lymph node.

Tumor (T) In the eighth edition of the IASLC/AJCC, lung cancer staging project significant innovations were introduced into the definitions of the T descriptor. In particular, the eighth edition includes for the first time special definitions for carcinoma in situ (Tis) and for minimally invasive carcinomas (T1mi). Tis are less than 3-cm noninvasive tumors that histologically display a pure lepidic growth pattern. T1mi are less than 3-cm tumors that histologically

display a predominant lepidic growth pattern; however, they also have a small (3 to 5 cm) are subcategorized as T2a >3 to 4 cm, T2b >4 to 5 cm. T3 tumors are defined as >5 up to 7 cm and T4 tumors are defined as >7 cm. Other important tumor characteristics that

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SECTION XI  Chest

TABLE 58.2  Proposed stage grouping for

the Eighth Edition of the TNM Classification for Lung Cancer OCCULT CARCINOMA

TX

N0

M0

Stage 0 Stage IA1

Tis T1a(mi) T1a T1b T1c T2a T2b T1a-c T2a T2b T3 T1a-c T2a–b T3 T4 T4 T1a-c T2a–b T3 T4 T3 T4 Any T Any T Any T

N0 N0 N0 N0 N0 N0 N0 N1 N1 N1 N0 N2 N2 N1 N0 N1 N3 N3 N3 N2 N3 N3 Any N Any N Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1a M1b M1c

Stage IA2 Stage IA3 Stage IB Stage IIA Stage IIB

Stage IIIA

Stage IIIB

Stage IIIC Stage IVA Stage IVB

From Goldstraw P, Chansky K, Crowley J, et al. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2016;11:39-51. TNM, tumor, node, metastasis; Tis, carcinoma in situ; T1a(mi), minimally invasive adenocarcinoma. Note: Changes to the seventh edition are highlighted in bold and underlined.

dictate the T stage are involvement of the main bronchus/invasion of the visceral pleural/associated lobar or lung atelectasis in the T2 descriptor, invasion of the parietal pleura/chest wall/phrenic nerve/ parietal pericardium or associated separate tumor nodule(s) in the same lobe as the primary tumor in the T3 descriptor, and invasion of the diaphragm/mediastinum/heart/great vessels/trachea/recurrent laryngeal nerve/esophagus/vertebral body/carina or separate tumor nodule(s) in a different ipsilateral lobe to that of the primary tumor in the T4 descriptor. Contrast-enhanced CT of the chest is the main imaging modality used to determine the T stage. MRI of the chest wall may assist in identifying chest wall involvement and in staging of superior sulcus tumors.  Lymph Nodes (N) The node descriptor (N0–N3) is defined according to the extent of lymph node metastasis along a predefined lymph node map. There are 14 lymph node stations: stations 10 to 14 are confined to the lung, and metastasis to these nodes indicates N1 disease if ipsilateral to the tumor and N3 disease if contralateral to the tumor; stations 9 to 2 are confined to the mediastinum, and metastasis to

these nodes indicates N2 disease if ipsilateral to the tumor and N3 disease if contralateral to the tumor; station 1 are supraclavicular or suprasternal or low cervical nodes, and metastasis to these nodes indicates N3 disease. The nodal characteristics and designations did not change in the eighth edition of the IASLC lung cancer staging project. However, a recommendation is made to define nodal involvement not only by the N0 to N3 descriptors, but also by quantifying the number of involved lymph nodes. In particular, nodal quantification by the number of involved nodal stations is defined as follows: N1a: involvement of a single N1 nodal station; N1b: involvement of multiple N1 nodal stations; N2a1: involvement of a single N2 nodal station without N1 involvement (skip metastasis); N2a2: involvement of a single N2 nodal station with N1 involvement; and N2b: involvement of multiple N2 nodal stations. Prognosis worsens as the number of involved nodal stations increases, but N1b and N2a1 have the same prognosis. Asamura and colleagues24 have shown that the five-year survival rates in the population of patients who underwent complete resection for the different N subcategories were: N1a, 59%; N1b, 50%; N2a1, 54%; N2a2, 43%; and N2b, 38%. FDG-PET combined with contrast-enhanced CT is the main imaging modality used to determine the N stage. Hilar and mediastinal nodes that are suspected to be involved by cancer (>1 cm) or have positive FDG uptake are in the majority of cases sampled to confirm tumor metastasis.  Metastases (M) The eighth edition of lung cancer stating system has refined the categorization of the M descriptor. It defines two M descriptors, M0 and M1, with M1 being subcategorized to M1a, M1b, and M1c. M1a indicates endothoracic metastasis (malignant pleural/ pericardial effusion or malignant pleural/pericardial nodules or separate tumor nodule in a contralateral lobe). M1b indicates the presence of a single extrathoracic metastasis in a single organ. M1c indicates the presence of a multiple extrathoracic metastases in a single organ or in multiple organs. Remarkably, M1a and M1b tumors have similar prognosis; however, since they represent different forms of metastatic involvement and require different diagnostics and therapeutics, they were separately categorized. FDG-PET combined with contrast-enhanced CT is the main imaging modality used to determine the M stage. Brain MRI is used to identify brain metastasis. Suspected metastatic lesions may be samples in order to confirm NSCLC diagnosis or if biopsy results will alter the treatment plan. Otherwise routine sampling of metastatic lesions in not performed. Stages. The eighth edition of lung cancer stating system has refined and expanded the lung cancer stage definitions to produce a more precise tool to predict prognosis and guide treatment plan (Fig. 58.15). 

Results of Treatment for Lung Cancer The choice of initial therapy (whether single-modality or multimodality therapy) depends on the patient’s clinical stage at presentation and on his or her functional class and comorbidities. Treatment options may vary, even among different subsets of patients within the same clinical stage. Pretreatment staging is the critical step before initiating therapy. With current efforts, 5-year survival rates by pathologic stage are 90% for stage IA1, 85% for stage IA2, 80% for stage IA3, 73% for stage IB, 65% for stage IIA, 56% for stage IIB, 41% for stage IIIA, 24% for stage IIIB, and 12% for stage IIIB. The 5-year survival rates by clinical stage are 13% for

CHAPTER 58  Lung, Chest Wall, Pleura, and Mediastinum

1601

TABLE 58.3  Anatomic limits of the nodal stations of the International Association for the

Study of Lung Cancer Lymph Node Map and their grouping in nodal zones. LYMPH NODE STATION NO.

ANATOMIC LIMITS

Supraclavicular Zone 1: Low cervical, supraclavicular, and sternal • Upper border: Lower margin of cricoid cartilage notch nodes • Lower border: Clavicles bilaterally and, in the midline, the upper border of the manubrium; 1R designates right-sided nodes, and 1L designates left-sided nodes in this region • For lymph node station 1, the midline of the trachea serves as the border between 1R and 1L Upper Zone 2: Upper paratracheal nodes

3: Prevascular and retrotracheal nodes

4: Lower paratracheal nodes

Aortopulmonary Zone 5: Subaortic (aortopulmonary window)

6: Para-aortic nodes (ascending aorta or phrenic)

Subcarinal Zone 7: Subcarinal nodes

Lower Zone 8: Paraesophageal nodes (below carina)

9: Pulmonary ligament nodes

Hilar/Interlobar Zone 10: Hilar nodes

• 2R: Upper border: Apex of the right lung and pleural space and, in the midline, the upper border of the manubrium • Lower border: Intersection of caudal margin of innominate vein with the trachea • Similar to lymph node station 4R, 2R includes nodes extending to the left lateral border of the trachea • 2L: Upper border: Apex of the lung and pleural space and, in the midline, the upper border of the manubrium • Lower border: Superior border of the aortic arch • 3a: Prevascular • On the right: Upper border, apex of chest; lower border, level of carina; anterior border, posterior aspect of sternum; posterior border, anterior border of superior vena cava • On the left: Upper border, apex of chest; lower border, level of carina; anterior border, posterior aspect of sternum; posterior border, left carotid artery • 3p: Retrotracheal • Upper border, apex of chest; lower border, carina • 4R: Includes right paratracheal nodes and pretracheal nodes extending to the left lateral border of the trachea • Upper border: Intersection of caudal margin of innominate vein with the trachea • Lower border: Lower border of the azygos vein • 4L: Includes nodes to the left of the left lateral border of the trachea, medial to the ligamentum arteriosum • Upper border: Upper margin of the aortic arch • Lower border: Upper rim of the left main pulmonary artery

• Subaortic lymph nodes lateral to the ligamentum arteriosum • Upper border: The lower border of the aortic arch • Lower border: Upper rim of the left main pulmonary artery • Lymph nodes anterior and lateral to the ascending aorta and aortic arch • Upper border: A line tangential to the upper border of the aortic arch • Lower border: The lower border of the aortic arch

• Upper border: The carina of the trachea • Lower border: The upper border of the lower lobe bronchus on the left; the lower border of the bronchus intermedius on the right

• Nodes lying adjacent to the wall of the esophagus and to the right or the left of the midline, excluding subcarinal nodes • Upper border: The upper border of the lower lobe bronchus on the left; the lower border of the bronchus intermedius on the right • Lower border: The diaphragm • Nodes lying within the pulmonary ligament • Upper border: The inferior pulmonary vein • Lower border: The diaphragm

• Includes nodes immediately adjacent to the mainstem bronchus and hilar vessels, including the proximal portions of the pulmonary veins and main pulmonary artery • Upper border: The lower rim of the azygos vein in the right, upper rim of the pulmonary artery on the left • Lower border: Interlobar region bilaterally Continued

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SECTION XI  Chest

TABLE 58.3  Anatomic limits of the nodal stations of the International Association for the

Study of Lung Cancer Lymph Node Map and their grouping in nodal zones.—cont’d LYMPH NODE STATION NO.

ANATOMIC LIMITS

11: Interlobar nodes

• Between the origins of the lobar bronchi • Optional notations for subcategories of station: • 11s: Between the upper lobe bronchus and bronchus intermedius on the right • 11i: Between the middle and lower bronchi on the right

Peripheral Zone 12: Lobar nodes 13: Segmental nodes 14: Subsegmental nodes

Adjacent to the lobar bronchi Adjacent to the segmental bronchi Adjacent to the subsegmental bronchi

Adapted from: Rusch VW, Asamura H, Watanabe H, et al. The IASLC lung cancer staging project: a proposal for a new international lymph node map in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol. 2009;4:568–577.

Supraclavicular zone 1 Low cervical, supraclavicular, and sternal notch nodes 1L

1R

2R

2L

Upper zone 2R Upper paratracheal (right) 2L Upper paratracheal (left) 3a Prevascular 3p Retrotracheal 4R Lower paratracheal (right) 4L Lower paratracheal (left)

14L

4R 14R

10R

4L 10L

13R 11R 7 14R

12R 13R

8

9

6

Superior mediastinal nodes

Aorta

5 mPA

Aortic nodes AP zone 5 Subaortic 6 Para-aortic (ascending aorta or phrenic)

13L 12L 11L 12L 13L 14L

Inferior mediastinal nodes Subcarinal zone 7 Subcarinal Lower zone 8 Paraesophageal (below carina) 9 Pulmonary ligament N1 nodes Hilar/interlobar zone 10 Hilar 11 Interlobar Peripheral zone 12 Lobar 13 Segmental 14 Subsegmental

3a

3p

Vena cava Trachea Esophagus

FIG. 58.14

stage IVA and 0% for stage IVB. Treatment for lung cancer can broadly be grouped into three major categories, as follows: 1. Stage I disease and stage II disease indicate the presence of tumor that is contained within the lung and that may be completely resected with surgery. Anatomic resection of the lobe where the tumor resides with complete sampling of mediastinal lymph nodes is the treatment of choice. The key aim of this treatment approach is to achieve complete resection of the tumor and its intralobar draining lymph nodes. In certain cases, sublobar anatomic resections may be considered for small and peripheral tumors. Nonanatomic resections (wedge resection) are considered inferior to anatomic resection and should be performed only when more extensive

surgery cannot be tolerated by the patient (due to reduced pulmonary reserve for example). Stereotactic body radiation therapy (SBRT) has had good early results (local control rates of 90% at 3 years) in selected patients that cannot withstand surgical resection.25 2. Stage IV disease (metastatic disease) and stage IIIB disease (advanced disease presenting either as a relatively small tumor with N3 nodes or as a large tumors with N2 nodes) are not typically treated by surgery except in patients requiring surgical palliation. Systemic therapies for metastatic disease are common. Chemoradiation is often used in stage IIIB disease. Targeted therapies and immunotherapy are providing encouraging results in properly screened and selected patient groups.

CHAPTER 58  Lung, Chest Wall, Pleura, and Mediastinum

FIG. 58.14­—cont’d (A) The International Association for the Study of Lung Cancer (IASLC) lymph node map, including the proposed grouping of lymph node stations into “zones” for the purposes of prognostic analyses. (B) A–F: Illustrations of how the IASLC lymph node map can be applied to clinical staging by computed tomography scan in axial (A–C), coronal (D), and sagittal (E, F) views. The border between the right and left paratracheal region is shown in A and B. (From Rusch VW, Asamura H, Watanabe H, et al. The IASLC lung cancer staging project: A proposal for a new international lymph node map in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol. 2009;4:568–577.) Ao, Aorta; AV, azygos vein; Br, bronchus; IA, innominate artery; IV, innominate vein; LA, ligamentum arteriosum; LIV, left innominate vein; LSA, left subclavian artery; PA, pulmonary artery; PV, pulmonary vein; RIV, right innominate vein; SVC, superior vena cava.

1603

1604

SECTION XI  Chest patients. Some centers have had good results with resection and reconstruction of the trachea, atrium, great vessels, or other mediastinal or vertebral structures. These are complex operations requiring dedicated multidisciplinary teams during the preoperative phase and multispecialty teams in the operating room. Patients with tracheoesophageal fistula have a limited life expectancy, and palliative care with stent placement would be recommended. 

100% 80% 60% 40%

Local Therapy for Early-Stage Non–Small Cell Lung Cancer

20% 0% 0

24

48

72

Months Proposed

Events / N

MST

24 Month

60 Month

IA1 IA2 IA3 IB IIA IIB IIIA IIIB IIIC IVA IVB

68 / 781 505 / 3105 546 / 2417 560 / 1928 215 / 585 605 / 1453 2052 / 3200 1551 / 2140 831 / 986 336 / 484 328 / 398

NR NR NR NR NR 66.0 29.3 19.0 12.6 11.5 6.0

97% 94% 90% 87% 79% 72% 55% 44% 24% 23% 10%

92% 83% 77% 68% 60% 53% 36% 26% 13% 10% 0%

FIG. 58.15  Overall survival by clinical stage according to the eighth edition of the lung cancer staging project. (From Goldstraw P, Chansky K, Crowley J, et al. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2016;11:39–51.) MST, Median survival time.

3. Stage IIIA lung cancer indicates a locally advanced disease that may have a wide spectrum of presentations. Remarkably, the majority of stage IIIA tumors are too advanced for consideration of resection; however, if complete resection is deemed possible, it may be associated with improved outcomes. In this clinical scenario, surgical resection is performed as part of a multimodality treatment protocol. In particular, resectable stage IIIA tumors are either small tumors that present with a low metastatic burden to the ipsilateral mediastinal (N2) lymph nodes or larger tumors that do not involve mediastinal lymph nodes (T4N0/1M0). These tumors, by their advanced nature, may be mechanically removed with surgery; however, surgery does not consistently control the micrometastases that exist within the general area of the operation or systemically. Combinations of chemotherapy and radiotherapy, and in recent years also immunotherapy, are used for locally advanced disease either in the adjuvant or neoadjuvant settings. A multidisciplinary team of experts usually predefines the desired treatment plan in each case.26 More broadly, lung carcinoma should be resected when the local disease can be controlled, the patient’s physical condition can tolerate the planned resection and reconstruction, and the anticipated operative morbidity and mortality are reasonable. Conditions such as superior vena cava syndrome, tumor invasion across the mediastinum into the main pulmonary artery, N3 nodal metastases, malignant pleural or pericardial disease, or extrathoracic metastases carry greater risk than benefit for resection in most

Stages I and II NSCLC can be treated safely with surgery and mediastinal lymph node dissection alone, and most patients have long-term survival. Anatomic resection with lobectomy, with systematic mediastinal lymph node dissection/sampling, is the procedure of choice for lung cancer confined to one lobe (Fig. 58.16). The American College of Surgeons Oncology Group defined a systematic sampling strategy for specific mediastinal lymph nodes. At a minimum, samples of nodal (not adipose) tissue from stations 2R, 4R, 7, 8, and 9 for right-sided cancers and stations 4L, 5, 6, 7, 8, and 9 for left-sided cancers should be obtained. Mediastinal lymphadenectomy should include exploration and removal of lymph nodes from stations 2R, 4R, 7, 8, and 9 for right-sided cancers and stations 4L, 5, 6, 7, 8, and 9 for left-sided cancers. Lesser operations, such as wedge resection or segmentectomy, may be considered for patients at greater risk for lobectomy. Segmentectomy may be appropriate in patients with peripheral small tumors that have a low metabolic activity on PET-CT. A retrospective propensity matched analysis comparing segmentectomy to lobectomy in stage I lung cancer has shown that at a mean follow-up of 5.4 years, comparing segmentectomy with lobectomy, no differences were noted in locoregional (5.5% vs. 5.1%, respectively; P = 1.00), distant (14.8% vs. 11.6%, respectively; P = 0.29), or overall recurrence rates (20.2% vs. 16.7%, respectively; P = 0.30). Furthermore, when comparing segmentectomy with lobectomy, no significant differences were noted in 5-year freedom from recurrence (70% vs. 71%, respectively; P = 0.467) or 5-year survival (54% vs. 60%, respectively; P = 0.258).27 Patients with NSCLC that invades into the chest wall may undergo resection with lobectomy with en-bloc chest wall resection. SBRT is another local control modality that may be applied in patients who are medically inoperable. Radiation dose and the number of fractions are determined according to tumor location and size. In general, SBRT is well tolerated with good early results. Prospective clinical trials have shown local control and overall survival rates with SBRT to be more than 85% and about 60% at 3 years (median survival, 4 years), respectively. Novel radiation protocols use advanced technologies to better plan and direct radiation delivery to the tumor while minimizing damage to the surrounding tissues. 

Neoadjuvant and Adjuvant Therapy Advanced stage lung cancer, particularly with extensive nodal spread, cannot typically be considered a disease effectively treated with a single modality. Survival after resection may be improved in selected patients with adjuvant chemotherapy. The International Adjuvant Lung Trial enrolled 1,867 patients with completely resected stage I to III NSCLC. These patients were randomly assigned to observation or chemotherapy. Radiation therapy was at the discretion of the institution. The treatment group received one of four cisplatin-based doublet adjuvant regimens. Survival was increased 5% in the adjuvant chemotherapy group. Consequently,

CHAPTER 58  Lung, Chest Wall, Pleura, and Mediastinum

1605

SURGICAL PATHOLOGY REPORT DIAGNOSIS: 1) LYMPH NODE, 4R, EXCISION: FRAGMENTS OF LYMPH NODE, NEGATIVE FOR MALIGNANCY. 2) LYMPH NODE, 2R, EXCISION: FRAGMENTS OF LYMPH NODE, NEGATIVE FOR MALIGNANCY. 3) LYMPH NODE, PRE-CARINAL, EXCISION: FRAGMENTS OF LYMPH NODE, NEGATIVE FOR MALIGNANCY. 4) LYMPH NODE, LEVEL 4, EXCISION: FRAGMENTS OF LYMPH NODE, NEGATIVE FOR MALIGNANCY. 5) LYMPHNODE, LEVEL 2L, EXCISION: FRAGMENTS OF LYMPH NODE, NEGATIVE FOR MALIGNANCY. 6) LYMPH NODE, LEVEL 7, EXCISION: FRAGMENTS OF LYMPH NODE, NEGATIVE FOR MALIGNANCY. 7) LYMPH NODE, LEVEL 8, EXCISION: INVOLVED BY METASTATIC ADENOCARCINOMA. 8) LYMPH NODE, LEVEL 11, EXCISION: 1 LYMPH NODE, NEGATIVE FOR MALIGNANCY (0/1). 9) LYMPH NODE, LEVEL 10, EXCISION: FRAGMENTS OF LYMPH NODE, NEGATIVE FOR MALIGNANCY. 10) LUNG, LEFT LOWER LOBE, LOBECTOMY: POORLY- DIFFERENTIATED ADENOCARCINOMA, SIMILAR TO PREVIOUS (SEE S10-37167), PREDOMINANTLY SOLID TYPE, 4.9 CM IN GREATEST EXTENT, INVADING INTO VISCERAL PLEURA; RESECTION MARGINS NEGATIVE FOR MALIGNANCY; LARGE VESSEL INVASION PRESENT; CENTRIACINAR EMPHYSEMA. 11) LYMPH NODE, LEVEL 5, EXCISION: FRAGMENTS OF LYMPH NODE, NEGATIVE FOR MALIGNANCY. COMMENT: These findings correspond to AJCC 7th Edition pathologic Stage IIIA (pT2a, pN2, pM n/a). Lung Carcinoma Summary Findings Specimen type: lobectomy Laterality: left Tumor site: lower lobe Tumor size: 4.9 x 4.1 x 3.8 cm Tumor focality: unifocal Histologic type: adenocarcinoma Histologic grade: poorly-differentiated Visceral pleural invasion: present (confirmed with elastin stain) Direct extension of tumor: limited to lung and visceral pleura Venous (large vessel invasion): present Arterial (large vessel invasion): negative Lymphatic (small vessel invasion): negative Treatment effect: n/a Margins: 1.1 cm from parenchymal margin Ancillary testing: EGFR mutational analysis: yes KRAS mutational analysis: yes Other (specify): ALK Pathologic staging (pTNM): IIIA Primary tumor: pT2a Regional lymph nodes: pN2 Distant metastasis: pM n/a

FIG. 58.16  Structured pathology report after left lower lobectomy. Lung carcinoma summary findings are helpful in identifying factors critical for pathologic staging and factors that may influence subsequent survival. Ancillary testing for mutational analysis of epidermal growth factor receptor (EGFR), KRAS, and ALK is done routinely.

all patients staged IB and IIB should be considered for adjuvant chemotherapy after resection. Surgery alone for stage IIIA (N2), IIIB, or IV lung cancer is infrequently performed; however, selected patients may benefit from a multidisciplinary approach to treatment. Resection for isolated brain metastasis is warranted for improvement in symptoms, quality of life, and survival rate. The primary lung tumor can be treated according to T and N stage. Additional treatment beyond resection is needed.28 Even with complete resection, patients with resectable NSCLC have poor survival. Preoperative therapy (induction/neoadjuvant) has been evaluated: preoperative paclitaxel and carboplatin followed by surgery was compared with surgery alone in patients with stage IB to IIIA NSCLC without N2 involvement. Overall survival (62 months vs. 41 months) and progression-free (33 months vs. 20 months) survival were higher with preoperative

chemotherapy, although the differences did not reach statistical significance.29 Further, a metaanalysis of randomized clinical trials evaluating preoperative chemotherapy in resectable NSCLCs has indicated that the overall survival of NSCLC patients receiving neoadjuvant chemotherapy was significantly improved compared to those in who had surgery alone (hazard ratio [HR] 0.84; 95% CI, 0.77–0.92; P = 0.0001).30 Other studies have shown that the benefit from preoperative chemotherapy is similar to that attained with postoperative chemotherapy. These results further confirm the recognition that operable NSCLC patients with disease stage IB or higher should be considered for preoperative chemotherapy. Induction chemoradiotherapy has been evaluated for treatment of clinical stage IIIA (N2) NSCLC. In one phase III trial, concurrent chemotherapy and radiotherapy followed by resection was compared with standard concurrent chemotherapy and definitive radiotherapy without resection. The median overall survival was

1606

SECTION XI  Chest

similar in both groups (∼23 months). Progression-free survival was better in the surgery group (12.8 months median vs. 10.5 months; P = 0.017). The authors reported pneumonectomy was associated with poor outcomes. In an exploratory analysis, overall survival was improved for patients who were found to have undergone induction chemoradiotherapy and lobectomy.31 In selected patients with resectable stage IIIA NSCLC, induction chemoradiotherapy followed by resection is an alternative treatment to chemoradiotherapy alone. Patients with local extension of lung cancer at the apex of the lung into the thoracic inlet may have characteristics of shoulder and arm pain, Horner syndrome, and occasionally paresthesia in the ulnar nerve distribution of the hand (fourth and fifth fingers) (Fig. 58.17). Patients with all these characteristics may be classified as having Pancoast syndrome. Pain comes from the C8 and T1 nerve roots. Sympathetic nerve involvement may result in Horner syndrome (miosis, ptosis, anhidrosis, and enophthalmos). Typically, the first, second, and third ribs are involved and require resection, but the bony spine and intraforaminal spaces can also be involved. MRI is necessary, in addition to CT, to plan the surgical procedure. Preoperative therapy includes chemoradiotherapy. 

Treatment of Metastatic Disease Metastatic disease (stage IV NSCLC) is usually incurable. Performance and quality of life decline. Patients and families should be informed of the diagnosis and potential outcomes of treatment.

A

Treatment decisions should take into consideration the wishes of the patient and family, and realistic expectations should be set and monitored during therapy. Nevertheless, in recent years, a growing number of biologic and immunologic therapies have been approved for the treatment of advanced NSCLC. Utilization of such therapeutics and their incorporation into conventional anti NSCLC protocols (chemotherapy and radiation) has significantly expanded the therapeutic options for patients with advanced inoperable NSCLC (stages IV and IIIB). Modern NSCLC therapeutics is based on genetic and immunologic phenotyping of the tumor. Treatment is often tailored according to disease characteristics and according to the patients’ functional status. NSCLC tumors may be categorized as oncogene addicted, as highly sensitive to immunotherapy, and as tumors that are less likely to respond to either targeted or immunologic therapies (Figs. 58.18 and 58.19).32 Oncogene addicted tumors are treated with specific small molecules and antibodies that target key NSCLC driving mutations (epidermal growth factor receptor [EGFR], BRAF, ALK, ROS, and MET). Resistance to such therapies eventually develops; however, newer and more efficient second line agents are continuously being developed. To illustrate, osimertinib a novel EGFR tyrosine kinase inhibitor (TKI) had significantly greater efficacy than platinum therapy plus pemetrexed in patients with T790M-positive (a mutation conferring resistance to first line EGFR TKI) advanced NSCLC (including

B

FIG. 58.17  The patient is a 50-year-old man with a right superior sulcus tumor. Diagnostic imaging revealed a right apical mass and destruction of the posterior aspect of the second rib. Transthoracic biopsy was positive for poorly differentiated adenocarcinoma (non–small cell lung carcinoma). Endobronchial ultrasound for mediastinal staging was negative; cervical mediastinoscopy was also negative. Induction chemoradiotherapy was given with 48 Gy in 24 fractions over 1 month with chemotherapy (carboplatin AUC of 5 + pemetrexed 500 mg/m2). (A) Computed tomography (CT) scan of the chest demonstrates the mass is present in the apex of the chest with complete destruction of the posterior aspect of the right second rib and cortical erosion of the right T2 vertebral body secondary to the mass. The patient is left hand–dominant. (B) Magnetic resonance imaging of the thoracic spine demonstrates a medial right apical lung mass consistent with a Pancoast tumor involving the right lateral aspect of the T2 vertebral body, articular facet, and transverse process. There was also extension into the neural foramen and involvement of the nerve roots on the right at T1-2 and T2-3. There was no extension into the central canal or involvement of the spinal cord. CT scan of the head demonstrated no acute findings involving the brain. Complete resection was performed with a two-surgeon team, a thoracic surgeon and neurosurgeon. The patient required a right upper lobectomy with en-bloc chest wall and vertebral body resection and mediastinal lymph node dissection. Spine stabilization was required.

CHAPTER 58  Lung, Chest Wall, Pleura, and Mediastinum those with CNS metastases) in whom disease had progressed during first-line EGFR-TKI therapy (progression-free survival of (10.1 months vs. 4.4 months; HR 0.30; 95% CI, 0.23–0.41; P < 0.001). Tumors that are considered to be highly sensitive to immunotherapy are treated with immune checkpoint inhibitors that block the PD-1/PD-L1 and CTLA4/CD80/CD86 pathways. In particular, immunotherapy is effective against tumors

ERBB2/3

EGFR 27%

3%

30 days) and increased operative mortality. Surgery in the newborn period is the only realistic option for long-term survival in infants born with HLHS. Outcomes for surgical palliation of HLHS have come to be synonymous with the reputation of the treating center and surgeons. As with tricuspid atresia, patients with HLHS require a staged palliative approach. In the experiences of all centers, the first stage is the most challenging and risk-laden. The various first-stage options are described in the following sections. Neonatal Cardiac Transplantation Transplantation is a theoretically attractive option in infants with HLHS that replaces the malformed heart with a structurally

cending aorta is seen arising from a markedly hypoplastic left ventricle. The ductus arteriosus is large, providing forward flow to the systemic circuit. The right ventricle is hypertrophied, and the pulmonary artery is enlarged. (From Wernovsky G, Bove EL. Single ventricle lesions. In: Chang AC, Hanley FL, Wernovsky G, et al, eds. Pediatric cardiac intensive care. Baltimore, MD: Williams & Wilkins; 1998.)

normal one. Leonard Bailey was an influential champion of this approach and was the first to report exciting results with transplantation in newborns with HLHS.46 Furthermore, although there is an ever-present risk for rejection and infection in children with heart transplants, long-term meaningful survival is possible, and the quality of life of the recipients is good. The option of cardiac transplantation is limited by the small numbers of suitable donor hearts, and most children with HLHS are unable to survive the wait time for a donor graft. This situation has led most centers to abandon cardiac transplantation as the primary mode of therapy for most neonates with HLHS.  Norwood Reconstruction After initial work and success at Boston Children’s Hospital, Norwood and colleagues47 gained international attention at the Children’s Hospital of Philadelphia for developing and implementing a reconstructive technique to palliate newborns with HLHS; this methodology now carries the widely used eponym of the Norwood procedure. This procedure was gradually refined as experience accrued. The most common method involves surgical connection of the divided main pulmonary artery to the reconstructed aortic arch. In almost all children with HLHS, there is associated aortic arch hypoplasia with coarctation. A critical feature of the operation is to reconstruct the aortic arch to provide unrestricted systemic blood flow. Most surgeons use some form of prosthetic material, usually pulmonary artery homograft patching. Some surgeons have reported accomplishing the arch reconstruction without the necessity of additional material. After reconstructing the aortic arch, the divided main pulmonary artery is anastomosed to the arch and small ascending aorta to create a neoaortic confluence providing systemic output from the right ventricle. The challenging feature of the reconstruction involves the accurate connection of this often-miniscule ascending aorta to the confluence of the arch and main pulmonary artery stump.

1670

SECTION XI  Chest

Aorta Main pulmonary artery

C A

B FIG. 59.41  Norwood procedure for first-stage palliation of hypoplastic left heart syndrome. (A), The main pulmonary artery is divided proximal to the bifurcation, the ductus arteriosus is ligated and divided, and the aortic arch is opened from the level of the transected main pulmonary artery to a point distal to the ductal insertion in the descending aorta. (B) A segment of homograft is cut to an appropriate size and shape. This is sutured into place, creating an unobstructed outflow from the right ventricle to the pulmonary artery and aorta. (C) Polytetrafluoroethylene tube graft is placed from the innominate artery to the right pulmonary artery. The atrial septectomy is done while the patient is under circulatory arrest. (From Castaneda AR, Jonas RA, Mayer JE, et al. Hypoplastic left heart syndrome. In: Cardiac surgery of the neonate and infant. Philadelphia, PA: Saunders; 1994.)

The risk for torsion and coronary insufficiency is high. The final element of the classic Norwood reconstruction is the creation of a controlled source of pulmonary blood flow in the form of a modified BT shunt (Fig. 59.41).  Sano Modification of the Norwood Operation Achieving survival after the Norwood operation is challenging, involving innumerable technical and medical details. At best, after a Norwood procedure, the patient is fragile, with a delicate balance between systemic and pulmonary blood flow. This fact and the observation of widely disparate outcomes for the procedure have led to many important advances in the treatment of these children. One issue relates to the difficulty of balancing the systemic to pulmonary artery shunt, which lowers diastolic blood pressure (and coronary perfusion pressure) and volume loads the heart. Sano and associates48 from Okayama University in Japan were the first to report a series of infants undergoing a successful Norwood procedure with the modification of a right ventricle–pulmonary artery conduit rather than a Blalock shunt. The theoretical advantage of this approach is the increase in diastolic pressure, creating a physiology more similar to a banded circulation rather than shunted circulation. Early reports with this method were encouraging, although patients appeared to become more rapidly desaturated as they aged compared with the shunted patients. The long-term effects of the right ventriculotomy on cardiac function are unknown. In one report, patients undergoing the Norwood operation were randomly assigned to receive a right ventricle-to-pulmonary artery shunt or modified BT shunt. Transplantation-free survival was higher 12 months after randomization in the right ventricle-to-pulmonary artery shunt group, as was the rate of unplanned reinterventions and complications.49

More recent updates on the same cohort revealed no difference in transplant-free survival at 6 years after randomization between the right ventricle to pulmonary artery shunt group and the modified BT shunt group. However, the right ventricle to pulmonary artery group did have a greater number of catheter-based interventions.50  Hybrid Procedure The notion of a combined therapy between interventional cardiology and surgery for the first-stage palliation of HLHS has achieved significant attention. The idea is to minimize the risk of the first operation by banding the branch pulmonary arteries and delivering a stent into the ductus to maintain patency. This hybrid arrangement is designed to allow newborn survival so that a more complete reconstruction may be performed later in infancy in a larger child. There appears to be a significant learning curve with this approach, as with any new procedure, and the incidence of complications warrants further study. Data have shown that the prevalence of necrotizing enterocolitis after the hybrid procedure is significant and comparable to reports after the Norwood procedure.51 A recent meta analysis revealed increased early mortality and worse 1-year transplant-free survival in patients undergoing the hybrid procedure compared to the Norwood. However, it is noted that the hybrid procedure was preferentially utilized in higher risk patients thus making it difficult to draw firm conclusions.52 In addition, concerning features include the effect of the banding on long-term pulmonary artery growth, the fact that cardiac perfusion is still retrograde through the aortic arch, and the risk profile of the more extensive reconstruction later in life. The true place for this mode of therapy is unclear at the present time, but it represents an important direction of advancement to optimize the opportunity of survival for these children. 

CHAPTER 59  Congenital Heart Disease Fontan Operation The long-term goal of single-ventricle palliation is to optimize ventricular function and promote systemic oxygen delivery. As noted earlier, patients with a single ventricle who are shunted or banded have ongoing concerns, including systemic desaturation, continued intracardiac mixing, and chronic cardiac volume overload. The current strategy for addressing these concerns uses a direct connection between the branch pulmonary arteries and systemic venous return, as initially proposed by Fontan in the early 1970s. The Fontan operation is now the treatment of choice for children born with all varieties of single ventricle and provides acceptable long-term palliation in suitable patients. However, the Fontan circulation is not normal and even in the best of circumstances results in significant alteration in normal cardiorespiratory physiology. The Fontan circulation is established by connecting the systemic venous return directly into isolated branch pulmonary arteries without an intervening power source. Thus, blood flow in the Fontan circuit is passive, being promoted only by the pressure differential between the systemic venous system and pulmonary venous atrium. An impediment to flow in the systemic-to-pulmonary pathway results in a poor Fontan outcome. Established criteria for creating an effective Fontan circulation include the ability to connect the systemic venous return surgically to the pulmonary arteries in an unobstructed manner, normal pulmonary artery architecture and resistance, normal pulmonary venous drainage and low left atrial pressure, absence of significant A-V valve regurgitation, good ventricular function (and low ventricular end-diastolic pressure), an unobstructed systemic arterial outlet, and good aortic valve function. Compromise of any of these elements may compromise the quality of the Fontan circulation. The Fontan operation has undergone several technical modifications in the almost 40 years of successful application to patients with single-ventricle physiology. Many patients underwent an atriopulmonary connection in which the open right atrial appendage was directly anastomosed to the pulmonary artery bifurcation with surgical closure of the ASD. Many of these patients present as adults with extreme dilation of the right atrium, with resulting sluggish flow, hepatic congestion, and atrial dysrhythmias (Fig. 59.42). Today, the most widely practiced modification of the Fontan operation is the total cavopulmonary connection. First described by DeLeval, this operation involves connection of the divided SVC to the superior and inferior aspects of the right pulmonary artery (typically offset), along with the creation of a channel to direct the IVC flow into the pulmonary arteries. The channel may be created using a surgically created lateral tunnel in the right atrium (Fig. 59.43) or interposing a conduit between the IVC and pulmonary arteries (extracardiac Fontan) (Fig. 59.44). The change from a volume-loaded circulation in patients with a single ventricle who are shunted or banded to a Fontan circulation results in acute volume unloading of the systemic ventricle. In the chronic overloaded heart, this acute change may be poorly tolerated, with resultant diastolic dysfunction and decreased ventricular compliance. To deal with this problem, patients with a single ventricle typically undergo an intervening stage of palliation in the form of a bidirectional, superior cavopulmonary anastomosis (Glenn shunt). The bidirectional Glenn shunt is constructed by anastomosing the cephalad end of the divided SVC to the superior aspect of the right pulmonary artery (Fig. 59.45). Other sources of pulmonary blood flow are typically eliminated, and the heart is volume-unloaded; however, systemic cardiac output is maintained because the IVC return is preserved. After the Glenn shunt, the

1671

FIG. 59.42  Angiogram of a dilated right atrium in a patient with an atriopulmonary Fontan connection.

patients are not fully saturated; typically, patients have saturations of approximately 80%. Over time, the unloaded ventricle remodels, and the patient is promoted to reoperation and completion of the Fontan circulation. Perioperative care of a patient after a Fontan procedure can be challenging. The acute changes in cardiac volume loading may negatively affect cardiac output. Even in patients with supposedly ideal Fontan connections, the central venous pressure acutely increases to 12 to 15 mm Hg. Consequences of this increased venous pressure include pleural effusions, hepatic congestion, and ascites. In marginal Fontan candidates, some surgeons routinely place an intentional leak, or fenestration; the goal here is to preserve systemic ventricular volume loading and decrease systemic venous congestion at the expense of some degree of desaturation caused by the right-to-left shunting. The practice of routine fenestration after the Fontan operation has been examined, and some early data have shown that excellent outcomes can be achieved with highly selective application of a fenestration, which mitigates the risks associated with such a procedure, including hypoxia and systemic embolism.53 Any impediment to passive pulmonary blood flow will inhibit Fontan flow and result in right heart failure. Positive pressure ventilation, especially elevated levels of positive end-expiratory pressure, impedes pulmonary blood flow in the Fontan patient. Conversely, early extubation and effective spontaneous ventilation will improve pulmonary blood flow in the Fontan patient. Data have suggested that early extubation in the operating room for patients after the Fontan procedure improves hemodynamics, decreases the length of stay for patients, and decreases hospital costs. The chronic complications of living with a Fontan circulation are still unfolding and include chronic hepatic congestion and cirrhosis, protein-losing enteropathy, atrial dysrhythmias, and venous stasis disease. Management of patients with failing Fontan circulations is especially challenging. These patients are at high risk for severe cardiac compromise while undergoing general anesthesia with positive pressure ventilation or any procedure

1672

SECTION XI  Chest

SVC Ao RPA PA PA

Ao ASD

RPA

Incisions

SVC

RA

Conduit RAA

A IVC

A Graft

B

PA

FIG. 59.44  (A) Extracardiac Fontan procedure. (B) Creation of a fenestraAo ASD SVC Baffle

IVC

B FIG. 59.43  (A) and (B), Lateral tunnel Fontan procedure. (Adapted from Lok JM, Spevak PJ, Nichols DG. Tricuspid atresia. In: Nichols DG, Ungerleider RM, Spevak PJ, et al, eds. Critical heart disease in infants and children. Philadelphia, PA: Mosby; 2006:813.) Ao, Aorta; ASD, atrial septal defect; IVC, inferior vena cava; PA, pulmonary artery; RA, right atrium; RPA, right pulmonary artery; SVC, superior vena cava.

involving large fluid shifts, including abdominal surgery. Patients with chronic hepatic congestion may develop a coagulopathy related to a decrease in factor production. 

MISCELLANEOUS ANOMALIES Vascular Rings and Pulmonary Artery Slings

Vascular Rings Vascular rings are abnormalities of the aortic arch and its branches, compressing the trachea, esophagus, or both. The ring may be complete or partial. Categorization of the defects is useful for description: • Complete vascular rings • Double arch: Equal arches or left or right arch dominant (Fig. 59.46) • Right arch: Left ligamentum arteriosus from anomalous left subclavian artery

tion in an extracardiac Fontan procedure using a graft between the extracardiac conduit and right atrial appendage (RAA). (Adapted from Lok JM, Spevak PJ, Nichols DG. Tricuspid atresia. In: Nichols DG, Ungerleider RM, Spevak PJ, et al, eds. Critical heart disease in infants and children. Philadelphia, PA: Mosby; 2006:814.) Ao, Aorta; IVC, inferior vena cava; PA, pulmonary artery; RPA, right pulmonary artery; SVC, superior vena cava.

• R  ight arch: Mirror image branching, with left ligamentum from descending aorta • Partial vascular rings • Left arch: Aberrant right subclavian artery • Left arch: Innominate artery compression The double aortic arch is the most common form of complete ring. Two arches arise from the ascending aorta, forming a true ring. The left arch is usually smaller. The right arch–left ligamentum complex is formed from persistence of the right fourth arch and regression of the left fourth arch. The anomalously arising left subclavian artery is often associated with a diverticulum at its base (Kommerell diverticulum). In partial rings, the most common form is an aberrant right subclavian artery arising distal to the left subclavian artery with a left arch. The right subclavian artery passes behind the esophagus from left to right. Innominate artery compression arises from a more posterior and leftward origin of the innominate artery from a left arch, leading to anterior compression of the trachea.  Pulmonary Artery Slings A pulmonary artery sling occurs when the left pulmonary artery arises from the right pulmonary artery, passing leftward between the trachea and the esophagus. The ligamentum arteriosum attachment from the main pulmonary artery to the undersurface of the aorta forms a vascular ring around the trachea but not the esophagus. The trachea may be compressed, the cartilage may be soft, or there may be intrinsic stenosis of the trachea in the form of complete cartilage rings. 

CHAPTER 59  Congenital Heart Disease

1673

ANTERIOR SVC

Ligamentum arteriosum

LSA Ao

Az

LPA

MPA

LCC

RPA

Esophagus PA

Trachea Ascending aorta

RSA RCC

RPA

A POSTERIOR IVC

RPA RA

FIG. 59.45  Bidirectional Glenn shunt. (Adapted from Lok JM, Spevak PJ,

RSA

Nichols DG. Tricuspid atresia. In: Nichols DG, Ungerleider RM, Spevak PJ, et al, eds. Critical heart disease in infants and children. Philadelphia, PA: Mosby; 2006:809.) Ao, Aorta; Az, azygos vein; IVC, inferior vena cava; PA, pulmonary artery; RPA, right pulmonary artery; SVC, superior vena cava.

Diagnosis and Indications for Intervention Symptoms reflect the degree of tracheal and esophageal compression from complete rings as well as the presence of coexistent tracheomalacia or stenosis. Upper respiratory symptoms predominate, with a characteristic brassy cough, recurrent respiratory infections, failure to thrive, and sometimes esophageal motility problems. In children, documentation of a ring is an indication for surgery. Older patients are often asymptomatic. Initially, the diagnosis is based on a high index of suspicion, and barium swallow is the first investigation. Echocardiography can document an abnormal head and neck vessel branching pattern, excluding intracardiac abnormalities. MRI provides complete anatomic detail.  Surgery Most vascular rings are accessible through a left posterolateral thoracotomy; the exception is a left arch with right-sided ligamentum. Division of the ring and, in the case of double arch, preservation of the dominant arch is performed. Preservation of the recurrent laryngeal nerve is important. Initial experience with endoscopic robotically assisted repair of vascular rings has also been reported. Pulmonary artery slings are approached through the midline; the use of cardiopulmonary bypass facilitates tracheal reconstruction and relocation of the right pulmonary artery (Fig. 59.47). Repair can be achieved with low risk. Symptoms may take months to resolve, with slow resolution of the underlying tracheomalacia. 

Coronary Artery Anomalies Anomalies occur as a result of anomalous origin, termination, courses, and aneurysm formation. Of these variables, only an anomalous left coronary artery rising from the pulmonary artery (ALCAPA) and coronary artery fistulas are discussed here.

SVC

IVC

RCC Trachea Esophagus

LCC LSA

Lig. arteriosum

B FIG. 59.46  Double aortic arch, anterior (A) and posterior (B) views. (Adapted from Jonas RA. Comprehensive surgical management of congenital heart disease. New York, NY: Oxford University Press; 2004:499.) IVC, Inferior vena cava; LCC, left common carotid artery; Lig., ligamentum; LPA, left pulmonary artery; LSA, left subclavian artery; MPA, main pulmonary artery; RA, right atrium; RCC, right common carotid artery; RPA, right pulmonary artery; RSA, right subclavian artery; SVC, superior vena cava.

Anomalous Left Coronary Artery Rising From the Pulmonary Artery An ALCAPA is a rare, often lethal lesion in early infancy. Untreated, the mortality rate approaches 90%. Anatomy and pathophysiology. Developmentally, failure of the normal connection of the left coronary artery bud to the aorta results in an abnormal connection to the pulmonary artery. The abnormal origin can be situated in the main pulmonary artery or proximal branches. Associated abnormalities are rare but important to recognize because lowering of the pulmonary artery pressure by PDA ligation or closure of a VSD can be fatal if the ALCAPA is not noted. In utero, with equal pulmonary arterial and aortic pressures, satisfactory perfusion of the ALCAPA can

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SECTION XI  Chest

B

Stenotic portion excised

A

C Tracheal anastomosis

FIG. 59.47  Method for the management of a pulmonary artery sling with associated tracheal stenosis, using cardiopulmonary bypass. (A) Tracheal resection of the involved segment. (B) Anterior translocation of the left pulmonary artery after transection of the trachea. (C) Direct anastomosis of the trachea. (From Castaneda AR, Jonas RA, Mayer JE, et al. Vascular rings, slings, and tracheal anomalies. In: Cardiac surgery of the neonate and infant. Philadelphia, PA: Saunders; 1994.)

occur. After birth, the pulmonary artery pressure falls, and left coronary artery perfusion decreases. Ischemia causes impaired ventricular function and myocardial infarcts and leads to left ventricular dilation. Papillary muscle dysfunction causes mitral regurgitation. Early coronary collateral development may prevent ongoing infarction.  Diagnosis and indications for intervention. ALCAPA is suspected in any infant with mitral regurgitation, ventricular dysfunction, or dilated cardiomyopathy. Infants present with low cardiac output and systemic heart failure. Feeding may also precipitate sudden death and angina in infants. Sudden death has been described in older children. The ECG may reflect ischemic changes. The echocardiogram is usually diagnostic. However, because this diagnosis is often confused with dilated cardiomyopathy, there is an argument in favor of catheterizing all patients with dilated cardiomyopathy in whom the coronary artery anatomy cannot be clearly defined on echocardiography. Secondary findings of dilated cardiac chambers and segmental wall motion abnormalities together with mitral regurgitation prompt a search for an ALCAPA. Diagnosis of an ALCAPA is an indication for intervention.  Surgery. A degree of ventricular dysfunction is usually present. Preoperative inotropic support and optimization of hemodynamics may be required before surgical intervention. Severe cardiomyopathy rarely may necessitate cardiac transplantation. Current experience indicates that creation of a dual coronary system is safe and reproducible and offers the best opportunity for recovery of function. Operative considerations include optimal myocardial protection and prevention of left heart distention. Direct reimplantation of the ALCAPA into the ascending aorta is the procedure of choice (Fig. 59.48). Sometimes, limited mobility of the

B PA

C

AO

A

FIG. 59.48  Direct reimplantation of anomalous left coronary artery rising from the pulmonary artery (ALCAPA). (A) Excision of ALCAPA from the pulmonary artery (PA). (B) Aortic reimplantation of the coronary ostium into the aorta. (C) Reconstruction of the PA with autologous pericardium. (From Vouhe PR, Tamisier D, Sidi D, et al. Anomalous left coronary artery from the pulmonary artery: Results of isolated aortic reimplantation. Ann Thorac Surg. 1992;54:621–626.) AO, Aorta.

coronary artery precludes reimplantation, and a surgically created aorta–pulmonary artery–coronary artery tunnel is created; this is known as the Takeuchi procedure. Ligation of the ALCAPA is not recommended. Postoperative management is directed toward maintaining adequate coronary perfusion and cardiac output. Mechanical

CHAPTER 59  Congenital Heart Disease support of the heart may be temporarily required. Mitral regurgitation usually improves, and valve replacement is rarely necessary. Current intervention has a low operative mortality. Risks for nonsurvival relate to preoperative ventricular dysfunction and cardiogenic shock. The Takeuchi repair is associated with tunnel complications such as obstruction, leak, aortic valve damage, and RVOTO in the long-term.  Coronary Arteriovenous Fistula and Aneurysms Isolated coronary artery fistula is more rare than ALCAPA. Drainage of coronary artery fistula is reported to terminate more commonly in the right side of the heart or pulmonary artery than in the left side of the heart. A shunt from the high-pressure coronary artery system into a low-pressure cardiac chamber may result in coronary steal and some degree of cardiac volume overload. Coronary artery aneurysms are associated with Kawasaki disease. Diagnosis and indications for intervention. Presentation depends on the amount of functional compromise produced by the ischemia and volume overload. Echocardiography may be able to delineate the anomaly, but coronary angiography is diagnostic. Details of coronary anatomy are essential for determining intervention. Interventional catheterization is useful for the obliteration of fistulas and terminal aneurysms.  Surgery. If the lesion is not amenable to transcatheter intervention, surgery is indicated. Options include suture ligation without bypass, cardiopulmonary bypass, and aneurysmectomy with closure of the fistula. Early and late mortality rates are low. Risk factors for death and ventricular dysfunction relate to coronary artery insufficiency and infarction after fistula ligation or aneurysmectomy.54 

Ebstein Anomaly of the Tricuspid Valve Ebstein anomaly of the tricuspid valve is a rare defect in which the tricuspid valve attachments are displaced into the right ventricle to varying degrees. Ebstein anomaly includes a spectrum of abnormalities involving a degree of displacement of the tricuspid valve, variable right ventricular size, and variable pulmonary outflow obstruction. Associated abnormalities are ASD, pulmonary atresia, and ccTGA. The posterior and septal leaflets of the tricuspid valve are variably displaced to the apex of the right ventricle, which results in an atrialized portion of the right ventricle. The anterior leaflet remains large and sail-like. The major hemodynamic issue is tricuspid incompetence with decreased pulmonary blood flow and, if an ASD is present, right-to-left shunting causing cyanosis. Long-standing tricuspid incompetence leads to volume overload of an abnormal right ventricle. Variable pulmonary outflow tract obstruction limits effective pulmonary blood flow. If adequate pulmonary blood flow requires continued ductal patency, the need for neonatal intervention is almost certain. Diagnosis and Intervention The more severe forms of Ebstein anomaly manifest with cyanosis in infancy. Critically ill neonates tend to have a severe form of the disease, with a grossly inefficient right ventricle compounded by the high pulmonary resistance of the neonate or by pulmonary valve atresia. The mortality rate in this group is high. Older patients present in heart failure and may have cyanosis. Supraventricular dysrhythmias and the preexcitation syndrome (WolffParkinson-White syndrome) are associated with Ebstein anomaly. Echocardiography is diagnostic. Critically ill neonates have poor survival rates, and surgery is indicated only after stabilization with PGE1 and controlled ventilation. In older patients, cyanosis and

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Anterior leaflet

A

Plication of atrialized chamber

B

FIG. 59.49  Repair of Ebstein malformation using the Carpentier method. (A) The anterior and posterior leaflets of the tricuspid valve are detached from the annulus. (B) The atrium is plicated, reducing the annular diameter. The detached leaflets are reattached to the annulus. (From Castaneda AR, Jonas RA, Mayer JE, et al. Ebstein’s anomaly. In: Cardiac surgery of the neonate and infant. Philadelphia, PA: Saunders; 1994.)

heart failure are indications to intervene, although earlier intervention in asymptomatic patients, before excessive right ventricular dilation, is being more actively pursued.  Surgery In critically ill neonates, after stabilization, palliation with a systemic-to-pulmonary artery shunt may be required. The Starnes operation has allowed salvage in previously hopeless cases. This operation consists of patch closure of the tricuspid orifice, atrial septectomy, and a systemic-to-pulmonary artery shunt.55 In patients with less severe forms of this disease, tricuspid valve repair or replacement is also an option. Surgical techniques for the treatment of Ebstein anomaly have been evolving, and outcomes are improving for this challenging group of patients (Fig. 59.49).56 

Mitral Valve Anomalies Most abnormalities of the mitral valve are associated with other complex lesions (e.g., Shone complex). More commonly, mitral disease in children is inflammatory in nature—that is, rheumatic disease or infective endocarditis. It may also be associated with collagen vascular disease and Marfan syndrome. Mitral Stenosis Mitral stenosis is caused by obstruction at a supravalvular, valvular, or subvalvular level, singly or in combination. Supravalvular stenosis is caused by a ring of fibrous tissue above the annulus of the mitral valve or attached to the proximal leaflets. Valvular stenosis involves the leaflets, with commissural fusion occurring with or without hypoplasia of the valve ring. Hypoplasia of the mitral valve is often associated with left ventricular hypoplasia. Frequently, the leaflets and subvalvular apparatus are also dysplastic. Fusion of the leaflets can lead to an accessory orifice and produce mitral stenosis at a purely valvular level (so-called doubleorifice mitral valve). Three types of subvalvular stenosis have been recognized—parachute mitral valve, hammock valve, and absence of one or both papillary muscles. Mitral regurgitation is a result of secondary annular dilation, congenital isolated clefts of the valve, and prolapse of the leaflets from abnormal chordae or papillary muscle insertion.

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Echocardiography is diagnostic. Intervention includes balloon valvuloplasty, particularly for selected forms of rheumatic mitral stenosis, and surgical intervention. Intervention is timed to avoid irreversible sequelae related to chronic volume overload or pulmonary hypertension. Surgical intervention is aimed at preserving the mitral valve, and valvuloplasty techniques have a valuable place in children. Prosthetic valves are the least desirable option. Bioprosthetic or tissue valves need to be avoided in children. Supraannular placement of the prosthesis may be necessary. Repeat placement is ensured. 

SUMMARY This chapter provides a basic overview of the major congenital cardiac lesions and a framework for the diagnosis and treatment of these conditions. For most patients, the diagnosis of CHD, whether surgically treated or not, carries lifelong implications. For patients with CHD presenting for noncardiac surgery, a thorough understanding of the patient’s unique anatomy and physiology is mandatory when planning a rational management strategy. The reader is directed to several excellent texts on CHD for a more thorough review of each of the lesions reviewed in this chapter.

SELECTED REFERENCES Bailey LL, Nehlsen-Cannarella SL, Doroshow RW, et al. Cardiac allotransplantation in newborns as therapy for hypoplastic left heart syndrome. N Engl J Med. 1986;315:949–951. This classic reference describes the first report of cardiac transplantation in newborns with hypoplastic left heart syndrome (HLHS). Although limited in its applicability because of limited donor organs, neonatal cardiac transplantation has provided children born with HLHS a new option for survival.

Blalock A, Taussig HB. The surgical treatment of malformations of the heart in which there is pulmonary stenosis or pulmonary atresia. JAMA. 1945;128:189–202. This landmark article describes the surgical procedure that initiated the era of elective cardiac surgery. The study reported the initial experience with palliative surgical treatment of patients with pulmonary stenosis or pulmonary atresia using the Blalock-Taussig shunt.

Fontan F, Baudet E. Surgical repair of tricuspid atresia. Thorax. 1971;26:240–248. This article represents a milestone in the evolution of surgical management of patients with single-ventricle physiology. It described the first corrective operation for patients with tricuspid atresia. Although previous palliative procedures, provided by various systemic-to-pulmonary artery shunts, improved the clinical condition of patients, systemic blood was still a mixture of oxygenated and deoxygenated blood. The Fontan operation redirected superior and inferior vena cava blood flow to the lungs so that only oxygenated blood returned to the heart and subsequently to the systemic circulation.

Kirklin JW, Dushane JW, Patrick RT, et al. Intracardiac surgery with the aid of a mechanical pump-oxygenator system (gibbon type): report of eight cases. Mayo Clin Proc. 1955;30:201–206. This landmark article demonstrated that open repairs of congenital cardiac defects using mechanical pump oxygenator systems could be performed with minimal risk to patients.

Mustard W. Successful two-stage correction of transposition of the great vessels. Surgery. 1964;55:469–472. This classic reference describes one of the initial surgical approaches to the treatment of transposition of the great arteries (d-TGA). Although the arterial switch operation is now the surgical treatment of choice for d-TGA, there are many adult patients with congenital heart disease who have been palliated with the Mustard operation. Understanding the operation and resulting physiology is critical to general surgery management strategies for noncardiac operations.

Norwood WI, Lang P, Casteneda AR, et al. Experience with operations for hypoplastic left heart syndrome. J Thorac Cardiovasc Surg. 1981;82:511–519. In this landmark article, Norwood and colleagues reported the outcomes of what was then a new reconstructive surgical technique to palliate newborns with hypoplastic left heart syndrome (HLHS). Until the Norwood operation, the only option for survival of patients with HLHS was cardiac transplantation. At most centers today, the Norwood operation is the primary mode of therapy for most neonates with HLHS.

Sano S, Ishino K, Kawada M, et  al. Right ventricle-pulmonary artery shunt in first-stage palliation of hypoplastic left heart syndrome. J Thorac Cardiovasc Surg. 2003;126:504–509. This classic reference describes the right ventricle–to–pulmonary artery conduit used in the Norwood procedure. This novel procedure, named after the author, Sano, allowed for more hemodynamic stability postoperatively from the Norwood procedure and improved intrastage survival.

Senning A. Surgical correction of transposition of the great vessels. Surgery. 1959;45:966–980. This classic reference describes the initial surgical approach to management of transposition of the great arteries (d-TGA). Although the arterial switch operation is currently the surgical treatment of choice for d-TGA, there are many adult patients with congenital heart disease in the community who have had the Senning operation. Understanding the operation and resulting physiology is critical to general surgery management strategies for noncardiac operations.

Starnes VA, Pitlick PT, Bernstein D, et  al. Ebstein’s anomaly appearing in the neonate. A new surgical approach. J Thorac Cardiovasc Surg. 1991;101:1082–1087.

CHAPTER 59  Congenital Heart Disease This classic reference describes the first report of a new surgical approach to Ebstein anomaly in neonates. The procedure was named after the surgeon, Starnes. This approach has provided children born with severe Ebstein anomaly a new option for survival.

Ungerleider RM, Meliones JN, McMillian KN, et  al. Critical Heart Disease in Infants and Children. 3rd ed. Philadelphia, PA: Elsevier; 2019. This text provides a comprehensive and current review of heart disease in infants and children. It contains numerous surgical drawings and diagnostic images to supplement the didactic material.

Warden HE, Cohen M, Read RC, et al. Controlled cross circulation for open intracardiac surgery: physiologic studies and results of creation and closure of ventricular septal defects. J Thorac Surg. 1954;28:331–341. This landmark article described the technique of cross-circulation to facilitate cardiopulmonary bypass and intracardiac repair of congenital heart lesions. Warden and colleagues documented the successful use of cross-circulation to correct defects such as ventricular septal defect.

Wilcox B, Cook A, Anderson R. Surgical Anatomy of the Heart. 3rd ed. Cambridge, UK: Cambridge University Press; 2004. This text provides an excellent reference manual for understanding the complex anatomy of the heart. It contains color photographs and diagrams and is an invaluable resource for any student of cardiac surgery.

REFERENCES 1. Blalock A, Taussig HB. The surgical treatment of malformations of the heart in which there is pulmonary stenosis or pulmonary atresia. J Am Med Assoc. 1945;128:189–202. 2. Warden HE, Cohen M, Read RC, et al. Controlled cross circulation for open intracardiac surgery: physiologic studies and results of creation and closure of ventricular septal defects. J Thorac Surg. 1954;28:331–341; discussion, 341–333. 3. Kirklin JW, Dushane JW, Patrick RT, et al. Intracardiac surgery with the aid of a mechanical pump-oxygenator system (gibbon type): report of eight cases. Proc Staff Meet Mayo Clin. 1955;30:201–206. 4. Marelli A, Gilboa S, Devine O, et al. Estimating the congenital heart disease population in the United States in 2010—what are the numbers? J Am Coll Cardiol. 2012;59; E787–E787. 5. Marelli AJ, Ionescu-Ittu R, Mackie AS, et al. Lifetime prevalence of congenital heart disease in the general population from 2000 to 2010. Circulation. 2014;130:749–756. 6. Levey A, Glickstein JS, Kleinman CS, et  al. The impact of prenatal diagnosis of complex congenital heart disease on neonatal outcomes. Pediatr Cardiol. 2010;31:587–597.

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7. Morris SA, Ethen MK, Penny DJ, et al. Prenatal diagnosis, birth location, surgical center, and neonatal mortality in infants with hypoplastic left heart syndrome. Circulation. 2014;129:285–292. 8. American Board of Thoracic Surgery. American Board of Thoracic Surgery. https://www.abts.org. Retrieved September 26, 2019. 9. Mullins CE. Cardiac Catheterization in Congenital Heart Disease: Pediatric and Adult. Malden, MA: Blackwell Futura; 2006. 10. American Board of Internal Medicine www.abim.org. American Board of Internal Medicine. Retrieved September 26, 2019. 11.  Accreditation Council for Graduate Medical Education (ACGME). Congenital Cardiac Surgery Programs. https://a pps.acgme.org/ads/Public/Reports/ReportRun. Retrieved September 24, 2019. 12. Wilcox BR, Cook AC, Anderson RH. Surgical Anatomy of the Heart. 3rd ed. Cambridge, MA: Cambridge University Press; 2004. 13. Morin RL, Gerber TC, McCollough CH. Radiation dose in computed tomography of the heart. Circulation. 2003;107:917–922. 14. Andropoulos DB, Stayer SA, Russell IA, et  al. Anesthesia for Congenital Heart Disease. 2nd ed. Hoboken, NJ: WileyBlackwell; 2010. 15. Kintrup S, Malec E, Kiski D, et al. Extubation in the operating room after fontan procedure: does it make a difference? Pediatr Cardiol. 2019;40:468–476. 16. Licht DJ, Shera DM, Clancy RR, et  al. Brain maturation is delayed in infants with complex congenital heart defects. J Thorac Cardiovasc Surg. 2009;137:529–536; discussion 536–527. 17. Noonan PM, Desai T, Degiovanni JV. Closure of an aortopulmonary window using the amplatzer duct occluder II. Pediatr Cardiol. 2013;34:712–714. 18. Hopkins RA, Bert AA, Buchholz B, et al. Surgical patch closure of atrial septal defects. Ann Thorac Surg. 2004;77:2144– 2149; author reply 2149–2150. 19. Vida VL, Zanotto L, Tessari C, et al. Minimally invasive surgery for atrial septal defects: a 20-year experience at a single centre. Interact Cardiovasc Thorac Surg. 2019;28:961–967. 20. Farooqi M, Stickley J, Dhillon R, et al. Trends in surgical and catheter interventions for isolated congenital shunt lesions in the UK and Ireland. Heart. 2019;105:1103–1108. 21. Knepp MD, Rocchini AP, Lloyd TR, et al. Long-term follow up of secundum atrial septal defect closure with the amplatzer septal occluder. Congenit Heart Dis. 2010;5:32–37. 22. Clark JB, Chowdhury D, Pauliks LB, et  al. Resolution of heart block after surgical removal of an amplatzer device. Ann Thorac Surg. 2010;89:1631–1633. 23. Piatkowski R, Kochanowski J, Scislo P, et al. Dislocation of amplatzer septal occluder device after closure of secundum atrial septal defect. J Am Soc Echocardiogr. 2010;23:1007. e1001–e1002. 24. Slesnick TC, Nugent AW, Fraser Jr CD, et al. Images in cardiovascular medicine. incomplete endothelialization and late development of acute bacterial endocarditis after implantation of an amplatzer septal occluder device. Circulation. 2008;117:e326–e327. 25. Neill CA, Ferencz C, Sabiston DC, et al. The familial occurrence of hypoplastic right lung with systemic arterial supply and venous drainage “scimitar syndrome”. Bull Johns Hopkins Hosp. 1960;107:1–21. 26. Balzer D. Current status of percutaneous closure of ventricular septal defects. pediatr therapeut. Pediatr Therapeut. 2012;2:1000112.

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27. Rastelli GC, Weidman WH, Kirklin JW. Surgical repair of the partial form of persistent common atrioventricular canal, with special reference to the problem of mitral valve incompetence. Circulation. 1965;31:31–35. 28. Bakhtiary F, Takacs J, Cho MY, et al. Long-term results after repair of complete atrioventricular septal defect with twopatch technique. Ann Thorac Surg. 2010;89:1239–1243. 29. Beckerman Z, De Leon LE, Zea-Vera R, et al. High incidence of late infective endocarditis in bovine jugular vein valved conduits. J Thorac Cardiovasc Surg. 2018;156:728–734. e722. 30. Chen JM, Glickstein JS, Davies RR, et  al. The effect of repair technique on postoperative right-sided obstruction in patients with truncus arteriosus. J Thorac Cardiovasc Surg. 2005;129:559–568. 31. Balasubramanian S, Marshall AC, Gauvreau K, et  al. Outcomes after stent implantation for the treatment of congenital and postoperative pulmonary vein stenosis in children. Circ Cardiovasc Interv. 2012;5:109–117. 32. Morales DL, Zafar F, Heinle JS, et al. Right ventricular infundibulum sparing (RVIS) tetralogy of fallot repair: a review of over 300 patients. Ann Surg. 2009;250:611–617. 33. Mustard WT. Successful two-stage correction of transposition of the great vessels. Surgery. 1964;55:469–472. 34. Senning A. Surgical correction of transposition of the great vessels. Surgery. 1959;45:966–980. 35. Dibardino DJ, Allison AE, Vaughn WK, et al. Current expectations for newborns undergoing the arterial switch operation. Ann Surg. 2004;239:588–596; discussion 596–588. 36. Yacoub MH, Radley-Smith R. Anatomy of the coronary arteries in transposition of the great arteries and methods for their transfer in anatomical correction. Thorax. 1978;33:418–424. 37. Ly M, Belli E, Leobon B, et al. Results of the double switch operation for congenitally corrected transposition of the great arteries. Eur J Cardio Thorac Surg. 2009;35:879–883; discussion 883–874. 38. Bacha EA, McElhinney DB, Guleserian KJ, et  al. Surgical aortic valvuloplasty in children and adolescents with aortic regurgitation: acute and intermediate effects on aortic valve function and left ventricular dimensions. J Thorac Cardiovasc Surg. 2008;135:552–559, 559 e551–e553. 39. Sharabiani MT, Dorobantu DM, Mahani AS, et  al. Aortic valve replacement and the ross operation in children and young adults. J Am Coll Cardiol. 2016;67:2858–2870. 40. Shinkawa T, Bove EL, Hirsch JC, et  al. Intermediate-term results of the ross procedure in neonates and infants. Ann Thorac Surg. 2010;89:1827–1832; discussion 1832. 41. Booth JH, Bryant R, Powers SC, et al. Transthoracic echocardiography does not reliably predict involvement of the aortic valve in patients with a discrete subaortic shelf. Cardiol Young. 2010;20:284–289.

42. Donald JS, Naimo PS, d’Udekem Y, et al. Outcomes of subaortic obstruction resection in children. Heart Lung Circ. 2017;26:179–186. 43. Cowley CG, Orsmond GS, Feola P, et  al. Long-term, randomized comparison of balloon angioplasty and surgery for native coarctation of the aorta in childhood. Circulation. 2005;111:3453–3456. 44. Mery CM, Guzman-Pruneda FA, Carberry KE, et al. Aortic arch advancement for aortic coarctation and hypoplastic aortic arch in neonates and infants. Ann Thorac Surg. 2014;98:625– 633; discussion 633. 45. Morales DL, Scully PT, Braud BE, et  al. Interrupted aortic arch repair: aortic arch advancement without a patch minimizes arch reinterventions. Ann Thorac Surg. 2006;82:1577– 1583; discussion 1583–1574. 46. Bailey LL, Nehlsen-Cannarella SL, Doroshow RW, et  al. Cardiac allotransplantation in newborns as therapy for hypoplastic left heart syndrome. N Engl J Med. 1986;315:949–951. 47. Norwood WI, Lang P, Casteneda AR, et al. Experience with operations for hypoplastic left heart syndrome. J Thorac Cardiovasc Surg. 1981;82:511–519. 48. Sano S, Ishino K, Kado H, et al. Outcome of right ventricleto-pulmonary artery shunt in first-stage palliation of hypoplastic left heart syndrome: a multi-institutional study. Ann Thorac Surg. 2004;78:1951–1957; discussion 1957–1958. 49. Ohye RG, Sleeper LA, Mahony L, et al. Comparison of shunt types in the norwood procedure for single-ventricle lesions. N Engl J Med. 2010;362:1980–1992. 50. Newburger JW, Sleeper LA, Gaynor JW, et  al. Transplantfree survival and interventions at 6 years in the SVR trial. Circulation. 2018;137:2246–2253. 51. Luce WA, Schwartz RM, Beauseau W, et  al. Necrotizing enterocolitis in neonates undergoing the hybrid approach to complex congenital heart disease. Pediatr Crit Care Med. 2011;12:46–51. 52. Cao JY, Lee SY, Phan K, et al. Early outcomes of hypoplastic left heart syndrome infants: meta-analysis of studies comparing the hybrid and norwood procedures. World J Pediatr Congenit Heart Surg. 2018;9:224–233. 53. Salazar JD, Zafar F, Siddiqui K, et  al. Fenestration during Fontan palliation: now the exception instead of the rule. J Thorac Cardiovasc Surg. 2010;140:129–136. 54. Valente AM, Lock JE, Gauvreau K, et al. Predictors of longterm adverse outcomes in patients with congenital coronary artery fistulae. Circ Cardiovasc Interv. 2010;3:134–139. 55. Starnes VA, Pitlick PT, Bernstein D, et al. Ebstein’s anomaly appearing in the neonate. a new surgical approach. J Thorac Cardiovasc Surg. 1991;101:1082–1087. 56. Brown ML, Dearani JA, Danielson GK, et al. The outcomes of operations for 539 patients with ebstein anomaly. J Thorac Cardiovasc Surg. 2008;135:1120–1136, 1136 e1121–e1127.

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60

Acquired Heart Disease: Coronary Insufficiency Shuab Omer, Faisel G. Bakaeen

OUTLINE Coronary Artery Anatomy and Physiology Anatomic Considerations Physiology and Regulation of Coronary Blood Flow History of Coronary Artery Bypass Surgery Atherosclerotic Coronary Artery Disease Pathogenesis Fixed Coronary Obstructions Clinical Manifestations and Diagnosis of Coronary Artery Disease Clinical Presentation Physical Examination Diagnostic Testing Cardiac Catheterization and Intervention Indications for Coronary Artery Revascularization Coronary Artery Bypass Grafting Versus Contemporaneous Medical Therapy Percutaneous Coronary Intervention Versus Medical Therapy Coronary Artery Bypass Grafting Versus Balloon Angioplasty or Bare-Metal Stents Coronary Artery Bypass Grafting Versus Drug-Eluting Stents Left Main Coronary Artery Disease Proximal LAD Artery Disease Completeness of Revascularization Left Ventricular Systolic Dysfunction Revascularization Options for Previous CABG Unstable Angina/Non–ST-Segment Elevation Myocardial Infarction ST-Segment Elevation Myocardial Infarction–Acute Myocardial Infarction Preoperative Evaluation Technique of Myocardial Revascularization: Conventional On-Pump Cardiopulmonary Bypass

Adjuncts to Coronary Artery Bypass Grafting Transesophageal Echocardiography Inotropes and Pharmacotherapy Intraaortic Balloon Pump Postoperative Care Pulmonary Care Discharge From the Intensive Care Unit Outcomes Medical Adjuncts for Postoperative Management Alternative Methods for Myocardial Revascularization Cardiopulmonary Bypass With Hypothermic Fibrillatory Arrest On-Pump Beating-Heart Bypass Off-Pump Coronary Artery Bypass Grafting Minimally Invasive Direct Coronary Artery Bypass Robotics: Totally Endoscopic Coronary Artery Bypass Transmyocardial Laser Revascularization Hybrid Procedures Technical Aspects of Reoperative Coronary Artery Bypass Grafting Mechanical Complications of Coronary Artery Disease Left Ventricular Aneurysm Ventricular Septal Defect Mitral Regurgitation Coronary Artery Bypass Grafting and Special Populations of Patients Patients With Diabetes Older Patients Women Patients With Renal Disease Obese Patients Acknowledgments

Ischemic heart disease (IHD) is the predominant public health problem worldwide. Coronary heart disease (43.8%) is the leading cause of death attributable to cardiovascular disease (CVD) in the United States, followed by stroke (16.8%), high blood pressure (9.4%), heart failure (9.0%), diseases of the arteries (3.1%), and other CVDs (17.9%). It is estimated that by 2035, more than 130 million adults in the U.S. population (45.1%) are projected to have some form of CVD, and total costs of CVD are expected to reach $1.1 trillion in 2035, with direct medical costs projected to reach $748.7 billion and indirect costs estimated to reach $368 billion.1–3

Despite recent advances in percutaneous intervention, coronary artery bypass grafting (CABG) still remains the most effective treatment for coronary artery disease (CAD) and is the most commonly performed open cardiac procedure in the United States.

CORONARY ARTERY ANATOMY AND PHYSIOLOGY Anatomic Considerations The coronary arteries, the predominant blood supply to the heart, arise from the sinuses of Valsalva. They are the first arterial branches of the aorta, and two are usually present. The coronary arteries are

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SECTION XI  Chest TABLE 60.1  Anatomic architecture of

coronary arteries. NAMED VESSELS

BRANCHES

Left main coronary artery

Left anterior descending Circumflex coronary Ramus intermedius Diagonal arteries Septal perforators Obtuse marginal branches Left posterolateral artery Acute marginal artery Posterior descending artery Right posterolateral artery

Left anterior descending Circumflex coronary artery Right coronary artery

LM CA RC LAD Diag. OM

Acute PD

FIG. 60.1  Anatomy of normal coronary artery vasculature. CA, Circumflex artery; LAD, left anterior descending; LM, left main; OM, obtuse marginal; PD, posterior descending; RC, right coronary.

designated right and left according to the embryologic chamber that they predominantly supply. The left coronary artery (LCA) arises from the left coronary sinus, which is located posterior; the right coronary artery (RCA) arises from the right coronary sinus, which is located anterior. The LCA, also called the left main coronary artery, averages approximately 2 to 3 cm in length and courses in a left posterolateral direction, winding behind the main pulmonary artery trunk and then splitting into the left anterior descending (LAD) and left circumflex arteries. The LAD courses in an anterolateral direction to the left of the pulmonary trunk and runs anteriorly over the interventricular septum. The diagonal branches of the LAD supply the anterolateral wall of the left ventricle (LV). The LAD is considered the most important surgical vessel because it supplies more than 50% of the LV mass and most of the interventricular septum. The LAD has several septal perforating branches that supply the interventricular septum from its anterior aspect. The LAD extends over the interventricular septum up to the apex of the heart, where it may form an anastomosis with the posterior descending artery (PDA), which is typically a branch of the right coronary system (Fig. 60.1). The circumflex artery passes in the atrioventricular (AV) groove and gives off the obtuse marginal branches that extend toward but do not quite reach the apex of the heart. The obtuse marginal branches are designated numerically from proximal to distal. The circumflex coronary artery usually terminates as the left posterolateral branch after taking a perpendicular turn toward the apex. The term ramus intermedius is used to designate a dominant coronary vessel that arises from the occasional trifurcation of the LCA. This branch can be intramyocardial and difficult to locate at times. The RCA supplies most of the right ventricle as well as the posterior part of the LV. The RCA emerges from its ostium in the right coronary sinus and passes deep in the right AV groove. At the superior end of the acute margin of the heart, the RCA turns

posteriorly toward the crux and usually bifurcates into the PDA over the posterior interventricular sulcus and right posterolateral artery. The RCA also supplies multiple right ventricular branches (i.e., the acute marginal branches). On occasion, the PDA arises from both the RCA and LCA, and the circulation is considered to be codominant. The AV node artery arises from the RCA in approximately 90% of patients. The sinoatrial node artery arises from the proximal RCA in 50% of patients. Although the source of the PDA is often used clinically to define dominance of circulation in the heart, anatomists define it according to where the sinoatrial node artery arises. Table 60.1 summarizes the hierarchy of the coronary artery anatomy. All the epicardial conductance vessels and septal perforators from the LAD give rise to a multitude of branches, termed resistance vessels, that penetrate into the ventricular wall. These vessels play a crucial role in oxygen and nutrient exchange with the myocardium by forming a rich capillary plexus. This plexus offers a low-resistance sink that allows arterial blood flow to increase unimpeded when oxygen demand rises. This is important because the myocardial vascular bed extracts oxygen at its full capacity, even in low-demand circumstances, thereby allowing no margin for further oxygen extraction when demand is high. An intricate network of veins drains the coronary circulation, and the venous circulation can be divided into three systems: the coronary sinus and its tributaries, the anterior right ventricular veins, and the thebesian veins. The coronary sinus predominantly drains the LV and receives 85% of coronary venous blood. It lies within the posterior AV groove and empties into the right atrium. The anterior right ventricular veins travel across the right ventricular surface to the right AV groove, where they enter directly into the right atrium or form the small cardiac vein, which enters into the right atrium directly or joins the coronary sinus just proximal to its orifice. The thebesian veins are small venous tributaries that drain directly into the cardiac chambers and exit primarily into the right atrium and right ventricle. Understanding of the anatomy of the coronary sinus is essential for placement of the retrograde cardioplegia cannula during cardiopulmonary bypass (CPB). 

Physiology and Regulation of Coronary Blood Flow Aortic pressure is a driving force in the maintenance of myocardial perfusion. During resting conditions, coronary blood flow is maintained at a fairly constant level over a wide range of aortic perfusion pressures (70–180 mm Hg) through the process of autoregulation. Because the myocardium has a high rate of energy use, normal coronary blood flow averages 225 mL/min (0.7–0.9 mL per gram of myocardium per minute) and delivers 0.1 mL/g/min of oxygen

CHAPTER 60  Acquired Heart Disease: Coronary Insufficiency BOX 60.1  Unique features of coronary

blood flow.

• Autoregulated over wide pressure ranges • Blood flow: 0.7–0.9 mL per gram of myocardium per minute • 75% oxygen extraction • Coronary sinus blood is the most deoxygenated blood in the body • 4- to 7-fold increase in flow with increased demand • 60% blood flow occurs during diastole • Flow-limited oxygen supply

to the myocardium. Under normal conditions, more than 75% of the delivered oxygen is extracted in the coronary capillary bed, so any additional oxygen demand can be met only by increasing the flow rate. This highlights the importance of unobstructed coronary blood flow for proper myocardial function. Box 60.1 summarizes the unique features of coronary blood flow. In response to increased load, such as that caused by strenuous exercise, the healthy heart can increase myocardial blood flow four- to sevenfold. Blood flow is increased through several mechanisms. Local metabolic neurohumoral factors cause coronary vasodilation when stress and metabolic demand increase, thereby lowering the coronary vascular resistance. This results in increased delivery of oxygen-rich blood, mimicking the phenomenon of reactive hyperemia. When a transient occlusion to the coronary artery is released (e.g., during the performance of a beating-heart operation), blood flow immediately rises to exceed the normal baseline flow and then gradually returns to its baseline level. The autoregulatory mechanism responsible is guided by several metabolic factors, including carbon dioxide, oxygen tension, hydrogen ions, lactate, potassium ions, and adenosine. Adenosine, a potent vasodilator and a degradation product of adenosine triphosphate, accumulates in the interstitial space and relaxes vascular smooth muscle. This results in vasomotor relaxation, coronary vasodilation, and increased blood flow. Another substance that plays an important role is nitric oxide, which is produced by the endothelium. Without the endothelium, coronary arteries do not autoregulate, suggesting that the mechanism for vasodilation and reactive hyperemia is endothelium dependent. Extravascular compression of the coronaries during systole also plays an important role in the regulation of blood flow. During systole, the intracavitary pressures generated in the LV wall exceed intracoronary pressure, and blood flow is impeded. Hence, approximately 60% of coronary blood flow occurs during diastole. During exercise, increased heart rate and reduced diastolic time can compromise flow time, but this can be offset by vasodilatory mechanisms of the coronary vessels. Buildup of atherosclerotic plaques and fixed coronary occlusion significantly impair coronary arterial compensatory mechanisms while heart rate is elevated. This forms the basis for exercise-induced stress tests, in which abnormal physiologic responses to increased physical activity unmask underlying CAD. 

HISTORY OF CORONARY ARTERY BYPASS SURGERY One of the first attempts at myocardial revascularization was made by Arthur Vineberg from Canada.4 He operated on a series of patients who presented with symptoms of myocardial ischemia and implanted the left internal mammary artery (LIMA) into the myocardium by creating a pocket. The operation did not entail a direct anastomosis to any coronary vessel and was performed on a beating heart through a left anterolateral thoracotomy. Dr. David

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TABLE 60.2  Evolution of surgical coronary

artery interventions: timeline. 1950

A. Vineberg

1953

J. H. Gibbon

1962 1964 1964

F. M. Sones M. E. DeBakey T. Sondergaard

1964

D. A. Cooley

1968

R. Favoloro

1973 1979

V. Subramanian G. Buckberg

Direct implantation of mammary artery into myocardium First successful use of cardiopulmonary bypass machine Successful cineangiography First successful coronary artery bypass grafting Introduced routine use of cardioplegia for myocardial protection Routine use of normothermic arrest for all cardiac cases First large series showing success of coronary artery bypass grafting Beating-heart coronary artery bypass grafting First use of blood cardioplegia as preferred method for arrested myocardial protection

Sabiston, Jr., performed the first CABG with venous grafting on April 4, 1962, in a patient with an occluded RCA. A saphenous vein graft (SVG) was taken from the leg and anastomosed from the ascending aorta to the RCA. Unfortunately, the patient had a stroke and died shortly thereafter. Michael DeBakey performed a successful aortocoronary SVG in 1964. At the Cleveland Clinic, Mason Sones, who is credited with inventing cardiac catheterization, and cardiac surgeon, Rene Favaloro, helped establish CABG surgery as a planned and consistent therapy in patients with angiographically documented CAD. The development of the heart-lung machine and its successful clinical use by John Heysham Gibbon in the 1950s, along with the advancement of cardioplegia techniques in later years by Gerald Buckberg, allowed surgeons to perform coronary anastomosis on an arrested (nonbeating) heart with a relatively bloodless field, thus increasing the safety and accuracy of the coronary bypass. In the 1990s, the advent of devices that could atraumatically stabilize the heart provided another pathway for the development of off-pump techniques of myocardial revascularization. Today, an armamentarium of techniques ranging from conventional onpump CABG to minimally invasive robotic and percutaneous approaches is available to manage CAD. Table 60.2 summarizes the timeline of major historical events in the development of surgery for myocardial revascularization. 

ATHEROSCLEROTIC CORONARY ARTERY DISEASE Coronary atherosclerosis is a process that begins early in the patient’s life. Epicardial conductance vessels are the most susceptible and intramyocardial arteries, the least. Risk factors for atherosclerosis include elevated plasma levels of total cholesterol and lowdensity lipoprotein cholesterol, cigarette smoking, hypertension, diabetes mellitus, advanced age, low plasma levels of high-density lipoprotein cholesterol, and family history of premature CAD. Epidemiologic evidence suggests that coronary artery atherosclerosis is closely linked to the metabolism of lipids, specifically low-density lipoprotein cholesterol. The development of lipid-lowering drugs has resulted in a significant reduction in mortality. In one observational study of patients who received statin therapy and were known to have CAD, statin treatment was associated with improved survival in all age groups. The greatest survival benefit was found in those patients in the highest quartile of plasma levels of high-sensitivity C-reactive protein, a biomarker of inflammation

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SECTION XI  Chest Modality MRI Ultrasound Fluorescence PET Target

+ + – –

+ + + +

+ + + +

+ – + +

+ ± – –

+ + + +

Flow-mediated vasodilation

Adhesion molecules

Macrophages

MMPs Cathepsin

Lipid core Fibrous cap

αvβ3 integrin

Fibrin Platelets αIIbβ3 integrin Tissue factor

Endothelial dysfunction

Endothelial activation

Inflammation

Proteolysis Apoptosis

Angiogenesis

Thrombosis

Process

+ + + +

Thrombus Fibrous cap Monocyte recruitment

↓NO production

Lipid-rich necrotic core

Internal elastic lamina

Angiogenesis

Approximate I American Heart Association lesion stage

II

III

IV

V

αvβ3 integrin

Apoptotic cell

Collagen fibril

Endothelial cell

MMP

Platelet

Smooth muscle cell

VCAM1, ICAM, selectins

Fibrin

VI

Foam cell

LDL

FIG. 60.2  Components of atherosclerotic plaque. Thinning of the fibrous cap eventually results in plaque rupture and extrusion of highly thrombogenic lipid-laden material into the coronary artery. This causes an acute occlusion of the coronary artery, resulting in myocardial infarction. (Adapted from Choudhury RP, Fuster V, Fayad ZA. Molecular, cellular and functional imaging of atherothrombosis. Nat Rev Drug Discov. 2004;3:913–925.) ICAM, Intercellular adhesion molecule; LDL, low-density lipoprotein; MMP, matrix metallopeptidases; MRI, magnetic resonance imaging; PET, positron emission tomography; VCAM1, vascular cell adhesion molecule 1.

and CAD. Animal and human studies have demonstrated that statin therapy also modifies the lipid composition within plaques by lowering the amount of low-density lipoprotein cholesterol and stabilizing the plaque through various mechanisms, including reduced macrophage accumulation, collagen degradation, reduced smooth muscle cell protease expression, and decreased tissue factor expression.

Pathogenesis The primary cause of CAD is endothelial injury induced by an inflammatory wall response and lipid deposition. There is evidence that an inflammatory response is involved in all stages of the disease, from early lipid deposition to plaque formation, plaque rupture, and coronary artery thrombosis. Vulnerable or high-risk plaques that are prone to rupture have the following characteristics: a large, eccentric, soft lipid core; a thin fibrous cap; inflammation within the cap and adventitia; increased plaque neovascularity; and evidence of outward or positive vessel remodeling. Thinner fibrous caps are at a higher risk for rupture, probably because of an imbalance between the synthesis and the degradation of the extracellular matrix in the fibrous cap that results in an overall decrease in the collagen and matrix components (Fig. 60.2). Increased matrix breakdown caused by matrix degradation by an inflammatory cell-mediated metalloproteinase or reduced production of extracellular matrix results in thinner fibrous caps. Not all plaque ruptures are symptomatic; whether they are depends on the thrombogenicity of the plaque’s components. Tissue factor within the lipid core of

the plaque, secreted by activated macrophages, is one of the most potent thrombogenic stimuli. Rupture of a vulnerable plaque may be spontaneous or caused by extreme physical activity, severe emotional distress, exposure to drugs, cold exposure, or acute infection. 

Fixed Coronary Obstructions More than 90% of patients with stable IHD (SIHD) have advanced coronary atherosclerosis caused by a fixed obstruction. Atherosclerotic plaques of the coronary arteries are concentric (25%) or eccentric (75%). Eccentric lesions compromise only a portion of the lumen; through vascular remodeling, the arterial lumen may remain patent until late in the disease process. The impact of an arterial stenosis on coronary blood flow can be appreciated in the context of the Poiseuille law. Reductions in luminal diameter up to 60% have minimal impact on flow, but when the cross-sectional area of the vessel has decreased by 75% or more, coronary blood flow is significantly compromised. Clinically, this loss of flow often coincides with the onset of exertional angina. A 90% reduction in luminal diameter results in resting angina. 

CLINICAL MANIFESTATIONS AND DIAGNOSIS OF CORONARY ARTERY DISEASE Clinical Presentation Clinically, IHD has two predominant modes of presentation: • Stable angina

CHAPTER 60  Acquired Heart Disease: Coronary Insufficiency • A  cute coronary syndrome: ST-segment elevation myocardial infarction (STEMI) and its complications, non-STEMI (NSTEMI), and unstable angina (UA) Anginal pain is the main presenting symptom of IHD. It typically lasts minutes. The location is usually substernal, and pain can radiate to the neck, jaw, epigastrium, or arms. Anginal pain is precipitated by exertion or emotional stress and relieved by rest. Sublingual nitroglycerin also usually relieves angina within 30 seconds to several minutes. On presentation, angina must be classified as stable or unstable. Patients are said to be having UA if the pain is increasing (in frequency, intensity, or duration) or occurring at rest. Such patients should be transferred promptly to an emergency department. Patients, especially female and elderly patients, sometimes present with atypical symptoms, such as nausea, vomiting, midepigastric discomfort, or sharp (atypical) chest pain. In the Women’s Ischemic Syndrome Evaluation (WISE) study, 65% of women with ischemia presented with atypical symptoms.5 The term acute coronary syndrome has evolved to refer to a constellation of clinical symptoms that represent myocardial ischemia. It encompasses both STEMI and NSTEMI. Myocardial infarction (MI) often is manifested as crushing chest pain that may be associated with nausea, diaphoresis, anxiety, and dyspnea. Symptoms of the hypoperfusion that follows MI may include dizziness, fatigue, and vomiting. Heart rate and blood pressure may be initially normal, but both increase in response to the duration and severity of pain. Loss of blood pressure is indicative of cardiogenic shock and indicates a poorer prognosis. At least 40% of the ventricular mass must be involved for cardiogenic shock to occur. Mechanical complications of MI include acute ventricular septal defect (VSD), papillary muscle rupture, and free ventricular rupture. They usually occur approximately 7 to 10 days after the initial MI. 

Physical Examination Some clinical findings are generic and are related to the systemic manifestations of atherosclerosis. Eye examination may reveal a copper wire sign, retinal hematoma or thrombosis secondary to vascular occlusive disease, and hypertension. Corneal arcus and xanthelasma are features noticed in cases of hypercholesterolemia. Other clinical manifestations are caused by sequelae of CAD (Box 60.2). A thorough vascular evaluation is essential for any patient who presents with CAD because atherosclerosis is a systemic process. In addition, if surgery is being planned, the extremities should be evaluated for any previous surgical scars or fractures that could potentially preclude conduit harvest. 

Diagnostic Testing Biochemical Studies Patients suspected of having an acute coronary syndrome should undergo appropriate blood testing. Levels of creatine kinase muscle and brain subunits (CK-MB) and troponin T or I should be assessed at least 6 to 12 hours apart. Additional laboratory tests include a complete blood count, comprehensive metabolic panel, and lipid profile (total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol). Elevated brain natriuretic peptide and C-reactive protein levels suggest a worse outcome.  Chest Radiography The chest radiograph is helpful in identifying causes of chest discomfort or pain other than CAD. Chest radiography does not detect CAD directly; it only identifies sequelae, such as

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BOX 60.2  Sequelae of coronary artery

disease.

Clinical Manifestations • Abnormal neck vein pulsations, which may be seen in patients with secondor third-degree heart block or CHF • Bradycardia—a subtle presentation of ischemia involving the right coronary territories and a possible sign of heart block • Weak or thready pulse suggestive of ectopic or premature ventricular beats • Third heart sound that is noted with elevated left ventricular filling pressures/CHF • Fourth heart sound, which is commonly heard in patients with acute and chronic CAD • Mitral regurgitant heart murmurs caused by ischemic papillary muscles • Ejection systolic murmur indicative of aortic stenosis, which can contribute to coronary ischemia • Holosystolic murmurs caused by ventricular septal rupture • Manifestations of CHF, such as rales, hepatomegaly, right upper abdominal quadrant tenderness, ascites, and marked peripheral and presacral edema CAD, Coronary artery disease; CHF, congestive heart failure.

cardiomegaly, pulmonary edema, and pleural effusions, that are indicative of heart failure. From a surgical standpoint, preoperative chest radiography is important because it can identify obvious abnormalities, such as porcelain aorta, lung masses, effusion, and pneumonias, that may affect further workup or prompt a change in operative strategy.  Resting Electrocardiography A 12-lead resting electrocardiogram (ECG) should be obtained in all patients with suspected IHD or sequelae thereof. The ECG is evaluated for evidence of LV hypertrophy, ST-segment depression or elevation, ectopic beats, or Q waves. In addition, arrhythmias (atrial fibrillation or ventricular tachycardia) and conduction defects (left anterior fascicular block, right bundle branch block, left bundle branch block) are suggestive of CAD and MI. Persistent ST-segment elevation or an evolving Q wave is consistent with myocardial injury and ongoing ischemia. Fifty percent of patients with significant CAD nonetheless have normal electrocardiographic results, and 50% of ECG recordings obtained during chest pain at rest will be normal, indicating the inaccuracy of the test. Patients with SIHD tend to have a worse prognosis if they have the following abnormalities on a resting ECG: evidence of prior MI, especially Q waves in multiple leads or an R wave in V1 indicating a posterior infarction; persistent ST-T wave inversions, particularly in leads V1 to V3; left bundle branch block, bifascicular block, second- or third-degree AV block, or ventricular tachyarrhythmia; or LV hypertrophy.6  Functional (Stress) Tests In patients with suspected stable ischemic CAD, functional or stress testing is used to detect inducible ischemia. These are the most common noninvasive tests used to diagnose SIHD (Box 60.3). All functional tests rely on the principle of inducing cardiac ischemia by using exercise or pharmacologic stress agents, which increase myocardial work and oxygen demand, or by causing vasodilation-elicited heterogeneity in induced coronary flow. Whether ischemia is induced, however, depends on the severity of both the stress imposed (e.g., submaximal exercise can fail to produce ischemia) and the flow disturbance. Approximately 70% of

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SECTION XI  Chest

BOX 60.3  Stress tests to identify coronary

artery disease.

Exercise Stress ECG • Bruce protocol • Five 3-minute bouts of treadmill exercise • Determines the ischemia threshold • 12 metabolic equivalents of energy expenditure needed for complete test • Low cost and short duration • Highly sensitive in multivessel disease  Limitations • Suboptimal sensitivity • Low detection rate of one-vessel disease • Nondiagnostic with abnormal baseline ECG • Poor specificity in premenopausal women • Many cannot accomplish the 12 metabolic equivalents for a complete test or an appropriate heart rate response  Exercise and Pharmacologic Stress SPECT Perfusion Imaging • Simultaneous evaluation of perfusion and function • Higher sensitivity and specificity than exercise ECG • Quantitative image analysis  Limitations • Long procedure time with Technetium-99m • Higher cost • Radiation exposure • Poor-quality images in obese patients  Exercise and Pharmacologic Stress Echocardiography • Higher sensitivity and specificity than exercise ECG • Comparable value with dobutamine stress • Short examination time • Identification of structural cardiac abnormalities • Simultaneous evaluation of perfusion with contrast agents • No radiation  Limitations • Decreased sensitivity for detection of one-vessel disease or mild stenosis • Highly operator dependent • No quantitative image analysis • Poor imaging in some patients • Infarct zone poorly defined ECG, Electrocardiogram; SPECT, single-photon emission computed tomography.

coronary stenoses are not detected by functional testing. Because abnormalities of regional or global ventricular function occur later in the ischemic cascade, they are more likely to indicate severe stenosis; thus, such abnormalities have a higher diagnostic specificity for SIHD than do perfusion defects, such as those seen on nuclear myocardial perfusion imaging (MPI). Exercise versus pharmacologic testing. In patients capable of performing routine activities of daily living without difficulty, exercise testing is preferred to pharmacologic testing because it induces greater physiologic stress than drugs can. This may make exercise testing the better means of detecting ischemia as well as providing a correlation to a patient’s daily symptom burden and physical work capacity not offered by pharmacologic stress testing.

The treadmill protocols initiate exercise at 3.2 to 4.7 metabolic equivalents of the task (METs) and increase by several METs every 2 to 3 minutes of exercise (e.g., modified or standard Bruce protocol). Performance of most activities of daily living requires approximately 4 to 5 METs of physical work. Patients unable to perform moderate physical activity and those with disabling comorbidities should undergo pharmacologic stress imaging instead.  Diagnostic accuracy of stress testing for SIHD

Exercise electrocardiography (Bruce protocol). The criterion for diagnosis of ischemia is an ECG showing 1-mm horizontal or downsloping (at 80 milliseconds after the J point) ST-segment depression at peak exercise. The diagnostic sensitivity and specificity of this sign is 61%. It is lower in women than in men7,8 and lower than that of stress imaging modalities.  Exercise and pharmacologic stress echocardiography. These tests rely on detecting new or worsening wall motion abnormalities and changes in global LV function during or immediately ­after stress. In addition to the detection of inducible wall motion abnormalities, most stress echocardiography includes screening images to evaluate resting ventricular function and valvular abnormalities. Pharmacologic stress echocardiography is usually performed using dobutamine with an end point of producing wall motion abnormalities. Vasodilator agents such as adenosine can be used to the same effect. The diagnostic sensitivity is 70% to 85% for exercise and 85% to 90% for pharmacologic stress echocardiography. The use of intravenous ultrasound contrast agents, by improving endocardial border delineation, can result in improved diagnostic accuracy.  Exercise and pharmacologic stress nuclear myocardial perfusion imaging. Myocardial perfusion single-photon emission computed tomography (SPECT) generally is performed with rest and with stress. Technetium-99m agents are generally used; one of these, thallium Tl 201, has limited applications (e.g., viability) because of its higher radiation exposure. Pharmacologic stress is generally induced with vasodilator agents administered by continuous infusion (adenosine, dipyridamole) or bolus injection (regadenoson). The diagnostic end point of nuclear MPI is a reduction in myocardial perfusion after stress. The diagnostic accuracy for detection of obstructive CAD of exercise and pharmacologic stress nuclear MPI has been studied in detail.9,10 Studies suggest that nuclear MPI’s sensitivity ranges from 82% to 88% for exercise and 88% to 91% for pharmacologic stress, and its diagnostic specificity ranges from 70% to 88% and 75% to 90% for exercise and pharmacologic stress nuclear MPI, respectively. For myocardial perfusion SPECT, global reductions in myocardial perfusion, such as in the patients with left main or three-vessel CAD, can result in balanced reduction and an underestimation of ischemic burden.  Echocardiography From a surgical standpoint, most patients with SIHD should undergo preoperative echocardiography. Echocardiography provides information not only for surgical planning but also regarding prognosis. A resting left ventricular ejection fraction (LVEF) of 35% is associated with an annual mortality rate of 3% per year. Resting two-dimensional Doppler echocardiography provides information on cardiac structure and function, including identifying the mechanism of heart failure and differentiating systolic from diastolic LV dysfunction. Echocardiography can identify LV or

CHAPTER 60  Acquired Heart Disease: Coronary Insufficiency

1685

left atrial dilation, identify aortic stenosis (a potential non-CAD cause of angina-like chest pain), measure pulmonary artery pressure, quantify mitral regurgitation, identify LV aneurysm, identify LV thrombus (which increases the risk of death), and measure LV mass and the ratio of wall thickness to chamber radius—all of which predict cardiac events and mortality.11,12  Multidetector Computed Tomography From a surgical standpoint, multidetector computed tomography (CT) has two pertinent applications in the management of CAD: to detect CAD and to inform the planning of grafting sites for CABG by providing additional information about coronary lesions, especially calcification and the course of coronary arteries. It also gives additional pertinent information about aortic disease and calcification, which might profoundly influence surgical decision making. However, the timing of cardiac CT should be carefully weighed against the risk of renal injury as a result of contrast nephropathy. Although revascularization decisions are currently made on the basis of coronary angiography, there have been tremendous improvements in temporal and spatial resolution of cardiac CT that make it useful for this purpose as well. Coronary CT angiography (CCTA) can now provide high-quality images of the coronary arteries.13 When it is performed with 64-slice CT, CCTA has a sensitivity of 93% to 97% and a specificity of 80% to 90% for detecting obstructive CAD.14–17 The potential advantages of CCTA over standard functional testing for CAD screening include the high negative predictive value of CCTA for obstructive CAD. This can reassure caregivers that it is a sensible strategy to provide guideline-directed medical therapy (GDMT) and to defer consideration of revascularization. Among the greatest potential advantages of CCTA over conventional angiography, in addition to documentation of stenotic lesions, is that CCTA can assess remodeling and identify nonobstructive plaque, including calcified, noncalcified, and mixed plaque.18 

FIG. 60.3  Left coronary angiogram showing hemodynamically severe lesions in the left anterior descending artery (small arrow) and the circumflex artery (large arrow).

Magnetic Resonance Imaging Myocardial first-pass perfusion magnetic resonance imaging has been considered a good alternative to nuclear cardiac ischemia and viability testing. However, the procedure has not gained widespread popularity because special training and expertise are required to perform this type of imaging and to interpret the results. 

Cardiac Catheterization and Intervention Coronary catheterization is the “gold standard” for diagnosis of CAD. Coronary angiography defines coronary anatomy, including the location, length, diameter, and contour of the epicardial coronary arteries; the presence and severity of coronary luminal obstructions; the nature of the obstruction; the presence and extent of angiographically visible collateral flow; and coronary blood flow. The classification for defining coronary anatomy that is still used today was developed for the Coronary Artery Surgery Study (CASS)19 and further modified by the Balloon Angioplasty Revascularization Investigation (BARI) study group.20 This scheme assumes that there are three major coronary arteries: the LAD, the circumflex, and the RCA, with a right-dominant, left-dominant, or codominant circulation. The extent of disease is defined as one-vessel, two-vessel, three-vessel, or left main disease; a luminal diameter reduction of at least 70% is considered to be significant stenosis (Figs. 60.3 and 60.4). Left main disease, however, is defined as stenosis of at least 50% (Fig. 60.5). Despite being recognized as the traditional gold standard for clinical assessment

FIG. 60.4  Right coronary angiogram showing hemodynamically significant lesion (arrow). The right coronary artery terminates as a posterior descending artery in the right dominant system.

of coronary atherosclerosis, this test is not without limitations. There is marked variation in interobserver reliability, and investigators have found only 70% overall agreement among readers with regard to the severity of stenosis; this was reduced to 51% when restricted to coronary vessels rated as having some stenosis by any reader. Also, angiography provides only anatomic data and is not a reliable indicator of the functional significance of a given

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SECTION XI  Chest Fractional Flow Reserve Angiography can underestimate the severity of CAD, especially LCA disease.24,25 This underestimation may be due to the lack of a reference segment or to very ostial or distal disease. Therefore, in cases with intermediate lesions, FFR has emerged as a helpful modality. FFR is measured by passing a sensor guidewire into the LAD or circumflex vessels for LCA lesions. Thereafter, the flow reserve in the artery is checked by using adenosine to induce hyperemia in the coronary system. An FFR below 0.75 is considered to signify ischemia-producing lesions. Some studies have used a threshold of 0.8. 

FIG. 60.5  Coronary angiogram showing critical left main coronary artery stenosis (arrow).

coronary stenosis unless a technique such as fractional flow reserve (FFR) is used to provide information about the physiologic effects of the stenosis. FFR is measured by passing a sensor guidewire into the LAD or circumflex vessels for LCA lesions. Thereafter, the flow reserve in the artery is checked by using adenosine to induce hyperemia in the coronary system, which is discussed in the next section on FFR. In addition, angiography cannot distinguish between vulnerable and stable plaques. In angiographic studies performed before and after acute events and early after MI, plaques causing UA and MI commonly were found to be 50% obstructive before the acute event and were therefore angiographically “silent.”19,20 Diagnostic testing methods to identify vulnerable plaque and, therefore, the patient’s risk of MI are being intensely studied, but no gold standard has yet emerged. Despite these limitations of coronary angiography, the extent and severity of CAD as revealed angiographically remain important predictors of long-term patient outcomes.21,22 In the CASS registry23 of medically treated patients, the 12year survival rate of patients with normal coronary arteries was 91% compared with 74% for those with one-vessel disease, 59% for those with two-vessel disease, and 40% for those with threevessel disease. Importantly, besides informing the decision whether to intervene surgically or with percutaneous coronary intervention (PCI), the salient characteristics of coronary lesions (e.g., stenosis severity, length, and complexity and presence of thrombus), the number of lesions threatening regions of contracting myocardium, the effect of collaterals, and the volume of jeopardized viable myocardium also can afford some insight into the potential consequences of subsequent vessel occlusion and therefore the haste with which surgery should be scheduled. PCI techniques in current use include balloon dilation, stentsupported dilation, atherectomy and plaque ablation with a variety of devices, thrombectomy with aspiration devices, specialized imaging, and physiologic assessment with intracoronary devices. Coronary artery stents were the first substantial breakthrough in the prevention of restenosis after angioplasty. Although stent recoil and compression are not completely insignificant problems, the greatest cause of lumen loss in stented coronary arteries is neointimal hyperplasia. This is the principal mechanism of in-stent stenosis and results from inappropriate cell proliferation—hence, the advent of cytotoxic drug-eluting stents (DESs).

Intravascular Ultrasonography Intravascular ultrasonography (IVUS) provides high-quality crosssectional images of the coronary system. It is done by inserting an IVUS wire into the LAD or circumflex artery and gradually pulling it out while obtaining real-time images of the coronary system. In indeterminate lesions of the LCA, an IVUS minimum luminal diameter of 2.8 or a minimum luminal area of 6 mm2 suggests a physiologically significant lesion.  Hybrid Imaging Hybrid imaging has the potential of taking coronary artery assessment one step further by combining the advantages of two different modalities to give both anatomic and physiologic information in one snapshot. Hybrid imaging can combine positron emission tomography (PET) and CT or SPECT and CT, thus allowing combined anatomic and functional testing. In addition, novel scanning techniques make it possible to use CCTA alone to assess perfusion and FFR, in addition to coronary anatomy. Interestingly, these combined assessments can produce a fused image in which physiologic information about flow is combined with information about the anatomic extent and severity of CAD, plaque composition, and arterial remodeling. Robust evidence to support the use of hybrid imaging is lacking at this point, despite its reported accuracy in predicting cardiac events with both ischemic and anatomic markers. The strength of combined imaging is that it provides anatomic information to guide the interpretation of ischemic and scarred myocardium as well as information to guide therapeutic decision-making. Hybrid imaging also can overcome technical limitations of myocardial perfusion SPECT or myocardial perfusion PET by providing anatomic correlates to guide interpretative accuracy, and it can provide the functional information that an anatomic technique like CCTA or magnetic resonance angiography lacks; however, use of hybrid techniques requires increasing the radiation dose. 

INDICATIONS FOR CORONARY ARTERY REVASCULARIZATION Per the most current American College of Cardiology/American Heart Association guidelines, the only class Ia indication for PCI is acute STEMI. In all other indications, CABG has superior class based on current evidence (Table 60.3). These guidelines are based on the existing literature, which spans four decades. Many of the studies on which current recommendations are based were conducted in the 1970s and 1980s.

Coronary Artery Bypass Grafting Versus Contemporaneous Medical Therapy In the 1970s and 1980s, three landmark randomized controlled trials (RCTs) established the survival benefit of CABG compared

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TABLE 60.3  Guidelines for coronary revascularization. CORONARY ARTERY LESIONS Unprotected Left Main CABG PCI

RECOMMENDATIONS I IIa—For SIHD when both of the following are present: • Cardiac catheterization reveals a low risk of PCI procedural complications with a high likelihood of good long-term outcome (low SYNTAX score 22, ostial or trunk left main). • Significantly increased risk of adverse surgical outcomes (STS-predicted risk of operative mortality 5%) IIa—For UA/NSTEMI if not a CABG candidate IIa—For STEMI when distal coronary flow is TIMI flow grade 3 and PCI can be performed more rapidly and safely than CABG IIb—For SIHD when both of the following are present: • Cardiac catheterization reveals a low to intermediate risk of PCI procedural complications and an intermediate to high likelihood of good long-term outcome (low–intermediate SYNTAX score of 33, bifurcation left main) • Increased risk of adverse surgical outcomes (moderate–severe COPD, disability from prior stroke, or prior cardiac surgery; STS-predicted operative mortality 2%) III: Harm—For SIHD in patients (versus performing CABG) with unfavorable anatomy for PCI and who are good candidates for CABG

Three-Vessel Disease With or Without Proximal LAD Artery Disease CABG I IIa—It is reasonable to choose CABG over PCI in patients with complex threevessel CAD (SYNTAX score 22) who are good candidates for surgery PCI IIb—Of uncertain benefit Two-Vessel Disease With Proximal LAD Artery Disease CABG I PCI IIb—Of uncertain benefit Two-Vessel Disease Without Proximal LAD Artery Disease CABG IIa—With extensive ischemia IIb—Of uncertain benefit without extensive ischemia PCI IIb—Of uncertain benefit One-Vessel Proximal LAD Artery Disease CABG IIa—With LIMA for long-term benefit PCI IIb—Of uncertain benefit One-Vessel Disease Without Proximal LAD Artery Involvement CABG III: Harm PCI III: Harm LV Dysfunction CABG IIa—LVEF 35% to 50% IIb—LVEF 35% without significant left main CAD PCI Insufficient data Survivors of Sudden Cardiac Death With Presumed IschemiaMediated VT CABG I PCI I No Anatomic or Physiologic Criteria for Revascularization CABG III: Harm PCI III: Harm Class I: benefit ≫> risk. Procedure should be performed. Class IIa: benefit ≫ risk. Additional studies with focused objectives needed. It is reasonable to perform procedure. Class IIb: benefit ≥ risk. Additional studies with broader objectives and additional registry data may be needed. Procedure treatment may be considered. Class III: no benefit or Class III: harm From Reference 28. CABG, Coronary artery bypass grafting (major adverse events occurred less frequently with CABG); CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; LAD, left anterior descending; LIMA, left internal mammary artery; LV, left ventricle; LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention; SIHD, stable ischemic heart disease; STEMI, ST-elevation myocardial infarction; STS, Society of Thoracic Surgeons; SYNTAX, Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery; TIMI, thrombolysis in myocardial infarction; UA/NSTEMI, unstable angina/non–ST-elevation myocardial infarction; VT, ventricular tachycardia.

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with medical therapy without revascularization in certain patients with SIHD: the Veterans Affairs Cooperative Study,26 European Coronary Surgery Study,27 and CASS.22 Subsequently, a 1994 metaanalysis of seven studies in which 2649 patients were randomly assigned to medical therapy or CABG24 showed that CABG offered a survival advantage over medical therapy for patients with LCA or three-vessel CAD. The studies also established that CABG is more effective than medical therapy for relieving anginal symptoms. These studies have been replicated only once during the past decade. In Medicine, Angioplasty, or Surgery Study II (MASS II), patients with multivessel CAD who were treated with CABG were less likely than those treated with medical therapy to have a subsequent MI, to need additional revascularization, or to experience cardiac death in the 10 years after randomization.25 Surgical techniques and medical therapy have improved substantially during the intervening years. Some critics state that if CABG were compared with GDMT in RCTs today, the relative benefits in terms of survival and angina relief observed several decades ago might no longer be observed. However, it should also be understood that the concurrent administration of GDMT, which most post–cardiac surgery patients now receive, may also substantially improve long-term outcomes in patients treated with CABG in comparison with those receiving medical therapy alone. Thus, the survival difference might still favor CABG over GDMT. 

Percutaneous Coronary Intervention Versus Medical Therapy Although contemporary interventional treatments have lowered the risk of restenosis compared with earlier techniques, metaanalyses have not shown that the use of bare-metal stents (BMS) confers a survival advantage over balloon angioplasty26,27 or that the use of DES confers a survival advantage over BMS.28 Evaluation of trials of PCI conducted during the last 30 years show that, despite improvements in PCI technology and pharmacotherapy, PCI has not reduced the risk of death or MI in patients without recent acute coronary syndrome. The findings from individual studies and systematic reviews of PCI versus medical therapy can be summarized as follows: • PCI reduces the incidence of angina • PCI has not been demonstrated to improve survival in stable patients • PCI may increase the short-term risk of MI • PCI does not lower the long-term risk of MI 

Coronary Artery Bypass Grafting Versus Balloon Angioplasty or Bare-Metal Stents From a review of multiple RCTs comparing CABG with balloon angioplasty or BMS, the following conclusions can be drawn28: • Survival was similar for CABG and PCI (with balloon angioplasty or BMS) at 1 year and 5 years. Survival was similar for CABG and PCI in patients with one-vessel CAD (including those with disease of the proximal portion of the LAD artery) or with multivessel CAD • Incidence of MI was similar at 5 years • Procedural stroke occurred more commonly with CABG than with PCI (1.2% vs. 0.6%) • Relief of angina was more effective with CABG than with PCI at 1 year and 5 years • At 1 year after the index procedure, repeated coronary revascularization was performed less often after CABG than after PCI (3.8% vs. 26.5%). This was also found after 5 years of

follow-up (9.8% vs. 46.1%). This difference was more pronounced with balloon angioplasty than with BMS. 

Coronary Artery Bypass Grafting Versus Drug-Eluting Stents Multiple observational studies comparing CABG and DES implantation have been published, but most of them had short (12– 24 months) follow-up periods. A large RCT comparing CABG and DES implantation in patients with three-vessel or left main disease has been published, called the Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) trial, in which 1800 patients (of a total of 4337 who were screened) were randomly assigned to undergo DES implantation or CABG. Major adverse cardiac events (a composite of death, stroke, MI, or repeated revascularization during the 3 years after randomization) occurred less frequently in CABG patients (20.2%) than in DES patients (28.0%; P = 0.001). The rates of death and stroke were similar; however, MI (3.6% for CABG, 7.1% for DES) and repeated revascularization (10.7% for CABG, 19.7% for DES) were more likely to occur with DES implantation. In SYNTAX, the extent of CAD was assessed by using the SYNTAX score, which is based on the location, severity, and extent of coronary stenoses, with a low score indicating less complicated anatomic CAD. In post hoc analyses, a low score was defined as 22 or lower; intermediate, 23 to 32; and high, 33 or higher. The occurrence of major adverse cardiac events correlated with the SYNTAX score for DES patients but not for those undergoing CABG. At 12-month follow-up, the primary end point was similar for CABG and DES in those with a low SYNTAX score. In contrast, major adverse cardiac events occurred more often after DES implantation than after CABG in those with an intermediate or high SYNTAX score. At 3 years of follow-up, the mortality rate was greater in patients with three-vessel CAD treated with PCI than in those treated with CABG (6.2% vs. 2.9%). The differences in major adverse cardiac events of those treated with PCI or CABG increased with an increasing SYNTAX score. Although the utility of using a SYNTAX score in everyday clinical practice remains uncertain, it seems reasonable to conclude from SYNTAX and other data that the outcomes of patients undergoing PCI or CABG in those with relatively uncomplicated and lesser degrees of CAD are comparable, whereas in those with complex and diffuse CAD, CABG appears to be preferable. At 5-year follow-up, a similar trend was seen, with CABG superior to PCI for intermediate or high SYNTAX scores.29 

Left Main Coronary Artery Disease CABG or PCI Versus Medical Therapy for Left Main CAD CABG confers a survival benefit over medical therapy in patients with LCA CAD. Subgroup analyses from RCTs performed three decades ago demonstrated a 66% reduction in relative risk of death with CABG, with the benefit extending to 10 years.23,24  Studies Comparing PCI Versus CABG for Left Main CAD Of all patients undergoing coronary angiography, approximately 4% are found to have LCA CAD, 80% of whom have s­ ignificant (70% diameter) stenoses in other epicardial coronary arteries. Published cohort studies have found that major clinical o­ utcomes for ostial LCA are similar with PCI or CABG 1 year after revascularization and that mortality rates are similar at 1 year, 2 years, and 5 years of follow-up; however, the risk of needing target ­vessel revascularization is significantly higher with stenting than with CABG.

CHAPTER 60  Acquired Heart Disease: Coronary Insufficiency Multiple RCTs have looked at this topic: the SYNTAX trial,29 the Study of Unprotected Left Main Stenting versus Bypass Surgery (LE MANS) trial, the Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease (PRECOMBAT) trial, the Percutaneous Coronary Angioplasty Versus CABG in Treatment of Unprotected Left Main Stenosis (NOBLE) trial,30 and the Everolimus-Eluting Stents or Bypass Surgery for Left Main Coronary Artery Disease (EXCEL) trial.31 The results from these RCTs suggest (but do not definitively prove) that major clinical outcomes in selected patients with LCA CAD are similar with CABG and PCI at 1- to 2-year follow-up, but repeated revascularization rates are higher after PCI than after CABG. RCTs with extended follow-up of 5 years are required to provide definitive conclusions about the optimal treatment of LCA CAD. In the NOBLE trial comparing PCI versus CABG, Kaplan-Meier 5-year estimates of major adverse cardiac event (MACE) were 28% for PCI (121 events) and 18% for CABG (80 events) (hazard ratio, 1.51; 95% confidence interval, 1.13–2.00), exceeding the limit for noninferiority, and CABG was significantly better than PCI (P = 0.0044). As-treated estimates were 28% versus 18% (1.48, 1.11– 1.98; P = 0.0069). Comparing PCI with CABG, 5-year estimates were 11% versus 9% (1.08, 0.67–1.74; P = 0.84) for all-cause mortality, 6% versus 2% (2.87, 1.40–5.89; P = 0.0040) for nonprocedural MI, 15% versus 10% (1.50, 1.04–2.17; P = 0.0304) for any revascularization, and 5% versus 2% (2.20, 0.91–5.36; P = 0.08) for stroke.30  Revascularization Options for LCA CAD Although CABG has been considered the gold standard for unprotected LCA CAD revascularization, PCI has more recently emerged as a possible alternative mode of revascularization in carefully selected patients. Lesion location is an important determinant when PCI is considered for unprotected LCA CAD. Stenting of the LCA ostium or trunk is more straightforward than treatment of distal bifurcation or trifurcation stenoses, which generally requires a greater degree of operator experience and expertise. In addition, PCI of bifurcation disease is associated with higher restenosis rates than PCI of disease confined to the ostium or trunk. Although lesion location influences technical success and long-term outcomes after PCI, location exerts a negligible influence on the success of CABG. In subgroup analyses, patients with LCA CAD and a SYNTAX score of 33 with more complex or extensive CAD had a higher mortality rate with PCI than with CABG. Physicians can estimate operative risk for all CABG candidates by using a standard instrument, such as the risk calculator from the Society of Thoracic Surgeons (STS) database. These considerations are important factors when one is choosing among revascularization strategies for unprotected LCA CAD and have been factored into revascularization recommendations. Use of a Heart Team approach has been recommended in cases in which the choice of revascularization is not straightforward. The patient’s ability to tolerate and to comply with dual antiplatelet therapy is also an important consideration in revascularization decisions. Experts have recommended immediate PCI for unprotected LCA CAD in the setting of STEMI. The impetus for such a strategy is greatest when LCA CAD is the site of the culprit lesion, antegrade coronary flow is diminished (e.g., thrombolysis in MI flow grade 0, 1, or 2), the patient is hemodynamically unstable, and it is believed that PCI can be performed more quickly than CABG. When possible, the interventional cardiologist and cardiac surgeon should decide together on the optimal form of

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revascularization for these patients, although it is recognized that they are usually critically ill and therefore not amenable to a prolonged deliberation or discussion of treatment options. 

Proximal LAD Artery Disease Multiple studies have suggested that CABG confers a survival advantage over contemporaneous medical therapy for patients with disease in the proximal segment of the LAD artery. Cohort studies and RCTs, as well as collaborative analyses and metaanalyses, have shown that PCI and CABG result in similar survival rates in these patients. 

Completeness of Revascularization Most patients undergoing CABG receive complete or nearly complete revascularization, which seems to influence long-term prognosis positively.32,33 In contrast, complete revascularization is accomplished less often in patients receiving PCI (e.g., in 70% of patients), and the extent to which the incomplete initial revascularization influences outcome is less clear. Rates of late survival and survival free of MI appear to be similar in patients with and without complete revascularization after PCI. Nevertheless, the need for subsequent CABG is usually higher in those whose initial revascularization procedure was incomplete (compared with those with complete revascularization) after PCI. 

Left Ventricular Systolic Dysfunction Several older studies and a metaanalysis of the data from these studies reported that patients with LV systolic dysfunction (predominantly mild to moderate in severity) had better survival with CABG than with medical therapy alone. In the Surgical Treatment for Ischemic Heart Failure (STICH) trial of CABG and GDMT in patients with an LVEF of 35% with or without viability testing, both treatments resulted in similar rates of survival (i.e., freedom from death from any cause, the study’s primary outcome) after 5 years of follow-up. In the same study at 10 years, the rates of death from any cause, death from cardiovascular causes, and death from any cause or hospitalization for cardiovascular causes were significantly lower among patients who underwent CABG in addition to receiving medical therapy than among those who received medical therapy.34,35 Only limited data are available comparing PCI with medical therapy in patients with LV systolic dysfunction. The data that exist at present on revascularization in patients with CAD and LV systolic dysfunction are more robust for CABG than for PCI, although data from contemporary RCTs in this population of patients are lacking. The choice of revascularization method in patients with CAD and LV systolic dysfunction is best based on clinical variables (e.g., coronary anatomy, presence of diabetes mellitus, presence of chronic kidney disease), magnitude of LV systolic dysfunction, preferences of the patient, clinical judgment, and consultation between the interventional cardiologist and the cardiac surgeon. 

Revascularization Options for Previous CABG In patients with recurrent angina after CABG, repeated revascularization is most likely to improve survival in patients at highest risk, such as those with obstruction of the proximal LAD artery and extensive anterior ischemia. Patients with ischemia in other locations and those with a patent LIMA to the LAD artery are unlikely to experience a survival benefit from repeated revascularization.36 Cohort studies comparing PCI and CABG among post-CABG patients report similar rates of midterm and long-term survival

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after the two procedures. In patients with previous CABG who are referred for revascularization for medically refractory ischemia, factors that may support the choice of repeated CABG include vessels unsuitable for PCI, multiple diseased bypass grafts, availability of the internal mammary artery (IMA) for grafting of chronically occluded coronary arteries, and good distal targets for bypass graft placement. Factors favoring PCI over CABG include limited areas of ischemia causing symptoms, suitable PCI targets, patent graft to the LAD artery, poor CABG targets, and comorbid conditions. 

Unstable Angina/Non–ST-Segment Elevation Myocardial Infarction The main difference between treating a patient with SIHD and a patient with UA/NSTEMI is that the impetus for revascularization is stronger in the treatment of UA/NSTEMI because myocardial ischemia occurring as part of an acute coronary syndrome is potentially life-threatening, and associated angina symptoms are more likely to be reduced with a revascularization procedure than with GDMT.37 Thus, the indications for revascularization are strengthened by the acuity of presentation, the extent of ischemia, and the likelihood of achieving full revascularization. The choice of revascularization method is generally dictated by the same considerations used to decide between PCI or CABG for patients with SIHD. 

ST-Segment Elevation Myocardial Infarction–Acute Myocardial Infarction Percutaneous Coronary Intervention Versus Medical Management for Acute Myocardial Infarction In general, PCI confers a greater survival advantage than thrombolytics as an initial treatment for STEMI–acute MI (AMI), and the use of delayed PCI as an adjunct to therapy, including therapy with thrombolytics, does not affect survival. In the Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO) IIb trial,38 the 30-day rate of the composite end point of death, nonfatal MI, and nonfatal disabling stroke was 9.6% for PCI patients and 13.7% for recipients of thrombolytics. Prospective observational data collected from the Second National Registry of Myocardial Infarction between June 1994 and March 1998 included data from a cohort of 27,080 consecutive patients with AMI associated with ST-segment elevation or left bundle branch block. These patients were all treated with primary angioplasty. The study revealed that the adjusted odds of mortality were significantly higher (62% vs. 41%) for patients with door-to-balloon times longer than 2 hours. The longer the doorto-balloon time, the higher the mortality risk, emphasizing that door-to-balloon time has a significant impact on outcomes for patients with AMI.39 On the basis of this evidence, PCI facilities have been required to establish a target door-to-balloon time of no longer than 90 minutes. Depending on the available facilities in a particular region, it is the responsibility of emergency medical services personnel to determine whether that goal can be achieved by transferring the patient to a PCI-capable facility. If this cannot be accomplished, a medical management strategy should be considered, with the goal being a door-to-needle time of 30 minutes or less.40  Role of Coronary Artery Bypass Grafting Although an increasing number of patients undergo catheterization early after AMI, the initial treatment is directed by the interventionalist, which has significantly diminished the role of

emergency CABG. In general, patients who undergo CABG early after AMI are sicker, and efforts to improve myocardial function are typically refractory to medical therapy. These patients typically have a higher incidence of comorbidities and are more likely to require intraaortic balloon pump (IABP) insertion. The optimal timing of CABG after AMI is not well established. A review of California discharge data identified 9476 patients who were hospitalized for AMI and subsequently underwent CABG. Of these, 4676 (49%) were in the early CABG group and 4800 (51%) were in the late CABG group. The mortality rate was highest (8.2%) among patients who underwent CABG on day 0 and declined to a nadir of 3.0% among patients who underwent CABG on day 3. The mean time to CABG was 3.2 days. Early CABG was an independent predictor of mortality, suggesting that CABG may best be deferred for 3 days or more after admission for AMI in nonurgent cases.41 The Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock (SHOCK) trial has shown the survival advantage of emergency revascularization versus initial medical stabilization in patients in whom cardiogenic shock developed after AMI. A subanalysis that compared the effects of PCI and CABG on 30-day and 1-year survival showed that survival rates were similar at both time points. Among SHOCK trial patients randomly assigned to undergo emergency revascularization, those treated with CABG had a greater prevalence of diabetes and worse CAD than those treated with PCI. However, survival rates were similar. In patients with AMI, CABG is usually performed in conjunction with an operation to treat a specific complication, such as refractory postinfarction angina, papillary muscle rupture with mitral regurgitation, and infarction VSD. The rationale for urgent or emergent surgery is often based on high early mortality risk from mechanical complications. 

Preoperative Evaluation The success of coronary artery revascularization depends on proper workup and patient selection. Currently, a multidisciplinary approach with cardiologists and cardiac surgeons is needed to give the patient the most appropriate form of revascularization based on guidelines (Fig. 60.6). Comorbidities that affect CABG outcomes and that are typically incorporated into risk models include age, gender, urgency of the procedure, ejection fraction, need for mechanical circulatory support, MI, smoking status, use of immunosuppressive drugs, prior coronary interventions, hypertension, diabetes, peripheral vascular disease (PVD), and cerebrovascular disease. In addition, the severity of angina, as designated by the Canadian Cardiovascular Society classification of angina, and the New York Heart Association classification of congestive heart failure (CHF) are important risk variables. The following are essential components of a preoperative workup for CABG patients: • Detailed history and physical examination, including conduit evaluation • Review of medications, including angiotensin-converting enzyme inhibitors, beta blockers, antiplatelet agents, and anticoagulants • Carotid duplex ultrasonography in patients who have clinical bruit or are at high risk for cerebrovascular disease • Cardiac echocardiography to evaluate ventricular function and the structural integrity of valves and chambers • Cardiac viability study in patients with depressed LVEF, chronic total occlusions, frailty, and high-risk operations to decide between PCI and CABG

CHAPTER 60  Acquired Heart Disease: Coronary Insufficiency

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PRESENCE OF CAD With anatomic indication for revascularization

Surgical risk stratification by multidisciplinary team Prohibitive or high risk for CABG such as: NO

ADVANCED COPD on HOME O2, FRAIL, DEMENTIA, RECENT HEMORRHAGIC STROKE, CHILD B OR C CIRRHOSIS, ADVANCED CANCER WITH SHORT LIFE EXPECTANCY, NONVIABLE MYOCARDIUM. PROHIBITIVE SURGICAL RISK

YES

PCI VS MEDICAL MANAGEMENT

Unprotected Left Main

3V CAD

2V CAD Prox. LAD

1 V CAD Prox. LAD

LV DYSFUNCTION

SCD survivor

CABG: 1A PCI: IIB(Ostial or trunk)

CABG: I PCI: IIB

CABG: I PCI: IIB

CABG: IIA PCI: IIB

CABG: IIA PCI: Uncertain

CABG: I PCI: I

FIG. 60.6  Surgical decision-making tree for coronary revascularization. CABG, Coronary artery bypass grafting; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; LAD, left anterior descending; LV, left ventricle; PCI, percutaneous coronary intervention; SCD, sudden cardiac death (sudden cardiac arrest).

• C  ardiac catheterization to delineate the coronary anatomy • Chest radiography • Coagulation and platelet profile, comprehensive metabolic panel, and complete blood count Depending on the findings of these tests, patients may need additional workup. In emergency circumstances, several of these tests may be skipped so that immediate revascularization can be performed. 

Technique of Myocardial Revascularization: Conventional On-Pump Cardiopulmonary Bypass Box 60.4 outlines all the major steps of an on-pump CABG operation. Positioning and Draping General anesthesia with a single-lumen endotracheal tube is the anesthetic technique of choice. After anesthetic induction and placement of necessary access and monitoring lines, the patient is positioned supine, with or without a roll underneath the shoulder blades according to the surgeon’s preference. The arms are tucked beside the patient with appropriate padding to minimize the chance of any nerve injury. A warming blanket is typically

placed underneath the patient to assist in rewarming after controlled hypothermia during CPB. The entire chest, abdomen, and lower extremities are prepared. Circumferential preparation of the lower extremities is important because the leg may have to be maneuvered during harvesting of the saphenous vein conduit. If radial artery harvesting is being contemplated, the arm also has to be circumferentially prepared and positioned 90 degrees from the bedside on an arm board because most patients have a multilumen central line in the internal jugular vein or a Swan-Ganz catheter. Anchor points on the drapes are designated appropriately to allow CPB circuit lines to be secured without compromising sterility.  Cardiopulmonary Bypass CPB is the establishment of extracorporeal oxygenation and perfusion of the human body by diverting all returning venous blood from the body to the heart-lung machine and returning the oxygenated blood in a controlled, pressurized manner. In essence, most blood flow to the heart and lungs is bypassed. Establishment of CPB is a critical step for any major cardiac procedure and allows complete control of the operation. The basic components of an extracorporeal heart pump circuit are venous cannulas to drain the returning venous blood, venous

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reservoir that collects blood by gravity, oxygenator and heat exchanger, perfusion pump, blood filter in the arterial line, and arterial cannula (Fig. 60.7). The blood conduits are designed to BOX 60.4  Major steps in on-pump

coronary artery bypass grafting.

• Induction of anesthesia and establishment of intraoperative monitoring adjuncts • Positioning and draping • Median sternotomy or appropriate approach • Harvest and evaluation of blood conduits • Heparinization and cannulation for cardiopulmonary bypass • Establishment of cardiopulmonary bypass • Myocardial arrest and protection • Identification of target vessels and construction of distal anastomoses • Restoration of myocardial electromechanical activity • Creation of proximal anastomoses • Weaning from cardiopulmonary bypass • Evaluation for and establishment of necessary adjuncts—inotropes, intraaortic balloon pump, pacing wires • Reversal of anticoagulation and establishment of hemostasis • Evaluation of surgical sites and establishment of surgical drainage • Closure of sternotomy

minimize turbulence, cavitation, and changes in blood flow velocity, which are detrimental to the integrity of component blood cells. Because the circuit contains a dead space created by the tubing and pump, a certain volume of nonblood solution is necessary to prime the pump and tubing. The priming solution consists of a balanced salt solution and, often, a starch solution. Homologous blood or fresh-frozen plasma may be added if the patient is anemic or if a bleeding problem is anticipated. The circuit has multiple access ports or sites from which to obtain blood samples for laboratory studies and into which to infuse blood, blood products, crystalloids, or drugs. Supplemental components include a cardiotomy suction system to collect undiluted or clean blood from open cardiac chambers and the surgical field. This blood is filtered, de-aired, and returned to the bypass pump. Diluted field blood and blood that has mixed with inflammatory cytokines or fat are collected through a separate device that concentrates washed red cells before returning them directly to the patient. A cardioplegia infusion device consists of a separate pump, reservoir, and heat exchanger. It is used to deliver cold, potassiumenriched blood or crystalloid solutions into the coronary circulation to arrest and to protect the heart. Use of CPB requires suppression of the clotting cascade with heparin because the surgical wound and components of the bypass pump are powerful stimuli for thrombus formation. A strict

Sump

Antegrade cardioplegia

Retrograde cardioplegia Venous reservoir Gravity drain Cardioplegia pump

Centrifugal pump

Oxygenator

Heat exchanger

FIG. 60.7  Schematic of total cardiopulmonary bypass circuit. All returning venous blood is siphoned into a venous reservoir and is oxygenated, and temperature is regulated before being pumped back through a centrifugal pump into the arterial circulation. The most common site for inflow cannulation is the ascending aorta; alternative sites include the femoral arteries and the right axillary artery in special circumstances. A parallel circuit derives oxygenated blood that is mixed with cold (4°C) cardioplegia solution in a 4:1 ratio and administered in antegrade or retrograde fashion to induce cardiac arrest. Cardioplegia solution is administered antegrade into the aortic root and retrograde through the coronary sinus. During the retrograde administration of cardioplegia solution, the efflux of blood from the coronary ostium is siphoned off through the sump drain, a return parallel circuit connected to the venous reservoir (not shown) that also helps to keep the heart decompressed during the arrest phase.

CHAPTER 60  Acquired Heart Disease: Coronary Insufficiency anticoagulation protocol should be enforced before CPB is initiated. The pump prime is premixed with 4 U/mL heparin, and the patient is systemically heparinized with 300 U/kg before cannulation. An activated clotting time obtained approximately 3 minutes after heparin administration should be more than 400 seconds before cannulation is begun and should be maintained for more than 450 seconds throughout CPB, with intermittent doses given as needed during the operation. The usual pumps are roller head pumps, which consist of circumferential tubing that is compressed by a roller on the outside, thereby forcing blood in one direction. This pump mechanism is associated with higher rates of hemolysis compared with centrifugal pumps, so roller head pumps are used only in cardiotomy suction and cardioplegia pumps. The main systemic pump is a centrifugal pump that consists of a vortex polyurethane-embedded magnetic cone housed in a conical chamber. The vortex spins at approximately 2000 to 5000 rpm, thereby generating enough centrifugal force to pump blood. Because the flow is entirely caused by a nonturbulent vortex generated by a finless cone, this mechanism is almost atraumatic to the blood cells and is therefore associated with less hemolysis than the roller head pump mechanism (Fig. 60.8).  Neurologic Protection During Cardiopulmonary Bypass The incidence of stroke after CPB is approximately 1.5%, but neurocognitive deficits are more frequent. Thus, several steps should be taken during CPB to minimize the risk of neurologic insult, including maintaining adequate cerebral perfusion, minimizing fat microemboli by eliminating the unnecessary use of cardiotomy suction, minimizing aortic manipulation by using single-clamp techniques when feasible, and instituting moderate hypothermia. The oxygen consumption of a patient on CPB at normal temperatures averages 80 to 125 mL/min/m2, similar to that of an anesthetized adult not on bypass. However, with the use of hypothermia, the oxygen consumption is markedly lower, and the flow rate can be reduced to less than 2.2 L/min/m2. This is because the mean oxygen consumption of the body decreases by 50% for every 10°C decrease in body temperature. Below 28°C, a flow rate of 1.6 L/min/m2 may be safe for as long as 2 hours. Significant

FIG. 60.8  Main centrifugal pump used in most cardiopulmonary bypass circuits. The entire unit is sterile molded and contains a finless cone that spins at 2000 to 5000 rpm, generating a powerful yet nonturbulent vortex. A flow meter (shown) must be used with these pumps because the ultimate volume of flow depends on outflow resistance rather than on pump speed. The conventional roller head pumps are still used for the auxiliary circuits, such as cardiotomy suction and cardioplegia circuits.

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disadvantages of using systemic hypothermia to accommodate lower flow rates include the extra time required to rewarm the patient and associated changes in the reactivity of blood elements, particularly platelets. These changes may increase the rewarmed patient’s propensity for bleeding.  Median Sternotomy The most common approach for performing CABG is a median sternotomy, although anterolateral thoracotomy is used in certain circumstances. A traditional sternotomy incision commences at the midpoint of the manubrium and is carried down to the xiphoid. The sternum is split through the middle with a sternal saw. It is essential that gentle upward force and a backward tilt be applied to the saw to prevent it from engaging the lung or soft tissues in the anterior mediastinum. Once the sternotomy is completed, the periosteum of the posterior table is cauterized, and a passive hemostatic agent such as bone wax or a reconstituted mixture of vancomycin may be used to prevent bleeding from the marrow. The most important consideration during the sternotomy is staying in the midline because the most common cause of sternal dehiscence is an off-midline sternotomy and the consequent technically suboptimal closure. Other potential problems associated with the sternotomy include indirect injury to the liver and direct injury to the heart, innominate vein, and lungs.  Conduit Choice and Harvesting Left internal mammary artery. In a seminal study from the Cleveland Clinic, Loop and colleagues42 have shown improved 10-year survival in patients who received a LIMA graft; patients who received an SVG had 1.6 times the risk of death that LIMA graft recipients had. The long-term patency rate of the LIMA graft has been shown to be approximately 95% and 90% at 10 and 20 years, respectively. The best patency rates are achieved when the LIMA is used as an in situ pedicled graft and is anastomosed to the LAD.  Bilateral internal mammary artery. Observational studies from major CABG centers suggested that the use of bilateral IMA (BIMA) grafts improves survival and significantly reduces the need for reoperation without increasing mortality. However, early results from a randomized trial demonstrated that compared with SVGs, BIMA grafts are associated with a higher (twofold) incidence of deep sternal wound infection. BIMA grafts are best used by experienced surgeons in younger, nondiabetic, nonobese patients. Four major studies that tilted the balance in favor of BIMA grafts were the two Cleveland Clinic studies (1999 and 2004), in which propensity scores were used to match single and BIMA graft recipients; the Oxford metaanalysis (2001); and a retrospective study from Japan (2001). Skeletonization of the IMA grafts may reduce the wound complication rate. The ART trial has revealed no significant difference in mortality and cardiovascular events with the use if BIMA at 5 years. At 10-year follow-up of the ART trial among patients who were scheduled for CABG and had been randomly assigned to undergo bilateral or single internal-thoracic-artery grafting, there was no significant difference between-group difference in the rate of death from any cause at 10 years in the intention-to-treat analysis.43 The IMA is harvested after the sternotomy is completed. A specially designed mammary retractor is used to elevate the appropriate hemithorax, typically the left for harvesting the LIMA. Adequately exposing the undersurface of the sternum is essential for successful harvest of the IMA (Fig. 60.9). The artery may be harvested as a pedicle that includes the two venae comitantes and surrounding soft

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SECTION XI  Chest

Sternum Anterior intercostal branches Left internal mammary artery Accompanying internal Phrenic mammary vein nerve Subclavian vein Left lung

Left internal mammary artery bypass Saphenous vein bypass

FIG. 60.9  Surgeon’s view of the left internal mammary artery (LIMA) as it is being harvested. A mammary retractor is used to elevate the left hemithorax to provide adequate visualization. The LIMA is dissected away from the chest wall as a pedicle with its accompanying venae comitantes. Low-voltage electrocautery with no-touch technique is crucial for the atraumatic harvest of this important conduit. Understanding of its relation to the phrenic nerve and subclavian veins is important to avoid injury to these structures during LIMA harvest.

tissue from the level of the subclavian vein to the level of the bifurcation of the artery into the superior epigastric and musculophrenic branches. The alternative method of harvesting is the skeletonized harvest, in which only the IMA is dissected away from the chest wall. The basic principle of harvesting the IMA relies exclusively on the no-touch technique, use of low-voltage electrocautery, and clipping of the anterior intercostal branches. Care must be taken during the harvest to identify the course of the phrenic nerves and to avoid injury to them. This is particularly important while harvesting the right IMA because the phrenic nerve is more closely related to it at the level of the second or third intercostal space. The IMA is a fragile vessel, and direct handling or undue traction should be avoided because it may cause traumatic dissection of the vessel. The distal end of the IMA should be divided only after the patient is fully heparinized to avoid thrombosis of the conduit. Once the IMA is divided, the distal end is spatulated appropriately to fashion the anastomosis.  Greater saphenous vein. Vein grafts have a patency rate of 90% at 1 year.44 Beyond 5 years after surgery, graft atherosclerosis develops in a substantial number of SVGs. Historically, by 10 years, only 60% to 70% of SVGs are patent, and 50% of those have angiographic evidence of atherosclerosis. While the sternotomy is being done, a separate team begins harvesting saphenous or radial artery conduits. Saphenous vein harvesting can be performed by open or endoscopic techniques. The conventional method of open vein harvesting involves making a long incision along the entire length of the harvested vein. Alternatively, a bridging technique can be used in which multiple 1- to 2-inch incisions are made, with intact bridges of skin between them. The most common complications associated with long open incisions are pain, slow wound healing, and dehiscence, which is compounded by the fact that a significant number of CABG patients have diabetes or PVD. The use of endoscopic or bridging techniques significantly alleviates but does not entirely eliminate these problems. There are some centers that avoid endoscopic vein harvesting entirely on the assumption that the technique is too traumatic to the vein itself, may be associated with intimal trauma, and may impair the long-term patency of the conduit. However, a recent randomized trial (REGROUP)

Saphenous vein bypass

FIG. 60.10  Typical configuration for a three-vessel coronary artery bypass. The left internal mammary artery is anastomosed to the left anterior descending artery. Aortocoronary bypasses are created with reversed saphenous vein to the distal right coronary artery and an obtuse marginal branch of the circumflex coronary artery. The circumflex coronary artery is usually avoided as a target for bypass because its location well inside the atrioventricular groove makes it difficult to visualize.

demonstrated the safety and efficacy of endoscopic vein harvesting.45 These reports were based on post hoc analyses of data from trials designed to address other aspects of coronary revascularization. Once the vein is extracted and the branches are ligated, the graft is soaked in a heparin solution while awaiting implantation. The veins are typically used in a reversed fashion and hence may not require valvotomy. A typical configuration of a three-vessel coronary artery bypass graft is shown in Fig. 60.10. Alternative conduits may be needed in patients who have had previous coronary bypass, peripheral vascular surgery with the use of vein conduits, or lower extremity amputations and in those who have unusable saphenous vein conduits because of severe varicosities of the saphenous vein. Other manifestations of venous insufficiency or disease may also pose problems. In addition, patients who have severely calcified ascending aortas may not be amenable to a vein-based aortocoronary bypass because anastomosis to the ascending aorta is complicated. In these cases, alternative bypass strategies include total arterial revascularization with BIMA pedicles (Fig. 60.11). In addition, the IMA may be used as the main conduit from which further arterial conduits may be Christmas-treed in an off-pump setup so that any aortic manipulation is avoided.  Other conduits

Radial artery. The radial artery graft is easily harvested and can reach all coronary territories, making it an attractive option for an arterial conduit. Both the Radial Artery Patency Study and the Radial Artery versus Saphenous Vein Patency study showed

CHAPTER 60  Acquired Heart Disease: Coronary Insufficiency

Right internal mammary artery bypass

Left internal mammary artery bypass

Radial artery bypass

FIG. 60.11  Total arterial revascularization by use of bilateral mammary artery and radial artery conduits. The right internal mammary artery, bypassed to an obtuse marginal branch, is routed behind the aorta, and the pulmonary artery is routed through the transverse sinus.

radial artery grafts to have better patency than SVGs on 5-year angiographic follow-up. However, the radial artery is associated with a significantly higher incidence of conduit spasm and string sign. In addition, to date, no study has shown a survival advantage of radial artery over SVG grafting. Also, patency is much worse if the radial grafts are not placed on critically stenotic vessels.  Gastroepiploic artery. The gastroepiploic artery is rarely used today, although some centers in Asia still use gastroepiploic grafts and continue to report acceptable outcomes associated with them. Evidence from RCTs and a recent metaanalysis suggests that the saphenous vein has better early (6-month) and midterm (3-year) graft patency than the right gastroepiploic artery when it is used for RCA revascularization.  Total Arterial Revascularization More than 90% of all CABG operations performed in the United States, United Kingdom, and Australia involve only one arterial graft.46,47 The LIMA and SVG remain the standard CABG grafts; SVGs account for most of the conduits used. In an effort to ameliorate the shortcomings of SVGs, which are vulnerable to atherosclerosis and stenosis over time, some centers have been heavily emphasizing total arterial revascularization in which the LIMA, right IMA, and radial arteries are used. Results from retrospective series have shown some survival benefit with total arterial revascularization, as would be expected. However, there are certain pragmatic reasons that total arterial revascularization has not totally replaced the use of SVGs: • Concern about arterial spasm: Arterial grafts, particularly radial grafts, are prone to spasm, and their use necessitates vasodilator administration

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• U  se of arterial grafts appropriate only for severely stenotic arteries as they are more vulnerable to competitive flow compared to veins: Most experts would not use a radial graft unless there is at least 70% stenosis and probably 90% or more for larger vessels such as the main right coronary • Inadequate length: As an in situ graft, the right IMA is typically not long enough to reach the PDA, mid or distal circumflex, or distal LAD and cannot be used easily as a sequential graft. It can, however, be used as a free graft • Concern about sternal nonunion and mediastinitis: There is a higher risk of sternal nonunion and mediastinitis with the use of BIMA grafts versus SVGs. Most experts will not use BIMA grafts in patients with poorly controlled diabetes, severe PVD, use of steroids, severe chronic obstructive pulmonary disease, or morbid obesity. Also, in the event that BIMA is used, most would recommend the skeletonized technique of BIMA harvest with preservation of the intercostal blood supply • Longer operative times: Using BIMA grafts obviously prolongs operative times Because of all these practical considerations, multiarterial revascularization has not become as popular as would be expected, and most surgeons would offer total arterial revascularization only to younger patients because of their longer life expectancy.  Cannulation for Cardiopulmonary Bypass Cannulation for the establishment of CPB commences after conduit harvest and preparation are completed, the pericardium is opened, and the thymus is divided along the embryologic fusion plane. The patient is fully heparinized at a dose of 3 mg/kg. A purse-string is created on the anterior surface of the distal ascending aorta at the cannulation site. The aortic purse-string should involve only a partial thickness of the aorta, incorporating the adventitia and media but entirely avoiding the intimal layer. It is essential that the cannulation site be free of calcified plaques or atheroma to minimize the chance of embolization and cannulation site bleeding. Manual palpation, the commonly practiced method of assessment, is unreliable. Doppler transesophageal or epiaortic ultrasonographic guidance should be used whenever aortic disease is suspected. Also, the presence of calcium elsewhere in the ascending aorta may preclude safe clamp application. Although cannulation of the aorta may be a simple task, loss of control of the aortic cannulation site or inadvertent dissection could lead to a disastrous situation. With a sharp scalpel, the adventitia is teased, and a full-thickness stab incision is made. The aortic cannula is inserted with the outflow bevel aimed toward the aortic arch. Tourniquet snares are used to secure the cannula in position and are tied. After the cannula is de-aired, it is connected to the arterial line of the CPB circuit. Alternative sites of arterial cannulation include the femoral artery and right axillary artery, which are used in reoperations or cases in which concomitant complex aortic and arch reconstruction may be required. Axillary artery cannulation is usually achieved with an 8-mm graft anastomosed end to side to the axillary artery. For venous cannulation, a purse-string is then placed around the right atrial appendage. The tip of this appendage is amputated, and a dual-stage venous cannula is inserted and positioned with the tip at the level of the diaphragm. The basket of the dual-stage cannula should rest in the main chamber of the right atrium to capture drainage from the superior vena cava into the right atrium (Figs. 60.12 and 60.13). 

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SECTION XI  Chest

Aortic cannula

Pulmonary artery

Aortic crossclamp Ascending aorta

Venous cannula

Antegrade cardioplegia cannula Retrograde cardioplegia cannula

FIG. 60.12  Surgeon’s view of the heart after cannulation. The crossclamp isolates the aortic root and coronary vessels from the rest of the systemic circulation. This allows administration of cardioplegia solution in a closed circuit and prevents the systemic blood from washing the cardioplegia solution out of the coronary system during the arrest phase. Applying the cross-clamp prevents active blood flow through the coronary arteries and thus allows the surgeon to perform the distal anastomoses in a bloodless field.

FIG. 60.13  Aortic cannula (top): The specially designed tip is angulated to allow laminar flow of blood into the aortic arch. Dual-stage venous cannula (bottom): The first stage is the fenestrated basket that usually rests at the level of the hepatic veins and captures all venous return from the inferior vena cava. The second-stage basket is located such that it remains within the right atrium and captures venous return from the superior vena cava, azygos vein, coronary sinus, and direct collateral drainage into the right atrium. The venous drainage is a passive siphon aided by gravity.

Cardiac Arrest and Myocardial Protection The initiation of CPB allows the heart to be stopped. To achieve cardiac arrest, a large dose of potassium solution (cardioplegia) is injected into the coronary vessels. This requires the coronary blood flow to be completely isolated from the systemic circulation, which is done by applying a cross-clamp to the ascending aorta proximal to the aortic cannula. There are several different delivery options for cardioplegia solutions. One involves taking a balanced approach; the cardioplegia solution is administered antegrade through the ascending aorta proximal to the cross-clamp and then retrograde through a coronary sinus catheter inserted through a purse-string suture placed in the right atrium by use of special cannulas (Fig. 60.14). The extensive collateralization among the coronary veins and arteries and the paucity of valves in the coronary vein system ensure a relatively

FIG. 60.14  Retrograde cardioplegia cannula (bottom) used to administer cardioplegia solution into the coronary sinus. The self-inflating balloon distends, forming a seal only when cardioplegia solution is administered. Antegrade cardioplegia cannula (top) used to administer cardioplegia solution into the aortic root. The side port functions as a sump.

homogeneous distribution of cardioplegia solution when the retrograde approach is used. Patients with high-grade proximal lesions, especially those with suboptimal collateral vessels, may benefit from the application of both techniques. After the initial administration of cardioplegia solution, additional doses are usually administered every 15 to 20 minutes. An antegrade cardioplegia line with a Y-connector to the circuit is inserted into the ascending aorta. This allows antegrade administration of cardioplegia solution and also sumping and decompression of the ascending aorta while cardioplegia solution is administered retrogradely into the coronary sinus. The sump drain also functions to keep the coronary arteries free of any blood, thus providing the surgeon with a bloodless field in which to fashion the distal anastomoses. In addition, the sump drain performs the important function of decompressing the LV while the heart is arrested (see Figs. 60.7 and 60.12). The most important task for ensuring myocardial protection is establishing complete diastolic arrest with an unloaded heart. In this state, the myocardial consumption of adenosine triphosphate is extremely low and allows maximal preservation of myocytes. In conventional CABG with total CPB, the decompression of the ventricle by off-loading, systemic cooling, topical cooling, and diastolic arrest of the heart with potassium cardioplegia solution serves to decrease myocardial oxygen consumption. Approximately 40% of the myocardial metabolic demand is eliminated when total CPB is established before diastolic arrest and cooling are instituted.  Target Identification and Distal Anastomosis Once successful diastolic arrest of the heart is accomplished, the target coronary arteries to be bypassed are identified. Some of the epicardial conductance vessels are intramyocardial and therefore may not be directly visible. Once a target vessel is identified, it is opened with a sharp blade. Typically, the arteriotomy is approximately 5 mm long. The conduit, which is prepared and spatulated, is then grafted in an end-to-side fashion with running 7-0 or 8-0 Prolene suture. This component of the operation is technically the most challenging and requires precision. The flow and integrity of each vein conduit are tested by flushing it with cold blood or cardioplegia solution mix. The LIMA to left descending artery anastomosis is usually the last one to be performed (Fig. 60.15) because it is best to avoid manipulating the heart once this anastomosis is completed in case avulsion of the LIMA conduit occurs. Bypassing the PDA and obtuse marginal targets requires lifting the apex of the heart out of the pericardium.

CHAPTER 60  Acquired Heart Disease: Coronary Insufficiency

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Left internal mammary artery bypass

Saphenous vein bypass

FIG. 60.16  Alternative configuration for a three-vessel coronary artery

FIG. 60.15  Technique of constructing the distal anastomoses: left internal mammary artery to left anterior descending artery, magnified surgeon’s view. A 5-mm longitudinal arteriotomy is made on the coronary artery to be bypassed. The distal end of the left internal mammary artery is spatulated to an appropriate size match. A 7-0 Prolene suture is used to create the anastomosis with a parachuting technique.

Typically, a single segment of conduit is anastomosed to each planned distal target. On occasion, a single conduit can be used to supply blood to two targets, which is known as a sequential anastomosis. This is a good technique to use when there is a shortage of available vein conduits or when the target vessels are small; in these cases, use of this technique ensures a higher rate of blood flow through the vein conduit, reducing the risk of graft thrombosis (Fig. 60.16). As the last distal anastomosis is being completed, the patient is warmed back to physiologic temperature. The cross-clamp is released after the final dose of warm cardioplegia solution is administered, which helps in scavenging the accumulated free radicals in the myocardium. A partial clamp is then applied to the ascending aorta, and the proximal anastomoses are constructed in an end-toside fashion with running 5-0 Prolene suture. If there are concerns about the quality of the aorta, use of a partial clamp is typically avoided in favor of a single-clamp technique, which involves constructing the proximal anastomoses on an arrested heart, as for the distal anastomoses. In patients in whom the ascending aorta is calcified or a free IMA pedicle needs to be used, a branching pattern of proximal anastomoses is made. This conserves vein length to a certain extent but also minimizes the number of aortotomies, especially if the ascending aorta is short or a concomitant aortic procedure has been performed. The ascending aorta is allowed to de-air as the aortic clamp is released, after which the vein grafts are de-aired. 

bypass. The left internal mammary artery is anastomosed sequentially to a diagonal branch and to the distal left anterior descending artery. Aortocoronary bypasses are constructed with reversed saphenous vein in sequential configuration to the left posterolateral artery and an obtuse marginal branch of the circumflex coronary artery. The ideal configuration depends on the extent and distribution of the coronary blockages.

Separation from Cardiopulmonary Bypass Separation from CPB commences once the following physiologic criteria have been met: • Resumption of rhythmic electromechanical activity • Attainment of physiologic temperature above 36.5°C • Availability of adequate reserve blood volume • Restoration of normal systemic potassium levels • Resumption of ventilation with an acceptable arterial blood gas level A few other actions that may be considered at this point are placement of temporary pacing wires and insertion of an IABP, if needed. Typically, the CPB flows are progressively decreased as the following parameters are closely observed: • Data from the Swan-Ganz catheter • Direct visual observations of cardiac function and chamber volume • The transesophageal echocardiogram Most patients have a transient systemic inflammatory response, causing vasodilation that becomes more pronounced as they are warmed. Thus, restoration of volume with intravascular fluids or administration of vasopressors may be necessary to maintain systemic blood pressure. Inotropic agents may be used if ventricular function is not adequate. Separating patients from CPB is primarily the surgeon’s responsibility but requires dynamic communication with the perfusionist and anesthesiologist. After CPB is discontinued, the venous cannula is removed and the purse-string is tied down. Once it is confirmed that the heart is

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providing satisfactory perfusion, protamine is administered. Close monitoring is needed because adverse reactions to protamine range from transient hypotension to fatal anaphylaxis. Such reactions necessitate the resumption of CPB. 

pressure, cardiac output, and peripheral perfusion while minimizing myocardial stress. Urine output is the most reliable indicator of peripheral organ perfusion. 

Hemostasis As protamine is being administered, hemostasis is expeditiously accomplished. As the patient rewarms, blood vessels that had been hemostatic may dilate and rebleed. Persistent bleeding should alert the surgeon to the following possible causes: aspects of the surgical technique, platelet dysfunction, inadequate protamine reversal, and hypothermia. The administration of blood and blood products may be necessary. 

For patients whose profound myocardial dysfunction is unresponsive to volume resuscitation and significant pharmacologic therapy, IABP support may be indicated. The IABP is a special Silastic balloon with a capacity of 40 to 60 mL that is positioned in the descending aorta just beyond the origin of the left subclavian artery. The balloon is designed to be actively inflated and deflated during each cardiac cycle; its timing is controlled by a specially designed computer with input from an arterial line tracing or ECG. Intra-aortic balloon counterpulsation has the benefit of decreasing myocardial work and oxygen consumption while increasing coronary perfusion. The balloon is actively deflated just before systolic contraction begins, thereby decreasing LV impedance and assisting in the ejection of blood. The balloon then actively inflates at the time of aortic valve closure; that is, it is timed to occur at the dicrotic notch of the arterial line tracing. This increases the diastolic perfusion pressure and improves coronary blood flow, both of which decrease the time-tension index and increase the diastolic pressure-time index, thereby increasing the myocardial oxygen supply-to-demand ratio. The use of IABP is absolutely contraindicated in patients with aortic regurgitation and aortic dissection. It is relatively contraindicated in patients with PVD or aortic aneurysm. 

Sternal Closure and Completion of Surgery The chest tube and temporary pacing wires should be checked for appropriate positioning. The sternum is approximated with stainless steel wires. The soft tissues and skin are closed in layers with absorbable sutures. 

ADJUNCTS TO CORONARY ARTERY BYPASS GRAFTING Transesophageal Echocardiography Use of transesophageal echocardiography (TEE) enables the assessment of ventricular wall motion abnormalities and the detection of any chamber or valve anomalies that may change the strategy of the operation. Examples of TEE findings that may affect the conduct of the operation include an incidentally discovered large patent foramen ovale or fibroelastoma of the valves. New-onset or worsening mitral regurgitation after CABG suggests inferior wall ischemia and may indicate reevaluation of the bypass grafts or valve repair or replacement. Also, TEE helps in assessing ejection fraction and the volume status of the heart after surgery. 

Inotropes and Pharmacotherapy Cardioplegic arrest causes transient myocardial ischemia and lactic acid accumulation. After perfusion is reestablished, the ventricles are stiffer and require higher filling pressures to maintain adequate stroke volume. Also, CPB may cause significant third spacing and vasodilation. Thus, epinephrine as an inotropic agent is ideal to maintain adequate contractility in the initial recovery phase and during separation from CPB. Alpha agonists such as norepinephrine, phenylephrine, and vasopressin may be used to counteract the effects of inflammatory vasodilation. In patients with depressed myocardial function, such as left- or right-sided heart failure, dobutamine or a phosphodiesterase inhibitor such as milrinone may be required to enhance myocardial contractility and to decrease afterload or pulmonary vascular resistance. Because hypotension is a common side effect of these drugs, the systemic volume must be adequate, and an alpha agonist may be required. Calcium channel blockers or nitroglycerin may be needed in patients with preexisting hypertension. It is essential to maintain a mean arterial pressure higher than 60 mm Hg in the initial postoperative period, but hypertension should be avoided because it puts stress on a myocardium that is trying to recover and increases the risk of bleeding from anastomotic suture lines. Blood pressure management requires a thorough understanding of physiologic and pharmacologic principles. It is a balancing act geared toward maintaining adequate systemic

Intraaortic Balloon Pump

POSTOPERATIVE CARE Postoperative care in the intensive care unit (ICU) begins with a thorough physical and hemodynamic assessment. Mediastinal chest tube drainage should be recorded and assessed hourly. Initial ventilator settings should be set to match those in the operating room. Further adjustments in ventilator settings are made according to the postoperative blood gases. High positive end-expiratory pressure should be avoided in patients with hemodynamic instability. The ideal mode of ventilation is that with which the surgical or intensive care team is comfortable. A portable chest radiograph is obtained to confirm the position of the endotracheal tube, central lines, Swan-Ganz catheter, and IABP and to identify any pneumothorax, atelectasis, pulmonary edema, or pleural effusions. Initial laboratory studies should include hemoglobin, hematocrit, electrolyte, blood urea nitrogen, creatinine, and arterial blood gas levels and platelet count, prothrombin time, and partial thromboplastin time. The patient should have an ECG monitor that can assess ST-T wave abnormalities; an arterial line to measure arterial blood pressure; and a line to measure central venous pressure, pulse oximetry, and core temperature. In select patients, pulmonary artery pressures and cardiac output are monitored continuously with a Swan-Ganz catheter. Neurologic assessment should be completed as soon as the patient wakes up to ensure that no cerebrovascular accident has occurred. The primary considerations during the first 12 hours after the operation should be maintaining adequate blood pressure and cardiac output, correcting coagulation defects and electrolyte levels, stabilizing intravascular volume, and normalizing the peripheral vascular resistance. This often involves administration of crystalloid solutions, blood or blood products, inotropic agents, calcium, and vasodilators or vasoconstrictors.

CHAPTER 60  Acquired Heart Disease: Coronary Insufficiency

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Some of the goals in the postoperative period are as follows: • A  voiding marked elevations in blood pressure • Maintaining adequate perfusion pressure (60–80 mm Hg) • Maintaining core body temperature higher than 36.5°C by warming the patient with forced hot air blankets • Maintaining adequate cardiac output and a cardiac index of 2.2 L/min/m2 • Keeping mixed venous oxygenation at 60% • Reducing afterload, as appropriate, to minimize myocardial work • Volume resuscitation with crystalloid or blood products, as necessary • Maintaining hemoglobin level higher than 8 g/dL, or higher than 10 g/dL in older patients or those with severe cerebrovascular disease • Maintaining homeostatic pH. Metabolic acidosis may be caused by hypoperfusion from low cardiac output, poor resuscitation, hypovolemia, or end-organ ischemia from embolism. • Monitoring neurologic and peripheral vascular status • Maintaining a sinus or perfusing rhythm at a rate of 70 to 100 beats/min • Monitoring for and treating postoperative cardiac arrhythmias • Ensuring adequate pain control to minimize fluctuations in blood pressure and myocardial stress • Keeping blood glucose levels below 180 mg/dL. Standardized insulin-infusion regimens should be initiated, if needed

In cardiac surgery, operative mortality has traditionally included 30-day and in-hospital mortality. The mortality figure for CABG is 1% to 3% in most modern series. Risk-adjusted outcomes have become the gold standard for reporting and comparing cardiac surgery outcomes. The STS database is the largest and most authoritative voluntary national database to date. The STS has developed a risk calculator that estimates morbidity and mortality for a given patient’s risk profile. The observed-to-expected mortality ratio for a given surgeon or institution can then be determined. 

Pulmonary Care

Tamponade. Pericardial tamponade is caused by the formation of pericardial clot and compression of the heart. The condition should be suspected if there is evidence of low cardiac output, hypotension coincident with tachycardia, and elevated central venous pressure. The quantity of mediastinal drainage is an unreliable predictor of tamponade, although an abrupt decline in mediastinal chest tube drainage should raise suspicion of tamponade caused by absence of an exit path for the blood. Widening of the mediastinum on chest radiography and echocardiographic evidence of a pericardial effusion should confirm the diagnosis. If a Swan-Ganz catheter is in place and right- and left-sided heart pressures are monitored, the central venous pressure and pulmonary capillary wedge pressure are usually elevated and equal. The earliest manifestation of tamponade is an acute drop in mixed venous oxygen saturation. After the diagnosis is made, the patient should be returned to the operating room for evacuation of the clot and relief of the compression. If the patient’s condition is rapidly deteriorating, the sternotomy incision may have to be reopened at the bedside.  Postoperative bleeding. The combination of heparinization, hypothermia, CPB, and protamine reversal is associated with increased risk for bleeding after CABG. Post-CABG bleeding that requires transfusion or reoperation is associated with a significant increase in morbidity and mortality risk. A minority of patients having cardiac procedures (15%–20%) consume more than 80% of all blood products transfused at operation. Blood must be viewed as a scarce resource that carries significant risks and unproven benefits. There is a high-risk subset of patients who require multiple preventive measures to reduce the chance of postoperative bleeding. Nine variables stand out as important indicators of risk (Box 60.5). Available evidence-based blood conservation techniques include the following: • Administration of drugs that increase preoperative blood volume (e.g., erythropoietin) or decrease postoperative bleeding

It is desirable to separate patients from the ventilator as soon as they awaken, are hemodynamically stable with minimal chest tube drainage, and can maintain a satisfactory spontaneous tidal volume and respiratory rate. Coughing and deep breathing exercises with appropriate sternal precautions are essential for postoperative recovery. Suboptimal postoperative pulmonary function may indicate additional therapy, including the use of bronchodilators, mucolytics, and chest physical therapy. Although β-adrenergic bronchodilators and N-acetylcysteine are useful adjuncts, they also can induce atrial fibrillation. After extubation, it is important to provide the patient with sufficient pain relief to minimize emotional distress, poor coughing, and reluctance to begin ambulation. Unrelieved pain can also be a source of tachycardia, hypertension, myocardial ischemia, atelectasis, hypoxia, and pneumonia. 

Discharge From the Intensive Care Unit Before the patient leaves the ICU, unnecessary lines and catheters should be removed. Chest tubes are removed approximately 48 hours postoperatively, when the combined drainage is less than 200 mL per shift and chest radiography reveals no effusion. Removal of temporary atrial and ventricular pacing wires is often deferred to the third postoperative day. 

Outcomes Hospital Mortality Seven core variables—emergency of operation, age, prior heart surgery, gender, LVEF, percentage stenosis of LCA, and number of major coronary arteries with more than 70% stenosis—have the greatest impact on CABG mortality. Other variables are important but have minimal impact when added to these core variables; these include recent MI (70 years) and hypertension are consistent risk factors for both types. History of previous neurologic

abnormality, diabetes, and atherosclerosis of the aorta are risk factors for type I. Significant atherosclerosis of the ascending aorta mandates a surgical approach that will minimize the possibility of atherosclerotic emboli. Patients with concomitant carotid stenosis are at an elevated risk for neurologic complications. One approach used in such patients involves a staged procedure in which the more symptomatic and more critical vascular bed is addressed first. Otherwise, a combined approach may be used, but this poses a greater overall risk.  Mediastinitis. The incidence of deep sternal wound infection is 1% to 2% in modern-era CABG. Risk factors include obesity, reoperation, diabetes, and duration and complexity of operation. Using a BIMA graft can increase the risk of sternal wound complications in high-risk patients. The use of perioperative antibiotics and a strict protocol aimed at controlling the blood glucose level to less than 180 mg/dL by continuous intravenous infusion of insulin has been shown to reduce the incidence of mediastinitis significantly. Early debridement and muscle flap closure improve outcome. More recently, good outcomes have also been reported with the use of wound vacuum-assisted closures after adequate debridement.  Renal dysfunction. Mangano and coworkers have reported a 7.7% incidence of postoperative renal dysfunction in CABG patients and mortality rates of 0.9%, 19%, and 63% in patients without postoperative renal dysfunction, patients with postoperative renal dysfunction but without need for dialysis, and patients who required dialysis, respectively. The 63% figure was confirmed in a large Veterans Administration study. 

Medical Adjuncts for Postoperative Management The following drugs are considered essential components of the postoperative management of CABG patients: • Aspirin administration, 81 to 325 mg orally or rectally, is begun on the same day after CABG, unless the patient is bleeding because of platelet dysfunction. This is a quality-of-care index and has been shown to improve long-term graft patency • Beta blocker administration should begin after all inotropes have been discontinued. The goal is to maintain a heart rate of 60 to 80 beats/min and adequate mean perfusion pressures • Afterload reduction is important in all patients with a low LVEF. Afterload reduction is commenced after all inotropes are discontinued and adequate beta blockade is achieved. The angiotensin-converting enzyme inhibitors are first-line drugs for afterload reduction. Creatinine levels should be monitored • For antiarrhythmic treatment, amiodarone is used in many cardiac centers as prophylaxis against or treatment of atrial fibrillation. This drug should be used with caution in patients with preexisting interstitial lung disease and those taking warfarin. A prolonged Q-T interval is a contraindication • Administration of furosemide, a diuretic, is begun on the first postoperative day; the goal is to maintain a negative fluid balance. Chest radiography, creatinine levels, physical examination, and input-output charts help guide the dose of furosemide 

ALTERNATIVE METHODS FOR MYOCARDIAL REVASCULARIZATION Cardiopulmonary Bypass With Hypothermic Fibrillatory Arrest Hypothermic fibrillatory arrest is a good on-pump alternative to conventional cardioplegic arrest and avoids the use of the aortic

CHAPTER 60  Acquired Heart Disease: Coronary Insufficiency cross-clamp. Although cardioplegic arrest offers maximal myocardial protection while providing a stable, immobile target for the distal anastomoses, not all patients are amenable to cardioplegiabased arrest. In patients with an extensively calcified aorta, crossclamp application may be precarious and associated with an elevated incidence of stroke. In these cases, a hypothermic fibrillatory arrest strategy may be used in which aortic manipulation is minimized. Once CPB is initiated, the patient is cooled to 28°C. The heart typically begins fibrillating at approximately 32°C. An LV sump is usually introduced through the right superior pulmonary vein to ensure LV decompression. Handling of the distal and proximal targets is similar to off-pump CABG (OPCAB) techniques because the coronary arteries are still fully perfused while the anastomoses are being performed. Vessel loops or occluders may be needed. In patients with extensive aortic calcification, there may not be any room to place an aortic cannula in or a proximal vein graft on the ascending aorta. In these cases, the right axillary artery may be used for arterial perfusion, and the saphenous vein can be anastomosed to the innominate artery if it is free of disease, or a total arterial vascularization approach should be considered with the use of one or both mammary arteries. Once the anastomoses are completed, the patient is rewarmed to physiologic temperature and the heart is defibrillated into sinus rhythm. The use of hypothermic fibrillatory arrest is contraindicated in patients with significant aortic valve incompetence because the ventricle would distend with the regurgitant blood once fibrillation sets in, and no stroke volume is generated. Increased ventricular wall tension and energy consumption could lead to myocardial ischemia. 

On-Pump Beating-Heart Bypass On-pump beating-heart bypass is a selective strategy used for patients who have a very low LVEF and have suffered a recent MI. The logic behind this approach is that the myocardium is severely compromised and would poorly tolerate further ischemic compromise. Despite currently available techniques for myocardial protection, cardioplegic arrest is always associated with a certain degree of ischemia. This is especially true in patients with severe CAD and a stunned myocardium, in whom uniform protection of the ventricle with cardioplegia may be difficult to achieve, and an on-pump beating-heart strategy can be considered. The coronary arteries continue to be perfused, and exposure and handling of the anastomoses are similar to those for OPCAB. The use of CPB offloads the ventricle and offers a safety margin to manipulate the heart and to visualize all the targets that need to be bypassed. Use of IABP should be considered for most of these patients because their hemodynamic state is precarious to begin with. 

Off-Pump Coronary Artery Bypass Grafting The main rationale for using OPCAB was to avoid the adverse effects of CPB related to the systemic inflammatory response caused by contact of blood components with the surface of the bypass circuit. This hypothesis, although not supported by much sound scientific clinical data, spawned the belief that CPB contributed to various adverse outcomes, including postoperative bleeding, neurocognitive dysfunction, thromboembolism, fluid retention, and reversible organ dysfunction. Because OPCAB eliminated the use of a CPB circuit and could potentially reduce some of these pump-associated complications, there was a great enthusiasm for OPCAB. In fact, throughout Asia and particularly in India, 95% of CABG operations are still performed off-pump.

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In a nationwide review of the STS database by Bakaeen and colleagues, the use of off-pump procedures peaked in 2002 (23%) and again in 2008 (21%), followed by a progressive decline in off-pump frequency to 17% by 2012. Interestingly, after 2008, off-pump rates declined among both high-volume and intermediate-volume centers and surgeons, and currently in the United States, this technique is used in fewer than one in five patients who undergo surgical coronary revascularization. A minority of surgeons and centers, however, continue to perform OPCAB in most of their patients. This decline in OPCAB is presumably due not only to the procedure’s technical complexity and steep learning curve but also, and more important, to the decreased long-term patency, higher rate of incomplete revascularization, and inferior long-term survival associated with OPCAB. Data from multiple studies have not supported the belief that OPCAB decreases inflammatory mediator release. Some investigators have shown that even though complement activation may be reduced, there is no difference in production of cytokines and chemokines that modulate neutrophils and platelets.43,48 In addition, myocardial ischemia by itself activates complement such as C5b-9. Thus, great caution should be used in interpreting studies regarding activation of the inflammatory cascade. The Randomized On/Off Bypass (ROOBY) trial was a prospective RCT of CABG and OPCAB that involved 2203 patients at 18 Veterans Affairs medical centers. There was no difference in 30-day mortality or short-term major adverse cardiovascular events. The OPCAB patients received significantly fewer grafts per patient. One-year rates of cardiac-related death (8.8% vs. 5.9%; P = 0.01) and major adverse events (9.9% vs. 7.4%; P = 0.04) were significantly higher in the OPCAB group. Furthermore, graft patency was significantly lower in the OPCAB group (82.6% vs. 87.8%; P < 0.001). The results did not differ when the operation was performed by a resident or attending physician or by a highor low-volume surgeon. The Surgical Management of Arterial Revascularization Therapy (SMART) trial examined long-term survival and graft patency in a prospective RCT involving 297 patients who underwent isolated elective CABG or OPCAB. After 7.5 years of follow-up, there was no difference in mortality or late graft patency between OPCAB and on-pump CABG. Although recurrent angina was more common in the OPCAB group, this difference did not reach statistical significance. Hence, this study, performed by one of the world’s experts in OPCAB surgery, could not demonstrate any superiority of OPCAB over on-pump CABG. Another prospective study, the Coronary Artery Bypass Surgery Off or On Pump Revascularization Study (CORONARY) trial, involved 4752 patients randomly assigned to either CABG or OPCAB at 79 centers in 19 countries. There were no significant differences in the incidence of recurrent angina between the OPCAB (0.9%) and CABG (1.0%) groups, but the need for repeated revascularization was higher in the OPCAB group, and the difference approached statistical significance (1.4% OPCAB vs. 0.8% CABG; P = 0.07). The CORONARY trial included twice as many participants as the ROOBY trial. Each off-pump procedure was performed by an experienced surgeon who had more than 2 years of experience and had performed more than 100 OPCAB cases. Trainees were not allowed to be the primary surgeon. The rate of crossover from the off-pump to the on-pump group was lower in the CORONARY trial (7.9% versus 12.4%), suggesting a higher level of surgical expertise. Despite the improved technical experience of

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highly qualified off-pump surgeons, the need for revascularization remained higher in the off-pump group. In the German Off-Pump Coronary Artery Bypass Grafts in Elderly Patients (GOPCADE) trial, patients aged 75 years and older scheduled for isolated bypass surgery were randomly assigned to on-pump or off-pump surgery. The trial was undertaken to attempt to define the potential benefits of OPCAB in an elderly group of high-risk patients with multiple comorbidities. The study involved 2539 patients from 12 centers. The primary end point was the composite of death or major adverse events (MI, cerebrovascular accident, acute renal failure requiring renal replacement therapy, or need for repeated revascularization) within 30 days and within 12 months after surgery. The secondary end points included operating room time, duration of mechanical ventilation, transfusion requirements, and ICU and hospital length of stay. There was no difference in the primary composite end point (7.0% off-pump vs. 8.0% on-pump; P = 0.40). However, additional revascularization procedures within 30 days were more frequent in the off-pump group (1.3% vs. 0.3%; P = 0.03). Patients in the off-pump group were less likely to receive blood products; however, the study had no protocols to determine when transfusions should be given. There was no difference in any of the other secondary end points. The mean number of grafts was significantly lower in the off-pump group (2.7 vs. 2.8; P < 0.001). The investigators concluded that OPCAB did not improve outcomes in these elderly high-risk patients. Furthermore, concerns were raised that the increased need for early repeated revascularization and the decreased number of grafts in the off-pump group would lead to an increased incidence of future cardiovascular events, thus exposing these elderly patients to increased morbidity and mortality. These findings have dampened the enthusiasm for OPCAB at most centers. However, it is our practice to offer OPCAB to patients with single-vessel CAD in the LAD system. The technique and operative strategy of OPCAB differ significantly from those of on-pump CABG. Certain adjuncts are needed to provide adequate exposure of the coronary vessels. Because the heart is fully contractile and maintaining systemic perfusion, the manipulation should proceed in a planned and systematic manner. Both the pleural spaces are opened to allow the heart to rotate into either side to allow the surgeon to visualize the targets, especially the lateral and inferior wall. The more critical areas of the myocardium are revascularized first, which minimizes ischemia time, improves myocardial reserve, and permits more complex manipulation of the heart for the other targets. Mammary artery–based pedicles are typically approached first because these do not require a proximal anastomosis, thus providing immediate coronary blood flow to the bypassed vessel. Once the target vessel is selected, a small area of the coronary artery is exposed proximal and distal to the planned area of anastomosis to allow placement of vessel loops or bulldog clamps for proximal and distal control. A coronary occluder may also be used. Two stabilizers are used to stabilize the myocardium (Fig. 60.17). The fork-octopus has a suction padded tip and is attached to a multifunctional arm. The fork is positioned so that the limbs straddle the coronary target, and suction is applied, which attaches the device to the myocardium while the arm is secured in position. The other device consists of a suction cup that is applied to the apex of the heart and is used to lift it out of the chest to expose its posterior aspect. A sling attached to the posterior pericardium allows the heart to be elevated out and enhances visualization of the posterior targets.

FIG. 60.17  Off-pump coronary artery bypass with vacuum-assisted multiarticulating arms to position and to stabilize the myocardium. This minimizes the movement of the heart, allowing the surgeon to feasibly perform the distal anastomoses. Here, the stabilizer is positioned in preparation for creating a bypass to the left anterior descending artery.

Full heparinization is not needed; in general, 50% of the usual dose is used. Success of the operation requires coordinated efforts between the surgeon and anesthesiologist so that adequate systemic perfusion is maintained throughout the operation while allowing a comfortable milieu in which the surgeon can operate. Short-acting beta blockers to slow the heart rate and alpha constrictors to maintain systemic perfusion pressures are important adjuncts for this procedure. The postoperative management of OPCAB patients is significantly different from that of patients who undergo conventional CABG, primarily because of the reduced inflammatory effects, which are more prominent in patients who have undergone CPB. The OPCAB patients do not manifest the vasodilatory response or massive fluid shifts seen with CPB. Rather, these patients are more like those who have undergone major general surgery and require early deep venous thrombosis and balanced postoperative fluid management. In our practice, all patients who undergo OPCAB are given aspirin and clopidogrel (Plavix) on the day of surgery. 

Minimally Invasive Direct Coronary Artery Bypass Minimally invasive direct coronary artery bypass (MIDCAB) describes any technique of coronary artery bypass that uses a minimally invasive approach, such as an anterolateral thoracotomy (Fig. 60.18), ministernotomy, or subxiphoid approach, without the use of a robot. Most MIDCABs are performed on the beating heart and involve vascularization of the anterior wall. A metaanalysis of all published outcome studies of MIDCAB grafting performed from January 1995 through October 2007 has revealed early and late (>30 days) death rates of 1.3% and 3.2%, respectively. Of the grafts that were studied angiographically immediately after

CHAPTER 60  Acquired Heart Disease: Coronary Insufficiency

Left internal mammary pedicle

Left anterior descending artery Pericardium

Off-pump vacuumassisted stabilizer

FIG. 60.18  Left thoracotomy approach for performing off-pump left internal mammary to left anterior descending bypass. This is commonly used in the minimally invasive direct coronary artery bypass approach. Multiarticulating stabilizers are essential for this technique.

surgery, 4.2% were occluded and 6.6% had a significant stenosis (50%–99%). At 6-month follow-up, 3.6% were occluded and 7.2% had significant stenosis. Long-term follow-up results and further prospective RCTs comparing MIDCABs with standard revascularization procedures in large patient cohorts are needed. Although MIDCAB offers several advantages, such as the avoidance of sternotomy and CPB, it is subject to the same limitations as OPCAB in addition to its own technical challenges and limited revascularization territory. 

Robotics: Totally Endoscopic Coronary Artery Bypass With the popularity of robotic technology in other surgical specialties, robotic totally endoscopic coronary artery bypass (TECAB) has been in use at select centers. Robotically assisted microsurgical systems have the theoretical advantage of enhancing surgical dexterity and minimizing the invasiveness of otherwise conventional coronary artery surgery. The da Vinci system (Intuitive Surgical, Mountain View, CA) is the most commonly used system. It consists of three major components: surgeon-device interface module, computer controller, and specific patient interface instrumentation. It allows real-time surgical manipulation of tissue, advanced dexterity in multiple degrees of freedom, and optical magnification of the operative field, all through minimal access ports. The technology has seen significant use in valve repair operations and other surgical specialties as well. With regard to coronary artery bypass, TECAB can be performed on-pump or totally off-pump, and multivessel TECAB is currently a reality. However, operating times and conversion rates are much higher with this technology. More important, it is technically more difficult and expensive, and it has a steep learning curve. Long-term data regarding its durability and safety are unavailable at this point. In the largest TECAB series to date (about 500 cases), success and safety rates were 80% (n = 400) and 95% (n = 474), respectively. Intraoperative conversion to larger thoracic incisions was required in 49 (10%) patients. The median operative time was 305 minutes (range, 112–1050 minutes), and the mean lengths

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of stay in the ICU and in the hospital were 23 hours (range, 11– 1048 hours) and 6 days (range, 2–4 days), respectively. Independent predictors of success were single-vessel TECAB (P = 0.004), arrested-heart TECAB (P = 0.027), non–learning curve case (P = 0.049), and transthoracic assistance (P = 0.035). The only independent predictor of safety was EuroSCORE (P = 0.002). Interestingly, the mean time per anastomosis was 27 minutes (range, 10–100 minutes), which is significantly longer than an average surgeon would take to accomplish an open anastomosis (i.e., well below 10 minutes per anastomosis). Also, the LIMA injury rate was high (n = 24; 5%).49 All these data point to less than perfect procedures and technology that require further development before they can replace open CABG, which has an excellent track record and is a proven and reproducible procedure. The current limitations of robotic TECAB include its lack of applicability to all patients, prolonged operating room time, limited access to all vessels, difficulty in achieving multiarterial coronary grafting, cost, and limited training opportunities. However, over time, robotic surgery is likely to become a niche specialty for a subset of surgeons who treat a specific population of patients. 

Transmyocardial Laser Revascularization Patients with chronic, severe angina refractory to medical therapy who cannot be completely revascularized with percutaneous catheter intervention or CABG present clinical challenges. Transmyocardial laser revascularization (TMLR), either as sole therapy or as an adjunct to CABG surgery, may be appropriate for some of these patients. The STS Evidence-Based Workforce has reviewed available evidence and recommends the use of TMLR for patients with an LVEF greater than 0.30 and Canadian Cardiovascular Society class III or class IV angina that is refractory to maximal medical therapy. These patients should have reversible ischemia of the LV free wall and CAD corresponding to the regions of myocardial ischemia. In all regions of the myocardium, the CAD must not be amenable to CABG or PCI. The TMLR procedure uses a high-energy laser beam to create myocardial transmural channels that were originally thought to provide direct access to oxygenated blood in the LV cavity. This is no longer considered to be the mechanism whereby TMLR reduces the symptoms of IHD. Although some local neovascularization has been documented, the magnitude of changes does not account for any substantive increases in myocardial perfusion. One mechanism that has been proposed relates to a local effect on cardiac neuronal signaling. It has been hypothesized that local tissue injury by TMLR damages ventricular sensory neurons and autonomic efferent axons, which leads to local cardiac denervation and anginal relief. Regardless of the mechanism, TMLR therapy is associated with a reproducible improvement in symptoms. Patients who undergo TMLR show a persistent improvement in Canadian Cardiovascular Society angina class. This improvement is observed in 60% to 80% of patients within 6 months after the operation. 

Hybrid Procedures It is generally accepted that the LIMA to LAD anastomosis is the single most important component of CABG and confers longterm benefits unmatched by those of any other intervention. State-of-the-art PCIs with DES have produced outcomes competitive with those of vein grafts to non-LAD targets. This has led to an integrated approach to coronary revascularization, termed the hybrid procedure. The hybrid procedure consists of a minimally invasive LIMA to LAD anastomosis in conjunction with PCI of non–LAD-obstructed coronary arteries.

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This approach has met with initial success, but many potential pitfalls exist. The procedural costs may be greater than those of either CABG or DES implantation alone. The timing and staging of the procedures are uncertain, and limited data are available on long-term outcomes. 

Vascular clamp on internal mammary

Previous left internal mammary conduit New reversed saphenous vein graft

Technical Aspects of Reoperative Coronary Artery Bypass Grafting Within 5 years, 15% of CABG patients experience a recurrence of symptoms, typically angina. This increases to approximately 40% within 10 years. Recurrent symptoms almost always indicate either progression of disease in the native coronary circulation or graft disease. In most cases, the indications for coronary angiography, PCI with or without stenting, or repeated CABG are the same as for the first operation. Patients who are considered candidates for reoperative CABG are usually older, have more diffuse CAD, and have diminished ventricular function. Factors that increase the risk for reoperation include the absence of an IMA graft, younger age at the time of the index operation, prior incomplete revascularization, CHF, and New York Heart Association class III or class IV angina. The technical aspects of reoperative CABG differ significantly from those of the index procedure. Reentry into the chest and dissection of the old grafts are sometimes challenging. Preparation for femoral cannulation for femorofemoral bypass or axillary cannulation should be considered with preemptive availability of blood products. Redo sternotomy is typically completed with an oscillating saw or after the heart is dissected away from the sternum through a subxiphoid approach. Injury to the right ventricle or to the aorta or vein grafts is of potential concern. A poorly placed LIMA graft from the prior operation is also at risk during the sternotomy. If a cardiac or vascular injury is identified, an assistant holds the sternum together to prevent further bleeding, and expeditious cannulation of alternative sites is begun with the institution of CPB. Preoperative CT scans are helpful in planning the operation. Once the sternotomy is completed, the rest of the adherent cardiac structures are dissected away from the underside of the sternum to allow placement of a sternal retractor. No retractor should be placed unless the heart is adequately dissected away; this will result in disruption of the aorta or right ventricle, which may be difficult to control. The next steps are geared toward establishing sites for cannulation. The right atrium and aorta are dissected first; then, the rest of the heart is dissected away from the pericardium, which may be performed on CPB. The areas of previous cannulation and vein grafts are the most adherent regions, whereas the diaphragmatic aspect is least adherent and provides a good starting point to gain entry into the correct plane. Manipulation of the old grafts should be kept to a minimum to avoid distal coronary bed microembolization. Isolation of the LIMA pedicle is often necessary and should be carefully performed with the ability to start bypass rapidly if an inadvertent injury occurs (Fig. 60.19). The rest of the operation proceeds in a similar fashion to primary CABG and can be performed on-pump or off-pump. In some cases, the procedure can be performed through a left anterolateral thoracotomy approach. Typically, this approach is used in patients with previous mediastinitis or multiple sternotomies or when an extensive area of the heart is adherent to the sternum, precluding a safe entry. The vein conduit is anastomosed to the descending aorta in these cases (Fig. 60.20).

Old saphenous vein grafts

FIG. 60.19  Redo coronary artery bypass grafting. The cannulation is similar to that used in a first-time coronary artery bypass operation in most cases. However, identification of coronary targets is much more difficult because of scarring. The course of the prior grafts is useful in identifying the targets. In addition to clamping of the aorta above the previous vein grafts, the left internal mammary pedicle should be dissected and clamped separately, if feasible. A single-clamp technique is preferred because it avoids the tedious and potentially dangerous dissection around the proximal aorta that may be needed to place a partial side-biting clamp.

To summarize, some of the unique difficulties that can be encountered in redo CABG are as follows: • Injury to heart during sternotomy • Injury to mammary pedicle • Limited space on ascending aorta for placement of new grafts • Inability to identify distal targets because of scars and adhesions • Limited availability of conduits • Increased risk of perioperative MI because atheroembolic embolization from diseased vein grafts and diffuse CAD preclude optimal cardioplegia • Increased bleeding because of higher inflammatory response and a more raw surface • Injury to pulmonary artery during cross-clamping of the aorta In most published series, the mortality rate of reoperative CABG patients exceeds that of primary CABG patients. 

MECHANICAL COMPLICATIONS OF CORONARY ARTERY DISEASE Left Ventricular Aneurysm The incidence of ventricular aneurysm after AMI has been declining because of early interventional therapies. Of LV aneurysms, 90% are the result of a transmural MI secondary to an acute occlusion of the LAD. Patients may develop an aneurysm (pseudoaneurysm) as early as 48 hours after infarction, but most patients develop one within weeks. Approximately two thirds of patients who develop ventricular aneurysms remain asymptomatic. The 10-year survival rate is 90% for asymptomatic patients and 50% for symptomatic patients. The most common causes of death are arrhythmias (>40%), CHF (>30%), and recurrent MI (>10%). The risk of thromboembolism is low, so long-term anticoagulation is not recommended unless there is a mural thrombus. The

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Old saphenous vein graft

New saphenous vein graft

FIG. 60.20  Left thoracotomy approach for recurrent coronary artery disease. This approach avoids the hazards of a difficult redo sternotomy and is used as an alternative in some cases. New saphenous vein graft: descending thoracic aorta to obtuse marginal bypass.

diagnosis is usually made by echocardiography. Thallium imaging or PET is useful for determining the extent of the aneurysm and viability of adjacent regions. Surgery for LV aneurysm is indicated if the patient is scheduled to undergo CABG for symptomatic CAD, there is contained rupture or evidence of a false aneurysm, or the patient has a thromboembolic event despite anticoagulation. The 5-year postoperative survival rate has been reported to range between 60% and 80%. In general, surgical repair or resection in conjunction with CABG results in angina relief and resolution of heart failure symptoms for most patients. Surgical ventricular restoration is a technical term that describes the surgical resection of the aneurysm and reconstruction of the native ventricular geometric shape. This is ideally performed with CPB and without cardioplegic arrest as long as the aortic valve is competent. The aneurysm is usually recognized by the paradoxical movement of the walls compared with the rest of the viable LV myocardium. The aneurysm is opened, and a purse-string Fontan stitch is placed at the junction of the viable and nonviable myocardium, which can be manually palpated on the beating heart. A Dacron or bovine pericardial patch is used to exclude the aneurysm, and the aneurysm is closed over the patch. Two potentially acute complications that require surgical intervention are postinfarction VSD and postinfarction mitral regurgitation caused by papillary muscle rupture. 

Ventricular Septal Defect This occurs in less than 1% of patients and is associated with acute LAD occlusion. The defect is more common in men than in women (3:2) and typically is manifested within 2 to 4 days of the infarction. However, a VSD that occurs in the first 6 weeks after an

infarct is still considered acute. The VSD is usually located in the anterior or apical aspect of the ventricular septum. Approximately 25% of affected patients have a posterior VSD caused by an inferior wall MI due to occlusion of the RCA system or a distal branch LCA. A full-thickness infarct is a prerequisite for VSD formation. A new, loud, systolic cardiac murmur after an MI suggests the diagnosis; echocardiography is effective for determining the size and character of the VSD as well as the degree of left-to-right shunting. Right-sided heart catheterization typically shows an increase in oxygen saturation levels in the right ventricle and pulmonary artery. The defect is usually approximately 1 to 2 cm in size. After the diagnosis is established, patients should undergo immediate left-sided heart catheterization to characterize the degree of CAD and the magnitude of LV dysfunction and to detect any mitral valve insufficiency. Approximately 60% of patients with an infarction VSD have significant CAD in an unrelated vessel. The mortality rate in untreated patients is high; 25% of patients die within 24 hours of refractory heart failure. Survival rates of patients at 1 week, 1 month, and longer than 1 year are 50%, 20%, and less than 3%, respectively. Patients who are considered candidates for surgery should be treated early with closure of the defect and concomitant CABG. In the absence of refractory heart failure and hemodynamic instability, the survival rate may be as high as 75%. The infarct exclusion technique is used to repair the VSD and is one of the most technically challenging procedures. The LV is opened longitudinally on the infarct, and the defect is evaluated. Multiple VSDs may be present, and necrotic myocardium is debrided to viable tissue. A prosthetic Dacron patch or bovine pericardium is then sutured to the LV side of the septal defect and brought out through the ventriculotomy, where it is incorporated into the closure (Fig. 60.21).

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Ventriculotomy Patch Felt buttress

Anterior surface of heart

FIG. 60.21  Infarct exclusion technique for repair of acute ventricular septal defect secondary to acute myocardial infarction. A ventriculotomy is made through the zone of infarct, and all necrotic muscle is debrided. The repair is accomplished with a patch placed on the left ventricular aspect of the septum. Felt buttresses are used to reinforce the closure of the ventriculotomy, and it is essential that all sutures be incorporated into healthy myocardium to ensure durability of the repair.

In this method, the posterior aspect of the patch is thus anchored to the remnant viable septum, and the anterior aspect is incorporated with the free ventricular wall, forming the neo–interventricular septum. Felt strips are used to buttress the closure. In addition to the traditional repair of postinfarction VSD, there has been recent enthusiasm about transcatheter closure of postinfarction VSD. This obviates a pump run in an otherwise tenuous patient. In both patients treated surgically and with transcatheter closure, temporary circulatory support in the form of extracorporeal membrane oxygenation or ventricular assist device can be lifesaving. 

Mitral Regurgitation Approximately 40% of patients who sustain an AMI develop chronic ischemic mitral regurgitation (IMR) detectable by color flow Doppler echocardiography. In 3% to 4% of cases, the degree of mitral regurgitation is moderate or severe. The cause of chronic IMR is ischemic papillary muscle dysfunction and LV dilation associated with mitral annular dilation and restriction of the posterior leaflet. The operation for chronic IMR is usually performed on an elective basis. It consists of complete myocardial revascularization and mitral valve repair with the use of an annuloplasty ring. Acute IMR may result from papillary muscle necrosis and rupture caused by occlusion of the overlying epicardial arteries that give rise to the penetrating vessels that supply the papillary muscles. The posterior papillary muscle is involved three to six times

Cross-section of heart

FIG. 60.22  Mechanical complication of acute myocardial infarction. Acute papillary muscle rupture (shown here) and acute ventricular septal defect are two sequelae in a patient with extensive zones of infarct. Acute papillary muscle rupture results in acute mitral regurgitation that is manifested as cardiogenic shock and immediate pulmonary decompensation. If the patient is a surgical candidate, mitral valve replacement is the only option.

more often than the anterior muscle (Fig. 60.22), and either the entire trunk of the muscle or one of the heads to which chordae attach may rupture partially or totally. In most cases, prompt surgical intervention provides the best chance for survival. Predictors of in-hospital death include CHF, renal insufficiency, and multivessel CAD. Emergent surgical treatment usually involves mitral valve replacement and concomitant CABG. The hospital mortality rate may be as high as 50% in acute cases. Mitral repair should not be attempted in such cases because it may not be feasible in papillary muscle rupture; it requires prolonging the cross-clamp time (compared with replacement), which is not ideal in acute cases. Operations on patients with acute mechanical complications from MI are challenging; the surgeon has to anticipate and be prepared for placement of an LV assist device if the patient cannot be separated from CPB (Fig. 60.23). 

CORONARY ARTERY BYPASS GRAFTING AND SPECIAL POPULATIONS OF PATIENTS Patients With Diabetes Mortality and morbidity rates after CABG are higher in diabetic patients than in the general population. The BARI trial showed that diabetic patients with multivessel disease benefit more from CABG than from any other treatment. Similarly, the FREEDOM trial also demonstrated superiority of CABG over PCI. 

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Patients With Renal Disease Renal insufficiency is also an independent risk factor for mortality after CABG. A preoperative serum creatinine level higher than 1.4 to 2.5 mg/dL is independently associated with a twofold increase in mortality. In a retrospective study of 59,576 patients who underwent CABG or PCI, CABG had a survival benefit in patients with a serum creatinine level higher than 2.5 mg/dL. The 1-, 2-, and 3-year survival rates were 84.1%, 77.4%, and 65.9%, respectively, for CABG compared with 70.8%, 51.9%, and 46.1%, respectively, for PCI. This effect was more dramatic in diabetic patients. 

Obese Patients The incidence of postoperative renal failure, prolonged ventilation, and sternal wound infection is significantly higher in obese patients than in normal-weight patients. Both extremes of weight are risk factors for CABG-related mortality. 

ACKNOWLEDGMENTS We would like to acknowledge Scott Weldon and Michael DeLaflor for graphic services, and Johnny Airheart for photographic support.

SELECTED REFERENCES FIG. 60.23  An axial flow left ventricular assist device, which can be used as temporary mechanical support or a bridge to transplantation for a patient in end-stage cardiomyopathy due to coronary artery disease not amenable to bypass surgery. The inflow of blood into the pump is from the apex of the left ventricle. The blood is then pumped into the ascending aorta through specially designed grafts that are incorporated into the pump. The axial flow pumps are less bulky and relatively easy to implant. They have only a single moving part, which is the axial impeller.

Older Patients Approximately 10% of patients who undergo CABG are older than 80 years. Older age is an independent predictor of surgical morbidity and mortality and a nonroutine discharge status. Although CABG should not be denied to patients on the basis of age alone, it should be considered during risk assessment. Appropriate arrangements should be made beforehand with the expectation that only one in five postoperative patients will be able to go home without additional support. 

Women Although women in every age group have a lower incidence of CAD than men, CAD is still the leading cause of death in women in the United States. Historically, serious manifestations and associated complications of CAD in women were considered uncommon. Examination of the STS database in two separate studies has revealed that the operative mortality rate is higher in women, 3.2% versus 2.6% in men. With evolving strategies, studies have been designed to evaluate specific aspects of coronary artery bypass that would benefit women. For example, OPCAB has produced favorable outcomes in women. A review of 42,477 patients in the STS National Cardiac Database revealed that women have a significantly greater adjusted risk of death and prolonged ventilation and longer length of stay than do men who undergo on-pump CABG. In contrast, among OPCAB cases, women had a lower risk of reexploration than men did and a similar risk of death, MI, and prolonged ventilation and hospital stay. 

Chu D, Bakaeen FG, Dao TK, et al. On-pump versus off-pump coronary artery bypass grafting in a cohort of 63,000 patients. Ann Thorac Surg. 2009;87:1820–1826. This study was a nationwide comparison of on-pump versus off-pump coronary artery bypass surgery in the United States. The study highlighted the fact that off-pump coronary artery bypass does not produce lower postoperative mortality or stroke rates than conventional on-pump coronary artery bypass. Furthermore, off-pump coronary artery bypass was associated with longer hospital stays and higher hospital costs.

Edwards FH, Carey JS, Grover FL, et  al. Impact of gender on coronary bypass operative mortality. Ann Thorac Surg. 1998;66:125–131. This study analyzed the outcomes of more than 300,000 patients from the Society of Thoracic Surgeons database and used multivariate analysis and risk model stratification to examine the outcomes of female patients. Female gender was shown to be an independent predictor of higher mortality in low- to moderate-risk patients but not in high-risk patients.

Influence of diabetes on 5-year mortality and morbidity in a randomized trial comparing CABG and PTCA in patients with multivessel disease: the Bypass Angioplasty Revascularization Investigation (BARI). Circulation. 1997;96:1761–1769. Follow-up results from the initial randomized controlled trial established that patients with treated diabetes mellitus who were assigned to undergo coronary artery bypass grafting (CABG) had a striking reduction in mortality compared with patients who underwent percutaneous transluminal coronary angioplasty. This benefit was attributed predominantly to the use of the left internal mammary artery conduit in CABG.

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Loop FD, Lytle BW, Cosgrove DM, et al. Influence of the internal-mammary-artery graft on 10-year survival and other cardiac events. N Engl J Med. 1986;314:1–6. This retrospective study of 5931 coronary artery bypass grafting patients operated on at a single institution compared the outcomes of patients who had an internal mammary artery (IMA) graft with those of patients who had only vein grafts. The findings of this landmark study established the superiority of the IMA over any other conduit. During a 10-year period, patients who had only vein grafts had a 1.6 times higher risk of mortality than those who had mammary grafts.

Lopes RD, Hafley GE, Allen KB, et al. Endoscopic versus open vein-graft harvesting in coronary-artery bypass surgery. N Engl J Med. 2009;361:235–244. This retrospective study evaluated the effects of endoscopic vein harvesting on the rate of vein graft failure and on clinical outcomes. Endoscopic vein harvesting was shown to be independently associated with vein graft failure and adverse clinical outcomes compared with open vein harvesting.

Parisi AF, Khuri S, Deupree RH, et al. Medical compared with surgical management of unstable angina: 5-year mortality and morbidity in the Veterans Administration Study. Circulation. 1989;80:1176–1189. This prospective, multicenter Veterans Administration randomized controlled trial compared surgical and medical management and established that, for patients with triple-vessel coronary disease, surgical intervention better promotes survival than medical management.

Peduzzi P, Kamina A, Detre K. Twenty-two-year follow-up in the VA Cooperative Study of Coronary Artery Bypass Surgery for Stable Angina. Am J Cardiol. 1998;81:1393–1399. This study compared the 22-year results of initial coronary artery bypass grafting surgery with saphenous vein grafts with those of initial medical therapy with regard to survival, the incidences of myocardial infarction (MI) and reoperation, and symptomatic status in 686 patients with stable angina who participated in the Veterans Affairs Cooperative Study of Coronary Artery Bypass Surgery. This trial provided strong evidence that initial bypass surgery did not improve survival for low-risk patients and did not reduce the overall risk of MI. The early survival benefit with surgery in high-risk patients did not translate to comparable long-term survival rates for both treatment groups.

Serruys PW, Morice MC, Kappetein AP, et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe. N Engl J Med. 2009;360:961–972.

This was a landmark contemporary study of percutaneous coronary intervention (PCI) with drug-eluting stents versus coronary artery bypass grafting (CABG). The primary end point was a major adverse cardiac or cerebrovascular event (i.e., death from any cause, stroke, myocardial infarction (MI), or repeated revascularization) during the 12-month period after randomization. Rates of major adverse cardiac or cerebrovascular events at 12 months were significantly higher in the PCI group (17.8% vs. 12.4% for CABG; P = 0.002), in large part because of an increased rate of repeated revascularization (13.5% vs. 5.9%; P < 0.001); as a result, the criterion for noninferiority was not met. At 12 months, the rates of death and MI were similar between the two groups; stroke was significantly more likely to occur with CABG (2.2% vs. 0.6% with PCI; P = 0.003). The investigators concluded that CABG remains the standard of care for patients with three-vessel or left coronary artery disease because the use of CABG, compared with PCI, resulted in lower rates of the combined end point of major adverse cardiac or cerebrovascular events at 1 year.

Serruys PW, Ong AT, van Herwerden LA, et  al. Five-year outcomes after coronary stenting versus bypass surgery for the treatment of multivessel disease: the final analysis of the Arterial Revascularization Therapies Study (ARTS) randomized trial. J Am Coll Cardiol. 2005;46:575–581. The final results of the Arterial Revasularization Therapies Study were summarized and showed that the overall rate of major adverse cardiac and cerebrovascular events was higher in patients who underwent coronary artery stenting than in those who underwent coronary artery bypass grafting. This difference was driven by the increased need for repeated revascularization in the stent group.

Shroyer AL, Grover FL, Hattler B, et  al. On-pump versus off-pump coronary-artery bypass surgery. N Engl J Med. 2009;361:1827–1837. This study was a randomized, multicenter Veterans Affairs trial that compared conventional coronary artery bypass grafting with off-pump coronary artery bypass (OPCAB) in 2203 patients. The primary end point was a composite of death from any cause, repeated revascularization, or nonfatal myocardial infarction within 1 year after surgery. At 1-year follow-up, the OPCAB patients had worse composite outcomes and poorer graft patency. The presumed benefit of fewer neuropsychological adverse outcomes was not found in OPCAB patients.

Taggart DP, Altman DG, Gray AM, et  al. Randomized trial of bilateral versus single internal-thoracic-artery grafts. N Engl J Med. 2016;375:2540–2549.

CHAPTER 60  Acquired Heart Disease: Coronary Insufficiency

The use of bilateral internal thoracic (mammary) arteries for coronary artery bypass grafting (CABG) may improve long-term outcomes as compared with the use of a single internal t­ horacic artery plus vein grafts. Patients undergoing CABG were randomized to undergo single or bilateral internal thoracic artery grafting in 28 cardiac surgical centers in 7 countries. Among patients undergoing CABG, there was no significant difference between those receiving single internal thoracic artery grafts and those receiving bilateral internal thoracic artery grafts regarding mortality or the rates of cardiovascular events at 5 years of followup. There were more sternal wound complications with bilateral internal thoracic artery grafting than with single internal thoracic artery grafting. Ten-year follow-up is ongoing.

Velazquez EJ, Lee KL, Jones RH, et  al. Coronary-artery bypass surgery in patients with ischemic cardiomyopathy. N Engl J Med. 2016;374:1511–1520. The survival benefit of a strategy of coronary artery bypass grafting (CABG) added to guideline-directed medical therapy, as compared with medical therapy alone, in patients with coronary artery disease, heart failure, and severe left ventricular systolic dysfunction remains unclear. This study randomized patients with very low ejection fraction (65 years], Drugs/ alcohol concomitantly (HAS-BLED) scoring system developed in 2010 from data in the Euro Heart Survey to assess 1-year risk of major bleeding in patients taking anticoagulants with atrial fibrillation.12 

Interventional Management Early intervention is associated with improved long-term survival for patients with MS compared to patients in whom intervention is delayed until the development of symptomatology. Fiveyear survival is 62% for NHYA Class III patients, and 15% for Class IV patients.13 The current American Heart Association/

TABLE 61.3  CHADS2 and CHADS2-VASc score for atrial fibrillation stroke risk and

recommended anticoagulation. CHADS2 SCORE C H A D S V A Sc

Congestive heart failure Hypertension Age ≥ 75 years Diabetes mellitus Prior stroke, TIA or thromboembolism

POINTS* 1 1 1 1 2

CHADS2 - VASc SCORE Congestive heart failure Hypertension Age ≥ 75 years Diabetes mellitus Prior stroke, TIA, or thromboembolism Vascular disease Age 65–74 years Sex category (female)

POINTS* 1 1 2 1 2 1 1 1

CHADS2: Score of 0, low risk; 1, moderate risk; 2–6, high risk. CHADS2-VASc: Score of 0 (male) or 1 (female), low risk; 1, moderate risk (male); 2–9, high risk. TIA, Transient ischemic attack. Recommended therapy for moderate or high risk is typically oral anticoagulant, with well-controlled vitamin K antagonist (VKA, e.g., warfarin with time in therapeutic range >70%), or a Non-VKA Oral Anticoagulant (NOAC, e.g., dabigatran, rivaroxaban, edoxaban, or apixaban). *Points for each risk factor are additive.

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SECTION XI  Chest

American College of Cardiology (AHA/ACC) guidelines accordingly recommend intervention for MS in patients with symptomatic severe or asymptomatic very severe MS (valve orifice area 30% Consider for severe MR and LVEF ≤30% Severe primary MR and LV dysfunction (LVEF 30%–60% and/or LVESD ≥40 mm)** Reasonable for severe MR and preserved LV function (LVEF ≥60% and LVESD 30%. – Class I, Level C. ***In the ESC/EACTS guidelines,14 surgery considered in symptomatic patients with severe MR, LVEF 50% but severe LV dilatation (LVESD >50 mm or LVEDD >70 mm) Class IIa, Level B. ^By definition, symptomatic AI is categorized as severe.

The appropriate surgical intervention for patients with secondary MR is less clearly defined than for primary MR, with a growing understanding of the role of ventricular pathology in perpetuating ischemic MR undermining previous recommendations for using (exaggerated or undersized ring annuloplasty) mitral repair to correct this pathophysiology. Specifically, randomized controlled trial data from the Cardiothoracic Surgical Trials Network showed no difference in overall LV remodeling

or survival for patients undergoing repair versus replacement, but a higher 2-year rate recurrence rate for moderate or severe MR with repair versus replacement (59% vs. 4%, P < 0.001).23 Likewise, while the addition of MV repair to patients undergoing CABG with moderate ischemic MR did significantly decrease the incidence of residual moderate or severe residual MR versus the CABG-alone group (11% vs. 32%, P < 0.001), MV repair failed to improve mortality.24 In the 2017 ACC/

CHAPTER 61  Acquired Heart Disease: Valvular AHA guidelines, chordal sparing mitral valve replacement was consequently given a IIa indication over downsized annuloplasty repair for severely symptomatic patients with chronic secondary MR, and the usefulness of repair downgraded to “uncertain” with a IIb recommendation for patients with moderate ischemic MR undergoing CABG.10 A variety of new techniques, including papillary muscle “sling” procedures, are also consequently being tested to address primary subvalvular and ventricular pathology as the primary focus of secondary MR repair.25 

AORTIC STENOSIS The normal aortic valve orifice measures 3 to 5 cm2. Aortic valve stenosis to less than half this size causes hemodynamic obstruction and a transvalvular pressure gradient as the primary pathophysiology of AS. This gradient induces compensatorily increased ventricular pressure generated through Frank Starling mechanisms and concentric LV hypertrophy via parallel replication of sarcomeres as a response to increased myocardial wall tension. Wall tension thereby normalizes according to the law of Laplace, and a compensated state preserving the systolic function of a hypertrophied but nondilated LV may persist for many years. Two-thirds of patients who progress to severe AS develop myocardial ischemia as a result of the increased work and consequently elevated myocardial oxygen demands of the hypertrophied ventricle, which must generate increased ejection pressures over prolonged systolic intervals against the increased afterload of the narrowed aortic valve. Myocardial ischemia, particularly in the subendocardial region, is accentuated by the reduction of perfusion gradients during diastolic coronary flow intervals across the hypertrophied, hyperpressurized myocardial wall. Resultant cell death and myocardial fibrosis leading to cardiomyopathy may then exacerbate heart failure. Myocardial hypertrophy can also precipitate ventricular diastolic dysfunction, which typically occurs prior to the onset of systolic dysfunction. Decreased ventricular compliance leads to increased left ventricular end-diastolic pressure (LVEDP), prolonged LV relaxation time, and shortened diastolic filling time. These increased pressures are transmitted back through the LA and pulmonary circulation, leading to pulmonary congestion. Pulmonary hypertension and right heart failure may develop in severe cases. Eventually, maximal ventricular hypertrophy is reached, and an adequate pressure gradient can no longer be achieved, resulting in inadequate cardiac outputs and overt, self-reinforcing systolic LV failure. Increased LA pressure and consequent LA dilatation also increase the risk for atrial arrhythmias in patients with AS, albeit less commonly than in patients with mitral valve disease. The loss of normal atrial contraction severely compromises filling of the noncompliant ventricle, leading to a sometimes precipitous decrease in cardiac output. Reduced forward flow can further increase LVEDP and aggravate the symptoms of heart failure. Presyncope and syncope are unusual sequelae of AS related to inadequate (cerebral) organ perfusion, typically caused by inadequate forward flow through the restrictive aortic valve. Symptoms are typically associated with periods of peripheral vasodilatation such as occurring during exercise or in changing from recumbent to standing positioning when increased cardiac output is required to maintain peripheral vascular filling.

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Diagnosis of Aortic Stenosis Symptoms and Signs Patients with AS will typically remain asymptomatic for an extended time. The onset of symptoms occurs when the valve orifice area decreases to approximately 1 cm2, which marks a critical point in the natural history of the disease. The classic symptoms of AS typically progress from the appearance of angina and (pre-) syncope to the occurrence of dyspnea associated with heart failure (pneumonic: “ASD”). Whereas angina is the presenting symptom of AS in 35% of patients, syncope is a relatively sporadic event that is the presenting symptom in 15% of patients. Although heart failure typically appears late in the course of AS, dyspnea or other heart failure symptoms are presenting signs in 50% of patients.  Physical Exam The diagnosis of AS based upon physical findings is frequently made prior to the onset of symptoms. The typical finding of AS is a crescendo-decrescendo ejection murmur best heard along the left sternal border and that radiates to the upper right sternal border and carotid arteries. The apical impulse in AS is forceful and slightly enlarged. If heart failure develops, the apical impulse may become laterally displaced. The characteristic carotid upstroke of AS has a slow rate of rise and a reduced peak (pulsus parvus et tardus) and may have an associated thrill.  Diagnostic Testing Nonspecific findings of AS on chest radiography include a bootshaped heart typical of concentric hypertrophy of the left ventricle, calcification of the valvular cusps, and poststenotic dilatation of the aorta. Roentgenographic signs of heart failure may ensue. Electrocardiographic changes are similar to that seen for MR. Echocardiography allows the precise assessment of aortic valve anatomy, calcification, and effective orifice size, measured by planimetry. Ventricular hypertrophy and function can also be assessed. As with MS, Doppler echo allows measurement of transvalvular pressure gradients and valve area as a derived function (e.g., severe AS: Doppler velocity >4 m/sec = mean aortic valve gradient >40 mm Hg = valve area 45 mm >27.5 mm/m2 ≥55 mm Any size ≥55 mm ≥60 mm ≥55 mm

COMMENT All patients, including BAV Patients with Marfan syndrome BAV with risk factors for dissection Selected patients with Marfan syndrome When aortic valve is being intervened on For patients with a small body size All patients Signs or symptoms of local compression When TEVAR possible Open repair (less for Marfan syndrome) All patients

Adapted from Erbel R, Aboyans V, Boileau C, et al. 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: Document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). Eur Heart J. 2014;35:2873–2926. BAV, bicuspid aortic valve; TEVAR, thoracic endovascular aortic repair.

(USPSTF) issued a more limited recommendation for one-time screening for AAA using ultrasonography of men between 65 and 75 years of age who have a personal smoking history and selective screening for nonsmokers.43 For women the recommendations remain controversial. The USPSTF concluded that there was insufficient evidence to recommend routine screening in women who smoke and recommended against routine screening in nonsmoking women. One issue that may have biased these results is the paucity of women in large screening trials. In one metaanalysis that looked at a combination of four studies with over 125,000 patients enrolled, less than 10,000 subjects were women.44 Payer policies regarding reimbursement may not track either of these recommendations. Medicare, for instance, because of the Screening Abdominal Aortic Aneurysms Very Efficiently (SAAAVE) Act, reflects an intermediate approach in offering a screening benefit for men with a personal smoking history and men or women with a family history of AAA, although only as a part of the initial Welcome to Medicare physical examination. In a single-institution study of ruptured AAAs, only 17% of patients would have been eligible for screening.45 Following the initial detection of a nonsurgical aneurysm, surveillance is necessary in addition to optimal medical management. Ideally, surveillance should be low-cost, high-sensitivity, and pose minimal harm to the patient. For the abdominal aorta, ultrasound follow-up is advisable. Those patients with a known AAA who do not have appropriate surveillance may have up to a sixfold increase in rate of rupture.46 The Society for Vascular Surgery Clinical Practice Council recommends the following screening intervals based on aneurysm size (maximum external aortic diameter) and associated risk of rupture:19 • 70%),133 and BTAI may have been involved in 33% of the motor vehicle deaths in 2010.134 Although the entire aorta is susceptible to BTAI, the most common site of injury is at the isthmus (approximately 54%– 66%) based on autopsy studies135 and is typically a transverse tear. There are different proposed mechanisms for the pathogenesis of BTAI based on the variety of mechanical forces potentially being applied to the aorta. One proposed mechanism is “stretching” of the aortic wall secondary to intrinsic weakness at the isthmus and rather immobile distal descending aorta relative to the arch and ascending aorta.136 Another hypothesis includes bending, torsion, and shearing stresses over the spine in high impact injuries.137 A third is the Archimedes Lever Hypothesis that proposes a lever system where the long arm is the proximal aorta and aortic arch, the short arm is the aortic isthmus, and the great vessels serve as

CHAPTER 62  The Aorta

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Intima Media Adventitia Grade I Intimal tear

Grade II Intramural hematoma

Grade III Pseudoaneurysm

Grade IV Rupture

FIG. 62.7  Classification of blunt thoracic aortic injury.

a fulcrum.138 Simulations of lateral impact motor vehicle crashes have shown that the magnified forces mediated by the “long arm” provide sufficient strain on the “short arm” to result in rupture.138 It is likely that a combination of all of mechanisms play a role in BTAI etiology. The classification of BTAI is based on the extent of the damage to the aortic wall layers. There are four different grades ranging from intimal tear (grade I) to rupture (grade IV), each with different management strategies (Fig. 62.7). Grade I injuries do not cause any changes to the external aortic contour and is best visualized with either CTA or IVUS as angiogram may be interpreted as normal. Grade II injury causes an abnormal aortic contour that can be visualized on CTA, IVUS, or angiography. Grade III and IV injuries can be visualized with any imaging modality. At the time of the American Association for the Surgery of Trauma multicenter trial of BAI (AAST I trial), aortography was the most common diagnostic modality and the standard treatment was open operative repair if the patient was stable.139 The most common finding on plain film chest radiograph is a widened mediastinum, but it may also show apical pleural cap, loss of the aortopulmonary window, rightward deviation of the mediastinal structures or endotracheal tube (if present), or depression of the left mainstem bronchus. Multidetector CTA is now the gold standard diagnostic modality for BTAI in the updated AAST.139 Modern treatment has changed dramatically with treatment options of aggressive blood pressure control and increasing indications for endovascular repair. Current guidelines by the SVS recommend expectant management with strict blood pressure control and serial imaging (repeat CTA in six weeks) for grade I injuries—as most heal spontaneously140—and repair of grades II to IV injuries. In Arthurs and colleagues’ review, 68% of patients with BTAI surviving to treatment were treated medically, but aortic repair independently improved survival after controlling for associated injuries.132 For medical management of grade I BTAI, Fabian and colleagues recommended maintenance systolic blood pressure less than 100 mm Hg or mean arterial pressure less than 80 mm Hg along with heart rate control less than 100 beats per minute.139 These parameters were achieved using intravenous β-blockade (esmolol or labetalol).139 Nitroprusside was added if satisfactory blood pressure not achieved with β-blockers alone. Since the first report of endovascular repair of a traumatic injury to the thoracic aorta in 1997 by Kato and colleagues,141 data have increased substantially to support use of endovascular stent

graft over traditional open repair. Earlier experience did not show a difference in mortality rates between open and endovascular repair (19% vs. 18%, respectively).132 Improvements in techniques and technology have led to consistently reduced rates of mortality (8%–9% vs. 19%), paraplegia (0.5%–3% vs. 3%–9%), and endstage renal disease (5% vs. 8%) as well as a comparable stroke rate (2.5% vs. 1%).142 The Society of Vascular Surgery recommends that for those undergoing repair that the timing is within 24 hours in the absence of other serious injuries, repaired immediately after other injuries have been treated, or at the latest before the patient is discharged from the hospital.140 They also advocate endovascular repair in anatomically suitable candidates with selective revascularization of the left SCA, routine heparin administration (at a lower dose than elective TEVAR), general anesthesia, and open femoral exposure.140 The presence of an adequate 2-cm proximal seal zone in many cases requires partial or complete coverage of the left SCA, as the aortic isthmus is the most common site of injury. According to the SVS practice guidelines, the decision to perform revascularization of the left SCA is individualized and must consider the status of the right vertebral anatomy and posterior circulation, availability of surgical expertise, condition of the patient, and presence of other injuries.140 Revascularization is accomplished with a carotid subclavian bypass. Patients with ascending aorta or aortic arch injuries should undergo open repair if feasible, as they are not candidates for endovascular repair. 

SPECIFIC CONSIDERATIONS IN SURGICAL MANAGEMENT The surgical management of aortic disease, whether open, endovascular, or a hybrid approach, is continuously being refined as new techniques, devices, and understanding of disease processes evolve. What follows is not meant to be a “how I do it” synopsis but rather a brief summary of special considerations for specific pathologies with an appreciation that every patient presents a unique set of challenges.

Acute Type A Aortic Dissection Open surgical repair of an acute TAAD remains the standard of care when the patient is a surgical candidate. As reported by IRAD, in tertiary medical centers with expertise in the treatment of acute TAAD in the years from 1995 to 2013, the proportion of patients relegated to medical management declined from 21% to 10% with a corresponding decline in surgical mortality rate from 25%

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SECTION XII  Vascular

to 18%.143 Relative contraindications to surgery would include advanced age,144 multiple comorbidities, and neurologic status. Stamou and colleagues did not see a difference in operative mortality or major morbidity in a comparison between patients older than 70 years and those younger,145 but octogenarians do not fare as well.146 IRAD data has shown no difference in outcomes for octogenarians treated with surgical versus medical intervention.147 The presence of cerebrovascular accident or coma has a significant impact on hospital survival, but for patients who undergo surgical repair there is improved survival compared to medical management. In 84.3% of patients presenting with cerebrovascular accident who underwent surgical repair, there was resolution of the neurologic deficit.148 Softer contraindications include concern for the risk of bleeding secondary to antithrombotic medication,83 and the patient’s refusal for blood transfusions (i.e., in the case of a Jehovah Witness). Once the decision is made to proceed with surgery, the primary goal of surgery is the elimination of the entry tear and obliteration of the false lumen in the aortic root and ascending aorta. Successful completion of these goals will often address secondary issues, such as aortic valve insufficiency and distal visceral malperfusion. Specific considerations are the cannulation strategy, cerebral protection, conduct of cardiopulmonary bypass, and the proximal and distal extent of resection and repair. Traditionally, femoral cannulation was the primary access for establishing arterial inflow for cardiopulmonary bypass due in part to the ability to rapidly establish access via surgical cut-down or percutaneously. The decision as to which vessel to approach is paradoxical in the sense that the femoral artery most likely to be in continuity with the true lumen is the one without the pulse (due to true lumen collapse). The clinical situation in which true lumen collapse was occurring and the wrong vessel cannulated would result in high circuit line pressures. Malperfusion from femoral cannulation is uncommon. Axillary artery access grew popular in part by the ability to use this approach as part of a selective cerebral perfusion technique during periods of circulatory arrest.149 Additional benefits include the avoidance of atheroembolization and false lumen perfusion.150 Other approaches include arterial access via the apex of the left ventricle with the cannula traversing the aortic valve,151 direct cannulation of the true lumen after transection of the ascending aorta (“Samurai” technique152), and echo-guided cannulation of ascending aorta/arch using a Seldinger technique.153 With some exceptions, acute TAAD repair is performed with a period of hypothermic circulatory arrest. The initial approach to the arch reported by DeBakey and colleagues154 included a multicatheter approach to the great vessels and one of the femoral arteries to provide arterial inflow without circulatory arrest. Hypothermic circulatory arrest (Table 62.3) allows the establishment of a bloodless field allowing for the evaluation of the distal ascending aorta and arch to confirm intimal integrity, ensures graft continuity to the true lumen, and assists in obliteration of the false lumen.155 Profound hypothermic circulatory arrest provides 30 to 40 minutes of protective cerebral time; deep hypothermia alone should be sufficient for open-distal and hemi-arch repairs. The use of unilateral selective antegrade (SACP) or bilateral antegrade cerebral circulatory perfusion extends this protective time. With the adjunct of SACP, moderate hypothermia has been shown to be safe and effective.156 Cerebral perfusion during SACP (with right axillary cannulation) is via the right carotid and assumes the absence of right carotid stenosis and an intact Circle of Willis. Concern for coagulopathy secondary to hypothermia has been

TABLE 62.3  Level of hypothermia and

duration of circulatory arrest.

LEVEL Mild hypothermia Moderate hypothermia Deep hypothermia Profound hypothermia

NASOPHARYNGEAL TEMPERATURE (ºC)

ESTIMATED SAFE DURATION OF CIRCULATORY ARREST (MIN)

28.1–34 20.1–28 14.1–20 ≤14

1.3) SVS grades 0 (none), 1 (mild), 2 (moderate), and 3 (severe). GRADE

ABI

0 1 2 3

≥0.80 0.6–0.79 0.4–0.59 ≤0.39

ANKLE SYSTOLIC PRESSURE

TP, TcPO2 ≥60 mm Hg 40–59 mm Hg 30–39 mm Hg 100 mm Hg 70–100 mm Hg 50–70 mm Hg 0.5 to ≤2 cm around the ulcer • Local tenderness or pain • Local warmth • Purulent discharge (thick, opaque to white, or sanguineous secretion) Local infection involving only the skin and the subcutaneous tissue (without involvement of deeper tissues and without systemic signs as described below). Exclude other causes of an inflammatory response of the skin (e.g., trauma, gout, acute Charcot neuroosteoarthropathy, fracture, thrombosis, venous stasis) Local infection (as described above) with erythema >2 cm, or involving structures deeper than skin and subcutaneous tissues (e.g., abscess, osteomyelitis, septic arthritis, fasciitis), and No systemic inflammatory response signs (as described below) Local infection (as described above) with the signs of SIRS, as manifested by two or more of the following: • Temperature >38°C or 90 beats/min • Respiratory rate >20 breaths/min or PaCO2 12,000 or 97% and 2-year survival >70%), medium-risk (30-day survival 95%–97% or 2-year survival 50%–70%), or high-risk (30day survival 2 seconds) may represent substantial shunting of blood from the peripheral tissues to the central organs, which may occur with cardiogenic or hypovolemic shock. The respiratory rate for a normal newborn ranges from 40 to 60 breaths/min, with a tidal volume of 6 to 10 mL/kg. Nasal flaring, grunting, intercostal and substernal retractions, and cyanosis are symptoms and signs of respiratory distress. Infants are obligate nasal and diaphragmatic breathers, and therefore any condition that obstructs the nasal passages (e.g., nasogastric tube) or interferes with diaphragmatic function may severely compromise respiratory status. In addition, the newborn airway is quite small, with an average tracheal diameter of 2.5 to 4 mm, and it can easily be plugged with airway secretions.  At birth, the lungs are considered functionally immature and continue to develop new terminal bronchioles and alveoli until 6 to 8 years of age. The neonatal lung has fewer type II pneumocytes, which produce surfactant, a lipoprotein mixture of phospholipid, protein, and neutral fats. Surfactant regulates alveolar surface tension, thereby increasing functional residual capacity. Lecithin, the most predominant phospholipid, can be measured in amniotic fluid, and the lecithin-to-sphingomyelin ratio is used to determine fetal lung maturity. Hence, premature infants are at greater risk for alveolar collapse, hyaline membrane formation, and barotrauma from mechanical ventilatory support. Exogenous surfactant therapy has had a major impact on the management of premature infants. This has resulted in improved survival and decreased incidence of bronchopulmonary dysplasia, a condition characterized by oxygen dependence, radiologic abnormality, and chronic respiratory symptoms beyond the first 28 days of life.  

Immunology Infants have lower levels of immunoglobulins (IgA, IgG, and IgM) and of the C3b complement at birth and therefore are at higher risk for systemic infection. Sepsis work-up for neonates has largely remained the same with surveillance cultures, including cerebrospinal fluid, and complete blood count as well as C-reactive protein levels. Infants are also at risk for potential septic sources

1845

arising from invasive monitoring lines and interventions such as prolonged endotracheal intubation, umbilical vascular catheters, and bladder catheterization. An empirical antibiotic regimen is often started based on subtle clinical suspicions (e.g., decreased tolerance of enteral feeding, temperature instability, reduced capillary refill, tachypnea, irritability). Antibiotic therapy is targeted at common bacterial pathogens, such as Group B beta-hemolytic streptococcus, methicillin-resistant Staphylococcus aureus, and Escherichia coli. 

FLUIDS, ELECTROLYTES, AND NUTRITION Fluid and Electrolytes Fluid and electrolyte balance must be carefully assessed in pediatric surgical patients, especially in smaller neonates with a narrow margin for error. Due to higher insensible water losses through a thin immature skin barrier, fluid requirements for premature infants can be substantial. Insensible water losses are directly related to gestational age, which range from 45 to 60 mL/kg/day for premature infants weighing less than 1500 g to 30 to 35 mL/kg/day for term infants. Radiant heat warmers, phototherapy for hyperbilirubinemia, and respiratory distress can result in additional fluid losses. During the first 3 to 5 days of life, physiologic water loss can total up to 10% of the body weight. Fluid requirements are calculated according to body weight. During the first few days of life, the fluid recommendations are on the conservative side; however, infants require 100 to 130 mL/kg/day for maintenance fluids by the fourth day of life. Surgical conditions such as gastroschisis and necrotizing enterocolitis (NEC) demand a significantly higher volume. Urine output and osmolarity are good indicators of adequate tissue perfusion. The ideal minimum urine output in a newborn is 1 to 2 mL/kg/day. Infants can respond to prerenal azotemia by concentrating urine only up to approximately 700 mOsm/kg. The daily requirements for so­ dium and potassium are 2 to 4 and 1 to 2 mEq/kg, respectively. These requirements are usually met with 5% dextrose in 0.45% normal saline with 20 mEq/L of potassium at the calculated maintenance rate. Fluid losses from gastric drainage, ostomy output, or diarrhea should also be carefully assessed and replaced with an appropriate solution. Gastric losses should be replaced in equal volumes with 0.45% normal saline with 20 mEq/L of potassium. Diarrheal, pancreatic, and biliary losses are replaced with isotonic lactated Ringer solution. Hypovolemia due to acute hemorrhage should be corrected with prompt transfusion of blood products at a bolus of 10 to 20 mL/kg of packed red blood cells, plasma, or 5% albumin. 

Nutrition Energy requirements vary substantially from infancy to childhood and also under different clinical conditions. Appropriate weight gain remains the most reliable crude indicator of adequate caloric intake. Total daily caloric requirements and the weight curve plateau with age. Nearly 50% of the energy in term infants younger than 2 weeks and 60% of energy in premature infants weighing less than 1200 g is consumed for growth. A general guideline for the enteral calorie requirement of infants is 120 calories/kg/day to achieve an ideal weight gain of ∼1% of body weight per day. Breast milk and standard infant formulas contain 20 calories/ ounce. Formulas with higher calorie density are available for those who are unable to consume sufficient volumes to meet their calorie requirements or those with strict fluid restriction. Breast milk is the ideal form of enteral nutrition. However, hypoallergenic, lactose-free to amino-acid-based formulas are available to meet the specific needs of infants with particular GI tract conditions.

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SECTION XIII  Specialties in General Surgery

In general, infants with a stressed gut are given continuous enteral feedings and then transitioned to gastric bolus feedings. Toleration of enteral feeding is carefully monitored by assessing for abdominal girth, gastric residuals, and stool output. Carbohydrates are stored mainly as glycogen in the liver and muscles. Because newborn liver and muscle mass is disproportionately smaller than that of adults, infants are susceptible to hypoglycemia with risks of seizure and neurologic impairment. The minimum glucose infusion rate for neonates is 4 to 6 mg/kg/min. This rate must be calculated daily while the infant is receiving parenteral nutrition. For total parenteral nutrition (TPN), the glucose infusion rate is increased daily in increments of 1 to 2 mg/kg/min to a maximum value of 10 to 12 mg/kg/min. Hyperglycemia from a less than ideal glucose infusion rate should be avoided because it can lead to rapid hyperosmolarity and dehydration. Hyperglycemia could also reflect an underlying sepsis and therefore, should be investigated. The average protein intake is ∼15% of total daily calories and ranges from 2 to 3.5 g/kg/day in infants. By 12 years of age, this protein requirement is reduced in half and approaches the adult requirement (1 g/kg/day) by 18 years of age. The provision of greater amounts of protein relative to nonprotein (carbohydrate plus fat) calories will result in rising blood urea nitrogen levels, resulting in a nonprotein calorie-to-protein calorie ratio (when expressed in grams of nitrogen) greater than 150:1. For infants receiving parenteral nutrition, protein administration usually starts at 0.5 g/kg/day and advances in daily increments of 0.5 g/kg/day to a target goal of approximately 3.5 g/kg/day. Fat is a major source of nonprotein calories. Linoleic acid, an 18-carbon chain with two double bonds, is considered an essential fatty acid, and its deficiency results in dryness, rash, and desquamation of skin. In pediatric patients, fat is provided as a major source of calories to prevent the development of essential fatty acid deficiency. The lipid requirements for growth are significant, and fat is a robust calorie source. Similar to protein, fat infusions are started at 0.5 g/ kg/day and advanced up to 2.5 to 3.5 g/kg/day. In infants with unconjugated hyperbilirubinemia, fat is administered with caution because fatty acids may displace bilirubin from albumin. The free unconjugated bilirubin may then cross the blood-brain barrier and can lead to kernicterus, resulting in mental retardation. TPN is reserved for infants for whom adequate daily enteral nutrition cannot be achieved. Infants only have energy reserve to withstand periods of starvation as few as 2 to 3 days. Thus, an infant’s need for parenteral nutrition should be addressed promptly. The total TPN infusion rate is kept at a steady-state to meet daily fluid requirements, and the concentration of nutrients is gradually increased daily until goals are met. Infants with surgical conditions often become cholestatic, typically caused by prolonged TPN support, however, other causes should be ruled out. Serum bile acid levels are usually elevated first, then direct bilirubin concentration, followed by liver enzyme levels. The ideal treatment for TPN-associated cholestasis is restoring enteral feeding. The use of omega-3 fat emulsion (Omegaven) has been critical in preventing TPN-induced cholestasis.1 A medium-chain triglyceride–containing formula is used, and if an infant is receiving total enteral nutrition, fat-soluble vitamins should be supplemented. 

HEAD AND NECK LESIONS Dermoid and Epidermoid Cysts Dermoid and epidermoid cysts are slow-growing benign lesions that typically occur in the scalp and the skull. These cysts usually arise from part of the dermal or epidermal tissues, forming a small

cyst filled with normal skin components. Dermoid cysts may contain hair, teeth, and skin glands. Epidermoid cysts typically have only epidermal tissue and keratin debris. They commonly occur on the forehead, lateral corner of the eyebrow, anterior fontanelle or in the postauricular space. They are generally asymptomatic but may increase in size over time and can often become osteolytic. Most scalp lesions require only the clinical exam for diagnosis and subsequent surgical excision. However, imaging studies (e.g., ultrasound) can be critical to identify midline lesions such as a communicating cephalocele. 

Lymphadenopathy Enlarged lymph nodes presenting as small, mobile, discrete clusters in the anterior cervical triangle are one of the most common conditions referred for a pediatric surgical evaluation, biopsy, or possible excision. They usually occur along the sternocleidomastoid muscle border, often in clusters. The exact cause is unknown but presumed to be multifocal. A detailed history and physical examination are sufficient to determine whether surgery is indicated. The use of ultrasound has become widely prevalent and can, at times, identify those nodes with central necrosis requiring surgical intervention. Occasionally, lymph nodes presenting as fixed, nontender, progressively enlarging nodes in the supraclavicular region should raise a suspicion for a serious underlying etiology. Constitutional symptoms such as night sweats and weight loss should prompt a thorough investigation with chest radiography, which could detect mediastinal adenopathy. Acute, bilateral cervical lymphadenitis from respiratory viral infections (e.g., adenovirus, influenza virus, respiratory syncytial virus) require observation alone. S. aureus and Group A streptococcus are responsible for the majority of acute pyogenic lymphadenitis. Cat-scratch disease is a self-limited infectious condition characterized by painful regional lymphadenopathy. A gram-negative bacillus, Bartonella henselae, is responsible for the majority of cases. A history of exposure to cats is helpful but not always present. Indirect immunofluorescent antibody testing has only moderate specificity. Polymerase chain reaction assay of a lymph node biopsy specimen is a more useful study for diagnosis. Cat-scratch disease is usually self-limited. A less common infectious cause of cervical lymphadenitis is nontuberculous mycobacterial infection. The nodes are fluctuant, with a violaceous appearance of the overlying skin. The diagnosis is made by positive cultures for nontuberculous acid-fast bacilli along with a tuberculin skin test. Surgical excision is usually indicated because most nontuberculous mycobacteria are resistant to conventional chemotherapy. 

Cystic Hygroma Cystic hygroma is a multiloculated cyst lined by endothelial cells occurring as a result of lymphatic malformation. Most involve the lymphatic jugular sacs and present in the posterior neck region. Other common sites are the axillary, mediastinal, inguinal, and retroperitoneal regions, and approximately 50% of these cystic lesions are present at birth. Cystic hygromas are soft cystic masses that can distort the surrounding structure, including the airway. A large cystic mass of the neck in the fetus can pose a significant threat to airway at birth. Prenatal ultrasound and fetal magnetic resonance imaging (MRI) studies can better demonstrate the extent of disease along with its mass effect on the airway. If present, a careful coordination of surgical intervention, ex-utero intrapartum treatment (EXIT) procedure, at the time of delivery can be life-saving, though this is more likely with solid tumors such as teratomas. Cystic hygromas are prone to infection and

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hemorrhage into the mass. MRI is useful in outlining the extent of lymphatic channels. Complete excision with tedious isolation and ligation of lymphatic branches is the surgical goal. Aggressive blunt and electrocautery dissection, as well as radical resection, must be avoided, as this can lead to recurrence or infection due to incomplete control of lymphatics. When a safe, complete surgical excision is not feasible, injection with sclerosing agents, such as bleomycin, doxycycline, or OK-432 derived from Streptococcus pyogenes, should be considered as an effective nonsurgical option.2 

is present in the neck. Ultrasound or radionuclide imaging may be useful to identify the ectopic thyroid gland in the neck. The Sistrunk procedure, first described in 1928, is the gold standard operation for thyroglossal duct cysts. It involves complete excision of the cyst in continuity with its tract, the central portion of the hyoid bone, and the tract interior to the hyoid bone extending to the base of the tongue. Failure of complete resection results in cyst recurrence in as high as 40% to 50% of cases. 

Thyroglossal Duct Cyst

Branchial cleft remnants present as lateral neck masses. Embryologically, the structures of the head and neck are derived from six pairs of branchial arches, their intervening clefts, and pouches. Congenital cysts, sinuses, or fistulas result from failure of these structures to regress, persisting in aberrant locations. The location of these remnants generally dictates their embryologic origin and guides the subsequent operative approach. Failure to understand the embryology may result in incomplete resection or injury to adjacent structures. Branchial lesions can manifest as sinuses, fistulas, or cartilaginous rests in infants. The clinical presentation ranges from a continuous mucoid drainage, a fistula or sinus, or an infected cystic mass. Branchial remnants may also be palpable as cartilaginous lumps or cords corresponding with a fistulous track. Dermal pits or skin tags may also be present. First branchial anomalies are typically located in the front or back of the ear, or in the upper neck near the mandible. Fistulas typically course through the parotid gland, deep or through branches of the facial nerve, and end in the external auditory canal. The second branchial cleft anomalies are the most common type. The external ostium of these remnants is located along the anterior border of the sternocleidomastoid muscle, usually in the vicinity of the upper half to lower third of the muscle. A tortuous and long course of the fistula tract can be found, which requires stepladder counter-incisions in order to excise the fistula track completely. Typically, the fistula penetrates the platysma, ascends along the carotid sheath to the level of the hyoid bone, and turns medially to extend between the carotid artery bifurcations. The fistula courses adjacent to the hypoglossal and glossopharyngeal nerves, behind the posterior belly of the digastric and stylohyoid muscles to end in the tonsillar fossa or other nasopharyngeal spaces. Third branchial cleft remnants usually do not have associated sinuses or fistulas and are located in the suprasternal notch or clavicular region and can descend into the mediastinum. They present more commonly as cysts in toddlers and older children. These most often contain cartilage and present clinically as a firm mass or subcutaneous abscess. 

An upper-midline cystic neck lesion in toddlers is a thyroglossal duct cyst until proven otherwise (Fig. 67.1). It originates at the base of the tongue at the foramen cecum and descends through the central portion of the hyoid bone. Although thyroglossal duct cysts may occur anywhere from the base of the tongue to the thyroid gland, most are found at, or just below, the hyoid bone. A thyroid diverticulum develops as a median endodermal thickening at the foramen cecum in the embryonic stage of development. The thyroid diverticulum descends in the neck and remains attached to the base of the tongue by the thyroglossal duct. Also, as the thyroid gland descends to its normal pretracheal position, the ventral cartilage of the second and third branchial arches forms the hyoid bone. Hence, the intimate anatomic relationship of the thyroglossal duct remnant exists with the central portion of the hyoid bone. The thyroglossal duct normally regresses by the time the thyroid gland reaches its final position. When the elements of the duct persist despite complete thyroid descent, a thyroglossal duct cyst may develop. Failure of normal caudal migration of the thyroid gland results in a lingual thyroid in which no other thyroid tissue

Branchial Cleft Remnants

EXTRACORPOREAL LIFE SUPPORT

FIG. 67.1  Thyroglossal duct cyst presents as a midline neck mass. Thyroglossal duct cyst can extend up to its origin at the foramen cecum. (From Josephs MD. Thyroglossal duct cyst. In: Chung DH, Chen MK, ed. Atlas of pediatric surgical techniques. Philadelphia, PA: Elsevier Saunders; 2010:28–33.)

Extracorporeal life support (ECLS) is a cardiopulmonary bypass delivering temporary life support for the critically-ill patient with acute respiratory and/or cardiac failure. ECLS achieves sufficient gas exchange, with carbon dioxide removal and oxygenation of blood to maintain normal circulatory support. Since its first reported neonatal experience in 1976, ECLS has not only become a standard therapeutic option for cardiopulmonary failure that is refractory to maximal medical therapy, but it also has become widely used for a variety of clinical applications, such as extracorporeal cardiopulmonary resuscitation (eCPR). Although the exact role of eCPR in neonatal and pediatric resuscitation remains controversial and yet to be determined, the use of eCPR has become a common practice in many hospitals around the globe.3 There

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are over 800 centers around the world contributing registry data to the Extracorporeal Life Support Organization database (ELSO registry data; July 2019).

Indications The major indications for neonatal extracorporeal membrane oxygenation (ECMO) include meconium aspiration, respiratory distress syndrome, PPHN, sepsis, and congenital diaphragmatic hernia (CDH). Meconium aspiration is the most common application for neonatal ECMO with the highest survival rate (>90%). Indications for neonatal ECMO vary among institutions. In general, ECMO is indicated when an infant’s overall cardiopulmonary function deteriorates to a point of ∼80% predicted mortality. Two guidelines have been used as predictors for survival without ECMO: the alveolar-arterial difference in the partial pressure of oxygen (Pao2 − Pao2 [also known as AaDo2]) and the oxygen index. AaDo2 greater than 610 for longer than 8 to 12 hours and AaDo2 greater than 620 for 6 hours, associated with extensive barotrauma and severe hypotension requiring inotropic support, are considered to be criteria for ECMO. The oxygen index is calculated as the fraction of inspired oxygen (usually 1.0) × mean airway pressure × 100 divided by Pao2. An 80% mortality is observed with an oxygen index greater than 40. Contraindications are severe prematurity due to a high risk of intracranial bleeding, weight less than 2 kg, presence of an intracranial bleed (grade II intraventricular hemorrhage), and a nonreversible pulmonary disease such as congenital alveolar dysplasia. Additional exclusion criteria include the presence of cyanotic congenital heart disease or major genetic defects that preclude survival, as well as intractable coagulopathy. 

Physiology The right internal jugular vein and common carotid artery are used for venoarterial cannulations because of vessel sizes to accommodate cannulas and collateral circulation. The ECLS circuit is composed of a silicone rubber bladder that collapses when venous return is diminished, roller pump, membrane oxygenator, heat exchanger, tubing, and connectors. The basic principle of ECLS is that desaturated mixed venous blood from the right atrium drains through the venous cannula to the bladder and is pumped to the membrane oxygenator, where carbon dioxide is removed and oxygen is added. The oxygenated blood then passes through the heat exchanger and is returned to the patient through the arterial cannula. Systemic anticoagulation to prevent clotting of the ECLS circuit puts patients at risk for bleeding complications. Indicators of lung recovery include an increasing Pao2, improved lung compliance, and clearing of the chest radiograph. As the pulmonary function recovers, the patient is trialed off bypass by clamping the cannulas. If tolerated, the patient is taken off ECLS on moderate conventional ventilatory settings. Venovenous bypass using a double-lumen single cannula placed via the right internal jugular vein has the advantage of avoiding carotid arterial cannulation. Often, perfusion of well-oxygenated blood through venovenous ECMO restores hemodynamic stability. In older pediatric, as well as adult, patients, venous cannulas can be placed via both the internal jugular and femoral veins to achieve venovenous ECMO circulation. Bleeding is the most common complication of ECLS, and it can occur anywhere from catheter sites and surgical sites such as the thoracic cavity to intracranial bleeds. Gestational age is the most significant predictor of intracranial hemorrhage on ECLS, and premature infants less than 34 weeks of gestational age are at highest risk. Other complications include seizures, neurologic impairment, real failure requiring hemofiltration or hemodialysis, hypertension, infection, and mechanical malfunction of membrane oxygenator, pump, and heat exchanger, as well as the cannulas themselves. 

DIAPHRAGMATIC CONDITIONS Congenital Diaphragmatic Hernia The overall incidence of CDH is 1 in 2000 to 5000 live births. CDH is diagnosed prenatally in most cases and occurs more commonly on the left side (84%); bilateral defects occur but are rare (2%). A hernia sac is present 10% to 15% of the time and must be ex­cised at the time of repair. Despite multimodality treatment strategies, such as fetal tracheal occlusion, ECMO, inhaled nitric oxide, and permissive hypercapnia, the overall survival rate remains at 70% to 90%. True survival data for CDH is somewhat distorted by the fact that infants with more severe CDH are often stillborn, and therefore not captured by the registry. The lung area to head circumference ratio (LHR) is a sonographic predictor of prognosis and is determined by taking the product of the longest two perpendicular linear measurements of the lung contralateral to CDH and is divided by head circumference. An LHR of less than 1 and an abnormal liver position at 24 weeks of gestation are strong predictors of unfavorable outcomes. Fetal MRI is also used at many centers to determine fetal lung volume, as well as ratio of lung to the spinal fluid signal intensity.4 

Pathogenesis In the embryo, the pleuroperitoneal cavities become separated by the developing membrane during 8 to 10 weeks of gestation. When the pleuroperitoneal canal persists, it leads to a posterolateral CDH defect. The posterolateral location of this hernia is known as Bochdalek hernia; it is distinguished from a CDH of the anteromedial location known as Morgagni hernia. Abdominal contents herniate into the thoracic cavity through the diaphragmatic defect, compressing the ipsilateral developing lung. These lungs have smaller bronchi, with less bronchial branching and less alveolar surface area. The ipsilateral lung is affected more severely, however, both lungs are affected by pulmonary hypoplasia. In addition, the pulmonary vasculature is significantly affected by the increased thickness of arteriolar smooth muscle. Arteriolar vasculature is also extremely sensitive to local and systemic vasoactive factors. Hence, the severity of pulmonary hypoplasia and pulmonary hypertension significantly affect the overall morbidity and mortality in CDH infants. 

Clinical Presentation The diagnosis of CDH is frequently made prenatally, as early as 15 weeks of gestation, during routine ultrasound evaluation. Infants who have a late onset of CDH (beyond 25 weeks of gestation) have a better overall survival. Herniation of the stomach and liver, polyhydramnios, and associated anomalies have been associated with poor outcomes. The delivery of a fetus with CDH should be planned at a hospital capable of providing advanced neonatal care, including ECMO. Most infants with CDH experience respiratory distress immediately after birth. The initial symptoms and signs may include grunting respiration, chest retractions, dyspnea, and cyanosis with a scaphoid abdomen. Decreased breath sounds, along with bowel sounds, may be auscultated over the chest with CDH. The shifting of heart sounds to the right (for left-sided CDH) is common. A significant preductal and postductal pulse oximetry differential indicates right-to-left shunting due to PPHN. The chest radiograph demonstrates multiple bowel loops in the thoracic cavity along with mediastinal shift (Fig. 67.2A). The differential diagnosis includes congenital cystic adenomatoid malformation, bronchogenic cyst, diaphragmatic eventration (Fig. 67.2B), and cystic teratoma. Typically, the infant does well for several hours after

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A

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B FIG. 67.2  (A) Congenital diaphragmatic hernia. Multiple gas-filled bowel loops are located in the left hemithorax, and the mediastinum is shifted to the right. (B) Left diaphragmatic eventration. Hemidiaphragm is elevated (arrow) from phrenic nerve injury-induced paralysis.

delivery during the “honeymoon period” and then begins to demonstrate worsening respiratory function. Therapeutic interventions are aimed at stabilizing and treating PPHN. In 10% to 20% of cases, CDH is diagnosed beyond the first 24 hours, when infants experience symptoms of feeding difficulties, respiratory distress, and pneumonia. In Morgagni hernias, the diagnosis is often delayed until childhood because most infants are asymptomatic. 

Management Open fetal surgery for CDH was first attempted in the late 1980s with initial success in fetuses without liver herniation. However, in fetuses with liver herniation and subsequent kinking of the umbilical vein reduction of the liver resulted in fetal demise; therefore, the trial was abandoned. Subsequently, fetal endoscopic tracheal occlusion (FETO) showed encouraging results in promoting lung growth by preventing the egress of pulmonary fluid and increasing intrabronchial pressure. However, a randomized controlled trial failed to show improved survival. A multicenter randomized trial, Tracheal Occlusion to Accelerate Lung Growth (TOTAL), which had been led by several European centers,5 is now enrolling patients in the United States. The evolution of fetal surgery and its clinical applications are discussed in Chapter 73. The postnatal management of CDH is directed toward stabilization of the cardiorespiratory status while minimizing iatrogenic injury from therapeutic interventions. Immediate securing of the airway with endotracheal intubation is critical; however, excessive mean airway pressure ventilation can lead to barotrauma along with compromised venous blood return to the heart. An orogastric tube is placed to prevent gastric distention, which may worsen the lung compression, mediastinal shift, and ability to ventilate. The major emphasis on gentle ventilatory management with permissive hypercapnia has resulted in improved survival for CDH infants. Inhaled nitric oxide is used widely for its pulmonary vasodilatory effect. The use of tolazoline, a nonselective α-adrenergic blocking agent, as a pulmonary vasodilator has not produced clinically significant results. Sildenafil, a phosphodiesterase-5 inhibitor, works by inducing pulmonary vascular smooth muscle relaxation and has been used in many centers with variable results. A retrospective cohort study showed an increasing trend in the use of a variety of vasodilators for CDH patients. 

Surgical Repair Infants with CDH not requiring ECMO can safely undergo operative repair soon after birth. Laparoscopic repair of CDH has gained popularity in recent years, but its overall benefit and effects on long-term outcome remain uncertain.6 The ideal timing of CDH repair on ECMO remains quite controversial; some advocate early operative repair on ECMO, whereas others recommend repair at the time of weaning from ECMO or even after decannulation. There are no indisputable prospective data on the ideal timing of CDH repair for those requiring ECMO support. A recent report suggested that CDH repair after ECMO therapy is associated with improved survival compared to repair while on ECMO.7 The preferred open approach for a posterolateral CDH is through a subcostal abdominal incision. The viscera are reduced into the abdominal cavity, and the posterolateral defect in the diaphragm is approximated with interrupted nonabsorbable sutures. The hernia defect is often quite large, with only a small leaflet of diaphragmatic tissue present anteromedially. Although primary repair of the defect is ideal, closure with excessive tension must be avoided in order to prevent hernia recurrence. Some advocate for the use of pledgeted sutures. A number of reconstructive techniques and materials are available for the repair of large hernia defects. The surgical technique of abdominal or thoracic muscle flaps may be considered, but a prosthetic material, such as a Gore-Tex patch, is most widely used. The advantages of a prosthetic patch are shorter operative time and a tension-free repair. Some advocate use of regenerative extracellular matrix biomaterials as an ideal biodegradable patch (e.g., Surgisis [Cook Medical Bloomington, IN] and AlloDerm [LifeCell, Branchburg, NJ]) to repair diaphragmatic hernia defects. In general, the chest tube is spared and postoperative radiographs show immediate mediastinal shift toward the center. The chest cavity quickly fills with serous drainage, which later gets absorbed as fluid status returns to baseline. During abdominal cavity closure, it can often be difficult to accommodate the reduced viscera from the thoracic cavity. A temporary abdominal silo may be considered, however allowing an incisional hernia with skin-only closure until the definitive fascia closure can be performed is an alternative surgical option. When CDH is repaired on ECMO, postoperative bleeding is a common major complication and therefore, meticulous hemostasis must be achieved.

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Long-term outcomes in infants with CDH vary. Some can develop a chronic condition due to PPHN and respiratory dysfunction. Moreover, infants who received aggressive and prolonged care in the neonatal intensive care unit have a high incidence of developmental delay, seizures, and hearing loss. Other morbidities for CDH survivors include chronic lung disease, scoliosis, growth retardation, pectus excavatum deformities, as well as gastroesophageal reflux (GER) disease and foregut dysmotility. 

confirmed by computed tomography (CT), which demonstrates a spherical nonenhancing, mucus-filled cystic mass, although an air-fluid level can be seen if the cyst communicates with the airway. Cysts within the pulmonary parenchyma typically communicate with a bronchus, whereas those in the mediastinum usually do not. Bronchogenic cysts are resected regardless of symptoms (Fig. 67.3A). Rare cases of malignant transformation have been reported. 

Eventration of Diaphragm

Congenital Pulmonary Airway Malformation

Abnormal elevation of the hemidiaphragm can significantly affect respiratory function. Eventration of the diaphragm can be congenital or acquired. Congenital eventration can occur due to birth trauma (Erb palsy) or due to an anatomic abnormality of the diaphragm. Erb palsy is a paralysis of the arm caused by injury to the brachial plexus, comprising the ventral rami of spinal nerves C5 to C8. These injuries typically result from shoulder dystocia during a difficult birth. Erb palsy commonly includes ipsilateral diaphragmatic paralysis due to traction injury of the phrenic nerves and upper portion of the brachial plexus. Acquired eventrations are usually secondary to iatrogenic phrenic nerve injury during open cardiac surgery. Elevation of the diaphragm is seen on chest radiographs (Fig. 67.2B); however, it can easily be misdiagnosed as CDH. The diagnosis is confirmed by dynamic visualization of the diaphragm using either fluoroscopy or ultrasound of the chest. Absent or paradoxical movement of the diaphragm on inspiration is diagnostic of eventration. When symptoms progress, resulting in respiratory distress or inability to wean from ventilatory support, repair is indicated. The surgical treatment of diaphragm event ration is an open or laparoscopic diaphragm plication in which the diaphragm is folded taut using multiple interrupted nonabsorbable sutures. 

CPAMs have been described as hamartomatous lesions in which a multicystic mass replaces normal lung tissue. They are connected to the tracheobronchial tree, and the blood supply is pulmonary. CPAMs can undergo malignant transformation, and rhabdomyosarcoma has been reported in older children. They are classified on the basis of their appearance on imaging, and confirmation is made by pathologic examination. According to the Stocker classification, type I lesions account for almost 75% of all cases and consist of a small number of large, 2- to 10-cm cysts that can compress normal lung parenchyma. Type II lesions have numerous cysts, usually measuring less than 1 cm in diameter. Type III lesions are rare and appear to be only a few millimeters in diameter;9 however, they are associated with mediastinal shift, hydrops, and a poor prognosis. Prenatal fetal MRI can be used to distinguish CPAM from other thoracic anomalies. If fetal distress occurs, options include fetal thoracotomy and thoracoamniotic shunting (if the fetus is 1500 U/mL), ferritin (>142 ng/mL), and neuron-specific enolase (>100 ng/mL) are nonspecific tumor biomarkers. CT scan shows characteristic calcifications within the tumor (Fig. 67.23). An MRI is helpful to detect spinal cord extension. An 131I-metaiodobenzylguanidine (MIBG) scan is particularly valuable in the detection of metastases since the norepinephrine analogue is selectively concentrated in sympathetic tissue. The 131I-MIBG scan is also used for the surveillance of treatment response and recurrence. The classic histopathologic feature of NB is a poorly differentiated tumor with small round blue cells. Fluorescent in situ hybridization is performed on tissue specimens to assess ploidy, MYCN amplification, and other chromosomal abnormalities. Neuroblastoma can be classified on the basis of neuroblastic differentiation and mitosis-karyorrhexis index (low, intermediate, or high), and the presence of Schwann cells. The Children’s Oncology Group currently stratifies patients into low-, intermediate-, or high-risk categories on the basis of the patient’s age at diagnosis, International Neuroblastoma Staging System (INSS) stage, tumor histopathology, DNA index, and MYCN amplification status.39 Localized tumors are resected primarily; advanced-stage tumors with extensive disease involving vital structures should undergo biopsy alone initially for tumor biology studies. After 5 cycles of induction therapy, complete resection or debulking achieving more than 90% resection confer the optimal disease-free and overall survival.40 Image-defined risk factor (Table 67.1) after neoadjuvant chemotherapy are useful predictors of complete surgical resection of neuroblastomas.41 The multimodality treatment strategies are based on disease risk group stratification (Table 67.2). Induction chemotherapy consists of a multidrug regimen, including but not limited to cyclophosphamide, doxorubicin, cisplatin, carboplatin, etoposide, and vincristine. However, the high-risk group of neuroblastomas frequently acquire chemotherapeutics resistance and

FIG. 67.23  Computed tomography scan of neuroblastoma demonstrating areas of calcification (arrows). (From Kim S, Chung DH. Pediatric solid malignancies: Neuroblastoma and Wilms’ tumor. Surg Clin North Am. 2006;86:469–487.)

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TABLE 67.1  Image-defined risk factor in neuroblastoma. TUMOR LOCATION

CRITERIA

Tumor involving two body compartments Neck

Neck-chest; chest-abdomen; abdomen-pelvis Tumor encasing carotid and/or vertebral artery and/or internal jugular vein Tumor extending to base of skull Tumor compressing the trachea Tumor encasing brachial plexus roots Tumor encasing subclavian vessels and/or vertebral and/or carotid artery Tumor compressing the trachea Tumor encasing the aorta and/or major branches Tumor compressing the trachea and/or principal bronchi Lower mediastinal tumor, infiltrating the costovertebral junction between T9 and T12 Tumor encasing the aorta and/or vena cava Tumor infiltrating the porta hepatis and/or the hepatoduodenal ligament Tumor encasing branches of the superior mesenteric artery at the mesenteric root Tumor encasing the origin of the coeliac axis, and/or of the superior mesenteric artery Tumor invading one or both renal pedicles Tumor encasing the aorta and/or vena cava Tumor encasing the iliac vessels Pelvic tumor crossing the sciatic notch More than one third of the spinal canal in the axial plane is invaded and/or the perimedullary leptomeningeal spaces are not visible and/or the spinal cord signal is abnormal Pericardium, diaphragm, kidney, liver, duodenopancreatic block, and mesentery Multifocal primary tumors Pleural effusion, with or without malignant cells Ascites, with or without malignant cells

Cervicothoracic

Thorax

Thoracoabdomen Abdomen/pelvis

Intraspinal Infiltration of adjacent structure Conditions recorded but not IDRFs

IDRFs, Image-defined risk factors.

TABLE 67.2  International Neuroblastoma Risk Group (INRG) pretreatment classification. INRG STAGE AGE (MO)

HISTOLOGIC CATEGORY GRADE

L1/L2 L1

GN, GNB intermixed Any, except GN/GNB

L2

M

MS

10 cm in greatest dimension, limited to the kidney Tumor extends into major veins or perinephric tissues but not T3 into the ipsilateral adrenal gland and not beyond Gerota fascia T3a Tumor grossly extends into the renal vein or its segmental (muscle-containing) branches, or tumor invades perirenal and/ or renal sinus fat but not beyond Gerota fascia T3b Tumor grossly extends into the vena cava below the diaphragm T3c Tumor grossly extends into the vena cava above the diaphragm or invades the wall of the vena cava T4 Tumor invades beyond Gerota fascia (including contiguous extension into the ipsilateral adrenal gland) Regional Lymph Nodes (N) Regional lymph nodes cannot be assessed NX No regional lymph node metastasis N0 Metastasis in regional lymph node(s) N1 Distant Metastasis (M) No distant metastasis M0 Distant metastasis M1 Stage Grouping T1 N0 M0 Stage I T2 N0 M0 Stage II T1 or T2 N1 M0 Stage III T3 N0 or N1 M0 T4 Any N M0 Stage IV From AJCC Cancer Staging Manual. In: Amin MB, Edge SB, Greene FL, et al, eds. 8th ed. Springer.

tumor, usually with a contrast-enhanced CT scan or MRI study of the abdomen and pelvis, as well as chest imaging, typically chest radiography. Also, based on clinical suspicion or abnormal results of laboratory studies, bone and brain imaging is performed. A key aspect of abdominal CT or MRI is evaluation of the renal vein and inferior vena cava as locally advanced renal cell carcinoma commonly forms tumor thrombus in these structures. The TNM staging system is listed in Table 74.2.47 Histologic grading is based on the Fuhrman nuclear grading system on a scale of I to IV.  Management The management of renal cell carcinoma has evolved in recent years. Historically, renal cell carcinoma was a surgical disease, and patients diagnosed with any renal mass underwent total radical nephrectomy. Now, select patients may undergo renal biopsy and active surveillance protocols. In the past, renal biopsies were fraught with high false-negative rates and low accuracy. Contemporary series show an accuracy rate of more than 90% in experienced centers with low complications and no reported incidence

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of tumor seeding given use of core-needle biopsy technique.46 Those patients who are appropriate for renal biopsy are patients considered for either active surveillance or renal ablation therapy. Active surveillance protocols have been developed for patients with incidentally diagnosed, small (