Surgical Pathology of the GI Tract, Liver, Biliary Tract and Pancreas E-Book
2648 pages
English

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Surgical Pathology of the GI Tract, Liver, Biliary Tract and Pancreas E-Book

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2648 pages
English

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Description

This one-of-a-kind reference provides a comprehensive and practical guide to help you interpret endoscopic biopsies and resection specimens of all organs related to the digestive system. The more than 2250 high quality illustrations, 30% more than in the first edition, help you recognize and diagnose any tissue sample under the microscope. Five new chapters, additional expert authors, expanded tables, and coverage of the current clinical approach to management and treatment options, particularly screening and surveillance recommendations for preneoplastic disorders, round out this unique reference.
  • Acts as a one-stop resource for the entire gastrointestinal system, liver, biliary tract, and pancreas.
  • Incorporates over 2250 high quality color illustrations so you can recognize and diagnose any tissue sample under the microscope.
  • Provides all the necessary tools to make a comprehensive diagnostic workup including data from ancillary techniques and molecular findings whenever appropriate.
  • Simplifies complex topics and streamlines decision-making using extensive tables, graphs, and flowcharts.
  • Helps you avoid diagnostic errors thanks to practical advice on pitfalls in differential diagnosis.
  • Uses a new “road map at the beginning of each chapter, as well as a new, more clinical focus to help you navigate through the book more quickly.
  • Reflects the latest classification and staging systems available so you can provide the clinician with the most accurate and up-to-date diagnostic and prognostic indicators, including key molecular aspects of tumor pathology.
  • Adds five new chapters including "Screening and Surveillance of the GI Tract , "Congenital and Developmental Disorders of the GI Tract , "Pediatric Enteropathies of the GI Tract", "Vascular Disorders of the GI Tract", and "Fatty Liver Disease".
  • Expands appropriate chapters with new coverage of the normal histology of the GI tract, liver, biliary tract and pancreas.
  • Uses expanded tables to outline specific differential diagnostic points helpful for surgical pathologists.
  • Discusses the key molecular aspects of tumor progression and risk assessment in all chapters that cover neoplastic disorders.
  • Helps you evaluate diagnostically challenging cases using diagnostic algorithms.
  • Increases the number of high quality photographs by at least 30% to include even more normal and abnormal tissue samples.
  • Updates all chapters to include the latest references, concepts, data, and controversies.
  • Incorporates expanded coverage of the pancreas and liver, eliminating the need for a separate text.

Sujets

Ebooks
Savoirs
Medecine
Médecine
Preeclampsia
Vómito
Cirrhosis
Marginal zone B-cell lymphoma
Women's Hospital of Greensboro
Liver
Hepatitis B
Ulceration
Benignity
Surgical pathology
Islet cell carcinoma
Neuroendocrine tumor
Systemic disease
Neuromuscular disease
Common variable immunodeficiency
Lymphoid leukemia
Diabetes mellitus type 1
Developmental disability
Carcinoid
Dysplasia
Necrotizing enterocolitis
Papilloma
Anal canal
Goblet cell
Pregnancy
Atrophic gastritis
Paraganglioma
Guideline
Neoplasm
Hyperplasia
Inborn error of metabolism
Carcinoma in situ
Colitis
Digestive disease
Acute pancreatitis
Gastritis
Cholangiocarcinoma
Fatty liver
Fibrosis
Gastrointestinal bleeding
Primary sclerosing cholangitis
Allotransplantation
Biliary atresia
Immunodeficiency
Inflammatory bowel disease
Budd?Chiari syndrome
Graft-versus-host disease
Steatosis
Squamous epithelium
Physician assistant
Hepatotoxicity
Renal cell carcinoma
Squamous cell carcinoma
Hepatitis A
Biopsy
Lesion
Bowel obstruction
Congenital disorder
Hirschsprung's disease
Alcoholic liver disease
Cholecystitis
Carcinoma
Eclampsia
Gallstone
Stomach cancer
Adenocarcinoma
Mentorship
Ascites
Bile duct
Gallbladder
Esophagitis
Endoscopy
Barrett's esophagus
Gastroesophageal reflux disease
Cyst
Hemorrhoid
Chronic
Bleeding
Tissue (biology)
Autoimmunity
Hypertension
Hepatitis C
Appendicitis
Peptic ulcer
Pancreatitis
Ulcerative colitis
Coeliac disease
Crohn's disease
Intestine
Lactose intolerance
Obesity
Diarrhea
X-ray computed tomography
Cystic fibrosis
Philadelphia
Diabetes mellitus
Polyp
Pancreas
Hepatitis
Infection
Psychology
Infectious disease
Gastroenterology
Function
Chemotherapy
Chromatin
Alcoholism
Appendix
Brushing
Father
Pathology
Portal
Extinction
Helicobacter pylori
Inflammation
Constipation
Copyright

Informations

Publié par
Date de parution 16 janvier 2009
Nombre de lectures 1
EAN13 9781437719598
Langue English
Poids de l'ouvrage 14 Mo

Informations légales : prix de location à la page 0,1318€. Cette information est donnée uniquement à titre indicatif conformément à la législation en vigueur.

Exrait

  • Expands appropriate chapters with new coverage of the normal histology of the GI tract, liver, biliary tract and pancreas.
  • Uses expanded tables to outline specific differential diagnostic points helpful for surgical pathologists.
  • Discusses the key molecular aspects of tumor progression and risk assessment in all chapters that cover neoplastic disorders.
  • Helps you evaluate diagnostically challenging cases using diagnostic algorithms.
  • Increases the number of high quality photographs by at least 30% to include even more normal and abnormal tissue samples.
  • Updates all chapters to include the latest references, concepts, data, and controversies.
  • Incorporates expanded coverage of the pancreas and liver, eliminating the need for a separate text.

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    Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas
    Second Edition

    ROBERT D. ODZE, MD, FRCP(C)
    Associate Professor of Pathology, Harvard Medical School
    Chief, GI Pathology Service, Brigham and Women’s Hospital, Boston, Massachusetts

    JOHN R. GOLDBLUM, MD
    Professor of Pathology, Cleveland Clinic Lerner College of Medicine
    Chairman, Department of Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio
    SAUNDERS
    Copyright
    SAUNDERS ELSEVIER
    1600 John F. Kennedy Blvd.
    Ste 1800
    Philadelphia, PA 19103-2899
    SURGICAL PATHOLOGY OF THE GI TRACT, LIVER, BILIARY TRACT, AND PANCREAS
    ISBN: 978-14160-4059-0
    Copyright © 2009, 2004 by Saunders, an imprint of 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. Permissions may be sought directly from Elsevier’s Rights Department: phone: (+1) 215 239 3804 (US) or (+44) 1865 843830 (UK); fax: (+44) 1865 853333; e-mail: healthpermissions@elsevier.com . You may also complete your request on-line via the Elsevier website at http://www.elsevier.com/permissions .


    Notice
    Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on their own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Editors assume any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book.
    The Publisher
    Library of Congress Cataloging-in-Publication Data
    Surgical pathology of the GI tract, liver, biliary tract, and pancreas / [edited by] Robert D. Odze, John R. Goldblum.—2nd ed.
    p.; cm.
    Includes bibliographical references and index.
    ISBN 978-1-4160-4059-0
    1. Gastrointestinal system—Surgery. 2. Liver—Surgery. 3. Biliary tract—Surgery. 4. Pancreas—Surgery. I. Odze, Robert D. II. Goldblum, John R.
    [DNLM: 1. Digestive System Surgical Procedures. 2. Pathology, Surgical—methods. 3. Digestive System—physiopathology. WI 900 S9608 2009]
    RD540.O396 2009
    617.4′3—dc22
    2008001963
    Acquisitions Editor: William Schmitt
    Developmental Editor: Liliana Kim
    Publishing Services Manager: Tina Rebane
    Senior Project Manager: Linda Lewis Grigg
    Design Direction: Karen O’Keefe-Owens
    Printed in China
    Last digit is the print number: 9 8 7 6 5 4 3 2 1
    Dedication
    To my family and particularly my late mother, Natasha, who is my hero in life.

    ROBERT D. ODZE, MD, FRCP(C)
    To those whom I hold most dear: my wife, Asmita; my children, Andrew, Ryan, Janavi, and Raedan; my dear mother, Bette; my late father, Raymond; and the rest of the Goldblum and Shirali families, whom I also cherish.

    JOHN R. GOLDBLUM, MD
    Contributors

    N. Volkan Adsay, MD, Professor, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Vice-Chair and Director, Department of Anatomic Pathology, Emory University Hospital, Atlanta, Georgia
    Benign and Malignant Tumors of the Gallbladder and Extrahepatic Biliary Tract Tumors of the Pancreas and Ampulla of Vater

    Lilian B. Antonio, MPH, Laboratory Supervisor, Department of Pathology, Mount Sinai Medical Center, New York, New York
    Liver Tissue Processing and Normal Histology

    Donald A. Antonioli, MD, Professor of Pathology, Department of Pathology, Harvard Medical School, Consultant and Senior Pathologist, Beth Israel Deaconess Medical Center, Emeritus Consultant in Gastrointestinal Pathology, Children’s Hospital, Boston, Boston, Massachusetts
    Polyps of the Small Intestine

    May R. Arroyo, MD, PhD, Assistant Professor, Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida
    Pediatric Liver Disease and Inherited, Metabolic, and Developmental Disorders of the Pediatric and Adult Liver

    Kamran Badizadegan, MD, Assistant Professor of Pathology and Health Sciences and Technology, Harvard Medical School, Assistant Pathologist in Gastrointestinal Pathology, Massachusetts General Hospital, Boston, Massachusetts
    Liver Pathology in Pregnancy

    Charles Balabaud, MD, Professor of Medicine, Groupe de Recherche pour l’Etude du Foie (GREF), University of Bordeaux 2 Faculty of Medicine, Staff Hepatologist, Hôpital Saint André CHU Bordeaux, Bordeaux, France
    Toxic and Drug-Induced Disorders of the Liver

    Kenneth P. Batts, MD, Clinical Associate Professor, Department of Pathology, University of Minnesota Medical School, Staff Pathologist, Department of Laboratory Medicine and Pathology, Abbott Northwestern Hospital, Minneapolis, Laboratory Director, Minnesota Gastroenterology, Maplewood, Director of Gastrointestinal Pathology, Hospital Pathology Associates, St. Paul, Minnesota
    Autoimmune and Chronic Cholestatic Disorders of the Liver

    Ana E. Bennett, MD, Staff Gastrointestinal and Liver Pathologist, Department of Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio
    Inflammatory Disorders of the Esophagus

    Paulette Bioulac-Sage, MD, Professor of Medicine, Groupe de Recherche pour l’Etude du Foie (GREF), University of Bordeaux 2 Faculty of Medicine, Staff Pathologist, Pellegrin Hospital and University Hospital, Bordeaux, France
    Toxic and Drug-Induced Disorders of the Liver

    Elizabeth M. Brunt, MD, Professor, Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, Staff Pathologist, Barnes-Jewish Hospital, St. Louis, Missouri
    Fatty Liver Disease

    Norman J. Carr, MBBS, FRCPath, FRCPA, Professor of Anatomical Pathology, University of Wollongong Graduate School of Medicine, Wollongong, New South Wales, Australia
    Epithelial Neoplasms of the Appendix

    Barbara A. Centeno, MD, Professor of Pathology, Department of Oncologic Sciences, University of South Florida College of Medicine, Full Member and Director of Cytopathology Laboratory, Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
    Diagnostic Cytology of the Biliary Tract and Pancreas

    James M. Crawford, MD, PhD ASSOCIATE EDITOR, Professor and Chair, Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida
    GI Tract Endoscopic and Tissue Processing Techniques and Normal Histology; Gallbladder, Extrahepatic Biliary Tract, and Pancreas Tissue Processing Techniques, and Normal Histology; Cirrhosis; Transplantation Pathology of the Liver; Pediatric Liver Disease and Inherited, Metabolic, and Developmental Disorders of the Pediatric and Adult Liver

    Jason A. Daniels, MD, Department of Pathology, Johns Hopkins University School of Medicine; Pathologist, Johns Hopkins Hospital, Baltimore, Maryland
    Inflammatory Disorders of the Appendix

    Anthony J. Demetris, MD, Starzl Professor of Transplant Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Director, Division of Transplantation Pathology, Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
    Transplantation Pathology of the liver

    Theresa S. Emory, MD, Clinical Associate Professor of Pathology, East Tennessee State University James H. Quillen College of Medicine, Johnson City, Tennessee
    Epithelial Neoplasms of the Appendix

    Francis A. Farraye, MD, MSc, Professor of Medicine, Division of Gastroenterology, Boston University School of Medicine, Clinical Director, Section of Gastroenterology, Boston Medical Center, Boston, Massachusetts
    GI Tract Endoscopic and Tissue Processing Techniques and Normal Histology; Screening and Surveillance Guidelines in Gastroenterology

    Linda D. Ferrell, MD, Professor and Vice Chair, Department of Pathology, University of California, San Francisco, School of Medicine; Director of Surgical Pathology, Department of Pathology, UCSF Medical Center, San Francisco, California
    Benign and Malignant Tumors of the Liver

    Judith A. Ferry, MD, Associate Professor, Department of Pathology, Harvard Medical School, Associate Pathologist, James Homer Wright Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts
    Lymphoid Tumors of the GI Tract, Hepatobiliary Tract, and Pancreas

    Robert M. Genta, MD, FACG, DTM&H, Chief for Academic Affairs, Caris Diagnostics, Inc., Irving, Staff Pathologist, Dallas VA Medical Center, Clinical Professor of Pathology and Medicine (Gastroenterology), University of Texas Southwestern Medical School, Dallas, Clinical Professor of Pathology and Medicine (Gastroenterology), Baylor College of Medicine, Houston, Texas
    Inflammatory Disorders of the Stomach

    Jonathan N. Glickman, MD, PhD, Assistant Professor, Department of Pathology, Harvard Medical School, Staff Pathologist, Brigham and Women’s Hospital, Consultant Pathologist, Children’s Hospital Boston, Boston, Massachusetts
    Epithelial Neoplasms of the Esophagus

    John R. Goldblum, MD, Professor of Pathology, Cleveland Clinic Lerner College of Medicine, Chairman, Department of Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio
    Inflammatory Disorders of the Esophagus; Mesenchymal Tumors of the GI Tract

    Fiona Graeme-Cook, MB, BCh, Assistant Professor, Department of Pathology, Harvard Medical School; Assistant Pathologist, Massachusetts General Hospital, Boston, Massachusetts
    Neuroendocrine Tumors of the GI Tract and Appendix

    Joel K. Greenson, MD, Professor of Pathology, University of Michigan Medical School, Pathologist, University of Michigan Health System, Ann Arbor, Michigan
    Inflammatory Disorders of the Large Intestine

    Elizabeth I. Harris, MD, Clinical Instructor in Anatomic Pathology, Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee
    Manifestations of Immunodeficiency in the GI Tract; Acute and Chronic Infectious Hepatitis

    Clara S. Heffess, MD, Chief, Endocrine Division, Department of Endocrine and Otorhinolaryngologic–Head & Neck Pathology, Armed Forces Institute of Pathology, Washington, DC
    Inflammatory, Infectious, and Other Non-neoplastic Disorders of the Pancreas

    Jason L. Hornick, MD, PhD, Assistant Professor, Department of Pathology, Harvard Medical School; Staff Pathologist, Brigham and Women’s Hospital, Consultant Pathologist, Dana-Farber Cancer Institute, Consultant in Gastrointestinal Pathology, Department of Pathology, Children’s Hospital Boston, Boston, Massachusetts
    Polyps of the Large Intestine

    Dale S. Huff, MD, Associate Professor, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Senior Pathologist, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
    Congenital and Developmental Disorders of the GI Tract

    Christine A. Iacobuzio-Donahue, MD, PhD, Associate Professor of Pathology and Oncology, Department of Pathology, Gastrointestinal/Liver Division, Johns Hopkins University School of Medicine, Pathologist, Johns Hopkins Hospital, Baltimore, Maryland
    Inflammatory and Neoplastic Disorders of the Anal Canal

    Brian C. Jacobson, MD, MPH, Assistant Professor of Medicine, Department of Gastroenterology, Boston University School of Medicine, Associate Director of Endoscopy, Boston Medical Center, Boston, Massachusetts
    GI Tract Endoscopic and Tissue Processing Techniques and Normal Histology

    Dhanpat Jain, MD, Associate Professor, Departments of Pathology and Internal Medicine (Digestive Diseases), Yale University School of Medicine, Attending Physician, Department of Pathology, Yale–New Haven Hospital, New Haven, Connecticut
    Neuromuscular Disorders of the GI Tract

    Jose Jessurun, MD, Professor of Pathology, Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota
    Infectious and Inflammatory Disorders of the Gallbladder and Extrahepatic Biliary Tract

    David S. Klimstra, MD, Professor of Pathology and Laboratory Medicine, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, Attending Pathologist and Chief of Surgical Pathology, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York
    Benign and Malignant Tumors of the Gallbladder and Extrahepatic Biliary Tract, Tumors of the Pancreas and Ampulla of Vater

    Laura W. Lamps, MD, Professor of Pathology, University of Arkansas for Medical Sciences College of Medicine, Little Rock, Arkansas
    Infectious Disorders of the GI Tract; Acute and Chronic Infectious Hepatitis

    Richard H. Lash, MD, Chief Medical Officer, Caris Diagnostics, Inc., Irving, Texas
    Inflammatory Disorders of the Stomach

    Gregory Y. Lauwers, MD, Associate Professor, Department of Pathology, Harvard Medical School; Director, Surgical Pathology and Gastrointestinal Pathology Service, Massachusetts General Hospital, Boston, Massachusetts
    Inflammatory Disorders of the Stomach; Epithelial Neoplasms of the Stomach

    Audrey Lazenby, MD, Professor and Interim Chair, Department of Pathology, University of Nebraska College of Medicine, Omaha, Nebraska
    Polyps of the Esophagus

    David N.B. Lewin, MD, Professor of Pathology, Department of Pathology, Medical University of South Carolina College of Medicine, Charleston, South Carolina
    Systemic Illnesses Involving the GI Tract

    Marta Ida Minervini, MD, Clinical Assistant Professor of Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, Chief Pathologist, Istituto Mediterraneo per Trapianti e Terapie Ad Alta Specializzazione, Palermo, Italy
    Transplantation Pathology of the Liver

    Kisha A. Mitchell, MD, Assistant Professor, Department of Pathology, Yale University School of Medicine, Attending Pathologist, Yale–New Haven Hospital, New Haven, Connecticut
    Vascular Disorders of the GI Tract

    Elizabeth Montgomery, MD, Department of Pathology, Johns Hopkins University School of Medicine, Director of Clinical Gastrointestinal Pathology, Department of Pathology, Johns Hopkins Hospital, Baltimore, Maryland
    Inflammatory Disorders of the Appendix

    Michael A. Nalesnik, MD, Professor of Pathology, University of Pittsburgh School of Medicine, Staff Pathologist, University of Pittsburgh Medical Center, Pittsburgh. Pennsylvania
    Transplantation Pathology of the Liver

    Amy E. Noffsinger, MD, Associate Professor, Department of Pathology, The University of Chicago Pritzker School of Medicine, Chicago, Illinois
    Epithelial Neoplasms of the Small Intestine

    Erin Rubin Ochoa, MD, FCAP, Staff Pathologist, Division of Transplantation Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
    Transplantation Pathology of the Liver

    Robert D. Odze, MD, FRCP(C), Associate Professor of Pathology, Harvard Medical School, Chief, GI Pathology Service, Brigham and Women’s Hospital, Boston, Massachusetts
    Inflammatory Disorders of the Esophagus; Inflammatory Disorders of the Stomach; Inflammatory Disorders of the Large Intestine; Polyps of the Stomach; Polyps of the Large Intestine; Epithelial Neoplasms of the Esophagus

    Stefan E. Pambuccian, MD, Associate Professor of Pathology, Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota
    Infectious and Inflammatory Disorders of the Gallbladder and Extrahepatic Biliary Tract

    Martha B. Pitman, MD, Associate Professor, Department of Pathology, Harvard Medical School, Associate Pathologist, Massachusetts General Hospital, Boston, Massachusetts
    Diagnostic Cytology of the Liver

    Arati Pratap, MD, Fellow, Section of Gastroenterology, Boston Medical Center/Boston University School of Medicine, Boston, Massachusetts
    Screening and Surveillance Guidelines in Gastroenterology

    Parmjeet Randhawa, MD, Professor of Pathology, University of Pittsburgh School of Medicine, Staff Pathologist, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
    Transplantation Pathology of the Liver

    Mark Redston, MD, Director of GI and Molecular Diagnostics, AmeriPath Northeast, Shelton, Connecticut
    Epithelial Neoplasms of the Large Intestine

    Marie E. Robert, MD, Associate Professor of Pathology and Internal Medicine, Department of Pathology, Yale University School of Medicine, Director, Program in Gastrointestinal Pathology, Yale– New Haven Hospital, New Haven, Connecticut
    Inflammatory Disorders of the Small Intestine

    Pierre Russo, MD, Professor, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Director, Division of Anatomic Pathology, Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
    Congenital and Developmental Disorders of the GI Tract; GI Tract Enteropathies of Infancy and Childhood

    Eizaburo Sasatomi, MD, PhD, Assistant Professor, Department of Pathology, Division of Liver and Transplantation Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
    Transplantation Pathology of the Liver

    Leslie H. Sobin, MD, Professor of Pathology, Department of Pathology, Uniformed Services University of the Health Sciences F. Edward Hébert School of Medicine, Bethesda, Maryland, Chief, Division of Gastrointestinal Pathology, Department of Hepatic and Gastrointestinal Pathology, Armed Forces Institute of Pathology, Washington, DC
    Epithelial Neoplasms of the Appendix

    Arief Suriawinata, MD, Assistant Professor of Pathology, Department of Pathology, Dartmouth Medical School, Pathologist, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
    Liver Tissue Processing and Normal Histology

    Swan N. Thung, MD, Professor, Department of Pathology and Department of Gene and Cell Medicine, Mount Sinai School of Medicine, Attending Pathologist, Mount Sinai Medical Center, New York, New York
    Liver Tissue Processing and Normal Histology

    Dina G. Tiniakos, MD, PhD, Assistant Professor, Laboratory of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
    Fatty Liver Disease

    Jerrold R. Turner, MD, PhD, Professor of Pathology and Associate Chairman for Academic Affairs, Department of Pathology, The University of Chicago Pritzker School of Medicine, Chicago, Illinois
    Polyps of the Stomach

    Helen H. Wang, MD, DrPH, Associate Professor, Department of Pathology, Harvard Medical School, Director of Cytopathology, Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
    Diagnostic Cytology of the GI Tract

    Ian R. Wanless, MD, CM, FRCPC, Professor of Pathology, Department of Pathology, Dalhousie University Faculty of Medicine, Staff Pathologist, Department of Pathology and Laboratory Medicine, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada
    Cirrhosis; Vascular Disorders of the Liver

    Kay Washington, MD, PhD, Professor of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee
    Manifestations of Immunodeficiency in the GI Tract; Acute and Chronic Infectious Hepatitis

    Bruce M. Wenig, MD, Professor of Pathology, Albert Einstein College of Medicine, Bronx, Chairman, Department of Pathology and Laboratory Medicine, Beth Israel Medical Center, St. Luke’s-Roosevelt Hospitals, New York, New York
    Inflammatory, Infectious, and Other Non-neoplastic Disorders of the Pancreas

    A. Brian West, MD, FRCPath, Professor of Pathology and Vice-Chair, Department of Pathology, Yale University School of Medicine, Director of Anatomic Pathology, Department of Pathology, Yale–New Haven Hospital, New Haven, Connecticut
    Vascular Disorders of the GI Tract

    Joseph Willis, MD, Associate Professor of Pathology, Case Western Reserve University School of Medicine, Vice Chair of Pathology for Clinical Affairs, University Hospitals Case Medical Center, Cleveland, Ohio
    Developmental Disorders of the Gallbladder, Extrahepatic Biliary Tract, and Pancreas

    Jacqueline L. Wolf, MD, Associate Professor, Department of Medicine, Harvard Medical School, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
    Liver Pathology in Pregnancy

    Tong Wu, MD, PhD, Associate Professor of Pathology, University of Pittsburgh School of Medicine, Staff Pathologist, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
    Transplantation Pathology of the Liver

    Rhonda K. Yantiss, MD, Associate Professor of Pathology, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, Attending Physician, Department of Pathology and Laboratory Medicine, New York–Presbyterian Hospital, New York, New York
    Polyps of the Small Intestine
    Preface
    Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas was originally conceived on the basis of our perceived need in academic surgical pathology for a textbook that includes diseases of all organs traditionally considered part of the field of “gastrointestinal pathology”—the tubular gut, liver, gallbladder, biliary tract, and pancreas—all under one cover. The second edition represents a significant improvement over the first edition in many ways, outlined in the following few paragraphs:
    1 Overall, the book is 40% larger. For instance, five new chapters have been added, and these are titled “Screening and Surveillance Guidelines in Gastroenterology,” “Congenital and Developmental Disorders of the GI Tract,” “GI Tract Enteropathies of Infancy and Childhood,” “Vascular Disorders of the GI Tract,” and “Fatty Liver Disease.”
    2 Additional sections on normal histology of the GI tract, pancreatico-biliary tract, and liver have been added to chapters 1 , 29 , and 36 , respectively.
    3 Tables to outline specific differential diagnostic points helpful for surgical pathologists at the level of the microscope have been increased in number and expanded.
    4 The number (and quality) of color photographs have been increased by at least 30%.
    5 A succinct and clinically relevant discussion of the key molecular aspects of tumor progression and risk assessment have been added to all chapters that cover neoplastic disorders.
    6 An outline has been added to the beginning of all chapters in order to expedite searching for specific topics of interest.
    7 All chapters have been updated to include the most current references, concepts, data, and controversies.
    8 Diagnostic algorithms have been added to many chapters in order to simplify the evaluation of diagnostically challenging entities.
    9 The new edition includes an online version that readers can access from any laptop computer, world-wide.
    In the second edition, we have, once again, paid special attention to providing only the most relevant, up-to-date clinical, etiologic, and management information necessary for surgical pathologists to make clinically relevant diagnoses. This continues to be a morphology-based textbook with particular emphasis on histologic methods that can help differentiate diseases based on evaluation of biopsy and resection specimens. However, gastroenterologists, surgeons, and residents/fellows in training may also find this textbook of interest because of the accent on clinical-pathologic associations. The second edition is even more user friendly than the first edition, and it is organized in a method that helps pathologists gain access to diagnostic information quickly without having to waste time leafing through the index and turning pages. The overall organization of the textbook remains the same as in the first edition: part 1 represents disorders of the gastrointestinal tract; part 2, the gallbladder, extrahepatic biliary tract, and pancreas; and part 3, the liver. In each part, an introductory chapter on pertinent tissue processing techniques and normal histology, and a wellillustrated chapter on diagnostic cytology of each of the major organ systems, are included. Subsequent chapters in each section are separated into general disease categories, such as systemic disorders, inflammatory disorders, polyps, epithelial neoplasms, and other types of neoplasms, similar to the method used by pathologists to evaluate tissue specimens. In addition, the liver section is divided into chapters based on major patterns of injury, recapitulating the approach to liver biopsy assessment. Of course, all chapters were written by pathologists with a special interest or expertise in a particular field. Finally, the editors have paid careful attention to providing a consistent style of writing, structure, and content from chapter to chapter.
    We are confident that the second edition represents a bigger, better, and, ultimately, state-of-the-art textbook on the pathology of the gastrointestinal system, liver, biliary tract, and pancreas that can be enjoyed by pathologists and clinicians worldwide.

    ROBERT D. ODZE, MD, FRCP(C), JOHN R. GOLDBLUM, MD
    Acknowledgments
    As in the first edition, many individuals contributed greatly to the conception, editing, and production of this textbook. The editors are appreciative of all the technical, administrative, and support staff involved in the production of this textbook and, particularly, Kendra Glueck-Abramson and Kathleen Ranney at the Brigham and Women’s Hospital and Cleveland Clinic, respectively. We would also like to thank William Schmitt, Liliana Kim, and Linda Grigg for their patience, support, and endless dedication to helping us produce an excellent quality textbook, and John Alpert for his book cover layout.
    From a professional point of view, I am greatly indebted to my longtime friends and mentors Dr. Donald Antonioli, who, unfortunately, has recently retired from academic pathology and Dr. Harvey Goldman, who continues to represent a pillar of knowledge in GI pathology. Their continued support and helpful advice during the long and sometimes tedious process of creating a textbook was very much appreciated. As all academic pathologists realize, creating a textbook of this magnitude requires a great deal of time and support, which was provided to me initially by Dr. Ramsy Cotran and later by Dr. Michael Gimbrone. For that, I am grateful. Similarly, Dr. Goldblum would like to acknowledge his mentor in gastrointestinal pathology, Dr. Henry Appelman.
    On a personal level, I would like to thank all members of my family, Pilar, and my extended family in Boston, for their love, friendship, advice, and support in my personal and professional endeavors. In addition, I am eternally grateful and fortunate to have had the opportunity to benefit from the inspiration and love of my late dear mother, Natasha Odze, whose courage, wisdom, and outlook on life has always served as the basis for my own personal and academic endeavors. My heart goes out to all other individuals who have close family members or friends suffering from Alzheimer’s disease or senile dementia.
    Finally, we would like to thank all of the authors of the second edition for their excellent contributions and for the patience required to labor through the editorial process. We are particularly grateful to Dr. James Crawford for his role as Associate Editor of this textbook.

    ROBERT D. ODZE, MD, FRCP(C), JOHN R. GOLDBLUM, MD
    Table of Contents
    Copyright
    Dedication
    Contributors
    Preface
    Acknowledgments
    Part 1: Gastrointestinal Tract
    Section I: General Pathology of the GI Tract
    Chapter 1: GI Tract Endoscopic and Tissue Processing Techniques and Normal Histology
    Chapter 2: Screening and Surveillance Guidelines in Gastroenterology
    Chapter 3: Diagnostic Cytology of the GI Tract
    Chapter 4: Infectious Disorders of the GI Tract
    Chapter 5: Manifestations of Immunodeficiency in the GI Tract
    Chapter 6: Systemic Illnesses Involving the GI Tract
    Chapter 7: Neuromuscular Disorders of the GI Tract
    Chapter 8: Congenital and Developmental Disorders of the GI Tract
    Chapter 9: GI Tract Enteropathies of Infancy and Childhood
    Chapter 10: Vascular Disorders of the GI Tract
    Section II: Inflammatory Disorders of the GI Tract
    Chapter 11: Inflammatory Disorders of the Esophagus
    Chapter 12: Inflammatory Disorders of the Stomach
    Chapter 13: Inflammatory Disorders of the Small Intestine
    Chapter 14: Inflammatory Disorders of the Large Intestine
    Chapter 15: Inflammatory Disorders of the Appendix
    Section III: Polyps of the GI Tract
    Chapter 16: Polyps of the Esophagus
    Chapter 17: Polyps of the Stomach
    Chapter 18: Polyps of the Small Intestine
    Chapter 19: Polyps of the Large Intestine
    Section IV: Epithelial Neoplasms of the GI Tract
    Chapter 20: Epithelial Neoplasms of the Esophagus
    Chapter 21: Epithelial Neoplasms of the Stomach
    Chapter 22: Epithelial Neoplasms of the Small Intestine
    Chapter 23: Epithelial Neoplasms of the Large Intestine
    Chapter 24: Epithelial Neoplasms of the Appendix
    Chapter 25: Neuroendocrine Tumors of the GI Tract and Appendix
    Section V: Nonepithelial Neoplasms of the GI Tract
    Chapter 26: Mesenchymal Tumors of the GI Tract
    Chapter 27: Lymphoid Tumors of the GI Tract, Hepatobiliary Tract, and Pancreas
    Section VI: Anal Pathology
    Chapter 28: Inflammatory and Neoplastic Disorders of the Anal Canal
    Part 2: Gallbladder, Extrahepatic Biliary Tract, and Pancreas
    Chapter 29: Gallbladder, Extrahepatic Biliary Tract, and Pancreas Tissue Processing Techniques, and Normal Histology
    Chapter 30: Diagnostic Cytology of the Biliary Tract and Pancreas
    Chapter 31: Developmental Disorders of the Gallbladder, Extrahepatic Biliary Tract, and Pancreas
    Chapter 32: Infectious and Inflammatory Disorders of the Gallbladder and Extrahepatic Biliary Tract
    Chapter 33: Benign and Malignant Tumors of the Gallbladder and Extrahepatic Biliary Tract
    Chapter 34: Inflammatory, Infectious, and Other Non-neoplastic Disorders of the Pancreas
    Chapter 35: Tumors of the Pancreas and Ampulla of Vater
    Part 3: Liver
    Chapter 36: Liver Tissue Processing and Normal Histology
    Chapter 37: Diagnostic Cytology of the Liver
    Chapter 38: Acute and Chronic Infectious Hepatitis
    Chapter 39: Autoimmune and Chronic Cholestatic Disorders of the Liver
    Chapter 40: Toxic and Drug-Induced Disorders of the Liver
    Chapter 41: Fatty Liver Disease
    Chapter 42: Cirrhosis
    Chapter 43: Vascular Disorders of the Liver
    Chapter 44: Transplantation Pathology of the Liver
    Chapter 45: Liver Pathology in Pregnancy
    Chapter 46: Pediatric Liver Disease and Inherited, Metabolic, and Developmental Disorders of the Pediatric and Adult Liver
    Chapter 47: Benign and Malignant Tumors of the Liver
    Index
    Part 1
    Gastrointestinal Tract
    Section I
    General Pathology of the GI Tract
    CHAPTER 1 GI Tract Endoscopic and Tissue Processing Techniques and Normal Histology

    BRIAN. C. JACOBSON, JAMES. M. CRAWFORD, FRANCIS. A. FARRAYE

    Introduction
    Bowel Preparation
    Methods for Obtaining Tissue Specimens
    Endoscopic Pinch Biopsy
    Endoscopic Snare Polypectomy
    Endoscopic Mucosal Resection
    Methods of Processing Tissue for Pathologic Evaluation
    Formalin
    Flow Cytometry
    Electron Microscopy
    Endoscopy-Induced Artifacts
    Pathologic Features of a Healing Biopsy Site
    Methods for Obtaining Cytology Specimens
    Brush Cytology
    Fine-Needle Aspiration
    Normal Histology of the Tubal Gut
    Esophagus
    Stomach
    Small Intestine
    Colon
    Appendix
    Rectum and Anus
    Lymphatics Node Drainage and Lymphatics of the Tubal Gut

    Introduction
    Endoscopy provides a unique opportunity to visualize the mucosal surface of the GI tract. When considered within the context of a specific clinical picture, endoscopic images may be all that is needed to make a specific diagnosis, or provide sound clinical management. 1 However, more often than not, endoscopists need to sample tissue. Examination by a qualified pathologist of specimens obtained at endoscopy is a routine and critical part of managing patients with disorders of the alimentary tract. The purpose of this opening chapter is to orient the pathologist to the clinical and technical considerations unique to specimens obtained endoscopically from the alimentary tract. This is followed by a discussion of the normal anatomy of the tubal gut.

    Bowel Preparation
    The effectiveness of endoscopy depends, in part, on the quality of bowel preparation. 2 Preparation of the upper GI tract for endoscopy consists, at minimum, of a 6-hour fast. Preparation for colonoscopy is achieved by use of oral purging agents, either with or without enemas. Most colonoscopy preparation regimens include the use of a clear liquid diet for 1 to 3 days, cleansing with oral polyethylene glycol (PEG)-electrolyte solution or sodium phosphate lavage solutions, and use of oral laxatives or prokinetic agents, such as magnesium citrate, metoclopramide, cisapride, and senna, as well as rectal enemas ( Table 1-1 ). In general, vomiting is reported more frequently with oral PEG-based high-volume lavage regimens than with oral bowel prokinetics. 3 However, nausea, vomiting, and abdominal cramps are comparable between PEG lavage and oral sodium phosphate regimens. 4 PEG lavage regimens reportedly provide more consistent cleansing. 5 , 6 Purgative- and laxative-based regimens are more likely to cause flattening of surface epithelial cells, goblet cell depletion, and lamina propria edema; normo-osmotic electrolyte solutions, such as PEG-based solutions, are better agents for preserving mucosal histology. 7 In the most severe form of mucosal damage from purgatives, sloughing of the surface epithelium, neutrophilic infiltration of the lamina propria, and hemorrhage may be encountered, and the changes may even resemble mild pseudomembranous colitis. 8 Chemical-induced colitis, from inadequate cleansing of endoscopic instruments, also has been reported. Mucosal changes in this situation may resemble pseudomembranous colitis, both endoscopically and microscopically. 9
    TABLE 1-1 Common Preparation Methods for Colonoscopy 48-hr clear liquid diet, 240-mL magnesium citrate PO, senna derivative laxative (e.g., X-Prep), 12 hr NPO. 48-hr clear liquid diet, senna derivative laxative, rectal enema, 12 hr NPO. 24-hr clear liquid diet, 240 mL magnesium citrate PO, or 4 L PEG-electrolyte lavage, * 12 hr NPO. 24-hr clear liquid diet, 2 L PEG-electrolyte lavage, cascara-based laxative, 12 hr NPO. 24-hr clear liquid diet, oral sodium phosphate, † magnesium citrate PO, 12 hr NPO. 24-hr clear liquid diet, oral sodium phosphate, rectal enema.
    NPO, nulla per os (nothing by mouth); PEG, polyethylene glycol; PO, per os (by mouth).
    * PEG-electrolyte solutions include CoLyte, GoLYTELY, NuLytely, Klean-Prep, and Norgine.
    † Oral sodium phosphate solutions include Fleets Phosphosoda, De Witt Phosphosoda.

    Methods for Obtaining Tissue Specimens
    There is a limited number of methods available for obtaining tissue during endoscopy. This section describes several of these methods and the common situations in which they are used.

    ENDOSCOPIC PINCH BIOPSY
    Pinch biopsy, performed with the use of a biopsy forceps during endoscopy, is the most frequent form of tissue sampling; the biopsy site is usually fully visualized at the time of sampling. Suction capsule biopsy requires fluoroscopic guidance to position a long tube with the biopsy apparatus, and is done separately from endoscopy without visualization. Suction capsule biopsy, without bowel visualization, is still performed in some centers, but it is less successful than endoscopy-guided biopsies in obtaining tissue and, thus, has fallen out of favor. 10 Pinch biopsies may be small or large (the latter are referred to as “jumbo” biopsies) and can be obtained with or without use of electrocautery. Electrocautery has value for hemostasis and destruction of residual tissue, but introduces burn artifact into the harvested tissue.
    All standard biopsy forceps have a similar design ( Fig. 1-1 ). The sampling portion consists of a pair of small cups, or a paired set of teeth, that are in apposition when closed. In this manner, they can be passed through the 2.8-mm-wide channel of a standard gastroscope or colonoscope. Some biopsy forceps have a spike at the base of the cup or teeth to help seat the forceps against the mucosa. The spike also helps to impale multiple biopsy specimens before the forceps is removed from the endoscope.

    FIGURE 1-1 Endoscopic biopsy forceps. A , The biopsy forceps has been opened, revealing two sets of gripping “teeth” and a central spike used to impale the tissue. B , The biopsy forceps in use: the biopsy forceps is pressed against the mucosa and subsequently closed to obtain a tissue sample.
    After insertion into the endoscope and emerging from the distal end, routine biopsy forceps can be opened to a 4- to 8-mm width. The opened forceps is pressed against the mucosal surface for tissue sampling. Large-cup (jumbo) biopsy forceps have jaws that open to a width of 7 to 9 mm. The biopsy forceps is closed against the mucosal surface, and the endoscopist pulls the forceps away from the mucosa to remove the fragment of tissue. This method often yields samples that include muscularis mucosae, except in regions such as the gastric body, where the mucosal folds are quite thick. 11 The submucosa is sampled occasionally with either standard or jumbo forceps. 12 The sample size varies according to the amount of pressure the endoscopist applies to the forceps. In addition, application of a fully opened biopsy forceps flush against the mucosa before closure usually yields larger pieces of tissue, compared with those obtained by tangential sampling or incomplete opening of the forceps. In general, biopsy specimens are 4 to 8 mm in length. 13 , 14 The forceps shape does not impart a significant difference in either size or adequacy of biopsy specimens. 13 Single-use disposable biopsy forceps also have been shown to provide excellent samples. 15 In essence, there are no differences in the quality of tissue samples obtained among the dozen or more biopsy forceps currently available, so the primary considerations in the selection of an endoscopic biopsy forceps are usually related to cost and ease of use. 16
    After obtaining biopsy specimens and removing the forceps from the endoscope, an assistant dislodges the tissue fragments from the forceps with a toothpick or a similar small, sharp instrument. The tissue is then placed into a container containing appropriate fixative, and labeled according to instructions provided by the endoscopist.
    Specimens obtained with a jumbo forceps often exceed 6 mm or greater in maximum diameter, but these are not necessarily deeper than standard biopsies. Rather, a jumbo forceps provides more mucosa for analysis. This is particularly useful during surveillance tissue sampling, such as in patients with Barrett’s esophagus or ulcerative colitis. Jumbo biopsy forceps are as safe as standard biopsy forceps. 17 However, use of jumbo forceps is limited by its diameter because it cannot fit through a standard endoscope accessory channel. Jumbo forceps require a 3.6-mm-diameter channel characteristic of therapeutic endoscopes, which may be less comfortable for patients. In addition, although jumbo biopsy specimens are larger than standard biopsy specimens, this does not necessarily mean samples will be of greater diagnostic value. 18
    The most common indication for mucosal biopsy is for diagnosis of a mucosal abnormality at endoscopy. In addition, it is advantageous to sample normal-appearing mucosa during the evaluation of many conditions to establish “background” features of the mucosa, such as in gastroesophageal reflux disease, nonulcer dyspepsia, diarrhea, and surveillance of premalignant conditions, including Barrett’s esophagus and inflammatory bowel disease. The ampulla of Vater may be sampled during surveillance for adenomatous change in familial adenomatous polyposis because the lifetime incidence of ampullary adenomas in these patients exceeds 50%. 19 Biopsy of biliary or pancreatic strictures may be carried out under fluoroscopic guidance during endoscopic retrograde cholangiopancreatography (ERCP) with the use of either standard or specially designed small biopsy forceps. 20 Even gallbladder lesions noted at ERCP may be amenable to endoscopic biopsy. 20 Endoscopy-directed biopsies are extremely safe. In one study of 50,833 consecutive patients who had an upper en-doscopy, none had any biopsy-associated complications. 17
    Occasionally, an endoscopist uses a specialized insulated biopsy forceps to sample a small polyp (“hot biopsy”). Remaining tissue is then ablated in situ using electrocautery. 21 Unfortunately, cautery artifact in such small tissue samples often makes histologic interpretation difficult (or impossible). 11 , 22 In addition, the electrocautery technique carries an excessive risk of perforation due to deep tissue burn, particularly in the cecum and ascending colon. 23 , 24 Finally, destruction of residual dysplastic tissue by electrocautery may be incomplete in as many as 17% of cases. 25

    ENDOSCOPIC SNARE POLYPECTOMY
    During endoscopy, a loop of wire may be placed around a polypoid lesion that protrudes into the lumen of the gut for the purpose of removing the polyp ( Fig. 1-2 ). This technique is used primarily for colonic polyps, but polyps throughout the alimentary tract may be excised in this manner. Depending on their size, excised polyps are either retrieved through the suction channel of the endoscope, or held by the snare after resection while the colonoscope is removed from the patient. Loss of excised polyps in recesses of the intestinal lumen is an infrequent occurrence.

    FIGURE 1-2 Endoscopic snare polypectomy. A , An open metal snare extends out of a protective plastic sheath. B , A polypectomy snare has been placed over a pedunculated polyp and tightened around the polyp stalk. Electrical current is applied through the metal loop of the snare, which helps cut through the stalk and cauterize blood vessels.
    Many endoscopists have reported successful removal of diminutive polyps (<0.5 cm in diameter) during both “hot” (with electrocautery) and “cold” (without electrocautery) snare polypectomy. 26 , 27 These endoscopists use small metal snares, termed mini-snares , that open to a size of either 1 to 2 cm or 2 to 3 cm. Polyps greater than 0.5 cm in diameter are amenable to snare polypectomy, although the size of the polyp that can be excised may be limited by the size of the loop placed around it (and the endoscopist’s estimation of perforation risk). Alternatively, large polyps may be removed in a piecemeal fashion and submitted to pathology in several parts. This usually requires multiple transections of the lesion until the entire polyp has been removed. 21 One caveat with this technique is that identifiable tissue margins may be lost, so that the pathologist is often unable to determine the status of the resection margins.
    A hot snare allows the endoscopist to apply current to a metal wire that cuts through pedunculated polyps at the base. This assists tissue cutting and coagulation. Electrocautery also minimizes bleeding from larger blood vessels located in the stalk of the polyp. Cold polypectomy, without electrical current, avoids use of cautery, thereby limiting the amount of burn artifact in the specimen and minimizing the risk of perforation. In general, the risk of perforation from either mechanical or electrical injury is minimal, but is greater in portions of the colon that are covered by a free serosal surface, such as the transverse colon. Information on the relative risk of clinically significant hemorrhage after “hot” polypectomy is limited, but the risk is generally considered low (0.4%). 28 , 29 A recent large cross-sectional study from South Korea established that loop polypectomy is only rarely performed without electrical current (“cold”), and this is usually inadvertent owing to failure of application of electrical current. 30 Absence of electrical current is associated with an increased risk of clinically significant postpolypectomy hemorrhage. A higher risk of postpolypectomy hemorrhage also occurs in patients with pedunculated polyps larger than 1.7 cm or with a stalk diameter larger than 0.5 cm, sessile polyps, and malignant lesions. 31
    For polyps excised in one piece, by either hot or cold polypectomy, the polyp base constitutes the surgical margin of resection. This is true for both pedunculated and sessile polyps. For polyps removed by hot snare polypectomy, the cauterized portion of the specimen constitutes the surgical margin. An artificial stalk can be created when large sessile lesions are loop-excised. A true pedunculated polyp, with a stalk, has a narrow base that persists after removal; the base of a sessile polyp is usually as wide as the mucosal surface that is sampled.
    Snares are available in a variety of shapes and sizes. Newer types of snares can be rotated, which provides the endoscopist with greater control of snare placement. The choice of snare size is typically based on the size of the lesion being removed. The selection of a particular snare shape usually reflects personal choice.
    Snare polypectomy is performed in a similar fashion, whether colonic, esophageal, gastric, or small bowel lesions are removed. In fact, the ampulla of Vater may be resected by standard snare techniques when an ampullary lesion is noted. 32 The risk of perforation during snare polypectomy is less than 0.1%, 33 , 34 and perforation generally results from transmural burn secondary to cautery. One technique aimed at decreasing the risk of perforation is to pull the snared polyp away from the mucosa so that less cautery is applied to the underlying tissue.
    Another commonly used method is saline-assisted pol-ypectomy. 35 , 36 A small needle is passed through the endoscope and is inserted into the gut wall adjacent to the polyp. A bolus of normal saline is then injected. Fluid collects within the submucosal plane, thereby “lifting” the mucosal-based polyp away from the muscularis propria. A standard snare polypectomy is then performed, but the cushion of saline insulates the deeper tissue layers from electrical current. Saline-assisted polypectomy is usually reserved for large sessile polyps and, theoretically, results in a decreased rate of polypectomy-associated perforation.

    ENDOSCOPIC MUCOSAL RESECTION
    The use of a liquid cushion to expand the submucosa and minimize transmural cautery damage is a principal component of endoscopic mucosal resection (EMR). This technique is commonly used to resect premalignant and malignant lesions confined to the mucosa. 37 In general, EMR requires some measure of confidence that a lesion is, in fact, confined to the mucosa or submucosa. Many endoscopists now rely on endoscopic ultrasonography (EUS) to determine the depth of a particular lesion before EMR. The accuracy of high-frequency EUS (15 or 20 MHz) may be as great as 95% for determining whether a lesion is limited to the mucosa, 37 but the availability of EUS and variation in operator experience may limit its general utility.
    Several variations of the EMR technique are currently used. Many rely on submucosal injection of liquid, but there is currently no agreement as to the type or quantity of liquid that should be injected. 38 Some endoscopists advocate the use of saline alone. Others add diluted epinephrine to saline in an attempt to constrict small blood vessels at the base of the lesion. Submucosal fluid collections are absorbed. Hence, to lengthen the time that the submucosal cushion lasts, and thus maximize the time available for performing a safe resection, investigators have used hypertonic solution of 3.5% saline or 50% dextrose. Others advocate the use of sodium hyaluronate instead of saline. The quantity of liquid injected also varies. In general, there is agreement that the target lesion should appear endoscopically to be raised by the cushion of liquid before EMR. In fact, failure to lift the lesion despite the generous use of submucosal saline (the so-called nonlifting sign) may be a sensitive indicator that a lesion has spread deeper into the bowel wall. 39
    Two major types of resection techniques are used—those that do not use suction and those that do. When suction is not used, the endoscopist uses a dual-channel endoscope. A snare, passed through one instrument channel, is opened and placed around the lesion. A biopsy forceps passed through the second channel is used to grab the lesion and pull the mucosa through the snare even farther away from the muscularis propria. The snare is then closed around the base of the tented lesion, and electrocautery is applied ( Fig. 1-3 ). This method is referred to as a lift-and-cut technique , or a strip biopsy . 37 , 40

    FIGURE 1-3 Endoscopic mucosal resection (EMR). A , EMR 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). B , EMR by aspiration: saline is injected into the submucosa, and the tissue is elevated (1). The lesion is aspirated into a plastic cap at the end of the endoscope, and the snare is closed around the lesion (2). The ensnared lesion is released from the cap (3). Electrosurgical current is applied, and the resected lesion is trapped within the cap by aspiration (4). ( A and B reused by permission of the publisher. 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 50:819-822, 1999.)
    Suction methods of EMR incorporate the use of a cap fitted onto the tip of an endoscope. The cap presents an open surface to the mucosa and creates a short chamber into which the target lesion can be aspirated and held by suction, with the latter applied through a single-channel endoscope. A specialized snare is opened in the cap before aspiration of the lesion. Once the mucosa has been drawn into the cap, the snare may be closed around the lesion and cautery applied in the usual fashion. 37 This technique, also called aspiration mucosectomy , has been widely successful for removing lesions throughout the GI tract. 41
    A newer EMR technique is similar to aspiration mucosectomy. However, once a lesion is suctioned into the cap, a tiny rubber ring is released around the base of the lesion, similar to the method used during endoscopic variceal ligation. Once suction is released, the lesion appears contained within a “pseudopolyp” that can be removed by snare cautery. This is known as band-ligation EMR ( Fig. 1-4 ).

    FIGURE 1-4 Band-ligation endoscopic mucosal resection. A , A region of endoscopically visible high-grade dysplasia in the esophagus. B , A rubber band ligator has been applied to the base of the lesion after aspiration of the mucosa and submucosa into a cap affixed to the end of the endoscope. The result is a polypoid area containing the dysplastic tissue. C , The pseudopolyp has been resected by snare cautery and can be retrieved for tissue processing. D , The region where dysplasia was present has been removed, leaving a clean-based ulcer.
    EMR allows the endoscopist to attempt an en bloc resection and thus potentially completely resect an early malignant lesion. En bloc resection is limited, however, to small lesions (1.5 to 2 cm in largest diameter). 40 If deep margins are positive for neoplasia, surgical resection of the affected region is advocated. 42 Current indications for EMR include superficial carcinoma of the esophagus, or stomach, in patients who are nonoperative candidates, unifocal high-grade (or low-grade) dysplasia in Barrett’s esophagus, and large, flat colorectal adenomas regardless of the degree of dysplasia (which might otherwise require piecemeal resection). EMR as a form of primary therapy for small, superficial cancer has not gained popularity in the United States, but is often used in Japan. 37 , 40 , 42 EMR may also be indicated as a form of primary therapy for small submucosal lesions, such as rectal carcinoid tumors or leiomyomas. In many cases, the submucosal lesion can be completely resected 43 ( Fig. 1-5 ).

    FIGURE 1-5 Resection of a submucosal carcinoid in the rectum. A , A 1-cm mass is seen below the mucosa of the rectum. Endoscopic ultrasonography demonstrated that the mass arises in the submucosa. B , After endoscopic mucosal resection, the tumor has been “shelled out.” C , Nests of neuroendocrine cells form a tumor confined to the rectal submucosa. There were no tumor cells at the resection margins.
    Major complications of EMR include bleeding and perforation. Bleeding occurs in less than 1% to 20% of cases and varies depending on the size of the lesion and its location. 37 , 40 , 42 Clinically significant bleeding is rare and usually amenable to endoscopic hemostatic cauterization. Perforation rates are generally lower than 2%. EMR also provides large specimens for pathologic analysis even in the absence of complete resection. Success rates of en bloc resection of early gastric cancers range from 36% to 74%. 40 , 42

    Methods of Processing Tissue for Pathologic Evaluation
    A general framework for processing biopsy specimens is provided in Table 1-2 .
    TABLE 1-2 Techniques of Processing Tissue Specimens Obtained by Endoscopy Technique Comment Formalin fixation Routine processing of all alimentary tract biopsies; immediate immersion in fixative. Permits immunohistochemistry, molecular analysis. Flow cytometry Suspected hematologic malignancy; fresh tissue in sterile culture medium. Electron microscopy Suspected poorly differentiated malignancy, infection (e.g., Whipple’s disease, microsporidiosis); immediate immersion in electron microscopy fixative. Electron microscopy fixative only Suspected systemic mastocytosis, for which plastic-embedded thick sections with toluidine blue staining are optimal for identifying mast cells. Microbial culture Suspected viral, fungal, or parasitic infection; sterile tissue. Biochemical analysis Suspected metabolic deficiency (e.g., disaccharidase deficiency); frozen tissue. Cytogenetics * Suspected neoplasm (benign or malignant); fresh tissue in sterile culture medium. Cell culture * Suspected neoplasm (benign or malignant); fresh tissue in sterile culture medium.
    * Usually for investigational purposes only.

    FORMALIN
    Of the many types of fixatives used for human tissue, 10% buffered formalin remains the standard and is well suited for mucosal biopsies of the gastrointestinal tract. It is inexpensive, harmless to the tissue specimen even after long periods of time, and is compatible with most of the stains commonly used for morphologic assessment. Hollende’s solution, B5, and Bouin’s fixative have been used for mucosal biopsies because of better preservation of nuclear morphology compared with formalin. However, the heavy metal content of these fixatives creates biohazard disposal problems that are greater than those of formaldehyde-based fixatives. These fixatives also interfere with isolation of nucleic acid from tissue; finding substitute fixatives and new tissue processing techniques are active areas of scientific investigation.
    On occasion, the formaldehyde in formalin may be irritating to the eyes and upper respiratory tract of personnel. There also is public debate over its potential as a carcinogen. 44 However, the level at which formalin is considered carcinogenic is considered well above the level that causes sensory irritation, which has a threshold of 1.0 part per million (ppm). 45 Proper ventilation should be used to maintain exposure below 1.0 ppm. This is the lowest concentration that may exert a cytotoxic effect in humans. 44 , 46 This consideration applies to pathology suites. Typical occupational exposure in endoscopy suites is exceedingly brief, so that special ventilation is not usually required in that hospital area.
    Alimentary tract biopsy specimens should be placed in a volume of formalin fixative that is at least 10 times greater than that of the tissue, and the fixative should surround the specimen completely. For routine processing, it is a common mistake to place specimens on saline-soaked gauze for delivery to the pathology suite because severe drying may occur. Complete fixation of these biopsies should always occur at the bedside. Formaldehyde diffuses into tissue at a rate of approximately 1.0 mm per hour at room temperature. 47 Thus, up to 1 hour is often needed adequately to fix a specimen with a diameter greater than 1.0 mm. More time is needed for larger specimens. Controlled microwave fixation at 63° to 65° C can greatly speed the process and is useful for rapid processing of specimens. 48

    Orientation of Formalin-Fixed Tissue Obtained at Endoscopy
    Esophageal, gastric, and colonic mucosal biopsies do not require precise orientation before tissue processing and embedding. Until the mid-1980s, most peroral small intestinal biopsies were obtained by either a Crosby suction capsule or a Quinton hydraulic assembly. 49 , 50 These two methods were performed fluoroscopically and therefore did not permit direct visualization of the alimentary tract. Biopsies obtained by these methods were carefully oriented under a dissecting microscope before fixation and em-bedding. Direct endoscopic biopsy of the small intestine replaced the fluoroscopy with suction capsule biopsy procedure by the late 1980s 51 , 52 ; biopsies obtained by this technique are not usually oriented before immersion in fixative, processing, and embedding. Rather, microscopic examination of multiple tissue sections usually permits identification of portions of the small intestinal mucosa that are well oriented and thus can be assessed satisfactorily for tissue architecture.
    In contrast, processing of an endoscopic polypectomy specimen in the pathology suite requires diligent effort. 53 The size and surface configuration (bosselated or villiform) of the polyp should be noted, and the base of the polyp should be identified and described as to whether it is sessile or contains a cylindrical stalk. Regardless of the configuration of the stalk, the base of the polyp should always be inked. Ink and cautery artifact on a microscopic slide are valuable landmarks for locating the relevant resection margins. Small polyps (<1 cm in diameter) should be bisected along the vertical plane of the stalk so that the surgical margin is included. Both halves of the specimen can then be submitted in one cassette.
    Section levels should be numbered consecutively; the first level is the one normally located closest to the middle of the polyp stalk. Large polyps (≥1 cm in diameter) may be sectioned differently if the polyp head is too wide to fit into a single cassette. First, the polyp should be bisected along its long axis and fixed overnight in formalin. Once fixed, the sides of the polyp may be trimmed away from the stalk on a vertical axis and submitted in separate cassettes that are labeled accordingly. The middle of the polyp, including the base, should be sectioned vertically and submitted in an appropriate number of cassettes. If a stalk is identified histologically, the status of the margins should always be noted in the surgical pathology report.
    If the polyp has been excised in a piecemeal fashion, the size, color, surface configuration (bosselated or villiform), and aggregate dimensions of the tissue fragments should be noted. It is important to note the number of tissue fragments received in the pathology suite.

    FLOW CYTOMETRY
    Gastrointestinal lesions suspected of representing a lymphoproliferative process are usually submitted for histology, but should also be processed for flow cytometry. 54 Biopsy specimens intended for flow cytometric analysis, such as gastric biopsies of a mass lesion, should be placed in sterile culture medium and delivered as rapidly as possible to the flow cytometry laboratory. Ideally, this should occur within several hours, but storage of specimens at 4°C overnight is an acceptable alternative.
    Upon receipt in the laboratory, the tissue specimen is disaggregated and a cell suspension is prepared. Cocktails of fluorescently labeled antibodies appropriate to the diagnostic question are applied to the cell suspension. Current flow cytometry machines can analyze 5000 to 10,000 cells per second, measuring multiple wavelengths of laser-induced fluorescence simultaneously, thus permitting rapid and highly efficient analysis of cell populations. This technique cannot be performed on fixed tissue. It is, therefore, incumbent on the endoscopist to consider the possibility of a lymphoproliferative disorder at the time of endoscopy to ensure that tissue is preserved in a fresh state.

    ELECTRON MICROSCOPY
    For the uncommon instances in which electron microscopy of an alimentary tract biopsy is contemplated, tissue samples should be placed directly into the appropriate fixative, which usually consists of a mixture of paraformaldehyde and glutaraldehyde. Unlike formaldehyde-based fixatives, bifunctional glutaraldehyde fixatives penetrate only about 0.5 mm into the tissue. Thus, tissue fragments to be placed in fixative for subsequent electron microscopy should, ideally, measure less than 1.0 × 1.0 × 1.0 mm 3 in maximal dimension. Indications for electron microscopy of endoscopic biopsy specimens are now largely limited to examination of unusual tumors. 55 However, this technique is also helpful in cases of unknown diarrhea in children, and in patients with AIDS, for detection of parasitic organisms.

    Endoscopy-Induced Artifacts
    Many types of tissue artifacts may be introduced into tissues as a result of bowel preparation, endoscopic trauma, or tissue handling. Some of these are listed in Table 1-3 . Histologic features of artifacts are provided in Table 1-4 . The most common type of artifact (or effect) is lamina propria edema and intramucosal hemorrhage (“scope trauma”), as illustrated in Figure 1-6 . Other effects include aggregation and clumping of inflammatory cells in the lamina propria, surface flattening, mucin depletion, and even erosion and influx of air into the tissue (pseudolipomatosis). 56 - 58 The most common histologic artifacts include cautery and crush artifacts ( Fig. 1-7 ). Cautery artifact as a result of hot biopsies is, in fact, a normal and expected component of endoscopic polypectomy with electrocautery. Specifically, the region of cauterization may provide a useful landmark of the surgical margin.
    TABLE 1-3 Endoscopic Events that May Affect Tissue Analysis Event Comment Trauma (tissue hemorrhage) “Scope trauma” (due to mechanical damage from endoscope) or excessive mechanical manipulation for access before biopsy Cautery artifact Excessive use of electrical current during “hot” biopsy Crush artifact Excessive use of mechanical force during pinch biopsy Inadequate sampling depth Absence of submucosa (e.g., evaluate submucosal lesion, rule out amyloid) Inadequate sampling location Absence of muscularis mucosa (for evaluation for Hirschsprung’s disease)   Insufficient regional sampling (e.g., of “normal-appearing” mucosa) Chemical colitis 56 , 57 Inadequate rinsing of cleaning solution from the endoscope Laxative-induced changes 58 Edema, damage to surface epithelium from exposure to oral and rectal laxatives Air-drying Postbiopsy healing Failure to immerse specimen promptly in fixative Sampling of a previous biopsy site during subsequent endoscopy Wrong fixative Formalin rather than fixative for electron microscopy; suboptimal but not irretrievable No fresh tissue Failure to preserve fresh tissue; precludes flow cytometry, cytogenetics
    TABLE 1-4 Histologic Artifacts Related to Endoscopy Event Feature “Scope trauma” Mucosal lamina propria hemorrhage or edema Bowel prep- related changes Clumping of inflammatory cells, mucin depletion, epithelial degenerative changes, focal neutrophilic infiltration, hemorrhage, edema, air in mucosa (pseudolipomatosis) Insufflation of air at endoscopy Air spaces within mucosa or submucosa (pseudolipomatosis) Cautery artifact Coagulated, eosinophilic tissue without cellular or nuclear detail Crush artifact Compressed tissue with markedly elongated, wavy nuclear remnants and no identifiable architecture Chemical colitis from inadequate cleaning of the endoscope Degenerative damage to, or sloughing of, surface epithelium, intraepithelial neutrophils and congestion, focal intramucosal hemorrhage Laxative-induced changes Lamina propria edema and neutrophilic infiltration, flattening or sloughing of mucosal surface epithelium, decreased goblet cell numbers Air-drying Eosinophilic and compressed tissue and loss of nuclear detail at edge of tissue fragment Postbiopsy healing See Table 1-5

    FIGURE 1-6 Endoscopic appearance of “scope trauma.” A , A duodenal fold is swollen owing to lamina propria edema induced by passage of an endoscope; the region shows a subtle ring of mucosal hemorrhage. B , The colonic mucosa demonstrates multifocal areas of mucosal hemorrhage after withdrawal of the colonoscope; these were not present during initial advancement of the colonoscope into the colon.
    (Photographs courtesy of Dirk Van Leeuwen, Dartmouth Mary Hitchcock Medical Center, Lebanon, NH.)

    FIGURE 1-7 Histologic artifacts in endoscopic biopsies. A , Cautery artifact: mucosal architecture is obliterated, leaving a heat-induced coagulum with holes in the tissue and no appreciable cellular architecture. Cautery artifact is an expected component of a “hot biopsy” and is a useful guide for identifying the base of a polypectomy sample. B , Crush artifact: the pinch site at the base of a biopsy is shown in the center of the image. All architectural details are lost, and basophilic nuclear material is crushed against eosinophilic matrix and cellular debris. C and D , Hemorrhage, edema, mucin depletion, and artificial shearing of the surface epithelium as a result of bowel preparation procedures and endoscopic trauma. E , Pseudolipomatosis of the colonic mucosa secondary to insufflation of air at the time of endoscopy.

    Pathologic Features of a Healing Biopsy Site
    After endoscopic biopsy, the tissue healing process takes a considerable amount of time ( Table 1-5 ). Blood clot and granulation tissue form within several hours after biopsy, 59 as illustrated in Figure 1-8A and B . Routine superficial biopsies that involve only mucosa and submucosa typically reepithelialize within 48 hours after biopsy (see Fig. 1-8C ). Ulcers that penetrate into the muscularis propria often take 3 to 6 days to reepithelialize (see Fig. 1-8D ). Notably, after superficial biopsy, there is no increased risk of perforation during subsequent insufflation (as from repeat endoscopy or from barium enema), even immediately after the biopsy. The risk of perforation after a deep biopsy, one that involves the muscularis propria, returns to baseline after 3 to 6 days. 59 Regardless of the maximum depth of biopsy penetration (submucosa or muscularis propria; pinch biopsy or loop resection of a polyp), after several weeks a residual submucosal scar may remain, either with (see Fig. 1-8E ) or without (see Fig. 1-8F ) atrophy of the mucosa.
    TABLE 1-5 Pathologic Features of a Healing Mucosal Biopsy Site Time Feature Immediate Blood clot with coagulum Hours Acute inflammation; granulation tissue reaction 2 days * Reepithelialization of inflamed biopsy site by ingrowth of epithelial cells from adjacent preserved epithelium; early formation of submucosal scar 1-4 wk Restoration of mucosa with rudimentary glandular architecture, maturation of submucosal scar Months Residual minimal mucosal architectural distortion, submucosal scar
    * Longer with deep biopsies that involve the muscularis propria.

    FIGURE 1-8 Healing mucosal biopsy sites. Healing of the colonic mucosa and submucosa after endoscopic biopsy is shown. A , Gross photograph of a resected colon specimen 2 days after endoscopic biopsy, with an arrow demonstrating the original biopsy site. B , Two days after endoscopic polypectomy, the biopsy site shows ulceration, inflammation, and granulation tissue reaction. C , Four days after biopsy, the mucosa shows architectural distortion and a thin, attenuated layer of surface epithelium. D , Four days after a loop polypectomy, an attenuated layer of epithelium covers portions of the biopsy site, but the ulcer is still present. E , Three weeks after biopsy, submucosal scarring and rudimentary crypt restoration are noted. F , One month after biopsy of a prominent mucosal fold, the submucosa shows scarring, and there is focal architectural distortion in the mucosa.
    Pathologists should be aware of changes associated with colonic biopsy site repair in order not to misinterpret architectural distortion of the mucosa as evidence in favor of inflammatory bowel disease.

    Methods for Obtaining Cytology Specimens
    See also Chapters 3 , 30, and 37.

    BRUSH CYTOLOGY
    Brush cytology is a method used for broad sampling of the mucosal surface. 60 , 61 Cytology brushes, whether reusable or disposable, have a common design. A cytology brush consists of bristles, usually composed of nylon fibers, that branch off a thin metal shaft that runs lengthwise within a protective plastic sheath. The various cytology brushes that are currently available do not seem to vary in terms of performance characteristics. 62 The cytology brush is passed through an accessory channel of an endoscope. The end of the sheath is passed out of the tip of the endoscope, and the bristle portion of the brush is then extended from the sheath. The brush is rubbed back and forth several times along the surface of the lesion, or stricture, and is then pulled back into the sheath. The sheath is then withdrawn from the endoscope, and the brush is pushed out of the sheath, thus exposing the bristles. The bristle portion of the brush may be cut off, placed into fixative, and sent in its entirety to the cytopathology laboratory. Alternatively, the bristles can be rolled against a glass slide in the endoscopy suite. The slides should be sprayed with fixative immediately, or submerged within it, and subsequently delivered to the cytopathologist. If smears are made in the endoscopy suite, little additional benefit is derived from inclusion of the bristles for cytopathologic analysis. 63

    FINE-NEEDLE ASPIRATION
    Fine-needle aspiration (FNA) is another method used for obtaining tissue for cytology. 64 - 66 FNA needles may be used during standard endoscopy or during EUS. EUS provides endoscopists with the ability to sample tissue from parenchymal lesions and lymph nodes, as well as fluid from cystic lesions. EUS provides real-time imaging to ensure that the intended target is localized and sampled. The needles used for FNA during endoscopy are hollow 19- to 25-gauge needles, often fitted with a central stylet to avoid gathering of intervening tissue. Once the lesion of interest has been identified, the sheath is pushed out of the endoscope, and the needle is advanced into the target tissue either under fluoroscopic guidance (during ERCP) or under ultrasonographic guidance (during EUS). If a stylet is present, it is then removed, and suction is applied to a syringe at the proximal end of the needle. While suction is applied, the endoscopist moves the needle forward and backward within the lesion, thereby filling the distal needle lumen with tissue. The needle is then withdrawn into the sheath, and the entire apparatus is removed from the endoscope. Complications from FNA biopsy occur in less than 2% of cases and include bleeding and, in the setting of pancreatic mass FNA, acute pancreatitis.

    Normal Histology of the Tubal Gut

    ESOPHAGUS
    The adult human esophagus measures about 25 cm in length. For the endoscopist, the length of the esophagus is measured as the anatomic distance from the incisor teeth. The esophagus usually begins at 15 cm, and the gastroesophageal junction (GEJ) is located at 40 cm. The 3-cm segment of the proximal esophagus (at 15 to 18 cm from the incisors), at the level of the cricopharyngeus muscle, is referred to as the upper esophageal sphincter . The 2- to 4-cm segment just proximal to the anatomic GEJ (at 36 to 40 cm from the incisors), at the level of the diaphragm, is referred to as the lower esophageal sphincter . Both “sphincters” are physiologic because there are no anatomic landmarks that outline these high-pressure regions in relationship to the underlying esophageal musculature.
    In keeping with the structural organization of the entire alimentary tract ( Fig. 1-9 ), the wall of the esophagus consists of a mucosa, submucosa, muscularis propria, and adventitia. The mucosa has a smooth, glistening, pink-tan surface. It has three components: a nonkeratinizing stratified squamous epithelial layer, and an underlying lamina propria and muscularis mucosae ( Fig. 1-10 ). The basal cell zone of the squamous epithelium occupies 10% to 15% of the total thickness of the epithelial layer. A small number of specialized cell types, such as endocrine cells, Langerhans’ cells, and lymphocytes, are typically present in the deeper portion of the squamous epithelium. The intraepithelial lymphocytes are T cells. 67 Melanocytes may be present in the esophagus in 3% to 8% of normal individuals. 68 , 69

    FIGURE 1-9 Microanatomy of the tubal gut. A , Esophagus. B , Stomach. C , Small intestine. D , Colon.
    (Reproduced with permission from Crawford JM: Principles of anatomy. In Rustgi AK, Crawford JM [eds]: Gastrointestinal Cancers: Biology and Clinical Management. Philadelphia, WB Saunders, 2003, pp 121-131.)

    FIGURE 1-10 Normal histology of the esophageal mucosa. Stratified nonkeratinizing squamous mucosa rests on loose lamina propria, which contains supporting vasculature and scattered inflammatory cells.
    The lamina propria is the nonepithelial (mesenchymal) portion of the mucosa, located above the muscularis mucosae. It consists of areolar connective tissue and contains vascular and neural structures, and scattered inflammatory cells. Finger-like extensions of the lamina propria, termed papillae , extend into the epithelial layer. These papillae usually extend to one third to one half of the thickness of the epithelial layer. In esophagitis (e.g., reflux esophagitis), the papillae extend into the upper third of the epithelial layer.
    The muscularis mucosae is a thick layer of longitudinally oriented smooth muscle bundles. The submucosa consists of loose connective tissue containing blood vessels, a rich network of lymphatics, and a sprinkling of inflammatory cells, with occasional lymphoid follicles, nerve fibers (including the ganglia of Meissner’s plexus), and submucosal glands. Submucosal glands connect to the lumen of the esophagus by squamous epithelium–lined ducts. Submucosal glands are scattered along the entire esophagus but are more concentrated in the upper and lower portions. Submucosal glands are suspended within the delicate mesenchyme of the submucosa. They have a simple acinar structure, and resemble salivary glands in that they contain mucous cells surrounding a central lumen, in a radial fashion. Their mucin-containing fluid secretions help lubricate the esophagus. Submucosal glands also secrete biologically active peptides, such as those from the trefoil factor family 3 (TTF3) 70 ; these peptides play a role in mucosal protection and repair. Identification of a squamous duct and submucosal mucous glands is considered a definitive anatomic landmark of the tubular esophagus . In the deep portion of the submucosa, the gland ducts contain two discrete layers of cuboidal cells, which become progressively more squamoid at higher levels of the submucosa and mucosa. A mild, concentric, chronic inflammatory infiltrate is commonly noted surrounding the gland ducts.
    Endoscopic biopsies of the esophagus yield squamous epithelium, lamina propria, and muscularis mucosae. Sampling of the submucosa is variable. The anatomic landmarks change in patients with Barrett’s esophagus: the lamina propria no longer lies only underneath the epithelial layer, but is also located between the glands. A newly developed muscularis mucosae lies directly underneath the glands. This layer of muscularis mucosae represents the superficial layer of a “double muscularis” in patients with Barrett’s esophagus. 71

    STOMACH
    The stomach is a large saccular organ with a volume of 1200 to 1500 mL, but it has a potential capacity of over 3000 mL. It extends from just left of the midline superiorly, where it is joined to the esophagus, to just right of the midline inferiorly, where it connects to the duodenum. The stomach begins at the GEJ, considered to be the most proximal point of the gastric folds. The stomach ends at the pylorus, where the muscularis propria thickens to create the pyloric sphincter . The concavity of the right, inner curve of the stomach is termed the lesser curvature , and the convexity of the left, outer curve is considered the greater curvature . The angle along the lesser curve, termed the incisura angularis , marks the approximate point at which the stomach narrows before its junction with the duodenum. The stomach is divided into five anatomic regions. The cardia is a narrow (0.1 to 0.4 cm in length) conical portion of the stomach located immediately distal to the GEJ. The fundus is the dome-shaped portion of the proximal stomach that extends superolateral to the GEJ. The body , or corpus , comprises the remainder of the stomach proximal to the incisura angularis. The stomach distal to the incisura is considered the antrum , which is demarcated from the duodenum by the pyloric sphincter.
    The gastric wall consists of mucosa, submucosa, muscularis propria, and serosa. The interior surface of the stomach exhibits coarse rugae (“folds”). These infoldings of mucosa and submucosa extend longitudinally and are most prominent in the proximal stomach. The rugae flatten when the stomach is distended. A finer, mosaic-like pattern is delineated by small furrows within the mucosa. Finally, the delicate texture of the mucosa is punctuated by millions of gastric foveolae, or “pits,” which lead to the mucosal glands.
    The normal gastric mucosa has two main epithelial compartments: the superficial foveolar (meaning “leaf-like”) compartment and the deeper glandular compartment. The foveolar compartment is relatively uniform throughout the stomach. In contrast, the glandular compartment exhibits major differences in thickness and composition in different regions of the stomach ( Fig. 1-11 ). The foveolar compartment consists of mucous cells that line the entire mucosal surface, and gastric pits ( foveolae ). The tall, columnar mucin-secreting foveolar cells contain basal nuclei and crowded, small, relatively clear mucincontaining granules in the supranuclear region of the cytoplasm. Deep in the gastric pits are the so-called mucous neck cells , which have a lower content of mucin granules and are thought to be the cell progenitors of both the surface epithelium and the gastric glands. Mitoses may be identified in this region because the entire gastric mucosal surface is normally replaced completely every 2 to 6 days. The glandular compartment consists of gastric glands, which vary between the different anatomic regions of the stomach:
    • In the cardia, the glands contain either pure mucous cells, or a mixture of mucous and oxyntic cells, for a length of 0.1 to 0.4 cm in most individuals (see Chapter 12 ). In a small proportion of individuals, a portion of the circumference of the cardia may contain only pure oxyntic glands.
    • Oxyntic glands (also called fundic glands ) are found in the fundus and body, and contain parietal cells, chief cells, and scattered endocrine cells. The term oxyntic is derived from the Greek oxynein , and means “acid-forming.”
    • Antral and pyloric glands are identical and contain both mucus-secreting cells and endocrine cells. At the proximal junction of the antrum with the gastric corpus, the glands usually show a mixture of mucous and oxyntic glands. This histologic junction migrates proximally a few centimeters with age. Distally, where the pyloric mucosa enters the proximal duodenum, the small intestinal mucosa (see later) appears to override the mucous glands. In turn, the mucous glands quickly transition to a location below the level of the muscularis mucosae, to form the duodenal Brunner’s glands.

    FIGURE 1-11 Normal histology of the stomach. A , Cardiac mucosa, high-power view, showing simple mucous glands (and some oxyntic glands) underlying the surface epithelium. B , Oxyntic mucosa, low-power view, showing the thickness of the glandular mucosa. C , Antral mucosa, low-power view, showing a slightly thinner mucosa, with mucous glands only.
    Gastric gland cell types include the following:
    • Mucous cells populate the mucous glands of the cardia and antral regions and secrete mucus and pepsinogen II. The mucous neck cells in the oxyntic glands of the body and fundus secrete mucus as well as group I and II pepsinogens.
    • Parietal cells line mainly the upper half of the oxyntic glands in the fundus and body. They are recognizable by their bright eosinophilia on H&E stain, which is attributable to the abundance of mitochondria. Scattered parietal (and chief) cells can be seen in the antrum as well, particularly in the proximal transition zone with the true antrum.
    • Chief cells are concentrated at the base of oxyntic glands in the fundus and body, and are responsible for secretion of the proteolytic proenzymes pepsinogen I and II . Chief cells are notable for their basophilic cytoplasm, and, ultrastructurally, are classic protein-synthesizing cells, having an extensive subnuclear rough endoplasmic reticulum, a prominent supranuclear Golgi apparatus, and numerous apical secretory granules.
    • Endocrine (or enteroendocrine ) cells are scattered among the epithelial cells of the oxyntic and mucous glands (see Chapter 25 for details). The cytoplasm of these triangle-shaped cells contains small, brightly eosinophilic granules that are concentrated on the basal aspect of the cell. These cells can act in an “endocrine” fashion by releasing their products into the circulation, or in a “paracrine” fashion through secretion directed into the local tissue. In antral mucosa, most endocrine cells consist of gastrinproducing G cells . In the body, the endocrine cells produce histamine, which binds the H 2 receptor on the parietal cells, and leads to an increased acid production. These cells are also referred as enterochromaffin-like cells . Other enterochromaffin-like cells in the oxyntic glands include D cells (which produce somatostatin) and X cells (which produce endothelin). These cells play an important role in modulating acid production.

    The Gastric Cardia
    The stomach begins at the most proximal aspect of the gastric folds. The gastric cardia is viewed as an anatomic region of the stomach of approximately 0.1 to 0.4 cm in length located at the proximal cone of the gastric cavity, just distal to the squamocolumnar mucosal boundary (the “Z”-line) in normal individuals. Traditionally, the gastric cardia is viewed as having “cardiac” mucosa, which is a mucinous, glandular mucosa typically lacking oxyntic glands (which contain chief and parietal cells) (see Fig. 1-11A ). However, some individuals may show a mixture of both types of glands (mucous and oxyntic; see later; see also Chapter 12 for details).
    The strict (physiologic) definition of the GEJ is actually manometric, in that the high-pressure zone of the lower esophageal sphincter defines the true distal end of the esophagus. Because manometry is not a normal part of routine endoscopy and the GEJ passes through the diaphragmatic orifice, the performance of endoscopy on a live, breathing patient makes it difficult to identify precisely the true anatomic location of the GEJ region. The flaring of the gastric cavity on retroflexion of the endoscope is considered a reliable indicator of the beginning of the stomach. However, an axial hiatal hernia, or the proximal migration of the squamocolumnar mucosal junction in the setting of gastroesophageal reflux (whether physiologic or pathologic), also makes it very difficult to identify the anatomic site of the most proximal stomach at the time of endoscopy.
    The origin and nature of epithelium in the cardia region of the stomach is controversial. In 1997, Öberg and colleagues 72 found that endoscopic biopsies obtained at and below the GEJ in 334 patients showed absence of cardia-type mucinous glands in 26% of patients. Patients who did have cardiac mucosa were also significantly more likely to have gastroesophageal reflux disease. Chandrasoma and coworkers 73 reported that the presence of cardia-type gastric mucosa or “oxyntocardiac mucosa” (combined oxyntic and mucous glands) in the GEJ correlated with acid reflux. These authors concluded that all cardia-type mucosa in the GEJ region represents metaplastic transformation of the squamous epithelium as a result of reflux. In another autopsy study by the same group, 74 the entire circumference of the GEJ was examined histologically in 18 patients, and cardia-type mucosa was completely absent in 10 (56%). These findings were contradicted by Kilgore and associates, 75 who found cardia-type mucosa at the GEJ in all 30 pediatric autopsies examined, a population considered to be at low risk for gastroesophageal reflux disease. Other investigators also have found either mucous glands or mixed mucous glands in most, if not all, patients at the GEJ, even in patients without any gastroesophageal reflux disease history ( Table 1-6 ).

    TABLE 1-6 The Gastric Cardiac Mucosa: Key Publications
    A summary of the objective evidence and the controversies surrounding the nature of the cardia was reported by Odze in 2005. 83 In that evidence-based review, the preponderance of evidence indicates that the true gastric cardia is an extremely short segment (<0.4 cm) of mucosa that is typically composed of pure mucous glands, or mixed mucous/oxyntic glands. Notably, these glands are histologically indistinguishable from metaplastic mucinous columnar epithelium of the distal esophagus characteristic of Barrett’s esophagus. In patients with gastroesophageal reflux disease, the length of cardia-type mucosa increases and extends proximally above the level of the anatomic GEJ into the distal esophagus. Thus, intestinal metaplasia of either the true gastric cardia or esophageal metaplastic columnar epithelium may occur. For a more detailed discussion of the gastric cardia and intestinal metaplasia of the GEJ region, the reader is referred to Chapter 12 .

    SMALL INTESTINE
    The adult small intestine is approximately 6 m in length. The colon (large intestine) is about 1.5 m in length. The first 25 cm of small intestine, the duodenum, is retroperitoneal; the jejunum marks the entry of the small intestine into the peritoneal cavity. The remainder of the small intestine is intraperitoneal until it enters the colon at the ileocecal valve. The demarcation between the jejunum and ileum is not a clearly defined landmark; the jejunum arbitrarily constitutes the proximal third of the intraperitoneal portion, and the ileum the remainder.
    The most distinctive feature of the small intestine is its mucosal lining, which is designed to provide maximal surface area for the purpose of food absorption. It is studded with innumerable villi ( Fig. 1-12A,B ). These extend into the lumen as finger-like projections covered by epithelial lining cells. The central core of lamina propria contains blood vessels, lymphatics, a small population of lymphocytes, eosinophils, and mast cells, and scattered fibroblasts and vertically oriented smooth muscle cells. Between the bases of the villi are the pitlike crypts of Lieberkühn, which contain stem cells that replenish and regenerate the epithelium. The crypts extend down to the muscularis mucosae. The muscularis mucosae is a smooth, continuous sheet that serves to anchor the configuration of villi and crypts alike. In normal individuals, the villus-to-crypt height ratio is about 4 : 1 to 5 : 1, but this is variable. For instance, in the proximal duodenum, the villus-to-crypt height ratio may reach only 2 : 1 to 3 : 1. Within the duodenum are abundant submucosal mucous glands, termed Brunner’s glands . They can be observed immediately distal to the pyloric channel. These glands secrete bicarbonate ions, glycoproteins, and pepsinogen II, and, except for their submucosal location, are virtually indistinguishable from the mucous glands of the distal stomach.

    FIGURE 1-12 Normal histology of the small intestine. A , Low-power image, showing the plica circulares protruding into the lumen, lined by mucosa. B , Medium-power image, showing tall villi and short crypts. C , High-power image of a villus, showing enterocytes with basal nuclei and an apical “brush border.”
    The surface epithelium of the small intestinal villi contains three principal cell types. Columnar absorptive cells are recognized by the dense array of microvilli on their luminal surface (the “brush border”), and an underlying mat of microfilaments (the “terminal web”; see Fig. 1-12C ). Interspersed regularly between absorptive cells are mucin-secreting goblet cells , and a few endocrine cells , described later. Goblet cells in the small intestine contain mainly acidic sialated mucins, identifiable by the Alcian blue stain performed at pH 2.5 (acidic). Within the crypts reside stem cells, goblet cells, more abundant endocrine cells, and scattered Paneth cells . Paneth cells contain apically oriented, bright eosinophilic granules that contain growth factors and a variety of antimicrobial proteins (such as cryptdins , also called defensins) which play a role in mucosal innate immunity against bacterial infection. 84 Paneth cells are located throughout the small intestine and in the proximal portion of the colon, including the cecum, ascending colon, and proximal portion of the transverse colon. They normally are absent from the distal transverse colon, the descending and sigmoid colon, and rectum.

    Endocrine Cells
    A diverse population of endocrine cells is scattered among the epithelial cells that line the small intestinal villi and small and large intestinal crypts (see also Chapter 25 ). Comparable cells are present in the epithelium lining the pancreas, biliary tract, lung, thyroid, and urethra. Gut endocrine cells exhibit characteristic morphologic features. In most cells, the cytoplasm contains abundant fine eosinophilic granules that harbor secretory products. The main portion of the cell is located at the base of the epithelium, and the nucleus resides on the luminal side of the cytoplasmic granules. The number of endocrine cells in the small intestine is greater than in the colon. The greatest diversity of endocrine cell types is in the duodenum and jejunum, becoming less diverse distally. 85 5-Hydroxytryptamine–containing endocrine cells are present in all regions of the intestine (small and large) and comprise the single largest endocrine cell population. A minor proportion of these cells contain substance P. The second largest cell population is glicentin cells, which are more numerous in the ileum and colon. Somatostatin cells occur throughout the alimentary tract. Cells that store cholecystokinin, motilin, secretin, or gastric inhibitory polypeptide are more numerous in the duodenum and jejunum compared with the ileum. Gastrin cells are few, and occur exclusively in the proximal duodenum. There are many other peptides and bioactive compounds released by endocrine cells in the small intestine and colon, including β-endorphin, pro-gamma-melanocyte–stimulating hormone, β-lipotropin, neurotensin, glicentin, glucagon, and pancreatic polypeptide (see Chapter 25 for details).
    Histologic distinction between endocrine cells and Paneth cells is based on the size and color of the eosinophilic cytoplasmic granules. Although both cell types are pyramidal in shape, with broad bases that narrow toward the crypt lumen, endocrine cells are small (about 8 μm in height), do not extend to the surface of the epithelial layer, and contain abundant small deeply eosinophilic granules. Paneth cells are larger (about 20 μm in vertical height) with a luminal apical plasma membrane, and contain a population of larger, coarse, and brightly eosinophilic granules.

    The Intestinal Mucosal Immune System
    Humans are exposed to an enormous load of environmental antigens through the GI tract, and the ultrastructural surface area of the GI tract exposed to environmental antigens far exceeds that of the skin and pulmonary tract. The immune system must balance antigenic tolerance against immune defense. The function of the intestinal immune system is best addressed on the basis of its anatomy, almost all features of which can be identified by routine light microscopy ( Fig. 1-13 ; see also Chapter 27 ). Throughout the small intestine and colon are nodules of lymphoid tissue , which lie either within the mucosa or within both the mucosa and the submucosa. Lymphoid nodules distort the surface epithelium to produce broad domes rather than villi; within the distal ileum confluent areas of dense lymphoid tissue become macroscopically visible as Peyer’s patches . The surface epithelium overlying lymphoid nodules contains both columnar absorptive cells and M (membranous) cells , the latter found only in the small and large intestinal lymphoid sites. These cells cannot be readily identified by light microscopy. M cells are capable of transporting antigenic macromolecules, intact, from the lumen to the underlying lymphocytes, thus serving as an important afferent limb of the intestinal immune system .

    FIGURE 1-13 Normal mucosa-associated lymphoid tissue from the ileum, in which confluent lymphoid aggregates in the mucosa and submucosa form Peyer’s patches.
    Throughout the intestines, T lymphocytes are scattered within the surface epithelium, usually at the base of the epithelial layer. These T cells are referred as intraepithelial lymphocytes (IELs) , and are generally of the cytotoxic CD8 + phenotype. However, there is remarkable diversity of T-cell subtypes, some unique to the intestine. 86 In normal small intestinal villi, IELs normally decrease in number from the base toward the tip. 13 CD3 immunohistochemistry can aid in the detection of IELs, particularly because some lymphocytes have irregular nuclear borders, which makes their identification on H&E stain more difficult. 87 In healthy individuals, the duodenum normally contains less than 26 to 29 IELs per 100 epithelial cell nuclei, with a mean of 11 and 13 IELs per 100 epithelial nuclei in H&E- and CD3-stained sections, respectively. 88 The range of IEL counts among healthy individuals can vary widely, between 1.8 to 26 per 100 epithelial nuclei, and there is no correlation between IEL counts and the villus-to-crypt height ratios. 89 The mean number of IELs decreases progressively in the distal small intestine and colon. 90 , 91 Normal villus IEL counts in the terminal ileum are in the range of 2 IELs per 100 epithelial nuclei. 92 A normal IEL count in the ileum does not preclude abnormality in the duodenum. 93 A modest elevation in IEL counts accompanies many types of inflammatory conditions of the colon. 92
    The lamina propria contains helper T cells (CD4 + ), educated B cells, and plasma cells. The lamina propria plasma cells secrete dimeric IgA, IgG, and IgM, which enter into the splanchnic circulation. IgA is transcytosed directly across enterocytes, or across hepatocytes, for secretion into bile; both are mechanisms for delivering IgA into the intestinal lumen. Finally, other antigen-presenting cells located in the lamina propria include macrophages and dendritic cells. The intestinal lymphoid nodules and mucosal lymphocytes, together with isolated lymphoid follicles in the appendix and mesenteric lymph nodes, constitute the mucosa-associated lymphoid tissue (MALT). Although most prominent in the small intestine, the concept of MALT has relevance to both the stomach (as an acquired anatomic compartment) and the colon (in which it also is normally present; see Chapter 27 for details).

    COLON
    The colon is subdivided into the cecum and the ascending, transverse, and descending colon. Unlike the jejunum and ileum, whose anatomic location and mechanical attachment to the posterior abdomen are entirely dictated by the mesentery, the anatomic locations of the colonic segments are established by other means. The bulbous cecum and the ascending colon constitute the entire portion of the colon on the right side of the abdomen, and are fixed in location. Although peritoneal membrane covers their ventral surfaces, the dorsal aspect of both the cecum and ascending colon adhere directly to the posterior abdominal wall. (The appendix, which inserts into the cecum just below the insertion of the ileum into the cecum, is an intra-abdominal viscus, being entirely covered with peritoneum.) The transverse colon begins at the hepatic flexure, and swings across the most ventral aspect of the abdominal cavity to reach the splenic flexure. The transverse colon is suspended by the lesser omentum, which reflects off the greater curvature of the stomach. In turn, the greater omentum hangs from the transverse colon. The descending colon is adherent to the left posterior abdominal wall, similar to its counterpart (the ascending colon) on the right side of the peritoneal cavity. The sigmoid colon begins at the pelvic brim and loops ventrally into the peritoneal cavity. The sigmoid colon is the only portion of the colon suspended entirely by mesentery. Thus, it may be subject to redundancy that may, rarely, lead to volvulus. Distally, the colon is adherent to the posterior wall of the pelvis beginning at the rectum, at about the level of the third sacral vertebra. Halfway along the 15-cm length of rectum, it passes between the crura of the peroneal muscles to exit the abdominal cavity.
    In normal adults, the length of the colon is quite variable, but generally measures in the range of 0.8 to 1.1 m. From the endoscopist’s perspective, the rectal canal is approximately 15 cm in length, beginning at the anal verge. The variable length of the sigmoid colon makes identification of further landmarks less reliable, but the splenic flexure is located about 0.4 m proximal to the anal verge, and the hepatic flexure about 0.7 m proximal.
    The anatomy of the wall of the colon is unique in that the external layer of the muscularis propria is discontinuous. Instead, three longitudinal strips of smooth muscle lie on top of the inner continuous circumferential smooth muscle layer of the muscularis propria. These longitudinal strips are termed the tinea coli . One strip is located at the attachment of the mesentery to the colon. The second and third strips are located equidistantly at about 120 and 240 degrees around the circumference of the colon. Each strip is approximately 0.5 cm in width, and becomes more prominent distally. The tinea coli begin at the cecum, so that the bulbous end of the cecum is creased by the outer two tinea coli as they arc to their respective locations on the opposite sides of the cecal wall. Notably, throughout the entire length of colon, arteries and veins penetrate through the continuous inner muscle layer at the edges of the tinea coli. These blood vessels constitute the circumferential ramifications of the mesenteric vasculature. Hence, there are three double tracks of holes in the inner muscle coat, owing to the orifices created by the penetrating vasculature. It is through these holes that diverticula usually protrude (see Chapter 8 ). Small tags of adipose tissue, the epiploic appendages , also are attached to the colon, at the edges of the nonmesenteric tinea coli 120 and 240 degrees around the circumference of the colon. Two double tracks of intermittent epiploic appendages are thus created along the entire length of the colon. Protruding diverticula can be difficult to identify because they are in the same circumferential location as the epiploic appendages and may, in fact, protrude into epiploic appendages.
    The cecum has the widest diameter of the colon, as well as the highest wall tension. Despite this fact, the mural thickness of the normal cecum is only about 0.2 cm. The mural thickness increases gradually over the length of the colon, and reaches about 0.4 cm in the sigmoid colon, which corresponds to the increasingly solid nature of the luminal contents. The lack of a continuous outer longitudinal muscle layer in the muscularis propria implies that the circumferential inner smooth muscle layer dictates the real diameter of the colon. The diameter varies irregularly from mildly pinched constrictions to intervening dilated segments, each about 2 to 4 cm in length. From the luminal aspect, the constrictions are termed haustral folds , and are prominent anatomic features during endoscopy.
    The ileum inserts into the cecum at the ileocecal valve . This is a prominent circumferential lip of mucosa and fatty submucosa, which extends about 0.5 to 1 cm into the cecal lumen. The luminal opening may be slit-shaped or oval. The thickness of the “lip” is about 0.3 cm, but it may be thicker in some individuals. The proximal aspect of the ileocecal valve contains small intestinal mucosa, and the distal aspect has colonic mucosa. The mucosal transition occurs at the level of the abrupt luminal convexity of the valve. This structure represents the mechanism that minimizes reflux of cecal contents into the ileum. Whether the “valve” restricts flow of ileal contents into the cecum has never been established; it does not constitute a real muscular sphincter.
    The function of the colon is to reclaim luminal water and electrolytes. Unlike the mucosa of the small intestine, the colonic mucosa has no villi, and is flat. The mucosa is punctuated by numerous straight, nonbranching tubular crypts that extend down and touch the muscularis mucosae ( Fig. 1-14A ). The surface epithelium is composed of columnar absorptive cells, which have shorter and less abundant microvilli than those in the small intestine, and goblet cells. The crypts contain abundant goblet cells, endocrine cells (see the discussion of small intestine, previously), and undifferentiated crypt cells. Paneth cells are occasionally present at the base of crypts in the cecum and the ascending and proximal transverse colon. IELs are present throughout the colonic mucosal epithelium. Normal counts are less than 5 IELs per 100 epithelial nuclei. 91

    FIGURE 1-14 Normal histology of the colon. A , Low-power view, showing the mucosa overlying the submucosa and muscularis propria. B , Medium-power view, showing characteristic flat colonic mucosa. C , Medium-power view, showing colonic mucosa with anthemic folds.
    Two sources of potential diagnostic error arise from the normal variation in colonic mucosal microanatomy. First, on occasion, the normal colonic mucosa exhibits undulation of the surface, so-called anthemic folds (see Fig. 1-14C ). This is a normal variant. A particular feature of this variant is that crypts that arise at the base of the undulations appear to branch into the upper third of the mucosal layer. Confusion arises when these crypts are interpreted as evidence of “architectural distortion” characteristic of chronic colitis. Thus, crypt branching is considered definitive only when it occurs in the lower third of the mucosal layer. Second, in the immediate vicinity of a mucosal lymphoid nodule, the crypts are typicallydistorted. 94 Although this may be obvious if the tissue section transects a lymphoid nodule, a tissue section near, but not through, a lymphoid nodule will reveal only disorganized crypts. Scanning multiple serial sections helps identify the lymphoid nodule.

    APPENDIX
    The vermiform appendix is a narrow, worm-shaped structure that protrudes from the posteromedial aspect of the cecum, 2 cm (or less) below the insertion of the ileum into the cecum. The appendix is located at the proximal root of the outer tinea coli of the cecum. Because the anterior tinea coli of the cecum is generally quite prominent, it serves as a guide to locate the appendix. The length of the normal appendix is quite variable, from 2 to 20 cm in length. Its diameter is quite consistent and uniform along its length, about 0.3 to 0.5 cm. It has a rudimentary mesentery only on a portion of its length. The intraperitoneal location of the appendix also is variable. The appendix may lie behind the cecum, hang over the brim of the pelvis, or lie in front or behind the ileum. However, in any individual, the location is relatively fixed.
    The appendix is completely invested by peritoneum, and has both an inner circumferential and a fully circumferential, outer longitudinal muscle layer of the muscularis propria. The mucosa of the appendix is colonic in type. However, the most prominent feature is the abundance of lymphoid tissue that lies within both the lamina propria and submucosa ( Fig. 1-15 ). The lymphoid tissue is particularly prominent in younger individuals, and dissipates gradually over the person’s lifetime. The concept that the appendix undergoes normal “fibrous obliteration” late in life has long been postulated. More likely, alterations to the lumen of the appendix reflect a life of clinically silent inflammatory conditions (see Chapter 15 ).

    FIGURE 1-15 Normal histology of the appendix, low-power view. Mucosa-associated lymphoid tissue in the mucosa and submucosa is visible.

    RECTUM AND ANUS
    The rectum begins within the abdominal cavity and tapers rapidly to the base of the pelvis. The discontinuous tinea coli converge, unite, and again constitute a complete outer longitudinal smooth muscle layer of the muscularis propria. Where the rectum exits the peritoneal cavity to enter the anal canal, it is completely invested by both inner and outer smooth muscle coats of the muscularis propria, and acquires an adventitia rather than a serosal covering.
    There are subtle differences in the normal histology of the distal rectal mucosa. 94 Compared with nonrectal colonic mucosa, distal rectal mucosa exhibits crypts that are not as closely spaced and are slightly shorter ( Fig. 1-16 ). Unlike the rest of the colon, the crypts do not extend directly down to the muscularis mucosae. The crypts may be slightly dilated or tortuous, and somewhat less numerous. The surface epithelium may be slightly cuboidal rather than tall columnar. The intervening lamina propria contains a moderate number of lymphocytes, plasma cells, macrophages, and occasional neutrophils. Scattered muciphages are common in the lamina propria of the rectum, particularly in older adults. Presumably, they represent the vestiges of previous mucosal injury. It is important to recognize the simplified and somewhat distorted mucosal architecture of the distal rectal columnar mucosa as normal, and not indicative of true “architectural distortion” characteristic of chronic inflammatory bowel disease.

    FIGURE 1-16 Normal histology of the rectum, showing the more rudimentary glands, lack of extension down to the muscularis mucosae, and mild crypt distortion.
    The anal canal is a complex anatomic structure that shows considerable individual variation of mucosal histology 95 (discussed in detail in Chapter 28 ). First, it is critical to understand the macroscopic anatomy of the anal canal ( Fig. 1-17 ). The rectal vault descends into the muscular anal canal, which is composed of the muscularis propria of the anal canal (the internal anal sphincter), and the anorectal skeletal musculature (the external anal sphincter). The external anal sphincter is a complex arrangement of perineal muscle fibers, the most proximal of which is the puborectalis muscle (sling). The puborectalis muscle loops from the pubis bone around the upper portion of the anal canal and back to the pubis, and imparts a sharp mucosal angle to the posterior aspect of the rectal vault. As the rectum enters the anal canal, the transverse folds of the colorectal mucosa end, and the mucosa aligns along the long axis into 6 to 10 vertical anal columns . The anal columns terminate about halfway down the anal canal, with interconnecting semicircular anal valves that delineate discrete mucosal recesses termed the anal sinuses . Anal mucin-producing glands empty into the anal sinuses. These anal valves and sinuses are particularly prominent in children, but become less pronounced with age. The anal columns may actually protrude into the lumen, earning the name anal papillae . The circumferential ring of anal valves and sinuses is termed the dentate line . Immediately below the dentate line is a zone of smooth mucosa, which flares at the anal verge to become anal skin, which is visible upon external examination. The overall distance of the anal canal, in vivo, averages 4.2 cm in normal adults.

    FIGURE 1-17 Macroscopic anatomy of the anal canal.
    The mucosa of the anal canal is divided into three zones according to the type of epithelial lining. The upper third, above the anal columns, is rectal columnar mucosa. Next is the anal transitional zone , which spans the distance of the anal columns down to the dentate line, about 1 cm in length. Distal to the dentate line is a nonkeratinizing stratified squamous mucosa; at the anal verge this becomes keratinized skin, and contains adnexal structures typical of perineal skin.
    It is the mucosa of the anal transitional zone that is the most variable ( Fig. 1-18 ). In some instances, nonkeratinizing anal squamous mucosa may extend up the anal columns and transition directly into the columnar rectal mucosa at its most proximal extent. However, in many individuals, a transitional mucosa is present that consists of four to nine cell layers that are neither squamous nor columnar, but rather stratified cuboidal or polygonal and overlie a basal cell layer. Occasional mucin goblet cells may be present as well. Transitional mucosa may be present, especially in the anal sinuses, extending proximal from the nonkeratinizing squamous mucosa of the lower anal canal and transitioning to rectal columnar mucosa proximally. Regardless of whether the anal canal mucosa is columnar, transitional, or nonkeratinizing squamous, this region retains the designation of the anal transitional zone .

    FIGURE 1-18 Normal histology of the anal canal. A , Mucosal squamocolumnar transition at the top of an anal column. B , Mucosal transition from transitional mucosa (left) to anal squamous mucosa (right) , at the lip of an anal sinus. C , Anal transitional mucosa. D , Anal verge, with epidermis overlying dermal sebaceous glands.

    LYMPH NODE PRAINAGE AND LYMPHATICS OF THE TUBAL GUT
    General principles of lymphatic drainage are straight-forward 96 : lymphatics in the mucosa or submucosa drain through the muscularis propria, then either enter into larger lymphatic channels located in the perivisceral adventitia, or into a pedicle or mesentery. There are, however, key anatomic features in each segment of the tubal gut.

    Esophagus
    The mucosal anatomy of the esophagus bears one key difference from the remainder of the tubal gut, in that the squamous mucosa overlies a definitive layer of lamina propria, which is supported by the muscularis mucosae and submucosa. In the stomach, small intestine, and colon, the lamina propria is intimately interdigitated between the epithelium, so that the base of epithelial glands or crypts lies directly on the muscularis mucosae. Hence, unlike elsewhere, in the esophagus there is a rich mucosal plexus of lymphatics in the lamina propria oriented predominantly in a longitudinal direction. 97 This plexus connects with less extensive plexuses in the submucosa and muscularis propria, and eventually drains to regional lymph nodes. Because of this arrangement, esophageal cancers can display early and extensive intramucosal, submucosal, and mural spread along the axis of the esophagus, well beyond the margins of grossly visible tumor.

    Stomach
    In the stomach, lymphatic channels are absent from the superficial lamina propria but are present in the interglandular region of the deeper portions of the mucosa. 98 They converge into thicker channels that pierce the muscularis mucosae and enter a submucosal plexus. From there, they drain into the lymphatic plexus between the circular and longitudinal layers of the muscularis propria, which runs along the muscle fibers to form a polygonal meshwork. Valves are present in this intramural network. From there, larger lymphatic channels track along the major arteries and veins into the gastric and colonic mesenteries.

    Small Intestine
    The lymphatic drainage of the small intestine is distinct. 99 In the lamina propria of each villus are three or more lymphatic channels that run parallel to one another along the long axis. Given the heavy flow of chylomicrons and fatty droplets from the absorptive epithelium to the lymphatic space, the endothelial lining typically contains numerous gaps. These lymphatic channels collect into central lacteals located within the deeper part of the villi, which have a continuous endothelial lining and a reticulin fiber sheath to which smooth muscle fibers attach. The smooth muscle fibers are oriented longitudinally in the villi as well, and intermittently contract to force lymph along the channels. The lacteals anastomose with each other at the base of each villus, and form an expanded sinus network, the intravillous lymphatic sinus. Penetrating lymphatic channels then traverse the muscularis mucosae to enter an extensive submucosal lymphatic plexus. This latter plexus drains through lymphatics in the muscularis propria to large conducting lymphatics in the mesentery and, thence, to the major lymphatic ducts located mainly parallel to the larger vascular structures and at the mesenteric root.

    Colon
    In the colon, a lymphatic plexus lies just underneath the muscularis mucosae. This plexus sends small branches into the deep mucosa at the level of the bases of the colonic crypts. 100 The submucosal plexus drains to an intramural lymphatic plexus located between the inner circular and outer discontinuous longitudinal layers of the muscularis propria ( Fig. 1-19 ). Intramucosal, submucosal, and mural lymphatic channels may be sites for microscopic metastasis. However, unlike in the esophagus, extensive longitudinal microscopic spread of colon cancer is exceedingly rare because there is a virtual absence of microscopic colonic cancer more than 2 cm proximal or distal to the macroscopic tumor mass. 101 As in the small intestine, lymphatic channels exiting the colonic wall enter into a predominantly radial pattern of drainage in the mesocolon.

    FIGURE 1-19 Schematic of lymphatic system that drains the colon wall. Terminal twigs of the lymphatics lie just above the muscularis mucosae, at the base of the lamina propria. There are occasional dilated lymphatic spaces that span the muscularis mucosae. There is a limited submucosal lymphatic plexus, and plexuses within the muscularis propria. Immediately adjacent to the muscularis propria are epicolic lymph nodes, which drain towards the mesenteric root through paracolic, intermediate, and principal lymph nodes (not shown) .
    (Reproduced with permission from Crawford JM: Principles of anatomy. In Rustgi AK, Crawford JM [eds]: Gastrointestinal Cancers: Biology and Clinical Management. Philadelphia, WB Saunders, 2003, pp 121-131.)
    The existence of lymphatic channels located immediately above the muscularis mucosae is often overlooked by pathologists, particularly in light of the fact that there are abundant data to suggest that carcinomas confined to the mucosa (intramucosal) are not at significant risk of lymphatic metastasis. 102 Indeed, these lymphatic channels are very difficult to identify on routine H&E-stained tissue sections. However, invasive adenocarcinomas may be visible within intramucosal lymphatic channels ( Fig. 1-20A ), and other striking examples of intramucosal lymphatics may also be encountered (see Fig. 1-20B–E ). The reason why pure intramucosal carcinomas almost never metastasize through lymphatics is therefore unknown.

    FIGURE 1-20 Lymphatics in the colonic mucosa. A , Colonic adenocarcinoma, present within lymphatic channels at the base of the lamina propria. B and C , Angiodysplasia, low-power image, with intramucosal hemorrhage lifting the epithelium off the muscularis mucosae. Lymphatic channels are evident on the luminal aspect of the muscularis mucosae. ( B , Masson trichrome stain; C , factor VIII immunostain). D and E , Angiodysplasia, medium-power image; same tissue sections as B and C , respectively. A normal submucosal lymphoid aggregate is present in D .

    Lymph Nodes
    The esophagus drains into numerous lymph node groups: five directly adjacent to the esophagus in paratracheal, parabronchial, paraesophageal, pericardial, and posterior mediastinal locations ( Fig. 1-21 ). The cervical esophagus also drains into the internal jugular and cervical lymph nodes, upper tracheal lymph nodes, and potentially supraclavicular lymph nodes. The infradiaphragmatic portion of the esophagus drains into the left gastric nodes along the lesser curvature, and the ring of lymph nodes surrounding the cardia.

    FIGURE 1-21 Lymph nodes of the esophagus are separated into six regional node systems.
    (Reproduced with permission from Crawford JM: Principles of anatomy. In Rustgi AK, Crawford JM [eds]: Gastrointestinal Cancers: Biology and Clinical Management. Philadelphia, WB Saunders, 2003, pp 121-131.)
    Lymphatics from the gastric wall drain into numerous lymph nodes distributed in chains along the greater and lesser curvatures, in the cardia region, and in the splenic hilum ( Fig. 1-22 ). As detailed by Fenoglio-Preiser and colleagues, 97 the drainage patterns are as follows:
    • Lesser curvature and lower esophagus: left gastric lymph nodes
    • Pylorus: right gastric and hepatic lymph nodes along the course of the hepatic artery
    • Cardia: pericardial lymph nodes surrounding the GEJ and left gastric lymph nodes
    • Proximal portion of the greater curvature: pancreatosplenic lymph nodes in the hilum of the spleen
    • Distal part of the greater curvature: right gastroepiploic lymph nodes in the greater omentum, and to the pyloric lymph nodes at the head of the pancreas

    FIGURE 1-22 Lymph nodes that drain the stomach and pancreas are separated into (1) lesser curvature and left gastric lymph nodes; (2) right gastric lymph nodes; (3) hepatic hilar lymph nodes; (4) pericardial and (5) paraesophageal lymph nodes; (6,7) pancreatosplenic lymph nodes; (8) gastroepiploic lymph nodes in the greater omentum; (9) pancreaticoduodenal lymph nodes; (10) para-aortic lymph nodes; and (11) celiac lymph nodes. The celiac lymph nodes drain into the cisterna chyli (not shown) , and from there into the thoracic duct.
    (Reproduced with permission from Crawford JM: Principles of anatomy. In Rustgi AK, Crawford JM [eds]: Gastrointestinal Cancers: Biology and Clinical Management. Philadelphia, WB Saunders, 2003, pp 121-131.)
    Effluents from all lymph node groups ultimately pass to the celiac nodes surrounding the main celiac axis.
    There are about 200 mesenteric lymph nodes in the small and large intestinal mesentery. Small mesenteric lymph nodes lie along the radial and arcuate ramifications of the distal mesenteric vasculature subjacent to the bowel wall ( Fig. 1-23 ). Larger ones lie along the primary arcades and major intestinal arteries, especially near the bifurcation of major vessels. The major lymph node groups are located at the root of the superior and inferior mesenteric arteries. These lymphatics converge in lymph nodes located at the mesenteric root. Lymph fluid passes from there to the cisterna chyli , a lymphatic sac that lies in the retroperitoneum behind the aorta and immediately below the diaphragm ( Fig. 1-24 ). The cisterna chyli gives rise to the thoracic duct, which tracks alongside the aorta into the thorax. From there, it runs between the aorta and azygos vein, and receives lymphatic branches from the posterior mediastinal structures, intercostals, jugular, subclavian, and bronchomediastinal ducts before emptying into the angle between the left internal jugular and left subclavian veins.

    FIGURE 1-23 Diagrammatic representation of the vascular supply of the small intestine and colon. Radially oriented mesenteric arteries are interconnected by arcuate arteries, providing extensive anastomoses between regions of the arterial circulation. Terminal arteries pen-etrate the muscularis propria and ramify in an extensive arteriolar network in the submucosa. Terminal arterioles enter the mucosa to supply intramucosal capillary arcades. Mucosal blood exits through venules back into the submucosa and then by veins through the muscularis propria into the mesenteric venous system. Unlike the mesenteric arterial system, there are only limited anastomotic connections between mesenteric veins, and drainage is essentially linear into the portal venous system. Not shown are the lymphatic channels that accompany the major blood vessels of the mesentery; the vascular architecture provides orientation for location of small mesenteric lymph nodes lying along the radial and arcuate arteries, especially at the bifurcations of the arteries.
    (Reproduced with permission from Crawford JM: Principles of anatomy. In Rustgi AK, Crawford JM [eds]: Gastrointestinal Cancers: Biology and Clinical Management. Philadelphia, WB Saunders, 2003, pp 121-131.)

    FIGURE 1-24 Lymph node drainage of the splanchnic root and liver. Lymph from the intestines gathers along the mesenteric roots (not shown) and travels immediately cephalad to the cisterna chyli , at the celiac root on the ventral aspect of the aorta, and then to the thoracic duct. The hepatic corpus drains primarily through lymphatics in the portal tree (not shown) and then exits through the hepatic hilum, into lymph nodes adjacent to the hepatic artery. These drain toward the celiac root and cisterna chyli. There is limited lymphatic drainage of the corpus into lymphatics that are situated along the hepatic veins, which collect into lymph nodes alongside the inferior vena cava. The liver capsule collects lymph from the superficial portions of the liver corpus, draining anteroinferiorly toward the hilum and hepatic artery lymph nodes, and posterosuperiorly toward lymph nodes of the inferior vena cava, mediastinum, and the paraesophageal/diaphragmatic region.
    (Reproduced with permission from Crawford JM: Principles of anatomy. In Rustgi AK, Crawford JM [eds]: Gastrointestinal Cancers: Biology and Clinical Management. Philadelphia, WB Saunders, 2003, pp 121-131.)
    Distal rectal lymphatics drain laterally along the course of the inferior hemorrhoidal vessels, and from there into para-aortic lymph nodes to end in the hypogastric, obturator, and internal iliac nodes. Alternatively, they follow the superior rectal artery to drain into lymph nodes in the sigmoid mesocolon near the origin of the inferior mesenteric artery. Lymphatic drainage from the anus is into the endopelvic fascia along the lateral aspect of the ischiorectal space, thence to the genital femoral sulcus on either side, and ultimately to the inferomedial group of superficial inguinal lymph nodes. Some anal canal lymphatics connect with the rectal lymphatics, whereas others may drain to the common iliac, middle and lateral sacral, lower gluteal, external iliac, or deep inguinal lymph nodes.

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    CHAPTER 2 Screening and Surveillance Guidelines in Gastroenterology

    ARATI. PRATAP, FRANCIS. A. FARRAYE

    Surveillance in Patients with Barrett’s Esophagus
    Surveillance in Patients with Chronic Gastritis and Intestinal Metaplasia or Dysplasia
    Surveillance in Patients with Inflammatory Bowel Disease
    Screening and Surveillance Guidelines for Colon Polyps
    Definition and Clinical Considerations
    Initial Management of Polyps
    Management of Small Polyps
    Management of Large Pedunculated Polyps
    Management of Large Sessile Polyps
    Postpolypectomy Surveillance
    Management of Malignant Polyps
    Colonoscopic Surveillance after Colon Cancer Resection
    Interaction of GI Endoscopists and Pathologists
    This chapter focuses on clinical gastroenterologic issues of interest to pathologists, including the endoscopic diagnosis and management of Barrett’s esophagus, the management of intestinal metaplasia in the setting of chronic gastritis, and surveillance in patients with inflammatory bowel disease, colonic polyps, and colon cancer.

    Surveillance in Patients with Barrett’s Esophagus
    Most authorities recommend that patients with chronic reflux symptoms of 5 years or longer undergo an upper endoscopy to screen for Barrett’s esophagus. The benefits of screening programs for Barrett’s esophagus are controversial because of a lack of sufficient evidence to support an improvement in survival rates or cost-effectiveness of such programs. 1 Furthermore, there is only indirect evidence to suggest that patients diagnosed with adenocarcinoma while undergoing surveillance have an increased chance of survival. Nevertheless, the current standard of care dictates that if Barrett’s esophagus is diagnosed, the patient should be entered into an endoscopic surveillance program for early detection of dysplasia and adenocarcinoma. 2 In the recent past, endoscopic surveillance was undertaken only in patients medically fit to undergo esophagectomy. However, with the advent of nonsurgical ablative endoscopic techniques (e.g., photodynamic therapy, multipolar electrocautery, argon plasma coagulation) and endoscopic mucosal resection, the number of patients eligible for surveillance has increased. Recent experience with endoscopic mucosal resection suggests that it may, in fact, represent the treatment of choice in patients with high-grade dysplasia or intramucosal adenocarcinoma in the setting of Barrett’s esophagus. 3 - 5 Aggressive treatment of reflux with proton pump inhibitors is warranted prior to surveillance endoscopy because active inflammation with repair can mimic dysplasia. Endoscopic surveillance is performed by obtaining four-quadrant biopsies at 2-cm intervals with the use of jumbo biopsy forceps. In addition, specific attention is paid to mucosal abnormalities such as ulcers, irregular lesions, nodules, and polyps. In the future, newer imaging modalities, including narrow band imaging and chromoendoscopy, may also allow more targeted biopsies. 6 , 7
    The recommended interval of surveillance for dysplasia in patients with Barrett’s esophagus is every 3 years after two negative endoscopies 1 year apart. In the presence of biopsy-proven low-grade dysplasia, repeat endoscopy is recommended within 6 months. If no dysplasia is found, then yearly endoscopy is recommended until no dysplasia is present on two consecutive examinations. Patients with flat high grade dysplasia confirmed by an expert GI pathologist should undergo a repeat endoscopy within 3 months. The prevalence of cancer in resection specimens of patients who have undergone an esophagectomy for high-grade dysplasia ranges from 5% to 41%, and the rate of progression to cancer in patients with high-grade dysplasia approaches 30% at 10 years. Options for patients with flat high grade dysplasia include intensive surveillance (every 3 months), esophagectomy, or ablative therapies. High grade dysplasia with mucosal irregularity should undergo endoscopic mucosal resection. A summary of recommendations from the American College of Gastroenterology on endoscopic surveillance intervals in patients with Barrett’s esophagus is presented in Table 2-1 .
    TABLE 2-1 Dysplasia Grade and Surveillance Interval Dysplasia Documentation Follow-up None Two EGDs with biopsy within 1 yr Endoscopy every 3 yr Low Grade
    • Highest grade on repeat EGD with biopsies within 6 mo
    • Expert pathologist confirmation 1 yr interval until no dysplasia × 2 High Grade
    • Mucosal irregularity
    • Repeat EGD with biopsies to rule out EAC within 3 mo
    • Expert pathologist confirmation
    ER
    Continued 3 mo surveillance or intervention based on results and patient
    EGD, esophagogastroduodenoscopy; ER, endoscopic resection; EAC, esophageal adenocarcinoma.
    Wang KK, Sampliner RE: Updated guidelines 2008 for the diagnosis, surveillance, and therapy of Barrett’s esophagus. Am J Gastroenterol. 103:788-797, 2008.

    Surveillance in Patients with Chronic Gastritis and Intestinal Metaplasia or Dysplasia
    The most common causes of chronic gastritis include Helicobacter pylori , environmental exposures including smoking, and autoimmune processes. Endoscopically obtained biopsies from patients with chronic gastritis may reveal intestinal metaplasia. A study from the United States revealed that 13% of patients at low risk for gastric cancer, and 50% of patients at higher risk, had intestinal meta-plasia on biopsies from normal-appearing gastric mucosa. 8 Although gastric intestinal metaplasia (incomplete type) is considered a premalignant lesion, the overall risk of gastric cancer in patients with gastric intestinal metaplasia is very low. However, those with dysplasia have an approximately 100-fold increased risk of gastric cancer. 8
    Currently, in the United States where the incidence of gastric cancer is low, endoscopic surveillance of patients with gastric intestinal metaplasia is not recommended in those at low risk for gastric cancer. 9 Low-risk patients include those living in developed countries, whites without any family history of gastric cancer, and people without dysplasia on gastric biopsy. The likelihood that endoscopic surveillance of low-risk patients with intestinal metaplasia increases detection of curable gastric cancer is very low and thus not likely to be cost-effective. Furthermore, intestinal metaplasia is a histologic lesion, not visible endoscopically. This makes endoscopic surveillance difficult, as numerous biopsies mapping the stomach would be needed to obtain a significant yield.
    Surveillance in patients with intestinal metaplasia at a high risk for gastric cancer is controversial. High-risk patients include those with a family history of gastric cancer, Hispanics, blacks, and immigrants from higher-risk geographic locations. No formal recommendations or data that support the implementation of an endoscopic surveillance program in high-risk patients with gastric intestinal metaplasia exist at this time. The American Society of Gastrointestinal Endoscopy concluded that patients at increased risk for gastric cancer on the basis of ethnic background or family history may benefit from surveillance, although there was no specific recommendation on the frequency of endoscopy. 9 If surveillance is performed, the American Society of Gastrointestinal Endoscopy recommends that endoscopic surveillance with gastric biopsies should incorporate a topographic mapping of the entire stomach histologically. 9
    More uniform consensus exists for the management of patients with dysplasia in gastric biopsies. These patients should be placed in an endoscopic surveillance program, although no recommendation has been issued on the frequency of surveillance endoscopy. The Society for Gastrointestinal Endoscopy recommends that patients with confirmed high-grade dysplasia on gastric biopsies be considered for gastrectomy or endoscopic mucosal resection. 9 Recent studies using magnification chromoendoscopy have shown that this technique is useful in identifying precancerous gastric lesions. 10 We expect that recommendations regarding appropriate intervals for surveillance endoscopy, and the use of new techniques, will be formalized in the near future.

    Surveillance in Patients with Inflammatory Bowel Disease
    Although no prospective randomized studies have been performed to evaluate the efficacy of surveillance colonoscopy to detect dysplasia or colorectal cancer in inflammatory bowel disease, it has become the standard of care to offer colonoscopy to these patients. The available data suggest a reduction in mortality from colorectal cancer in patients with inflammatory bowel disease who are undergoing surveillance. 11 Surveillance colonoscopy should optimally be performed when the patient is in remission, because active inflammation may hinder the histologic diagnosis of dysplasia. Current guidelines from the Crohn’s and Colitis Foundation of America consensus group recommend that colonoscopic surveillance begin 8 to 10 years after the diagnosis of colitis in patients with pancolitis or left-sided colitis. A repeat colonoscopy should be performed within 1- to 2-years. After two negative examinations, the interval is every 1 to 3 years, as long as the duration of disease does not exceed 20 years. After 20 years of disease, colonoscopy should again be performed at 1- to 2-year intervals. 12 - 15 Patients with proctitis or distal proctosigmoiditis are not at an increased risk for the development of colorectal cancer and thus do not need to undergo surveillance.
    Numerous studies have demonstrated that the risk of colorectal cancer is increased in patients with longstanding and extensive colitis, and in patients with primary sclerosing cholangitis. Recent studies have correlated the severity of colonoscopic macroscopic as well as histologic inflammation and the risk of colorectal cancer. 16 Patients with coexisting primary sclerosing cholangitis should begin surveillance colonoscopy at the time of diagnosis of liver disease, and then annually thereafter regardless of the extent of disease. 13 , 15 Although not included in formal recommendations, patients with a family history of colon cancer are also candidates for shorter surveillance intervals.
    Accumulating evidence suggests that patients with extensive Crohn’s colitis should also undergo endoscopic surveillance. Recent studies have shown an increased risk of colorectal cancer in patients with long-standing Crohn’s disease, strictures, and fistulas involving the colon. 17 - 20 In one study, the cumulative probability of detecting dysplasia or cancer in patients with Crohn’s colitis after a negative initial screening colonoscopy was 22% by the time of the third follow-up colonoscopy. 18 Recent guidelines recommend beginning surveillance colonoscopy 8 to 10 years after disease onset. Interval examinations should be performed according to the same time schedule as that proposed for patients with ulcerative colitis. 13
    There is wide variability in the practice of surveillance by gastroenterologists as well as inconsistency in the management of patients with dysplasia. 21 , 22 Current guidelines recommend obtaining 33 total colonic biopsies using jumbo forceps. This was based on a retrospective analysis that revealed a 90% positive predictive value for dysplasia with 33 biopsy specimens, and a 95% positive predictive value with greater than 56 specimens. 23 In practice, most endoscopists obtain four-quadrant biopsies at 10-cm intervals from the cecum to the rectum. It is also recommended that in patients with ulcerative colitis, fourquadrant biopsies should be taken every 5 cm in the distal sigmoid and rectum. 13 Other endoscopists obtain six specimens from each of the following sections: cecum and ascending colon, transverse colon, descending colon, sigmoid, and rectum. Additional biopsies should be obtained of any suspicious mucosal lesions. A recent study found that in 79% to 89% of cases, dysplasia (e.g., irregular mucosa, strictures, polypoid lesions, or masses) in ulcerative colitis was visible to the endoscopist. 24 The finding of dysplasia of any grade needs to be confirmed by a pathologist with special expertise in GI pathology. For patients with indefinite dysplasia, colonoscopy should be repeated at a shorter interval of 3 to 6 months. 13 The Crohn’s and Colitis Foundation guidelines recommend proctocolectomy in cases of high-grade dysplasia, but there is no formal consensus on the recommendation of proctocolectomy for patients with low-grade dysplasia. 22 Most authorities recommend proctocolectomy in patients with more than one focus of low-grade dysplasia, or a single repetitive focus on more than one colonoscopy. Many authorities now recommend proctocolectomy in patients with even a single focus of low-grade dysplasia, since this has been shown to be associated with concurrent adenocarcinoma in 20% of patients, and to progress to higher grades of dysplasia in 50% of cases. 25 Patients with low-grade dysplasia, who elect against colectomy, should undergo repeat surveillance colonoscopy on a 3- to 6-month basis. These guidelines apply to flat dysplasia.
    The treatment of a dysplastic “polyp” in patients with ulcerative colitis or Crohn’s colitis is evolving. If a wellcircumscribed adenomatous polyp is found proximal to the highest extent of histologically demonstrable colitis, it should be managed as a simple adenoma. Dysplasiaassociated lesions or masses (DALMs) were first identified by Blackstone and colleagues in 1981 and were associated with a high rate of colorectal cancer at colectomy. 26 More recently, a raised dysplastic lesion with the appearance of sporadic adenoma has been termed an adenoma-like DALM. 27 In contrast, poorly circumscribed lesions with indistinct borders and an irregular surface, or plaquelike lesions, have been termed nonadenoma-like DALMs. The endoscopist must make a distinction between an adenoma-like DALM and a nonadenoma-like DALM, since these lesions overlap histologically. Patients with ulcerative colitis who develop an adenoma-like DALM may undergo polypectomy and continued endoscopic surveillance if no other areas of flat dysplasia are detected in the adjacent mucosa or elsewhere in the colon, because the risk of adenocarcinoma is negligible. 13 , 28 , 29 It is recommended that at least four biopsies be taken immediately adjacent to the polyp to appropriately exclude flat dysplasia. Follow-up colonoscopy should be performed within 6 months, and thereafter at regular surveillance intervals if no dysplasia is found. In contrast, patients with nonadenoma-like DALM are generally referred for colectomy because of its high rate of association with synchronous or metachronous cancer. Recommendations for the management of flat and polypoid dysplasia are shown in Figure 2-1 .

    FIGURE 2-1 Suggested surveillance strategy in patients with inflammatory bowel disease and dysplasia.
    (From Itzkowitz SH, Harpaz N: Diagnosis and management of dysplasia in patients with inflammatory bowel diseases. Gastroenterology 126:1634-1648, 2004.)
    Three recent studies have demonstrated that the use of chromoendoscopy can greatly increase the detection rate of dysplasia in patients with ulcerative colitis who have been enrolled in a surveillance program. Chromoendoscopy with targeted biopsies revealed significantly more dysplastic lesions than conventional colonoscopy with random biopsies. The overall sensitivity of chromoendoscopy for predicting neoplasia was 93% to 97%. 30 - 32 Given these findings, the Crohn’s and Colitis Foundation consensus guideline has endorsed the use of chromoendoscopy in surveillance colonoscopy by trained endoscopists. 13 As more data regarding chromoendoscopy become available and new techniques are developed, guidelines for surveillance endoscopy in patients with inflammatory bowel disease will no doubt be refined to reflect these advances. 27 , 33 It is also likely that molecular biology techniques may play a more important role in the future as an adjunct to endoscopic biopsy. 34

    Screening and Surveillance Guidelines for Colon Polyps
    The following is a review of the management of colonic polyps in patients who do not have inflammatory bowel disease. 35 , 36 This summary includes surveillance after polypectomy and after resection for colorectal cancer, and the approach to the patient with a malignant polyp.

    DEFINITION AND CLINICAL CONSIDERATIONS
    Small (<1 cm) tubular adenomas are extremely common and have a low risk of becoming malignant. Only a small proportion of these develop histologic features of high-grade dysplasia or cancer. Advanced adenomas are defined as any polyp greater than 1 cm in diameter, and any polyp regardless of size that is villous or contains a focus of high-grade dysplasia. Efforts to reduce colon cancer are now shifting mainly to strategies to reliably detect and resect advanced adenomas before they become malignant rather than focusing on identifying small tubular adenomas. Currently, 70% of polyps removed at colonoscopy are adenomas. Approximately 70% to 85% of these are tubular, 10% to 25% are tubulovillous, and less than 5% are villous adenomas. 37

    INITIAL MANAGEMENT OF POLYPS
    Colonoscopy is the most accurate method for detecting polyps and allows immediate biopsy and resection. 38 It has quickly replaced fecal occult blood testing, flexible sigmoidoscopy, and barium enema as the primary screening modality, although those remain approved methods to screen for colorectal cancer in the asymptomatic patient. Most patients who have a polyp detected by barium enema or flexible sigmoidoscopy, especially if large or multiple, should undergo colonoscopy to excise the lesion or lesions and search for additional neoplasms. The decision to perform colonoscopy for patients with polyps smaller than 1 cm in diameter must be individualized and depends on the patient’s age, comorbidities, and past or family history of colorectal neoplasia. Complete colonoscopy should be done at the time of every initial polypectomy to detect and resect all synchronous adenomas. Additional colonoscopic examinations may be required after resection of a large sessile adenoma, if there are multiple adenomas, if the quality of the colonic preparation was suboptimal, or if the colonoscopist is not reasonably confident that all adenomas have been found and resected.

    MANAGEMENT OF SMALL POLYPS
    Small polyps (<1 cm and either sessile or pedunculated) can be resected by a number of different techniques, both with and without electrocautery. However, the monopolar hot biopsy forceps has limitations and risks, including bleeding and perforation, that need to be carefully considered. Considering that a small adenoma is a dysplastic lesion, resection of any small polyp is justified. Currently, there is no evidence that small, distally located hyperplastic polyps carry an increased risk for colorectal cancer. Thus, a traditional hyperplastic polyp found during flexible sigmoidoscopy is not, by itself, an indication for colonoscopy. However, there is accumulating evidence that certain variants of hyperplastic-appearing or serrated polyps may indeed be a precursor to colorectal cancer. For example, traditional serrated adenomas have recently been linked to the development of sporadic microsatellite unstable adenocarcinomas. Hyperplastic-appearing polyps at risk for such progression are usually large, sessile, and found proximally in the colon. These have been called atypical hyperplastic polyps, sessile serrated polyps, or sessile serrated adenomas, among other terms (see Chapter 19 for details).
    Thus, an evolving consensus among gastroenterologists is that large proximally located, hyperplastic-appearing serrated polyps be managed in the same way as adenomas. 39 , 40 Data also conflict as to whether small distal adenomas predict the presence of proximal, clinically significant adenomas. Recent studies seem to indicate that there is no increased risk of proximal adenomas or neoplasia in patients with small distal adenomas found on flexible sigmoidoscopy. 41 , 42 However, it has become standard care that any adenoma found on sigmoidoscopy is an indication for colonoscopy.

    MANAGEMENT OF LARGE PEDUNCULATED POLYPS
    Endoscopic resection of large polyps can be challenging because of the risks of hemorrhage, perforation, and incomplete resection. Most endoscopists resect large pedunculated polyps using a hot snare. However, in certain large centers, endoscopic mucosal resection has been shown to be successfully used for large pedunculated polyps with flat broad stalks. 43
    Large pedunculated polyps (>1 cm in diameter) resected in one piece should be examined by the pathologist for adequacy of resection. The guidelines for polyp specimen processing were discussed in Chapter 1 . Piecemeal resection of large pedunculated polyps impedes, but does not preclude, pathologic assessment of adequacy of resection. However, in this instance, the pathologist depends on the endoscopist to deliver a readily available stalk.

    MANAGEMENT OF LARGE SESSILE POLYPS
    The prevalence of large sessile polyps is approximately 0.8% to 5.2% in patients undergoing colonoscopy. Malignancy is found in 5% to 22% of these polyps. These polyps tend to recur locally after resection, and one recent study quoted a rate as high as 46%. 44 This same study found that the recurrence rate could be reduced to 3.8% with repeated endoscopic procedures and the use of argon plasma coagulation. Another recent study found that the use of endoscopic mucosal resection for resection of large sessile polyps led to a cure rate at 1-year surveillance of 100% if the polyp was removed intact, and 96% if the polyp was removed piecemeal. 45
    Assessment of the adequacy of excision of a large sessile polyp (>2 cm) is problematic and depends on both the endoscopist’s assessment of whether a residual lesion is present and the pathologist’s ability to identify resection margins with confidence. This includes the issue of whether a large sessile polyp is resected intact or piecemeal. Hence, the endoscopist may tattoo the polypectomy site with India ink after endoscopic resection to facilitate visualization during a subsequent endoscopic procedure.
    A patient who has undergone colonoscopic excision of a large sessile polyp in piecemeal fashion should undergo follow-up colonoscopy in 2 to 6 months to verify complete removal. If residual polyp tissue is present, it should be resected, and the completeness of this resection should be documented within another 2- to 6-month interval. Once complete removal has been established, subsequent surveillance needs to be individualized on the basis of the endoscopist’s judgment. If complete resection is not possible after two or three procedures, the patient should be considered for surgical resection. 46

    Postpolypectomy Surveillance
    Because a large number of patients with adenomas are being identified by colonoscopy, the burden placed on medical resources (i.e., the timely availability of colo-noscopy) is increasing dramatically. 47 Thus, the U.S. Multi-Society Task Force on Colorectal Cancer and the American Cancer Society recently revised the recommendations for surveillance colonoscopy in patients after polypectomy. The new guidelines, which emphasize stratification of patients into high- and low-risk groups ( Table 2-2 ), are based on the assumption that the initial screening colonoscopy was of optimal quality. A high-quality procedure is defined as one that reaches the cecum, has an excellent colonic preparation, and has a withdrawal time from the cecum to the anus of at least 6 minutes. 46
    TABLE 2-2 Risk Factors for Development of Metachronous Advanced Adenomas High Risk Low Risk
    • 3 to 10 adenomas
    • Any adenoma greater than 1 cm
    • Adenoma with villous features
    • High-grade dysplasia
    • No adenomatous polyps
    • 1 to 2 small (<1 cm) tubular adenomas with low-grade dysplasia
    After an initial colonoscopy has been performed with complete polypectomy, patients deemed to be at low risk of developing metachronous advanced adenomas should have a follow-up colonoscopy performed in 5 to 10 years. The exact length of follow-up in these patients is determined by clinician judgment and patient comfort. Low-risk patients include those with only one to two small (<1 cm) tubular adenomas with only low-grade dysplasia. Patients at high risk for developing advanced adenomas should undergo repeat colonoscopy in 3 years ( Table 2-3 ). This includes patients with 3 to 10 adenomas, any adenoma larger than 1 cm, or any adenoma with villous or high-grade dysplasia. If the follow-up colonoscopy is normal or shows only one or two small tubular adenomas with low-grade dysplasia, the interval for the next surveillance colonoscopy can be extended to 5 years. Family history and proximal location may also predict metachronous, advanced adenomas. Currently, the data are insufficient to include these two variables as possible risk factors, and thus they were not included in the formulation of the Multi-Society Task Force guidelines. 48 , 49 However, family history of colon cancer in a first-degree relative does increase the risk of colorectal cancer. Thus, clinicians need to individualize follow-up in these cases. It should also be noted that interobserver variability with regard to diagnosis of villous components and high-grade dysplasia in an adenoma is high. 50 Thus, reproducible histologic criteria must be developed by pathologists so that future prospective outcome studies can accurately predict the fate of patients with “advanced” adenomas.
    TABLE 2-3 Guidelines for Postpolypectomy Surveillance after Initial Colonoscopy Low-risk patients Follow-up colonoscopy in 5 to 10 yr. Precise timing should be based on clinical judgment, patient comfort, and family history. High-risk patients Follow-up colonoscopy in 3 yr, provided that piecemeal polypectomy was not performed and the adenomas are completely removed. If follow-up endoscopy is normal or reveals only 1 to 2 small tubular adenomas with low-grade dysplasia, the interval for subsequent examination should be 5 yr. Small hyperplastic rectal polyps Repeat colonoscopy in 10 yr, as in average risk guidelines. (exception: patients with hyperplastic polyposis syndrome)
    From Winawer SJ, Zauber AG, Fletcher RH, et al: Guidelines for colonoscopy surveillance after polypectomy: A consensus update by the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society. CA Cancer J Clin 56:153-159; quiz 184-185, 2006.

    Management of Malignant Polyps
    A malignant polyp is defined as an adenomatous polyp with cancer invading the submucosa; favorable and unfavorable histologic features are reviewed in Table 2-4 . Guidelines from the American College of Gastroenterology for the management of malignant polyps are reviewed in Table 2-5 . 36
    TABLE 2-4 Malignant Colonic Polyps: Favorable and Unfavorable Features Favorable Unfavorable Cancer is well differentiated to moderately differentiated (grade I or II) Cancer is poorly differentiated (grade III) Absence of lymphovascular invasion Lymphovascular invasion is present Carcinoma is ≥2 mm from deep margin Cancer is <2 mm from deep margin
    TABLE 2-5 Malignant Colonic Polyps: Management Findings Management Pedunculated polyp with favorable histology No change in surveillance regimen Sessile polyp with favorable histology Follow-up colonoscopy in 3 to 6 mo; if no evidence of residual adenoma or cancer on follow-up, return to regular surveillance. Pedunculated or sessile polyp; at least one unfavorable histologic feature Consider surgical resection.
    From Bond JH: Polyp guideline: Diagnosis, treatment, and surveillance for patients with colorectal polyps. Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 95:3053-3063, 2000.
    No further treatment is indicated after colonoscopic resection of a malignant polyp if the endoscopic and pathologic criteria listed in Table 2-4 are fulfilled. Patients with a malignant pedunculated polyp with favorable criteria may be observed in the same way as patients with a history of advanced colonic adenomas. Patients with a malignant sessile polyp that shows favorable prognostic criteria should have follow-up colonoscopy within 3 to 6 months to check for residual neoplastic tissue at the polypectomy site. After one negative follow-up examination, the clinician may revert to a standard surveillance regimen.
    When a patient’s malignant polyp has poor (“unfavorable”) prognostic features, the relative risk of surgical resection should be weighed against the risk of death from metastatic carcinoma. If a malignant polyp is located in a part of the lower rectum that may require an abdominal-perineal resection, local excision, rather than standard cancer resection, may be justified. In brief, the risk of local recurrence or lymph node metastasis from an invasive carcinoma in a colonoscopically resected malignant adenomatous polyp is considered less than the risk of death from colonic surgery if the following criteria are fulfilled:
    • The polyp is considered to be completely excised by the endoscopist and is submitted in toto for pathologic examination.
    • In the pathology laboratory, the polyp is fixed and sectioned so that it is possible for the pathologist to accurately determine the depth of invasion, grade of differentiation, and completeness of the excision of the carcinoma.
    • The cancer is not poorly differentiated (grade III).
    • There is no evidence of vascular or lymphatic involvement.
    • The margin of excision is not involved. Invasion of the stalk of a pedunculated polyp in itself is not an unfavorable prognostic finding as long as the cancer does not extend within 2 mm of the deep margin of stalk resection.
    A recent study 51 that evaluated the outcome of endoscopic polypectomy of malignant polyps versus surgery based on histologic characteristics found that in those with “favorable” characteristics, endoscopic polypectomy alone seemed to be sufficient.

    Colonoscopic Surveillance after Colon Cancer Resection
    Patients who have undergone resection for colon cancer should be entered into a surveillance program to detect early recurrence of the initial primary cancer and to detect metachronous colorectal neoplasms. Only patients with stage I, II, or III colon or rectal cancers should be candidates for surveillance colonoscopy. Numerous studies have found that 2% to 7% of patients with colorectal cancer have one or more synchronous cancers in the colon and rectum at the time of initial diagnosis. 52 It has also been shown that in surveillance groups after cancer resection there is an annual incidence for metachronous cancers of 0.35% per year. 52
    On the basis of the available data, patients should undergo a high-quality perioperative clearing by colonoscopy in nonobstructive tumors, and by CT colography or double-contrast barium enema in obstructing tumors. A subsequent colonoscopy should be performed within 3 to 6 months or intraoperatively in patients with obstructing tumors. Surveillance endoscopy should be performed in all patients 1 year after resection because of the high yield of detecting early metachronous cancers. If the first surveillance colonoscopy is negative, the next examination needs to be done at a 3-year interval. If that procedure is also normal, then the subsequent colonoscopy should be done at 5-year intervals. The Multi-Society Task Force recommendations for surveillance in patients after colorectal cancer resection are reviewed in Table 2-6 .
    TABLE 2-6 Colonoscopy Recommendations for Surveillance after Cancer Resection
    1. Patients with colon and rectal cancer should undergo high-quality perioperative clearing. In the case of nonobstructing tumors, this can be done by preoperative colonoscopy. In the case of obstructing colon cancers, computed tomography colonography with intravenous contrast or double-contrast barium enema can be used to detect neoplasms in the proximal colon. In these cases, a colonoscopy to clear the colon of synchronous disease should be considered 3 to 6 mo after the resection if no unresectable metastases are found during surgery. Alternatively, colonoscopy can be performed intraoperatively.
    2. Patients undergoing curative resection for colon or rectal cancer should undergo a colonoscopy 1 yr after the resection (or 1 yr after a colonoscopy performed to clear the colon of synchronous disease). This colonoscopy at 1 yr is in addition to the perioperative colonoscopy for synchronous tumors.
    3. If the examination performed at 1 yr is normal, then the interval before the next subsequent examination should be 3 yr. If that colonoscopy is normal, then the interval before the next subsequent examination should be 5 yr.
    4. After the examination at 1 yr, the intervals before subsequent examinations may be shortened if there is evidence of hereditary nonpolyposis colorectal cancer or if adenoma findings warrant earlier colonoscopy.
    5. Periodic examination of the rectum to identify local recurrence, usually performed at 3- to 6-mo intervals for the first 2 or 3 yr, may be considered after low anterior resection of rectal cancer. The technique used is typically rigid proctoscopy, flexible proctoscopy, or rectal endoscopic ultrasound. These examinations are independent of the colonoscopic examinations for detection of metachronous disease.

    Interaction of GI Endoscopists and Pathologists
    An American College of Gastroenterology review on quality improvement in colonoscopy stressed the great importance of the interaction between the pathologist and GI endoscopist in the management of patients. 53 The quality improvement targets identified to improve the care provided to patients undergoing colonoscopy and polypectomy are indicated in Table 2-7 .
    TABLE 2-7 Quality Improvement Targets in Colonoscopy Improvement Goal Percentage of adenomas with villous elements <10% Reports using the terms carcinoma in situ or intramucosal adenocarcinoma None Designation of the degree of dysplasia in adenomas as low grade or high grade 100% Use of the terms mild, moderate , or severe to describe dysplasia and adenomas None Adequate characterization of malignant polyps (resection line “margin,” degree of differentiation, presence or absence of vascular [or lymphatic] invasion) 100%
    From Rex DK, Bond JH, Winawer S, et al: Quality in the technical performance of colonoscopy and the continuous quality improvement process for colonoscopy: Recommendations of the U.S. Multi-Society Task Force on Colorectal Cancer. Am J Gas-troenterol 97:1296-1308, 2002.

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    CHAPTER 3 Diagnostic Cytology of the GI Tract

    HELEN. H. WANG


    Specimen Types
    Specimen Preparations
    Value and Accuracy of Specimens
    Normal Morphology
    Esophagus
    Stomach
    Small Intestine
    Large Intestine
    Infections
    Candida
    Herpes Simplex Virus
    Cytomegalovirus
    Helicobacter pylori
    Giardia
    Atypical Mycobacteria
    Cryptosporidia
    Microsporidia
    Inflammatory, Reactive, or Metaplastic Changes
    Nonspecific Changes
    Pemphigus
    Barrett’s Epithelium
    Neoplastic Lesions
    Squamous Dysplasia or Carcinoma
    Glandular Dysplasia or Carcinoma
    Endocrine Tumors
    Mesenchymal Tumors
    Lymphoid Tumors
    The popularity of GI cytology for the diagnosis of infection and malignancy has waxed and waned over the past few decades. The ability to distinguish between high-grade dysplasia or carcinoma in situ and invasive carcinoma in biopsy specimens and the more prevalent expertise of surgical pathology cause some to consider cytology an unnecessary duplication of GI mucosal biopsies. 1 , 2 However, the combined use of endoscopy, ultrasound guidance, and fine-needle aspiration has expanded the horizons of GI cytology. 3


    SPECIMEN TYPES
    Types of GI tract specimens commonly received in the cytology laboratory include endoscopic brushings and ultrasound-guided endoscopic fine-needle aspirations. Endoscopic fine-needle aspirations have enabled endoscopists to reach farther than they can with biopsy forceps to sample mural lesions, including lesions adjacent to the GI tract. The nonendoscopic specimens obtained with either the balloon- or mesh-type samplers have been evaluated in the research setting to ascertain their usefulness in the surveillance of populations at high risk for esophageal carcinoma. 4 - 6

    SPECIMEN PREPARATIONS
    Direct smears can be made from materials collected on the endoscopic brush, in the needle, or on the balloon and mesh samplers; these can then be either fixed immediately in 95% ethanol and stained with the Papanicolaou method or left to air-dry and stained with Diff-Quik (Dade-Behring, Inc., Deerfield, IL) or Wright-Giemsa stain. Alternatively, the material can be rinsed into a medium such as CytoLyt (Cytyc Corporation, Marlborough, MA) or 50% ethanol. The specimen can then be processed by a concentration method, such as either ThinPrep Processor (Cytyc Corporation, Marlborough, MA) or cytospin, to make slides that are then stained with the Papanicolaou method.

    VALUE AND ACCURACY OF SPECIMENS
    Cytology specimens have some advantages over specimens obtained by endoscopic biopsy. The brush can sample a wider area and the fine needle can reach deeper lesions than can be reached by biopsy forceps. Also, both the brush and the fine needle are less invasive than biopsy forceps and less likely to cause bleeding. In addition, cytology has shorter turnaround time than histology. Direct smears can be ready for review within minutes with no compromise of the quality of the preparation (unlike frozen sections of biopsy specimens, which compromise the quality of the final or permanent preparation). However, as mentioned, cytology is limited in its ability to distinguish between high-grade dysplasia or carcinoma in situ and invasive carcinoma.
    In spite of the potential duplication of cytology and biopsy, the literature has consistently shown that the highest diagnostic yield is obtained with the combined use of these specimens. 7 - 9 The yield of cytology is significantly higher when the brushing is performed before rather than after the biopsy. 10

    Normal Morphology

    ESOPHAGUS
    Intermediate-type squamous cells with abundant cytoplasm and vesicular nuclei are seen in the normal eso-phagus ( Fig. 3-1 ). Superficial-type squamous cells with abundant cytoplasm and small pyknotic nuclei can also be seen in small numbers. Single cells and clusters of ciliated columnar cells from the respiratory tract with no clinical significance may be seen rarely.

    FIGURE 3-1 Brushing specimen from a normal esophagus composed predominantly of intermediate squamous cells. Scattered inflammatory cells are also noted in this field (Papanicolaou).

    STOMACH
    Gastric surface foveolar cells can shed as single cells or in sheets. When in sheets, the columnar cells with abundant cytoplasm, regularly spaced nuclei, and open chromatin arrange in a honeycomb or palisaded pattern ( Fig. 3-2 ), depending on the orientation. When they are shed as single cells, they often lose their cytoplasm to become naked nuclei. In endoscopic fine-needle aspiration specimens, the sheets of foveolar cells can mimic cells from a mucinous neoplasm, and the single naked nuclei, because of their small monomorphic appearance, can mimic cells from a pancreatic endocrine tumor.

    FIGURE 3-2 A sheet of benign gastric foveolar cells in a slightly distorted honeycomb pattern with evident columnar cells in palisading arrangement at the periphery is seen in this gastric brushing specimen. The presence of small nucleoli in some of the cells may indicate reactive change (Papanicolaou).

    SMALL INTESTINE
    The lining cells of the small intestine can be easily distinguished from gastric foveolar cells by the presence of goblet cells. On low magnification, the specimen typically has a Swiss cheese appearance, with the “holes” representing either goblet cells or gland openings of the crypts ( Fig. 3-3 ). On high magnification, the absorptive cells have either finely granular or vacuolated cytoplasm, and the goblet cells have single large mucin vacuoles and crescent-shaped nuclei with rounded contours. The striated border of the absorptive cells may be seen at the periphery of the sheets.

    FIGURE 3-3 A complex sheet of small intestinal–type epithelium is seen in this duodenal brushing specimen. It has a Swiss-cheese appearance, with the “holes” representing either goblet cells or gland openings of the crypts (Papanicolaou).

    LARGE INTESTINE
    Normal epithelium is characterized on cytology by sheets or strips of tall columnar cells with abundant cytoplasm and basal nuclei. Partial or complete openings of the colonic crypts may be seen ( Fig. 3-4 ).

    FIGURE 3-4 A sheet of normal colonic columnar epithelial cells is present in this colonic brushing specimen. A gland opening is seen in the left half of the field (Papanicolaou).

    Infections
    Most infectious agents that affect human hosts can infect the GI tract. Some infectious agents have a predilection for the GI tract. The more common ones are discussed in this section.

    CANDIDA
    Candida almost exclusively involves the esophageal portion of the GI tract and can occur in both immunocompetent and immunocompromised patients. Brushings are in fact more sensitive than biopsy specimens in the detection of esophageal candidiasis. 7 Contamination by oral candida is usually not a problem because the brush is contained within a sheath when it is passed into and out of the endoscope and is expelled from the sheath only to sample the lesion. The organisms appear as pink to purple pseudohyphae and yeast forms on Papanicolaou stain ( Fig. 3-5 ). Reactive squamous cells as well as inflammatory cells are often noted in the background.

    FIGURE 3-5 Pseudohyphae and yeast forms from Candida species are seen in this esophageal brushing specimen. Inflammatory cells and debris are in the background (Papanicolaou).

    HERPES SIMPLEX VIRUS
    Herpes simplex virus infection can theoretically affect epithelial cells anywhere along the GI tract, but it is most commonly seen in the esophagus. Multinucleation, nuclear molding, ground-glass chromatin, and eosinophilic intranuclear inclusions are the characteristic features of infected cells ( Fig. 3-6 ).

    FIGURE 3-6 A Cowdry type B inclusion characterized by an eosinophilic intranuclear body surrounded by a halo is seen in the center of the field, from an esophageal brushing of herpetic esophagitis (Papanicolaou).

    CYTOMEGALOVIRUS
    Cytomegalovirus infection affects epithelial, stromal, and endothelial cells along the GI tract and is characterized by large cells with a single large basophilic intranuclear inclusion with a perinuclear halo ( Fig. 3-7 ). Intracytoplasmic textured inclusions can occasionally be seen in the affected cells.

    FIGURE 3-7 Both intranuclear and intracytoplasmic inclusions are seen in this cytomegalovirus-infected cell from an esophageal brushing. The intranuclear inclusion is a large amphophilic to basophilic body surrounded by a halo, and the intracytoplasmic inclusion is characterized by small, granular, basophilic to amphophilic bodies (Papanicolaou).

    HELICOBACTER PYLORI
    Helicobacter pylori infection occurs exclusively in the stomach and perhaps is the most common infection of the GI tract. These organisms can be demonstrated either on imprint smears of gastric biopsies or on brush cytology specimens. 11 Imprint and brushing cytology specimens are comparable in sensitivity (88%) and specificity (61%) with histologic examination of sections stained with hematoxylin and eosin and modified Giemsa. 11 The benefits of imprint and brushing cytology are the rapid results, high specificity, and low cost. However, the efficacy of cytologic detection of these organisms depends on the extent of colonization by the organism. When present in a large quantity, they are evident even at low magnification, but they can be difficult to identify when present in small numbers. On Papanicolaou stain, H. pylori organisms appear as faintly basophilic, S-shaped rods admixed with mucus in the vicinity of glandular cell clusters ( Fig. 3-8 ). Special stains, such as a triple stain, combining silver, hematoxylin and eosin, and alcian blue at pH 2.5, can enhance their detection by cytology. 12

    FIGURE 3-8 Numerous S-shaped organisms consistent with Helicobacter pylori are present in the mucus adjacent to a sheet of epithelial cells on a gastric brushing specimen (Diff-Quik).

    GIARDIA
    Giardia affects the duodenum of both immunocompetent and immunocompromised hosts. Brush cytology is a useful method for detecting Giardia because the organisms are on the luminal surfaces of the intestinal epithelial cells. They are flat, gray, pear shaped, and binucleate, with four pairs of flagella ( Fig. 3-9 ). 13

    FIGURE 3-9 A pear-shaped, gray, binucleate Giardia organism is seen in the center of the field, from a duodenal brushing specimen (Papanicolaou).

    ATYPICAL MYCOBACTERIA
    Because atypical mycobacteria accumulate within macrophages in the lamina propria, very rigorous brushing is required for the infected macrophages to be included in the cytology sample. The presence of isolated foamy histiocytes on the smear should raise the level of suspicion of an atypical mycobacterial infection ( Fig. 3-10 ). In general, the organisms are present in large numbers. On Diff-Quik-stained smears, the mycobacteria form numerous rod-shaped negative images, either within the histiocytes or in the background ( Fig. 3-11 ). 14 Special stains for acid-fast bacilli are necessary to confirm the diagnosis.

    FIGURE 3-10 A histiocyte with abundant granular cytoplasm is present in this duodenal brushing specimen from an HIV-infected man. On special stain, the cell is shown to be filled with acid-fast bacilli, consistent with atypical mycobacteria (Papanicolaou).

    FIGURE 3-11 Numerous negative images of rod-shaped organisms are seen within and outside the histiocyte in the center of the field (from the same case as in Figure 3-7 ) (Diff-Quik).

    CRYPTOSPORIDIA
    Cryptosporidia can involve any glandular epithelium of the GI tract in HIV-infected patients and can be detected by examination of stool and cytology specimens. 15 Cryptosporidia are 2- to 5-μm round basophilic bodies on the luminal surfaces of the epithelial cells. Therefore, they are seen only when the plane of focus is shifted to the surfaces of the cells where the organisms reside ( Fig. 3-12 ). When in doubt, confirmatory Gomori’s methenamine-silver stain can be applied.

    FIGURE 3-12 Many 2- to 5-μm-diameter, round, basophilic bodies are seen on the surface of this sheet of gastric epithelial cells on a brushing specimen (Papanicolaou).

    MICROSPORIDIA
    Microsporidia can also be detected on cytologic specimens, such as stool, nasal secretions, duodenal aspirates, and bile, as well as on brushing specimens from the duodenum and biliary tract. 16 - 18 On Papanicolaou stain, they appear in aggregates as brightly eosinophilic, rod-shaped or ovoid organisms, measuring 1 to 3 μm in diameter ( Fig. 3-13 ). They are present in epithelial cells as well as in inflammatory cells. When in the epithelial cells, they are in the supranuclear portion of the cytoplasm and therefore they (like cryptosporidia) are seen at a slightly different plane of focus from that of the epithelial nuclei.

    FIGURE 3-13 Several 1- to 3-μm-diameter eosinophilic rods are in the cytoplasm of the cell in the center of this duodenal brushing specimen. They are typically found in the supranuclear portion of the cytoplasm (Papanicolaou).

    Inflammatory, Reactive, or Metaplastic Changes

    NONSPECIFIC CHANGES
    Any injury to the mucosa can evoke a nonspecific inflammatory or reactive epithelial change. When the injury is sufficient to result in ulceration, the change (i.e., the epithelial repair) can become so extreme that it may mimic a malignancy. It is often difficult to determine whether the reparative epithelium is of glandular or squamous origin. Although epithelial repair is characterized by prominent eosinophilic nucleoli, they are usually neither huge nor numerous (i.e., more than three or four) ( Fig. 3-14 ). The atypical stromal cells or their stripped nuclei from granulation tissue can also be quite alarming ( Fig. 3-15 ). In spite of striking nuclear enlargement of such cells, hyperchromasia is absent. Instead, they have fine, homogeneous chromatin and a thin, smooth nuclear membrane.

    FIGURE 3-14 A sheet of reactive epithelial cells is seen in this esophageal brushing specimen. The cells have sharp cellular borders and are variably enlarged with prominent nucleoli. The nuclear membranes in some cells appear wavy but without sharp angles or indentations. A few inflammatory cells are superimposed on or infiltrating this sheet. It is difficult to be certain whether these cells are squamous or glandular (Papanicolaou).
    (Courtesy of Dr. Mark Roth of the National Cancer Institute, Rockville, MD.)

    FIGURE 3-15 A single, atypical, ovoid to spindle-shaped cell with enlarged nuclei and prominent nucleoli is seen in a gastric brushing specimen from a patient with resection-proven benign gastric ulcer with abundant granulation tissue at the ulcer bed (Papanicolaou).
    Both cellular arrangements and the features of individual cells are useful in distinguishing between severe reactive and neoplastic changes. Cells with reactive or reparative changes are usually arranged in flat sheets without three-dimensionality or prominent cell dyshesion. In contrast, dyshesion, presented either as “feathering” (dissociation of cells) at the periphery of cell clusters or as the dispersion of numerous isolated cells, is usually evident with neoplasms, as is three-dimensionality. In addition, the enlarged nuclei in reactive or reparative changes usually have uniform size and a similar number of small, prominent nucleoli. These again are in contrast to the variation in nuclear and nucleolar size and shape as well as the chromatin pattern in the neoplastic lesions. Specific types of reactive cells may also be seen, such as those with radiation-induced changes ( Fig. 3-16 ). As in other organs, the cells are proportionally enlarged, with metachromatic cytoplasm and nuclear or cytoplasmic vacuoles.

    FIGURE 3-16 A group of proportionally enlarged epithelial cells showing prominent nucleoli and finely vacuolated cytoplasm is seen on this esophageal brushing specimen from a patient with previous radiation therapy for squamous cell carcinoma (Papanicolaou).

    PEMPHIGUS
    Rarely, pemphigus vulgaris, an autoimmune disease of the skin and mucous membrane that attacks the intercellular junctions and causes a suprabasilar bleb or blister as well as acantholysis, may affect the esophagus. Numerous acantholytic cells are usually present. The characteristic cells are round to polygonal, uniform, parabasal-sized isolated cells. 19 , 20 The cytoplasm is dense and may have perinuclear eosinophilic staining or a clear halo. The cells appear atypical because of the high nucleus-to-cytoplasm ratio, the enlarged nuclei, and the prominent, multiple, even irregular nucleoli ( Fig. 3-17 ). A bar- or bullet-shaped nucleolus is characteristic. 21 However, the cells have smooth nuclear membranes and pale, fine, and even chromatin. Normal mitotic figures can be seen. These atypical cells resemble those in repair except for the increased number of single cells.

    FIGURE 3-17 A loose group of parabasal-sized squamous cells with dense cytoplasm and prominent nucleoli can be seen in this esophageal brushing specimen from a patient known to have pemphigus vulgaris (Papanicolaou).

    BARRETT’S EPITHELIUM
    Cytology is not the optimal tool for the diagnosis of Barrett’s epithelium. When glandular epithelial cells are seen in a cytology specimen, it is difficult to be certain whether they represent cells from the gastric side of the esophagogastric junction or metaplastic glandular cells from the esophagus. It has also been shown that cytology is neither sensitive nor specific for the detection of goblet cells, 22 , 23 a hallmark of Barrett’s epithelium, in part because of the absence of a blue hue of acid mucin with the Papanicolaou stain. However, a long segment of Barrett’s epithelium is more readily appreciated by cytology because of the reduced probability of sampling error. 22 Its appearance is similar to that of the lining epithelium of the small intestine, with a Swiss cheese pattern at low magnification and goblet cells with single, large cytoplasmic vacuoles on high magnification ( Fig. 3-18 ). The honeycomb arrangement of the glandular cells in Barrett’s epithelium usually tends to be slightly more irregular than that of normal small intestinal epithelium.

    FIGURE 3-18 A sheet of glandular cells, some with large vacuoles expanding the cytoplasm and crescent-shaped nuclei, is seen on a brushing specimen from the esophagogastric junction, consistent with Barrett’s esophagus (Papanicolaou).

    Neoplastic Lesions

    SQUAMOUS DYSPLASIA OR CARCINOMA
    Squamous dysplastic cells of the esophagus have morphology similar to that of the dysplastic cells on cervicovaginal Pap smears ( Box 3-1 ). 24 The cellular features of squamous cell carcinoma vary with the degree of differentiation ( Boxes 3-2 and 3-3 ).

    BOX 3-1 Squamous Dysplasia ( Figs. 3-19 and 3-20 )

    • Some but not all of the malignant features to varying degrees, such as increased nucleus-tocytoplasm ratio, nuclear enlargement, hyperchromasia, irregular nuclear membrane, and aberrant chromatin pattern
    • Fewer atypical cells than carcinoma
    • Absent tumor diathesis

    FIGURE 3-19 A dysplastic squamous cell is surrounded by a few reactive-appearing squamous cells. The dysplastic cell shows mild hyperchromasia, nuclear membrane irregularity, and chromatin aberration, but it still has a fair amount of cytoplasm. Therefore, it is considered low grade (Papanicolaou).
    (Courtesy of Dr. Mark Roth of the National Cancer Institute, Rockville, MD.)

    FIGURE 3-20 Compared to the dysplastic cell in Figure 3-16 , this dysplastic squamous cell has more pronounced nuclear membrane irregularity and a much higher nucleus-to-cytoplasm ratio, and is, therefore, considered high grade (Papanicolaou).
    (Courtesy of Dr. Mark Roth of the National Cancer Institute, Rockville, MD.)

    BOX 3-2 Well-Differentiated Squamous Cell Carcinoma ( Fig. 3-21 )

    • Predominantly isolated cells with sharp cytoplasmic borders and variable cell shapes, such as round, oval, or spindle shaped
    • Hyperchromatic or pyknotic nuclei with obscured chromatin and irregular, angulated nuclear contours
    • Keratinized cytoplasm
    • Prominent necrosis or tumor diathesis and keratinaceous debris in the background

    BOX 3-3 Moderately and Poorly Differentiated Squamous Cell Carcinoma ( Fig. 3-22 )

    • Less striking keratinization of the cytoplasm
    • Tumor cells in crowded, haphazardly arranged cell clusters with indistinct cell borders
    • Vesicular chromatin with prominent nucleoli

    FIGURE 3-21 A keratinized squamous cell with a hyperchromatic nucleus characteristic of well-differentiated squamous cell carcinoma is present in this esophageal brushing specimen (Papanicolaou).

    FIGURE 3-22 In contrast to the cells seen in Figure 3-18 , tumor cells from a poorly differentiated squamous cell carcinoma have vesicular chromatin and occasional prominent nucleoli. The single-cell pattern, dense basophilic cytoplasm, and endoplasmic and ectoplasmic demarcation in a cell close to the center of the field suggest squamous differentiation (Papanicolaou).

    GLANDULAR DYSPLASIA OR CARCINOMA
    Glandular dysplasia and carcinoma in the esophagus usually arise in the setting of Barrett’s epithelium. The precursor lesions of adenocarcinoma in the stomach and in the intestine can present as either polypoid or flat dysplastic lesions. Adenomas of the stomach and dysplasia of the esophagus or stomach are similar in cytologic appearance. Although the few studies on this topic were based on very small numbers of cases 22 , 23 , 25 , 26 and were insufficient to provide definitive conclusions on the usefulness of cytologic surveillance, 27 the preliminary results appear promising. Low-grade dysplasia may be difficult to distinguish from artifactual crowding, whereas high-grade dysplasia may be confused with either severe reparative change or invasive carcinoma ( Boxes 3-4 , 3-5 , and 3-6 ).

    BOX 3-4 Low-Grade Glandular Dysplasia ( Fig. 3-23 )

    • Architectural abnormality (e.g., stratification manifested as crowding and overlapping on cytology)
    • Elongated nuclei with increased nucleus-to-cytoplasm ratio
    • Mild hyperchromasia and absent or inconspicuous nucleoli
    • Minimal or negligible dyshesion

    BOX 3-5 High-Grade Glandular Dysplasia ( Fig. 3-24 )

    • Both architectural and cellular abnormalities
    • Atypical cells in haphazardly arranged sheets and clusters, or singly as a result of dyshesion
    • Cellular abnormalities similar to those seen in invasive adenocarcinoma but less pronounced

    BOX 3-6 Adenocarcinoma ( Fig. 3-25 )

    • Increased cellularity
    • Abnormal cellular arrangements, such as isolated cells, “feathering” at the edges of cellular groups, and haphazard crowding within the groups
    • Variable degrees of gland formation by atypical cells
    • Atypical cellular features, such as nuclear pleomorphism, high nucleus-to-cytoplasm ratio, nuclear enlargement, chromatin aberration, and irregular nuclear membrane with or without nucleoli
    • Possibility of tumor diathesis (old blood and necrotic debris) in the background

    FIGURE 3-23 A strip of stratified columnar cells with slightly enlarged and elongated nuclei is seen in an esophageal brushing specimen from a patient with biopsy-proven low-grade dysplasia in Barrett’s esophagus is seen (Papanicolaou).

    FIGURE 3-24 A sheet of haphazardly arranged and overlapped atypical cells with granular cytoplasm in a clean background is seen in an esophageal brushing specimen from a patient with biopsy-proven high-grade dysplasia in Barrett’s esophagus. The nuclei show chromatin aberration and occasional nucleoli, but the cells do not appear to be malignant (Papanicolaou).

    FIGURE 3-25 Compared with the cells in Figure 3-21 , the cells in this gastric brushing from a well-differentiated adenocarcinoma show significant three dimensionality and a more pronounced haphazard arrangement. Red blood cells are apparent in the background. Although the individual cells do not appear anaplastic or obviously malignant, the much increased cellularity and marked architectural abnormality indicate an invasive adenocarcinoma (Papanicolaou).
    The amount and characteristics of the cytoplasm of the tumor cells depend on the degree of differentiation. Appearance varies from abundant vacuolated or granular cytoplasm to scant dense cytoplasm that is difficult to distinguish from that of a poorly differentiated squamous cell carcinoma.
    Signet ring cell carcinoma, a type of adenocarcinoma that occurs most commonly in the stomach, is worthy of special consideration because it can be difficult to detect on both cytologic and histologic preparations. Because the malignant cells infiltrate predominantly the lamina propria, they are often not included in the brush cytology sample unless mucosal ulceration is present. The reactive or reparative epithelial changes associated with an ulcer can distract the attention of the pathologist from the real lesion. In addition, the numerous inflammatory cells from the ulcer can obscure the scattered, isolated tumor cells ( Box 3-7 ).

    BOX 3-7 Signet Ring Cell Carcinoma ( Fig. 3-26 )

    • Prominent inflammation in the background with reactive or reparative epithelial changes
    • Isolated cells with moderate to abundant vacuolated cytoplasm and no phagocytic material in cytoplasm
    • Variable degrees of nuclear atypia

    FIGURE 3-26 Two cells with abundant vacuolated cytoplasm and nuclei with slightly irregular nuclear membranes and prominent nucleoli are seen in this gastric brushing specimen of a biopsy-proven signet ring cell carcinoma. No phagocytic material is seen in the vacuolated cytoplasm (Papanicolaou).
    Even when detected, some signet ring cells have such bland nuclei that they can be mistaken for histiocytes, which have intracytoplasmic phagocytized material and a very low nucleus-to-cytoplasm ratio. A high degree of suspicion is the best safeguard against failure to detect a signet ring cell carcinoma by cytology. When in doubt, immunocytochemical studies can be applied to the cytologic material to determine whether the phenotype of the cells of interest is epithelial or histiocytic. Carcinoma cells should be positive for epithelial markers, such as keratin and epithelial membrane antigen, whereas histiocytes express CD-68 as detected by the KP-1 antibody.

    ENDOCRINE TUMORS
    GI endocrine tumors are classified into three major categories: (1) well-differentiated endocrine tumors, (2) welldifferentiated endocrine carcinomas, and (3) poorly differentiated endocrine (small cell) carcinomas. 28 The distinction of well-differentiated endocrine tumors from well-differentiated endocrine carcinomas is primarily based on features that cannot be evaluated on cytologic preparations, including size and site of the lesion, presence of local invasion, angioinvasion, patterns of hormone production, and metastases. Additional parameters of this classification that can be evaluated to some extent on cytologic preparations include cytologic atypia, mitotic index, and proliferative rate as assessed by MIB-1 staining. Along the GI tract, the small intestine is the most common site for such tumors, followed by the rectum and appendix, 29 with the stomach a distant fourth. These tumors account for less than 1% of all gastric malignancies. 30 However, cytologic specimens from the appendix, ileum, and rectum are virtually never seen. Our experience with cytology of GI endocrine tumors has primarily involved tumors in the stomach and duodenum ( Box 3-8 ).

    BOX 3-8 Well-Differentiated Endocrine Tumor or Carcinoma (Carcinoid Tumor) ( Fig. 3-27 )

    • Dyshesive monomorphic epithelial cells
    • Plasmacytoid appearance of the cells with eccentric round to oval nuclei and moderate amount of basophilic dense cytoplasm
    • Tendency to lose cytoplasm and to present as stripped nuclei
    • “Salt-and-pepper” chromatin pattern

    FIGURE 3-27 A loose cluster of epithelial cells and a few single monomorphic epithelial cells are seen in this duodenal brushing specimen from a carcinoid tumor. The eccentric nuclei give the cells a plasmacytoid appearance (Papanicolaou).
    The term carcinoid tumor encompasses all welldifferentiated endocrine tumors and carcinomas. 31 The tendency of these tumor cells to lose their cytoplasm causes them to mimic small cell lymphoma because of their small size and characteristic monomorphism. Such stripped nuclei can be distinguished from low-grade small cell lymphoma by their complete absence of cytoplasm and finely granular (“salt-and-pepper”) chromatin pattern. Of course, one should always find intact cells to confirm the diagnosis. Poorly differentiated endocrine carcinomas (small cell carcinomas) of the GI tract are similar to those seen elsewhere and are characterized by small cells with scant cytoplasm, showing nuclear molding and a finely dispersed chromatin pattern. Mitoses and necrosis are also prominent features of these tumors.

    MESENCHYMAL TUMORS
    Mesenchymal tumors common in the GI tract include leiomyomas (predominantly of the muscularis mucosae of the esophagus and colorectum), GI stromal tumors, and leiomyosarcomas. Because of their submucosal or mural location, these tumors are not normally accessible by endoscopic brush unless the tumor is ulcerated. Endoscopic fine-needle aspiration with or without ultrasound guidance is the preferred method of sampling. Specimens from leiomyomas usually consist of sparse bland cohesive spindle cells arranged in parallel lines with evenly spaced nuclei and abundant intercellular fibrillary matrix. 32 However, specimens from GI stromal tumors and leiomyosarcomas are usually cellular with loose and crowded fragments and individual spindle or epithelioid cells ( Box 3-9 ).

    BOX 3-9 GI Stromal Tumor ( Fig. 3-28 )

    • Cellular specimen with fascicles, clusters, and sheets of spindle or epithelioid cells, or both
    • Cell groups spread out thinly on the slide despite their large size
    • Prominent small blood vessels
    • Possibility of numerous single cells and naked nuclei
    • Delicate fibrillary cytoplasm with wispy cytoplasmic extensions and indistinct cell borders
    • Ovoid to spindle shaped and occasional wavy nuclei
    • Uncommon high-grade features, such as marked nuclear atypia, frequent mitoses, and necrosis

    FIGURE 3-28 A , A hypercellular fascicle of spindle-shaped cells is seen in this endoscopic gastric fine-needle aspiration specimen of a GI stromal tumor (Papanicolaou). B , On higher magnification, the cells have fibrillary cytoplasm and ovoid to spindle-shaped bland nuclei (Papanicolaou).
    The individual cells of GI stromal tumors have a tendency to lose their cytoplasm to become stripped, spindle-shaped or round to oval nuclei. 33 , 34 Perinuclear or paranuclear vacuoles are present in some cells. Delicate cytoplasm and prominent nuclear palisading have also been noted. 35 The tumor cells may appear spindly or epithelioid. 36 , 37 Although leiomyosarcomas tend to show more significant nuclear pleomorphism and atypia as well as a less prominent vascular pattern than GI stromal tumors, 38 , 39 immunocytochemistry or polymerase chain reaction analysis of c- kit (or both) is needed to make the definitive distinction between the two. A majority of GI stromal tumors show strong diffuse positivity for CD117 (c- kit ), whereas leiomyosarcomas are typically positive for desmin and actin 38 , 40 and negative for CD117.
    Although immunocytochemical staining for CD117 is useful in confirming a cytologic diagnosis of GI stromal tumor, the diagnosis of malignancy still depends on evaluation of the resected specimen. Most recently, detection of a c-kit mutation in a fine-needle aspiration specimen was found to be promising in predicting malignant behavior, although absence of mutation does not preclude malignancy. 41

    LYMPHOID TUMORS
    The cytologic appearance of lymphoma of the GI tract depends on its subtype. With adequate material and a combination of morphology and flow cytometry, a diagnosis of lymphoma can be established on the basis of a cytology specimen. 42 The large cell type usually does not pose any diagnostic difficulty on morphology because large malignant lymphoid cells are sufficiently atypical to raise the suspicion of a malignancy ( Fig. 3-29 ). The challenge is to recognize them as being lymphoid and to distinguish them from poorly differentiated epithelial or mesenchymal tumors. Their lymphoid nature may in fact be easier to identify on cytology than in a small biopsy specimen. Large cell lymphoma cells shed as isolated, relatively monomorphic, large atypical cells with scant cytoplasm, vesicular nuclei, and a single large nucleolus or multiple prominent nucleoli. 43 The absence of any true cohesion is the principal diagnostic feature of a lymphoma. Although a poorly differentiated carcinoma may shed predominantly as single cells, cell clusters can usually be found after a careful search. In addition, a poorly differentiated carcinoma often has more abundant cytoplasm, which may or may not be vacuolated, and a greater degree of nuclear pleomorphism than a large cell lymphoma. Immunocytochemical staining facilitates the distinction between lymphoma and carcinoma.

    FIGURE 3-29 Gastric brushing from a biopsy-proven large B-cell lymphoma shows a monomorphic population of large atypical cells with scant cytoplasm and central large prominent nucleoli. Apoptotic bodies and a few inflammatory cells are noted in the background (Papanicolaou).
    A low-grade small cell lymphoma, such as a lymphoma of the mucosa-associated lymphoid tissue (MALToma), can be difficult to diagnose by cytology because it may be mistaken for an inflammatory process ( Box 3-10 ), as it may contain a polymorphous population of small, intermediate-sized, and large cells. 44 , 45 The dominant cell population is usually intermediate-sized lymphoid cells that contain a moderate amount of cytoplasm, show slight nuclear membrane irregularities, and have inconspicuous or completely absent nucleoli (see Fig. 3-30 ). These cells may show “plasmacytoid” morphology on air-dried preparations. Diagnosing MALT lymphoma by cytology is challenging. A definitive diagnosis is usually made by cytology in only 50% of the cases, 44 , 46 and reactive follicular hyperplasia is often erroneously diagnosed. 45

    BOX 3-10 Lymphoma of the Mucosa-Associated Lymphoid Tissue (MALToma) ( Fig. 3-30 )

    • Predominance of small to medium-sized lymphocytes in an apparently inflammatory specimen
    • Monomorphism and subtle atypia in the lymphoid population

    FIGURE 3-30 Endoscopic fine needle aspiration of a biopsy-proven gastric malt lymphoma shows a monomorphic population of medium-sized lymphoid cells with slightly irregular nuclear membrane and occasional nucleoli. Each of these cells may be mistaken for a reactive lymphocyte. The presence of many similar-appearing lymphoid cells raises the suspicion of a lymphoma (Papanicolaou).
    (Courtesy of Dr. Martha Pitman, Massachusetts General Hospital, Boston.)

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    CHAPTER 4 Infectious Disorders of the GI Tract

    LAURA W. LAMPS

    Viral Infections of the GI Tract
    Cytomegalovirus
    Herpesvirus
    Enteric Viruses
    Adenovirus
    Human Papillomaviruses
    Human Immunodeficiency Virus
    Bacterial Infections of the GI Tract
    Acute Self-Limited Colitis
    Major Causes of Bacterial Enterocolitis
    Clostridial Diseases of the Gut
    Mycobacterial Infections of the GI Tract
    Spirochetal Infections of the GI Tract
    Other Causes of Sexually Transmitted Bacterial Proctocolitis
    Miscellaneous Bacterial Infections
    Fungal Infections of the GI Tract
    Parasitic Infections of the GI Tract
    Protozoal Infections
    Helminthic Infections
    GI infections are a major cause of morbidity and mortality worldwide. As the number of transplant patients and those with other immunocompromising conditions increases, and as global urbanization and transcontinental travel become more frequent, the surgical pathologist must be familiar with infectious diseases that were once limited to tropical regions of the world, or the realm of esoterica.
    The goal of the surgical pathologist in evaluating GI specimens for infectious colitis is twofold. First, acute self-limited processes and infectious processes must be differentiated from chronic idiopathic inflammatory bowel disease (ulcerative colitis or Crohn’s disease). Second, dedicated attempts must be made to identify the specific infecting organisms. 1 In recent years, the surgical pathologist’s ability to diagnose infectious processes in tissue sections has grown exponentially with the advent of new histochemical stains, immunohistochemistry, in situ hybridization, and polymerase chain reaction (PCR) analysis. As these techniques have developed, our knowledge of the specific histologic patterns of inflammation related to various organisms has also increased.
    Most enteric infections are self-limited. Patients who undergo endoscopic biopsies generally have chronic or debilitating diarrhea or systemic symptoms, or they are immunocompromised. A discussion with the gastroenterologist regarding symptomatology and colonoscopic findings, as well as knowledge of travel history, food intake (such as sushi or poorly cooked beef), sexual practices, and immune status, can aid immeasurably in evaluation of biopsies for infectious diseases.

    Viral Infections of the GI Tract
    The type of viral infection and the manifestations of disease vary with the site of infection and the immune status of the patient.

    CYTOMEGALOVIRUS

    Clinical Features
    Cytomegalovirus (CMV) infection may develop anywhere in the GI tract, from mouth to anus, in both immunocompromised and immunocompetent persons. CMV is best known as an opportunistic pathogen in patients with a suppressed immune system, including those with AIDS, and after solid organ or bone marrow transplantation. 2 Primary infections in healthy persons are generally self-limited. Symptoms vary with the immune status of the patient and the site of infection. The most common clinical symptoms are diarrhea (either bloody or watery), abdominal pain, fever, and weight loss. 2 A rare, but important, entity associated with pediatric CMV infection is hypertrophic gastropathy and protein-losing enteropathy resembling Ménétrier’s disease.
    In addition, secondary CMV may be superimposed on chronic GI diseases, such as ulcerative colitis and Crohn’s disease. In such cases, CMV superinfection is associated with exacerbations of the underlying disease, steroid-refractory disease, toxic megacolon, and a higher mortality rate. In fact, some authorities recommend immunohistochemical evaluation for CMV as part of the routine evaluation of biopsies in patients with steroid-refractory ulcerative colitis. 3

    Pathologic Features
    CMV causes a remarkable variety of gross lesions. Ulceration is the most common. Ulcers may be single or multiple, and either superficial or deep. Segmental ulcerative lesions and linear ulcers may mimic Crohn’s disease. Other gross lesions include mucosal hemorrhage, pseudomembranes, and obstructive inflammatory masses.
    The histologic spectrum of CMV infection is varied, ranging from minimal inflammation to deep ulcers with prominent granulation tissue and necrosis ( Fig. 4-1A ). Characteristic “owl’s eye” viral inclusions may be seen on routine H&E preparations and can be either intra-cytoplasmic or intranuclear (see Fig. 4-1B ). Inclusions are preferentially found in endothelial cells and stromal cells, and only rarely in epithelial cells. Unlike adenovirus and herpes, CMV inclusions are often found deep in ulcer bases rather than at the edges of ulcers or in the superficial mucosa. Adjacent nuclei may be enlarged, appear smudged, or have a ground-glass appearance, but they lack typical inclusions. Associated histologic features include cryptitis, a mixed inflammatory infiltrate usually including numerous neutrophils, and mucosal ulceration. 2 Crypt abscesses, crypt atrophy and loss, and numerous apoptotic enterocytes may be seen as well. 4 Character-istic inclusions, with virtually no associated inflammatory reaction, may occur in immunocompromised patients.

    FIGURE 4-1 A, Colonic ulcer caused by cytomegalovirus with granulation tissue and necrosis at the base. B, Characteristic “owl’s-eye” inclusions are seen in endothelial cells in the ulcer base.
    In biopsy specimens, the diagnosis may be easily missed when only rare inclusions are present. Examination of multiple levels, and use of immunohistochemistry, may be invaluable in detecting the rare cells containing an inclusion. Other diagnostic aids include viral culture, PCR assays, in situ hybridization, and serologic studies and antigen tests. Isolation of CMV in culture, however, does not imply active infection, as virus may be excreted for months to years after a primary infection. 2

    Differential Diagnosis
    The differential diagnosis of CMV includes primarily other viral infections, particularly adenovirus. 5 Adenovirus inclusions are usually crescent shaped, generally located in surface epithelium, and only intranuclear in location. CMV inclusions have an “owl’s eye” morphology, are generally located in endothelial or stromal cells, and exist in either the nucleus or cytoplasm. The ballooning degeneration phase of adenovirus infection, just before cell lysis, most closely resembles CMV.
    Distinction between CMV infection and graft-versus-host disease in bone marrow transplant patients may be particularly difficult, because the clinical and histologic features are similar. Immunohistochemistry or in situ hybridization studies should be used to rule out CMV infection in this setting, because failure to identify CMV infection could result in delay of antiviral therapy. 4 Furthermore, these conditions may coexist. Graft-versus-host disease is favored when there is abundant apoptosis associated with crypt necrosis and dropout, in the setting of minimal inflammation. The presence of viable nests of endocrine cells favors graft-versus-host disease.

    HERPESVIRUS

    Clinical Features
    Herpetic infection may occur throughout the GI tract but is most common in the esophagus and anorectum. Although herpes infections of the gut are often seen in immunocompromised patients, they are not limited to this group.
    Patients with herpetic esophagitis present with odynophagia, dysphagia, chest pain, nausea, vomiting, fever, and GI bleeding. Many have disseminated herpes infection at the time of diagnosis. 6 Herpetic proctitis is the most common cause of nongonococcal proctitis in homosexual men. Patients generally present with severe anorectal pain, tenesmus, constipation, discharge, hematochezia, and fever. Concomitant neurologic symptoms (difficulty in urination and paresthesias of the buttocks and upper thighs) are also well described, as is inguinal lymphadenopathy. 6

    Pathologic Features
    Ulcers are the most common gross finding in the esophagus, and these are usually associated with an exudate. However, many patients have a nonspecific erosive esophagitis. In herpetic proctitis, the presence of perianal vesicles is common. Proctoscopic findings include ulceration and mucosal friability. Vesicles are occasionally seen in the rectum or anal canal. 6 , 7
    Typical histologic findings, regardless of site, include focal ulceration, neutrophils in the lamina propria, and an inflammatory exudate that often contains sloughed epithelial cells ( Fig. 4-2A ). In the anorectum, perivascular lymphocytic cuffing and crypt abscesses may be seen as well. Characteristic viral inclusions and multinucleate giant cells are present in only a minority of biopsy specimens ( Fig. 4-2B ). 7 The best place to search for viral inclusions is in the squamous epithelium at the edges of ulcers and in sloughed cells in the exudate. Viral culture is the most valuable diagnostic aid. Immunohistochemistry and in situ hybridization are also specific.

    FIGURE 4-2 Typical herpetic inclusions are seen in the squamous epithelium at the edge of an esophageal ulcer.

    Differential Diagnosis
    The differential diagnosis predominantly includes other viral infections including CMV and varicella-zoster, which may also infect the GI tract. 8 Mixed infections are common in many situations in which herpetic infection is found. In immunocompetent patients, herpetic infection is often self-limited; immunocompromised persons may be at risk for dissemination and life-threatening illness.

    ENTERIC VIRUSES
    Some common enteric viruses known to cause diarrhea include, but are not limited to, adenovirus, rotavirus, coronavirus, echovirus, enterovirus, astrovirus, and Norwalk virus. 9 - 11 Many enteric viruses do not cause disease. Others seldom if ever cross the stage of the surgical pathologist, because they are detected in stool samples rather than biopsy specimens. On rare occasions, when the surgical pathologist obtains biopsy from a patient with viral enter-itis, nonspecific biopsy findings include villous fusion, epithelial reactive and degenerative changes, and a mononuclear cell infiltrate in the lamina propria ( Fig. 4-3 ).

    FIGURE 4-3 Villous fusion, surface reactive and degenerative changes, and a mononuclear cell infiltrate are nonspecific features that can be seen in biopsies from patients with gastroenteritis caused by enteric viruses.

    ADENOVIRUS
    Adenovirus infection is second only to rotavirus as a cause of childhood diarrhea. However, it has gained attention in recent years as a cause of diarrhea in immunocompromised patients, especially those with AIDS. Virtually all patients present with diarrhea, sometimes accompanied by fever, weight loss, and abdominal pain. Characteristic inclusions may be seen, especially in immunocompromised patients, in the nuclei of surface epithelial cells (particularly goblet cells), sometimes accompanied by epithelial degenerative changes. 5 , 12 Useful aids to help in the diagnosis of adenovirus infection include immunohistochemistry, stool examination by electron microscopy, and viral culture. This entity is discussed further and illustrated in Chapter 5 .

    HUMAN PAPILLOMAVIRUSES
    HPV has been implicated in the pathogenesis of esophageal papillomas, esophageal squamous cell carcinomas, anal condylomas, and anal squamous cell carcinomas. These entities are discussed in detail in Chapters 16 , 20 , and 28 .

    HUMAN IMMUNODEFICIENCY VIRUS
    Histologic abnormalities of the bowel mucosa have been noted in HIV-positive patients both with and without diarrhea. These features include crypt hypertrophy, increased numbers of apoptotic enterocytes, and villus atrophy. The changes resemble those seen in mild graft-versus-host disease and chemotherapy-related mucosal injury. 13 Many patients have chronic diarrhea, but some are asympto-matic. Some authors support use of the term AIDS enteropathy to describe these morphologic findings, provided that the bowel has been adequately sampled and all other infectious causes have been excluded. 13 Others believe that this is a poorly understood term that does not clearly represent a specific disease entity and thus should be avoided. Chronic idiopathic esophageal ulcers have also been described in association with HIV; this entity is discussed in Chapter 5 .
    Other viruses that affect the GI tract include measles (rubeola) and varicella-zoster, which may cause ulcerative gastroenteritis. In addition, some DNA viruses have been implicated in the pathogenesis of sporadic chronic idiopathic intestinal pseudo-obstruction.

    Bacterial Infections of the GI Tract
    Bacterial diarrhea is a worldwide health problem, with Escherichia coli, Salmonella, Shigella , and Campylobacter being the most common pathogens. Many bacterial infections of the gut are related to ingestion of contaminated water or food, or foreign travel. Although these organisms are usually recovered by culture, surgical pathologists may play a valuable role in diagnosis. Despite the dizzying array of bacterial infections that may affect the GI tract, most of these organisms produce a spectrum of histologic features that may be broadly categorized as follows ( Table 4-1 ):
    • Organisms that produce mild or complete absence of histologic changes (e.g., Vibrio cholerae and Neisse-ria gonorrhoeae )
    • Organisms that produce histologic features of acute infectious self-limited colitis (ASLC) or focal active colitis, such as Shigella and Campylobacter
    • Organisms that produce specific or characteristic histologic features, such as pseudomembranes, granulomas, or viral inclusions

    TABLE 4-1 Classification of Bacterial Infections of the Gl Tract by Histologie Pattern

    ACUTE SELF-LIMITED COLITIS
    The ASLC pattern is the most common pattern in enteric infections. Typical histologic features include neutrophils in the lamina propria, with or without crypt abscesses and cryptitis, preservation of crypt architecture, and lack of basal plasmacytosis. 1 , 14 The acute inflammatory component is often most prominent in the middle to upper levels of the crypts. Lack of crypt distortion, Paneth cell metaplasia and basal lymphoplasmacytosis help to distinguish ASLC from inflammatory bowel disease. The changes may be focal, as in focal active colitis, or diffuse.
    Because most patients do not present at endoscopy until several weeks after the onset of symptoms, pathologists usually are not exposed to the classic histologic features of acute infectious colitis. This is important, as the resolving phase of infectious colitis is more challenging to diagnose. At this stage, only occasional foci of neutrophilic cryptitis and only patchy increases in lamina propria inflammation may be found, and these may, in fact, contain abundant plasma cells and increased intraepithelial lymphocytes. As these features are also seen in Crohn’s disease or even lymphocytic colitis, it is important to be aware of the patient’s symptoms (particularly acute versus chronic onset), and, ideally, the culture results, because the exact diagnosis may be difficult to resolve on histologic grounds alone. The pathologic details of specific bacterial infections follow.

    MAJOR CAUSES OF BACTERIAL ENTEROCOLITIS

    Vibrio cholerae and Related Species
    V. cholerae is the causative agent of cholera, an important worldwide cause of watery diarrhea and dysentery that may lead to significant dehydration and death. Despite the severity of the illness, V. cholerae is a noninvasive, potent toxin-producing organism that causes minimal or no histologic changes. Rare nonspecific findings such as small bowel mucin depletion and a mild increase in lamina propria mononuclear cells have been reported. 15 Other species, such as Vibrio hollisae and Vibrio parahaemolyticus , can also cause severe gastroenteritis.

    Escherichia coli
    E. coli is the most common gram-negative human pathogen. The diarrheogenic E. coli are classified into five groups, based primarily on serotyping. If pathogenic E. coli are suspected, the clinical laboratory should be notified to search for them specifically, as they may be missed on routine culture.


    Enterotoxigenic E. coli and enteropathogenic E. coli .
    These noninvasive E. coli cause nonbloody diarrhea. Enterotoxigenic E. coli is a major cause of traveler’s diarrhea, as well as food-borne outbreaks in industrialized nations. 16 Enteropathogenic E. coli is predominantly an infection of infants and neonates. The gross and microscopic pathology of neither has been well described in humans.

    Enteroinvasive E. coli .
    The pathology of enteroinvasive E. coli has not been well described in humans either. These organisms are similar to Shigella genetically and in their clinical presentation and pathogenesis, so they may be similar in their pathology as well. Symptoms include diarrhea (generally mucoid and watery but nonbloody), tenesmus, fever, malaise, and abdominal cramps. Enteroinvasive E. coli is transmitted via contaminated cheese, water, and person-to-person contact. These organisms are a cause of traveler’s diarrhea. 17 They produce a severe dysentery-like illness as well as bacteremia, which can be a particular problem in AIDS patients.

    Enteroadherent E. coli .
    These noninvasive E. coli are similar to enteropathogenic E. coli . Both have been increasingly recognized as causes of chronic diarrhea and wasting in patients with AIDS. Although endoscopic findings are usually unremarkable, right colon biopsies more often yield pathologic findings. Histologic examination shows degenerated surface epithelial cells with associated intraepithelial inflammatory cells. A coating of adherent bacteria on the surface epithelium is the most prominent feature, which may stain gram-negative ( Fig. 4-4 ). 18

    FIGURE 4-4 Enteroadherent Escherichia coli in a patient with AIDS. A coating of gram-negative rods with little inflammatory reaction is noted at the surface of the colonic mucosa (Gram).
    (Courtesy of Dr. Mary Bronner.)

    Enterohemorrhagic E. coli .
    The most common strain of enterohemorrhagic E. coli is O157:H7. This pathogen gained national attention in 1993 when a massive outbreak in the western United States was linked to contaminated hamburger meat. Although contaminated meat is the most frequent mode of transmission, infection may also occur through contaminated water, milk, produce, and person-to-person contact. Enterohemorrhagic E. coli produces a cytotoxin similar to that of Shigella dysenteriae ; however, there is no tissue invasion. Affected persons may develop hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura. Children and older adults are at particular risk for grave illness. 19
    GI symptoms usually consist of bloody diarrhea with severe abdominal cramps and mild or no fever. Nonbloody, watery diarrhea may occur in some. Only one third of patients have fecal leukocytes. Endoscopically, patients may have colonic edema, erosions, ulcers, and hemorrhage, and the right colon is usually more severely affected. The edema may be so marked that it causes obstruction, and surgical resection may be required to relieve this or to control bleeding. The histopathologic features include marked edema and hemorrhage in the lamina propria and submucosa, with associated mucosal acute inflammation and necrosis ( Fig. 4-5 ). Microthrombi may be present in small-caliber blood vessels, and pseudomembranes may occasionally be present as well. 20 , 21

    FIGURE 4-5 Enterohemorrhagic Escherichia coli . The hemorrhagic necrosis, acute inflammatory exudates, and crypt withering are very similar to the features of ischemic colitis.
    Routine stool cultures cannot distinguish O157:H7 from normal intestinal flora, because microbiologic diagnosis requires screening on selective agar. An immunohistochemical stain for this organism has recently been described.
    The differential diagnosis includes Clostridium difficile -related colitis, idiopathic inflammatory bowel disease, and especially ischemic colitis, from which enterohemorrhagic E. coli may be histologically indistinguishable. In cases of the latter, knowledge about the specific clinical situation, age and demographics of the patient, type of onset of illness, and type of diarrhea, along with endoscopic findings, may aid in distinguishing ischemic from E. coli infection.

    Salmonella
    These gram-negative bacilli are transmitted through food and water and are prevalent where sanitation is poor. They are an important cause of both food poisoning and traveler’s diarrhea.


    Typhoid (enteric) fever (S. typhimurium).
    Patients with typhoid fever typically present with abdominal pain, headache, a rise in fever over several days, and occasionally constipation. There is often an abdominal rash and leukopenia. Diarrhea, which begins in the second or third week of infection, is initially watery but may progress to severe GI bleeding. 22
    Any level of the alimentary tract may be involved, but the characteristic pathology is most prominent in the ileum, appendix, and colon, and is associated with Peyer’s patches. Grossly, the bowel wall is thickened, and raised nodules may be seen corresponding to hyperplastic Peyer’s patches. Aphthous ulcers overlying Peyer’s patches, linear ulcers, discoid ulcers, or full-thickness ulceration and necrosis are common as the disease progresses. There may be associated suppurative mesenteric lymphadenitis. Perforation and toxic megacolon may complicate typhoid fever. 22 - 24 Occasionally, the mucosa is grossly normal or only mildly inflamed and edematous. 24 , 25
    Histiocytes are the predominant inflammatory cell. Following hyperplasia of Peyer’s patches, acute inflammation of the overlying epithelium develops. Eventually, macrophages, mixed with occasional lymphocytes and plasma cells, infiltrate and obliterate the lymphoid follicles; neutrophils are not prominent. 23 Necrosis then begins in the Peyer’s patch and spreads to the surrounding mucosa, which eventually ulcerates. The ulcers are typically very deep, with the base at the level of the muscularis propria. Typhoid fever occasionally shows features more consistent with acute self-limited colitis, including prominent neutrophils, cryptitis, crypt abscesses, and overlying fibrinous exudate. 24 , 25 Granulomas are occasionally seen as well.

    Nontyphoid Salmonella species.
    Nontyphoid Salmonella species (e.g., Salmonella enterica and Salmonella muenchen ) generally cause self-limited gastroenteritis. Endoscopic findings include mucosal redness, ulceration, and exudates; the pathologic features are those of nonspecific ASLC. Occasionally, significant crypt distortion is seen. 25
    The differential diagnosis of typhoid fever includes yersiniosis and other infectious processes, as well as Crohn’s disease, and there may be significant histologic overlap between them ( Table 4-2 ). 23 , 25 Neutrophils and granulomas are often more prominent in Crohn’s disease and in yersiniosis. The differential diagnosis of nontyphoid Salmonella includes other causes of acute self-limited infectious colitis, as well as ulcerative colitis. 17 In addition, Salmonella infection may complicate preexisting idiopathic inflammatory bowel disease. Although significant crypt distortion has been reported in some cases of salmonellosis, it is generally more pronounced in ulcerative colitis. Clinical presentation and stool cultures may be invaluable in sorting out the differential diagnosis.
    TABLE 4-2 Infectious Mimics of Chronic Idiopathic Inflammatory Bowel Disease Mimics of Crohn’s Disease Cytomegalovirus Salmonella typhimurium Shigella species Yersinia species Mycobacterium tuberculosis Aeromonas species Lymphogranuloma venereum Amebiasis Mimics of Ulcerative Colitis Shigella species Nontyphoid Salmonella species Amebiasis

    Shigella
    Shigella are virulent, invasive, gram-negative bacilli that cause severe watery or bloody diarrhea (or both). They are a major cause of infectious diarrhea worldwide. The organism is usually transmitted by water contaminated with feces. It has the highest infectivity rate of all of the enteric gram-negative bacteria, so symptoms may result from ingestion of a very low number of organisms. Infants, young children, and malnourished or debilitated patients are most commonly affected. Symptoms include abdominal pain, fever, and diarrhea that is initially watery but later turns bloody. Chronic disease is rare.
    Grossly, the large bowel is typically affected (the left side usually more severely), but the ileum may be involved as well. The mucosa is hemorrhagic, with exudates that may form pseudomembranes. Ulcerations are variably present. Histologically, early disease has the features of acute self-limited colitis with cryptitis, crypt abscesses (often superficial), and ulceration. Pseudomembranes similar to C. difficile infection may be seen, as well as aphthous ulcers similar to those seen in Crohn’s disease. As the disease continues, there is increased mucosal destruction with many neutrophils and other inflammatory cells in the lamina propria. Marked architectural distortion mimicking idiopathic inflammatory bowel disease is well described. 26
    The differential diagnosis of early shigellosis includes primarily other enteroinvasive infections, particularly those caused by E. coli and C. difficile . Shigellosis, particularly later in the course of the disease, may be extremely difficult to distinguish from Crohn’s disease or ulcerative colitis, both endoscopically and histologically. 1 Stool cultures and clinical presentation may be very helpful.

    Campylobacter
    These gram-negative organisms are major causes of diarrhea worldwide and are the most common stool isolate in the United States. 27 Campylobacter is found in contaminated meat, water, and milk, and it is a common animal pathogen. Campylobacter jejuni is most commonly associated with food-borne gastroenteritis. Campylobacter fetus and the other less common species are more often seen in immunosuppressed patients and homosexual men. 19 Patients typically have fever, malaise, abdominal pain (often severe), and watery diarrhea, which may contain blood and leukocytes. 28 Most infections are self-limited, especially in healthy patients. Of note, Guillain-Barré syndrome and reactive arthropathy are associated with Campylobacter infection. 27
    Endoscopic findings include friable colonic mucosa with associated erythema and hemorrhage. Histologic examination shows features of acute self-limited colitis. Interestingly, C. jejuni has been demonstrated by molecular methods in almost 20% of patients who have the focal active colitis pattern of inflammation on colon biopsy. 29 Mild crypt distortion may occasionally be seen, although crypt architecture is normally well preserved. 28

    Yersinia
    Yersinia enterocolitica and Yersinia pseudotuberculosis are the species that cause human GI disease. Yersinia is one of the most common agents of bacterial enteritis in western and northern Europe, and the incidence is rising in both Europe and the United States. These gram-negative coccobacilli may cause appendicitis, ileitis, colitis, and mesenteric lymphadenitis. Although yersiniosis is usually a self-limited process, chronic infections (including chronic colitis) have been well documented. Immunocompromised and debilitated patients, as well as patients on deferoxamine or with iron overload, are at risk for serious disease.
    Yersinia preferentially involves the ileum, right colon, and appendix, and it may cause a pseudoappendicular syndrome. In addition, it is responsible for many isolated cases of granulomatous appendicitis. 30 Grossly, involved bowel has a thickened, edematous wall with nodular inflammatory masses centered on Peyer’s patches. Aphthous and linear ulcers may be seen. Involved appendices are enlarged and hyperemic, similar to that seen in suppurative appendicitis; perforation is often seen. Involved lymph nodes may show gross foci of necrosis.
    Both suppurative and granulomatous patterns of inflammation are common and are often mixed. Y. enterocolitica has not typically been associated with discrete granulomas, but it has been characterized by hyperplastic Peyer’s patches with overlying ulceration, acute inflammation, hemorrhagic necrosis, and palisading histiocytes. 31 GI infection with Y. pseudotuberculosis has characteristically been described as a granulomatous process with central microabscesses, almost always accompanied by mesenteric adenopathy ( Fig. 4-6A ). 32 There is significant overlap between the histologic features of Y. enterocolitica and Y. pseudotuberculosis infection, however, and either species may show epithelioid granulomas with prominent lymphoid cuffing (see Fig. 4-6B ), lymphoid hyperplasia, transmural lymphoid aggregates, mucosal ulceration, and lymph node involvement. 30 Gram stains are usually not helpful, but cultures, serologic studies, and PCR assays may be useful in confirming the diagnosis.

    FIGURE 4-6 A, Lymphoid hyperplasia with necrotizing granulo-matous inflammation and prominent microabscess formation in appendicitis caused by Yersinia pseudotuberculosis . B, Epithelioid granulomas with prominent lymphoid cuffs in Yersinia enterocolitica infection.
    The major differential diagnosis includes other infectious processes, particularly those caused by mycobacteria and Salmonella . Acid-fast stains and culture results help distinguish mycobacterial infection. The specific clinical features, and the presence of greater numbers of neutrophils, microabscesses, and granulomas may help to distinguish yersiniosis from salmonellosis.
    Crohn’s disease and yersiniosis may be very difficult to distinguish from one another, and, in fact, have a long and complicated relationship. Both disorders may show similar histologic features, including transmural lymphoid aggregates, skip lesions, and fissuring ulcers. In fact, isolated granulomatous appendicitis has frequently been interpreted as representing primary Crohn’s disease of the appendix (see Chapter 15 ). However, patients with granulomatous inflammation confined to the appendix rarely develop generalized inflammatory bowel disease. 33 Features that favor a diagnosis of Crohn’s disease include cobblestoning of mucosa, presence of creeping fat, and histologic changes of chronicity including crypt distortion, thickening of the muscularis mucosa, and prominent neural hyperplasia. However, some cases are simply indistinguishable on histologic grounds alone.

    Aeromonas
    Aeromonas species, initially thought to be nonpathogenic gram-negative bacteria, are increasingly recognized as causes of gastroenteritis in both children and adults. The motile Aeromonas hydrophila and Aeromonas sobria most often cause GI disease in humans. The typical presentation is bloody diarrhea, sometimes chronic, accompanied by nausea, vomiting, and cramping pain. The diarrhea may contain mucus as well as blood. The duration of illness varies widely, ranging from a few days to several years, indicating that Aeromonas infection can cause chronic colitis. 34 - 38
    Endoscopically, signs of colitis, including edema, friability, erosions, exudates, and loss of vascular pattern, may be seen. The features are often segmental and may mimic ischemic colitis or Crohn’s disease. 34 Pancolitis mimicking ulcerative colitis has also been described. The histologic features are usually those of acute self-limited colitis. However, ulceration and focal architectural distortion may be seen in some instances ( Fig. 4-7 ). 34 - 38

    FIGURE 4-7 Focal cryptitis and architectural distortion from a right colon biopsy in a case of culture-proven Aeromonas infection.
    Stool cultures are critical to diagnosis. The differential diagnosis includes other infectious processes, ischemic colitis, and chronic idiopathic inflammatory bowel disease. Culture helps to exclude other infections, but when architectural distortion is present in a patient with chronic symptoms, it may be difficult to distinguish between Aeromonas infection, Crohn’s disease, and ulcerative colitis. In fact, some authorities recommend culturing for Aeromonas in all patients with refractory chronic inflammatory bowel disease.

    CLOSTRIDIAL DISEASES OF THE GUT
    Clostridial organisms are some of the most potent toxigenic bacteria in existence and are very important gut pathogens. This group of bacteria is responsible for pseudomembranous/antibiotic-associated colitis (usually C. difficile ), necrotizing jejunitis or pig-bel (usually Clostridium perfringens [ welchii ]), neutropenic enterocolitis (often Clostridium septicum ), and botulism ( Clostridium botulinum ). 39



    C. difficile-related colitis
    C. difficile infection is most commonly related to prior antibiotic exposure (especially orally administered), because the organisms cannot infect in the presence of normal flora. 39 It is the most common nosocomial GI pathogen. The majority of patients are older adults, although infection is certainly not limited to this patient group. In addition, C. difficile infection has increased significantly in patients with chronic idiopathic inflammatory bowel disease, and it negatively affects clinical outcome in terms of hospitalization and need for colectomy. 40 , 41
    The range of disease is variable, from mild diarrhea to fully developed pseudomembranous colitis to fulminant disease with perforation or toxic megacolon. 42 , 43 Watery diarrhea is almost always present initially and may be accompanied by abdominal pain, cramping, fever, and leukocytosis. Bloody diarrhea is sometimes seen. Symptoms can occur up to several weeks after discontinuation of antibiotic therapy. 42
    Endoscopically, classic pseudomembranous colitis shows yellow-white pseudomembranes, most commonly in the left colon, that bleed when scraped. The distribution is often patchy, and the rectum may be spared. 42 Atypical findings include mucosal erythema and friability without pseudomembranes. Typical histologic findings may be seen, however, in the absence of gross pseudomembranes. Histologically, the classic features of pseudomembranous colitis-“volcano” lesions with intercrypt necrosis and ballooned crypts-give rise to the laminated pseudomembrane composed of fibrin, mucin, and neutrophils ( Fig. 4-8A-C ). The ballooned glands are filled with neutrophils and mucin, and they often lose the superficial epithelial cells. 43 The degenerated goblet cells often spill into the lumen of degenerated and necrotic crypts, and they mimic signet ring cell carcinoma. In fact, this feature is helpful to distinguish the condition from ischemic colitis, as the latter does not normally show this feature. More severe and prolonged pseudomembranous colitis may lead to full-thickness mucosal necrosis. Less characteristic lesions, usually focal active colitis with occasional crypt abscesses but lacking pseudomembranous features, have been well described in association with a positive C. difficile toxin assay. 43

    FIGURE 4-8 A, Early pseudomembranous colitis with ballooned crypts containing neutrophils and intercrypt necrosis but no pseudomembrane. B, Intercrypt necrosis giving rise to early “volcano” lesion. C, Classic “volcano” lesion with laminated pseudomembrane composed of fibrin, mucin, and neutrophils.
    It is important to note that pseudomembranous colitis is a descriptive diagnosis, not a specific diagnosis. Although most cases of pseudomembranous colitis are related to C. difficile , other infectious entities, as well as ischemic colitis, may have a similar endoscopic and histologic appearance. A hyalinized lamina propria favors the diagnosis of is-chemia; other features, such as crypt withering, pseudomembranes, and mucosal necrosis, may be seen in either entity. 44 Endoscopically, pseudomembrane formation is more frequent in pseudomembranous colitis, although it can be seen in ischemia as well. History of antibiotic use and stool assay for C. difficile toxin may be invaluable in resolving the differential diagnosis.

    C. perfringens (welchii).
    C. perfringens causes diarrhea related to food poisoning and is also a cause of antibiotic-associated and nosocomial diarrhea. The notorious pig-bel (segmental necrotizing enterocolitis) is caused by C. perfringens type C; it usually follows a meal rich in infected meat. It is most common in Southeast Asia and New Guinea, where it was initially described following ritual pork feasting. Similar cases have been described after eating binges in Western countries. Symptoms include abdominal pain, bloody diarrhea, and vomiting, often with abdominal distension. Complications include perforation, obstruction, bowel gangrene, and septicemia with shock and rapid death. Mild or subacute forms have also been described. 45
    Involvement is predominantly seen in, but is not limited to, the jejunum. The bowel is often dusky gray-green, similar in appearance to ischemia. The necrotic areas may be segmental and focal, with intervening areas of normal mucosa. The mucosal exudate may be similar to that seen in pseudomembranous colitis, but inflammation and necrosis often become transmural and lead to perforation. Histologically, the mucosa is edematous, necrotic, and ulcerated, with a heavy acute inflammatory infiltrate at the edges of ulcers. Pneumatosis may be present in severe cases, particularly in the mucosa and submucosa. Small vessel vasculitis and microthrombi may be seen. 45 Gram-positive bacilli typical of clostridia can be found in the necrotic exudate.

    C. septicum.
    Neutropenic enterocolitis (typhlitis) is a serious complication of both chemotherapy-related and primary neutropenia. Most patients have received chemotherapy within the previous month before the onset of colitis. C. septicum has been frequently reported as a causative agent, especially in adults; other commonly implicated bacteria include other clostridial species, E. coli , Pseudomonas , and Enterococcus . 46 , 47 An association with CMV has also been noted. Patients usually present with GI hemorrhage, fever, abdominal pain and dis-tension, and diarrhea. 46 Perforation is a well-described complication.
    The right colon is preferentially involved, although the ileum and other sites in the colon may be affected as well. Gross findings include diffuse dilation and marked edema of the bowel, with varying severity of ulceration and hemorrhage. 46 Exudates and pseudomembranes resembling C. difficile colitis are common. Microscopically, changes range from mild hemorrhage to prominent submucosal edema, ulceration, marked hemorrhage, and necrosis, typically with a striking absence of inflammatory cells ( Fig. 4-9 ). Pneumatosis may occur rarely if the inciting organism is gas producing. However, a few neutrophils may sometimes be found despite peripheral neutropenia. Occasionally, organisms can be detected in the wall of the bowel or in mucosal or submucosal blood vessels on Gram stain.

    FIGURE 4-9 Typhlitis (neutropenic enterocolitis) in a chemotherapy patient. Ulceration with hemorrhage, prominent submucosal edema, mucosal ulceration and necrosis, and an exudate containing numerous bacteria and yeast are typical features. Neutrophils are scarce.
    The differential diagnosis includes ischemic colitis and pseudomembranous colitis. The appropriate clinical setting and dearth of inflammatory cells favor a diagnosis of necrotizing enterocolitis.

    MYCOBACTERIAL INFECTIONS OF THE GI TRACT



    Mycobacterium tuberculosis.
    This organism remains common in developing countries and immigrant populations. There has also been a remarkable resurgence of tuberculosis in Western countries, due in large part to AIDS but also caused by institutional overcrowding and immigrant populations. GI symptoms (rather than pulmonary) may be the initial presentation. In fact, primary GI tuberculosis has been well documented. Symptoms and signs are nonspecific and include weight loss, fever, abdominal pain, diarrhea, and a palpable abdominal mass. 48 , 49 Mesenteric adenopathy is common.
    Grossly, the ileocecal and jejunoileal areas are most commonly involved, followed by the appendix and as-cending colon 48 , 49 ; the ileocecal valve is often deformed and gaping. Rectal, anal, duodenal, and gastroesophageal involvement are much less frequent but are well described. Strictures and ulcers (often occurring together) are the most common endoscopic findings, along with thickened mucosal folds and inflammatory nodules. The ulcers are often circumferential and transverse. Multiple and segmental lesions with skip areas are common. Large inflammatory masses, usually involving the ileocecum, may be seen, and well-described complications include obstruction, perforation, and hemorrhage. 48 - 50 Anal and perianal disease have also been reported, but rarely. 51
    The characteristic histologic lesion consists of caseating, often confluent, granulomas, present at any level of the gut wall ( Fig. 4-10A ); a rim of lymphocytes may be present at the periphery of the granulomas. Granulomas may be rare, or remote, with hyalinization and calcification. Aphthous ulcers, as well as inflammation of submucosal vessels, may be present. Acid-fast stains sometimes demonstrate organisms in granulomas or necrotic areas (see Fig. 4-10B ), but culture is usually required for definitive diagnosis. In addition, PCR assays are available. Skin tests with purified protein derivative are unreliable in immunocompromised or debilitated patients.

    FIGURE 4-10 A, Colonic Mycobacterium tuberculosis with mucosal and submucosal confluent, caseating granulomas. B, Rare acid-fast organisms are seen in the necroinflammatory infiltrate (Ziehl-Neelsen).
    The differential diagnosis includes other granuloma-tous infectious processes, especially yersiniosis and fungal disease ( Table 4-3 ). 30, 52 - 54 The granulomas of yersiniosis are typically noncaseating, with striking lymphoid cuffs, but there may be considerable histologic overlap. Crohn’s disease may be very difficult to distinguish from tuberculosis. Features favoring Crohn’s disease are the presence of linear rather than circumferential ulcers, transmural lymphoid aggregates, deep fistulas and fissures, and mucosal changes of chronicity that are present away from areas of granulomatous inflammation. 52 Tuberculosis also commonly lacks mucosal cobblestoning. Atypical mycobacteria, such as Mycobacterium kansasii and Mycobacterium bovis , may cause a similar pathologic picture.

    TABLE 4-3 Features Useful in Diagnosing Mycobacterium tuberculosis, Yersinia , and Crohn’s Disease

    Mycobacterium avium-intracellulare complex
    This is the most common mycobacterium isolated from the GI tract. Symptoms include diarrhea, abdominal pain, fever, and weight loss, and often reflect systemic infection. Endoscopy is usually normal, although white nodules, small ulcers, or hemorrhages may be seen. The small bowel is preferentially involved, but colonic and gastroesophageal involvement may be present, as well as mesenteric adenopathy. 55 , 56
    Immunocompetent patients typically manifest a granulomatous response, with or without necrosis. Immunocompromised patients generally have villi distended by a diffuse infiltration of histiocytes containing bacilli ( Fig. 4-11A ), with little inflammatory response other than occasional poorly formed granulomas. 55 The bacilli stain with acid-fast stains, as well as periodic acid-Schiff (PAS) and Gomori’s methenamine silver (GMS). Culture and PCR assays may also be helpful. Organisms are generally abundant in the immunocompromised host (see Fig. 4-11B ) but may be hard to detect in healthy patients. The differential diagnosis includes Whipple’s disease and other infectious processes.

    FIGURE 4-11 A, Small bowel villi are distended by clusters of histiocytes containing Mycobacterium avium-intracellulare , with little associated inflammatory response. B, The histiocytes are packed with numerous acid-fast organisms typical of M. avium-intracellulare (Ziehl-Neelsen).
    (Courtesy of Dr. Jesse McKenney.)

    SPIROCHETAL INFECTIONS OF THE GI TRACT



    Syphilis (Treponema pallidum) .
    GI syphilis predominantly involves the anorectum, although other sites may be infected as well, particularly the stomach. 56 , 57 Patients are often asymptomatic, 56 - 58 but pain, constipation, bleeding, and discharge may be present.
    Gross findings in primary syphilis include anal chancres and an associated mild proctitis. Signs of secondary syphilis typically appear 6 to 8 weeks later and include masses, a mucocutaneous rash, or condyloma lata (raised, moist, smooth warts that secrete mucus and are associated with itching and a foul odor). 56 , 58 Inguinal adenopathy is typical. The gross signs of primary and secondary infection sometimes coexist.
    Gastric involvement may be either an early or a late manifestation of syphilis. The most common presenting sign is upper GI bleeding, and patients typically have antral erosions, ulcers, or features of gastritis endoscopically. 57 Ulcers may have irregular, heaped-up edges that mimic malignancy.
    Histologically, syphilitic chancres typically contain a dense mononuclear cell infiltrate with prominent plasma cells. Syphilitic proctitis is very nonspecific, often showing features of acute self-limited or focal active colitis, with or without an increase in plasma cells ( Fig. 4-12A ). Syphilitic gastritis more often features a dense plasmacytic infiltrate. 57 However, the glands may be relatively spared by inflammation. Granulomas have been reported, and occasion-ally prominent, proliferative capillary endothelial cells are noted. 59 , 60 Darkfield examination, silver impregnation stains (see Fig. 4-12B ), serologic studies, and immunohistochemistry may be helpful diagnostic aids.

    FIGURE 4-12 A, Syphilitic proctitis featuring neutrophilic cryptitis, crypt abscesses, and a striking plasmacytic infiltrate in the lamina propria. B, Numerous spirochetes are seen with silver impregnation staining (Warthin-Starry).
    A, (Courtesy of Dr. Amy Hudson.) B, (Courtesy of Drs. Rodger Haggitt and Mary Bronner.)
    The gross differential diagnosis of chancre includes anal fissures, fistulas, or traumatic lesions. In general, condyloma acuminata are more dry and keratinized than condyloma lata. The histologic differential diagnosis primarily includes other infectious processes, including Helicobacter pylori infection in the stomach. If the plasma cell infiltrate is very prominent and monomorphic, plasmacytoma should also be considered.

    Intestinal spirochetosis.
    Intestinal spirochetosis is usually seen in homosexual men, although it has been described in a wide variety of conditions including diverticular disease and ulcerative colitis, and in patients with adenomas. It probably represents infection by a group of related organisms. 61 Patients with this histologic finding often have symptoms such as diarrhea or anal pain and discharge, but it is not clear that spirochetosis causes these symptoms, and many immunocompromised patients have other infections (especially gonorrhea) that complicate the clinical picture. However, symptomatic patients do appear to respond to antimicrobial therapy. 61 - 63 Any level of the colon may be involved, even the appendix. Typically, endoscopic abnormalities are either mild or completely absent.
    On H&E, spirochetosis resembles a fuzzy, “fringed” blue line at the luminal border of the colonic mucosa ( Fig. 4-13A ). Tissue invasion by organisms is not seen, and the changes can be very focal. Most cases show no associated inflammatory infiltrate, although occasionally an associated cryptitis is present. The organisms stain intensely with Warthin-Starry or similar silver stains (see Fig. 4-13B ). They also stain with alcian blue (pH 2.5) and PAS. 64

    FIGURE 4-13 A, Spirochetosis characterized by a fuzzy, “fringed” blue line at the luminal border of the colonic mucosa. B, Organisms stain intensely with silver impregnation staining (Warthin-Starry).
    The differential diagnosis primarily consists of other organisms with a prominent glycocalyx, which does not stain with silver impregnation stains. Occasionally, enteroadherent E. coli can induce a similar histologic appea-rance, but E. coli are gram-negative and lack spirillar morphology.

    OTHER CAUSES OF SEXUALLY TRANSMITTED BACTERIAL PROCTOCOLITIS
    Although herpes simplex virus is the most common etiologic agent of infectious proctocolitis among homosexual men, N. gonorrhoeae, T. pallidum , and Chlamydia are also frequent causes. Patients generally present with anal discharge, pain, diarrhea, constipation, bloody stools, and tenesmus. Proctoscopic findings range from normal to erythema, mucosal friability, and surface erosions. 58



    Chlamydia trachomatis.
    Serotypes L1, L2, and L3 cause lymphogranuloma venereum (LGV). Anal pain is usually severe and accompanied by bloody discharge and tenesmus. 59 - 65 The anorectum is the most common site, but LGV has been described in the ileum and colon as well. 65 The inflammatory infiltrate is variable; most patients have a lymphoplasmacytic infiltrate in the mucosa and submucosa, but neutrophils may be prominent as well. Granulomatous inflammation is sometimes present. Histologic features mimicking Crohn’s disease have been described. 65 , 66 In addition, LGV may produce a striking “follicular” proctitis. 65 Culture, direct immunofluorescence studies, and immunohistochemistry may serve as valuable diagnostic aids.

    Granuloma inguinale.
    Calymmatobacterium granuloma-tis (recently reclassified as Klebsiella granulomatis ) causes anal and perianal disease that may resemble LGV, although extension into the rectum favors a diagnosis of LGV. 66 Warthin-Starry or Giemsa stain aids in visualizing the Donovan bodies typical of granuloma inguinale.

    Neisseria gonorrhoeae.
    Gonorrhea has been reported in up to 20% of homosexual men and is frequently asymptomatic. The anorectum (alone or in combination with the pharynx and urethra) is a common site of infection. Neisseria meningitidis has also been isolated from the anorectum of homosexual men. Proctoscopic examination is usually unremarkable. Most biopsies in rectal gonorrhea are normal; some reveal a mild increase in neutrophils and mononuclear cells, or focal cryptitis. 67 Gram-negative cocci are occasionally seen on a Gram stain of anal discharge, and culture can be a valuable diagnostic aid.

    MISCELLANEOUS BACTERIAL INFECTIONS



    Bacterial esophagitis.
    Bacterial esophagitis is rare, usually found in immunocompromised or debilitated patients. Implicated bacteria include Staphylococcus aureus, Lactobacillus acidophilus , and Klebsiella pneumoniae . Endoscopic findings include ulceration, pseudomembrane formation, and hemorrhage. Histologic findings include acute inflammation and necrosis, with bacteria demonstrable in the wall of the esophagus. 68

    Phlegmonous gastritis and enteritis.
    Phlegmonous enteritis, gastritis, and esophagitis have all been well documented. This is a suppurative, primarily submucosal inflammatory process, characterized by marked edema. The causative organisms vary and include E. coli , clostridial organisms, Proteus , staphylococci, and group A streptococci. 69 , 70 Most patients are debilitated, and many have cirrhosis or alcoholic liver disease. 70 Affected patients may have nonspecific GI or systemic symptoms, or phlegmonous disease may be found incidentally at autopsy. Patients typically develop an acute abdomen, sometimes complicated by hematemesis or vomiting of purulent material.
    Any portion of the alimentary tract may be involved. Typically, the gut wall is markedly thick and edematous. Occasionally, gas-producing organisms such as C. perfringens may lead to the formation of gas bubbles in the submucosa (“emphysematous” changes) ( Fig. 4-14 ). Although the mucosa may be red and friable, discrete ulceration is rarely present. Histologically, there is intense edema and acute inflammation located predominantly in the submucosa, and there may be transmural involvement as well. 70 The mucosa may be spared or sloughed entirely, especially in the stomach. Venous thrombosis may complicate the picture, causing ischemic changes. Gram stain may show organisms in the bowel wall, which is diagnostic.

    FIGURE 4-14 Emphysematous enteritis caused by Clostridium perfringens . Note transmural necrosis and mucosal sloughing with associated gas bubbles in the gut wall.
    (Courtesy of Dr. David Owen.)

    Actinomycosis (Actinomyces israelii) .
    This filamentous anaerobic gram-positive bacterium is a normal inhabitant of the oral cavity and the upper GI tract. Rarely, it produces a chronic, nonopportunistic GI infection. 71 Infection is usually in a solitary site, and it may occur at any level of the GI tract. Symptoms include fever, weight loss, abdominal pain, and, occasionally, a palpable mass. Perianal fistulas and chronic (often granulomatous) appendicitis have both been described. In fact, sometimes actinomycosis is associated with diverticular disease. Grossly, inflammation may produce a large, solitary mass, with or without ulceration, and infiltration into surrounding structures. 72
    The organism typically produces actinomycotic (“sulfur”) granules, consisting of irregular round clusters of bacteria rimmed by eosinophilic, clublike projections (Splendore-Hoeppli material). The inflammatory reaction is predominantly neutrophilic, with occasional abscess formation ( Fig. 4-15 ). Palisading histiocytes and giant cells, as well as frank granulomas, often surround the neutrophilic inflammation. There may be an associated fibrotic response. Gram stain reveals the filamentous, gram-positive organisms. GMS and Warthin-Starry stains are also used to show these organisms.

    FIGURE 4-15 Actinomycotic (“sulfur”) granule consisting of irregularly rounded clusters of bacteria bordered by Splendore-Hoeppli material and an acute inflammatory exudate.
    (Courtesy of Dr. George F. Gray, Jr.)
    The gross differential diagnosis includes peptic ulcer, lymphoma, and carcinoma. The histologic differential diagnosis includes primarily other infectious agents, particularly Nocardia . Unlike Nocardia , all actinomycetes are not acid-fast. Care should also be taken not to confuse actinomycosis with fungi, or other bacteria, that form clusters and chains but are not truly filamentous, such as Pseudomonas and E. coli .

    Whipple’s disease (Tropheryma whippelii).
    Whipple’s disease typically presents in middle-aged white men with chronic weight loss, arthritis, malabsorption, and lym-phadenopathy. Many patients also have significant neuropsychiatric manifestations. 73
    The small bowel is most often affected, although colonic and appendiceal involvement may be seen as well. Endoscopically, mucosal folds are thickened and coated with yellow-white plaques, often with surrounding erythema and friability. Histologically, the characteristic lesion results from massive infiltration of the lamina propria and submucosa with foamy macrophages ( Fig. 4-16A ). The infiltrate often blunts and distends villi. Involvement may be diffuse or patchy. There is usually no associated mononuclear inflammatory infiltrate, but varying numbers of neutrophils may be present. The lamina propria may contain small foci of fat, and overlying vacuolization of enterocytes may occur as well. 74

    FIGURE 4-16 Whipple’s disease. A, Villi are distended by an infiltrate of foamy macrophages. B, The Whipple bacillus stains intensely with periodic acid-Schiff.
    ( A and B courtesy of Dr. George F. Gray, Jr.)
    Whipple’s bacillus was identified as T. whippelii , an actinobacterium, 84 years after Whipple initially reported this disease. This bacillus is strongly PAS positive (see Fig. 4-16B ); electron microscopy and PCR assays may be diagnostic as well. The differential diagnosis includes, predominantly, M. avium-intracellulare infection. However, rarely, other intracellular organisms such as Histoplasma and Rhodo-coccus may simulate Whipple’s disease.

    Rhodococcus equi.
    These gram-positive coccobacilli may, occasionally, infect humans, particularly the immunocompromised. GI infection presents as chronic (often bloody) diarrhea and is generally a manifestation of systemic involvement. R. equi produces inflammatory polyps, sometimes with associated mesenteric adenitis. Histologically, polyps consist of organism-laden macrophages that pack the mucosa and submucosa, often with an associated granulomatous response. Organisms stain with PAS and Gram stains, and they may be partially acid-fast. The histologic features may mimic infection with M. avium-intracellulare or Whipple’s disease. 75

    Rocky Mountain spotted fever (Rickettsia rickettsii).
    This disease is transmitted by bites of the common wood or dog tick. Many patients have significant GI findings, including nausea, vomiting, diarrhea, pain, and GI bleeding. These manifestations may precede the rash. Involvement of every portion of the GI tract has been documented. 76 Typical histologic findings include vasculitis, often with accom-panying nonocclusive microthrombi, and hemorrhage. The inflammatory infiltrate is composed of mononuclear cells with occasional lymphocytes, macrophages, and neutrophils. Immunofluorescence staining demonstrates the organism, and serologic studies may also be of use.

    Malakoplakia.
    This rare disorder may affect any portion of the GI tract. It consists of soft, yellow plaques containing a dense histiocytic infiltrate with characteristic Michaelis-Gutmann bodies ( Fig. 4-17 ). The majority of cases are associated with colorectal adenocarcinoma or some other immunocompromising condition. Numerous bacteria have been associated with GI malakoplakia, including E. coli, Klebsiella, Yersinia , mycobacterial organisms, and R. equi .

    FIGURE 4-17 This colon resection shows multiple nodules of malakoplakia characterized by a macrophage infiltrate and numerous Michaelis-Gutmann bodies.
    (Courtesy of Dr. Joel K. Greenson.)

    Bacillary angiomatosis.
    These pyogenic granuloma-like lesions occur in immunocompromised patients and mimic Kaposi’s sarcoma. They are usually associated with Bartonella quintana .

    Helicobacter pylori and Helicobacter heilmannii.
    These bacteria are discussed in detail in Chapter 12 .

    Fungal Infections of the GI Tract
    The importance of fungal infections of the GI tract has increased as the numbers of patients with organ transplants, AIDS, and other immunodeficiency states have risen. GI fungal infections occur mainly in immunocompromised patients, but virtually all have been described in immunocompetent persons as well. Signs and symptoms of GI fungal infections are, in general, similar, regardless of the type of fungus, and they include diarrhea, vomiting, melena, frank GI bleeding, abdominal pain, and fever. Esophageal fungal infections usually present with odynophagia and dysphagia. Fungal infections of the GI tract are often a part of a disseminated disease process, but GI symptoms and signs may be the presenting manifestations.
    Other fungal infections that occasionally involve the GI tract, but are not discussed here, include Blastomycosis dermatitidis, Paracoccidioides brasiliensis (South American blastomycosis), and Fusarium .




    Candida species
    Candida is the most common infection of the esophagus, but it may infect any level of the GI tract. The GI tract is a major portal for disseminated candidiasis, as Candida often superinfects ulcers that develop from other causes. Candida albicana is most common, but Candida tropicalis and Candida (Torulopsis) glabrata may produce similar manifestations. 77
    Grossly, the esophagus typically contains white plaques that can be readily scraped off to reveal ulcerated mucosa underneath. The gross features of candidiasis in the remainder of the GI tract are variable and include ulceration, pseudomembrane formation, and inflammatory masses ( Fig. 4-18A ). If vascular invasion is prominent, the bowel may appear infarcted. 78 Involvement may be diffuse or segmental.

    FIGURE 4-18 A, Colonic candidiasis featuring yellow-white plaques with associated marked mucosal ulceration. B, Gomori’s methenamine silver staining shows the mixture of budding yeast and pseudohyphae typical of Candida species.
    A, (Courtesy of Dr. Cole Elliott.)
    The associated inflammatory response ranges from minimal (especially in immunocompromised patients) to marked with prominent neutrophilic infiltrates, abscess formation, erosion or ulceration, and necrosis. Granulomas are occasionally present as well. Fungi may invade any level of the gut wall. Invasion of mucosal and submucosal blood vessels is sometimes a prominent feature in invasive Candida infection. 77 , 78 C. albicans and C. tropicalis produce a mixture of budding yeast forms, hyphae, and pseudohyphae (see Fig. 4-18 ). C. glabrata features tiny budding yeast forms (similar to those of Histoplasma ) but does not produce hyphae or pseudohyphae. 79

    Aspergillus species
    Aspergillus infection of the GI tract occurs almost exclusively in immunocompromised patients and is much less frequently seen in the esophagus than is candidiasis. Gross findings are similar to those seen with Candida infection. 78 The majority of patients with aspergillosis have coexistent lung lesions.
    The characteristic histologic lesion of aspergillosis is a nodular infarction consisting of a zone of ischemic necrosis centered on blood vessels containing fungal organisms ( Figs. 4-19 and 4-20 ). Fungal hyphae often extend outward from the infarct, in parallel or radial arrays. The inflammatory response ranges from minimal to marked, with a prominent neutrophilic infiltrate, and granulomatous inflammation may develop as well. 79 Transmural infarction of the bowel wall is common. The typical hyphae of Aspergillus are septate, and they branch at acute angles.

    FIGURE 4-19 Typical “target lesion” of aspergillosis, shown in the stomach, consisting of hemorrhagic infarction and necrosis centered on a blood vessel.

    FIGURE 4-20 A, Ischemic necrosis of the mucosa and submucosa in a case of gastric aspergillosis. B, Aspergillus organisms fill and penetrate a vessel in the submucosa (Gomori’s methenamine silver).

    Mucormycosis and related zygomycoses.
    The histologic lesions of mucormycosis and related zygomycoses are remarkably similar to those seen in aspergillosis. In contrast to Aspergillus , these organisms have broad, ribbon-like, pauciseptate hyphae that branch randomly at various angles. 79 Ulcers are the most common gross manifestation, often large with rolled, irregular edges that may mimic malignancy. These fungi may also superinfect previously ulcerated tissues. Patients with diabetes, or with other causes of systemic acidosis, are at increased risk for developing zygomycosis. 80

    Histoplasmosis.
    Histoplasma capsulatum is endemic to the central United States but has been described in many nonendemic areas as well. GI involvement occurs in more than 80% of patients with disseminated infection. Patients often present initially with signs and symptoms of GI illness, but they do not always have concomitant pulmonary involvement. 81
    The ileum is the most common site, but any portion of the GI tract may be involved. Gross lesions range from normal to ulcers, nodules, and obstructive masses. Often, a combination of these lesions is present. Histologic findings include diffuse lymphohistiocytic infiltrates and nodules, usually involving the mucosa and submucosa, with associated ulceration ( Fig. 4-21 ). These lesions are usually located over Peyer’s patches. Discrete granulomas, and giant cells, are present in only a minority of cases. In immunocompromised patients, large numbers of organisms may be seen with virtually no tissue reaction. 81 Histoplasma organisms are small, ovoid, usually intracellular yeast forms with small buds at the more pointed pole.

    FIGURE 4-21 Numerous Histoplasma organisms are seen distending histiocytes in the lamina propria on this Gomori’s methenamine silver stain.
    (Courtesy of Dr. Patrick J. Dean.)

    Cryptococcus neoformans.
    This fungus is an unusual but important cause of GI infection. Virtually all patients with GI cryptococcosis have hematogenously disseminated disease with multisystem organ involvement, and most have associated pulmonary and meningeal disease. 82
    Grossly, cryptococcal infection may be located anywhere in the GI tract. Endoscopic lesions include nodules and ulcers, sometimes associated with a thick white exu-date. However, the mucosa is normal in many cases. 82
    Histologic features include typical round-to-oval yeast forms with narrow-based budding; and cryptococci may show considerable variation in size. Occasionally, they produce hyphae and pseudohyphae. Often a halo effect can be seen with H&E staining, representing the capsule of the organism. Both superficial and deep involvement may occur, and lymphatic involvement is not uncommon. The inflammatory reaction is variable and depends on the immune status of the host, ranging from a suppurative, necrotizing inflammatory reaction, often with granulomatous features ( Fig. 4-22A ), to virtually no reaction such as in anergic hosts. 79 , 82 The mucopolysaccharide capsule stains with alcian blue, mucicarmine (see Fig. 4-22B ), and colloidal iron; GMS stains are positive as well. Unfortunately, capsule-deficient cryptococci can pose a diagnostic challenge, but most have sufficient capsular material left to be seen with mucin stains. 79 , 82

    FIGURE 4-22 This case of gastric cryptococcosis features a granulomatous reaction with associated giant cells and acute inflammation. A, A halo effect can be seen around the organisms. B, The round to oval yeast forms have a mucopolysaccharide capsule that stains with mucicarmine.
    (Courtesy of Dr. Kay Washington.)

    Pneumocystis carinii .
    Although the life cycle of this organism more closely resembles that of a protozoan, there is convincing molecular evidence indicating that P. carinii has greater homology with fungi. P. carinii pneumonia is a major cause of morbidity in the AIDS population, and extrapulmonary (including GI) involvement is not uncommon. 83
    Endoscopically, P. carinii infection resembles a nonspecific, often erosive, esophagogastritis or colitis, sometimes with small polypoid nodules. Microscopically, granular, foamy eosinophilic casts common to pulmonary infection may be seen in mucosal vessels or in the lamina propria ( Fig. 4-23 ). 83 As in the lung, a wide variety of inflammatory responses may occur, including granulomatous inflammation, prominent macrophage infiltrates, and necrosis.

    FIGURE 4-23 A, Small bowel resection showing the characteristic foamy casts of Pneumocystis carinii in the submucosa. B, Gomori’s methenamine silver stain highlights numerous cyst forms with central enhanced staining.
    (Courtesy of Dr. Henry Appelman.)
    The fungi can usually be correctly identified in tissue sections on the basis of morphologic criteria ( Table 4-4 ). Although organisms may be identifiable on H&E sections in heavy infections, GMS and PAS stains remain valuable diagnostic aids. However, culture is ultimately the gold standard for speciation. In fact, antifungal therapy may vary according to the specific type of fungus involved. Furthermore, fungi exposed to antifungal therapy or ambient air may produce bizarre and unusual forms. Helpful diagnostic aids, in addition to culture, include serologic assays, antigen tests, and immunohistochemistry.

    TABLE 4-4 Morphologic Features of Fungi Seen in the GI Tract
    The differential diagnosis of fungal infections includes other infectious processes, and occasionally Crohn’s dis-ease, ulcerative colitis, sarcoidosis, and ischemic colitis.

    Parasitic Infections of the GI Tract

    PROTOZOAL INFECTIONS
    Protozoa are prevalent pathogens in tropical and subtropical countries, but they cause some of the most common intestinal infections in North America and Europe as well. Immigration, increasing numbers of immunocompromised patients, use of institutional child-care facilities, and the development of improved diagnostic techniques have enhanced our understanding and recognition of these protozoa. 84 , 85 Many protozoal illnesses are diagnosed by examination of stool samples, but they are also important to the surgical pathologist.

    Entamoeba histolytica
    Approximately 10% of the world’s population is infected with the E. histolytica parasite, predominantly in tropical and subtropical regions. Male homosexuals in Western countries also commonly harbor this pathogen. Although some patients suffer a severe, dysentery-like, fulminant colitis, many others are asymptomatic or show only vague GI symptoms. 86 Complications include bleeding and dissemination to other sites, particularly the liver. Rarely, large inflammatory masses (amebomas) may form.
    Grossly, small ulcers are initially seen, but these may coalesce to form large, irregular, geographic or serpiginous ulcers. Ulcers may undermine adjacent mucosa to produce classic “flask-shaped” lesions ( Fig. 4-24A ), and there may be associated inflammation or inflammatory polyps as well. The intervening mucosa is often normal. The cecum is the most common site of involvement, but any portion of the large bowel or appendix may be infected. Fulminant colitis, resembling ulcerative colitis; pseudomembranous colitis, resembling that caused by C. difficile ; and toxic megacolon have all been described in association with E. histolytica infection. 87 Colonoscopy may be normal in asymptomatic patients or in those with mild disease. 86

    FIGURE 4-24 A, This entamebic ulcer is deep and flask-shaped, undermining adjacent normal mucosa. B, Entamoeba histolytica in the inflammatory exudates, containing ingested erythrocytes.
    Histologically, early lesions show a mild neutrophilic infiltrate. In more advanced disease, ulcers are often deep, extending into the submucosa, with undermining of adjacent normal mucosa (see Fig. 4-24A ). There is usually abundant necroinflammatory debris. The organisms are generally found in the purulent material. Invasive amebae are also occasionally present in the bowel wall. Adjacent mucosa is usually normal but may show gland distortion and inflammation. The organisms may be few in number. They resemble macrophages, with foamy cytoplasm and round, eccentric nuclei. The presence of ingested red blood cells (see Fig. 4-24B ) is pathognomonic of E. histolytica . 87 In asymptomatic patients or those with only mild symptoms, histologic changes may range from normal to a heavy mixed inflammatory infiltrate. Organisms may be particularly difficult (if not impossible) to detect in these patients. Invasive amebiasis does not generally occur in patients who have only mild, or absent, symptoms. 86
    Distinction of amebae from macrophages in inflammatory exudates may be difficult. However, amebae are trichrome and PAS positive. In addition, their nuclei are usually more rounded and paler, and have a more open nuclear chromatin pattern (see Fig. 4-24B ). Macrophages stain with alpha-1-antitrypsin and chymotrypsin, whereas amebae do not. The differential diagnosis of amebiasis also includes Crohn’s disease, ulcerative colitis, and other types of infectious colitis. Although some features of amebiasis may mimic idiopathic inflammatory bowel disease, many of the other diagnostic features of Crohn’s disease (e.g., transmural lymphoid aggregates, mural fibrosis, granulomas, neural hyperplasia) and ulcerative colitis (e.g., basal lymphoplasmacytosis, diffuse architectural distortion, pancolitis) are not typically present in amebiasis.

    Flagellates


    Giardia lamblia .
    Giardiasis is the leading GI protozoal disease in the United States. The overall prevalence rate is 2% to 7%, but it is up to 35% in day care centers. Patients often present with explosive, foul-smelling, watery diarrhea, abdominal pain and distension, nausea, vomiting, malabsorption, and weight loss. The infection may resolve spontaneously but often persists for weeks or months if left untreated. 88 , 89 The cyst, which is the infective form, is extremely hardy, is chlorine resistant, and may survive in water for several months. However, the mechanism by which these organisms cause GI illness is poorly understood.
    Endoscopic examination is generally unremarkable, and small intestinal biopsies are often normal in appearance. However, rarely, biopsies may show mild to moderate villous blunting and increased lamina propria inflammatory cells including neutrophils, plasma cells, and lymphocytes. Giardia trophozoites resemble pears that are cut lengthwise and contain two ovoid nuclei with a central karyosome at the luminal surface ( Fig. 4-25 ). 88 Tissue invasion is not a feature of this infection. Although Giardia is characteristically described as a small bowel inhabitant, colonization of the stomach and colon has also been reported. 88 Absence or a marked decrease of plasma cells in the lamina propria in a patient with giardiasis should alert the pathologist to the possibility of an underlying immunodeficiency disorder (see Chapter 5 ).

    FIGURE 4-25 Duodenal mucosa with numerous Giardia trophozoites at the luminal surface, without significant mucosal inflammation.
    (Courtesy of Dr. Rodger Haggitt.)

    Leishmania donovani and related species
    Leishmaniasis is endemic in over 80 countries in Africa, Asia, South and Central America, and Europe. 90 GI signs and symptoms include fever, abdominal pain, diarrhea, dysphagia, malabsorption, and weight loss. In fact, GI involvement is generally part of widely disseminated disease. Leishmaniae may be found at any level of the alimentary tract. The spectrum of endoscopic findings includes normal mucosa, focal ulceration, and changes of enteritis. 91
    Histologically, amastigote-containing macrophages are present in the lamina propria. In large numbers, macrophages may distend and blunt intestinal villi. An associated inflammatory infiltrate is normally absent. Amastigotes are round to oval, tiny organisms with a nucleus and kinetoplast in a “double-knot” configuration; they do not have typical flagella. They are highlighted by Giemsa staining. The differential diagnosis primarily includes other para-sitic and fungal infections. Leishmania may be confused with organisms such as Histoplasma and Trypanosoma cruzi . Leishmaniae are GMS negative, and they affect the lamina propria rather than the myenteric plexus. 90 , 91 Serologic studies and immunohistochemistry may aid in the diagnosis.

    Trypanosoma cruzi (Chagas’ disease)
    Chagas’ disease is one of the most serious public health problems in South America. Parasitic involvement of the enteric nervous system is common in this disease, and an achalasia-like megaesophagus and megacolon are the most frequent manifestations. 92 Histologically, there is inflammatory destruction of the myenteric plexus, with loss of up to 95% of neurons. However, the parasite is rarely visible in myenteric plexuses. 93 The differential diagnosis includes idiopathic primary achalasia as well as other visceral neuropathies. However, many of these latter disorders lack inflammation of the myenteric plexus. Unlike primary achalasia, Chagas’ disease usually involves other organ systems (especially the heart) or other areas of the GI tract. Nevertheless, often the differential is resolved only clinically.

    Ciliates


    Balantidium coli .
    This ciliate may produce a spectrum of clinical and pathologic changes similar to those produced by E. histolytica . B. coli cells are distinguished from amebae by their larger size, kidney bean-shaped nucleus, and, of course, the presence of cilia ( Fig. 4-26 ). 94

    FIGURE 4-26 Balantidium coli in the bowel wall. Note the large size, the kidney bean-shaped nucleus, and cilia.
    (Courtesy of Dr. David Owen.)

    Coccidians
    Coccidial infection is particularly important when considering the differential diagnosis of diarrhea in patients with AIDS, but it is also seen in healthy persons, including infants and children, in developing countries. 95 Transmission is normally via the fecal-oral route, either directly or via contaminated food and water. 96 All coccidians, except microsporidia (which is thought to be limited to immunocompromised patients) can cause diarrhea (often prolonged) in healthy patients, especially infants and children, travelers, and individuals who are institutionalized. Diarrhea may be accompanied by fever, weight loss, abdominal pain, and malaise. Stool does not usually contain red blood cells or leukocytes. In immunocompetent persons, infection is usually self-limited, but immunocompromised patients are at risk for chronic, severe diarrhea, with malabsorption, dehydration, and death. 96 Many coccidial infections are asymptomatic. Endoscopic findings are usually absent or mild and include mild erythema, mucosal granularity, mucosal atrophy, and superficial erosions.
    Although electron microscopy was once considered the gold standard for diagnosis, it is expensive and not widely used. Examination of stool specimens may be very helpful (particularly with special stains), but analysis of mucosal biopsy specimens is more sensitive. Enzyme-linked immunosorbent assay (ELISA) techniques, immunohistochemistry, and PCR studies are also available for diagnosis of these parasites. 95


    Cryptosporidium parvum .
    This organism is most common in the small bowel, but it may infect any segment of the GI tract. The characteristic biopsy appearance is that of a 2- to 5-μm basophilic spherical body that protrudes from the apex of the enterocyte ( Fig. 4-27 ). 97 The organisms are found in the crypts or in the surface epithelium. Associated mucosal changes include villous atrophy (occasionally severe), crypt hyperplasia, mixed inflammation, and crypt abscesses. Giemsa stain may aid in diagnosis, and immunohistochemical antibodies are available. Cryptosporidium may be distinguished from most other coccidians by their size and unique apical location. Although Cyclospora is similar in appearance, it is much larger (8 to 10 μm).

    FIGURE 4-27 Cryptosporidium parvum . The 2- to 5-mμ basophilic spherical bodies protrude from the apex of the enterocytes.
    (Courtesy of Drs. Mary Bronner and Rodger Haggitt.)

    Cyclospora cayetanensis .
    This organism most commonly infects the small bowel. Histologic changes in mucosal biopsies are similar to other coccidians. 98 This 8- to 10-μm parasite is normally located in enterocytes but, like Cryptosporidium , can be present in the cell surface. There are few detailed light microscopic descriptions of this parasite, and there is disagreement about their features in tissue sections. They may be either crescent or ovoid in shape, and they are sometimes located in a parasitophorous vacuole. 99 The organisms are acid-fast with modified Kinyoun or similar stains, and they are positive with auramine. However, they are GMS negative. The major differential diagnosis is with Cryptosporidium , but Cyclospora organisms are much larger ( Fig. 4-28 ), and they exhibit autofluorescence under epifluorescent light. 98 When crescent-shaped, the organisms may be confused with Isospora , which is generally larger.

    FIGURE 4-28 This patient with AIDS has both Cryptosporidium and Cyclospora infections. Cryptosporidia are 2 to 5 mμ in size and are located at the apex of the enterocytes (arrow) . The round to ovoid Cyclospora is similar in appearance but much larger (8 to 10 mμ).

    Isospora belli and related species.
    The small bowel is the most common site of Isospora infection, but the colon may also be involved. Isospora may also disseminate widely. Histologic changes include villous blunting, which may be severe, crypt hyperplasia, mixed inflammation, often with prominent eosinophils, and, in chronic infections, fibrosis of the lamina propria. Intraepithelial inclusions, both perinuclear and subnuclear, may be present at all stages of infection. Rarely, organisms are also present in the lamina propria or in macrophages. 100 , 101 When motile, these parasites are large and banana-shaped, but ( Fig. 4-29 ) as trophozoites they are round with a prominent nucleus. At some stages of infection, the parasites are surrounded by a parasitophorous vacuole. GMS and Giemsa stains are useful to highlight the organism. Isospora species are PAS positive but may be easily confused with goblet cells. They are differentiated from other coccidia by their large size and intracellular location. Also, patients with isosporiasis are more likely to have peripheral eosinophilia.

    FIGURE 4-29 Isospora belli. Banana-shaped intraepithelial inclusions (arrow) are seen in apical enterocytes.
    (Courtesy of Dr. Audrey Lazenby.)

    Microsporidia .
    Enterocytozoon bieneusi and Encephalitozoon intestinalis are the most common human pathogens in this group. They are usually present in the small bowel, but any level of the GI tract may be affected. Microsporidia are difficult to detect in H&E-stained sections. The histologic features include patchy villous blunting, vacuolization of the surface epithelium, and patchy lymphoplasmacytic infiltrates in the lamina propria. 102 , 103 A modified trichrome stain can aid greatly in the diagnosis ( Fig. 4-30 ), and the organisms also stain with Warthin-Starry and Brown-Brenn stains. Occasionally, microsporidial organisms in biopsy specimens demonstrate birefringence under polarized light because of their chitin-rich internal polar filament. However, this method is unreliable because spore birefringence is unpredictable and because microscopes and light sources vary.

    FIGURE 4-30 Tiny microsporidial organisms in enterocytes (modified trichrome).

    Toxoplasma gondii .
    GI toxoplasmosis is primarily a disease of immunocompromised hosts. Ulcers have been described and organisms are usually located in the ulcer base. Both crescent-shaped tachyzoites and tissue cysts containing bradyzoites may be present in tissue sections. Immunohistochemistry and PCR assays, as well as serologic tests, are useful diagnostic aids. 104

    Miscellaneous Protozoal Infections
    Dientamoeba fragilis is an ameba of low pathogenicity that occasionally causes diarrhea in affected patients. 105 , 106 A variety of other amebae are also, occasionally, associated with mild GI disease, including Entamoeba hartmanni, Entamoeba coli, Entamoeba polecki, Iodamoeba buetschlii , and Endolimax nana . Blastocystis hominis , another protozoan of low pathogenicity, may cause enteric disease when present in large numbers. 107 , 108 However, these organisms are only rarely seen in tissue sections. Indeed, when protozoa of low pathogenicity are identified in tissue sections, symptomatic patients should be evaluated for alternative causes of GI disease.

    HELMINTHIC INFECTIONS
    Although the most common method of diagnosing GI helminth infections is examination of stool for ova and parasites, these organisms are occasionally detected in biopsy or resection specimens. Hookworms, roundworms (both Ascaris and Enterobius ), and whipworms are the most common helminthic infections in man. 109 GI helminths have a worldwide distribution, but their clinical importance varies with the geographic region. They are more often a cause of serious disease in nations with deficient sanitation systems, poor socioeconomic status, and hot, humid climates. However, helminthic infections are seen in immigrants and in patients who travel to endemic areas, and they are an increasingly important problem in immunocompromised hosts. Nutritional problems caused by helminths can be severe and even life-threatening, especially in children. 109 The most common site of anatomic infection is the small bowel, although the stomach and large bowel may also be involved. 110

    Nematodes


    Enterobius vermicularis .
    Pinworms are one of the most common human parasites. They have a worldwide distribution but are more common in cold or temperate climates and in developed countries. They are extremely common in the United States and northwestern Europe. The infective egg resides in dust and soil, and transmission is believed to be by the fecal-oral route. The worms live and reproduce in the ileum, cecum, proximal colon, and appendix, and then the female migrates to the anus to lay eggs and die. The eggs and worms produce symptoms of pruritus ani. Although many infections are asymptomatic, appendicitis, vulvovaginitis, colitis, and peritoneal involvement have all been described. 110 , 111 Heavy infections may cause abdominal pain, nausea, and vomiting.
    The etiologic role of Enterobius in appendicitis and colitis is controversial. Although pinworms are detected in approximately 0.6% to 13% of resected appendices, their ability to cause mucosal damage has been a subject of debate. 112 Some believe that the lack of inflammation surrounding invasive pinworms indicates that the organism invades only after the appendix has been removed, thus to escape the decrease in oxygen tension. 111 However, Enterobius organisms are, in fact, capable of mucosal invasion, 111 and, like fecaliths, they can obstruct the appendiceal lumen and cause inflammation.
    The worms are 2 to 5 mm in length and thus may be seen with the naked eye ( Fig. 4-31 ). Although the mucosa of the GI tract often appears normal on examination, hemorrhage and ulceration may occur with tissue invasion.

    FIGURE 4-31 A, Appendix containing numerous pinworms. B, Section of worm showing cuticle and numerous eggs characteristic of Enterobius vermicularis .
    A, (Courtesy of Dr. George F. Gray, Jr.)
    Invasive pinworms incite little or no inflammatory reaction, but an inflammatory infiltrate composed of neutrophils and eosinophils may occur uncommonly. Granulomas, sometimes with necrosis, may develop as a reaction to degenerating worms or eggs. These have been described in the omentum and peritoneum, as well as in the appendix, anus, and colon in rare cases. 111 Primary Enterobius infection may be difficult to distinguish from infection complicating a preexisting inflammatory disorder, such as an inflamed anal fissure.

    Ascaris lumbricoides (roundworm)
    Ascaris is one of the most common parasites in humans. It has a worldwide distribution but is most common in tropical regions of the world. The worms are ingested from soil contami-nated with feces. Clinical findings are variable and include appendicitis, massive infection with obstruction and perforation, childhood growth retardation, and pancreaticobiliary obstruction. Giant worms (up to 20 cm in length) may be identified endoscopically or in resection specimens ( Fig. 4-32 ). Tissue damage occurs primarily at the anatomic sites of attachment. 110

    FIGURE 4-32 Ascaris atop colon cancer at resection.
    (Courtesy of Dr. George F. Gray, Jr.)

    Ancylostomiasis (hookworm).
    Hookworm ( Necator amer-icanus and Ancylostoma duodenale ) is a common parasite in all tropical and subtropical countries. The worms attach to the intestinal wall and withdraw blood from villous capillaries, which results in anemia. Other clinical symptoms include abdominal pain, diarrhea, hypoproteinemia, and cough with eosinophilia when the worms migrate. 109 Any level of the GI tract may be involved. Endoscopically, the worms (which measure about 1 cm in length) are visible to the naked eye. Histologic changes are often minimal but may include villous blunting and eosinophilic infiltration. 110 Pieces of worm are occasionally detected in biopsy specimens.

    Trichuris trichiura (whipworm)
    Whipworm is a soil helminth with a worldwide distribution. Although most infections are asymptomatic, some patients develop diarrhea, GI bleeding, malabsorption, anemia, and appendicitis. An ulcerative inflammatory process similar to Crohn’s disease and rectal prolapse have also been described. 109 , 110 The worms live in the small and large intestines, primarily the right colon and ileum. They may cause mucosal hemorrhage and ulceration. The worms are 3 to 5 mm in length and have a characteristic whiplike tail. They may be seen endoscopically. Histologically, the worms thread their anterior end under epithelium, which may produce enterocyte atrophy and an associated mixed inflammatory infiltrate. Crypt abscesses may also be present. 110 , 113

    Strongyloides stercoralis.
    S. stercoralis is a nematode with a worldwide distribution. In the United States, it is endemic in southeastern urban areas with large immigrant populations, and in mental institutions. Strongy-loides occurs primarily in adults, many of whom are hospitalized, suffer from chronic illnesses, or are immunocompromised. 114 , 115 Steroids and human T lymphotropic virus type-1 infection are also associated with strongyloidiasis. 116 Symptoms and signs include diarrhea, abdominal pain and tenderness, nausea, vomiting, weight loss, malabsorption, and GI bleeding. Mesenteric lymphade-nopathy may also occur. 117 GI manifestations may be accompanied by rash, eosinophilia, urticaria, pruritus, and pulmonary symptoms. 110 , 114 However, many patients are asymptomatic.
    The S. stercoralis worm penetrates the skin, enters the venous system, travels to the lungs, and then migrates up the respiratory tree and down the esophagus to eventually reach the small intestine. The female lives and lays eggs in the small intestine, thus perpetuating the organism’s life cycle. This autoinfective capability allows the organism to reside in the host and produce illness for a long time, upward of 30 years. In addition, widespread dissemination may occur in immunocompromised patients, causing severe and even fatal illness. 110 , 114
    Lesions may be seen in the stomach, as well as in the small and large intestine. Endoscopic findings include hypertrophic mucosal folds and ulcers. However, features typical of pseudomembranous colitis have also been reported. Histologically, both adult worms and larvae may be found in the crypts, but they may be difficult to detect. Adult worms typically have sharply pointed tails that may be curved ( Fig. 4-33 ). Other histologic features include villous blunting, ulcers (which may be fissuring), edema, and a dense eosinophilic and neutrophilic infiltrate. Granulomas are occasionally present as well. 110 , 114

    FIGURE 4-33 Strongyloides stercoralis infection in the small bowel. Typical worms with curved, sharply pointed tails are present in crypts and lamina propria, accompanied by a neutrophilic infiltrate.
    (Courtesy of Dr. James A. Waldron.)

    Anisakis simplex (anisakiasis) and related species.
    These nematodes parasitize fish and sea mammals, so humans ingest them by eating raw or pickled fish. The most common clinical manifestations are those of acute gastric anisakiasis, characterized by epigastric pain, nausea, and vomiting within 12 hours of ingestion of parasitized food. The symptoms may mimic peptic ulcer disease. 110 , 118 The allergenic potential of Anisakis species has also been recognized, and some patients with gastroallergic anisakiasis manifest both GI and hypersensitivity symptoms such as urticaria, angioedema, eosinophilia, and anaphylaxis. 118
    The stomach is the most frequent site of involvement, although the small bowel, colon, and appendix may also be involved. Endoscopic findings include mucosal edema, hemorrhage, erosions, ulcers, and thickened mucosal folds. Occasionally, larvae may be identified, and removed, endoscopically. Histologic findings include an inflammatory infiltrate rich in eosinophils, which may extend transmurally into serosal and mesenteric tissues ( Fig. 4-34 ). Eosinophilic microabscesses, granulomas, and giant cells may also develop. Inflammatory changes usually surround worms. Larvae (from 0.5 to 3.0 cm in length) are occasionally seen in tissue sections, but very rarely in stool samples. 119 , 120

    FIGURE 4-34 Gastric anisakiasis. Large Anisakis worm in the center of a submucosal eosinophilic and neutrophilic abscess.
    (Courtesy of Dr. David Owen.)

    Capillaria species (intestinal capillariasis)
    Capillaria infection is most common in the Philippines, Thailand, and other parts of Asia, although cases have been reported in nonendemic areas. The worms are ingested by eating infected raw fish. Clinical signs and symptoms include malabsorption accompanied by diarrhea and abdominal pain. The worms measure 2 to 4 cm in length and are most commonly found in the crypts of the small bowel, although they may also invade the lamina propria. Although there is usually an absence of an inflammatory reaction, villous blunting, mucosal sloughing, and mild inflammatory changes have been described. 109 , 121

    Trematodes


    Schistosomiasis.
    All Schistosoma species have the capability to cause significant GI disease. Patients generally present with diarrhea (often bloody), accompanied by anemia, weight loss, and protein-losing enteropathy. More dramatic GI presentations have also been described, such as profound dysentery-like illness, obstruction, perforation, intussusception, rectal prolapse, fistulae, and perianal abscesses. 110 , 122 Any level of the GI tract may be affected. Endoscopically, Schistosoma can be seen to cause inflammatory polyposis (particularly in the distal colon) with associated mucosal granularity, friability, punctate ulcers, and hemorrhages. Histologically, inflammatory polyps and mucosal ulcers, with associated granulomatous inflammation and an eosinophilic infiltrate, are typical. Eggs may be detected in histologic specimens and are sometimes calcified. 110 , 123 In fact, worms are occasionally seen in veins ( Fig. 4-35 ).

    FIGURE 4-35 A and B, Schistosoma worm in a vein in the submucosa of the small bowel. C, Calcified eggs in the appendiceal wall in a case of remote schistosomiasis.
    (Courtesy of Dr. Joe Misdraji.)

    Intestinal flukes ( Fasciolopsis buski and related species).
    Over 50 species of intestinal flukes have been described in humans, but most clinically significant infections are caused by F. buski, Echinostoma species, and Heterophyes species. 124 - 126 These flukes are most common in Asia. They are ingested with aquatic plants, and after maturation, the adult worm attaches to the proximal small bowel mucosa. 110 , 124 The majority of infections are asymptomatic. Symptoms, which usually occur as a result of heavy infection, include diarrhea, often alternating with constipation; abdominal pain; anorexia; nausea and vomiting; and malabsorption. Ileus, obstruction, and GI bleeding have also been described. The large worms (2 to 7.5 cm) may be seen endoscopically, and mucosal ulceration, inflammation, and abscess formation may occur at sites of tissue attachment.

    Cestodes
    Taenia saginata (beef tapeworm), Taenia solium (pork tapeworm), and Hymenolepis nana (dwarf tapeworm) may occasionally cause GI disease. Diphyllobothrium latum (fish tapeworm) is a rare cause of vitamin B 12 deficiency. 110 , 120

    Other Helminthic Infections
    The Central American nematode, Angiostrongylus costaricensis may cause dramatic, even fatal, ileocecal infection characterized by the presence of large obstructive inflammatory masses with perforation and mesenteric vessel thrombosis. 110 Trichinella spiralis is a rare cause of diarrhea. 110 Esophagostomiasis, a parasitic disease generally seen in nonhuman primates, may form deep inflammatory masses, predominantly in the right colon and appendix. 110
    The differential diagnosis of helminthic infections usually involves differentiation between the various types of worms. However, other entities to be considered include causes of ulcerative inflammation, eosinophilic infiltration, and granulomatous inflammation, such as tuberculosis, amebiasis, allergic enteritis, and Crohn’s disease.

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    CHAPTER 5 Manifestations of Immunodeficiency in the GI Tract

    ELIZABETH I. HARRIS, KAY. WASHINGTON

    Primary Disorders of Immune Deficiency
    Humoral Immunodeficiencies
    Combined Cellular and Humoral Immunodeficiencies
    Other Primary Immunodeficiencies
    Graft-versus-Host Disease
    Acute Graft-versus-Host Disease
    Chronic Graft-versus-Host Disease
    Neutropenic Enterocolitis
    The GI Tract in HIV Infection

    Primary Disorders of Immune Deficiency
    Many of the primary disorders of immune deficiency ( Table 5-1 ) are associated with GI pathology. Manifestations of immune deficiency in the GI tract can be broadly divided into three categories: (1) increased susceptibility to infection, (2) idiopathic chronic inflammatory conditions, and (3) increased risk for neoplasia. Although many GI disorders are infectious ( Table 5-2 ), chronic inflammatory conditions resembling celiac disease and inflammatory bowel disease ( Table 5-3 ) are seen in patients with various types of antibody deficiencies. Most of these disorders are probably the result of the inability of “dysfunctional” mononuclear cells to suppress deleterious immune responses. All patients with primary immune deficiencies are also at increased risk for neoplasia ( Table 5-4 ), most commonly non-Hodgkin’s lymphoma. In fact, the GI tract is often the primary site of involvement. 1 - 3 In addition to an increased risk for lymphoma, some of the primary immune deficiencies are associated with an increased risk for gastric adenocarcinoma 4 and colorectal carcinoma. 5
    TABLE 5-1 Molecular Basis of Primary Immunodeficiency Disorders * Disease Proposed Cause IgA deficiency Impaired IgA synthesis; mutation in TNFRSF13B in some cases Common variable immunodeficiency Impaired B-cell maturation; mutations in TNFRSF13B in 10%-15% X-linked agammaglobulinemia Mutation in Btk results in absence of Btk in B cells Hyper-IgM syndrome Absence of CD40 ligand on T cells Hyper-IgE syndrome Defect on chromosome 4; exact defect unknown Severe combined immunodeficiency Multiple defects; most common results from defect in common γ chain; others include adenosine deaminase deficiency, purine nucleoside deficiency, and T-cell receptor deficiencies Omenn’s syndrome Missense mutation in Rag 1, Rag 2 DiGeorge syndrome Thymic hypoplasia; deletion in chromosome 22q11.2 Chronic mucocutaneous candidiasis Heterogeneous disorder; mutation in AIRE gene in some * Wiskott-Aldrich syndrome Mutation in WASP gene involved in cell trafficking and motility Chronic granulomatous disease Mutation in gene for component of NADPH oxidase
    * From Tzung SP, Hackman RC, Hockenbery DM, et al: Lymphocytic gastritis resembling graft-vs.-host disease following autologous hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 4:43-48, 1998. NADPH, nicotinamide adenine dinucleotide phosphate.
    TABLE 5-2 GI Infections in Primary Immunodeficiency Disease GI Infections, Infectious Agents IgA deficiency Ciardia intestinalis, strongyloidiasis Common variable immunodeficiency G. intestinalis, Cryptosporidium, cytomegalovirus X-linked agammaglobulinemia G. intestinalis, Cryptosporidium, Salmonella , Campylobacter , rotavirus, coxsackievirus, poliovirus Hyper-IgM syndrome G. intestinalis, Cryptosporidium, Entamoeba histolytica, Salmonella , Histoplasma capsulatum Severe combined immunodeficiency Candida , Salmonella and other bacterial pathogens, cytomegalovirus, rotavirus, Epstein-Barr virus DiGeorge syndrome Candida Chronic mucocutaneous candidiasis Candida , H. capsulatum
    TABLE 5-3 Inflammatory GI Lesions in Primary Immunodeficiency Disease Manifestation IgA deficiency
    Celiac disease
    Food allergies
    Crohn’s disease–like lesion
    Nodular lymphoid hyperplasia Common variable immunodeficiency
    Multifocal atrophic gastritis ± intestinal metaplasia
    Villous atrophy
    Nodular lymphoid hyperplasia
    Crohn’s disease–like lesion
    Granulomatous enteropathy
    Colitis (ulcerative colitis–like; lymphocytic colitis) X-linked agammaglobulinemia
    Crohn’s disease–like lesion
    Perianal fistula and perianal abscess Hyper-IgM syndrome
    Nodular lymphoid hyperplasia
    Oral and perianal ulcers Severe combined immunodeficiency
    Graft-versus-host disease–like lesion, small bowel and colon
    Esophageal reflux Omenn’s syndrome Graft-versus-host disease–like lesion, small bowel and colon Chronic mucocutaneous candidiasis Atrophic gastritis Wiskott-Aldrich syndrome Crohn’s disease–like lesion involving colon Chronic granulomatous disease
    Esophageal and gastric outlet obstruction; Crohn’s disease–like lesion in small bowel; colitis (ulcerative colitis–like and Crohn’s disease–like)
    Pigmented macrophages
    TABLE 5-4 Malignancies Involving the GI Tract in Primary Immunodeficiency Disease GI Malignancy IgA deficiency
    Lymphoma
    Gastric adenocarcinoma Common variable immunodeficiency
    Gastric adenocarcinoma
    B-cell lymphoma, involving small bowel
    Adenocarcinoma of the colon, ± neuroendocrine features X-linked agammaglobulinemia
    Non-Hodgkin’s lymphoma
    Gastric adenocarcinoma
    Colorectal adenocarcinoma Hyper IgM syndrome
    Plasma cell proliferation
    Colorectal carcinoma Wiskott-Aldrich syndrome GI lymphoma Ataxia-telangiectasia Gastric adenocarcinoma

    HUMORAL IMMUNODEFICIENCIES

    Selective IgA Deficiency
    Selective IgA deficiency, defined as a serum IgA concentration of less than 50μg/mL, is the most common type of primary immunodeficiency, occurring in 1 in 600 individuals of northern European ancestry. 6 This disorder is 20 times more common in white Americans than in African Americans. 6 Defects in antibody production in patients with IgA deficiency represent a continuum with those seen in common variable immunodeficiency (CVID). In fact, 20% to 30% of IgA-deficient patients also have deficits in subclasses of IgG antibodies. Recently, mutations in the gene TNFRSF13B have been identified and shown to be associated with IgA deficiency. 7 - 9 This gene encodes a member of the tumor necrosis factor (TNF)-receptor superfamily, a transmembrane activator and calcium-modulator and cyclophilin-ligand interactor (TACI), which mediates isotype switching in B lymphocytes. Clinical manifestations of IgA deficiency range from absence of symptoms to multiple recurrent infections, generally involving mucosal surfaces; autoimmune disorders; allergic diseases; and malignancy. The clinical manifestations of IgA deficiency are typically milder than those seen in patients with CVID. Recurrent upper and lower respiratory tract infections are common in both disorders, and GI manifestations of IgA deficiency are similar to those associated with CVID. Infections are less common than might be expected (possibly because of compensation for lack of mucosal IgA by transport of IgM across the mucosa into the gut lumen) but include acute diarrheal illnesses due to bacterial enterocolitis, and chronic diarrhea due to persistent Giardia intestinalis infection. Chronic strongyloidia-sis has also been reported. 10
    Susceptibility to insulin-dependent diabetes mellitus and celiac disease may be inherited together with IgA deficiency; all three conditions are linked to particular major histocompatibility haplotypes and probably represent genetically linked susceptibilities in certain populations. The prevalence of celiac disease, the most common noninfectious GI complication of IgA deficiency, is 7.7% in children with IgA deficiency, compared with 1 in 500 in the general population. 11 Antigliadin IgA and endomysial IgA antibodies cannot be used as screening tools in this population. A spruelike illness characterized by chronic diarrhea with villous atrophy that does not respond to a gluten-free diet may occur in patients with IgA deficiency, and similarly it may occur in patients with CVID. The morphology of celiac disease that develops in the setting of IgA deficiency is similar to that in immunocompetent patients. Pernicious anemia complicating chronic atrophic autoimmune gastritis is associated with IgA deficiency more commonly than with CVID. As with other B-cell disorders, the incidence of Crohn’s disease and gastric adenocarcinoma appears to be increased in IgA deficiency. 12

    Common Variable Immunodeficiency
    Common variable immunodeficiency is not a common disorder despite its name. However, it is probably the most common symptomatic type of primary immunodeficiency. Clinical and immunologic features differ, but most patients present with recurrent bacterial infections, usually involving the upper and lower respiratory tract, which may lead to chronic lung disease and bronchiectasis. Patients may present at any age, from infancy to late adult life, and CVID affects males and females equally. Autoimmune manifes-tations, such as thyroid dysfunction, pernicious anemia, autoimmune hemolytic anemia, autoimmune thrombocytopenia, and rheumatoid arthritis, are common. Granulomatous involvement of skin and visceral organs mimicking sarcoidosis may also occur. 13 , 14 Chronic GI disorders resulting in malabsorption and weight loss occur in about 20% of patients with CVID.
    CVID is characterized immunologically by hypogammaglobulinemia involving multiple antibody classes. T-cell abnormalities are common; below-normal proliferative responses to mitogens are detected in 40% of patients. A relative lack of CD4 T cells is seen in 20%. 13 The common abnormality shared by IgA deficiency and CVID is failure of terminal maturation of B lymphocytes into plasma cells, which results in production of various immunoglobulin subtypes. A diagnosis of primary B-cell defect is favored in many patients, but in others, defective antigen responsiveness in T helper cells may be the underlying basis for the disorder. 15
    A genetic basis for CVID has long been suspected because of the observation that familial inheritance of CVID occurs in 20% of cases 16 and CVID and IgA deficiency tend to occur among members of the same family; individual family members may gradually convert from one disorder to the other. In multiple-case families, CVID is often present in parents, with IgA deficiency occurring in the offspring, consistent with the hypothesis that CVID may develop later in life as a more severe manifestation of a common defect involving immunoglobulin class switching. Studies of isotype switching led to the discovery of the gene TNFRSF13B , which encodes TACI. This gene is mutated in approximately 10% to 15% of patients with CVID and 5% of patients with IgA deficiency. 17 As mentioned earlier, TACI, a member of the TNF-receptor family, mediates isotype switching in B lymphocytes. TACI has also been shown to induce apoptosis in B cells, and this may be the basis for the susceptibility of patients with TACI mutations for autoimmune and lymphoproliferative disorders. 17
    Patients with CVID are at particular risk for chronic inflammatory disorders and malignancies of the GI tract. Development of inflammatory disorders is, in some cases, a response to acute or chronic infections, but in some patients the GI lesions are probably a manifestation of autoimmunity and may be associated with other disorders of autoimmunity. 18 In one large clinical study of patients with CVID, 22% had at least one autoimmune disease. The most common were idiopathic thrombocytopenia purpura (6%) and autoimmune hemolytic anemia (5%). 13

    INFECTIONS IN CVID
    Chronic infection with Giardia intestinalis is a common complication in patients with CVID, and it may or may not cause clinical symptoms. In some cases, malabsorption, steatorrhea, and villous abnormalities can be reversed if Giardia is eradicated. Small bowel mucosal abnormalities in giardiasis include villous blunting, increased intraepithelial lymphocytes, and nodular lymphoid hyperplasia. The trophozoite form of the organism can be identified on small bowel biopsy ( Fig. 5-1 ). The prevalence of Giardia infections in this population appears to be decreasing, but giardiasis remains a significant cause of chronic diarrhea in patients with CVID. 12

    FIGURE 5-1 Giardiasis. Numerous trophozoites are closely associated with the surface of this small bowel biopsy specimen from a patient with common variable immunodeficiency. The underlying epithelium is normal.
    Other GI infections are less common in patients with CVID. Cryptosporidiosis is only occasionally found. The prevalence of common bacterial intestinal infectious agents, such as Salmonella and Campylobacter , does not appear to be increased. Although prolonged antibiotic use is common in these patients, an increase in the incidence of pseudomembranous colitis has not been reported. 12 On occasion, viral and fungal organisms may also infect the GI tract in patients with CVID, but such infections are less common than in patients with AIDS. Cytomegalovirus infection involving the esophagus, stomach, jejunum, and ileocecal area, resulting in multiple ulcers and obstructing strictures, has also been reported in a patient with CVID. 19

    INFLAMMATORY DISORDERS AND MALIGNANCY IN CVID

    Stomach.
    In the stomach, a nonspecific increase in lamina propria lymphocytes may be detected in some patients with CVID ( Fig. 5-2A ); increased apoptosis of gastric epithelial cells is present in some cases. 18 In a study of gastric biopsies from 34 patients with CVID and dyspepsia, 41% of patients were infected with Helicobacter pylori . All H. pylori -positive patients and 20% of H. pylori -negative patients had chronic gastritis. In fact, 50% of patients infected with H. pylori also had multifocal atrophic gastritis. Among H. pylori -negative patients, 10% had multifocal atrophic gastritis. 20 Atrophic gastritis, resembling autoimmune atrophic gastritis on clinical and morphologic grounds (see Fig. 5-2B ) and resulting in pernicious anemia, may occur in the absence of demonstrable antiparietal cell antibodies in affected patents. Atrophic gastritis may develop at a very young age in patients with CVID. One child developed multifocal gastric adenocarcinoma at 11 years of age. 21 Adults with CVID are also at increased risk for gastric adenocarcinoma. 14 It has been estimated that patients with CVID have a 47-fold increased incidence of gastric carcinoma compared with the general population of Great Britain, 22 and that 5% to 10% of patients with CVID ultimately develop gastric carcinoma, usually many years after the onset of hypogammaglobulinemia.

    FIGURE 5-2 A, In common variable immunodeficiency, the gastric mucosa often contains a nonspecific mononuclear cell infiltrate. Note the absence of plasma cells. B, Loss of gastric glands leads to atrophic gastritis at a young age in patients with common variable immunodeficiency. Loss of parietal cells results in pernicious anemia and may occur in the absence of antiparietal cell antibodies.

    Small bowel.
    In the small bowel, spruelike manifestations with villous blunting occur in some patients with CVID and are associated with severe malabsorption, often requiring parenteral nutrition. Villous atrophy associated with CVID generally lacks the degree of crypt hyperplasia typical of celiac disease ( Fig. 5-3A ), but otherwise they may be indistinguishable on biopsy. In general, the lamina propria inflammatory infiltrate is not as prominent as in celiac disease, and enterocyte maturation is normal, with preservation of the brush border. 18 Most CVID patients with this type of small bowel pathology do not respond to a gluten-free diet, although an elemental diet may be beneficial. Plasma cells are absent or found only in very small numbers in the lamina propria in CVID patients. Surface intraepithelial lymphocytes are often markedly increased (see Fig. 5-3B ), even in the absence of villous atrophy. In some cases, an increase in apoptotic bodies is found in crypt epithelial cells (see Fig. 5-3C ).

    FIGURE 5-3 A, Villous atrophy associated with common variable immunodeficiency (CVID) may be severe and lead to profound malabsorption. Note the relatively sparse inflammatory infiltrate and the lack of crypt hyperplasia. B, The surface epithelium of the small intestine often contains a marked increase in the number of intraepithelial lymphocytes in CVID. C, An increase in crypt cell apoptosis is often found in small bowel biopsies, with villous atrophy, in CVID.
    Granulomatous enteropathy has also been reported in patients with CVID and may be associated with protracted diarrhea unresponsive to antibiotic therapy. Poorly formed, non-necrotizing granulomas are often detected in the lamina propria in multiple sites in the GI tract, including the stomach, small intestine, and colon. 23 Diarrhea generally resolves with intravenous immunoglobulin therapy.
    Nodular lymphoid hyperplasia (NLH) in the GI tract is characterized by multiple discrete hyperplastic lymphoid nodules in the lamina propria and submucosa of the small intestine ( Fig. 5-4 ), large intestine, or both, and is probably a result of chronic antigenic stimulation. The germinal centers of the follicles are composed of proliferating B cells with scattered tingible body macrophages; the mantle zones typically contain mature and immature B cells, and the extramantle zones usually reveal a mixture of cell types including B and T cells and macrophages. NLH is detected in up to 60% of patients with CVID, but it may also be seen in giardiasis, without antibody deficiency. 24 In contrast to NLH in CVID patients, plasma cells in nonimmunodeficient patients are present in the extramantle zones. NLH is not considered a malignant disorder. However, malignant lymphomas of the GI tract in patients with immunodeficiencies often arise in a background of NLH. In a child with CVID, clonal immunoglobulin gene rearrangements have been demonstrated in NLH in the GI tract. 25 Consistent with these observations, the most common malignancy in CVID is non-Hodgkin’s lymphoma, which affects approximately 8% of patients. 13 These lymphomas often originate in extranodal sites, such as the small bowel, which is the most common GI site. Most lymphomas are of B-cell origin, and include diffuse large B-cell lymphoma and follicular lymphoma. 14

    FIGURE 5-4 A, Nodular lymphoid hyperplasia in common variable immunodeficiency. Numerous small mucosal and submucosal nodules are present. B, Most of the lymphoid nodules contain enlarged germinal centers. Overlying villi are slightly distorted.
    Some patients with CVID develop chronic inflammatory processes involving the small or large bowel that clinically resemble inflammatory bowel disease. In some patients, the small bowel is the primary site of involvement, and the lesions resemble Crohn’s disease with transmural inflammation and small bowel obstruction. However, granulomas are generally not present in CVID-related Crohn’s disease-like disorders. 26

    Large bowel.
    Colitides that occur in CVID are quite variable in morphology. In some patients, the inflammatory process is limited to the colon and clinically mimics ulcerative colitis, with mucosal architectural distortion and crypt destruction. However, crypt distortion is usually less pronounced in CVID than in ulcerative colitis, with less crypt branching ( Fig. 5-5 ). Neutrophils are often prominent in the lamina propria and crypt epithelium. Also, in contrast to ulcerative colitis, plasma cells are not normally present in the lamina propria in CVID-associated colitis. In some cases, crypt destruction and mucosal distortion is accompanied by increased apoptosis, and in these cases, the histology may resemble colonic graft-versus-host disease. 18 Milder cases of colitis in CVID may resemble lymphocytic colitis, characterized by increased intraepithelial lymphocytes with minimal crypt distortion. 27 The etiology and pathogenesis of colitis in CVID patients remain largely unknown. The association of chronic GI inflammatory disorders and autoimmune disorders, and the resemblance of pathologic lesions to other disorders of immune dysregulation suggest that colitis associated with CVID may be autoimmune in origin.

    FIGURE 5-5 Colitis in common variable immunodeficiency may mimic inflammatory bowel disease, with crypt distortion and loss. The inflammatory infiltrate is relatively sparse in some cases, compared with ulcerative colitis, and plasma cells are not present.
    Adenocarcinoma of the colon has been reported in young patients with CVID. For example, small cell neuroendocrine carcinoma of the cecum was reported in a 16-year-old boy who died of liver metastases 5 months after diagnosis. 28 In another case, nine adenocarcinomas and 20 adenomas were present, synchronously, in the colon of a 22-year-old man with CVID. 29

    X-Linked Agammaglobulinemia
    Typically, patients with X-linked agammaglobulinemia (XLAG) are susceptible to bacterial infections because of the absence of all major circulating immunoglobulin subtypes. In fact, mature circulating B cells are typically low or completely absent. This disorder is characterized by an inability to produce antibodies to virtually all antigens. The molecular basis of XLAG was elucidated in 1993, when a defect in the Btk (Bruton’s tyrosine kinase) gene was first detected. 30 , 31 This gene encodes a nonreceptor tyrosine kinase expressed in B cell and myelomonocytic cell lineages, but not in T cells. Btk functions in intracellular signaling pathways essential for pre-B cell maturation, but the exact mechanism in which the defects in Btk lead to B-cell maturation arrest remains unclear. XLAG may have more phenotypic diversity than previously recognized. Adults with mild or even no clinical symptoms, but with deficiencies in Btk, have been described. 32 - 34
    GI manifestations are less common in patients with XLAG than in those with CVID. Age of onset of GI symptoms is younger than in CVID patients, and autoimmune diseases are less common. Small intestinal and colonic mucosal biopsies in XLAG patients without GI symptoms are notable only for the lack of plasma cells in the lamina propria, which imparts an empty appearance to the lamina propria. Crypt architecture is typically unremarkable, and villous blunting is usually not present. About one third of patients present initially with GI complaints, most commonly diarrhea or perirectal abscess. In one study, 10% of patients had chronic GI symptoms, ranging from persistent infection with G. intestinalis , Salmonella , or enteropathic Escherichia coli , to bacterial overgrowth. In this study, the etiology of chronic diarrhea was found in only half of the patients. 35 Chronic infection with rotavirus was also previously reported in this patient population. 36 Since biopsies are not routinely performed for this disorder, few descriptions of histopathologic findings are available. However, a moderate degree of villous blunting with crypt hyperplasia, and an increase in lamina propria inflammatory cells have been reported in the duodenum in acute infections. 37 Degenerative changes may also be noted in epithelial cells on the surface of villi, whereas crypt cells are usually spared. In fact, crypts undergo compensatory hyperplasia. The histologic changes of acute rotavirus infection have been reported to resemble celiac disease but with more patchiness of disease and quick reversion to normal after resolution of infection. 38
    In addition to GI infections, patients with XLAG may develop a chronic ulcerating inflammatory condition similar to Crohn’s disease, manifested by recurrent diarrhea, malabsorption, ulcers, and small bowel strictures ( Fig. 5-6 ). The inflammatory infiltrate is characterized by prominent lymphocytes, without plasma cells or granulomas. 18 , 39 In one case, enterovirus was detected by polymerase chain reaction in inflamed ileum and adjacent mesenteric lymph nodes, suggesting that infection may be responsible for the inflammatory disorder in some patients. 40

    FIGURE 5-6 A chronic inflammatory disorder, with fissuring necrosis and small intestinal ulcers, resembling Crohn’s disease occurs in some patients with X-linked agammaglobulinemia. Granulomas are typically absent.
    Patients with XLAG are at increased risk for malignancy, even in childhood. The most common malignancy is non-Hodgkin’s lymphoma involving the GI tract. Many of these cases occur in children under the age of 10 years. 41 In fact, there are rare reported cases of gastric adenocarcinoma 41 and colorectal adenocarcinoma. 5 The incidence of colorectal carcinomas in patients with XLAG is increased 30-fold. The mortality is 59-fold greater than in the normal European population. 5 In most reported cases, XLAG patients with colorectal carcinoma are in their 20s and present with advanced-stage tumors. In one reported case, multiple colorectal adenomas, in addition to carcinoma, were present. 5

    X-Linked Hyper-IgM Syndrome
    X-linked hyper-IgM syndrome (XHIM) is a disorder resulting from a mutation in the gene that codes for the CD40 ligand, which results in loss of isotype switching. In patients with this disorder, T cells lack the CD40 ligand and, thus, do not interact with CD40 on the surface of B cells, an event necessary for immunoglobulin class switching. These patients have very low levels of IgG and IgA, and normal or even elevated IgM levels. Patients are susceptible to pyogenic infections similar to those encountered in XLAG and, in addition, are susceptible to Pneumocystis carinii pneumonia. A variety of intracellular pathogens, such as mycobacterial species, fungi, and viruses (cytomegalovirus, adenovirus), have been implicated in causing disease in these patients. The most common sites of infection are the upper (approximately 88%) and lower respiratory tracts (approximately 83%), 42 followed by disseminated infection 43 and esophageal infection 44 with Histoplasma capsulatum .
    Diarrhea occurs in over half of affected patients, and it often follows a chronic course. 42 Chronic watery diar-rhea may be caused by Cryptosporidium , G. intestinalis , Salmonella , or Entamoeba histolytica infection. Nodular lymphoid hyperplasia involving the GI tract has been reported in about 5% of patients. 42 Lymphoid hyperplasia may also result in hepatosplenomegaly, lymphadenopathy, and tonsillar enlargement. 45 In fact, inflammatory bowel disease has also been reported in two patients with XHIM and chronic diarrhea. 42 Sclerosing cholangitis is a common (approximately 20% of European patients) and serious complication of XHIM, which is often related to chronic infection with Cryptosporidium . Some cases require liver transplantation. 42 In one European series, three of five patients infected with hepatitis B developed hepatocellular carcinoma. 42
    Patients with XHIM are prone to autoimmune hematologic diseases, including cyclical or chronic neutropenia with simultaneous oral and perianal ulcers. 42 Some patients develop a marked proliferation of IgM-producing plasma cells in the GI tract, liver, and gallbladder, usually in the second decade of life, which often proves fatal. 46 Small cell carcinoma of the colon has also been reported in this disorder, 47 and an increased incidence of liver and biliary tract tumors occurs as well. 48

    Hyper-IgE Syndrome (Job’s Syndrome)
    Hyper-IgE syndrome is a rare, autosomal dominant, multisystem disorder characterized by the development of recurrent staphylococcal skin abscesses, recurrent pneumonia with pneumatocele, elevated serum IgE, eczema, candidiasis, and eosinophilia. 49 The exact genetic defect has not been elucidated, but the disease locus has been mapped to chromosome 4. 50 In addition to findings related to the immune system, characteristic facial features, and dental and skeletal abnormalities have been reported in a cohort of 30 patients who were followed for a long period of time. 49 However, chronic diarrhea, and disorders resembling inflammatory bowel disease have not been reported in hyper-IgE syndrome. GI manifestations of this disease are usually limited to mucocutaneous candidiasis and tissue-invasive fungal infections with Cryptococcus that invade the esophagus 51 and colon. 52 Ileocecal histoplasmosis mimicking Crohn’s disease has been reported. 53 Perforation of the colon, probably related to infection with staphylococcal species, may develop as well, but this is rare. 54 Patients with hyper-IgE syndrome do not appear to be at increased risk for primary GI malignancies. However, associations with lymphomas of both B- and T-cell derivation have been reported. 55 , 56

    COMBINED CELLULAR AND HUMORAL IMMUNODEFICIENCIES

    Severe Combined Immunodeficiency
    Severe combined immunodeficiency (SCID) is a hetero-geneous group of congenital disorders characterized by defects in both B- and T-cell function. Children with SCID typically present in the first year of life with severe recurrent bacterial or viral infections. A number of molecular defects may result in SCID. Most are autosomal recessive; these include adenosine deaminase deficiency, accounting for 50% of autosomal recessive SCID; purine nucleoside deficiency; T-cell receptor deficiencies; Zap70 deficiency; JAK3 deficiency; and IL-7 receptor deficiency. 57 X-linked SCID resulting from a defect in the common gamma chain is the single most common type of SCID. 58 This type of SCID has a characteristic phenotype of absence of T and natural killer cells but normal B cell numbers, although the B cells are dysfunctional. 57
    GI disorders in SCID may be caused by a variety of infectious pathogens. Oral, esophageal, and perianal candidiasis is common. Children with SCID may develop profound diarrhea early in life. In general, GI biopsies from these patients show hypocellular lamina propria, without plasma cells or lymphocytes. Because these patients are susceptible to viral infections, examination of stool for viral particles may be indicated. In particular, rotavirus, normally a self-limited infection, may cause chronic diarrhea in affected children. Although villous blunting has been described in acute rotavirus infection in normal children 38 and in animal models, 59 the intestinal pathology of chronic rotavirus infection in SCID patients has not been described. Cytopathic viral infections, including cytomegalovirus and adenovirus infection, may be identified in GI biopsy specimens ( Fig. 5-7 ). Salmonella may also cause a type of chronic GI infection in SCID patients. SCID patients who receive nonirradiated blood products or who have had an allogeneic bone marrow transplant are susceptible to graft-versus-host disease (GVHD). In fact, a GVHD-like process affecting the colon and small intestine has also been described in SCID patients who have not undergone bone marrow transplantation. 60 , 61 Children with SCID may be at greater risk for reflux esophagitis than the normal population. 62

    FIGURE 5-7 A, Disseminated adenovirus may involve the GI tract in patients with severe combined immunodeficiency. In this case, the small bowel crypts are involved; in less severe cases, inclusions may be identified only in surface epithelium. B, Adenovirus-infected cells are typically not enlarged. Classic “smudge” cells, with a homogeneous nuclear staining pattern, are shown here.

    Omenn’s Syndrome
    Omenn’s syndrome is an autosomal recessive severe combined immunodeficiency disorder with clinical and pathologic features of GVHD. The immunologic hallmark of the disease is expansion of an oligoclonal population of T cells 63 combined with a near absence of B cells. 64 Infants with Omenn’s syndrome present with diffuse erythroderma, hepatosplenomegaly, lymphadenopathy, and failure to thrive; chronic diarrhea and alopecia are common. Hypereosinophilia and hypogammaglobulinemia are also characteristic features of this disorder. Paradoxically, serum IgE levels are usually increased, although B lymphocytes are not normally detectable in the circulation, lymph nodes, or skin. Activated circulating T cells are normal to increased in number but constitute an oligoclonal population. The underlying basis for these findings in Omenn’s syndrome is the impairment of the V(D)J recombination process as a result of mutations in Rag 1 or Rag 2, the recombination-activation genes. 64 , 65 Mutations in these genes were first identified in a subset of SCID patients, those with T − (-) SCID. The occurrence of this type of SCID and Omenn’s syndrome in the same kindred furnished the theory that Omenn’s syndrome was caused by mutations in the same genes. Differences between T − (-) SCID and Omenn’s syndrome may be explained by the presence of two defective alleles in SCID, and by the presence of a marginally functional allele that is capable of establishing the oligoclonal T cell population in patients with Omenn’s syndrome. 65 Infants with SCID and with maternal T-cell engraftment may exhibit GVHD symptoms indistinguishable on clinical grounds from symptoms of Omenn’s syndrome. 66 In fact, a diagnosis of Omenn’s syndrome depends on exclusion of this possibility by appropriate HLA typing or molecular analysis. Published accounts of the pathologic changes in Omenn’s syndrome are scant, but skin changes may resemble those of GVHD. 67 , 68 Numerous apoptotic crypt cells may be detected in colonic biopsies in a pattern similar to that seen in GVHD. Crypt injury and an increase in lamina propria eosinophils may also be present ( Fig. 5-8 ).

    FIGURE 5-8 Omenn’s syndrome. Focal crypt destruction associated with a focal increase in lamina propria eosinophils.

    OTHER PRIMARY IMMUNODEFICIENCIES

    DiGeorge Syndrome
    DiGeorge syndrome is caused by a microdeletion in chromosome 22q11.2, which leads to a congenital malformation of the third and fourth pharyngeal pouch, resulting in thymic and parathyroid hypoplasia. This disease is the most common microdeletion syndrome in humans and is estimated to affect 1 in 4000 live births. 69 T cells are markedly reduced in number, but B cells are normal in number and functionality. Midline anomalies affecting the GI tract, such as esophageal atresia and imperforate anus, are seen in some cases in association with DiGeorge syndrome, and watery diarrhea and malabsorption have been described but not well characterized. 70 Oral candidiasis is common. Dysphagia and feeding difficulties have been reported in infants with 22q11.2 deletion as well. 71

    Chronic Mucocutaneous Candidiasis
    Chronic mucocutaneous candidiasis comprises a hetero-geneous group of disorders characterized by persistent Candida infection of the skin, nails, and mucous membranes. Autoimmune disorders, and a polyglandular endocrinopathy syndrome including pernicious anemia, are common, occurring in over 50% of patients. There is a high association with thymoma and systemic lupus erythematosus. 72 Immune defects include disorders of T-cell immunity with variable B-cell involvement. The most common GI manifestation is esophageal candidiasis. Although superficial infection with Candida is a defining characteristic, infections with other fungi (e.g., H. capsulatum ) and bacteria are common. 73

    Wiskott-Aldrich Syndrome
    Wiskott-Aldrich syndrome, characterized by early onset of profound thrombocytopenia with small platelets, eczema, and recurrent infections, is inherited as an X-linked recessive disease. Platelets and T cells are most severely affected. The genetic basis of Wiskott-Aldrich syndrome, first described in 1994, is mutation of the WASP gene, which encodes an intracellular protein expressed exclusively in hematopoietic cells. 74 This protein is involved in transduction of signals from cell surface receptors to the actin cytoskeleton 75 and is important in cytoskeletal architecture, cell trafficking, and motility. 76 Diarrhea is reported in patients with this disorder but has been poorly characterized. 70 Bloody diarrhea in these patients is often attributed to thrombocytopenia. Thus, biopsies may not be performed because of the risk for hemorrhage. A Crohn’s disease-like inflammatory process, with a cobblestone appearance and inflammatory pseudopolyps of the mucosa involving the descending and transverse colon, has been reported in Wiskott-Aldrich syndrome. 77 Massive hemorrhage from aneurysms involving the liver, small bowel mesentery, and kidney has also been reported. 78

    Chronic Granulomatous Disease
    In chronic granulomatous disease (CGD), phagocytic cells are unable to reduce molecular oxygen to create the superoxide anion and its metabolites necessary for eradication of certain catalase-positive intracellular microbes. CGD is genetically heterogeneous, resulting from a mutation in any of four components of NADPH oxidase. The most common form of the disease, accounting for 70% of cases, is X-linked recessive; three other forms are autosomal recessive. 79 As a result of this defect, patients with CGD suffer from recurrent bacterial and fungal infections. Abscesses may occur in a variety of sites, and pneumonia is also common. Affected patients are also prone to develop a variety of inflammatory and rheumatic diseases, such as an inflammatory bowel disease-like condition and a lupus-like syndrome. GI manifestations are relatively rare in chronic granulomatous disease, but reported cases may be broadly grouped into obstructive and inflammatory categories.
    Obstruction may occur anywhere from the esophagus to the small bowel. Gastric outlet obstruction is more common in the X-linked form of the disease. 79 In some cases, obstruction is caused by infiltration of the viscus wall by pigment-laden macrophages (the histologic hallmark of CGD) or to granulomatous inflammation. In other cases, obstruction is reportedly secondary to a functional disturbance in GI motility, although in these cases, infiltration of the deep layers of the organ by macrophages was not completely excluded. Esophageal obstruction occurs in 1% of patients with CGD. 79 Biopsies of the esophageal mucosa generally show nonspecific findings or histologic evidence of reflux esophagitis 80 but may also demonstrate abundant pigmented macrophages. Involvement of the gastric antrum and pylorus is somewhat more common, occurring in 16% of patients. Gastric outlet obstruction may be the first manifestation of CGD. Granulomas, giant cells, and macrophages laden with brown-yellow fine pigment are commonly present in gastric biopsies, 81 but in some cases, only nonspecific inflammation is present. 82 Small bowel obstruction is relatively rare in CGD, but it is occasionally reported in the context of an inflammatory process. 83 In a review of small bowel and rectal biopsies from nine patients with CGD, pigment-laden macrophages were detected in the lamina propria at both sites. In the small bowel, macrophages were located deep in the mucosa adjacent to crypts, but when numerous they also extended up into the villus core ( Fig. 5-9 ). In rectal biopsies, the number of pigmented histiocytes was quite variable, ranging from rare scattered cells to large numbers of histiocytes accumulating between the bases of the crypts and the muscularis mucosae. Granulomas, with giant cells, were also present in rectal biopsies from some patients. In one of eight cases, distortion of crypt architecture, without crypt abscesses, was also seen. 84

    FIGURE 5-9 Chronic granulomatous disease. Accumulation of pigmented macrophages containing light brown dusky material in the small intestinal mucosa.
    Chronic inflammatory processes indistinguishable from inflammatory bowel disease, affecting the small and large bowel, may also occur in patients with CGD. 85 As with obstructive lesions of the GI tract, these manifestations are more common in the X-linked form of the disease. 79 Polymorphisms in genes unrelated to NADPH oxidase may modify the clinical phenotype of CGD; certain polymorphisms in the genes for myeloperoxidase and Fcγ receptors are strongly associated with GI complications. 86 Involve-ment of the small bowel in CGD may produce fistulae, longitudinal ulcers, stenosis, and non-necrotizing granulomatous inflammation that may be mistaken for Crohn’s disease. 87 , 88 Granulomas in intestinal lesions in CGD are often more florid than typically seen in Crohn’s disease, 87 but granulomas are not present in all cases. In a CGD patient with colitis, the presence of an acute and chronic inflammatory infiltrate confined to the colonic mucosa, crypt abscesses, and lack of granulomas were more suggestive of ulcerative colitis than Crohn’s disease. Architectural distortion of the crypts and ulceration were not as prominent as usually seen in ulcerative colitis. However, pigmented macrophages were present in the lamina propria. 85

    Miscellaneous Immune Deficiency Syndromes
    Other rare disorders of immunity occasionally associated with GI manifestations include leukocyte adhesion deficiency, in which delayed wound healing and susceptibility to bacterial and fungal infection lead to necrotizing enterocolitis. 89 A chronic inflammatory process with multiple aphthous ulcers involving the gastric antrum, terminal ileum, cecum, and right colon, which resolved with bone marrow transplantation, has also been reported in leu-kocyte adhesion deficiency. 90 Ataxia-telangiectasia, a chromosomal breakage syndrome, is associated with an increased risk for gastric adenocarcinoma. Bare lymphocyte syndrome (a deficiency in the major histocompatibility complex) is associated with oral candidiasis and persistent viral infections of the GI tract.

    Graft-versus-Host Disease

    ACUTE GRAFT-VERSUS-HOST DISEASE
    Acute GVHD involving the GI tract develops in up to 50% of allogeneic bone marrow transplant recipients. 91 Skin and liver are the most common organs involved. Indeed, the most common cause of persistent nausea and anorexia in patients beyond post-transplant day 20 is acute GVHD. 92 In fact, changes identical to those seen in GVHD after allogeneic transplantation may also be seen in the GI tract and liver after autologous stem cell transplantation and are considered to represent a form of GVHD resulting from a lack of regulation of immune mechanisms by the reconstituting immune system. 93 Acute GVHD-like changes in the GI tract after autologous transplantation are rare, occurring in gastric biopsies in only 4% of patients with upper GI tract symptoms. 94 Rarely, acute GVHD occurs after solid organ transplantation or blood transfusion as well. Symptoms indicative of GI tract involvement include profuse diarrhea, crampy abdominal pain, hemorrhage, anorexia, nausea, and vomiting. Severe GI bleeding and peritonitis have also been reported. 91 Involvement of the upper GI tract is slightly more common than involvement of the large bowel, although simultaneous involvement of both the upper and lower GI tract is common. 95
    On endoscopic examination, the appearance of GI mucosa in acute GVHD is variable, ranging from mucosal edema and erythema, to ulceration and mucosal sloughing. 96 The major and most characteristic histologic features of GVHD in the GI tract are epithelial cell apoptosis combined with a relatively sparse mononuclear inflammatory cell infiltrate ( Fig. 5-10A ). Apoptotic epithelial cells are found primarily in the regenerative compartment of the mucosa, such as the deep crypts in the colon and small intestine, and the neck area of gastric glands. In the colon, apoptotic cells are often particularly conspicuous, and thus are often referred to as “exploding” crypt cells. These cells contain intracytoplasmic vacuoles filled with karyorrhectic nuclear debris (see Fig. 5-10B ). 97 Apoptotic cells are usually smaller and less conspicuous in gastric mucosa than in the colon ( Fig. 5-11A ). In severe cases of acute GVHD, crypt abscesses may also be seen combined with progressive destruction, necrosis, and ultimately loss of crypts. In the most severe cases, mucosal sloughing and extensive ulceration may occur as well. In the stomach, granular eosinophilic necrotic cellular debris, without neutrophils, may be present in the lumen of injured gastric glands (see Fig. 5-11B ). 98 Villous blunting is usually present in the small bowel with GVHD. A grading system for acute GVHD of the colon has been proposed ( Table 5-5 ). 97 However, correlation with clinical symptoms and patient outcome is weak.

    FIGURE 5-10 Acute graft-versus-host disease (GVHD) involving colon. A, The lamina propria inflammatory infiltrate is relatively sparse. No crypt loss is seen in this example, although crypts are slightly distorted. B, Large apoptotic bodies, known as “exploding” crypt cells, are typical of colonic GVHD. C, An example of grade I acute GVHD in the colon, consisting of scattered single-cell apoptotic epithelial cells. D, Grade II acute GVHD showing epithelial apoptosis, crypt atrophy, and crypt abscesses.

    FIGURE 5-11 A, In the stomach, apoptotic bodies in glandular epithelium are small and inconspicuous in acute graft-versus-host disease (GVHD). B, In the gastric fundus, dilated glands containing granular eosinophilic debris are sometimes found in GVHD. As in the colon, the inflammatory infiltrate is relatively sparse.
    TABLE 5-5 Grading of Acute Graft-versus-Host Disease in the Colon Grade Histologic Features I Rare apoptotic cells, without crypt loss II Loss of individual crypts III More substantial crypt loss (loss of two or more contiguous crypts) IV Few or no identifiable crypts, often with mucosal ulceration
    From Sale GE, Shulman HM, McDonald GB, Thomas ED: Gastrointestinal graft-versus-host disease in man: A clinicopathologic study of the rectal biopsy. Am J Surg Pathol 3:291-299, 1979.
    The histologic changes that occur in the GI tract in acute GVHD are not entirely specific. For example, similar changes have been reported in colonic biopsies from patients with severe T-cell deficiencies, 61 malignant thymoma, 99 and CVID. 18 In bone marrow transplantation patients, the effects of cytoreductive therapy resemble GVHD in the early post-transplant period. Thus, a diagnosis of GVHD should be made with caution within 21 days after transplantation. Recurrence of hematologic malignancies, particularly acute lymphoblastic leukemia, may also mimic acute GVHD. 100 Cytomegalovirus infection may produce mucosal damage characterized by apoptotic epithelial cells, also mimicking acute GVHD. 101 Of course, differentiation of cytomegalovirus infection from GVHD relies on demonstration of viral inclusions. 102 Furthermore, because GVHD and cytomegalovirus infection may occur simultaneously, it may be difficult to separate the effects of each in GI tract biopsies. Features that favor a diagnosis of acute GVHD include severe crypt destruction and loss, the absence of mixed acute and chronic inflammation, absence of ischemic changes, and the presence of small clusters of preserved endocrine cells, particularly at the base of the mucosa. Endocrine cells are more resistant to the damaging effects of GVHD than are other types of crypt epithelial cells. Also, severe crypt injury and marked apoptosis in a biopsy with only scattered rare cytomegalovirus inclusions would favor GVHD as the major cause of mucosal injury, with cytomegalovirus more likely being a superimposed infection. Clostridium difficile infection has also been associated with GVHD and has been associated with a high nonrelapse mortality rate. It has been postulated that C. difficile toxin may predispose patients to more severe degrees of GVHD. 103 Use of proton pump inhibitor therapy has also been associated with the development of apoptotic cells in the gastric antrum, which may mimic the histologic changes seen in GVHD. 104 One must always be aware of the fact that many types of bowel preparation formulas may induce crypt cell apoptosis, which can be particularly marked in some individuals. However, in bowel preparation-related apoptosis, crypt destruction is not present. Also, bowel-preparation effect is often more prominent in the right colon than in the left colon and rectum. Finally, as indicated later, patients with AIDS often show nonspecific crypt cell degenerative changes, and apoptosis, which can mimic GVHD. In patients with AIDS, nuclear pyknosis (“dust”) may also be apparent in the lamina propria underneath the surface epithelium. The cause of this is unknown, but it has been postulated to represent a manifestation of AIDS enteropathy.

    CHRONIC GRAFT-VERSUS-HOST DISEASE
    The GI tract is less often implicated in chronic GVHD, which is defined as GVHD more than 100 days after transplantation. Clinically, chronic GVHD is similar to the manifestations of some types of collagen vascular diseases, such as scleroderma and Sjögren’s syndrome. In the liver, chronic GVHD may mimic primary biliary cirrhosis (see Chapters 14 and 44 ). 105 Chronic GVHD typically involves multiple organs, such as the salivary gland, mouth, eyes, and upper respiratory tract-organs not usually involved in acute GVHD.
    In chronic GVHD, dermal and submucosal fibrosis may resemble scleroderma. Involvement of oral squamous mucosa may lead to the development of painful ulcers. Involvement of minor salivary glands results in an oral sicca syndrome. In advanced cases, ulcers and submucosal fibrosis may also occur in the esophagus, which is the most commonly affected site in the GI tract. 106 Altered transit may lead to secondary reflux-related changes in the overlying mucosa. Small bowel involvement is less common and, when present, is usually associated with diarrhea. Patchy fibrosis of the lamina propria and submucosal fibrosis, with minimal mucosal changes, are characteristic findings. 106 In the colon, mild to moderate crypt distortion similar to that seen in ulcerative colitis has been reported in allogeneic bone marrow transplant patients, but it is unclear whether architectural distortion results from chronic GVHD or other factors. 107 Otherwise, expression of chronic GVHD in colonic biopsies may be completely normal, or it may reveal crypt disorder with fibrosis, crypt abscesses, or other features of inflammatory bowel disease.

    Neutropenic Enterocolitis
    Neutropenic enterocolitis (NEC) is a necrotizing inflammatory process predominantly affecting the cecum, terminal ileum, and ascending colon. It occurs most commonly in the setting of neutropenia. NEC that involves the cecum, often with hemorrhagic necrosis, has also been termed typhlitis. Absolute neutrophil counts of less than 1500/mm 3 are typical of this disorder. Historically, most patients with NEC have had acute leukemia, although NEC may develop in patients who have undergone stem cell or autologous bone marrow transplantation for solid malignancies. 108 , 109 NEC also occurs in patients with aplastic anemia, after renal transplant, and in individuals with other types of hematologic malignancies as well. Most, if not all, patients who develop NEC have received some form of chemotherapy in the previous 30 days. 110 Patients may present with clinical features suggestive of acute appendicitis, such as fever and right lower quadrant pain, but up to one third present with overt GI hemorrhage. 110 Rarely, a right lower quadrant mass may be palpable. The combination of abdominal pain, diarrhea, and fever is the most common presentation in the acute phase of NEC. 109
    On gross examination, the cecum, as well as any other affected portion of the GI tract, often appears thin, dilated, edematous, congested, and hemorrhagic. Pneumatosis intestinalis may be present, and in some cases it may be quite marked. Histologically, the mucosa appears hemorrhagic and covered with granular necrotic material. Of course, the characteristic finding in NEC is that necrotic areas of bowel show an absence of neutrophils and no other significant inflammatory reaction ( Fig. 5-12 ). Non-inflammatory mucosal (and even submucosal or transmural) necrosis, edema, and hemorrhage may mimic ischemic colitis, but ischemic colitis usually has more abundant inflammation, including neutrophils, and lamina propria hyalinization.

    FIGURE 5-12 Neutropenic enterocolitis. The mucosa is necrotic and hemorrhagic and lacks a significant inflammatory response. Sloughed epithelium is seen in the lumen.
    The pathogenesis of NEC is initiated with mucosal injury, primarily related to recent administration of chemotherapeutic agents and augmented by neutropenia. Subsequently, bacterial invasion of degenerated mucosa occurs, with Clostridium species implicated as the major offend-ers. Occasionally, clostridial organisms are detected not only on the mucosal surface but also in the underlying lamina propria, or even submucosa, within and surrounding small vascular spaces. This may be demonstrated more easily with the use of a Gram stain. Fungi, such as Candida species, may also be causative or contributing agents. Toxins produced by the clostridial organisms lead to edema and necrosis, perhaps by their effects on the vasculature, and this has been postulated as a reason for the ischemic appearance of the tissue in NEC. Distension of the bowel ultimately leads to decreased blood flow, which also adds an element of ischemic-type injury. Ultimately, most patients become septicemic. If left untreated, the prognosis is grave, but patients may survive with optimal medical and surgical management. Ultimately, adequate recovery is highly dependent on the restoration of an adequate neutrophil count.

    The GI Tract in HIV Infection
    GI illnesses are common in HIV-infected patients. Clinically, diarrhea, nausea, vomiting, anorexia, and abdominal pain are typical presenting symptoms. Prior to the use of new, highly effective antiretroviral agents, opportunistic infections caused by pathogens such as Isospora , Mycobacterium avium complex, microsporidia, Cryptosporidium , and cytomegalovirus were the most frequent causes of diarrhea, malabsorption, and wasting ( Table 5-6 ). Although the prevalence of intestinal pathogens has decreased dramatically in the past decade, from 85% in men with AIDS and diarrhea, to 12% now occurring almost exclusively in homosexual men, 111 current studies continue to show a high prevalence rate of GI dysfunction in HIV-infected patients. In fact, chronic diarrhea is reported in up to 25% of HIV-infected patients. In one study, it was not correlated with the degree of immune suppression. 111
    TABLE 5-6 HIV-Associated GI Diseases Infective Agent Neoplasia Ciardia intestinalis Kaposi’s sarcoma Cryptosporidium parvum Burkitt’s lymphoma Isospora belli Diffuse large B-cell lymphoma Mycobacterium avium complex Microsporidia Plasmablastic lymphoma Cytomegalovirus Anal squamous cell carcinoma Candida albicans Hodgkin’s lymphoma Listeria monocytogenes Strongyloides stercoralis Human herpesvirus-8 Epstein-Barr virus
    GI dysfunction, as manifested by D-xylose malabsorption, is common, even in early HIV disease, and it may be a manifestation of HIV enteropathy. HIV enteropathy is defined as a reduction in small bowel villous surface area associated with chronic diarrhea, in the absence of enteric pathogens. The pathogenesis of HIV enteropathy is not well understood. However, there is evidence to support the idea that diarrhea is probably directly related to local virus infection. Several studies have shown that HIV-infected patients show an improvement in clinical symptoms after initiation of highly active antiretroviral therapy (HAART). Studies of intestinal permeability, epithelial cell barrier function, and cytoskeletal integrity have demonstrated changes in HIV-infected subjects, which can occur after administration of antiviral agents. 112 Thus, some authors have suggested that medications should also be considered as a possible etiologic factor in the development of diarrhea and may even account for up to 45% of noninfectious cases. 113 Commonly implicated medications are nelfinavir, ritonavir, saquinavir, indinavir, and didanosine. In small bowel biopsies, HIV enteropathy is characterized by mild villous blunting but without crypt hyperplasia. 114 The degree of villous atrophy is typically less than that seen in celiac disease.
    The effective use of HAART therapy in the treatment of HIV has led to a gradual decline in the incidence of infectious diseases and an increase in the rate of HIV-associated malignancies (see Table 5-6 ). The most prevalent cancers in this population are Kaposi’s sarcoma and AIDS-related non-Hodgkin’s lymphoma. Kaposi’s sarcoma remains the most common HIV-associated malignancy, despite a decline in incidence following the widespread use of HAART therapy ( Fig. 5-13 ). Studies have reported GI involvement in 40% of cases at initial presentation and up to 80% at autopsy. 2 AIDS-related non-Hodgkin’s lymphomas are predominantly of B-cell lineage and include Burkitt’s lymphoma ( Fig. 5-14 ), diffuse large B-cell lymphoma (immunoblastic, centroblastic, and anaplastic variants), primary effusion lymphoma, and plasmablastic lymphoma. 2 , 3 The GI tract is the most common site of extranodal non-Hodgkin’s lymphomas, including Burkitt’s lymphoma and diffuse large B-cell lymphoma. 1 , 117 Classic primary effusion lymphoma affects the peritoneal cavity, whereas solid primary effusion lymphoma may be seen in extraserous sites such as the large intestine and lymph nodes. Plasmablastic lymphoma has been documented in the oral cavity and anorectum. 2 The development of these forms of HIV-associated malignancy is often attributable to coinfection by viruses, such as human herpesvirus-8 (Kaposi’s sarcoma-associated herpesvirus) and Epstein-Barr virus. In addition to these more common HIV-associated cancers, large database studies have shown an association of HIV infection with other types of malignancies as well as Hodgkin’s lymphoma, multiple myeloma, leukemia, anal squamous cell carcinoma, head-and-neck squamous cell carcinoma, esophageal carcinoma, and gastric carcinoma. 2 , 116 , 117

    FIGURE 5-13 Kaposi’s sarcoma of the colon. A proliferation of spindled cells in the mucosa replaces the colonic crypts and muscularis mucosae. Occasional slit-like spaces containing erythrocytes are present.

    FIGURE 5-14 A, Burkitt’s lymphoma in the rectum of an HIV-infected individual. Diffusely infiltrative atypical lymphocytes with scattered tingible body macrophages result in the characteristic “starry-sky” appearance. B, Same as A but higher magnification.

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    CHAPTER 6 Systemic Illnesses Involving the GI Tract

    DAVID N.B. LEWIN

    Introduction
    Cardiovascular Disorders
    Cardiac Surgery and Heart Transplantation
    Ischemic Disease
    Vascular Disorders
    Dermatologic Disorders
    Bullous Diseases
    Dermatogenic Enteropathy
    Dermatologic Disorders Associated with Malignancies of the GI Tract
    Endocrine Disorders
    Adrenal Gland
    Hypothalamus and Pituitary
    Pancreas
    Parathyroid
    Thyroid
    Multiple Endocrine Neoplasia
    Hematologic Disorders
    Hemorrhagic Disorders
    Thrombotic Disorders
    Megaloblastic Anemia
    Leukemia and Lymphoma
    Metabolic Disorders
    Acrodermatitis Enteropathica
    Plummer-Vinson Syndrome (Paterson-Brown Kelly Syndrome)
    Vitamin Disorders
    Lipoprotein Disorders
    Lysosomal Storage Disorders
    Amyloidosis
    Familial Mediterranean Fever (Familial Paroxysmal Polyserositis, Recurring Polyserositis)
    Pulmonary Disorders
    Reproductive Disorders
    Effects of Pregnancy and Exogenous Hormones
    Endometriosis
    Rheumatologic Disorders
    Scleroderma
    Dermatomyositis and Polymyositis
    Systemic Lupus Erythematosus
    Mixed Connective Tissue Disease
    Rheumatoid Arthritis
    Reactive Arthritis
    Sjögren’s Syndrome
    Hereditary Connective Tissue Disorders
    Urologic Disorders
    Acute Renal Failure
    Hemolytic-Uremic Syndrome
    Chronic Renal Failure
    Urinary Conduits
    Miscellaneous Disorders
    Chronic Granulomatous Disease
    Sarcoidosis
    Mastocytosis
    Neoplastic Disease

    Introduction
    Systemic illnesses commonly affect the GI tract. GI symptoms and morphologic changes can result from several different pathogenetic mechanisms, such as nonspecific or constitutional symptoms, pathologic changes common to intestinal and extraintestinal organs, secondary changes such as opportunistic infections or drug reactions, and metastatic disease. This chapter focuses on morphologic alterations in the GI tract due to disorders that primarily affect other organ systems.

    Cardiovascular Disorders

    CARDIAC SURGERY AND HEART TRANSPLANTATION
    GI complications following open heart surgery are uncommon, occurring in approximately 1% of cases; however, the mortality rate is high (approximately 30%). 1 , 2 Clinical features typically consist of GI hemorrhage secondary to stress ulceration, vascular insufficiency with ischemic necrosis of bowel, and acute diverticulitis. Additional risk factors for ischemia include end-stage renal disease, female sex, non-coronary artery bypass graft, and long pump times. 2
    In contrast to GI complications after open heart surgery, GI complications after cardiac transplantation have been reported in a much greater proportion of patients (up to 20%). 3 , 4 Complications include all of the hemorrhagic conditions mentioned previously. In addition, the use of steroids and immunosuppressive agents increases the risk of intestinal perforation, fistula formation, and infectious GI diseases. Finally, these patients are also at risk for post-transplantation lymphoproliferative disorders 5 (see Chapter 44 ).

    ISCHEMIC DISEASE
    Intestinal ischemic disease can be divided into two major subsets: nonthrombotic (approximately 60% of cases) and thrombotic (approximately 40% of cases). 6 Nonthrombotic causes of ischemic disease include decreased mesenteric blood flow secondary to cardiac failure, shock, atherosclerotic vascular disease, disseminated intravascular coagulation, vasculitis, and fibromuscular dysplasia. Thrombotic causes can be divided into arterial embolism, arterial thrombosis, and venous thrombosis. These are a heterogeneous group of disorders usually seen in elderly individuals. 7 Colonic ischemia, the most common disorder (typically nonthrombotic), has a favorable prognosis. Acute mesenteric ischemia, in contrast, has a poor prognosis, with a survival rate of only 50%. 6 Histologically, resultant lesions range from epithelial and lymphocytic apoptosis 8 to mucosal necrosis and transmural infarction of the bowel ( Fig. 6-1 ). Specifics concerning histology and pathology are discussed in Chapter 10 .

    FIGURE 6-1 Early ischemia of the colon. Intermediate magnification reveals atrophy and mucin depletion of the epithelium. A mild acute inflammatory infiltrate is present. Epithelial apoptosis is present as well. The lamina propria has a characteristic light pink, homogeneous appearance.

    VASCULAR DISORDERS
    Several generalized vascular disorders may involve the GI tract. These also affect a number of other organ systems, most notably the skin. These disorders can be divided into telangiectatic or endothelial proliferative lesions. They typically present with GI hemorrhage or vasculitis and may result in infarction.

    Hereditary Hemorrhagic Telangiectasia (Rendu-Osler-Weber Disease)
    This is an inherited vascular anomaly that shows widespread distribution of telangiectatic vessels. Approximately 33% of patients with this condition present with repeated bleeding episodes and iron deficiency anemia, 9 typically after the fourth decade of life. The lesions can be identified endoscopically in the GI tract and on the skin. Histologically, they are characterized by tufts of dilated small blood vessels with thinning and ballooning of the wall of the vessels and aneurysmal dilation.
    The lesions are treated endoscopically with thermal coagulation.

    Blue Rubber Bleb Nevus Syndrome (Bean’s Syndrome)
    This syndrome is characterized by cutaneous and GI cavernous hemangiomas. The lesions can be sporadic or inherited in an autosomal dominant fashion. The syndrome develops in both children and adults. The skin lesions, which occur most commonly on the upper limbs and trunk, consist of blue rubber nipples that are compressible when palpated and then subsequently refill. The GI lesions are similar; thus, patients often present with bleeding or anemia. 10 Histologically, the lesions in both the skin and the GI tract are cavernous hemangiomas. Polypoid lesions include large, dilated vascular spaces in the submucosa. Conservative excision is the treatment of choice. 11

    Kaposi’s Sarcoma
    Kaposi’s sarcoma is a relatively common finding in the GI tract of patients with HIV infection with severe immunologic impairment. 12 Among patients with established skin or lymph node disease, 50% have GI lesions; however, a majority of these (80%) are clinically silent. 13 The newer, highly active antiretroviral therapies have made GI lesions less frequent. 14 Patients may present with bleeding, obstruction, and even perforation. Endoscopically, the lesions are relatively distinctive, appearing as red macules or nodules. The diagnostic yield in endoscopic biopsy specimens is low owing to the predominantly submucosal location of the lesions. Because of this, lesions are not typically sampled for biopsy. Histologically, one sees a spindle cell proliferation within the submucosa and deep lamina propria with obliteration of the muscularis mucosae ( Fig. 6-2 ). The cells do not show much atypia. Characteristic slitlike spaces containing red blood cells are seen. The endothelial cells are spindled, but plumper (epithelioid) cells often are also present. Eosinophilic periodic acid-Schiff (PAS)-positive hyaline bodies can also be seen in the endothelial cells.

    FIGURE 6-2 Kaposi’s sarcoma in a gastric mucosal biopsy. A proliferation of spindle cells is present in the deep lamina propria. Slitlike spaces with red blood cells and extravasated red blood cells are present. Mild chronic gastritis is noted as well.

    Vasculitides (See Chapter 10 for details)
    In general, the GI tract is not typically the primary organ affected by systemic inflammatory vasculitides. Solitary GI tract involvement may occur, but only rarely. 15 Classification is based on the size of the involved blood vessels, the anatomic site, and the histologic characteristics of the lesions and the clinical manifestations of the patients. 16 Vasculitides may cause local or diffuse pathologic changes such as nonspecific paralytic ileus, mesenteric ischemia, submucosal edema, and hemorrhagic bowel perforation or stricture.

    TAKAYASU’S AND GIANT CELL ARTERITIS
    These are diseases of medium- to large-sized, muscular arteries, and are characterized by granulomatous inflammation of the vessel wall. Giant cell arteritis, which usually occurs in patients older than 50 years of age, shows granulomatous inflammation of the inner half of the media, centered on the internal elastic membrane. Intestinal involvement is unusual, but some patients may present with intestinal perforation. 17 Takayasu’s arteritis occurs rarely in the GI tract. 18 In contrast to giant cell arteritis, this disorder affects patients younger than 50 years of age. Morphologically, it may be indistinguishable from giant cell arteritis. However, early lesions show adventitial mononuclear cell infiltration with perivascular cuffing of the vasa vasorum.

    POLYARTERITIS NODOSA
    This is a form of systemic vasculitis that shows transmural necrotizing inflammation of small and medium-sized arteries, often in a segmental manner. Acute abdominal syndromes may be present in 30% of patients. 19 This is a disease primarily of young adults. Lesions have a pre-dilection for involvement of branching points and bifurcations of arteries. Aneurysmal dilation and localized vessel rupture may occur in some cases. Histologically, the vasculitis is characterized by the presence of a transmural inflammatory infiltrate within the vessel wall, and a marked infiltrate of neutrophils, eosinophils, and mononuclear cells. Commonly, fibrinoid necrosis of the vessel wall may be accompanied by thrombosis in the vessel lumen ( Fig. 6-3 ).

    FIGURE 6-3 Polyarteritis nodosa; high-power view of a medium-sized artery containing a heavy infiltrate of neutrophils and lymphocytes. Fibrinoid necrosis of the vessel wall is accompanied by partial thrombosis of the vessel lumen.

    WEGENER’S GRANULOMATOSIS
    This is a necrotizing granulomatous inflammatory vascular disorder that typically affects the lung and kidney, and involves small to medium-sized blood vessels. Affected patients usually have a positive antineutrophil cytoplasmic antibody (c-ANCA). Rare presentations include abdominal pain, which results from GI involvement. 20 Granulomatous inflammation in these cases can be confused with Crohn’s disease. 21

    CHURG-STRAUSS SYNDROME
    This syndrome is characterized by the presence of small vessel vasculitis, extravascular granulomas, asthma, and eosinophilia. GI manifestations occur in at least 30% of patients, but are inaugural in only 16%. 22 Typical GI symptoms include abdominal pain, diarrhea, and bleeding. Ulceration and frank perforation may occur. 23 These patients also have a positive c-ANCA. Granulomatous inflammation is similar to that in Wegener’s granulomatosis. However, eosinophils are usually more numerous, and patients often have associated asthma.

    THROMBOANGIITIS OBLITERANS (BUERGER’S DISEASE)
    This is a nonarteriosclerotic, segmental, inflammatory vaso-occlusive lesion that involves both medium-sized and small arteries. Histologically, the disorder is characterized by the presence of a prominent acute and chronic inflammatory infiltrate, with thromboses and small microabscesses within the thrombus material. The lesion occurs almost exclusively in young men who are habitual tobacco users. Sixteen cases of visceral-intestinal Buerger’s disease have been reported. 24

    BEHÇET’S DISEASE
    This is a form of chronic relapsing vasculitis, characterized by aphthous ulceration of the mouth, inflammatory lesions of the perineal region, and ulcerative lesions of the GI tract. The most frequent sites of GI involvement are the ileocecal region and the colon. Because of the presence of aphthous and ulcerative-type lesions, the disease may mimic Crohn’s disease. A lymphocytic inflammatory infiltrate of medium-to small-sized arteries and veins is typically present. Occasionally, fibrinoid necrosis is also noted. 25 These features are not characteristic of Crohn’s disease. Furthermore, Behçet’s disease does not show other typical features of Crohn’s disease, such as transmural lymphoid aggregates and deep fissuring ulceration.

    MICROSCOPIC POLYANGIITIS
    This disorder is believed to represent a hypersensitivity reaction. Other names include microscopic polyarteritis , hypersensitivity vasculitis , and leukocytoclastic vasculitis . Arterioles, capillaries, and venules are typically affected. Segmental fibrinoid necrosis of the vessel wall, with leukocytoclasia of neutrophils, is often noted. Immune deposits are not typically seen in this type of vasculitis, and most patients are perinuclear ANCA (p-ANCA) positive. Lesions may occur in the kidney and lung. However, GI involvement may occur in some cases. 26

    HENOCH-SCHÖNLEIN PURPURA
    This is a small vessel vasculitis that primarily affects children. It is believed to be caused by circulating IgA containing immune complexes that deposit within the walls of blood vessels. Abdominal pain occurs in 60% of patients; GI bleeding is present in 33%. 27 Endoscopic and histologic duodenitis have been described. 28

    CRYOGLOBULINEMIA
    This is another small vessel vasculitis caused by cryoglobulin immune deposits in small blood vessels; it is associated with cryoglobulins in the serum. Immune deposits are of the IgG-IgM type that may, in fact, be seen secondary to infection with the hepatitis C virus. 29 GI involvement often includes the liver and spleen. The intestinal tract is involved less commonly. 30

    DEGOS’ DISEASE
    Malignant atrophic papulosis (Degos’ disease) is a rare vascular disorder characterized by distinctive skin lesions associated with multiple GI infarctions. 31 Skin lesions typically consist of red papules that become umbilicated in the center. 32 The center eventually becomes porcelain white and atrophic. Lesions of the GI tract begin a few weeks, or months, after the onset of the cutaneous eruption. Symptoms usually consist of diffuse or localized pain; eventually, intestinal infarction and perforation, with peritonitis, occur. 33 , 34 The condition is often fatal. Histologically, the basic pathologic process is endovasculitis, characterized by endothelial cell swelling and proliferation, sometimes with fibrinoid necrosis within the intima of the blood vessel. The intima is the primary site of involvement. Typically, there is an absence of significant inflammation and necrosis in the media and adventitia. Organized thrombi are often present in the vessel lumen. Necrosis of the bowel wall is common. 35

    DIFFUSE HEMORRHAGIC GASTROENTEROPATHY
    This is an unusual disorder characterized by diffuse hemorrhagic mucosa in the stomach and small bowel. Luminal narrowing of capillaries and postcapillary venules in the lamina propria results from swelling and proliferation of the endothelial cells. Margination and emigration of neutrophils, as well as partial occlusion of some blood vessels by fibrin thrombi, are always present. 36 This is a type of localized small vessel vasculopathy of the upper GI tract.

    ENTEROCOLIC PHLEBITIS
    A number of unusual, isolated intestinal vasculitides have been described (see Chapter 10 for details); these disorders have been given a variety of descriptive names, such as lymphocytic phlebitis, necrotizing and giant cell granulomatous phlebitis, idiopathic myointimal hyperplasia of mesenteric veins, mesenteric inflammatory veno-occlusive disease, intramural mesenteric venulitis, and idiopathic colonic phlebitis. 37 All of these disorders are characterized by the presence of a lymphocyte-rich phlebitis with thrombotic obstruction of the veins ( Fig. 6-4 ). At later stages of disease, myointimal occlusive proliferation, without the inflammation, is typically seen. 38 Granulomatous and necrotizing inflammation may develop as well. Clinically, the patients have a favorable course postresection, typically without recurrence of intestinal ischemia or development of systemic vasculitis.

    FIGURE 6-4 Enterocolic phlebitis; high-power view of submucosal vein and artery. A lymphocytic inflammatory infiltrate is present adjacent to and involving the vein wall. The adjacent artery is uninvolved. Prominent vascular dilation is noted as well.

    Dermatologic Disorders
    Both the skin and the GI tract may become involved in a variety of disease processes. These lesions may be divided as follows:
    1 Primary dermatologic disorders that also involve the GI tract ( Table 6-1 ). These lesions are discussed in this section.
    2 Systemic disorders involving both the skin and the GI tract ( Table 6-2 ). These lesions are discussed in other areas of this chapter.
    3 Primary GI disorders with skin manifestations. Only skin disorders associated with malignancies of the GI tract are discussed in this chapter. The remaining lesions are discussed elsewhere in this textbook.
    TABLE 6-1 Primary Dermatologic Diseases Involving the GI Tract
    Bullous diseases
    Epidermolysis bullosa
    Pemphigus vulgaris
    Bullous pemphigoid
    Erythema multiforme
    Stevens-Johnson syndrome
    Dermatitis herpetiformis
    Dermatogenic enteropathy
    Eczema
    Psoriasis
    TABLE 6-2 Systemic Diseases Involving the Skin and GI Tract
    Vascular disorders
    Hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease)
    Kaposi’s sarcoma
    Blue rubber bleb nevus syndrome
    Necrotizing angiitis
    Degos’ disease (malignant atrophic papulosis)
    Metabolic disorders
    Acrodermatitis enteropathica
    Fabry’s disease (angiokeratoma corporis diffusum)
    Plummer-Vinson syndrome
    Rheumatologic and connective tissue disorders
    Scleroderma
    Dermatomyositis
    Systemic lupus erythematosus
    Polyarteritis nodosa
    Pseudoxanthoma elasticum
    Ehlers-Danlos syndrome
    Miscellaneous disorders
    Amyloidosis
    Familial Mediterranean fever
    Mastocytosis

    BULLOUS DISEASES
    The majority of primary dermatologic bullous disorders that involve the GI tract typically occur in conjunction with a skin disorder (excluding dermatitis herpetiformis). These typically involve the upper portion of the esophagus. Patients present with symptoms of dysphagia and odynophagia. Histologically, the lesions in esophageal squamous mucosa appear similar to those in the skin. The key distinguishing morphologic features are the level of the plane of separation (vesicle formation), the type of inflammatory infiltrate, and the presence or absence of acantholysis. Bullae rarely remain intact. Therefore, diagnosis of these lesions on GI biopsy specimens is challenging. The diagnosis is usually made on the basis of appropriate clinical information combined with biopsies of the skin lesions. In the esophagus, lesions often rupture and produce erosions; occasional fibrosis and stricture formation are also seen.

    Epidermolysis Bullosa
    Epidermolysis bullosa, a group of more than 12 genetically determined disorders that involve all organs lined by squamous epithelium, 39 is characterized by the formation of vesiculobullous lesions secondary to minor trauma. The site of cleavage can be in the dermis (dermolytic or dystrophic form), at the dermoepidermal junction (junctional form), or in the epidermis (epidermolytic or simplex form). Involvement of the GI tract occurs in 50% of patients with the dystrophic form and in 33% of patients with the junctional or simplex form. 40 Stricture and esophageal webs occur most frequently in the dystrophic form. However, they can also be seen rarely in the junctional or simplex form. 41 In addition, anal and perianal disease and perianal blistering are seen in all types. Histologically, this lesion is characterized by separation of the epithelium and formation of bullae, with little or no inflammatory infiltrate.

    Pemphigus Vulgaris
    Pemphigus vulgaris is a bullous disorder that affects middle-aged and older individuals. The bullae are superficial and flaccid. The lesion is an intraepidermal bulla formed by acantholysis (loss of intracellular bridges). Histologically, the cells lose their normal angular contours and become rounded. Basal keratinocytes typically remain attached to the epidermal basement membrane. The inflammatory infiltrate is variable; eosinophils and lymphocytes are the most common cells present in the epidermis, both surrounding and within the bullae and within the subjacent lamina propria. Standard biopsy forceps may provide only superficial biopsies that are inadequate for diagnosis. 42 Direct immunofluorescence for immunoglobulins is positive in the epidermal intercellular spaces. 43 The incidence of esophageal involvement is unclear. Some studies report endoscopic lesions in up to 80% of patients. 44 , 45 In addition, immunofluorescence performed on esophageal mucosa is usually positive in all patients with active disease. 46

    Bullous Pemphigoid
    Bullous pemphigoid is a subepidermal bullous disorder characterized by large, tense blisters on the skin. Mucosal involvement of the GI tract is much less common than in pemphigus vulgaris, 47 although one report described esophageal blisters in 4% of patients with typical bullous pemphigoid. 48 The histology of the bullous lesion has not been described. However, linear deposits of IgG and complement in the basement membrane of the esophagus, and occasionally in the stomach, similar to those found in the skin, have been described. 48 A single case of bullae in the colon has also been reported. 49

    Erythema Multiforme
    Erythema multiforme, as the name implies, is a cutaneous reaction pattern characterized by a combination of skin and mucosal lesions. The mucosal lesions usually occur on the lips or in the oral cavity and conjunctiva. However, the esophagus and, rarely, other regions of the GI tract may be involved. 50 Included in this group of disorders is the Stevens-Johnson syndrome (macular trunk lesions with mucosal involvement). 51 Many of these lesions occur secondary to drug reactions or, occasionally, infectious agents such as mycoplasmae. In the esophagus, lesions have been described as small white patches similar to those caused by Candida species infection. Histologically, superficial ulceration and marked intraepithelial lymphocytosis are often noted. Individual squamous cell necrosis most often involves the basal cells but may include the entire thickness of the epithelium as well. Lesions typically regress; thus, GI complications are typically not sampled for biopsy.

    Dermatitis Herpetiformis
    This is a pruritic vesicular dermatitis with a symmetrical distribution on the skin. Unlike previously discussed bullous disorders of the skin, this disease does not produce bullous lesions in the GI tract. Dermatitis herpetiformis is strongly associated with celiac disease. Approximately 70% of patients with dermatitis herpetiformis show evidence of villous atrophy on small bowel biopsy. 52 However, most patients are asymptomatic. Of patients with dermatitis herpetiformis, 90% are positive for endomysial autoantibodies 53 (typically seen with celiac sprue as well). Human leukocyte antigen associations are similar for both dermatitis herpetiformis and celiac sprue. Both the skin disease and the GI symptoms can be controlled by a gluten-free diet. 54

    DERMATOGENIC ENTEROPATHY
    Many GI symptoms and histologic findings have been described in patients with active psoriasis and eczema. Steatorrhea and malabsorption are not uncommon, and the terms dermatogenic enteropathy and psoriatic enteropathy have been applied to these syndromes. 55 , 56 Histologically, the duodenal mucosa shows an increase in the number of mast cells and eosinophils. A subset of patients have increased numbers of duodenal intraepithelial lymphocytes and antibodies to gliadin (suggestive of latent celiac sprue). 57 In addition, the colon may show increased lamina propria cellularity, active inflammation, and occasional gland atrophy in mucosal biopsies of patients with psoriasis without bowel symptoms. 58

    DERMATOLOGIC DISORDERS ASSOCIATED WITH MALIGNANCIES OF THE GI TRACT

    Acanthosis Nigricans
    This disorder consists of numerous brown, hyperpigmented, velvety skin plaques located in the axillae, groin, and flexural areas. The lesion has two major forms-one associated with internal malignancies and the other associated with insulin resistance. Microscopically, dermal lesions are characterized by diffuse hyperkeratosis and papillomatosis. Epithelial hyperplasia of the esophagus also has been described.
    When present, this lesion is usually associated with adenocarcinomas of the stomach and colon. At least one report suggests that it is caused by the production of transforming growth factor-α by tumor cells. 59

    Tylosis
    Focal nonepidermolytic palmoplantar keratoderma (tylosis) is a rare autosomal dominant inherited defect of keratini-zation. It is strongly associated with the development of squamous cell carcinoma of the esophagus, with tumors appearing in 95% of patients. 60 The skin lesion is characterized by thickening of the stratum corneum of the palms and soles. Molecular studies have mapped the defective gene to a small region on chromosome 17q25. 61 , 62 The same region has been implicated in the development of sporadic squamous cell carcinoma and Barrett’s esophagus-associated adenocarcinoma.

    Miscellaneous Disorders
    Several other nonspecific skin diseases are associated with GI neoplasms. 63 These include generalized dermal pigmentation, migratory thrombophlebitis, and seborrheic keratosis (Leser-Trélat sign). 64

    Endocrine Disorders
    Alterations in the secretion of endocrine hormones in endocrine disorders may have a variety of GI effects. Most of these produce functional GI symptoms such as vomiting, diarrhea, constipation, and abdominal pain secondary to changes in GI motility ( Table 6-3 ). Most of these diseases do not cause significant morphologic or histologic abnormalities; hence, they are described only briefly.
    TABLE 6-3 GI Manifestations of Endocrine Disorders Organ Endocrine Disorder GI Manifestation Adrenal Addison’s disease Anorexia, weight loss, abdominal pain, diarrhea   Pheochromocytoma Watery diarrhea, intestinal ischemia Hypothalamus and pituitary Acromegaly Increased incidence of colonic polyps and neoplasms Pancreas Diabetes Motility disorders, infections, abdominal pain   Gastrinoma Peptic ulcers, gastric fundic hyperplasia   VIPoma Watery diarrhea   Somatostatinoma Diabetes, steatorrhea   Glucagonoma Angular stomatitis and glossitis, giant intestinal villi Parathyroid Hyperparathyroidism Nausea, vomiting, abdominal pain   Hypoparathyroidism Malabsorption Thyroid Hyperthyroidism Hypermotility: diarrhea or steatorrhea   Hypothyroidism Decreased motility: reflux, bezoars, ileus, constipation   Medullary carcinoma Watery diarrhea
    VIP, vasoactive intestinal peptide.

    ADRENAL GLAND
    Addison’s disease (primary chronic adrenocortical insufficiency) may cause common GI disturbances, including anorexia, nausea, vomiting, and diarrhea. 65 Pheochromocytomas are characterized by hypertension due to high catecholamine levels. Intestinal pseudo-obstruction, megacolon, and even bowel ischemia have also been described and are thought to be secondary to the vasoconstrictive action of excess catecholamine levels. 66

    HYPOTHALAMUS AND PITUITARY
    The hypothalamus and pituitary function as a unit. Disorders of either one infrequently affect the GI tract. Hypopituitarism affects intestinal motility, as does hypothyroidism. Pituitary adenomas are part of the multiple endocrine neoplasia (MEN) syndrome, discussed later in this chapter. Of the hyperpituitary lesions, acromegaly is of interest with respect to GI neoplasia. Acromegaly is characterized by chronic growth hormone and insulin-like growth factor hypersecretion, usually due to a pituitary adenoma. It is associated with overgrowth of the musculoskeletal system and all organs, including the GI tract. It has been shown to increase epithelial cell proliferation in the colon, 67 and an increased prevalence of colonic adenomas and colonic carcinoma has been noted. 68 A less well-established increased risk of gastric carcinoma has also been suggested. 69

    PANCREAS
    Diseases of the exocrine and endocrine pancreas commonly affect the GI tract. These include pancreatic exocrine insufficiency, diabetes, and hormonal effects of functional pancreatic endocrine neoplasms. Pancreatic exocrine insufficiency typically gives rise to steatorrhea and malabsorption and is discussed further in Chapter 34 .
    Diabetes can involve significant GI symptoms. 70 These result from decreased motility secondary to autonomic nervous system dysfunction. Patients have symptoms such as abdominal pain, bloating, early satiety, nausea, and vomiting. Abdominal bloating appears to correlate best with decreased gastric emptying. 71 The delayed gastric emptying associated with gastric atony and gastric dilation is called gastroparesis diabeticorum , and an increased risk of bezoar formation is apparent. Patients can also experience periodic intractable diarrhea and crampy abdominal pain. Because of hypomotility, these patients are at risk for bacterial infection and malab-sorption. Patients are also at increased risk for Candida infection of the esophagus. 72 Histologic features are nonspecific. Neuropathic findings with silver stains have been described, 73 as have PAS-positive vascular deposits in the vessels of the submucosa. 74
    Excess hormonal production from the pancreatic islets of Langerhans can be a result of diffuse hyperplasia (nesidioblastosis) or pancreatic endocrine tumors. Many hormones, such as insulin, glucagon, somatostatin, pancreatic polypeptide, gastrin, adrenocorticotropic hormone, calcitonin, parathormone, and serotonin, can be produced by these lesions. All GI manifestations reflect altered digestive function and motility. 75

    PARATHYROID
    Both hyperparathyroidism and hypoparathyroidism can cause GI symptoms. GI symptoms are common in hyperparathyroidism; they occur in half of patients and may be the presenting symptom in 15% of cases. 76 These patients typically have abdominal pain, nausea, vomiting, and constipation. Many of these symptoms are thought to be due to hypercalcemia, which results in altered neuronal transmission and neuromuscular excitability. 77 Hypoparathyroidism can be associated with malabsorption and steatorrhea. The small intestinal mucosa is typically histologically normal, but rare associations with celiac sprue have been reported. 78

    THYROID
    Both hyperthyroidism and hypothyroidism can cause GI symptoms. Hyperparathyroidism produces hypermotility of the gut, and hypoparathyroidism causes hypomotility. Hyperthyroidism can result in rapid gastric emptying, watery diarrhea, and steatorrhea. 79 No constant structural changes in the mucosa or in the wall of the bowel have been consistently reported. Hypothyroidism can be associated with gastric bezoar formation, ileus, volvulus, constipation, and megacolon. 79 In patients with marked myxedema, dilation and thickening of the bowel wall with microscopic accumulation of mucopolysaccharide substances in the submucosa, muscularis propria, and serosa have been described. 80
    Thyroid neoplasms may also produce GI effects. Medullary carcinoma of the thyroid is a tumor of the calcitonin-producing endocrine C cells of the thyroid. Patients may have prominent “explosive” watery diarrhea as the result of ectopic hormone production. 81 Papillary carcinoma of the thyroid also can be associated with Gardner’s syndrome. 82

    MULTIPLE ENDOCRINE NEOPLASIA
    The MEN syndromes are a group of autosomal dominant inherited disorders associated with hyperplasia or neoplasms of several endocrine organs. Three main varieties of this syndrome can occur-MEN I, MEN IIa, and MEN IIb (or III). GI manifestations are caused by the products of endocrine proliferations. 83 Each of these syndromes is associated with a mutant gene locus-MEN I with the MENI gene locus, and MEN IIa and IIb with the RET gene locus. MEN I is associated with pancreatic endocrine tumors (often gastrinomas) and the Zollinger-Ellison syndrome, the latter of which is associated with gastric and duodenal disease. MEN IIb may be associated with ganglioneuromatosis, ganglion cell hyperplasia, and hypertrophy of the plexuses of Meissner and Auerbach in the GI tract. Chronic constipation, diarrhea, or both may be associated with MEN IIb. 84

    Hematologic Disorders

    HEMORRHAGIC DISORDERS
    Patients with bleeding disorders may develop spontaneous hemorrhage in any part of the GI tract. Ten to 25% of patients with hemophilia suffer from GI hemorrhage. 85 Von Willebrand’s disease, 86 heparin or warfarin overdose, vitamin K deficiencies, platelet deficiency, thrombotic thrombocytopenic purpura, and hemolytic-uremic syndrome can all result in hemorrhage of the GI tract. This is most commonly seen in the upper GI tract and typically is most prominent in the submucosa. It can be severe enough to involve the entire thickness of the bowel wall and give rise to an intramural hematoma. 87 More severe lesions can cause luminal narrowing, rigidity with obstruction, and, rarely, intussusception. 85

    THROMBOTIC DISORDERS
    Sickle cell anemia, 88 polycythemia rubra vera, 89 and other thrombotic disorders 90 can produce thrombosis, leading to infarction and hemorrhage of the intestines. Sickle cell anemia causes sickling of red blood cells and hyperviscosity of the blood and typically produces arterial/capillary obstruction. 88 It involves the watershed areas of the distal transverse colon and splenic flexure, which have the lowest oxygen tension. Sickled red blood cells may be found in the vessels. Polycythemia usually leads to venous obstruction of the portal and mesenteric veins. These lesions involve the deeper parts of the bowel wall, including the muscularis propria. Diagnosis is based on the finding of venous thrombi in the mesenteric and mesocolic tissues not in the field of infarction that occur in conjunction with appropriate clinical history.

    MEGALOBLASTIC ANEMIA
    Megaloblastic anemias are associated with deficiencies of folic acid and vitamin B 12 . These anemias are characterized by megaloblastic proliferation of actively growing cells, as is typically described in bone marrow aspirations, but also seen in the epithelial cells of the GI tract. Owing to impaired DNA synthesis, actively dividing cells in the gastric pits, small bowel, and colonic crypts typically show enlarged, immature-appearing nuclei ( Fig. 6-5 ). The nucleus-to-cytoplasm ratio3 is decreased. The overall numbers of mitotic figures are also reduced. In addition, PAS-negative, Alcian blue-negative cytoplasmic vacuoles have been described in duodenal enterocytes. 91 Megaloblastic anemia can be caused by pernicious anemia secondary to autoimmune gastritis; therefore, gastric findings of atrophic autoimmune gastritis may also be present.

    FIGURE 6-5 Nucleomegaly in megaloblastic anemia; high-power view of actively dividing cells evident in crypts of the small intestine. Many enlarged immature-appearing nuclei can be seen in the upper third of the crypt.

    LEUKEMIA AND LYMPHOMA
    Involvement of the GI tract is often noted in patients with leukemia and lymphoma. This can occur directly by tumor (primary or secondary), secondary to complications of disease, or secondary to therapy (see Chapter 27 for details).
    Autopsy studies have revealed GI involvement in 50% of patients with leukemia. 92 In secondary involvement of the GI tract by either leukemia or lymphoma, tumor infiltrates are often multifocal and may be present anywhere from the esophagus to the rectum. 93 These can cause aphthous-type ulcers (typical of leukemic infiltrations) or can result in polypoid, masslike, or large ulcers (typical of lymphomatous involvement). 94 The larger mass lesions can occasionally cause obstruction or intussusception. 95 Histologic features are typical of the particular type of leukemia or lymphoma. Malignant cells are typically found in the mucosal and submucosal tissue. Tissue should be collected for molecular and cytogenetic analysis because many leukemias and lymphomas include diagnostic and clinically important changes. 96 Primary lymphomas of the GI tract are often solitary lesions, although diffuse forms do occur (typically in the small bowel).
    Secondary effects of tumor overgrowth, or of chemotherapy, resulting in decreased numbers of platelets and inflammatory cells can lead to hemorrhagic lesions of the GI tract and opportunistic infections. In addition, neutropenic colitis, which is a necrotizing inflammatory disorder of the colon that occurs in neutropenic patients, can occur with chemotherapy and, rarely, as a complication of acute leukemia. 97 Finally, patients who have received a bone marrow transplant may develop graft-versus-host disease, which is characterized by apoptotic destruction of the epithelium throughout the GI tract. It typically presents with diarrhea. Histologically, it is characterized by apoptosis of the epithelial cells, followed by crypt and gland loss and, ultimately, mucosal erosion and ulceration. 98

    Metabolic Disorders

    ACRODERMATITIS ENTEROPATHICA
    This systemic disorder occurs secondary to zinc deficiency, which results from a congenital defect in absorption of dietary zinc. This disorder has recently been localized to a gene (SLC39A4) that codes for a transmembrane zinc uptake protein (hZIP4). 99 It typically presents after infancy and weaning (although rare cases have been described in adulthood 100 ). It is characterized by chronic diarrhea associated with failure to thrive, periorofacial dermatitis, paronychia, nail dystrophy, alopecia, susceptibility to infection, and behavioral change. Serum zinc levels are typically decreased. Treatment is provided in the form of oral zinc. Mucosal biopsy of the small bowel can be normal or can show mild, patchy villous lesions. Abnormal inclusion bodies have been described in Paneth cells on electron microscopy. 101 Acrodermatitis may also be due to zinc deficiency secondary to Crohn’s disease 102 and malnutrition. 103

    PLUMMER-VINSON SYNDROME (PATERSON-BROWN KELLY SYNDROME)
    This unusual syndrome has shown a recent decrease in incidence. 104 It is characterized by iron deficiency (its presumed cause), dysphagia, and esophageal webs. 105 Dermatologic findings of angular stomatitis, atrophic tongue, and brittle nails are also seen. Long-standing disease is associated with an increased incidence of postcricoid carcinoma. Iron repletion improves all lesions.

    VITAMIN DISORDERS
    In general, the majority of vitamin disorders are not associated with specific GI symptoms or lesions. Exceptions are brown bowel syndrome, thought to be due to a deficiency of vitamin E (discussed later), and pellagra associated with niacin deficiency. Multiple vitamin deficiencies are often noted in malabsorptive disorders. Vitamins, macronutrients, and minerals are thought to have a protective effect with respect to neoplasia of the GI tract, especially for esophageal 106 , 107 and gastric 108 malignancies. Deficiency in vitamin K or anticoagulation therapy leads to a decrease in coagulation factors and can result in hemorrhagic lesions throughout the body. 109
    In the GI tract, these range from focal petechial hemorrhages to frank exsanguination. No specific histologic features are associated with these lesions. Similarly, vitamin C deficiency (scurvy) can lead to hemorrhage and delayed wound healing. Deficiencies of folic acid and vitamin B 12 are associated with megaloblastic anemia and megaloblastic changes in the epithelial cells of the stomach and small intestine. 110 Also of interest, Olestra (a nonabsorbed fat replacement) may decrease the absorption of fat-soluble vitamins. 111

    Pellagra
    Pellagra is a vitamin deficiency that has major GI effects. It is due to a deficiency of niacin, either dietary (deficiency found in developing countries, alcoholics, and the elderly) or secondary to impaired absorption (such as with Crohn’s disease 112 or amyloidosis 113 ). It is characterized clinically by diarrhea, dermatitis, and dementia. Diarrhea is often bloody. However, patients can have steatorrhea. 114 The vitamin deficiency interferes with the normal renewal of epithelial tissue, hence the effects on the skin and GI tract. Endoscopically, approximately half of patients have lesions. However, all have microscopic inflammation. Endoscopic lesions range from redness and granularity to focal ulceration and more extensive confluent lesions. Microscopically, the inflammatory infiltrate is nonspecific. In the esophagus, mild to severe esophagitis is seen. 115 The small bowel may be normal or may show mild villous blunting and increased inflammatory cells in the lamina propria. 116 In the large bowel, a mild to moderate inflammatory infiltrate with features of colitis cystica superficialis (cystic dilation of the crypts and crypt abscess formation) has been described. Patients usually respond to niacin replacement therapy.

    LIPOPROTEIN DISORDERS

    Abetalipoproteinemia (see Chapter 9 for details)
    This is an autosomal recessive disorder characterized by a defect in the secretion of plasma lipoproteins that contain apolipoprotein B. Patients have steatorrhea, usually in infancy, with central nervous system symptoms such as disturbance in gait and balance and fatigue. 117 On peripheral smear, acanthocytes are usually prominent (in 50% of red blood cells). Laboratory findings show an absence of very low density lipoproteins, the presence of chylomicrons, and a reduction in triglycerides and other lipids. The defect occurs in a microsomal triglyceride transfer protein required for the secretion of plasma lipoproteins containing apolipoprotein B. 118 Normal intraluminal digestion of lipids occurs, along with transport of triglycerides and monoglycerides and their reesterification in enterocytes. However, lipids cannot be excreted on the basal lateral membrane of the enterocytes into blood and lymphatics. Histologically, this translates into prominent accumulation of fine lipid droplets within the basal aspect of the enterocytes ( Fig. 6-6 ). These can be stained with Oil Red O on frozen-section tissue or may be seen by electron microscopic examination. The overall architecture of the small bowel is normally well maintained. One pitfall in diagnosis is the similar appearance of lipid droplets identified in normal individuals after a recent lipid-rich meal. Thus, the diagnosis should be made only in fasting patients.

    FIGURE 6-6 Abetalipoproteinemia. A, High-power view of vacuolated epithelial cells that are clear-staining. B, Fat stain highlighting the fat in the surface epithelial cells.
    (From Lewin D, Lewin KJ: Small intestine. In Weidner N, Cote RJ, Suster S, et al [eds]: Modern Surgical Pathology. Philadelphia, WB Saunders, 2003, p 742.)

    Tangier Disease
    Tangier disease is an autosomal recessive disorder characterized by deposition of cholesteryl esters in the reticuloendothelial system, almost complete absence of high-density lipoprotein in the plasma, and aberrant cellular lipid trafficking. 119 Clinically, patients present with hepatosplenomegaly, enlarged tonsils, peripheral neuropathy, and, occasionally, diarrhea. Laboratory studies reveal low blood levels of high-density lipoprotein and cholesterol (due to lack of apoprotein A) and high levels of triglycerides. Endoscopically, the lesions are described as tiny yellow nodules or orange-brown spots. 120 Microscopic examination reveals clusters of foamy histiocytes in the lamina propria ( Fig. 6-7 ). Electron microscopic findings include intracytoplasmic vacuoles unbounded by membranes; these are often confluent in appearance 121 (see Chapter 9 for details).

    FIGURE 6-7 Tangier disease involving the colon. This condition represents a deposition of cholesterol esters in tissue histiocytes.

    LYSOSOMAL STORAGE DISORDERS
    Lysosomes, which are a major component of the intracellular digestive tract, contain hydrolytic enzymes made in the endoplasmic reticulum. These enzymes break down a variety of complex macromolecules that are either a component of the cell or are taken up by phagocytosis. Lysosomal storage disorders are inherited disorders (usually autosomal recessive) caused by lack of a functional enzyme or defective enzyme lysosome targeting. Substances typically accumulate within cells at the site where most of the degraded material is found; degradation typically occurs at this location.
    Storage disorders can be divided based on the biochemical nature of the accumulated metabolite into glycogenoses, sphingolipidoses (lipidoses), mucopolysaccharidoses, mucolipidoses, and others. Most of these diseases have prominent central or peripheral nervous system effects. 122 In general, except for Fabry’s disease, these diseases do not have significant GI effects. Case reports of malabsorption in GM1 gangliosidosis, 123 diarrhea in Niemann-Pick disease, 124 and diarrhea and vomiting in Wolman’s disease have been described. 125 The importance of these diseases is that depositions can be identified in a variety of cells in the GI tract (summarized in Table 6-4 ), typically in the phagocytic cells (macrophages) in the lamina propria. The histologic appearance typically reveals an accumulation of cells with foamy cytoplasm. The material may be positive for fat stains such as Oil Red O or Sudan black on frozen-section tissue or PAS stain, depending on the particular substance that has accumulated. Electron microscopic examination typically reveals enlarged, unusually shaped lysosomes. Historically, many of these diagnoses have been made on rectal biopsy with histochemical stains and subsequent electron microscopic examination. 126 - 128 This technique has largely been supplanted by specific enzyme content analysis of circulating lymphocytes or biopsy material. Differentiation among the common mimics of storage disorders is described in the next section.

    TABLE 6-4 Lysosomal Storage Diseases

    Fabry’s Disease
    This rare X-linked lipid storage disorder, caused by a deficiency of lysosomal α-galactosidase A, results in cellular deposition of glycolipids in many tissues. Clinically, these patients have involvement of multiple organ systems. Symptoms include excruciating pain in the extremities (acroparesthesia), skin vessel ectasia (angiokeratoma), corneal and lenticular opacity, cardiovascular disease, stroke, and renal failure. 129 GI symptoms are seen in 62% of male and 29% of female heterozygotes. 130 Features include vascular ectasia, 131 delayed gastric emptying, 132 diarrhea, and, rarely, ischemic bowel disease with perforation. 133 Histologically, glycolipid deposition is identified in vacuolated ganglion cells in Meissner’s plexus and in small blood vessels. By electron microscopy, laminated and amorphous intralysosomal “zebra-like” osmiophilic deposits occur in ganglion cells, smooth muscle fibers, and endothelial cells. 130

    Common Mimickers of Lysosomal Storage Diseases
    Common mimickers of lysosomal storage diseases are summarized in Table 6-5 . These are divided into two general categories-pigmented and nonpigmented. The majority of lesions result from a proliferation of histiocytes with either engulfed infectious organisms or cellular or extracellular material. Pigmented lesions, which are in the differential diagnosis of neuronal ceroid lipofuscinosis, include melanosis, pseudomelanosis, brown bowel syndrome, hemosiderosis, and barium granuloma. Nonpigmented lesions are in the differential diagnosis of all of the rest of the lysosomal storage diseases and include xanthoma, muciphages, Whipple’s disease, Mycobacterium avium complex infection, pseudolipomatosis, malakoplakia, granular cell tumors, signet ring adenocarcinoma, and malignant histiocytosis.

    TABLE 6-5 Macrophage Infiltrates in the Lamina Propria

    PIGMENTED LESIONS

    Melanosis.
    Melanosis coli is characterized by pigment deposition in macrophages in the lamina propria. Endoscopically, the bowel mucosa can appear normal or brownish in color, depending on the amount of pigment present. Occasionally, the pigment is so prominent that the mucosa shows multiple foci of tiny white polypoid lesions on a brown background. The white lesions represent normal or hyperplastic lymphoid aggregates that do not contain pigment. 134 Histologically, the pigment in macrophages has a dark brown, granular appearance, and these cells may be located anywhere in the lamina propria ( Fig. 6-8A ). It contains polymerized glycolipids, glycoproteins, and melanin (“melanized ceroid”) 135 and is typically associated with anthraquinone laxative use. However, a number of studies have shown an association with increased apoptosis of epithelial cells 135 , 136 (caused by laxatives as well as chronic colitis, 137 chronic granulomatous disease, 138 and bamboo leaf extract 139 ) and suggest that melanosis is a nonspecific marker of increased apoptosis.

    FIGURE 6-8 Pigmented cells mimicking lysosomal storage disease. A, Melanosis coli. Colonic mucosa containing lamina propria macrophages with dark brown, granular appearance. B, Pseudomelanosis. Duodenal mucosa containing macrophages with a black pigment. C, Barium. Colonic mucosa containing a gray, finely granular material in the lamina propria.

    Pseudomelanosis.
    This is a rare benign condition characterized by the presence of discrete, flat, small, brown-black spots typically in duodenal mucosa (speckled duodenum) but also reported in gastric mucosa. 140 It occurs in any age group and appears to be associated with upper GI bleeding, chronic renal failure, hypertension, or diabetes mellitus. 141 Unlike melanosis coli, it is not associated with anthraquinone laxatives. Microscopically, the black pigment is located subepithelially in mucosal macrophages, often at the tips of the villi (see Fig. 6-8B ). Histochemical studies have revealed the pigment to represent a mixture of iron sulfide, hemosiderin, lipomelanin, and ceroid. It is typically negative or only focally positive with iron stains. Electron microscopic studies have revealed the material to be located in lysosomes.

    Brown bowel syndrome.
    This is a rare acquired disorder associated with malabsorptive states and vitamin E deficiency. It is characterized by accumulation and deposition of lipofuscin pigment predominantly in the smooth muscle of the bowel, which gives a brown color to the bowel. It occurs most often in the small bowel. However, it can involve the colon or stomach as well. Vitamin E (α-tocopherol) is an antioxidant that prevents peroxidation of unsaturated fatty acids. It is postulated that a deficiency in this vitamin may result in oxidized lipids, which polymerize with polysaccharides to form the brown pigment. Histologically, the pigment is most prominent in the smooth muscle cells of the muscularis mucosae and propria (see Chapter 7 for photograph). Some pigmentation of macrophages, nerves, ganglia, and vascular smooth muscle also is usually noted. 142 The distribution of the pigment in conjunction with an appropriate clinical history often helps in differentiation of this lesion from the others described earlier. The pigment, which stains positive for PAS, acid-fast, and fat stains on unfixed tissues, also shows the typical bright yellow autofluorescence pattern of lipofuscin. Electron microscopic examination usually reveals mitochondrial damage as well as pigment concentrated in the perinuclear Golgi region. 143 Clinically, the pigment does not have any direct effect on the bowel, although defects in contractility, 144 intussusception, 145 and toxic megacolon have been reported. 146

    Hemosiderosis/hemochromatosis.
    In advanced iron overload disorders, iron is deposited in parenchymal cells throughout the body. In the GI tract, deposits are found most commonly in the parietal cells of the stomach, Brunner’s glands in the duodenum, and the epithelial cells of the gut. 147 , 148 Some minor amounts of pigment can also be seen in macrophages. The pigment appears as finely granular, dark brown to black particles. It stains positive with iron stains. The pigment needs to be differentiated from pseudomelanosis duodeni, which is typically larger and located predominantly in macrophages.

    Barium granuloma.
    This is a complication of barium examination, typically of the colon. It is secondary to extravasation of barium into the wall of the bowel secondary to mucosal injury, overinflation of the rectal balloon, or intrinsic inflammatory disease. 149 Endoscopically, it may present as a polypoid lesion and may mimic an adenoma or carcinoma. Histologically, one sees a granulomatous reaction surrounding gray, finely granular, refractile, PAS-negative material located in the cytoplasm of histiocytes and in the lamina propria (see Fig. 6-8C ). The material is not birefringent. Radiographs of the paraffin block can help reveal the presence of radiopaque material. 150

    NONPIGMENTED LESIONS

    Xanthoma.
    This is a fairly common lesion of the GI tract most commonly found in the stomach. The terms xanthoma , xanthelasma , lipid island , and xanthogranulo-matous inflammation have been used synonymously. Endoscopically, xanthomas appear as small yellow nodules or streaks on the mucosa. They represent an accumulation of lipid and cholesterol within macrophages. Microscopically, one sees a collection of macrophages containing foamy cytoplasm positive for fat stains on unfixed tissue ( Fig. 6-9A ). Immunohistochemical stains for α 1 -antitrypsin and monocyte chemotactic and activating factor are also typically positive, 151 whereas cytokeratin and mucin stains are negative. The lesions are typically associated with chronic inflammatory states, 152 but can be seen with malignancies. 151

    FIGURE 6-9 Nonpigmented cells mimicking lysosomal storage disease. A, Xanthoma. Gastric biopsy with abundant macrophages in the lamina propria. The macrophages have a bland central nucleus with foamy cytoplasm. B, Muciphages in the rectum. Rectal biopsy containing foamy macrophages with coarse, large cytoplasmic vacuoles in the superficial lamina propria. C, Pseudolipomatosis. Colonic biopsy with clear, unlined spaces in the lamina propria. D, Whipple’s disease. Small bowel biopsy shows expansion of the villus by numerous pink macrophages. A single clear space representing extracellular lipid is present in the tip of one of the villi. E, Mycobacterium avium complex infection. Small bowel biopsy with marked expansion of the lamina propria of the villi by pink, homogeneous macrophages. F, Malakoplakia. Colonic biopsy with infiltration of the lamina propria with macrophages. A marked acute inflammatory infiltrate is also seen. The macrophages contain small blue inclusions (Michaelis-Gutmann bodies). G, Granular cell tumor. Esophageal biopsy with infiltration of large granular cells in the lamina propria below the squamous epithelium. H, Signet ring cell adenocarcinoma. Gastric biopsy with infiltration of single cells in the lamina propria. Signet ring cells can be identified in the center of the photograph, just under the surface epithelium. They contain eccentrically located, enlarged atypical nuclei.

    Muciphages.
    These are mucin-rich phagocytes that accumulate as a result of mucosal damage. They are most common in the rectum (up to 40% of all rectal biopsies contain muciphages) 153 and are also commonly found in the lamina propria and in the stalk of adenomatous polyps. 154 Endoscopically, muciphages can present as polyps or nodules. Histologically, foamy histiocytes containing coarse cytoplasmic vacuoles are present in the superficial lamina propria (see Fig. 6-9B ). Mild fibrosis and architectural distortion may occur in cases associated with a previous injury. 155 Histochemical stains for d-PAS (PAS with diastase digestion) and Alcian blue at pH 2.5 and immunohistochemical stains for CD68 and lysozyme are positive in muciphages.

    Pseudolipomatosis.
    This is a common iatrogenic lesion caused by influx of air into the mucosa secondary to endoscopy-related trauma. It is a benign, transient lesion 156 that is characterized histologically by clear open spaces in the lamina propria or submucosa, representing trapped gas, without an epithelial or endothelial cell lining 157 (see Fig. 6-9C ). These clear spaces do not stain with any specific immunohistochemical or histochemical reaction.

    Whipple’s disease.
    This is a systemic infection caused by a cultivation-resistant bacterium, Tropheryma whippelii . In the GI tract, it is primarily found in the small bowel; however, it can involve the stomach, 158 esophagus, and colon as well. 159 Histologically, one sees characteristic abundant, pink-colored, foamy macrophages filling the lamina propria. These macrophages may contain small granules that are positive for d-PAS. Extracellular lipid is often present as well (see Fig. 6-9D ). Electron microscopic examination reveals intracellular and extracellular bacterial rods in various stages of disintegration. These bacteria are also found within IgA-positive plasma cells. 160 With the use of fluorescence in situ hybridization for ribosomal RNA, the active organism appears to be most prevalent near the tips of intestinal villi in the lamina propria. 161

    Mycobacterium avium complex infection
    This is a common pathogen in AIDS that may also be seen in other immunocompromised patients. 162 It typically affects the small bowel and colon. Endoscopically, the mucosa can appear normal or coarsely granular. 163 Histologically, abundant, variably sized sheets of foamy macrophages are seen in the lamina propria that cause widening of the villi (see Fig. 6-9E ). Diagnosis is made with acid-fast or Fite’s stain positivity; numerous elongated organisms are revealed within the macrophages. PAS stain typically reveals a relatively diffuse fibrillary staining pattern in macrophages, as opposed to the granular staining characteristic of Whipple’s disease. The organisms are typically intact, unlike the various stages of disintegration that are seen in Whipple’s disease.

    Malakoplakia.
    This is a rare bacterial infection that affects patients with an underlying macrophage phagolysosome defect (not typically seen in patients with AIDS). 164 It is usually caused by Escherichia coli or Klebsiella species. 165 It is often seen in the urinary tract. However, it can involve any portion of the GI tract. Endoscopically, the mucosa shows numerous soft yellow plaques on the mucosa. Rarely, a mass lesion composed of macrophages may develop as well. Histologically, one sees an infiltration of the lamina propria by neutrophils and abundant macrophages; the latter often contain nuclear grooves (see Fig. 6-9F ). Michaelis-Gutmann bodies, which are small, pale, intracytoplasmic concretions that stain for calcium and iron, are diagnostic. Macrophages also stain for d-PAS. Electron microscopic examination reveals degenerated bacilli in phagolysosomes, similar to those seen in Whipple’s disease. 166

    Granular cell tumor.
    These tumors are believed to be of neurogenic origin and are typically found in the esophagus, but they can occur anywhere in the GI tract. 167 Rare cases have been described in the small bowel and colon. 168 , 169 They are mostly benign, but malignant tumors have been described as well. The tumors typically present as nodules in patients with nonspecific GI symptoms. Histologically, these tumors include abundant epithelioid or histiocytic cells with distinct pink granular cytoplasm in the lamina propria or submucosa (see Fig. 6-9G ). The cells are positive for PAS (with diastase) and are strongly S100-positive. Electron microscopic examination reveals cells filled with giant autophagic vacuoles (lysosomes) that contain myelin-like debris of giant lysosomes.

    Signet ring cell adenocarcinoma.
    This tumor (described in detail in Chapters 21 and 23 ) shows an infiltration of malig-nant cells with clear cytoplasm and an eccentrically placed hyperchromatic nucleus (see Fig. 6-9H ). It is differentiated from other lesions by the presence of highly atypical nuclear features and by positivity with mucin and cytokeratin stains. 170

    Clear cell carcinoid tumor.
    A rare case has been reported of a gastric carcinoid composed entirely of clear cells with foamy cytoplasm. 171 Immunopositivity for endocrine markers such as chromogranin A or electron microscopic demonstration of dense core granules helps define the lesion.

    Malignant histiocytosis.
    Langerhans’ cell histiocytosis can involve any portion of the GI tract, either as part of generalized disease or as a separate primary entity. Involved areas may present as a polypoid or mass lesion. Histologically, one sees a mucosal infiltrate composed of Langerhans’ cells that have irregular, elongated nuclei and prominent nuclear grooves and folds. The cytoplasm of the tumor cells is abundant and finely granular. These tumors are usually associated with a prominent eosinophilic infiltrate as well. Similar to mucosa-associated lymphoid tissue (MALT) lymphoma, invasion and destruction of the epithelium are common. 172 Immunohistochemical stains for S100 and CD1a are intensely positive in tumor cells. Electron microscopic examination reveals Birbeck granules in the cytoplasm of tumor cells. 173

    AMYLOIDOSIS
    Amyloidosis is not a single disease but the product of a variety of diseases. The common feature of these diseases is extracellular deposition of amyloid proteins that stain with Congo red and show apple-green birefringence under polarized light. The proteins have a typical fibrillary appearance under electron microscopy. All amyloid fibrils are protein complexes with a common tertiary molecular structure, referred to as a twisted β-pleated sheet pattern .

    Classification
    Historically, amyloidosis has been classified according to its clinical presentation (localized versus diffuse) or its underlying cause (primary, secondary, hereditary, or endocrine related); more recently, the classification is determined on the basis of the biochemical composition of the amyloid fibrils ( Table 6-6 ). The most common types that involve the GI tract are AA, AL, and Aβ 2M. In addition to the more common proteins listed in the table, a number of other types of amyloid proteins have also been described, such as Aβ (β protein precursor), AapoA1 (apolipoprotein A1), ALys (lysozyme), ACys (cystatin C), and AGel (gelsolin). Finally, a novel and common amyloid protein, called portal amyloid , has also been described. 174 , 175 However, the chemical composition and immunohistochemical staining pattern of this type have not been characterized.

    TABLE 6-6 Amyloidosis

    Clinical Features
    GI involvement is common in all types of systemic amyloidosis (primary and secondary), ranging from 85% to 100%. 176 - 178 In addition, autopsy studies in the elderly (those older than 80 years of age) have identified GI amyloid deposits (portal amyloid) in 35% 174 to 57% 175 of all indi-viduals. This amyloid appears to be a senile amyloid type without clinical consequence. In most cases associated with systemic amyloidosis, patchy involvement of the GI tract is seen without associated symptoms. However, a variety of GI symptoms, such as bleeding, 179 pseudo-obstruction, 180 decreased motility, 181 and, rarely, perforation, 182 may occur. The greater the number of deposits and the more widespread the involvement, the higher the likelihood of clinical symptoms. Vascular involvement by amyloid produces fragility and rupture of affected vessels, which can lead to the development of petechial hemorrhage of the mucosa and ischemic disease and its manifestations. In fact, ulcerating lesions may mimic inflammatory bowel disease grossly. 183
    Amyloid infiltration within nerve 184 and muscle fibers 185 can cause motility disorders. Malabsorption may result from stasis and bacterial overgrowth. Finally, amyloidosis can occasionally present as a solitary mass lesion or polyp that mimics a malignant tumor. 186 Endoscopically, the mucosa may appear normal, or show a fine granular appearance with erosions, friability, and thickening of the valvulae conniventes. 187 , 188

    Pathologic Features
    Microscopically, amyloid deposits are extracellular and have a classic waxy, homogeneous appearance ( Fig. 6-10A ). Pink hyaline amyloid may contain small slitlike spaces caused by cracking during tissue processing. Histochemical stains for Congo red (the most specific), toluidine blue, crystal violet, fluorochrome, and thioflavine usually stain all types of amyloid (see Fig. 6-10B ). Amyloid also stains positive with the PAS reaction and negative with lipid and mineral stains. In general, AA amyloid seems to localize to capillaries, small arterioles, and the mucosa. AL amyloid is often found in the muscularis propria and in medium-sized to large vessels. Aβ 2M amyloid is found mainly in the muscularis propria and in small arterioles and venules, forming subendothelial nodular lesions. 189 Portal amyloid is usually limited to mesenteric veins as small dotlike or comma-like deposits in close proximity to elastic fibers. AL and AA forms also can be distinguished by pretreatment with potassium permanganate. This pretreatment abolishes the Congo red affinity of the AA fibrils but not that of the AL fibrils. 190 Immunohistochemical stains with antibodies to amyloid A, immunoglobulins lambda and kappa light chain amyloid fibril proteins, β 2 -microglobulin, and transthyretin characterize the majority of amyloid deposits (with the exception of portal amyloid). By electron microscopy, one sees an interlocking meshwork of fibrils that measure 7.5 to 10 nm in diameter with variable length.

    FIGURE 6-10 Amyloidosis. A, Intermediate-power view of a colonic mucosal biopsy. Homogeneous material is present in the vessels in the submucosa and as extracellular deposits. The overlying colonic mucosa is unremarkable. B, Same section and microscopic power as used in A stained with Congo red. The amyloid deposits have a bright orange-red appearance.
    Amyloidosis should be differentiated from arteriosclerosis in blood vessels and from collagen in the lamina propria, submucosa, and muscularis (in systemic sclerosis). Congo red stains can help with this differential diagnosis in that neither arteriosclerosis nor collagen stains with Congo red. One study suggests that Congo red stain may not be sensitive enough in patients with early amyloidosis in minute amounts. 191
    GI biopsy is a procedure commonly used to diagnosis amyloidosis. Rectal biopsies have a sensitivity of 85%, compared with a sensitivity of 54% for fat biopsies. 176 In the rectum, amyloid deposits are most commonly seen in small arterioles and veins in the submucosa; therefore, a deep suction biopsy is usually required for adequate evaluation. Some recent studies suggest that gastric or small bowel biopsies may have a sensitivity as high as 100% for the diagnosis of amyloidosis. 187 , 192

    FAMILIAL MEDITERRANEAN FEVER (FAMILIAL PAROXYSMAL POLYSEROSITIS, RECURRING POLYSEROSITIS)
    Familial Mediterranean fever is an inherited autosomal recessive disorder seen almost exclusively in Sephardic Jews, Arabs, Armenians, and people of Turkish descent. It is characterized by recurring and self-limiting attacks of febrile serosal inflammation involving the peritoneal, synovial, and pleural membranes. This disease typically begins in childhood or adolescence and recurs at irregular intervals throughout life. 193 GI involvement consists of acute inflammation limited to the serosal surfaces of the bowel (peritonitis). Repeated episodes may result in the formation of peritoneal adhesions that may cause obstruction. Systemic amyloidosis may also occur in untreated patients. The AA amyloid type is believed to develop as a consequence of recurrent inflammation. Furthermore, amyloid deposits in the lamina propria and the submucosal vessels may occur without symptoms. The disease is often treated with colchicine.

    Pulmonary Disorders
    Hypoxia-producing pulmonary disorders can lead to is-chemic injury of the GI tract. An increased incidence of peptic ulcer disease has also been described in patients with chronic obstructive pulmonary disease. 194 This is thought to be due to hypercapnia, which stimulates gas-tric acid secretion. Pneumonia, bronchitis, asthma, and idiopathic pulmonary fibrosis are all associated with gastroesophageal reflux disease (GERD). 195 It is also believed that GERD may cause or exacerbate several pulmonary diseases.

    Reproductive Disorders

    EFFECTS OF PREGNANCY AND EXOGENOUS HORMONES
    A number of GI problems may develop during pregnancy. Nausea, vomiting, and heartburn are common in the first trimester. Some studies suggest that this is secondary to human chorionic gonadotropin or estrogen secretion, 196 which leads to abnormalities in gastric myoelectrical activity and contractility. 197 Secondary esophagitis may develop as a result of severe vomiting. Reflux, peptic ulcers, Helicobacter pylori infection, and cholecystitis are also increased during pregnancy. In addition, constipation is a frequent problem during the late stages of pregnancy. Thrombosed external hemorrhoids, anal fissures, and rectal wall prolapse are all complications that can occur secondary to vaginal delivery. 198 Population studies suggest that maternal inflammatory bowel disease is associated with increased odds of preterm delivery, low birthweight, smallness for gestational age (Crohn’s disease), and congenital malformations (ulcerative colitis). 199 - 201 Pregnancy, however, does not seem to influence the course of inflammatory bowel disease. 202
    Oral contraceptive pills and exogenous estrogens are associated with nausea and vomiting. They also are associated with thrombosis and, thus, an increased risk for is-chemia of the small bowel and colon. 203

    ENDOMETRIOSIS

    Clinical Features
    Endometriosis is a condition characterized by the presence of endometrial glands or stroma outside of the uterus. It can involve any portion of the GI tract. The most common sites of involvement are organs in the pelvis such as the rectosigmoid colon, appendix, and small bowel. The GI tract is involved in 12% to 37% of cases. 204 Intestinal endometriosis is usually asymptomatic. However, when symptomatic, it typically presents with obstructive symptoms as a result of adhesions. Complete obstruction of the bowel lumen occurs in less than 1% of cases. 204 Other atypical presentations include diarrhea and GI bleeding. Symptoms are often temporally associated with the onset of menses.

    Pathologic Features
    Endometriosis may be solitary or multifocal, and it may present as a mass lesion or with volvulus, intussusception, luminal narrowing, or adhesions. Endometrial glands or stroma are usually present on the serosal surface but may involve any layer of the bowel wall. On cut surface, the endometriosis often appears sclerotic with punctate hemorrhagic or brown areas. Microscopically, this disorder is characterized by the presence of endometrial-type glands or stroma (smaller, slightly elongated cells that are packed together, often with intermingled red blood cells) and hemosiderin-laden macrophages ( Fig. 6-11 ). At least two of these three findings should be present for a diagnosis of endometriosis to be established with certainty. In addition, fibrosis and prominent smooth muscle proliferation may surround foci of endometriosis. Fresh hemorrhage may occur. Immunohistochemical staining for estrogen receptors is usually positive in both the glands and stromal cells. 205

    FIGURE 6-11 Endometriosis of the colon. A, Low-power view of the full thickness of the colon. Glandular epithelium containing blue mucin and dark blue endometrial stroma is identified in the muscularis propria of the colon. Marked muscular hypertrophy is also seen. B, High-power view of infiltrating, bland, well-formed glands with characteristic stroma.

    Differential Diagnosis
    Most important, the differential diagnosis includes invasive adenocarcinoma. This may be extremely problematic to differentiate on fine-needle aspiration specimens. On fine-needle aspiration, the glandular epithelium is preferentially aspirated and may show nuclear atypia, mimicking an adenocarcinoma. The finding of hemorrhage, hemosiderin-laden macrophages, and stromal cells helps establish a correct diagnosis. On histologic section, differentiation from adenocarcinoma depends on the finding of characteristic stroma and hemosiderin-laden macrophages, in addition to glandular epithelium. Endometriosis may occasionally be present in mucosal biopsies, 206 and can resemble colitis cystica profunda. If smooth muscle proliferation is prominent, differentiation from a leiomyoma can be achieved by deeper sectioning of the tissue to look for glandular epithelium. In difficult cases, colonic glands are positive for carcinoembryonic antigen, whereas endometrial glands are negative for this peptide. 207

    Rheumatologic Disorders
    Connective tissue disorders may affect the GI tract in a variety of ways. They can cause hypomotility secondary to muscle inflammation or atrophy, or ischemic disease secondary to vasculitis. A variety of lesions may also develop secondary to pharmacologic therapy of these disorders. Hypomotility is most commonly seen in scleroderma, mixed connective tissue disease, and polymyositis/dermatomyositis. Vasculitis predominates in systemic lupus erythematosus, rheumatoid arthritis, polyarteritis nodosa, and Behçet’s syndrome. The majority of these disorders are treated with anti-inflammatory drugs that can have major GI effects. For example, rheumatoid arthritis is typically treated with nonsteroidal anti-inflammatory drugs (NSAIDs), which can cause peptic ulceration and bleeding.

    SCLERODERMA (see Chapter 7 for details)
    Scleroderma (progressive systemic sclerosis) is a systemic disease of unknown cause characterized by inflammation, fibrosis, upregulated collagen production, and vasculitis. GI involvement is common and is typically characterized by hypomotility. Scleroderma can be part of the CREST syndrome ( c alcinosis, R aynaud’s p henomenon, e sophageal involvement, s clerodactyly, and t elangiectases). Scleroderma most commonly involves the esophagus; manometric abnormalities are seen in up to 90% of patients. 208 However, abnormalities of the entire GI tract can be noted as well. Colonic dysfunction has been reported in up to 20% of patients. 209
    In the esophagus, lower esophageal sphincter pressure is reduced and gastric emptying of the stomach is delayed. 210 Both of these factors increase the incidence of GERD, erosive esophagitis, and stricture formation. The small and large intestine may also be involved. Typical features include scattered wide-mouthed diverticula, 211 pseudo-obstruction, 212 and intestinal perforation. 213
    Pathologically, scleroderma is characterized by smooth muscle atrophy and replacement by collagenized fibrous tissue ( Fig. 6-12 ). The lesion most commonly affects the inner circular muscle layer but can involve the entire muscularis propria on occasion. Fibrous tissue can be highlighted by the trichrome stain, which reveals atrophy and loss of muscle tissue. Fibrosis may also involve the submucosa to a variable degree. 214 Muscular atrophy results in atony and dilation and produces wide-mouthed pseudodiverticula that can be identified radiographically. In addition, the small vessels of the bowel may show a proliferative endarteritis and mucinous changes of the media. 215 Rarely, ischemic ulcers can occur as a result.

    FIGURE 6-12 Scleroderma. Intermediate-power view of the colon stained with trichrome reveals atrophy and increased fibrosis of the inner circular layer of the muscularis propria.

    DERMATOMYOSITIS AND POLYMYOSITIS
    These are inflammatory myopathies that primarily involve skeletal muscle. However, skin involvement occurs also in dermatomyositis. These disorders may be associated with motor dysfunction of the GI tract. 216 The striated muscle of the cervical esophagus is most frequently affected when delayed esophageal emptying is common. 217 Histologic changes include chronic inflammation, edema, and muscle atrophy. Features can mimic scleroderma, but fibrosis is not prominent in these disorders.

    SYSTEMIC LUPUS ERYTHEMATOSUS
    This systemic multisystem autoimmune disease affects the GI tract in approximately 20% of patients. The development of vasculitis can lead to ischemia 218 and perforation in the GI tract. It also has been associated with malabsorption, protein-losing enteropathy, 219 and amyloidosis. 220

    MIXED CONNECTIVE TISSUE DISEASE
    This is a disease with features of scleroderma, systemic lupus erythematosus, and polymyositis. GI abnormalities are common. 221 GI features are similar to those of scleroderma, with motility dysfunction 222 and vasculitis being the most common complications.

    RHEUMATOID ARTHRITIS
    GI involvement occurs in 25% of patients with long-standing rheumatoid arthritis. 223 Notably, this occurs in the form of a necrotizing vasculitis that affects small to medium-sized arteries, similar to polyarteritis nodosa. The condition is usually asymptomatic. However, hemorrhage or even perforation may occur. 224 GI lesions can also be seen in association with long-term use of NSAIDs and, rarely, long-standing inflammation can lead to amyloidosis.

    REACTIVE ARTHRITIS
    This is a group of inflammatory disorders associated with arthritis (spondyloarthropathy). It includes psoriatic arthritis, Reiter’s syndrome, ankylosing spondylitis, and arthritis associated with inflammatory bowel disease. Most affected individuals (70%) 225 have chronic active colitis. Interestingly, clinical remission is always associated with normal gut histology. 226

    SJÖGREN’S SYNDROME
    Sjögren’s syndrome is a clinicopathologic entity characterized by dry eyes and mouth secondary to immune-mediated destruction of the lacrimal and salivary glands. Patients with Sjögren’s syndrome may develop immune-mediated destruction of the pharyngeal and esophageal glands with fissuring and ulceration of the pharynx and esophagus. Esophageal webs have been noted in up to 10% of patients. Atrophic gastritis, atrophy, and chronic inflammation of the esophageal glands have been noted as well. 227 Histologically, the salivary glands of the esophagus show a periductal and perivascular lymphocytic inflammatory infiltrate that can occasionally be quite marked.

    HEREDITARY CONNECTIVE TISSUE DISORDERS
    Hereditary connective tissue disorders, such as Ehlers-Danlos syndrome and pseudoxanthoma elasticum, result from a defect in collagen synthesis or structure. These defects result in thinning of the bowel wall and vascular structures 228 ; as a result, these patients are at increased risk for GI hemorrhage and perforation. 229 Patients with Ehlers-Danlos syndrome also have diaphragmatic hernias and GI diverticula. Upper GI tract hemorrhage occurs in 13% of patients with pseudoxanthoma elasticum. 230 In these cases, submucosal, yellowish, nodular lesions, similar to xanthoma-like skin lesions, may be noted. 231 Histologic examination typically reveals superficial mucosal hemorrhage, erosion, and elastic tissue degeneration of small and medium-sized arteries with calcified plaque formation.

    Urologic Disorders

    ACUTE RENAL FAILURE
    Postsurgical or trauma-associated acute renal failure often results in gastric or duodenal erosions, ulceration, and hemorrhage secondary to hypotension, stress, and multiorgan failure. 232

    HEMOLYTIC-UREMIC SYNDROME
    Hemolytic-uremic syndrome (HUS) is an acute onset of microangiopathic hemolytic anemia, thrombocytopenia, and renal dysfunction. Cases associated with E. coli infection often present with a GI prodrome that is difficult to differentiate histologically from an acute colitis. 233 Presentations mimicking intestinal intussusception 234 and ulcerative colitis have also been described. 235 During HUS, an associated colitis is seen in most patients, and there is a 1% to 2% incidence of colonic perforation. 236 Marked mucosal and submucosal edema and hemorrhage of the colon can occur, but inflammation is not usually significant ( Fig. 6-13 ). Microvascular angiopathy with endothelial cell damage and overt thrombosis may also be noted. 237

    FIGURE 6-13 Hemolytic-uremic syndrome secondary to E. coli infection. Intermediate-power view of mucosa with erosion, hemorrhage, edema, and a paucity of inflammation. Focal endothelial cell damage with thrombi is present.
    (Image courtesy of Dr. Elizabeth Montgomery, The Johns Hopkins University, Baltimore.)

    CHRONIC RENAL FAILURE
    A variety of GI lesions may develop in patients with chronic renal failure. These are mainly associated with uremia, long-term hemodialysis, or kidney transplantation.

    Uremia
    GI symptoms that are common among patients with uremia include gastroesophageal reflux, 238 nausea, vomiting, anorexia, epigastric pain, and upper GI hemorrhage. Early studies suggested an increased incidence of dyspepsia, ulcer disease, and H. pylori gastritis. However, recent studies indicate that the incidence of these conditions is not significantly different from that in the general population. 239 GI hemorrhage occurs in up to 15% of patients, accounts for 15% to 20% of all deaths in patients on long-term dialysis, and is often associated with angiodysplasia. Bleeding abnormalities may also occur as a result of platelet dysfunction. Mucosal abnormalities range from edema to ulceration and occur in 60% of patients who die from uremia. 240 The pathogenesis of uremic syndrome-associated GI tract disease is unclear. However, many manifestations of uremia are relieved by dialysis, which suggests a role for humoral factors. In addition, gastric mucosal calcinosis may be identified in patients with chronic renal failure or uremia, and in patients after renal transplantation. 241 Microscopically, calcinosis appears as small, white, flat plaques, or nodules, that contain amorphous basophilic deposits within the subepithelial compartment of the superficial lamina propria.

    Long-Term Hemodialysis
    Acute fluid loss during the process of dialysis can lead to hypotension and nonocclusive mesenteric ischemia. 242 , 243 Peritonitis secondary to bacterial infection and acute bowel obstruction secondary to incarcerated hernia into the catheter tract can also develop in patients on peritoneal dialysis. 244 Patients on dialysis are also susceptible to Salmonella species enteritis 245 and dialysis-associated β 2 -microglobulin amyloidosis. 246

    Kidney Transplantation
    GI complications are an important cause of morbidity and mortality in kidney transplant recipients. 247 Complications are mainly related to immunosuppression therapy. Patients are at risk for opportunistic infections, including Candida species, cytomegalovirus, herpesvirus, Cryptosporidium species, and Strongyloides species. These patients also are at increased risk for exacerbation of diverticulitis, for reasons unknown. 248

    URINARY CONDUITS
    Three basic types of urinary diversion have been used for congenital or malignant disorders-ureterosigmoidostomy, ileal neobladder, and antirefluxing colonic conduits.
    Ureterosigmoidostomy, whereby the ureter is implanted into the sigmoid colon, is associated with a greatly increased risk for colonic neoplasia at, or near, the site of anastomosis. 249 Hence, this type of diversion is no longer popular. Adenocarcinomas typically arise 15 to 25 years after surgery and are histologically identical to typical colon adenocarcinomas. Endoscopic surveillance biopsies are recommended to screen for epithelial dysplasia. 250 In addition to dysplasia, one may see inflammatory polyps, edema, crypt branching, and Paneth cell metaplasia. 249 , 251
    Creation of an ileal neobladder (Kock or Charleston pouch) is now the most common procedure performed in patients who require some form of urinary diversion. These pouches are created from a portion of ileum that is separated from the fecal stream. Thus, risk of malignancy has not been associated with these procedures. However, mucosal biopsy of these pouches may reveal histologic changes over time. Early changes (over the first year) include shortening of villi with loss of microvilli and decreased numbers of goblet cells. 252 Late changes (after 4 years) consist of marked flattening of the epithelium with epithelial stratification, similar to urothelium. 253 Dysplasia has not been described.
    Antirefluxing colonic conduits, using a segment of colon that is isolated from the fecal stream, appear to be associated with a lower degree of retrograde reflux and therefore a decreased incidence of pyelonephritis.

    Miscellaneous Disorders

    CHRONIC GRANULOMATOUS DISEASE
    This is a rare X-linked or autosomal recessive inherited disorder of phagocyte function. (see Chapter 9 for further details). It is characterized by recurrent infection in infants and children. 254 Affected children suffer from chronic infections, often with abscess formation, in many organs. The GI system is involved in approximately 25% of patients. 255 Patients may present with vitamin B 12 deficiency and an abnormal Schilling test result that is not corrected by the addition of intrinsic factor, as well as steatorrhea, obstruction, or bleeding. The defect lies in the inability of the body to destroy catalase-positive bacteria and fungi because of a lack of hydrogen peroxide production by phagocytic leukocytes. This condition may be diagnosed by the finding of a negative nitroblue tetrazolium assay or by other tests that reveal decreased bactericidal activity of leukocytes.
    The condition is characterized by necrosis and abscess and sinus tract formation, which may be seen in the form of gastric outlet obstruction, 255 , 256 perineal abscess, diffuse colitis, 257 or even esophageal narrowing. 258 Histologically, necrotizing lesions often have sparse and poorly formed granulomas, often with marked eosinophilia. Microorganisms are usually not detectable in the lesion. The mucosa of the small and large intestine shows clusters of enlarged macrophages, often located adjacent to the muscularis mucosae in the basal portion of the lamina propria. The macrophages range from 50 to 100μm in diameter and contain a golden-brown lipofuscin type of pigment ( Fig. 6-14 ). The pigment stains positively with fat stains and the PAS reaction. The pigment is refractile on standard histologic section as well. Rectal biopsy may show an increased number of inflammatory cells (including plasma cells, neutrophils, and eosinophils) in the lamina propria.

    FIGURE 6-14 Chronic granulomatous disease of the colon. Pigmented macrophages are present in the lamina propria and simulate the appearance of melanosis coli.
    The differential diagnosis includes other granulomatous disorders, such as mycobacterial and fungal infections, sarcoidosis, and inflammatory bowel disease. These lesions can be excluded by stains or cultures and by appropriate clinical history. Pigment-laden macrophages may resemble several storage disorders, such as Batten disease and brown bowel syndrome. Other storage disorders typically do not involve PAS-positive pigments. Whipple’s disease and M. avium complex infection have PAS-positive material but are not typically refractile. Finally, melanosis coli may have a similar pigment, but macrophages in this condition are usually more prominent in the superficial lamina propria and not usually present in the small intestine.

    SARCOIDOSIS
    Sarcoidosis rarely involves the GI tract. The stomach is the most common site of sarcoidosis, 259 although involvement of the entire GI tract has been reported. It occurs in middle-aged patients and is usually associated with pulmonary disease, although the GI tract may rarely be the first site of involvement. Sarcoidosis is characterized by an abnormal immune response and the formation of multiple noncaseating granulomas. This condition is also associated with high serum angiotensin-converting enzyme activity. 260 The cause is unknown. In patients with sarcoidosis, a high frequency of humoral autoimmunity (increased incidence of antibodies to H + ,K + -ATPase, gliadin, and endomysium) is seen. 261 However, there does not appear to be an increased incidence of pernicious anemia or celiac disease.
    The pathology of sarcoidosis is variable. The mucosa may show no abnormalities or may be severely involved, with a linitis plastica-like appearance of the stomach. 262 Ulceration and bleeding have been reported. Microscopically, the hallmark of sarcoidosis is the presence of noncaseating granulomas. These granulomas are composed of epithelioid histiocytes, with or without giant cells, and often associated with a rim of lymphocytes at the periphery ( Fig. 6-15 ). They may be present in any layer of the bowel wall and may be associated with tissue damage.

    FIGURE 6-15 Sarcoidosis. High-power view of a mucosal granuloma includes epithelioid histiocytes with a rim of lymphocytes. The lesion is present just above the muscularis mucosae in a small bowel biopsy.
    The importance of sarcoidosis lies in its differential diagnosis with other causes of granulomas (which are numerous) and with Crohn’s disease. Often the cause can be ascertained only with appropriate clinical history. Sarcoidosis is less common than Crohn’s disease in the GI tract and is more often seen in black patients. Mycobacterial infections (especially in patients with associated pulmonary disease) should also be considered. However, acid-fast stains may be performed on the granulomas in suspected cases. The purified protein derivative skin test may also help to differentiate between the two diseases. Essentially, a diagnosis of sarcoidosis can be established only after other diseases have been excluded.

    MASTOCYTOSIS
    Both systemic mastocytosis and urticaria pigmentosa (the skin form of mast cell disease) may have GI involvement by disease or by an increase in the number of mast cells. In systemic mastocytosis, 70% to 80% of patients have GI symptoms when a careful history is obtained. 263 Abnormalities include diarrhea, peptic ulcer pain, GI bleeding, nondyspeptic abdominal pain, urgency, and fecal incontinence. 264 A proportion of patients also have gastric acid hypersecretion caused by hyperhistaminemia. This can lead to ulcer disease and may even mimic the Zollinger-Ellison syndrome. Gastric erosions, duodenal ulceration or varices secondary to hepatic fibrosis, and portal hypertension can cause GI hemorrhage. 263
    The stomach and duodenum are most commonly involved. 265 A variety of changes can be seen, including focal urticaria-like mucosal lesions, edematous thickening of the mucosal folds, gastric erosions, and peptic-type ulcerations.
    Histologically, mastocytosis is characterized by an abnormal proliferation of tissue mast cells. The mast cell infiltrate is usually seen throughout the GI tract but predominantly in the mucosa and submucosa ( Fig 6-16A ). It is often associated with other inflammatory cells such as eosinophils (see Fig. 6-16B ). The infiltrate can be very dense. Associated and mild mucosal villous blunting may be seen. Secondary changes due to gastric acid hypersecretion, such as erosions, may be seen as well. Mast cells can be stained with chloroacetate esterase stains, with the Giemsa stain, and with immunohistochemical stains for CD117 (see Fig. 6-16C ) or mast cell tryptase. Patients with urticaria pigmentosa can also show increased numbers of mast cells in biopsies of the stomach and duodenum, although mast cell numbers do not correlate with elevated skin mast cell counts in this condition. 266

    FIGURE 6-16 Mastocytosis. A, Low-power view of duodenum with surface erosion and proliferation of mast cells and eosinophils in the submucosa beneath the Brunner glands, just above the muscularis mucosae. B, High-power view of mast cells with abundant eosinophils, and adjacent Brunner glands at the top of the image. C, Low-power view with CD117 immunohistochemical stain revealing abundant positive mast cells. A greater number of mast cells are present than appreciated with the H&E stain.
    Several recent studies suggest that increased mast cells are present in patients with irritable bowel syndrome and diarrhea. The term mastocytic enterocolitis has been recommended. These studies suggest that more than 20 mast cells per high-power field (normal being 13 to 15 ± 3 per high-power field) indicates a pathologically increased mast cell number. 267 - 270

    NEOPLASTIC DISEASE
    Neoplastic diseases from other sites may involve the GI tract in two ways: (1) by tumor invasion of the GI tract, and (2) indirectly through paraneoplastic syndromes.
    Tumors can invade the GI tract either by direct extension or by metastasis. Up to 20% of extraintestinal tumors metastasize to the bowel. 269 , 270 The most common neoplasms that directly involve the small or large intestine are carcinomas from the pancreas, prostate, urinary bladder, and female genital tract, or ovarian tumors through peritoneal seeding. Peritoneal seeding typically involves the serosal surface. Tumors that metastasize relatively frequently to the intestines are melanoma and carcinoma of the breast and lung. Primary carcinoma of the digestive tract may also metastasize to other parts of the intestinal tract, particularly the diffuse linitis plastica variant of gastric carcinoma. 271 Metastatic breast carcinoma, particularly the lobular type, can mimic primary signet ring cell carcinoma and may even have a linitis plastica appearance 272 ( Fig. 6-17 ). Immunohistochemical stains for estrogen and progesterone receptors, gross cystic fluid protein, and cytokeratin 5/6 are often positive in breast carcinoma, whereas cytokeratin 20, DAS-1, MUC5AC, and MUC6 are often positive in gastric carcinoma. 273 Epithelial malignancies that metastasize to the GI tract are typically differentiated from primary tumors of the GI tract by the lack of epithelial dysplasia or other (adenoma) precursor lesions adjacent to the tumor, and by the finding of prominent lymphatic invasion by metastatic lesions. Metastases are often multicentric as well. Furthermore, colonic tumors are usually cytokeratin 7 negative and cytokeratin 20 positive, whereas gastric or other foregut tumors are often cytokeratin 7 positive and cytokeratin 20 variable. 274

    FIGURE 6-17 Metastatic lobular carcinoma of the stomach. Intermediate-power view of a gastric biopsy shows an infiltrate of numerous small cells in the lamina propria. There is the suggestion of single-cell filing typical of lobular carcinoma of the breast. Signet ring cells are not identified.
    Paraneoplastic syndromes may develop secondary to release of hormones or antibodies from tumor cells. Typical examples include the watery diarrhea syndrome seen with bronchial carcinoid tumors and oat cell carcinoma of the lung. The syndrome is caused by the release of serotonin, which causes hypermotility of the gut. 275 Oat cell carcinoma can also lead to gastroparesis secondary to antibody (anti-Hu) production by the tumor. 276 Another example is Zollinger-Ellison syndrome caused by excessive gastrin production from gastrinomas. These patients often present with multiple duodenal ulcers secondary to gastrin-induced acid hypersecretion. 277

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    CHAPTER 7 Neuromuscular Disorders of the GI Tract

    DHANPAT. JAIN

    Neural Network of the GI Tract
    Esophagus
    Primary Achalasia
    Secondary Achalasia
    Idiopathic Muscular Hypertrophy of the Esophagus
    Stomach
    Pyloric Stenosis
    Small and Large Intestine
    Hirschsprung’s Disease
    Other Developmental Disorders of the Enteric Nervous System
    Intestinal Pseudo-Obstruction
    Miscellaneous Conditions
    Prognosis and Therapy
    Intestinal Dysmotility: Diagnostic Approach and Workup
    Knowledge of the organization of the neuromuscular apparatus of the GI tract is essential if its motility disorders are to be understood. The neuromuscular organization remains much the same throughout the GI tract, with some minor variations. 1 The smooth muscle forms a superficial thin layer (muscularis mucosae) separating mucosa from submucosa and a thick outer layer (muscularis propria). The muscularis mucosae is organized into inner circular and outer longitudinal layers, except in the esophagus, which has only a single layer of longitudinal muscle coat. Identification of these two distinct layers is often difficult on routine mucosal biopsy specimens. The proximal part of the muscularis propria of the esophagus is composed entirely of skeletal muscle, which gradually merges with smooth muscle distally. Variable amounts of skeletal muscle may be seen extending into the prox-imal half of the esophagus. Thus, esophageal motility is prone to systemic disorders of both smooth and skeletal muscle.
    In the stomach, an additional inner oblique muscle layer is also present. The outer longitudinal layer in the colon forms localized thick bands called taenia coli. The muscularis mucosae of the colon continues into the anal canal. The inner circular layer of the rectum continues distally and becomes thickened to form the internal anal sphincter. The external anal sphincter is formed by striated muscle and is connected to the skeletal muscle of the pelvic floor. The longitudinal muscles of the rectum continue between the two anal sphincters and finally break up caudally into multiple septa, which diverge fanwise throughout the subcutaneous part of the external sphincter to reach the skin; these are responsible for the characteristic corrugated appearance of the perianal skin. In addition, the fibers from the longitudinal coat and the internal sphincter extend into the submucosa to form a meshwork around the vascular plexuses (muscularis submucosa ani).

    Neural Network of the GI Tract
    The organization of the neural network in the GI tract is complex. The extrinsic nerve supply consists of both sympathetic and parasympathetic nerve fibers, which eventually culminate on the intrinsic neural plexuses. The sympathetic fibers originate in the prevertebral ganglia and run along the superior and inferior mesenteric arteries. The parasympathetic fibers run in the posterior branch of the vagus nerve. Generally, the intrinsic neural system is organized into three plexuses: the submucosal plexus (Meissner’s plexus), the deep submucosal plexus (Henle’s plexus), and the myenteric plexus (Auerbach’s plexus) ( Fig. 7-1 ). The most easily identified and prominent is the myenteric plexus, which is composed of clusters of ganglion cells connected by an intricate network of nerves in the space between the circular and longitudinal muscle layers. Although the ganglion cells and nerve bundles are easily identified in these plexuses, their intricate meshwork is not readily appreciated on H&E-stained sections. Whole-mount preparations, silver stains, or immunohistochemical methods are essential to visualize the overall neural meshwork ( Fig. 7-2 ). 2 , 3

    FIGURE 7-1 Section of normal colon showing the neural plexus: submucosal plexus (SP), deep submucosal plexus (DSP), and myenteric plexuses (MP) (S100 immunostain).

    FIGURE 7-2 A tangential section of muscularis propria showing myenteric ganglia in the complex neural network (S100 immunostain). This would not be evident in a well-oriented section.
    In addition to muscle fibers and the neural network, a third population of mesenchymal cells, known as the interstitial cells of Cajal (ICC), are critical for bowel motility. These cells generate a slow wave of depolarization and represent the pacemaker cells of bowel peristalsis. 4 , 5 Their function is, in turn, modulated by intrinsic and extrinsic neural inputs. These cells cannot be appreciated on routine sections, and most of our knowledge about their morphology and structural organization comes from painstaking ultrastructural studies. 6 - 8 Ultrastructurally, these cells show partial basal lamina, many intermediate filaments, darkly staining cytoplasm, abundant rough endoplasmic reticulum, sublamellar caveolae, oval indented nuclei, and lack of myosin filaments. Many of these features overlap with the features of smooth muscle cells. It has been shown that these cells express c-kit, a tyrosine kinase receptor. 9 Immunohistochemical stains using antibodies against c-kit have been used to visualize these cells. 10 - 12 ICC have an intricate network and form a close liaison between smooth muscle cells and nerve endings. They are most easily identified around the myenteric plexus, especially in the small bowel, from which their network extends into the inner and outer muscular coats ( Fig. 7-3A-D ). A distinct submucosal ICC plexus has also been recognized. Structural organization of these cells has been described in the various segments of the GI tract (from esophagus to anus), and minor differences in the regional distribution within each segment have been described. 13

    FIGURE 7-3 A, Section from small intestine showing interstitial cells of Cajal (ICC) extending into the inner circular and outer longitudinal layers of the muscularis propria (c-kit immunostain). A dense collection of ICC can be seen around the myenteric plexus. B, Section showing distribution of ICC in colon (c-kit immunostain). In contrast to the small intestine, fewer c-kit-positive ICC are present around the myenteric plexus, which may be difficult to appreciate with low magnification. C, High-power view of a tangential section of muscularis propria showing multiple processes of c-kit-positive ICC. In well-oriented sections, this morphology is difficult to appreciate. D, Semi-thin resin-embedded section showing ICC (arrows) around the myenteric ganglia (toluidine blue stain).
    Normal bowel motility depends on the interplay of smooth muscle, ICC, the intrinsic and extrinsic nerve supply, and various neuroendocrine peptides. Abnor-mality in any of these components may result in bowel dysmotility. The clinical manifestations of the disorders eventually depend on the extent and localization of the abnormality. Some of these disorders exhibit distinctive clinical features (e.g., idiopathic hypertrophic pyloric stenosis, Hirschsprung’s disease, achalasia); others have nonspecific manifestations. The pathogenesis of many of these conditions is still very poorly understood, and many disorders lack specific diagnostic histomorphology. The pathogenesis of some of the rare and familial forms is beginning to be understood, and underlying genes that play an important role are being recognized. Currently, the workup of bowel motility disorders remains a challenge for both clinicians and pathologists.

    Esophagus

    PRIMARY ACHALASIA

    General Comments
    Achalasia is a motor disorder of the esophagus characterized by failure of the lower esophageal sphincter to relax in response to swallowing. 14 , 15 It is an uncommon disorder: the overall prevalence has been estimated to be less than 10 cases/10 5 population. 16 Its incidence has been fairly static over the past 50 years. It involves both sexes equally and is primarily a disease of adults, predominantly affecting patients over 60 years of age. It is seen more frequently in North America, northwestern Europe, and Australia, and predominantly among whites.

    Pathogenesis
    The main pathologic feature is loss of myenteric ganglion cells. The cause of achalasia is unknown. Current data suggest that myenteric inflammation precedes the loss of ganglion cells, but the inciting events remain unknown. 17 Environmental factors, viral infection, autoimmune mechanisms, and genetic predisposition have all been implicated. There is some suggestion of familial aggregation. Rare familial forms associated with alacrima (absence of tears) and adrenocorticotropic hormone insensitivity are recognized (Allgrove’s, or triple-A, syndrome). 18 , 19 Occasional concordance in monozygotic twins and association with Down syndrome has also been reported. A significant association has been found with class II human leukocyte antigen (HLA) DQw1 in white patients. The alleles identified, HLA DQB1*0602, DQA1*0101, and DRB1*15, are the same alleles that have been found to be associated with a host of other autoimmune disorders, including multiple sclerosis and Goodpasture’s syndrome. Further support for an autoimmune mechanism is lent by cases reported in association with Sjögren’s and sicca syndromes, and the identification of anti-myenteric neuronal antibodies in some patients. 20 Recently, it has been shown that normal gastric fundus in an ex vivo model, when exposed to sera from achalasia patients, shows phenotypic and functional changes that mimic achalasia. 21 It has been speculated that a factor in the serum other than antineuronal antibody may be responsible for this phenomenon. 21 Varicella-zoster viral DNA has been shown in the myenteric plexus in rare cases by in situ hybridization. 22
    The pathogenesis of this condition is also poorly understood. Progressive inflammatory destruction of myenteric ganglion cells appears to be the critical underlying event, resulting in failure of the lower esophageal sphincter to relax in response to swallowing. 23 Peristalsis in the eso-phageal body is also decreased or absent. This results in progressive esophageal dilation with chronic stasis and hypertrophy of the esophageal musculature. Vasoactive intestinal polypeptide (VIP) was initially thought to be the major mediator of relaxation of the lower esophageal sphincter, and studies have shown loss or decrease in VIP-containing neurons in the distal esophagus. 24 , 25 Subsequently, it was established that nitric oxide is the prime esophageal inhibitory neurotransmitter; it colocalizes in the same ganglion cells as VIP. In addition, it has now been shown that intrinsic nitrergic ganglion cells are lost, or markedly decreased, in achalasia, and that loss of VIP ganglion cells is synonymous with loss of nitrergic ganglion cells. 26 , 27 Most earlier studies evaluated specimens at the time of autopsy or esophagectomy; thus the end stage of the disease was reflected. Study of esophagomyomectomy specimens lends some insight into the earlier sequence of events, although very early changes during the asympto-matic stages of the disease are largely unknown. 28 As the disease progresses, however, the inflammatory infiltrate decreases in intensity as the ganglionic cell loss and myenteric plexus degeneration become more prominent.

    Clinical Features
    Younger children (<5 years) and infants present with feeding aversion, failure to thrive, choking, recurrent pneumonia, nocturnal cough, aspiration, or nonspecific regurgitation. Older children and adults present with vomiting, chest pain, and dysphagia for solids and liquids. Heartburn is a common symptom even in untreated patients (about 50%), but only a minority of these patients have documented gastroesophageal reflux disease. 29 Diagnosis is confirmed with imaging studies and manometry. A barium study typically reveals reduced peristalsis with a characteristic beaklike deformity of the distal esophagus and dilation of the proximal esophagus. Manometry studies show abnormal peristalsis, increased intraluminal pressure, and incomplete and delayed relaxation of the lower esophageal sphincter. Endoscopy and endoscopic ultrasound are often performed to rule out coexisting mucosal pathology and to exclude secondary causes of achalasia (pseudoachalasia).

    Pathologic Features
    Grossly, the esophagus is dilated and the extent of dilation depends on the severity and duration of disease ( Fig. 7-4A ). It often contains stagnant and foul-smelling, partially digested food. The distal end is narrowed and strictured.

    FIGURE 7-4 A, Resection specimen from a case of achalasia showing a dilated proximal and narrow distal segment. B, Myenteric plexus in a patient with end-stage achalasia. There are no residual ganglion cells, and the chronic inflammatory cells are seen in and around a fibrotic nerve. C, Strong CD8 staining of lymphocytes within the myenteric plexus of a patient with end-stage achalasia.
    A, (Courtesy of Dr Henry Appleman.)
    The main histologic abnormality is seen in the myenteric plexus, although numerous secondary changes are often present throughout the esophageal wall, presumably secondary to prolonged stasis. Widespread, near-total to total loss of myenteric ganglion cells is seen. Somewhat better preservation of the ganglion cells may be seen in the most proximal part of the esophagus. 14 A variable amount of chronic lymphocytic infiltrate admixed with eosinophils, plasma cells, and mast cells is often seen around the myenteric nerves and residual ganglion cells (see Fig. 7-4B ). 28 Occasionally, lymphocytes may be seen infiltrating the cytoplasm of ganglion cells (ganglionitis). A majority of chronic inflammatory cells are CD3-positive T cells, most of which are CD8-positive (see Fig. 7-4C ), although the relative percentage of these cells decreases with disease progression. 23 , 30 A large subset of T cells appears to be resting or activated cytotoxic cells.
    Other changes frequently seen secondary to distal esophageal obstruction include muscularis propria hypertrophy, muscularis propria eosinophilia, and dystrophic calcification. Hypertrophied muscle may also show degenerative changes, including cytoplasmic vacuolation and liquefactive necrosis. The branches of the vagus nerve in the adventitia appear unremarkable in most cases, although degenerative changes in the vagus nerve and its dorsal motor nucleus have been described. 15 It has been postulated that these may be caused by a neurotrophic viral infection; however, no specific virus has been identified. 31 The mucosa also shows secondary changes, including diffuse squamous hyperplasia, increased intraepithelial lymphocytes (lymphocytic esophagitis), papillomatosis, basal cell hyperplasia, and nonspecific lamina propria inflammation. 32 Some of these changes mimic reflux esophagitis, although sustained lower esophageal pressure does not allow regurgitation of gastric contents in untreated cases. 33 After esophagomyotomy, gastroesophageal reflux develops in up to 50% of patients and can even lead to Barrett’s esophagus in some cases. 34 , 35

    Prognosis, Treatment, and Follow-Up
    Achalasia is a chronic disorder, and the treatment is largely palliative. Medications are often tried, but the best results are obtained with pneumatic dilation and esophagomyotomy of the lower esophageal sphincter. Resection is reserved for end-stage cases. These patients have a long-term risk for developing squamous cell carcinoma of the esophagus 34 , 36 (the risk is estimated to be 33 times higher than in the general population). 37

    SECONDARY ACHALASIA
    Signs and symptoms indistinguishable from primary achalasia may be encountered with other conditions such as Chagas’ disease, or in association with a neoplasm that directly invades the myenteric plexus or that occurs as a paraneoplastic phenomenon. 38 , 39 The malignancy most commonly associated with paraneoplastic achalasia is small cell carcinoma; however, rare associations with other tumors have also been recognized.
    Chagas’ disease, which is a rare cause of achalasia, results from infection with the protozoan Trypanosoma cruzi . 40 , 41 The infection is acquired through the bite of blood-sucking reduviid bugs. The geographic distribution of the disease is limited to certain parts of the world, such as South or Central America, and Africa. Chagas’ disease is uncommon in the United States and almost exclusively occurs in immigrants from countries where it is endemic, particularly Brazil. Any part of the GI tract may be affected, but the esophagus and the sigmoid colon are the most frequently involved sites, resulting in dysmotility and often massive dilation (e.g., megaesophagus, megacolon). In the esophagus, the symptoms closely resemble those of idiopathic achalasia; colonic involvement results in constipation and intestinal pseudo-obstruction. These features are seen in the chronic phase of the disease, and by the time symptoms are noted, the organisms can no longer be demonstrated in the myenteric plexus. Histologically, cases of Chagas’ disease cannot be distinguished from other causes of visceral neuropathy.

    IDIOPATHIC MUSCULAR HYPERTROPHY OF THE ESOPHAGUS
    Idiopathic muscular hypertrophy of the esophagus is a poorly understood condition of uncertain etiopathogenesis and clinical significance. Most cases are diagnosed at autopsy, although the condition can be diagnosed clinically with current imaging techniques and esophageal motility studies. 42 Some patients are symptomatic, with dysphagia, chest pain, vomiting, and weight loss, but many are asymptomatic. 43 Esophageal spasms and increased intraluminal pressure are believed to be the underlying mechanisms for the symptoms. Cases reported in the literature have occurred in adults, with no sex or racial predilection. Many patients with this disorder also have diabetes. Rare cases with possibly autosomal dominant inheritance have been reported that are associated with bilateral cataracts and Alport-like nephropathy. 44 Squamous cell carcinoma has also been described in some cases. 45 Pathologically, the muscularis propria appears markedly thickened, particularly toward the lower end ( Fig. 7-5 ). 43 Some cases show mild lymphocytic infiltration in the myenteric plexus. The majority of cases lack any evidence of muscle fiber degeneration, fibrosis, ganglion cell abnormalities, or neural plexus abnormalities. Clinically and pathologically, this disorder needs to be differentiated from idiopathic achalasia and infiltrative disorders of the esophagus.

    FIGURE 7-5 Idiopathic muscular hypertrophy of esophagus. A, Gross specimen showing marked thickening of the muscularis propria of the esophagus that is more prominent distally toward the gastroesophageal junction. Compare this with normal wall thickness of the stomach, and lack of any gross mucosal abnormalities. B, A cross section of hypertrophic muscle from this case, with side-by-side comparison with normal esophagus. C, Microscopy from this case shows hypertrophied muscularis propria and lack of any other associated histologic changes, including inflammation, fibrosis, muscle degeneration, or myenteric plexus abnormalities.

    Stomach

    PYLORIC STENOSIS
    Infantile and adult forms of this disorder are recognized. Infants present with projectile vomiting, usually within 2 to 4 weeks after birth. 46 , 47 It occurs in approximately 1 in 1000 live births, has a high familial incidence and a strong male preponderance, and classically occurs in the first born of the family. The incidence of this condition seems to be rising in some countries (Britain and Ireland) but decreasing in others (Canada and Denmark). 48 The etiology remains unclear. 49 Genetic predisposition and other environmental precipitating factors have been implicated (e.g., bottle feeding, respiratory distress syndrome). Prenatal use of erythromycin and other macrolide antibiotics has also been implicated as a risk factor; however, the evidence is not conclusive. 50 , 51
    The pathogenesis of this condition also remains unclear. No evidence of a mechanical obstruction has been found, and the pylorus can be easily intubated. 52 Uncoordinated peristalsis of the stomach and the pyloric musculature (“pylorospasm”) has been thought to be the underlying mechanism. Other factors that may play a role include immaturity of the enteric nervous system, hormonal imbalance between gastrin and somatostatin, redundancy of the overlying mucosa, lack of c-kit-positive ICC and lack of nitric oxide synthase. 53 - 58 Homozygous transgenic mice carrying inactivating genes for nitric oxide synthase develop hypertrophy of the pylorus. 59

    Clinical Features
    Infants present with progressive nonbilious vomiting, which gradually assumes a more characteristic projectile pattern. The hypertrophied pylorus can be palpated as an olive-sized epigastric mass, and gastric peristalsis may be visible. Some patients also have a congenital diaphragmatic hernia. Idiopathic hypertrophic pyloric stenosis is uncommon in adults 60 ; most adult cases are secondary to scarring caused by juxtapyloric peptic ulceration or tumors.

    Pathologic Features
    The pathologic features of adult and pediatric forms are similar. The pylorus is greatly thickened and appears fusiform. The proximal stomach may be dilated, depending on the severity and duration of obstruction. Microscopically, the inner circular coat of the pylorus is up to four times thicker than normal. Muscle fibers are disorganized, with increased intercellular collagen, sometimes associated with a mild lymphocytic infiltrate. The longitudinal muscle is frequently attenuated. The enteric nerve plexus is often hypertrophied and shows a relative increase in the number of Schwann cell nuclei. Glial cells show degeneration, characterized by pyknosis and vacuolation. ICC are markedly reduced or absent in the hypertrophied circular muscle, myenteric plexus, and longitudinal muscle, as shown by c-kit immunostains and ultrastructure. 53 Only the inner layer of the circular muscle shows somewhat preserved ICC.

    Treatment and Follow-Up
    Surgical myotomy is the definitive treatment, and pyloric hypertrophy disappears within a few months after the procedure. 61 Pyloric biopsy specimens studied several months after myotomy reveal restoration of abnormalities of the nerve fibers, glial cells, ICC, and neuronal nitric oxide synthase. 62 Long-term outcome is excellent. 63

    Small and Large Intestine

    HIRSCHSPRUNG’S DISEASE

    General Comments
    Hirschsprung’s disease is a heterogeneous group of disorders characterized by lack of ganglion cells resulting in bowel obstruction. 64 , 65 The most common form (75% to 80% of cases) involves the distal sigmoid colon and rectum (short-segment disease or classic Hirschsprung’s disease). In a smaller number of cases (10%), the disease extends proximally beyond the splenic flexure (long-segment disease). Rarely (5%), the entire bowel is devoid of ganglion cells (total bowel aganglionosis). Zonal aganglionosis, in which the absence of ganglion cells is patchy, is extremely rare, and surgical correction may fail. 66
    Classic Hirschsprung’s disease is a congenital disorder. The estimated incidence is about 1 in 5000 live births, and the disease shows a striking male preponderance (3-4.5 : 1). Rare acquired forms, as well as adult cases, have also been described. 67 Long-segment disease and total bowel aganglionosis show familial aggregation. However, clas-sic Hirschsprung’s disease usually occurs as a sporadic anomaly. A large number of associated conditions have been reported, including Down syndrome, cardiovascular malformations, neurofibromatosis, Waardenburg’s syndrome, Laurence-Moon or Bardet-Biedl syndrome, Ondine’s curse (Haddad syndrome), multiple endocrine neoplasia, and neuroblastoma, many of them belonging to the group of neural crest disorders (“neurocristopathies”). 65

    Pathogenesis
    The pathogenesis involves failure of the neural crest-derived ganglion cell precursors to appropriately migrate, colonize, and survive in the bowel during embryogenesis. Mutations in at least eight different genes that play a role in various stages of development and migration of the enteric ganglion cells have been recognized. 64, 65, 68 - 73 Mutations of the RET proto-oncogene, which are the most frequent, have been identified in 20% to 25% of short-segment cases, and 40% to 70% of long-segment cases. Mutations in other genes occur in less than 10% of cases. The mode of inheritance is variable. Familial forms of long- and short-segment disease are autosomal dominant with incomplete penetrance. However, variants associated with other congenital malformations are mostly autosomal recessive. Sporadic cases are thought to have variable patterns of inheritance.

    Clinical Features
    The earliest and most common presentation is delayed (>48 hours) passage of meconium in the newborn. Infants and older children tend to present with chronic constipation, frequently accompanied by abdominal distention and vomiting. Diagnosis is facilitated with imaging studies and rectal manometry, and established by suction mucosal biopsy. Enterocolitis, which is more commonly seen in patients with Down syndrome, is a serious and occasionally life-threatening complication. 74 The etiopathogenesis of enterocolitis is unknown. Defects in IgA secretion and infection by toxigenic bacteria have been implicated.

    Pathologic Features
    Examination of the colon reveals a distal narrow aperistaltic hypertonic segment, which is aganglionic, and a dilated proximal segment caused by obstruction ( Fig. 7-6A ). The involved segment reveals a complete lack of ganglion cells in all neural plexuses and relative hypertrophy of schwannian nerve elements (see Fig. 7-6B ). Normally, one to five ganglion cells are found in clusters for every 1 mm of normal rectal mucosa. Ganglion cells are typically large cells with prominent nucleoli and amphophilic to basophilic cytoplasmic Nissl’s granules. In newborns, the cells are often smaller, and neither nucleoli nor cytoplasmic granules are prominent, making their identification sometimes difficult. Their arrangement in clusters and their association with nerves facilitates recognition. Immuno-staining has been recommended in difficult cases using antibodies for neuron-specific enolase, RET oncoprotein, BCL-2, cathepsin D, PGP 9.5, or other neuronal markers, but in practice they are seldom useful. 65 , 75 , 76 In routine clinical practice, none of the generic neuronal markers offers a significant advantage over thorough histologic examination of H&E-stained preparations, and they need to be used with extreme caution. 77

    FIGURE 7-6 A, Resection specimen in a case of a short-segment (classic) Hirschsprung’s disease showing a dilated proximal and narrow aganglionic distal segment. B, Section of colon in a case of Hirschsprung’s disease showing submucosal neural hyperplasia and lack of ganglion cells. C, Acetylcholinesterase stain performed on a frozen section of a mucosal biopsy of the rectum from a patient with Hirschsprung’s disease, showing positively stained fibers in the submucosa, muscularis mucosae, and lamina propria. The presence of acetylcholinesterase-positive fibers in the muscularis mucosae and lamina propria supports the diagnosis of Hirschsprung’s disease.
    Although a full-thickness transmural biopsy specimen offers better assessment of the neural plexuses because it allows visualization of the more prominent Auerbach’s plexus, it requires general anesthesia and it introduces a risk of development of stricture and perforation. Thus, it is largely restricted to special cases. More commonly, rectal suction mucosal biopsies are obtained to establish a pre-operative diagnosis. The biopsy should include submucosa equal in thickness to the mucosa. However, in practice, this is not always possible. In addition, ganglion cells are scattered and fewer in number in the submucosa. Therefore, care must be exercised, and proper protocols (established at each institution) should be followed before the diagnosis is made ( Fig. 7-7 ). Absence of ganglion cells in the submucosa in an adequate biopsy specimen of the rectum located more than 2 cm above the pectinate line is diagnostic of Hirschsprung’s disease. 65 Although hypertrophy of nerves, by itself, should not be considered sufficient evidence to establish the diagnosis, it may represent a useful clue to support this possibility.

    FIGURE 7-7 Diagnostic approach to a suction mucosal biopsy for the workup of Hirschsprung’s disease and related disorders.
    When ganglion cells are not seen in adequately studied serial sections of mucosal biopsies, supportive evidence can be obtained with the use of histochemical stains for acetylcholinesterase. 78 In classic cases, acetylcholinesterase-positive nerve fibers are seen in the muscularis mu-cosae, as well as in lamina propria; these are lacking in biopsy specimens from normal individuals (see Fig. 7-6C ). Such fibers are few and difficult to demonstrate in newborns with Hirschsprung’s disease, and they tend to increase with age. Abnormalities of ICC have also been shown in some studies; however, it appears that this change is the result of the absence of ganglion cells and is of little diagnostic use. 79 , 80
    Preoperative biopsies are performed to establish the diagnosis before corrective surgery is planned, and each laboratory should establish its own protocol for handling such cases. Ideally, a specimen should be kept frozen and stained for acetylcholinesterase when indicated. Multiple serial sections must be examined before a definitive diagnosis is rendered. 65 The presence of ganglion cells in a colonic biopsy specimen rules out the possibility of conventional Hirschsprung’s disease. The 2 cm of rectum located immediately above the pectinate line normally has a paucity of ganglion cells with prominent nerve fibers, which may lead to an erroneous diagnosis of Hirschsprung’s disease. In such a situation, the biopsy specimen may reveal colonic to squamous transitional-type epithelium, indicating proximity to the pectinate line. The presence of this epithelium should be specifically mentioned in the pathology report. 65
    In addition, specific attention should be given to the presence or absence of mucosal inflammation in cases of Hirschsprung’s disease, which is not infrequent. Histopathologic changes can resemble acute colitis, with cryptitis and crypt abscesses (the self-limited colitis pattern), neonatal necrotizing enterocolitis, ischemic colitis, or pseudomembranous colitis ( Fig. 7-8 ). 74 , 81 , 82 Severe cases with transmural necrotizing inflammation may progress to perforation.

    FIGURE 7-8 A, Mild colitis in a patient with Hirschsprung’s disease showing a mild increase in lamina propria inflammatory cells, and cryptitis mimicking self-limited colitis. B, Another case of Hirschsprung’s disease-associated colitis mimicking pseudomembranous colitis.

    Treatment and Follow-Up
    Treatment involves surgical resection of the involved segment, followed by restoration of bowel continuity. This may be performed as a one-stage endorectal pull-through procedure, or it may occur in two stages, whereby definitive anastomosis is performed after initial colostomy. 65 Seromuscular biopsy specimens (full-thickness biopsy) need to be obtained for intraoperative frozen section evaluation to detect ganglion cells in specific segments before completion of the anastomosis, and also to confirm the lack of ganglion cells in the affected segment. However, frozen sections obtained for evaluation of ganglion cells are not without problems and should not replace a preoperative suction mucosal biopsy before the corrective procedure is attempted. 83 When the frozen section is obtained, a toluidine blue, Giemsa, or Diff-Quick stain, in addition to routine stains, may aid in identification of ganglion cells. The prognosis for surgically treated cases is satisfactory, and most patients are able to achieve continence.

    OTHER DEVELOPMENTAL DISORDERS OF THE ENTERIC NERVOUS SYSTEM
    In the heterogeneous group of developmental disorders of the enteric nervous system are hypoganglionosis, hyperganglionosis, and abnormal differentiation of ganglion cells. Enteric ganglia abnormalities may also result from systemic metabolic defects, such as lysosomal storage disorders. Neuropathic forms of familial intestinal pseudo-obstruction (discussed later) may be considered another form of developmental abnormality in this category.
    Clinically, these disorders resemble Hirschsprung’s disease, and although the acetylcholinesterase stain may mimic the pattern of Hirschsprung’s disease, histologic study fails to establish aganglionosis. Although diagnostic criteria for aganglionosis (Hirschsprung’s disease) are well established, objective criteria necessary to define and diagnose other enteric dysganglionoses are poorly established and often impractical to apply. 84 - 87 This has resulted in the use of many different terms, such as variant Hirschsprung’s disease, pseudo-Hirschsprung’s disease, and allied disorders of Hirschsprung’s disease.
    Hypoganglionosis refers to a reduction in the number of ganglia in neural plexuses, a decreased number of ganglion cells per ganglion, and a smaller size of ganglia. 88 This condition may exist in variable lengths of colon associated with Hirschsprung’s disease or as an isolated primary condition leading to intestinal pseudo-obstruction. It has been suggested that less than 10 ganglion cells per ganglion or less than two ganglions per millimeter constitutes hypoganglionosis. 88 These criteria have been established from 15-μm-thick frozen sections stained with lactate dehydrogenase and cannot be readily applied to paraffin-embedded sections with a different neuronal marker or H&E stain. 88
    Hyperganglionosis is characterized by an increased number of ganglion cells, or by the presence of ectopic ganglia in the lamina propria. Ectopic ganglion cells in the lamina propria are associated with nodular proliferations of ganglion cells (ganglioneuroma) that may occur as either a localized lesion or a diffuse condition (ganglioneuromatosis). The presence of isolated ganglion cells in deep lamina propria, by itself, is not considered pathologic. 89 Diffuse ganglioneuromatosis is almost always associated with multiple endocrine neoplasia (MEN IIB syndrome) and mutation in the RET proto-oncogene. Abnormalities of the ganglion cell in myenteric plexus have also been often referred to as intestinal neuronal dysplasia (IND), and two forms, IND-A and IND-B, are recognized. 90 IND-A is extremely rare and is characterized by sympathetic aplasia, myenteric hyperplasia, and colonic inflammation. 91 The clinical presentation includes episodes of obstruction, bloody stools, and diarrhea. Surgical resection is believed to be curative. IND-B is a controversial entity; it shows marked neural hypertrophy and an increased number of large ganglion cells in the neural plexuses. 85 , 92 The diagnostic criteria for IND-B have changed over time, and the diagnosis currently requires the presence of giant submucosal ganglia, defined as more than eight ganglion-cell cross sections per submucosal ganglion. These giant ganglia should constitute greater than 20% of all ganglia, and at least 25 submucosal ganglia should be evaluated. 87 Premature infants, and infants younger than 1 year, normally show higher numbers of ganglion cells per submucosal ganglion. Thus, it is recommended that a diagnosis of IND-B should be made only in children older than 1 year and younger than 4 years. 87
    An increase or a decrease in the number of ganglions may also be seen as a result of mechanical obstruction. A rare case has been reported that involved IND-B-type changes followed by degeneration of ganglion cells (hypoganglionosis), enteric plexus, and ICC, resulting from a mechanical obstruction caused by a Ladd’s band. 93 Such an adaptive response and neuronal plasticity have also been shown in animal models of mechanical bowel obstruction. 94 , 95 Despite several reports of IND-B and hypoganglionosis and many attempts to reach a consensus regarding diagnostic criteria, 87 , 96 , 97 these entities remain controversial, their clinical significance remains unclear, and even their existence is still in question. IND-B is now considered a histologic pattern that does not require surgical treatment.
    Ganglion cell density varies with age, site, and stretching of the tissues during processing. Subtle numerical alterations of ganglion cells are almost impossible to diagnose on routine suction mucosal biopsies. Quantitation of the neural plexuses, neural and glial stroma, and ganglion cells is extremely difficult even on conventionally oriented transmural biopsies. Alterations in specific subtypes of ganglion cells can be resolved only with special staining and electrophysiologic studies. 3 It is likely that underlying the subtle morphologic alteration of ganglion cells may be more marked functional changes that are not evident on routine studies, as shown in a study revealing increased nitric oxide synthase-producing ganglion cells in cases of IND. 98 Study of whole-mount sections, along with application of special stains, has been advocated to better characterize these lesions.

    INTESTINAL PSEUDO-OBSTRUCTION
    Intestinal pseudo-obstruction is defined as a clinical syndrome caused by inability of the bowel to propel its contents despite the absence of a mechanical obstruction. Both acute and chronic forms are recognized.

    Acute Intestinal Pseudo-Obstruction

    PARALYTIC ILEUS
    Paralytic ileus is the most common cause of intestinal pseudo-obstruction and generally occurs after abdominal surgery, abdominal trauma, or peritonitis. 99 The entire bowel becomes paralyzed and distended. The diagnosis is made on clinical grounds and treatment is supportive. 99 No specific histopathologic changes are recognized.

    ACUTE IDIOPATHIC INTESTINAL PSEUDO-OBSTRUCTION (OGILVIE’S SYNDROME)
    Ogilvie’s syndrome is a rare and potentially serious development in patients who have recently undergone surgery or are ill from other causes. 100 The etiopathogenesis is poorly understood, although temporary autonomic dysfunction is suspected. Patients demonstrate bowel dilation, most often confined to the right colon, which may lead to transmural ischemia and perforation, most frequently in the cecum. Histopathologic changes are nonspecific and mimic ischemia secondary to increased intramural pressure. The condition, in most instances, resolves with supportive care.

    Chronic Intestinal Pseudo-Obstruction
    Chronic intestinal pseudo-obstruction is caused by a variety of disorders that may affect various components of the bowel neuromuscular apparatus. 101 , 102 It most commonly involves the small intestine or the colon, or both. It may primarily involve the bowel (idiopathic) ( Table 7-1 ) or be part of a generalized or systemic disorder (secondary) ( Table 7-2 ). Among the idiopathic cases, four major categories have been recognized: those with abnormalities of the smooth muscle (myopathic form), those with abnormalities of the neural system (neuropathic form), those with ICC abnormalities, and those with abnormalities of neurohormonal peptides.

    TABLE 7-1 Chronic Idiopathic Intestinal Pseudo-Obstruction
    TABLE 7-2 Secondary Chronic Intestinal Pseudo-Obstruction A. Associated with systemic disorders  
    1. Progressive systemic sclerosis or polymyositis  
    2. Systemic lupus erythematosus  
    3. Progressive muscular dystrophy  
    4. Myotonic dystrophy  
    5. Fabry’s disease  
    6. Parkinson’s disease  
    7. Multiple sclerosis B. Endocrine and metabolic disorders  
    1. Diabetes mellitus  
    2. Hypothyroidism  
    3. Hypoparathyroidism  
    4. Pheochromocytoma  
    5. Acute intermittent porphyria C. Infiltrative disorders  
    1. Amyloidosis  
    2. Diffuse lymphoid infiltration  
    3. Eosinophilic gastroenteritis D. Paraneoplastic  
    1. Small cell carcinoma  
    2. Others F. Infections  
    1. Trypanosoma cruzi (Chagas’ disease)  
    2. Herpes virus  
    3. Cytomegalovirus  
    4. Epstein-Barr virus  
    5. Lyme disease D. Miscellaneous conditions  
    1. Ceroidosis (brown bowel syndrome)  
    2. Small intestinal diverticulosis  
    3. Radiation enteritis  
    4. Jejunoileal bypass H. Toxins and pharmacologic agents  
    1. Tricyclic antidepressants  
    2. Phenothiazines  
    3. Ganglionic blockers  
    4. Clonidine  
    5. Antiparkinsonism medication  
    6. Opiates (narcotic bowel syndrome)  
    7. Amanita phalloides toxin


    Clinical features.
    Many of the clinical features of chronic intestinal pseudo-obstruction are common to the various subtypes. In most cases, particularly the familial ones, symptoms begin in childhood. Some patients remain asymptomatic until middle age, and others are entirely asymptomatic. The diagnosis is often delayed for many years (median, 8 years), and repeated exploratory laparotomy or surgery is not uncommon in the clinical history of these patients. 103 Symptoms are typical of intestinal obstruction, with abdominal distention, pain, and vomiting. Distention may be gradual, but it may also become severe, especially when both the small intestine and the colon are involved. Generally, these patients have alternating diarrhea and constipation, rather than obstipation. Diarrhea is generally secondary to bacterial overgrowth resulting from stasis, and it may result in substantial weight loss. Perforation occurs rarely.

    PRIMARY CHRONIC INTESTINAL PSEUDO-OBSTRUCTION-MYOPATHIC FORMS
    Both sporadic and familial myopathic forms are recognized. 101 Care must be exercised before considering a case to be sporadic, because involved family members may be asymptomatic and a reliable family history may be difficult to elicit. Familial visceral myopathy may also involve other organs (urinary bladder or biliary tract), and it has been called hollow visceral myopathy. 104 , 105 Type I, the most common type, is characterized by redundant colon, esophageal dilation, megaduodenum, megacystis, and sometimes uterine inertia. Type II tends to show gastric dilation, slight small intestinal dilation often with formation of diverticula, ptosis, and external ophthalmoplegia. In type III, the entire GI tract, from esophagus to rectum, may be involved and show marked dilation. Type IV is characterized by gastroparesis, a tubular (narrow) small intestine, normal esophagus, and normal colon. 106 In general, sporadic cases resemble autosomal recessive familial type III visceral myopathy. Other rare forms, partially resembling type I and III, with an autosomal recessive mode of transmission and with esophageal and cardiac abnormalities have also been described. 107
    Although smooth muscle degeneration is thought to be responsible for bowel dysmotility, the etiopathogenesis for most of these cases remains obscure. Rare cases with actin or desmin abnormalities have been described. 108 , 109 In cases of “desmin myopathy,” systemic skeletal and cardiac muscle involvement is also commonly noted. Rare cases show a T-cell-rich inflammatory leiomyositis and are possibly autoimmune in nature. 110 A distinctive type of nonfamilial visceral myopathy has been described in young children from southern, central, and eastern Africa (African visceral leiomyopathy). 111 In some cases, absence of c-kit-positive ICC has been thought to be the underlying mechanism (see later). 112 It is likely that this is a heterogeneous group of disorders, and many of the histologic changes most likely represent end-stage disease. Many cases probably go unrecognized. Thus the spectrum of these disorders may be even wider than is currently known.

    Pathologic features.
    The involved segment is often dilated, and the bowel wall may appear thick, normal, or thin, depending on the degree of distention ( Fig. 7-9 ). Although often no mucosal pathology is noted initially, inflammation, ulceration, and ischemia may supervene secondary to stasis and extensive dilation. 101

    FIGURE 7-9 Visceral myopathy. A, Resection specimen of a colon shows thinning of the wall (upper segment) and thickening of the muscle (lower segment) . B, Resection specimen of colon shows massively dilated colon with flattening of the mucosal folds and thick wall. A short segment of normal colon has been placed by the side of the dilated colon for comparison.
    Microscopy reveals degeneration and fibrous replacement of the smooth muscle. Degenerative changes are most prominent in the muscularis propria, but they also affect the muscularis mucosae and thus may be identified in mucosal biopsy specimens. 113 The longitudinal layer tends to be more severely involved. However, rarely, only the inner circular layer is involved. 101 , 105 In these cases, distinction from scleroderma may be difficult. Muscle degeneration results in fibrosis, cytoplasmic vacuolation, variation in muscle fiber size, and thinning of the bowel wall ( Fig. 7-10A,C ). Fibrosis may be subtle and may require a trichrome stain to be fully appreciated (see Fig. 7-10B,D ). 101 Other changes include nuclear atypia, increased mitotic activity, and periodic acid-Schiff (PAS)-positive intracytoplasmic inclusions. 114 Ultrastructurally, cytoplasmic inclusions represent aggregates of degenerated myofibrils. 114 However, potential artifactual changes in the muscle are not uncommonly seen in surgical specimens ( Fig. 7-11 ). Rare cases with deficient smooth muscle α-actin show an absence of staining with smooth muscle actin antibodies, particularly in the inner circular muscle layer, 109 , 115 but the significance of this finding has recently been questioned and caution is warranted in interpreting this finding in clinical practice ( Fig. 7-12 ). 116 Electron microscopy shows nonspecific degenerative changes, which include mitochondrial vacuolation and may be the only diagnostic evidence of myopathy when light microscopy is normal. 101 , 105 , 111 , 117

    FIGURE 7-10 Visceral myopathy. A, Low-power view shows marked hypertrophy of both layers of the muscularis propria. B, A section of small intestine shows delicate interstitial fibrosis (trichrome stain). C, Higher magnification of the smooth muscle in the muscularis propria shows degenerative changes. D, Moderate interstitial fibrosis (trichrome stain).

    FIGURE 7-11 Artifactual cytoplasmic clearing and an appearance simulating cytoplasmic inclusions is seen not infrequently and should not be confused with myopathic change. Other findings associated with myopathic changes (e.g., nuclear pleomorphism, fiber size variation, interstitial fibrosis, increased mitosis, and ultrastructural changes) are typically absent.

    FIGURE 7-12 Visceral myopathy. Immunostain for smooth muscle actin shows lack of staining in the inner circular layer. The outer longitudinal layer appears normal. The significance of this finding is uncertain.

    CHRONIC INTESTINAL PSEUDO-OBSTRUCTION-NEUROPATHIC FORMS
    The neuropathic forms include abnormalities of the intrinsic or extrinsic neural network of the bowel, in both sporadic and familial forms. 101 , 118 The mode of inheritance may be autosomal dominant, autosomal recessive, or, rarely, X-linked. Autosomal recessive cases tend to show intranuclear inclusions in ganglion cells; some are characterized by mental retardation and basal ganglia calcification. The autosomal dominant variant does not show extraintestinal manifestations. The X-linked form is associated with a short small intestine, malrotation, and pyloric hypertrophy. 119
    The etiopathogenesis of the neurodegenerative changes remains obscure. Pathogenetic mechanisms that may be involved include altered calcium signaling, mitochondrial dysfunction, and free-radical injury. 120 Patients with rare autosomal recessive forms present with a progressive multisystem neurodegenerative disorder and abnormalities in mitochondrial DNA. 121 Many genes have been identified as being responsible for the syndromic forms of intestinal pseudo-obstruction, including thymidine phosphorylase (also known as endothelial cell growth factor-1), DNA polymerase gamma gene, and the transcription factor SOX10. 122 Mutations in thymidine phosphorylase have been shown to be responsible for familial cases of mitochondrial neurogastrointestinal encephalomyopathy, a disorder characterized by intestinal pseudo-obstruction, progressive external ophthalmoplegia, ptosis, polyneuropathy, and leukoencephalopathy. 123 , 124 Decreased ganglion cell survival may be a factor in some cases, as suggested by decreased BCL2 gene product in the enteric ganglion cells. 125 Some cases reveal inflammatory neuronal degeneration, which suggests an autoimmune or infectious etiology. 126 Neuronal autoantibodies are detected in some patients. 127 Some of these cases represent a paraneoplastic manifestation, and some remain idiopathic. 128

    Pathologic features.
    Gross findings are similar to those of other forms of intestinal pseudo-obstruction and do not help differentiate the various subtypes. Examination of routine sections is often unrevealing except in cases where neurons are markedly decreased in number, or when cytomegalovirus-like intranuclear inclusions can be identified in neurons. 118 , 129 , 130 Electron microscopy has revealed these inclusions to be proteinaceous material composed of curving filaments, and not viral particles. Some cases tend to show lymphocytic inflammation of the ganglions and myenteric plexus. 128 In addition, subtle degenerative changes in neurons and abnormal dendritic processes are also identified. 101 These changes are best appreciated with a silver stain on thick en-face or tangential embedded sections of the bowel, or whole-mount preparations. Silver stains also help identify abnormalities of argyrophobic and argyrophilic ganglion cell populations, but these stains are obsolete in current practice. Immunohistochemical markers that have been used include VIP, substance P-related tachykinins, nitric oxide synthase, neuropeptide Y, calcitonin gene-related peptide, and BCL2. These show abnormal expression in the enteric nervous system in the neuropathic forms but lack disease specificity and fail to differentiate primary from secondary changes. 103 , 128 Of these BCL2 has been more widely used as a marker of increased neuronal apoptosis and supports the idea of neuropathic changes. 125 Limited experience with these conditions, necessity of employing fastidious neuron-counting techniques, and tedious silver stains have limited the study of such cases to only a few highly specialized centers. Furthermore, artifactual changes in ganglion cells are frequently encountered in clinical practice and do not imply neuropathic changes ( Fig. 7-13 ).

    FIGURE 7-13 Artifactual cytoplasmic eosinophilia and pyknotic nuclei in a case of diverticulosis that mimics neuropathic changes.

    CHRONIC INTESTINAL PSEUDO-OBSTRUCTION-ICC ABNORMALITIES
    Recent insight into the role of ICC in bowel motility, possibly as the pacemaker cells of the bowel, has led to speculation that they may play a role in chronic idiopathic intestinal pseudo-obstruction. Steel mutant mice, which lack c-kit-positive ICC, show marked constipation and features suggestive of chronic intestinal pseudo-obstruction. 131 , 132 Also, blockade of the c-kit receptor results in severe disturbance of bowel motility. 133 Piebaldism in humans, a condition associated with inactivating c- kit mutations, is associated with life-long constipation. 134 , 135 It has recently been shown that some cases of intestinal pseudo-obstruction show near-total to total loss of c-kit-positive ICC. 112, 136 - 138 A rare case of ICC hyperplasia without underlying germline c- kit mutation and appearing as chronic idiopathic intestinal pseudo-obstruction in a pediatric patient has also been reported. 139

    Pathologic features.
    Routine stains may show changes typical of visceral myopathy, but some cases do not show any obvious histopathologic changes ( Fig. 7-14 ). Immunohistochemistry reveals near-total to total loss of c-kit-positive ICC in the involved segment (small bowel or colon, or both). Some cases may show the presence of ICC but their network may be abnormal, or only a subset of ICC (submucosal plexus) may be lacking; however, these abnormalities are difficult to appreciate on routine formalin-fixed tissues. 140 In rare cases with ICC hyperplasia, distinct bandlike proliferation of benign spindle cells between the two layers of muscularis propria can be appreciated even on H&E preparations. These cells stain strongly with c-kit antibody, which makes their recognition as ICC easier. 139

    FIGURE 7-14 Chronic idiopathic intestinal pseudo-obstruction. There are no significant histopathologic changes and a total absence of interstitial cells of Cajal in a section of the small intestine (c-kit immunostain).

    CHRONIC INTESTINAL PSEUDO-OBSTRUCTION-NEUROHORMONAL PEPTIDE ABNORMALITIES
    This ill-defined group includes cases of neuroblastoma and ganglioneuroblastoma associated with chronic intestinal pseudo-obstruction. 141 , 142 Tumor resection results in resolution of the pseudo-obstruction. VIP produced by tumor has been implicated as causing intestinal dysmotility. A rare case of pancreatic polypeptide cell hyperplasia associated with intestinal pseudo-obstruction has also been reported. 143

    Secondary Chronic Intestinal Pseudo-Obstruction

    SYSTEMIC DISORDERS
    Patients with scleroderma or progressive systemic sclerosis may have significant involvement of the bowel, resulting in a severe motility disorder that often requires surgical resection. 144 Clinically, esophageal involvement usually predominates. The inner circular layer is often preferentially involved, in contrast to primary visceral myopathy, which involves the outer longitudinal muscle layer preferentially. 101 , 145 In scleroderma, collagenous replacement of the muscle layer tends to be nearly complete, which is unlike the delicate form of interstitial fibrosis characteristic of primary visceral myopathy ( Fig. 7-15 ). Fibrosis may cause muscle weakness resulting in the formation of diverticula with square-mouthed ostia. Mucosal changes are nonspecific and secondary to the underlying motility problem (e.g., reflux esophagitis and villous blunting caused by bacterial overgrowth in the small bowel).

    FIGURE 7-15 Scleroderma. A, Complete replacement of the outer longitudinal layer of the muscularis propria by fibrosis. The inner circular layer here, unlike in most cases of scleroderma, is relatively well preserved. B, Extensive and coarse fibrosis in areas of partly preserved longitudinal layer of muscularis propria (trichrome stain). Compare this to the delicate interstitial fibrosis seen in visceral myopathy (see Fig. 7-10B ).
    Pseudo-obstruction, with muscle damage, may occur in patients with dermatomyositis (or polymyositis), systemic lupus erythematosus, myotonic dystrophy, and progressive muscular dystrophy. 144, 146 - 148 Amyloid deposition in the muscularis propria (myopathy) or myenteric plexus (neuropathy) may, uncommonly, present with intestinal pseudo-obstruction. AA-type amyloid is often deposited in the myenteric plexus, whereas AL-type amyloid is more often deposited in the muscularis propria. 149
    Parkinson’s disease, familial autonomic dysfunction, and Shy-Drager syndrome may be associated with dysmotility, but no specific pathologic changes are identified in these conditions. Diffuse polyclonal lymphoid infiltration of the small intestine is another rare condition of un-certain etiopathogenesis. 150 Intestinal pseudo-obstruction may also occur in patients with hypoparathyroidism, hypothyroidism, and pheochromocytoma. However, diabetes is by far the most common endocrine disorder associated with bowel dysmotility, and this may result from autonomic dysfunction, electrolyte abnormalities, and vasculopathy. Eosinophilic gastroenteritis and radiation enteritis may also result in intestinal pseudo-obstruction. Destruction of ganglion cells as a paraneoplastic syndrome has been well described in patients with small cell carcinoma of the lung, and rarely with other tumors as well. 151 - 153 In such cases, neuronal autoantibodies have been detected, and ganglionic destruction is likely to be immune mediated.

    DRUGS AND TOXINS
    A variety of pharmacologic agents (e.g., phenothiazines, tricyclic antidepressants, ganglionic blockers, clonidine, and antiparkinsonian medication) have a marked effect on bowel motility, and use or ingestion of naturally occurring toxins (e.g., from Amanita phalloides ) may result in intestinal pseudo-obstruction.

    INFECTIONS
    Viral infection, particularly infection with the herpes group, has been associated with systemic autoimmune disturbances and bowel dysmotility. Visceral involvement concurrent with varicella-zoster cutaneous involvement has been shown to result in dysmotility of the stomach, small intestine, colon, and anus. 154 , 155 Bowel dysfunction resolves with improvement of the cutaneous disease. Cytomegalovirus infection has also been implicated in intestinal pseudo-obstruction, especially in immunocompromised individuals. 156 , 157 In some cases, evidence of Epstein-Barr virus infection has been demonstrated by polymerase chain reaction and in situ hybridization studies of the myenteric plexus. 158 Histologically, the only clues may be the presence of inflammatory cells surrounding ganglia and myenteric plexus, or typical viral inclusions in the ganglion cells. Lyme disease and Chagas’ disease may involve the small or large intestine (or both), resulting in intestinal pseudo-obstruction. 41 , 159 , 160

    MISCELLANEOUS CONDITIONS

    Ceroidosis (Brown Bowel Syndrome)
    Ceroidosis is characterized by deposition of light brown, granular, lipofuscin-like pigment within the smooth muscle cells of the muscularis mucosae or the muscularis propria (or both) of any bowel segment ( Fig. 7-16 ). 161 , 162 Ultrastructurally, the granular electron-dense material contains myelin figures and abnormal distorted mitochondria. Ceroidosis has been seen in many processes associated with malabsorption, including celiac disease, Whipple’s disease, and chronic pancreatitis; vitamin E deficiency has also been implicated as an underlying factor. It is unclear whether this is a purely nonspecific morphologic marker of a systemic disease or represents a primary smooth muscle disorder.

    FIGURE 7-16 Brown bowel syndrome. Brownish discoloration is seen in the smooth muscle cells of the muscularis propria at low magnification. At higher magnification (inset) , the cytoplasmic pigment appears granular, light brown, and lipofuscin-like. No other abnormalities of the smooth muscle cells or muscularis propria are seen.
    (Courtesy of Dr. Thomas Smyrk.)

    Irritable Bowel Syndrome
    Irritable bowel syndrome is a common disorder of uncertain etiopathogenesis that most commonly affects women. Symptoms include a combination of diarrhea, constipation, bloating, and abdominal pain. Disturbance of bowel motility and enhanced visceral sensitivity have been implicated as etiologic factors. Colonoscopy is normal, and routine examination of mucosal biopsy specimens does not normally show any pathologic abnormalities. However, quantitative histologic studies, immunohistochemical analysis, and ultrastructural studies may show subtle alterations that include an increase in the number of lymphocytes, mast cells, and enterochromaffin cells. 163 These changes point to activation of the enteric immune system and neuroimmune interactions, but they have little value in the routine diagnostic evaluation of biopsy specimens from these patients. A biopsy is often performed merely to rule out other potential causes of the patient’s symptoms.

    Small Bowel Diverticulosis
    The most common types of small bowel diverticula are congenital in origin and include Meckel’s diverticulum and duodenal diverticulosis. Less commonly, acquired cases of small bowel diverticulosis are encountered secondary to neuromuscular abnormalities. 164 Diverticula result from mucosal outpouchings secondary to fibrosis-induced mural weakness. In cases with scleroderma-like morphologic changes, Raynaud’s phenomenon is frequently present, although clinical scleroderma is not evident. Some cases are related to known neurologic disease processes, such as Fabry’s disease.

    Severe Idiopathic Constipation (Slow-Transit Constipation, Arbuthnot Lane’s Disease)
    Severe idiopathic constipation is characterized by chronic constipation resulting from reduced colonic propulsive capacity, 165 , 166 and it most commonly affects young women. Onset of the disease may be seen in early childhood or late in life. Symptoms often persist despite use of laxatives. Melanosis coli is a common histologic finding. Such cases have often been labeled cathartic colon, but whether laxative abuse is the underlying cause remains a question. In severe and resistant cases, colectomy may have to be performed. This disorder most likely represents a heterogeneous group of disorders comprising myopathic, neuropathic, and ICC abnormalities. Decreased numbers of ganglion cells, intraganglionic neurofilaments, and ICC have been described. 165 , 167 , 168 Amphophilic, hyaline, and round to ovoid (4 to 22μm) cytoplasmic inclusions of unclear composition may be found in smooth muscle cells. 169 These inclusions are nonspecific and can be identified in normal colon or small bowel, as well as in Chagas’ disease.

    PROGNOSIS AND THERAPY
    Primary intestinal pseudo-obstruction of adulthood usually has a prolonged course of 20 to 30 years; infants and children tend to have a poorer prognosis and die at a young age. 103 Treatment is symptomatic and supportive, as no specific and effective therapy is known. Surgical resection may be undertaken in resistant cases, and a good outcome is expected in cases with limited bowel involvement. However, substantial resection of small or large bowel may be required, resulting in total parenteral nutrition dependence. Intestinal transplantation is gradually emerging as a possible treatment option in intractable cases. 170 The main causes of death in these patients are related to surgery, to total parenteral nutrition, or to transplantation complications. 103
    Prognosis and treatment of secondary intestinal pseudo-obstruction vary according to the underlying condition. Patients with progressive systemic sclerosis often die within 5 to 10 years as a result of renal, cardiac, or pulmonary complications. Patients with small cell carcinoma usually die within a year of extraintestinal manifestations. Cases associated with viral infection are generally self-limited. Intestinal pseudo-obstruction in cases associated with systemic diseases, such as systemic lupus erythematosus or amyloidosis, generally follow the course of the underlying disease.

    INTESTINAL DYSMOTILITY: DIAGNOSTIC APPROACH AND WORKUP
    Diagnosis of motility disorders remains a challenge for both clinicians and pathologists. Unfortunately, the pathogenesis of many dysmotility conditions remains poorly understood, and many disorders lack specific diagnostic pathologic features. Thus, any sound diagnostic approach to patients with intestinal derangements requires a careful evaluation of the clinical presentation, family history, history of medications, exposure to toxins, imaging and physical findings, and pathologic features. 171 Early onset of symptoms, in childhood or in the neonatal period, suggests a developmental or congenital etiology, whereas the majority of motility disorders diagnosed in adults are acquired or secondary. Many disorders, particularly chronic idiopathic intestinal pseudo-obstruction, have an insidious onset, and the chronic nature of the disease may not be obvious. A family history that is in fact positive often appears negative when the disease was mild or subclinical and affected individuals did not seek clinical attention.
    The presence of associated abnormalities (e.g., external ophthalmoplegia) and dilation of other segments of the GI tract or other viscera (e.g., duodenum, gallbladder, or urinary bladder) may point toward an inherited form of visceral myopathy. Careful evaluation of associated symptoms or signs can often lead to the primary cause of bowel dysmotility. Occasionally, the underlying systemic disorder may be diagnosed only after pathologic evaluation of bowel specimens, as in some collagen-vascular disorders such as scleroderma. A positive history of medication use, or exposure to toxin, is often difficult to evaluate because many patients consume multiple drugs, and the impact of the drugs on bowel motility may not be well known or previously reported. A positive history of a preceding viral illness should always be evaluated for a possible infectious or postinfectious cause of pseudo-obstruction. 154 , 155 In select cases, serology for circulating antineuronal and anti-smooth muscle antibodies may be helpful. 110 , 122
    Endoscopy, laparotomy, and radiology may help exclude mechanical causes of intestinal obstruction. GI ma-nometry, although not essential, also helps differentiate mechanical from functional obstruction. 122 , 171 It also helps differentiate neuropathic from myopathic causes of dysmotility. Other investigations, such as neurologic and autonomic tests, also play a role in the diagnostic workup. In the majority of patients seen in routine practice, intestinal obstruction is secondary to mechanical causes (e.g., adhesions, extrinsic compression, or internal hernia). At present, molecular and genetic tests play a very limited role in the diagnostic workup of motility disorders.
    From a pathologist’s point of view, a careful evaluation of the gross findings and use of a systematic approach to the histologic examination of tissue specimens are essential ( Table 7-3 ). Mucosal biopsies often show nonspecific findings. An appropriate diagnostic workup often requires a full-thickness biopsy, combined with electron microscopy and special stains. Whenever feasible, some tissue should be frozen, and some immediately fixed in glutaraldehyde for possible electron microscopy. Careful microscopic examination of the mucosal changes and the neuromuscular apparatus should be undertaken. Particular attention should be paid to the thickness of the muscle layers, myocyte morphology, pattern of fibrosis, number and morphology of ganglion cells, number and distribution of ICC, presence or absence of neural plexus hypertrophy or atrophy, and presence or absence of inflammation involving the neuromuscular apparatus. Inflammation surrounding the neural plexus, and ganglionitis, may point toward an infectious, paraneoplastic, or autoimmune neuropathy, whereas dense lymphocytic inflammation limited to the muscular layers may suggest autoimmune leiomyositis. 110 , 126 However, one should be cautious when evaluating inflammation within the neuromuscular apparatus, because secondary involvement with inflammatory disorders (e.g., inflammatory bowel disease) is more common than primary involvement. Neural hypertrophy and atrophy, although nonspecific, may indicate involvement of the neuromuscular apparatus and an underlying motility disorder. Artifactual cytoplasmic vacuolation and nuclear pyknosis in muscle and ganglion cells should be separated from true pathology (see Figs. 7-10 and 7-13 ).
    TABLE 7-3 Diagnostic Approach and Workup of Motility Disorders of the GI Tract H&E stain
    Evaluate number and morphology of ganglion cells, thickness of muscle layers, histology of muscle fibers
    Evaluate inflammation in the muscle layers, around the ganglion cells or neural plexuses, and the nature of inflammatory infiltrate Histochemical stains Trichrome Evaluate pattern of fibrosis Periodic acid–Schiff Evaluate cytoplasmic inclusions in smooth muscle fibers Congo red Rule out amyloidosis Immunohistochemical stains S100 Evaluate neural plexuses C-kit (CD117) Evaluate interstitial cells of Cajal Smooth muscle actin Decreased or absent staining in myopathic cases Desmin Decreased or absent staining in myopathic cases BCL2 Decreased staining in neuropathic cases Electron microscopy
    Evaluate degenerative changes in muscle fibers and ganglion cells, or abnormal mitochondria
    Evaluate for viral infections
    Evaluate interstitial cells of Cajal
    A panel of histochemical stains (trichrome, Congo red, and PAS) and immunohistochemical stains (S100, c-kit, smooth muscle actin, and desmin) is helpful in evaluating cases when routine histologic examination is either normal, nonspecific, or nondiagnostic. ICC are difficult to appreciate on H&E-stained tissue sections and need immunohistochemical analysis with c-kit antibody. ICC abnormalities should always be considered in the differential diagnosis, particularly when routine histology is unremarkable. Although the presence or absence of ICC is easily appreciated on routine tissue sections, subtle abnormalities of the deep muscular or submucosal ICC plexus are better evaluated in frozen tissue. 140 Quantitation of ICC and evaluation of their network are also difficult on routine tissue sections. 2 , 168 A more detailed evaluation of the enteric nervous system with an elaborate immunohistochemical antibody panel (VIP, substance P-related tachykinins, nitric oxide synthase, neuropeptide Y, calcitonin gene-related peptide, and BCL2) should be limited to select cases. Electron microscopy is extremely valuable in some cases, particularly when light microscopy is nondiagnostic. Many degenerative changes in the muscle, neuronal cells, or mitochondria can be detected only by ultrastructural examination.
    Unfortunately, despite extensive workup, many cases of primary intestinal dysmotility remain of unclear etiology and are a source of frustration for both pathologists and clinicians.

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    CHAPTER 8 Congenital and Developmental Disorders of the GI Tract

    PIERRE. RUSSO, DALE. HUFF

    Embryology and Anatomic Development of the GI Tract
    Esophagus
    Stomach
    Small and Large Intestines
    Molecular Mechanisms of Development
    Congenital Anomalies of the GI Tract
    Esophagus
    Stomach
    Small and Large Intestines
    Anorectal Malformations

    Embryology and Anatomic Development of the GI Tract
    The development of the mammalian digestive system and its genetic control mechanisms is highly conserved throughout phylogeny. Development of the GI tract proceeds through three major overlapping steps: formation of the gut tube during blastogenesis, differentiation of the specific segments of the digestive tract and its accessory organs during organogenesis, and histogenesis of the individual organs with their specialized cell types. 1 Major developmental milestones are outlined in Table 8-1 . The first two steps, development of the primitive gut tube during blastogenesis followed by organogenesis, take place during the embryonic period, which begins on the day of fertilization and ends on the 56th postconceptual day (8th week). The developing human is more susceptible to teratogenetic agents during the embryonic period than at any other period of development. The fetal period, which begins on postconceptual day 57 and ends at birth, is characterized by the final stages of rotation and fixation, as well as by continued elongation and histogenesis of the GI tract. An overview of these basic processes, especially as they pertain to the GI tract, is presented in Table 8-2 . The pattern of congenital anomalies of the GI tract varies depending on the developmental period in which they arise ( Table 8-3 ).
    TABLE 8-1 Developmental Milestones Event Time of First Expression Gastrulation Week 3 Gut tube largely closed Week 4 Liver and pancreas buds Week 4-5 Growth of intestines into cord Week 7 Intestinal villus formation Week 8 Retraction of intestines into abdominal cavity Week 10 Organ formation complete Week 12 Parietal cells detectable, pancreatic islets appear, bile secretion, intestinal enzymes detectable Week 12 Swallowing detectable Weeks 16 and 17 Mature motility Week 36
    From Montgomery RK, Mulberg AE, Grand RJ: Development of the human gastrointestinal tract: Twenty years of progress. Gastroenterology 116:702-731, 1999.

    TABLE 8-2 GI Development in the First 10 Weeks

    TABLE 8-3 Patterns of Congenital Anomalies Arising during Various Developmental Periods




    Blastogenesis.
    Blastogenesis extends from fertilization to day 28. During the first half of blastogenesis, the bilaminar disc and the basic body plan of dorsoventrality, rostrocaudal axis, and laterality are established. During the second half of blastogenesis, the midline developmental field directs the process of gastrulation, which establishes all three germ layers (endoderm, mesoderm, and ectoderm). The mammalian digestive system is derived from each of these layers-the epithelial lining from the endoderm, the muscle layers and supportive elements from the mesoderm, and the neurons of the enteric nervous system from the ectoderm. It is during this period that the basic plan of the GI tract is established through the inductive influences of the notochord, primitive streak, emerging mesoderm, and other anatomic components of the midline developmental field on the primitive endoderm. These inductive influences predetermine the sites of the specific segments of the GI tract and the primordia of its accessory organs of digestion. Simultaneously, during the 3rd and 4th weeks, cephalocaudad and lateral folding of the embryo converts the trilaminar germ disc into an elongated cylinder, and the resulting endodermal gut tube consists of the cranial foregut, a midgut open to the yolk sac via the vitelline duct, and a hindgut ( Fig. 8-1 ). The blood supply to the primitive gut is via derivatives of the vitelline arteries of the yolk sac. The celiac, superior mesenteric, and inferior mesenteric arteries vascularize the abdominal foregut, midgut, and hindgut, respectively, and by convention determine the boundaries of each ( Fig. 8-2 ).

    FIGURE 8-1 Sagittal midline sections of the embryo demonstrating cephalocaudal folding and its effect on the developing gut tube. A, Presomite embryo with the flat embryonic disc. B, End of the first month. The folding of the embryo has created the gut tube with foregut, midgut, and hindgut. The midgut communicates with the yolk sac.
    (From Sadler TW: Langman’s Medical Embryology, ed 8. Philadelphia, Lippincott Williams and Wilkins, 2000, p 99.)

    FIGURE 8-2 Primitive dorsal and ventral mesenteries. The celiac artery supplies the foregut. The superior mesenteric artery supplies the midgut, running through the mesentery and continuing toward the yolk sac as the vitelline artery.
    (From Sadler TW: Langman’s Medical Embryology, ed 8. Philadelphia, Lippincott Williams and Wilkins, 2000, p 273.)

    Organogenesis.
    Organogenesis extends from day 29 to day 56 (weeks 5 through 8). Suddenly, during the 5th week, the entire tubular GI tract, its major divisions, and its accessory organs of digestion, having been predetermined during blastogenesis, emerge from the imprinted primordium of the primitive endodermal tube. The abdominal portion of the foregut is divided into the esophagus, stomach, and proximal duodenum. The common origin of the trachea and esophagus from the foregut results in various forms of fistulas if separation is incomplete. The hepatic diverticulum arises from the proximal duodenum, its cephalic portion budding into the transverse septum (precursor of the diaphragm) to become the liver, and its caudal portion giving rise to the gallbladder and extrahepatic biliary tree. Dorsal and ventral pancreatic buds also emerge from the proximal duodenum.
    As elongation of the midgut proceeds much faster than growth of the embryo from the 6th week on, the intestine pushes out into the stalk of the yolk sac. As it does so, it rotates 90 degrees counterclockwise (as viewed from the front of the embryo) around the axis of the superior mesenteric artery, so that the cranial limb (prearterial in relation to the superior mesenteric artery) moves to the embryo’s right, and the caudal limb (postarterial) to the embryo’s left ( Fig. 8-3A,B ). Continued elongation, especially of the prearterial segment, results in a series of folds called the jejunoileal loops, the identity of which Keibel and Mall believed was retained in the adult. 2 The postarterial loop, most of which will form the colon, remains relatively straight. Around 63 days of life, under largely unknown influences, the intestines suddenly return to the abdominal cavity. As they return, there is a further anticlockwise, 180-degree rotation, which, added to the previous rotation, makes a total of 270 degrees (see Fig. 8-3C ). As a result, the third portion of the duodenum passes horizontally caudal and dorsal to the artery, and the proximal anchoring point comes to lie near the final position of the ligament of Treitz to the left of the artery. The superior mesenteric artery hangs over the ventral wall of the third portion of the duodenum. As the distal limb then rapidly returns, it swings ventral and rostral to the proximal loop, and the cecum comes to lie in the right abdomen near the liver (see Fig. 8-3D ). Rotation is completed by the 10th week, and fixation continues throughout fetal life as the mesenteries become adherent to the parietal peritoneum.

    FIGURE 8-3 Intestinal rotation. A and B, At the end of the 6th week, the intestinal loop herniates through the umbilicus and rotates 90 degrees counterclockwise. C, As the small intestine elongates, it forms the jejunoileal loops. During the 10th week, the loops retract into the abdominal cavity and rotate an additional 270 degrees counterclockwise. D, As the midgut completes its return, the cecum lies in the right upper quadrant. E, Separation of the liver and cecum, with the cecum assuming its definitive position in the right lower quadrant.
    (From Larsen WJ: Human Embryology, ed 2. Hong Kong, Churchill Livingstone, 1997, p 241.)
    The cecum and liver then separate by unknown mechanisms, the increasing distance occupied by the lengthening ascending colon, with the final position of the liver being in the right upper quadrant and that of the cecum being in the right lower quadrant (see Fig. 8-3E ). This separation is referred to, probably incorrectly, as cecal descent. See Estrada 3 for an extensive review and Kluth and colleagues 4 for a recent reevaluation of these events.

    Mucosal histogenesis.
    Mucosal histogenesis transforms the primitive undifferentiated epithelium of the gut tube into the specific epithelia of the final differentiated segments of the digestive tract. Although histogenesis begins in the late embryonic period, most of the histologic transformation occurs during fetal life. It begins with a transient phase of epithelial proliferation. The proliferating epithelium completely occludes the lumen of the duodenum, significantly narrows the lumen of the esophagus, and may mildly narrow the lumens of the cardia, pylorus, upper jejunum, and distal ileum. These proliferations may be accompanied by the transient formation of multiple antimesenteric diverticula in the duodenum, upper jejunum, and distal ileum. Some instances of congenital atresia, stenosis, or diverticula may be the result of abnormalities in the formation or resolution of the proliferative phase.

    ESOPHAGUS
    Ciliated columnar epithelium covers the epithelial surface of the midesophagus at 10 weeks and spreads to both ends by the 11th week ( Fig. 8-4 ). Stratified squamous epithelium begins to replace the ciliated columnar epithelium in the midesophagus at 16 weeks and spreads proximally and distally to cover the entire esophagus by birth except for the proximal esophagus, where islands of ciliated columnar epithelium may persist. These disappear shortly after birth. 5 - 7 Intestinal goblet cells in the distal esophagus have been rarely observed in the neonate and fetus, although positive staining with acidic mucins at the squamocolumnar junction in this age group is common. 8 Pancreatic acinar tissue has been observed in young children at the gastroesophageal junction, independent of Barrett’s esophagus, esophagitis, or gastritis. 9 The superficial cardiac glands of the lamina propria appear in the 13th week. The submucosal mucous glands appear in the 27th week. The circular muscle layer is present at 8 weeks, the longitudinal layer at approximately 13 weeks, followed by the muscularis mucosae. The waves of differentiation begin in the esophagus and propagate caudally, and then at the anorectal junction and propagate cranially. The two meet at the ileocecal junction. Ganglion cells become recognizable by 8 weeks. Their density peaks between 16 and 20 weeks, decreases with increasing gestational age until 30 weeks, and then becomes constant. 10

    FIGURE 8-4 Stratified, focally ciliated columnar epithelium in the esophagus of a 22-week-old fetus.

    STOMACH
    During the 5th week of life, differential growth of the dorsal wall of the stomach results in the formation of the greater curvature. Subsequent rotation of the stomach 90 degrees along a craniocaudal axis during the 7th week, followed by fixation of the second part of the duodenum to the dorsal body wall, forms the lesser sac of the peritoneal cavity. Prenatal ultrasound examinations have shown that the stomach continues to grow in a linear fashion from 13 to 39 weeks. Studies of the development of the mouse stomach have established that epithelial stem cells of the gastric pits reside in the neck region, producing different cell populations that move either upward or downward. 11 , 12 Intestinal villi appear in the cardia and pylorus, where they are normally abundant by 30 weeks ( Fig. 8-5 ). They disappear by birth.

    FIGURE 8-5 Gastric body mucosa of a 22-week-old fetus. The surface epithelium is villiform. Parietal cells are apparent in the glands, but chief cells are not observed.
    Intestinal metaplasia of cardiac or pyloric epithelium may be a dedifferentiation to the normal fetal condition. The cardiac mucosa is thought to arise from undifferentiated gastric mucosa and not from esophageal metaplasia. 13 Postnatal development of the stomach involves thickening of the glandular region with proliferation and maturation of the chief cells, which are relatively fewer in the neonatal stomach than in the adult, and which do not produce pepsin in the newborn. 14 Gastric pH is relatively high in the neonate and becomes comparable to that of adults by the age of 2 years. This may result partly from buffering by amniotic fluid but perhaps also from a relative lack of gastrin, the level of which increases in the first few postnatal months. 14

    SMALL AND LARGE INTESTINES
    In the duodenum, exuberant epithelial proliferation begins early in the 6th week and completely occludes the lumen by the end of the 6th week. The expanding mass of proliferating epithelium distends the duodenum proximal and distal to the hepatobiliary and pancreatic diverticula, imparting an hourglass shape to the duodenum, with the narrow waist at the level of the hepatobiliary and pancreatic ducts. A recent study suggests that the occlusion does not result from proliferation but from morphogenetic events involved in elongation of the duodenum. 15 Congenital duodenal atresia or stenosis often occurs at the site of this waist and may be associated with hepatobiliary and pancreatic duct abnormalities. Epithelial diverticula form along the antimesenteric border. By the 8th week the proliferation ends, the lumen is reestablished, and the diverticula disappear.
    Some authors 15 - 17 report similar, but less exuberant, nonocclusive proliferations accompanied by similar antimesenteric diverticula in the proximal jejunum and distal ileum. These begin in the 7th week and disappear by the 16th week. Villi and crypts appear first in the duodenum in the 8th week, spread to the mid small intestine by the 9th week, and reach the distal ileum by the 12th week. 18 , 19 The early intestinal mucosa consists of stratified epithelium, with gradual appearance of columnar epithelium, first at the apices and then along the sides of villi. By the 10th week, only intervillous epithelium remains stratified. 1 By 9 to 10 weeks, absorptive cells of the proximal intestine display a brush border with an array of microvilli. 20 Eosinophilic globules can frequently be observed within the fetal intestinal epithelium ( Fig. 8-6 ); these have been referred to as thanatosomes, and they seem to reflect apoptotic activity. 21 Cytologic differentiation of the crypts begins with the appearance of goblet cells in the 8th week, followed by Paneth cells and enteroendocrine cells in the 9th, and Segi’s cap 22 in the 20th week. The time of appearance and the electron microscopic features of enteroendocrine cells have been described in human embryos between 9 and 22 weeks gestation. 23 Brunner’s glands appear in the proximal duodenum in the 12th week. The histologic appearance of the small intestine resembles that of a newborn by 20 weeks. 24

    FIGURE 8-6 Small bowel of a 19-week-old fetus. The brightly eosinophilic globules observed in the surface epithelium are thanatosomes and may reflect apoptotic activity.
    Early development of the endoderm depends on molecular signaling pathways such as that of Wnt, which by stabilizing β-catenin allows it to translocate to the nucleus to activate transcription genes. Ablation of β-catenin in the notochord and primitive streak abrogates endoderm formation. 25 Numerous other transcription factors are important in intestinal development; these are reviewed by Montgomery and colleagues. 1 Math1, a basic loop-helix-loop transcription factor, appears to be a key regulator of the development of secretory cells (goblet, Paneth, and enteroendocrine cells), whereas absorptive cells appear to be Math1-independent. 26 Neonates have been reported with an absence of gut secretory cells. 27 Patients with mutations in a gene called neurogenin 3 have presented with malabsorptive diarrhea and a complete absence of enteroendocrine cells. 28 The enteric nervous system results from contributions from the sympathetic system, growing along the arterial supply, and from the parasympathetic system, with branches of the vagal nerve innervating the upper GI tract, whereas the pelvic splanchnic nerves innervate the descending colon and rectum. Postganglionic neurons are derived from neural crest cells, which appear in the fetal gut around 8 weeks and migrate in a craniocaudal direction, detected in the rectum by 12 weeks. 1 The development of the enteric nervous system is beyond the scope of this chapter, and recent references should be consulted. 29 - 33
    The colonic mucosa , like the intestinal epithelium, consists of a stratified epithelium beginning at around 8 weeks. At approximately the 10th week, villi with developing crypts cover the surface of the large intestine and persist until the 28th week. Therefore, intestinal villi are normally seen in the embryo not only in the small intestine but also in the cardia, pylorus, and colon ( Fig. 8-7 ). The intervillous surface epithelium differentiates into a single layer containing goblet cells by the 13th to 16th week. After birth, a 100-fold increase in the number of intestinal crypts occurs, along with an expansion of crypt cells. 14 The histogenesis of the muscular coats and the myenteric plexus is outlined in Table 8-4 . The development of the mucosal lymphoid system is outlined in Table 8-5 . The fetal mucosal lymphoid system has the capacity to respond to an abnormal intrauterine antigenic stimulus with the formation of germinal centers and plasma cells, possibly at as early as 20 weeks. The neonate responds to the antigenic stimulus of colonization at birth with the formation of germinal centers and plasma cells 2 to 4 weeks after birth.

    FIGURE 8-7 The large bowel of this 22-week-old fetus has a villiform epithelium, similar to that of the small bowel.

    TABLE 8-4 Age in Weeks at Beginning of Histogenesis of the Muscular Coats and Myenteric Plexus
    TABLE 8-5 Histogenesis of Mucosal Lymphoid Tissue Week Feature Intrauterine 7 Intraepithelial lymphocytes. 10 T cells with surface recognition 12 PHA responsive lymphocytes 14 Lymphocytes with phytohemagglutinin (PHA) cytotoxicity and ability to mediate graft-versus-host response 17-20 Mast cells in small intestine 21-24 Mast cells in large intestine; solitary lymphoid follicle in distal ileum, appendix, and colon 24 Peyer’s patches in distal ileum 40 Solitary lymphoid follicles in duodenum, rectum, and possibly stomach After Birth 2-4 Germinal centers and plasma cells
    From Huff DS: Developmental anatomy and anomalies of the gastrointestinal tract, with involvement in major malformative syndromes. In Russo P, Ruchelli E, Piccoli D (eds): Pathology of Pediatric Gastrointestinal and Liver Disease. New York, Springer, 2004, pp 3-37. With kind permission of Springer Science and Business Media.

    Molecular Mechanisms of Development
    Recent advances in our understanding of the molecular controls of gut development have flowed from studies of a number of vertebrate and invertebrate models, including Caenorhabditis elegans, Drosophila , sea urchins, zebrafish, and the mouse. These have highlighted the importance of cell-cell signaling in the formation and development of the various germ layers, and the coordination of these pathways by a relatively limited number of intercellular signaling pathways, such as the BMP, notch, homeobox, hedgehog, and Wnt pathways, as well as growth factors (epidermal growth factor, transforming growth factor-alpha) have all been implicated in various aspects of gut development. In Drosophila and in the mouse, there are regional differences in the specific expression of homeo-box (Hox) genes along the gut axis. 1 , 34 For example, hindgut defects in mice can be linked to defective expression of HOXD13 . 34
    Another family of signaling genes critical in cellular cross-talk is the hedgehog (Hh) family, which appears essential to anterior-posterior, dorsal-ventral, and radial patterning. Knockout and transgenic mouse models of various hedgehog components result in a variety of malformed phenotypes, ranging from esophageal atresia to persistent cloaca. 35 Vertebrate homologs of Hh exist in three forms: Sonic (Shh), Indian (Ihh), and Desert (Dhh), which have different but overlapping expression patterns. For example, Shh-/- mutant embryos die in utero and have overgrown duodenal villi resulting in occlusion analogous to duodenal stenosis in humans. Selective postnatal blocking of Hh signaling resulted in a wasting and runted phenotype characterized by diarrhea, with disorganized intestinal villi, hyperplastic crypts, and enterocyte vacuolization. 35
    Epigenetic factors may also contribute to different phenotypic development as well as disease susceptibility in genetically identical individuals. For example, different degrees of methylation of CpG groups in the agouti mouse, which can vary according to maternal intake of B group vitamins, may result in variation in coat colors. 36 Epigenetic factors also appear to play a role in postnatal development of the GI tract.

    Congenital Anomalies of the GI Tract
    The causes of anomalies of the GI tract include chromosomal abnormalities (numerical and structural), single gene defects, maternal diseases (especially diabetes), and maternal exposure to drugs, especially hydantoin (pyloric stenosis, duodenal and anal atresia). Causes of disruptions include inherited 37 and noninherited maternal and fetal thrombophilic diseases, intrauterine hypoxic/ischemic events, intrauterine infection including varicella, 38 iatrogenic vascular disruptions, 39 and maternal exposure to vasoactive drugs. 40 Other diseases of the embryo such as cystic fibrosis and epidermolysis bullosa underlie some GI anomalies. Deformations are limited to abnormal shapes of the liver and abnormal rotation and fixation associated with defects of the diaphragm, body wall, and umbilicus. The cause of most anomalies is unknown. Anomalies that arise after completion of organogenesis are often disruptions or deformations; otherwise the causes are not specific to any developmental period.

    ESOPHAGUS

    Short Esophagus
    A congenital short esophagus is a rare anomaly that, although present at birth, may never produce symptoms. It may be indistinguishable from a shortened esophagus that has resulted from long-standing hiatal hernia. In the congenital short esophagus, the intrathoracic stomach is supplied by segmental arteries from the descending thoracic aorta, rather than by intrathoracic extensions of the gastric artery, as observed in hiatal hernias. 7

    Esophageal Atresia and Tracheoesophageal Fistula
    Atresias and stenoses may occur at any site along the tract, but some sites are more commonly involved than others ( Table 8-6 ). Several disorders associated with multiple atresias and stenoses of the GI tract are listed in Table 8-7 . Esophageal atresia, with or without tracheoesophageal fistula, occurs in about 1 in 3000 live births. There is a slight male predominance. A history of polyhydramnios is found in the majority of patients with atresia. Esophageal atresia without fistula is associated with a small stomach 41 and absence of a GI gas pattern. A fistula from the distal esophageal segment allows passage of gastric contents into the respiratory tract, causing respiratory symptoms. Approximately 50% of patients have associated congenital anomalies. 42 , 43 Conditions associated with esophageal atresia and tracheoesophageal fistula are listed in Table 8-8 . Familial forms not associated with hereditary syndromes are probably multifactorial. 44
    TABLE 8-6 Occurrence of Atresia and Stenosis of the GI Tract Site Occurrence per Live Births * Percentage of All Intestinal Atresias Esophagus 1: 3000 — Stomach Rare — Duodenum 1: 1500 50% Jejunum 1: 2000 20% Ileum 1: 2000 25% Colon Rare 5% Rectum, anus 1: 5000 — Multiple — 15%
    * Occurrence per live births varies widely from series to series .
    From Huff DS: Developmental anatomy and anomalies of the gastrointestinal tract, with involvement in major malformative syndromes. In Russo P, Ruchelli E, Piccoli D (eds): Pathology of Pediatric Gastrointestinal and Liver Disease. New York, Springer, 2004, pp 3-37. With kind permission of Springer Science and Business Media.
    TABLE 8-7 Disorders with Multiple GI Atresias or Stenoses Familial intestinal polyatresia syndrome AR 153 Multiple GI abnormalities AR 62 Epidermolysis bullosa, lethal and nonlethal AR 154 Carmi syndrome (aplasia cutis) AR 155 Congenital immunodeficiency syndrome   Severe combined immunodeficiency syndrome AR, X 156 Other types not specified ? 157 - 161 Cystic fibrosis AR 120, 162 - 165 Gastroschisis Maternal vasoactive drug use 40
    AR, autosomal recessive; X, X-linked.
    Adapted from Jones. 178
    TABLE 8-8 Disorders Involving Esophageal Atresia and Tracheoesophageal Fistula VATER/VACTERL association 166 VACTERL-H syndrome 167 Oculodigitoesophageal duodenal syndrome 168 Anophthalmia and esophageal atresia 169 Chromosomal abnormalities Trisomy syndromes 13, 18, 21 22q11.2 deletion 170 Apert syndrome DiGeorge sequence 171 CHARGE association 172 Dyskeratosis congenita syndrome Fanconi pancytopenia syndrome Oculo-auricular-vertebral association (Goldenhar syndrome) 173 Maternal PKU embryopathy Metaphyseal dysplasia, McKusick type 174 Monozygotic twinning Opitz syndrome (Opitz G/BBB compound syndrome) 175 Waardenburg syndrome 176 Epidermolysis bullosa lethalis 154 Infantile sialic acid storage disorder 177
    CHARGE, coloboma of the eye, heart anomalies, choanal atresia, retardation of growth and development, genitourinary anomalies, and ear anomalies and deafness; PKU, phenylketonuria; VACTERL, vertebral anomalies, anal atresia, cardiac defect, tracheoesophageal fistula, renal and limb abnormalities.
    Adapted from Jones . 178*
    Gross 45 and Swenson and coworkers 46 proposed the most commonly used classifications of types of esophageal atresia and tracheoesophageal fistula. Figure 8-8 schematically depicts five common variations found in many current publications. The most common form, comprising about 85% of cases, consists of a blind-ending proximal pouch with a fistula from the trachea to the distal portion ( Fig. 8-9B ). The tracheal ostium of a fistula to the distal esophageal segment is often at the carina, but it may be higher in the trachea. Likewise, the ostium of a fistula to the proximal esophageal pouch is often in the upper trachea, but it is sometimes lower. The length of the distal segment varies. Some may be a short stump barely visible above the diaphragm, and some may be subdiaphragmatic. 47 Therefore, the distance between the upper esophageal pouch and the distal esophageal segment may be short or long, depending on these variations. Short-gap lesions are more easily, and successfully, repaired than long-gap lesions. A fistula from the upper esophageal pouch or the distal esophageal segment (or both) may arise from one or both bronchi forming a bronchoesophageal fistula (or fistulas). The trachea may be absent, in which case the distal trachea or both main bronchi arise from the esophagus. An esophageal stenosis may be present at the site of a tracheoesophageal fistula without esophageal atresia.

    FIGURE 8-8 Types of esophageal atresia and tracheoesophageal fistula. A, Blind proximal esophageal pouch, fistula from distal tracheal to distal esophageal segment (85% of cases). DE, distal esophageal segment; PE, proximal esophageal pouch; T, trachea. B, Esophageal atresia without a fistula; a “pure” esophageal atresia (8% of cases). C, Tracheoesophageal fistula without esophageal atresia, “H type” or “N type” fistula (4% of cases). D, Fistula from upper trachea to proximal esophageal pouch, blind distal esophageal segment (1% of cases). E, Fistula from upper trachea to proximal esophageal pouch, and fistula from distal trachea to distal esophageal segment (1% of cases).
    ( C, Skandalakis JE, Gray SW: The esophagus. In Skandalakis JE, Gray SW [eds]: Embryology for Surgeons. Baltimore, Williams & Wilkins, 1994, pp 65-112.); E, From Russo P, Ruchelli E, Piccoli D [eds]: Pathology of Pediatric Gastrointestinal and Liver Disease. New York, Springer, 2004, p 15; data from Stocker JT: The respiratory tract. In Stocker JT, Dehner LP [eds]: Pediatric Pathology. Philadelphia, Lippincott Williams and Wilkins, 2001, pp 445-517.

    FIGURE 8-9 The most common type of esophageal atresia and tracheoesophageal fistula. A, This is a variation with a blind proximal esophageal pouch (upper black arrow) and a wide mouthed fistula from the carina to the distal esophageal segment (lower black arrow) . The white arrow points to the hypoplastic gallbladder. The proximal part of the distal esophageal segment demonstrates agenesis of the muscularis propria. Tracheomalacia is present. T, tongue. B, Median section of another example. The blind proximal pouch is marked with an asterisk . The brown structure on the right opposite the proximal pouch is the thyroid gland. The fistula from the distal trachea has a narrow mouth (white arrow) and normal muscularis propria. This is a short gap lesion. The white arrowhead points to the distal trachea.
    (From Huff DS: Developmental anatomy and anomalies of the gastrointestinal tract, with involvement in major malformative syndromes. In Russo P, Ruchelli E, Piccoli D [eds]: Pathology of Pediatric Gastrointestinal and Liver Disease. New York, Springer, 2004, p 15. With kind permission of Springer Science and Business Media.)
    The abnormal embryologic process that leads to eso-phageal atresia and tracheoesophageal fistula is not known, although recent reconstructions of staged human embryos from the Carnegie Collection dispute the traditional concept that tracheoesophageal separation is accomplished by bidirectional growth of the tracheoesophageal septum and suggest that the origin of tracheoesophageal anomalies may be a “configurational abnormality” in the tracheoesophageal sulcus at approximately day 30. 48 Abnormalities of the hedgehog signaling pathway are likely involved. 35 The occasional coexistence of esophageal atresia and tracheoesophageal fistula with foregut duplications and bronchopulmonary foregut malformations suggests a common pathogenesis.
    The prognosis is poorer for infants of low birthweight and with associated anomalies, especially cardiac. Postoperatively, there is risk for anastomotic leaks leading to pneumonitis and mediastinitis. 49 Gastroesophageal reflux, resulting from abnormal peristalsis, is common, occurring in up to 50% of children. 50 Motility abnormalities after successful surgical repair have been attributed to histologic abnormalities of Auerbach’s plexus in the distal esophagus and stomach. 51 The proximal portion of the distal esophageal segment may lack a muscularis propria. Tracheomalacia and other tracheal anomalies are also common, occurring in 75% of patients, and these may, in some cases, be severe enough to require tracheostomy. 50 Ectopic gastric mucosa has been reported at the site of repair of an atresia. Chronic esophagitis and gastric metaplasia are late complications. 52
    Congenital esophageal stenosis has an incidence of about 1 in 50,000 live births and is caused by a congenital malformation of the esophageal wall resulting from a membranous diaphragm or web, 53 intramural tumors such as pancreatic heterotopias, 54 adenomyomas or leiomyomas, 55 , 56 or cartilage nodules suggestive of tracheobronchial remnants. 56 Membranous stenosis is most frequent in the middle third of the esophagus ( Fig. 8-10 ), 7 , 49 and tracheobronchial remnants are most frequent in the distal portion. These are associated with other anomalies in up to one third of cases, including tracheoesophageal fistula. 49 , 57 Concomitant atresias of other segments of the GI tract have been reported. Some patients with Hirschsprung’s disease and intestinal neuronal dysplasia have congenital GI atresias and stenoses including esophageal atresia. 58 Associations with congenital pyloric stenosis 59 and with duodenal atresia have been described. 60 A triad of esophageal atresia, duodenal atresia, and anorectal anomalies has been proposed as a new association. 61 An autosomal recessive syndrome called multiple GI anomalies syndrome, which consists of atresias of the esophagus, duodenum, extrahepatic biliary tree, and anorectal area together with hypoplasia of the pancreas, malrotation of the intestines, and hypospadias, has recently been described. 62 , 63 Associated malformations of the respiratory tract 64 include communicating 65 and noncommunicating bronchopulmonary foregut malformations, 66 abnormal pulmonary lobation, horseshoe lung, 67 pulmonary hypoplasia, and tracheobronchial malacia. 68 Unrecognized associated malformations may be the source of persistent symptoms after successful surgery. The typical symptoms, signs, and imaging features of gastric, duodenal, and jejunal atresia may be masked by a more proximal esophageal atresia. Conditions associated with esophageal atresia and tracheoesophageal fistula are listed in Table 8-8 . Familial forms not associated with hereditary syndromes are probably multifactorial. 44

    FIGURE 8-10 Esophageal stenosis. Endoscopic view of a membranous web.
    (Courtesy of Dr. Petar Mamula, Division of Gastroenterology, The Children’s Hospital of Philadelphia.)

    Esophageal Cysts and Duplications
    The GI malformations referred to as duplications represent an array of lesions with an equally confusing nomenclature. Other names used include dorsal enteric remnants, posterior mediastinal cysts, dorsal enteric cysts, enterocysts, enterogenous cysts, neurenteric cysts, persistent neurenteric canal, diverticula, giant diverticula, and thoracic duplications of the intestine. Much of the confusion results from the fact that these cysts may be lined by any type of epithelium derived from the alimentary or respiratory tract. A useful and simple classification proposed by Dimmick and Hardwick 18 divides them into two groups: (1) duplications and (2) neurenteric (dorsal enteric) cysts. Neurenteric remnant is a more appropriate term than neurenteric cyst , however, because a cyst is only one of several malformations included in this spectrum.
    Duplications are cystic or tubular replicas of a segment of the GI tract. They are directly contiguous with the segment from which they are associated. Anomalies of adjacent vertebrae, spinal cord, or dorsal body wall are not present. Any segment of the GI tract, from the mouth to the anus, may be involved ( Table 8-9 ). Cystic duplications, especially noncommunicating ones, may form an expanding intramural mass and cause stenosis or atresia with signs and symptoms of obstruction appropriate to the site. Upper esophageal duplications often produce respiratory obstruction.
    TABLE 8-9 Distribution of GI Duplications * Site % Esophageal 20 Thoracoabdominal 4 Gastric 7 Duodenal 5 Jejunoileal 44 Colonic 15 Rectal 5 Total 100
    * May include neurenteric cysts .
    From Bond SJ, Groff DB: Pediatric Surgery, vol 2. St. Louis, Gastrointestinal duplications. In O’Neill JA, Rowe MI, Grosfeld JL, et al (eds): Mosby, 1998, pp 1257-1267, a review of eight published series encompassing 457 duplications in 410 patients .
    Cystic duplications are partially intramural, or are attached to the wall, and they often share muscularis propria with the involved segment. The lumen of the cyst may communicate with the normal lumen. Histologic diagnostic criteria include (1) attachment to the esophagus, (2) enclosure by two muscle layers, and (3) a lining of epithelium. 57 Typically, the wall of the cyst is composed of all layers of the normal GI tract including inner and outer layers of muscularis propria and myenteric and submucosal plexuses ( Fig. 8-11 ). The mucosa is that of the segment from which the duplication is associated, but heterotopias of any other GI mucosa may be present. Cysts containing various epithelial types have also been referred to as enteric cysts ( Fig. 8-12 ). Gastric heterotopias are most common in esophageal and small intestinal duplications but also may be seen in duplications of the anorectum.

    FIGURE 8-11 Microscopic section of an esophageal duplication cyst from a 2-month-old male infant. The wall is composed of both circular and longitudinal muscle layers; the epithelium is stratified, columnar, and focally ciliated.

    FIGURE 8-12 Microscopic section of an enteric cyst. Posterior mediastinal cyst from an 11-month-old male is characterized by gastric mucosa and well-formed muscle layers.
    Tracheobronchial foregut duplications result from incomplete separation of the primitive lung bud from the foregut during the 4th to 9th week of gestation. They are located anteriorly and are usually lined by ciliated columnar epithelium; the wall may contain mucous glands and cartilage ( Fig. 8-13 ). The rare esophageal duplications with intramural cartilaginous heterotopias are sometimes confused with bronchogenic cysts. Bronchogenic cysts are attached to or adjacent to the bronchial tree, not the esophagus. The wall mimics bronchus and lacks esophageal muscularis propria with myenteric and submucosal plexuses. The lumen is lined with well-differentiated respiratory mucosa and is less likely than esophageal duplications to have extensive stratified squamous, gastric, or intestinal mucosa. Despite these differences, esophageal duplications may sometimes be difficult to differentiate from bronchogenic cysts.

    FIGURE 8-13 Microscopic section from a foregut duplication cyst from the anterior mediastinum of an 11-year-old boy is characterized by respiratory epithelium with cartilage and mucous glands in the wall.

    Neurenteric Remnants
    Neurenteric remnants, sometimes called the split notochord syndrome, 69 include diverticula, fistulas, cysts, and fibrous cords that originate from the dorsal midline of the GI tract, extend in a cranial direction, and attach to, or pass through, the vertebral column and spinal cord cranial to their enteric origins, and they may continue to the skin of the dorsal midline overlying the involved vertebra ( Fig. 8-14A ). They can be located at any level but are most common in the cervicothoracic and lumbosacral area. 70 The walls of the fistulas, diverticula, and cysts are composed of all of the normal layers of the GI tract. Neuroglial tissue and, less likely, leptomeningeal tissue are found in and around the lesions, close to or involving the vertebra and spinal cord (see Fig. 8-14B ). The mucosa may be indigenous to any segment of the GI tract, and several types may coexist. The most severe forms are part of malformation complexes lethal to the fetus or neonate and are diagnosed during a perinatal autopsy. Symptoms and signs in living patients relate to the GI tract, central nervous system, or midline of the back. GI manifestations are similar to those of duplications, described previously, and include respiratory distress, obstruction of the GI tract, obstruction of hepatobiliary and pancreatic ducts, and peptic ulceration with GI hemorrhage or perforation. Central nervous manifestations include abnormal function of the spinal cord associated with its malformations or compression, infectious meningitis associated with fistulas from the GI tract or the dorsal cutaneous surface of the meninges, and chemical meningitis from perforation of an intraspinal cyst.

    FIGURE 8-14 A, Dorsal enteric remnants. B, Microscopic section of a neurenteric cyst from a 1-year-old child. The wall of the cyst is composed of GI tissue with islands of neuroglial tissue (arrows) . The epithelial lining (mostly eroded) consists of a low cuboidal to focally columnar epithelium.
    ( A from Dimmick JE, Hardwick DF: Gastrointestinal system and exocrine pancreas. In Dimmick JE, Kalousek DK (eds): Developmental Pathology of the Embryo and Fetus. Philadelphia, JB Lippincott, 1992, pp 509-544.)

    STOMACH
    Congenital agastria is exceptionally rare; one case documents an esophagoduodenal junction with microscopic evidence of gastric mucosa. 71 Agastria can be part of the complex of anomalies in acephalic and acardiac fetuses. This condition is believed to result from an interruption in the normal vascular supply, as in the arterial disruption sequence in monozygotic twins with placental artery-artery shunts, resulting in absence of the head and heart, upper limbs, and foregut derivatives. 72 Microgastria is a rare malformation of the stomach that is almost always asso-ciated with multiple other congenital anomalies, including limb-reduction anomalies and the VACTERL sequence (vertebral anomalies, anal atresia, cardiac defect, tracheoesophageal fistula, and renal and limb abnormalities). 73 - 77 Isolated microgastria is extremely rare; case reports document successful treatment by gastric augmentation. 78 , 79 Patients can present with asplenia, hepatic symmetry, and intestinal malrotation. Dextroposition usually occurs in visceral situs inversus as part of asplenia-bilateral right-sidedness (Ivemark syndrome). In over 50% of cases, the liver is symmetrical, with the gallbladder, stomach, pancreas, and duodenum on the right side. 72 Reviews on the clinical and genetic aspects of laterality syndromes, as well as on the genetic control of left-right symmetry in vertebrate development, are available. 80 - 82 There are reports of isolated dextrogastria. 83 , 84

    Gastric Atresia and Stenosis
    Atresia and stenosis of the stomach are rare. Less than 1% of all atresias and stenoses of the GI tract are gastric. 85 Most involve the prepyloric antrum or the pylorus. The body is rarely involved. Most are membranous. Segmental stenosis of the body may result in an hourglass-shaped stomach. Pyloric atresia associated with epidermolysis bullosa is caused by a characteristic histopathologic lesion characterized by healing of a circumferential mucosal injury with exuberant granulation tissue that fuses the apposed mucosal surfaces, occluding the narrow pyloric channel, and matures into fibrous tissue. 86 , 87 Rarely, a large intramural pyloric pancreatic heterotopia or adenomyoma causes pyloric obstruction. 88
    More than 50% of patients with gastric atresia have a history of polyhydramnios. Infants with atresia or severe stenosis present with persistent nonbilious vomiting after the first feeding. Excessive salivation may mimic that of esophageal atresia. The first stools are less voluminous than usual, and subsequent stools decrease in volume and disappear. A single large gastric gas bubble and the absence of an intestinal gas pattern are noted at birth. Patients with mild stenosis may have less severe symptoms at birth, resulting in delayed diagnosis. The symptoms may be delayed for several years, making differentiation between congenital and acquired stenosis difficult. Most isolated nonsyndromic cases are sporadic, but some are familial, with an autosomal recessive inheritance pattern. A few are associated with some of the disorders of multiple GI atresias and stenoses (see Table 8-7 ). Pyloric atresia with atresia of the small intestine and colon is a recognized association. 89
    Infantile hypertrophic pyloric stenosis is a clinicopathologic entity distinct from congenital pyloric atresias and stenoses. Some reports have applied this term to the congenital pyloric atresias and stenoses discussed earlier, causing confusion between the two. 90 Infantile hypertrophic pyloric stenosis arises after birth. The incidence rose from about 1 per 1000 live births in the 1950s to some 6 to 8 per 1000 live births 30 years later. The cause for this increase is unclear, although it has been suggested that it correlates with an increase in breastfeeding. 91 An anomaly of local enteric innervation is suspected, with abnormalities of nitric oxide synthase-containing neurons. 91 Intrauterine and neonatal imaging studies detect no pyloric abnormalities in infants who subsequently develop infantile hypertrophic pyloric stenosis, and the lesion has rarely been diagnosed in fetuses. The pathology is characterized by concentric hyperplasia, hypertrophy, fibrosis, and elastosis of the pyloric muscularis, especially the circular layer, sometimes with mucosal erosions and inflammation. The clinical presentation is characterized by the onset of projectile vomiting at 3 to 5 weeks of age and visible gastric peristaltic waves. A palpable epigastric mass with the size and consistency of an olive and a distinctive appearance on ultrasound is usually present. Infantile hypertrophic pyloric stenosis is more often familial and has a higher male-to-female ratio than congenital lesions. The syndromes with which it is associated are different from those associated with the congenital lesions. 89 , 92

    Gastric Duplication
    Foregut duplications account for about 35% of all duplications of the GI tract, with gastric duplications accounting for about 7% (see Table 8-9 ). Gastric duplications involve the greater curvature. They generally do not communicate with the gastric lumen. Gastric duplication cysts are most often lined with gastric or enteric-type epithelium, although respiratory epithelium can be observed. 93 Associated anomalies, including duplications in other parts of the GI tract, are common. 94

    Neonatal Gastric Perforation
    Neonatal gastric perforation can be categorized as spontaneous or traumatic. Spontaneous cases are associated with asphyxia, very low birthweight, necrotizing enterocolitis, or steroid use, or they are idiopathic. Truly idiopathic cases are rare and appear to be associated with prematurity 95 and infection of the gastric wall with invasive Candida or Staphylococcus . 96 An abnormal distribution of pacemaker cells in the gastric wall resulting in hypomotility has been postulated in some cases. 97 Traumatic cases are usually the result of gastric intubation. Infants present with abdominal distention, respiratory distress, and pneumoperitoneum. 98

    SMALL AND LARGE INTESTINES

    Hernias and Abdominal Wall Defects
    Hernias represent a heterogeneous group of disorders that frequently involve the GI tract. The first three listed in ( Table 8-10 ) are discussed here, because they are particularly relevant to the developing intestinal tract and are often confused with one another.
    TABLE 8-10 Types of Hernias in Children Omphalocele (exomphalos) Gastroschisis (laparoschisis) Cloacal exstrophy Congenital diaphragmatic hernia Hernia of Morgagni Inguinal hernia Femoral hernia Umbilical hernia Epigastric hernia
    From Tovar JA: Hernias. In Walker AW, Gould GW, Kleinman RE, et al (eds): Pediatric Gastrointestinal Disease. Hamilton, ON, BC Decker, 2004, p 573 .

    OMPHALOCELE (EXOMPHALOS)
    An omphalocele is a defect of the anterior abdominal wall at the insertion of the umbilical cord. It occurs in 1 in 5000 to 1 in 20,000 live births, but this figure would probably be higher if stillbirths and aborted fetuses were included. 99 The umbilical cord at the site of the defect is replaced by a sac formed of amnion and peritoneum, which contains intestinal loops and sometimes parts of the liver ( Fig. 8-15 ). The defect can range in size from a few centimeters to large enough that a major portion of the anterior abdominal wall is involved. Muscle, fascia, and skin are absent at the site of the defect. 100 It is associated with chromosomal defects, particularly trisomies 13, 18, and 21, and with other disorders such as Beckwith-Wiedemann syndrome. 101 Other congenital anomalies, observed in 30% to 50% of these infants, include congenital heart disease, imperforate anus, and intestinal malrotation. The cause is unknown but probably involves failure of abdominal wall closure when the intestines return to the abdominal cavity. An association with maternal smoking during pregnancy has been found. 102 , 103 Omphalocele has been observed in mice mutant for the podocalyxin gene. 104 Most cases are now diagnosed on prenatal ultrasonography. The prognosis depends on associated malformations. Successful surgical treatment usually involves excising the membrane and covering the exposed viscera in a Silastic bag, followed by progressive reintegration of the contents into the abdominal cavity. 99 Intestinal necrosis resulting in short-bowel syndrome is a major complication.

    FIGURE 8-15 Omphalocele. The sac is located at the site of insertion of the umbilical cord and is covered by amnion. Loops of bowel are observed within the sac.

    GASTROSCHISIS (LAPAROSCHISIS)
    Gastroschisis results from a small (generally < 5 cm) defect of the abdominal wall just to the right of the umbilical cord insertion, allowing evisceration of bowel loops, stomach, and sometimes the gonads ( Fig. 8-16 ). It is distinguished from an omphalocele by the absence of a sac covering the eviscerated contents, and by normal insertion of the cord. The prevalence, which has increased in the past 30 years, is about 1 in 10,000 live births, and it would probably be higher if stillbirths and aborted fetuses were included. 99 The etiology is unknown; occlusion or disruption of the right omphalomesenteric artery has been proposed. 105 Exchanges between the fetal internal environment and the amniotic fluid in utero results in fetal malnutrition and growth retardation, and the serosa of the loops is exposed to inflammation-generating substances, resulting in edema and thickening of the loops. 99 Associated malformations and abnormal karyotypes are less frequent than those seen in infants with omphalocele. As the majority of cases are now detected by prenatal ultrasonography, prenatal interventions, such as repeated amniotic fluid exchange to remove inflammatory compounds in the amniotic fluid, have been proposed. 106 Elective cesarean section by 36 weeks of life, with early primary surgical repair, is the treatment of choice. 107 Interruption of vascular flow in utero to a portion of the bowel may result in focal atresia. An intra-abdominal “compartment” syndrome may develop after surgical repair, because of increased intra-abdominal pressure and decreased vascular perfusion that lead to necrosis of variable lengths of bowel. 99

    FIGURE 8-16 Gastroschisis. Loops of bowel and a portion of liver extravasate through a defect in the abdominal wall, which lies slightly to the right of the insertion of the umbilical cord. Eviscerated contents are not covered by a sac.

    CLOACAL EXSTROPHY
    Cloacal exstrophy is a very rare malformation that results from rupture of the cloacal membrane and failure of descent of the urorectal septum. 108 An omphalocele, containing an exteriorized bladder and prolapsed ileum, protrudes through a major defect in the abdominal wall. There is imperforate anus, and the many other abnormalities include abnormal and ambiguous genitalia, separated pubic bones, and vertebral anomalies.

    Congenital Atresias and Stenoses
    Approximately 75% of all intestinal stenoses and 50% of all intestinal atresias are duodenal (see Table 8-6 ). Intrinsic duodenal atresias and stenoses most often involve the first and second portions (the foregut portion) of the duodenum, in close proximity to the entrances of the biliary and pancreatic ducts. This explains the association of duodenal atresia with hepatobiliary and pancreatic duct abnormalities. 109 Approximately 75% of duodenal stenoses are immediately distal to the ampulla. The majority are membranous ( Fig. 8-17 ). Those of the third and fourth portions of the duodenum are often located at the duodenojejunal junction and are associated with malrotation and midgut volvulus. Ladd’s bands, resulting from incomplete absorption of the cecal and ascending colon mesenteries, can cause external compression and stenosis of the duodenum; they are usually associated with malrotation, preduodenal portal vein, and superior mesenteric artery syndrome ( Fig. 8-18 ).

    FIGURE 8-17 Membranous duodenal stenosis at the level of the ampulla of Vater. The upper probe goes through a tiny orifice in the membrane; the lower probe is in the ampulla.

    FIGURE 8-18 Duodenal stenosis caused by Ladd’s bands in a 39-week-old fetus with intestinal malrotation.
    Polyhydramnios and prematurity are common in patients with duodenal atresia. Vomiting begins at birth and is nonbilious if the obstruction is proximal to the ampulla of Vater, and bilious if the obstruction is distal to the ampulla. Intrauterine bilious vomiting may be associated with ulcers of the umbilical cord, necrosis of adjacent umbilical vessels, and fatal fetal hemorrhage into the amniotic fluid. The presence of ulcers of the umbilical cord should lead to a suspicion of duodenal or proximal jejunal atresia/stenosis distal to the ampulla. 110 The classic radiographic double-bubble sign, a dilated gas-filled duodenum proximal to the obstruction separated by the pylorus from a dilated gas-filled stomach, may not be seen if atresia of the esophagus or stomach is also present. The symptoms and signs of less severe stenoses may be mild and delayed, leading to delayed diagnosis and confusion with acquired obstruction. More than 50% of patients have additional congenital anomalies. 111 These include annular pancreas in 33% and malrotation in 28%, 112 both of which may be familial.
    Annular pancreas is a complete encircling of the second part of the duodenum by pancreatic tissue ( Fig. 8-19 ). It occurs with a frequency of 1 in 20,000 live births. 113 When it appears in infancy, it is associated with other anomalies in 75% of cases, including trisomy 21, tracheoesophageal fistula, and cardiac anomalies. 114 The age at presentation is determined by the severity of the obstruction and by associated anomalies, with one third of cases presenting in the neonatal period, one third during infancy, and one third later in life. 113 Symptoms in older children and adults may include recurrent vomiting resulting from partial obstruction, and pain resulting from gastritis and peptic ulcers. 113 Peptic symptoms result from gastric overdistention caused by the partial obstruction, with consequent hypergastrinemia, hyperchlorhydria, and ulceration. 115 The histology of the pancreas is unremarkable.

    FIGURE 8-19 Annular pancreas in a 17-day-old infant girl who presented with signs of duodenal obstruction. Polyhydramnios was noted during pregnancy. A ring of pancreas (arrow) completely surrounds the second portion of the duodenum.
    Any type of atresia or stenosis can occur in the jejunum and ileum . Approximately 95% are atresias; 5%, stenoses. Membranous lesions account for 19%; atresias with the blind ends connected by a cord, 31%; and atresias with no connection between the blind ends and with a defect in the mesentery, 46% ( Fig. 8-20 ). Although the jejunum and ileum are approximately equally involved, approximately one third involve the proximal jejunum; one third, the distal ileum; and the remaining one third, all other segments. Approximately 85% are single and 15%, multiple. These figures vary from study to study. 112 , 116

    FIGURE 8-20 Intestinal atresia. A, Two blind-ended segments connected by a portion of mesentery. The dilated proximal segment has ruptured. B, Multiple intestinal atresias.
    Two additional types are unique to the small intestine. The first is multiple atresias with a gross pathologic appearance that has been appropriately described as a string of sausages or a string of beads ( Fig. 8-21 ). The radiographic appearance has been described as a string of pearls. 117 The total length of the small bowel is extremely short. This condition is familial and autosomal recessive in many cases.

    FIGURE 8-21 Multiple intestinal atresias, or “string of sausages.” The GI tract, from the distal esophagus to the distal rectum, is displayed. The first atresia is at the duodenojejunal junction, and the duodenum is severely dilated. The ends of the atretic segments are connected by fibrous cords. The bowel is extremely short.
    (From Huff DS: Developmental anatomy and anomalies of the gastrointestinal tract, with involvement in major malformative syndromes. In Russo P, Ruchelli E, Piccoli D [eds]: Pathology of Pediatric Gastrointestinal and Liver Disease. New York, Springer, 2004, pp 3-37. With kind permission of Springer Science and Business Media.)
    The second unique type is the “apple peel” or “Christmas tree” atresia ( Fig. 8-22 ). A long segment of jejunum and ileum is missing between the two blind ends, which are not connected by a fibrous cord, and there is a large defect in the mesentery. The dilated proximal blind end is similar to that of any atresia, but the distal blind segment is spiraled like an apple peel around retrograde mesenteric arteries from the ileocolic, right colic, or inferior mesenteric artery. This atresia is also often familial and autosomal recessive, 118 and it is more frequently associated with other malformations than the usual types of jejunoileal atresia.

    FIGURE 8-22 “Apple peel” or “Christmas tree” atresia and heterotaxy. A, The in situ view shows the dilated proximal blind end in the left lower abdomen, the spiraled, dusky blind distal end in the lower midabdomen, absence of the mesentery between the two blind ends, the stomach on the right, symmetrical liver, midline gallbladder, and preduodenal portal vein. B, The “apple peel” appearance.
    (From Huff DS: Developmental anatomy and anomalies of the gastrointestinal tract, with involvement in major malformative syndromes. In Russo P, Ruchelli E, Piccoli D [eds]: Pathology of Pediatric Gastrointestinal and Liver Disease. New York, Springer, 2004, pp 3-37. With kind permission of Springer Science and Business Media.)
    The clinical presentation of proximal jejunal atresia/stenosis is similar to that of duodenal atresia/stenosis distal to the ampulla. The more distal the obstruction is, the less likely are polyhydramnios, immediate bilious vomiting at birth, and jaundice, and the more likely are generalized abdominal distention and early obstipation. Radiographically, proximal lesions are characterized by a few dilated loops of bowel with air-fluid levels, and distal lesions are characterized by numerous such loops. Associated congenital anomalies are less common than with atresia and stenoses in the esophagus, duodenum, rectum, and anus, because many are caused by disruptions in fetuses who have had normal development during blastogenesis and organogenesis. There are many associated disorders. 119 The risk for cystic fibrosis is more than 210 times higher in white infants with jejunoileal atresia than in those without the atresia. 120
    Colonic atresia or stenosis is rare. It may be part of any multiple GI atresia syndrome (see Table 8-7 ). Atresia of the ileum 121 or colon is seen in association with syndromic or nonsyndromic Hirschsprung’s disease. 122 The clinical presentation is usually that of rapidly progressive abdominal distention. Failure to pass meconium is common. No meconium is found in the rectum, which instead contains mucus. Radiographs demonstrate numerous loops of distended bowel, some with air-fluid levels, and with a low cutoff point. The presenting symptoms, signs, and radiographic changes of colonic atresia may be masked by an associated jejunoileal atresia.

    Malrotation
    Failure of the normal process of rotation and return to the abdomen of the intestinal loops may occur at any stage along the process. Normal rotation is probably a gradual continuous process, except for the return of the intestine to the abdomen and completion of the rotation, which are abrupt. Abnormalities of rotation do not correspond to any position encountered during normal rotation, 4 and patients differ somewhat in their anatomy. Despite this, many authors find that using the simplified classification of Estrada 3 facilitates description of these malformations. The three types frequently listed are nonrotation, mixed rotation, and reverse rotation. The position of the third portion of the duodenum relative to the superior mesenteric artery is crucial in differentiating them from normal, and from each other.
    Complete failure of rotation, or nonrotation , results in a right-sided jejunum and ileum, a low midabdominal cecum, and a colon residing in the left abdomen. Incomplete or mixed rotation, which is more common, results in the small bowel occupying mainly the right side of the abdomen, with the cecum generally residing in the right upper quadrant ( Fig. 8-23 ). All are associated with a short mesenteric attachment and midgut volvulus. With mixed rotation, the volvulus may occur in the first few days of life, whereas in the others, symptoms may be delayed or intermittent. The short mesenteric attachment can lead to twisting of the midgut around the pedicle of the superior mesenteric artery, with consequent bowel obstruction and vascular compromise. An unattached cecum, ascending colon, and hepatic flexure may be associated with Ladd’s bands binding the hepatic flexure to the third portion of the duodenum and to the right abdominal wall, sometimes resulting in duodenal obstruction.

    FIGURE 8-23 Malrotation of the incomplete or mixed type. The small bowel lies mostly in the right abdomen, and the colon in the left. The cecum and appendix are visible in the right upper quadrant.
    Reverse rotation is the rarest type, and its occurrence follows two errors of reentry of the bowel loops after the combined 270-degree counterclockwise rotation outside the abdominal cavity: (1) If the postarterial segment returns first, the small bowel lies ventral to the colon and superior mesenteric artery, with the colon behind. This may result in compression of the mesenteric arterial flow. 123 (2) If the prearterial segment returns first, the colon will occupy the right half of the abdomen, and the small bowel will lie in the left side. These cases can be associated with situs anomalies of other organs. 124 , 125
    Abnormal fixation and abnormal mesenteries of various segments form internal hernias. Right and left mesocolic hernias are two common forms. An unusually long mesentery of an unfixed cecum and ascending colon attached along, or to the right of, the midline, may be so redundant as to form an internal hernia pouch called a right mesocolic hernia. If, as in the case of nonrotation, the small bowel is in the right side of the abdomen, then the small bowel can become entrapped in the right mesocolic internal hernia, resulting in obstruction and strangulation. Similarly, an unusually long mesentery of an unfixed descending colon attached along the left side of the abdomen may be so redundant as to form a left mesocolic internal hernia ( Fig. 8-24 ). If the small bowel is located in the left abdomen, it can become entrapped in the left mesocolic hernia, resulting in obstruction and strangulation.

    FIGURE 8-24 Term female infant with trisomy 9 and multiple congenital anomalies. She had incomplete rotation of the bowel, with the small intestine located mainly in the right portion of the abdomen. The descending colon is unfixed and has a long mesenteric attachment.
    Malrotation occurs in about 3 per 10,000 live births and fetal deaths, 126 and 60% to 90% have associated malformations. 126 - 128

    Duplications
    Intestinal duplications, like foregut duplications, are directly contiguous with the segment from which they are associated. Duplications are dorsal to the intestine, usually mesenteric and sometimes intramural. 129 Duodenal duplications involve the concave medial border of the second portion adjacent to the hepatobiliary and pancreatic ductal systems. Cystic duodenal duplications may clinically mimic cho-ledochal cysts, cysts of the pancreatic duct, or pancreatic pseudocysts. Jejunal, ileal, and colonic duplications may cause intussusception or volvulus.
    Tubular duplications may be short or may involve entire segments, such as the entire esophagus and stomach combined, or the distal ileum, cecum, entire colon, and anus. Most are attached along the dorsal or mesenteric border ( Fig. 8-25 ). Some are attached to the lateral border, forming parallel, side-by-side segments referred to as double-barrel duplications. Rarely, the duplication has a separate mesentery and blood supply and is called a loop duplication. Communications between the lumen of a tubular duplication and the normal lumen are common and may be located at the proximal or distal end of the duplication, or at both ends. Multiple communications may occur. Double-barrel duplications of the colon, rectum, and anus are associated with duplications of part, or all, of the genitourinary tract and external genitalia, forming symmetrical or asymmetrical, right and left GI and genitourinary tracts and perineum. A tubular duplication with a proximal communication and a blind distal end forms an expanding mass that may obstruct the normal lumen or adjacent structures. Similarly, a cystic duplication may also cause obstruction of the involved segment ( Fig. 8-26 ).

    FIGURE 8-25 Tubular duplication, jejunum. The probe passes through a tubular duplication extending along the mesenteric side of the resected segment.

    FIGURE 8-26 A, Cystic duplication of the ileum, causing obstruction. B, Opened cystic duplication with a smooth lining that consists histologically of flattened enteric epithelium. C, Opened segment of ileum with a communicating duplication containing gastric mucosa with prominent rugal folds.
    The wall of a duplication is usually thick, with well-formed muscle layers. The epithelial lining may consist of gastric, intestinal, or respiratory-type epithelium, and it may contain heterotopic pancreatic rests. Complete excision is the treatment of choice. The embryogenesis of duplications is not well understood. An abnormally exuberant proliferative phase, a defective resolution of the proliferative phase, and a persistence of the normal transient diverticula seen in embryos are some possibilities. Some intestinal cystic duplications are probably disruptions with the same pathogenesis as atresias and stenoses. 130 Some may be caused by mild developmental abnormalities of the notochord, neurenteric canal, and related structures of the midline developmental field and, therefore, may be a forme fruste of neurenteric cysts.

    Congenital Diverticula, Including Omphalomesenteric Remnants and Meckel’s Diverticulum
    GI diverticula can be divided into mesenteric and antimesenteric diverticula. Mesenteric diverticula are thought to be primarily related to the neurenteric remnants and duplications just discussed. Antimesenteric diverticula are, with few exceptions, part of the spectrum of omphalomesenteric remnants including Meckel’s diverticulum ( Fig. 8-27 and Table 8-11 ).

    FIGURE 8-27 The spectrum of omphalomesenteric remnants. A, Meckel’s diverticulum. B, Meckel’s diverticulum attached to umbilicus by a solid cord. C, Omphalomesenteric cyst in a solid cord. D, Umbilical polyp (P). An umbilical sinus may be present. E, Patent omphalomesenteric fistula. Note: In B, C, and D, a diverticulum may not be present, and in D, a solid cord may not be present.
    (From Huff DS: Developmental anatomy and anomalies of the gastrointestinal tract, with involvement in major malformative syndromes. In Russo P, Ruchelli E, Piccoli D [eds]: Pathology of Pediatric Gastrointestinal and Liver Disease. New York, Springer, 2004, p 29. With kind permission of Springer Science and Business Media.)
    TABLE 8-11 Spectrum of Omphalomesenteric Remnants Type Percentage (Estimated)
    Meckel’s diverticulum
    Tip unattached
    Tip attached to umbilicus
    Tip attached to mesentery 90 — — — Solid cord 5 Fistula 3
    Cyst
    Intra-abdominal within solid cord
    In abdominal wall at umbilicus 1 — —
    Umbilical remnant
    Umbilical polyp
    Umbilical sinus 1 — — Total 100
    Omphalomesenteric vessel remnants
    From mesentery to umbilicus
    From Meckel’s diverticulum to umbilicus
    From Meckel’s diverticulum to mesentery — — — —
    Data from Huff DS: Developmental anatomy and anomalies of the gastrointestinal tract, with involvement in major malformative syndromes. In Russo P, Ruchelli E, Piccoli D (eds): Pathology of Pediatric Gastrointestinal and Liver Disease. New York, Springer, 2004, pp 3-37; Moses WR: Meckel’s diverticulum: A report of 2 unusual cases. N Engl J Med 182:251-253, 1947; Skandalakis JE, Gray SW: The small intestine. In Skandalakis JE, Gray SW (eds): Embryology for Surgeons. Baltimore, Williams & Wilkins, 1994, pp 184-241; Soderland S: Meckel’s diverticulum: A clinical and histological study. Acta Chir Scand Suppl 118:1-233, 1959.
    The omphalomesenteric (vitelline) duct is the last point to close after separation of the intestine from the yolk sac, usually by the 10th week of embryonic life. 100 The entire duct may remain patent and may drain intestinal contents at the umbilicus. The more common Meckel’s diverticulum results from persistence of the vitelline duct immediately adjacent to the bowel wall; it occurs in approximately 2% of individuals and accounts for approximately 90% of all omphalomesenteric remnants. The other variations are rare (see Table 8-11 ). The remnants are located from 15 to 167 cm proximal to the ileocecal valve, but most are 40 cm from the valve. 131 Although 75% of diverticula are from 1 to 5 cm in length, some are up to 26 cm long. 132 Meckel’s diverticula are composed of all layers of the normal intestinal wall, as are most cysts and fistulas. The mucosa is ileal. Heterotopias are common. Gastric mucosa is seen in half of all Meckel’s diverticula ( Fig. 8-28 ), in 62% of those with diverticulitis, in one third of fistulas, and occasionally in umbilical polyps. In diverticula, 94% of the gastric heterotopias are of the fundal type; in fistulas and umbilical polyps, 70% are fundal. 133 Pancreatic heterotopias are found in 5% of Meckel’s diverticula, where they can often be identified at the tip by gross examination, and occasionally in umbilical polyps. 45 Duodenal, colonic, and, rarely, biliary mucosa may be found. Omphalomesenteric remnants can be distinguished from urachal remnants by the presence of columnar or intestinal epithelium in the former, whereas the latter are lined by transitional epithelium. Malignancy in Meckel’s is rare, but when it occurs, it typically mimics the type of heterotopic epithelium from which it was derived.

    FIGURE 8-28 A, Meckel’s diverticulum from a 35-week-old stillborn. B, Meckel’s diverticulum largely lined by gastric mucosa with rugal folds.
    Twenty-five percent of omphalomesenteric remnants are symptomatic. 134 Fundal-type gastric mucosa causes ulcers, which present with pain, hemorrhage, and perforation leading to peritonitis. Meckel’s diverticulitis mimics appendicitis. Intussusception, volvulus around a solid cord or vascular remnant to the umbilicus, incarceration by a fibrous cord or vascular remnant, a knot formed by a long diverticulum around a loop of intestine-all lead to obstruction. Fistulas may drain intestinal contents and mucus at the umbilicus. Omphalomesenteric remnants are common in patients with multiple congenital anomalies, but other anomalies are infrequent in otherwise normal patients with a Meckel’s diverticulum.

    Heterotopias
    Heterotopic gastric mucosa can occur in duplications and diverticula of the alimentary tract, and more rarely as isolated lesions. They have been documented from the oropharynx to the rectum, and they can appear grossly as nodules, polyps, or erosions. 135 The heterotopias can secrete gastric acid, leading to inflammation, bleeding, perforation, and intussusception. 136 They can be detected by pertechnetate 99 m scintigraphy. Surgical excision is the treatment of choice. Heterotopic pancreatic tissue is most commonly noted in the stomach and proximal small bowel, 137 , 138 although it can be seen in the liver, spleen, umbilicus, and other sites. Heterotopic pancreatic tissue also affects small bowel stenoses, duplications, and diverticula. The majority of patients are asymptomatic. 138 Rare cases of adenocarcinoma arising in pancreatic heterotopias have been documented. 139 Histologically, these pancreatic remnants consist mostly of ducts and acini ( Fig. 8-29A,B ). A closely related lesion, consisting of ducts in association with smooth muscle hyperplasia and sometimes referred to as adenomyoma, is also considered to be a pancreatic heterotopia (see Fig. 8-29C ). 140

    FIGURE 8-29 Pancreatic remnant. A, Endoscopic view. B, Microscopic section shows acini, ducts, and endocrine tissue extending through the bowel wall. C, Section from another remnant is characterized by the presence of ducts with a marked smooth muscle component. These lesions have also been referred to as adenomyomas.
    A, (Courtesy of Dr. Petar Mamula, Division of Gastroenterology, The Children’s Hospital of Philadelphia).

    ANORECTAL MALFORMATIONS
    Anorectal anomalies constitute an important group of malformations occurring in about 1 in 2500 live births. 141 Approximately 60% occur in male and 40% in female infants. The pathogenesis and embryologic events surrounding these malformations are poorly understood. The early hindgut is the cloaca, a cavity formed at about 21 days gestation, into which the hindgut, tailgut, allantois, and mesonephric ducts empty. It is generally believed that during the 6th to 7th weeks of gestation, by a process of differential growth and apoptosis, the urorectal septum proliferates caudally toward the cloacal membrane and fuses with it, resulting in separate urogenital and anorectal sinuses. Perforation of the cloacal membrane occurs at about day 50. Interruptions of any of these steps can result in anorectal anomalies. 142
    Some studies suggest that, contrary to the traditional concepts, urorectal separation is not accomplished by the active caudal growth of the urorectal septum and that the urorectal septum is only passively involved in the process. 143 There is increasing evidence for the role of the hedgehog and homeobox families of genes in the pathogenesis of these anomalies. 144 Several classifications of the many variations within the spectrum of anorectal atresias and fistulas have been proposed. 145 - 147 The classification presented in Table 8-12 is adapted from the Wingspread classification 147 and the classification of Kiely and Pena. 148 Presumably, the higher the lesion the earlier the time of onset and the more severe the abnormality of development. 149 The list is arranged in descending order of the level of the lesion, with the highest at the top. The interposition of the uterus and vagina between the anorectum and urinary tract during the 9th and 10th weeks explains the difference in the fistulas seen in males and females. In males, two thirds are high lesions, and in females, two thirds are low lesions. 145 Rectal atresia is a high blind-ending rectum with a normal-appearing perineum, an intact anus, and a blind-ending anal canal. Anorectal agenesis is a high blind-ending rectum and an abnormal perineum with absence of the anus and anal canal ( Fig. 8-30 ). Anal agenesis is a low blind-ending rectum and an abnormal-appearing perineum with absence of the anus and anal canal. The most severe form of anorectal atresia is persistent cloaca, with or without a perineal opening. It is rare, more common in females, and there are many variations. The colon, genital tract, and urinary tract join together to form a common structure ( Fig. 8-31 ). If the perineal outlet is atretic, or severely stenotic, the cloaca may be massively cystic.
    TABLE 8-12 Types of Anorectal Atresias and Fistulas Atresia Fistula   Male Female Anorectal agenesis Rectocloacal Rectocloacal Rectovesicular Rectovesicular Rectoprostatic urethra Rectovaginal, high Without fistula Without fistula Rectal atresia Without fistula Without fistula Anal agenesis Rectobulbar urethra Rectovaginal, low rectovestibular Without fistula Without fistula Imperforate anus Anoraphe, perineal or scrotal Anovestibular   Anocutaneous Anocutaneous Anal stenosis Anocutaneous Anocutaneous None Anterior anus Anterior anus
    From Huff DS: Developmental anatomy and anomalies of the gastrointestinal tract, with involvement in major malformative syndromes. In Russo P, Ruchelli E, Piccoli D (eds): Pathology of Pediatric Gastrointestinal and Liver Disease. New York, Springer, 2004, pp 3-37. With kind permission of Springer Science and Business Media.

    FIGURE 8-30 Two varieties of anorectal atresia with fistulas. A, Median section after perfusion fixation. This is anorectal agenesis with a rectoprostatic urethral fistula at the level of the verumontanum. B, External view of perineum, scrotum, and penis. The patient has a flat perineum, anal agenesis, and an anoscrotal raphe fistula. The raphe is prominent, and water injected into the rectum under pressure distended the raphe and leaked from its widest point at the arrow .
    (From Huff DS: Developmental anatomy and anomalies of the gastrointestinal tract, with involvement in major malformative syndromes. In Russo P, Ruchelli E, Piccoli D [eds]: Pathology of Pediatric Gastrointestinal and Liver Disease. New York, Springer, 2004, pp 3-37. With kind permission of Springer Science and Business Media.)

    FIGURE 8-31 Cloacal anomaly. A, This 46 XX female neonate has a single perineal opening, fused labial folds, and a prominent phallus. B, Excised specimen showing a dilated duplex vagina communicating with the rectum through a single opening. Each probe is in one half of the duplex vagina; the lower portion of the dividing septum is incomplete. The probes exit through an opening common with the rectum, which has been opened. There was a narrow vesicovaginal fistula (not shown), which resulted in bilateral hydroureters and cystic dysplastic kidneys.
    The patients present with failure to pass meconium. In most patients, the anus is absent, severely abnormal, or displaced anteriorly. Up to 60% of patients have additional malformations. 148, 150 - 152 Patients with high lesions have a higher incidence of associated malformations than those with low lesions; the incidence is highest in patients with cloacal anomalies. Congenital heart disease, usually tetralogy of Fallot or ventricular septal defect, is seen in approximately 20%. GI anomalies are seen in 10% to 15%. Tracheoesophageal malformations predominate, and duodenal atresia and stenosis, malrotation, small and large intestinal atresias, and Hirschsprung’s disease are also found. Urinary tract anomalies are among the most common associated anomalies and have been reported in up to 60% in some series. Vesicoureteral reflux and renal agenesis or dysplasia are among the most common. Genital anomalies are as frequent as urinary anomalies and include cryptorchidism and hypospadias in males and bicornuate or septate uterus and septate vagina in females. Patterns of associated anomalies include multiple intestinal atresias, the CHARGE (coloboma of the eye, heart anomalies, choanal atresia, retardation of growth and development, genitourinary anomalies, and ear anomalies and deafness) and VACTERL associations, and many others listed by Huff 119 and Roberts and colleagues. 100

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    CHAPTER 9 GI Tract Enteropathies of Infancy and Childhood

    PIERRE. RUSSO

    The Intestinal Biopsy in Children
    Congenital Disorders of Intestinal Transport and Absorption
    Primary Enterocyte Abnormalities
    Microvillus Inclusion Disease
    Tufting Enteropathy (Epithelial Dysplasia)
    Autoimmune Enteropathy
    Neonatal Necrotizing Enterocolitis
    Lymphangiectasia
    Metabolic and Neoplastic Disorders
    Metabolic Disorders
    Neoplastic Disorders
    The aims of this chapter are to review diseases that cause severe chronic diarrhea and failure to thrive in early infancy. Diarrheal disorders place an enormous burden on the health of children throughout the world and are associated with significant morbidity and mortality even in industrialized countries, particularly in infants for whom dehydration is a major risk. Although accurate assessments are difficult to obtain, cases of severe chronic diarrhea resulting in growth failure are relatively infrequent in industrialized countries, even in tertiary-care referral practices. In contrast, in developing countries, chronic diarrheal diseases are an important cause of mortality in children, and they usually result from an acute infective process complicated by endemic malnutrition and inadequate access to proper health care. The World health Organization has reserved the term persistent diarrhea for this group of disorders, which by definition excludes hereditary defects in intestinal transport, celiac disease, and autoimmune and other chronic inflammatory enteropathies. 1 Acute diarrhea is usually infectious in nature and most frequently self-limited in industrialized countries. It is diagnosed by a combination of stool cultures and immunologic and molecular methods, and it only rarely requires endoscopy with biopsies.
    In contrast, chronic diarrhea , generally defined as lasting more than 2 weeks, often results in an extensive diagnostic workup, frequently including endoscopy with biopsies, especially when the patient has poor nutrition or growth. Clinical management of these patients is often difficult and may require lengthy hospitalization and use of parenteral nutrition. Chronic diarrhea occurring in the neonatal period presents particularly difficult diagnostic and therapeutic challenges. Avery and colleagues defined intractable diarrhea of infancy as a syndrome characterized by diarrhea of more than 2 weeks’ duration in young infants, in which an infectious etiology has been excluded. 2 Most of these cases remain undiagnosed, and the mortality rate is high.
    Significant advancements in the past three decades in diagnosis, parenteral nutrition, treatment of complications, use of immunosuppression, and, in some cases, small bowel transplantation have allowed improved survival and thus greater opportunity for diagnosis of affected patients. As a result, protracted diarrhea more accurately reflects conditions that result from chronic infections, immunodeficiencies, or food allergies, which are more amenable to conventional treatment. For the treating gastroenterologist, the type of diarrhea may provide clues to the diagnosis. Osmotic diarrhea results from the presence of unabsorbed or poorly absorbed solutes in the gut. There is an osmotic “gap” in the stool analysis (normal stool osmolarity = 2 × [Na+mEq/L + K + mEq/L] = 290). If electrolytes are lower, some other osmotic substance is contributing to osmotic load, signifying unmeasured particles, usually sugars and low-molecular-weight compounds. Typically, the diarrhea resolves with bowel rest or removal of the offending solute. 3 Congenital carbohydrate transport and enzymatic disorders, such as disaccharidase deficiency, are causes of osmotic diarrhea. 4 Secretory diarrhea results from abnormal secretion of electrolytes into the lumen. It can be primary, or secondary to severe mucosal injury, with impairment of water and electrolyte absorption. Secretory diarrhea does not resolve with bowel rest. It can result from congenital defects of ion absorption such as Na+/Cl − diarrhea, from loss of intestinal surface area as a result of diffuse mucosal disease, and from abnormal circulating mediators, including enteric hormones, neuropeptides, and bacterial enterotoxins. 4
    Disorders that cause intractable or protracted diarrhea ( Table 9-1 ), although most challenging from a diagnostic and therapeutic point of view, have provided important insights into enterocyte development and function, and intestinal immunity and tolerance. Entities such as microvillus inclusion disease, tufting enteropathy, and auto-immune enteropathy, described in the last 25 years, have added greatly to our understanding of intestinal structure and function. Other major categories of disorders causing chronic diarrhea, such as infections, immunodeficiencies (primary and secondary), gluten-sensitive enteropathy and other food allergies, and motility and pancreatic disorders are discussed in other chapters of this book.
    TABLE 9-1 Enteropathies of Infancy and Childhood Congenital transport and enzymatic deficiencies Glucose–galactose malabsorption Disaccharidase deficiency Fructose malabsorption Abetalipoproteinemia Chylomicron retention disease Sodium or chloride diarrhea Primary bile acid malabsorption Congenital absence of enteroendocrine cells ( NEUROG3 mutation) Primary enterocyte abnormalities Microvillus inclusion disease Tufting enteropathy Autoimmune enteropathy Necrotizing enterocolitis, short gut syndrome Lymphangiectasia Metabolic diseases and tumors

    The Intestinal Biopsy in Children
    Some diseases, such as congenital transport disorders, are associated with a normal biopsy. Others, such as autoimmune enteropathy or celiac disease, show variable degrees of villus atrophy with or without concomitant inflammation. Several entities, such as microvillus inclusion disease or tufting enteropathy, exhibit characteristic findings on intestinal biopsies ( Table 9-2 ).
    TABLE 9-2 Diagnostic Findings in Biopsies of the Small Intestine Intestinal Biopsy Differential Diagnosis Normal
    Sucrase–isomaltase deficiency
    Congenital lactase deficiency
    Fructose malabsorption
    Glucose–galactose malabsorption
    Congenital Na + or Cl − diarrhea Inflammatory lesions with or without villous atrophy
    Celiac disease
    Autoimmune enteropathy
    Protracted infectious diarrhea
    Immunodeficiency states (most)
    Bacterial overgrowth
    Cow’s milk or soy protein intolerance
    Chronic inflammatory bowel diseases Specific lesions
    • Fat-filled enterocytes
    • Ectatic lymphatics
    • Dense inspissated mucus
    • Epithelial abnormalities
    • Eosinophils
    • Absence or paucity of inflammatory cells
    Abetalipoproteinemia
    Anderson’s disease
    Lymphangiectasia
    Cystic fibrosis
    Microvillus inclusion disease
    Tufting enteropathy
    Eosinophilic gastroenteritides
    Severe combined immunodeficiency
    Agammaglobulinemia
    In clinical practice, biopsies obtained by endoscopic forceps have largely supplanted capsule biopsies. Advantages include greater ease of the procedure, greater patient comfort, avoidance of radiation exposure, direct visualization of the GI tract, and the possibility of obtaining multiple biopsies from several sites. This last consideration is especially important when there is focal involvement (Crohn’s disease, allergic enteropathy, neoplastic infiltrate). Additional samples may be snap-frozen (for disaccharidase analysis) or submitted for electron microscopy (for confirmation of microvillus inclusion disease). Despite initial reservations about the quality of biopsies obtained by forceps as compared with capsule biopsies, studies have shown that the histologic quality and interpretation are equivalent. 5 - 9
    The normal ratio of villus height to crypt depth in the duodenum is 2: 1 to 3: 1 in children. It is somewhat greater in adults, 10 and higher in the distal than in the proximal duodenum. 11 Normal histologic findings in the small bowel also vary according to geography and race, whether this is for genetic reasons, or results from environmental factors such as endemic infections, is unclear. Somewhat shorter villi and increased numbers of lamina propria mononuclear cells are reported in healthy individuals from developing countries compared with industrialized nations. 12 - 14 The “normal” number of intraepithelial lymphocytes also varies in different studies, although a ratio of 20 to 100 epithelial cells seems to be an acceptable average. 15 - 17 These are CD2+ and CD3+ T lymphocytes that belong to the mucosa-associated lymphoid tissue (MALT) system and have a CD8+ cytotoxic-suppressor phenotype. 18 The vast majority normally express the αβ T-cell receptor (TCR), and a small minority (< 10%), the γδ receptor. 19 Intraepithelial lymphocytes also express integrin αEβ 7, which binds to enterocyte cadherins. 20 TCRγδ-expressing intraepithelial lymphocytes are believed to mediate induction of oral tolerance. The lamina propria contains a mixture of plasma cells (mostly IgA-secreting), CD4+ T lymphocytes, and lesser numbers of eosinophils, histiocytes, and mast cells. 10 , 21 , 22 Newborns usually lack plasma cells in the first week of life but gradually acquire them during the first month of life, with IgM-containing plasma cells predominating. By 3 months of life, IgA plasma cells predominate. Normal numbers of plasma cells and normal ratios of IgA, IgM, and IgG antibodies are normally attained by the first year of life. 23

    Congenital Disorders of Intestinal Transport and Absorption
    Specific gene defects associated with various disorders of substrate transport have been recently characterized ( Table 9-3 ). These help provide an understanding of enterocyte function at the molecular level. Except for disorders associated with fat processing, small intestinal biopsies in these cases are generally normal or only very slightly abnormal. A normal-appearing small bowel mucosa from a patient with prolonged diarrhea, especially a young infant, should alert the clinician to these entities.
    TABLE 9-3 Congenital Intestinal Transport Disorders Substrate Disease Chromosome and Gene Defect Carbohydrates Glucose–galactose malabsorption 22q13.1; SGLT1 (SLC5A1) Disaccharidase deficiencies 3q25-26 Sucrase–isomaltase deficiency 2q21; LCT gene Congenital lactase deficiency 7q34; MGAM gene Glucoamylase deficiency Unknown Trehalase deficiency   Fat Cystic fibrosis 7q22.3-q23.1; CFTR gene Abetalipoproteinemia 4q22-24; MTP gene Hypobetalipoproteinemia 3p22; apoB gene Chylomicron retention disease 5q31.1; SARA2 gene Amino acids Lysinuric protein intolerance 14q11.2; SLC7A7   Hartnup’s disease 5p15; SLC6A18 Electrolytes and trace metals Congenital Cl − diarrhea 7q22-q31; DRA Congenital Na + diarrhea Unknown Vitamins Transcobalamin II deficiency 22q11.2 Cobalamin C deficiency   Bile acids Ileal Na + /bile salt transporter 13q 33; SLCWA2 Generalized Absence of enteroendocrine cells NEUROC3
    CFTR, cystic fibrosis transporter gene; DRA, downregulated in adenoma; LCT, lactase gene; MGAM, maltase–glucoamylase gene; MTP, microsomal triglyceride transporter; NEUROG3, neurogenin-3; SARA, Sar1-ADP ribosylation factor family; SGLT, sodium glucose-linked transporter; SLC, solute-carrier family.


    Carbohydrates
    Carbohydrate absorption begins with the breakdown of complex carbohydrates by salivary and gastric enzymes into oligosaccharides, which are then hydrolyzed to monosaccharides by specific disaccharidases located at the enterocyte brush border. Internalization of the hexose molecule is then mediated by “active” glucose absorption across the brush-border membrane by the Na+-dependent sodium/glucose-linked cotransporter (SGLT1). There are also facilitative hexose transporters located at the basolateral membrane. The latter have been cloned and functionally characterized in several different tissues (GLUT1, erythrocyte; GLUT2, hepatocyte; GLUT3, brain; GLUT4, muscle and fat; GLUT5, small intestine). 24 There are four major disaccharidase enzymes: sucrase-isomaltase, glucoamylase-maltase, trehalase, and lactase-phlorizin hydrolase (or lactase-glycosyl ceramidase). 25 Sucrase-isomaltase is responsible for the degradation of dietary sucrose. Glucoamylase-maltase hydrolyses starch into small polymers. Lactase-phlorizin hydrolase degrades lactose, the main carbohydrate in milk. Trehalose occurs mainly in mushrooms. Trehalase deficiency is extremely rare and is described in older children and adults.
    The expression of these enzymes on the intestinal brush border appears to follow a time-dependent sequence. Lactase-phlorizin hydrolase, highly expressed at birth, declines in early life in most people (although it persists through adult life in those of Northern European descent). Sucrase-isomaltase, undetectable at birth, reaches adult levels in the first few months of life. These changes coincide with the switch from milk to a solid diet. 26
    The clinical picture of congenital disaccharidase deficiency is an osmotic diarrhea resulting from the unabsorbed solute in the ileum. The more rapid intestinal transit results in more severe diarrhea in children than in adults. The appearance of the small intestine in these cases is unremarkable, and the diagnosis is normally established by measuring disaccharidase activity in homogenates of small bowel biopsies, or by breath-testing.
    Glucose-galactose malabsorption is an autosomal recessive disorder resulting from a mutation in the gene for SGLT1 (also known as sodium/glucose cotransporter, solute carrier family 5, member 1, and SLC5A1), located on chromosome 22 (see Table 9-3 ), 27 and results in an osmotic diarrhea resulting from unabsorbed solute in the gut. Fructose transport is mediated by the hexose transporter isoform GLUT5, located on chromosome 1. 28 , 29 In clinical practice, malabsorption of fructose, and that of a closely related sugar, sorbitol, are more likely a result of overfeeding with juices that contain high levels of these sugars, which may account for a significant proportion of cases of “toddler’s diarrhea,” also known as chronic nonspecific diarrhea of infancy. 24, 30 - 32
    Congenital disaccharidase and transporter deficiencies are rare and are much more often secondary, resulting from diffuse mucosal damage caused by infectious gastroenteritis, gluten-sensitive enteropathy, or other food allergies. Accelerated crypt shedding, resulting from mucosal injury, may outpace expression of brush border enzymes and transporter proteins, thus worsening the diarrhea and malabsorption. 33 This may be one reason that the use of tacrolimus, which reduces the rate of T-cell-driven crypt cell proliferation and shedding, has been found to be effective in conditions such as tufting enteropathy and autoimmune enteropathy. 33 , 34

    Lipids
    Fat absorption by enterocytes begins with emulsification and solubilization of cholesterol in the intestinal lumen by biliary lipids and salts. Most clinical disorders of fat malabsorption result from severe liver disease, pancreatic disease (such as cystic fibrosis), or extensive ileal resection (as in Crohn’s disease) with loss of the enterohepatic circulation of bile acids. Intestinal biopsies play a limited role in the diagnosis of these disorders. However, diseases involving abnormalities of fat transport within the enterocyte, although much less frequent, can result in vacuolization of the enterocyte in intestinal biopsies.
    Abetalipoproteinemia, hypolipoproteinemia, and chylomicron retention disease (Anderson disease) share many characteristics, such as fat malabsorption, low levels of serum lipids, failure to thrive in childhood, neurologic and visual problems resulting from malabsorption of fat-soluble vitamins, and the (diagnostic) accumulation of lipid droplets in enterocytes. These conditions are associated with disorders of apolipoproteins, which reside on the surface of chylomicrons. Apolipoproteins native to the intestine are apolipoprotein (apo) A-I, apo A-IV, and apo B, which has two forms: apo B-100 and apo B-48, both encoded by the same gene located on chromosome 2. 35 Localization of apolipoproteins in the Golgi apparatus and along the microvilli of enterocytes has been demonstrated by immunoelectron microscopy. 36
    Abetalipoproteinemia is an autosomal recessive disor-der characterized by the absence of apo B-containing lipoproteins. Patients have diarrhea and fat malabsorption, usually appearing within the first few months of life, with acanthocytosis, and with deficiencies in fat-soluble vitamins that result in retinitis pigmentosa and neurologic symptoms. There is clinical heterogeneity with signs and symptoms presenting in older patients in a significant proportion of cases. Serum levels of cholesterol and triglycerides are typically low, and they do not rise after a fatty meal. Fat-filled enterocytes are noted on intestinal biopsies of fasting patients, which on electron microscopy are irregular in size and generally not membrane bound ( Fig. 9-1 ). No lipid is noted in the extracellular space. The molecular basis for the defect is an absence of microsomal triglyceride transfer protein, responsible for assembly of lipoprotein particles, and for the proper folding of apo B, which prevents its premature degradation. 37 Hepatic biopsies in these cases typically reveal steatosis, with fibrosis evolving to cirrhosis in occasional patients. 38

    FIGURE 9-1 Lipid transport disorders. A, Abetalipoproteinemia. The intestinal biopsy reveals diffuse vacuolization of the enterocytes with preserved villus morphology. B, Ultrastructural appearance is characterized by variably sized lipid droplets filling the enterocytes. C, Chylomicron retention disorder. The histologic features are identical to those of abetalipoproteinemia. Electron microscopy reveals numerous membrane-bound lipid vacuoles.
    Hypobetalipoproteinemia is an autosomal dominant disorder characterized by low levels of apo B. Homozygous patients have a clinical and biochemical profile identical to that of patients with abetalipoproteinemia, with fat-filled enterocytes. Most heterozygous patients are asympto-matic, although rare cases have been described with lipid malabsorption early in life. 35
    Chylomicron retention (Anderson) disease is similar to homozygous hypobetalipoproteinemia and abetalipoproteinemia in its GI manifestations and impact on growth, although acanthocytosis is usually absent and neurologic and ocular abnormalities are much less severe. Also, in contrast to abetalipoproteinemia, serum fasting triglyceride levels are normal and hypocholesterolemia is less marked. The basis of the disorder, as the name implies, appears to be an inability to export chylomicrons from enterocytes into lacteals. 39 The histologic and ultrastructural appearance is similar to that of abetalipoproteinemia, although some observers have noted that the lipid droplets in chylomicron retention disease are more uniform and membrane bound than in abetalipoproteinemia. 40
    Minor degrees of enterocyte vacuolization (e.g., after a recent feed) are common in intestinal biopsies in infants; in these cases, vacuolation is neither as marked nor as diffuse as in abetalipoproteinemia or chylomicron storage disease. In addition, lipid droplets are present in the intercellular spaces and lacteals after feeding, whereas they are absent in these spaces in disorders that cause impaired lipid transport. 41 In contrast, lipid-containing macrophages are present in the lamina propria in several storage disorders, in which digestive symptoms can occasionally be significant, or for which an intestinal biopsy is obtained in the course of a workup for failure to thrive (see Metabolic Disorders, later).

    Amino Acids
    Disorders of amino acid transport rarely exhibit prominent GI manifestations, except for lysinuric protein intolerance , which results from mutations in the SLCA7 gene that codes for the dibasic amino acid transporter system. 42 This normally manifests as failure to thrive, with vomiting and diarrhea. One 5-year-old boy with chronic diarrhea was reported to have a flat gut on biopsy of the small intestine, and treatment with a gluten-free diet was unsuccessful. 43 Other complications associated with this disorder include lupus, hemophagocytic lymphohistiocytosis, 44 and sudden infant death. 45

    Electrolytes and Trace Elements
    The biology of intestinal ion transport is a complex field, with disorders ranging from rare selective deficiencies to multisystem disease such as cystic fibrosis. The understanding of solute transport is rapidly expanding as the individual transporter molecules that form part of the solute carrier family (SLC) class of proteins are cloned and functionally characterized. 46 , 47 Defects presenting primarily with severe diarrhea include congenital chloride diarrhea and congenital sodium diarrhea . Intestinal biopsy in these cases has been reported as either completely normal or showing only mild partial villus atrophy. 48

    Vitamins
    Congenital vitamin B 12 transport disorders include congenital intrinsic factor deficiency, a selective absence of intrinsic factor without any gastric anomaly; congenital pancreatic insufficiency, of various causes; and congenital selective vitamin B 12 malabsorption, which is an autosomal recessive disorder characterized by megaloblastic anemia, hepatosplenomegaly, vomiting, diarrhea, and proteinuria. 49 Selective vitamin B 12 malabsorption is related to an abnormal ileal cell-surface receptor protein, cubilin. 50 , 51 None of these disorders results in significant histologic changes in intestinal biopsies.
    A rare congenital disorder of vitamin B 12 metabolism, called cobalamin C deficiency, has also been described; patients present with diarrhea, renal failure, and systemic thromboemboli, in association with severe gastric atrophy. 52 Protein-losing enteropathy responsive to hydroxycobalamin treatment has been reported in one patient with this disorder, 53 presumably on the basis of the gastric anomaly.

    Bile Acids
    Heubi and colleagues 54 described a form of severe refractory diarrhea resulting from a primary disorder of bile acid absorption; intestinal biopsies were normal. A defect in the gene coding for an ileal Na+-dependent bile acid transporter, SLC10A2, has been found in this disorder. 55 Bile acid-related diarrheal illnesses are more commonly secondary to chronic pancreatic insufficiency, 56 or to loss of ileal surface, as in short gut syndrome due to necrotizing enterocolitis 57 or extensive ileal resection in Crohn’s disease. 58 , 59

    Absence of Enteroendocrine Cells
    Congenital absence of enteroendocrine cells has been recently reported in three boys associated with a mutation in the NEUROG3 gene. The affected patients were clini-cally characterized by a profound generalized malnutrition of all nutrients from birth. The intestinal biopsies in these patients were nondiagnostic by H&E, but absence of enteroendocrine cells was confirmed by immunohistochemistry with chromogranin ( Fig. 9-2 ). 60

    FIGURE 9-2 Enteroendocrine cell deficiency. A, Intestinal biopsy from a 10-month-old patient with NEUROG3 mutation, who presented with severe chronic diarrhea and also developed diabetes. The histologic features reveal villus atrophy and crypt hyperplasia. No significant inflammation is noted. B, Immunohistochemical staining for chromogranin reveals absence of enteroendocrine cells. C, Chromogranin staining on an age-matched normal small bowel.

    Primary Enterocyte Abnormalities
    The salient features of these disorders include early-onset secretory diarrhea, frequently within the first few days of life, refractory to medical therapy, requiring parenteral nutrition and, ultimately, bowel transplantation, with distinct epithelial abnormalities in small bowel biopsies.

    MICROVILLUS INCLUSION DISEASE

    Clinical Features
    Initially described by Davidson and colleagues in 1978, 61 and subsequently by investigators in other parts of the world, microvillus inclusion disease is characterized by refractory secretory diarrhea occurring within the first week of life. There is a roughly equal sex incidence. Occasional cases that appear later during the neonatal period may have a better prognosis. 62 Birth history is usually unremarkable, without evidence of polyhydramnios seen in congenital chloride diarrhea. Tests of small intestinal function are diffusely abnormal. 63 The pattern of inheritance appears to be autosomal recessive. 62 , 63 Hypophosphatemic rickets has been observed in one case with long-term treatment with parenteral nutrition. 64 A reported association with dihydropyrimidinase deficiency may represent a contiguous gene defect or may be merely coincidental. 65 A cluster of patients has been described from a Navajo reservation in Arizona. 66 , 67

    Pathologic Features
    Small bowel biopsies are characterized by severe villus atrophy, with little or no crypt hyperplasia and without significant inflammati