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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.

Subjects

Books
Savoirs
Medicine
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

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Published 16 January 2009
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EAN13 9781437719598
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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
S A U N D E R SCopyright
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
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Notice
Knowledge and best practice in this Celd 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 / [editedby] 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 1Dedication
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, MDContributors
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 GeneralHospital, 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,
BarnesJewish Hospital, St. Louis, Missouri
Fatty Liver DiseaseNorman 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 liverTheresa 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
In ammatory 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 Immunode, ciency 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
In ammatory, Infectious, and Other Non-neoplastic Disorders of thePancreas
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 In ammatory 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
SloanKettering 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, NebraskaPolyps 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
In ammatory Disorders of the Esophagus; In ammatory Disorders of the
Stomach; In ammatory 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 In ammatory 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, StaffPathologist, 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, DCEpithelial 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 Immunode, ciency 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
In ammatory, 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 PregnancyTong 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 eld of “gastrointestinal pathology”—the tubular gut, liver,
gallbladder, biliary tract, and pancreas—all under one cover. The second edition
represents a signi cant improvement over the rst 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 di; erentiate diseases based on evaluation of
biopsy and resection specimens. However, gastroenterologists, surgeons, and
residents/fellows in training may also nd this textbook of interest because of the
accent on clinical-pathologic associations. The second edition is even more user
friendly than the rst edition, and it is organized in a method that helps
pathologists gain access to diagnostic information quickly without having to waste
time lea ng through the index and turning pages. The overall organization of the
textbook remains the same as in the rst 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, inAammatory 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 eld. Finally, the editors have paid careful
attention to providing a consistent style of writing, structure, and content from
chapter to chapter.
We are con dent 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 rst 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 sta 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 bene t 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 su ering
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, MDTable 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 TractChapter 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 HistologyChapter 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
IndexPart 1
Gastrointestinal TractSection 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 speci c clinical picture, endoscopic images may be all that is needed
1to make a speci c diagnosis, or provide sound clinical management. However, more often than not,
endoscopists need to sample tissue. Examination by a quali ed 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
2The e%ectiveness of endoscopy depends, in part, on the quality of bowel preparation. 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
3regimens than with oral bowel prokinetics. However, nausea, vomiting, and abdominal cramps are
4comparable between PEG lavage and oral sodium phosphate regimens. PEG lavage regimens
5 6reportedly provide more consistent cleansing. , Purgative- and laxative-based regimens are more
likely to cause 0attening 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
7mucosal histology. In the most severe form of mucosal damage from purgatives, sloughing of the
surface epithelium, neutrophilic in ltration of the lamina propria, and hemorrhage may be
8encountered, and the changes may even resemble mild pseudomembranous colitis. Chemical-induced
colitis, from inadequate cleansing of endoscopic instruments, also has been reported. Mucosal changes
9in this situation may resemble pseudomembranous colitis, both endoscopically and microscopically.
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 0uoroscopic 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
10tissue and, thus, has fallen out of favor. 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
11mucosae, except in regions such as the gastric body, where the mucosal folds are quite thick. The
12submucosa is sampled occasionally with either standard or jumbo forceps. 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 0ush 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,
13 14biopsy specimens are 4 to 8 mm in length. , The forceps shape does not impart a signi cant
13di%erence in either size or adequacy of biopsy specimens. Single-use disposable biopsy forceps also

15have been shown to provide excellent samples. In essence, there are no di%erences 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
16use.
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 xative, 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
17Barrett’s esophagus or ulcerative colitis. Jumbo biopsy forceps are as safe as standard biopsy forceps.
However, use of jumbo forceps is limited by its diameter because it cannot t 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
18greater diagnostic value.
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 re0ux
disease, nonulcer dyspepsia, diarrhea, and surveillance of premalignant conditions, including Barrett’s
esophagus and in0ammatory bowel disease. The ampulla of Vater may be sampled during surveillance
for adenomatous change in familial adenomatous polyposis because the lifetime incidence of ampullary
19adenomas in these patients exceeds 50%. Biopsy of biliary or pancreatic strictures may be carried out
under 0uoroscopic guidance during endoscopic retrograde cholangiopancreatography (ERCP) with the
20use of either standard or specially designed small biopsy forceps. Even gallbladder lesions noted at
20ERCP may be amenable to endoscopic biopsy. 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
17complications.
Occasionally, an endoscopist uses a specialized insulated biopsy forceps to sample a small polyp (“hot
21biopsy”). Remaining tissue is then ablated in situ using electrocautery. Unfortunately, cautery artifact
11 22in such small tissue samples often makes histologic interpretation diK cult (or impossible). , In
addition, the electrocautery technique carries an excessive risk of perforation due to deep tissue burn,
23 24particularly in the cecum and ascending colon. , Finally, destruction of residual dysplastic tissue by
25electrocautery may be incomplete in as many as 17% of cases.
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=""
_diameter29_="" during="" both="" _e2809c_hote2809d_="" _28_with="" _electrocautery29_=""
26 27and="" _e2809c_colde2809d_="" _28_without="" snare=""> , 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
21removed. One caveat with this technique is that identi able 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 signi cant hemorrhage after “hot”
28 29polypectomy is limited, but the risk is generally considered low (0.4%). , A recent large
crosssectional 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
30current. Absence of electrical current is associated with an increased risk of clinically signi cant
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,
31and malignant lesions.



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
arti cial 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 re0ects
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
32when an ampullary lesion is noted. The risk of perforation during snare polypectomy is less than
33 340.1%, , 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.
35 36Another commonly used method is saline-assisted pol-ypectomy. , 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
37premalignant and malignant lesions con ned to the mucosa. In general, EMR requires some measure
of con dence that a lesion is, in fact, con ned 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
37lesion is limited to the mucosa, 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
38liquid, but there is currently no agreement as to the type or quantity of liquid that should be injected.
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 0uid 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
39deeper into the bowel wall.
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
37 40is applied (Fig. 1-3). This method is referred to as a lift-and-cut technique, or a strip biopsy. ,
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 tted 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,
37the snare may be closed around the lesion and cautery applied in the usual fashion. This technique,
also called aspiration mucosectomy, has been widely successful for removing lesions throughout the GI

41tract.
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
highgrade 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 aK xed 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
40diameter). If deep margins are positive for neoplasia, surgical resection of the a%ected region is
42advocated. Current indications for EMR include super cial 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, 0at colorectal adenomas regardless of the degree of dysplasia (which might
otherwise require piecemeal resection). EMR as a form of primary therapy for small, super cial cancer
37 40 42has not gained popularity in the United States, but is often used in Japan. , , EMR may also be
indicated as a form of primary therapy for small submucosal lesions, such as rectal carcinoid tumors or
43leiomyomas. In many cases, the submucosal lesion can be completely resected (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
37 40 4220% of cases and varies depending on the size of the lesion and its location. , , Clinically
signi cant 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
40 4236% to 74%. ,
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 Routine processing of all alimentary tract biopsies; immediate immersion in
fixation fixative. Permits immunohistochemistry, molecular analysis.
Flow cytometry Suspected hematologic malignancy; fresh tissue in sterile culture medium.
Electron Suspected poorly differentiated malignancy, infection (e.g., Whipple’s disease,
microscopy microsporidiosis); immediate immersion in electron microscopy fixative.
Electron Suspected systemic mastocytosis, for which plastic-embedded thick sections with















microscopy toluidine blue staining are optimal for identifying mast cells.
fixative only
Microbial culture Suspected viral, fungal, or parasitic infection; sterile tissue.
Biochemical Suspected metabolic deficiency (e.g., disaccharidase deficiency); frozen tissue.
analysis
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 xatives used for human tissue, 10% bu%ered 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 xative have been used for mucosal
biopsies because of better preservation of nuclear morphology compared with formalin. However, the
heavy metal content of these xatives creates biohazard disposal problems that are greater than those of
formaldehyde-based xatives. These xatives also interfere with isolation of nucleic acid from tissue;
nding substitute xatives and new tissue processing techniques are active areas of scienti c
investigation.
On occasion, the formaldehyde in formalin may be irritating to the eyes and upper respiratory tract of
44personnel. There also is public debate over its potential as a carcinogen. However, the level at which
formalin is considered carcinogenic is considered well above the level that causes sensory irritation,
45which has a threshold of 1.0 part per million (ppm). Proper ventilation should be used to maintain
exposure below 1.0 ppm. This is the lowest concentration that may exert a cytotoxic e%ect in
44 46humans. , 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 xative that is at least
10 times greater than that of the tissue, and the xative 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 xation of these biopsies should always
occur at the bedside. Formaldehyde di%uses into tissue at a rate of approximately 1.0 mm per hour at
47room temperature. Thus, up to 1 hour is often needed adequately to x a specimen with a diameter
greater than 1.0 mm. More time is needed for larger specimens. Controlled microwave xation at 63° to
4865° C can greatly speed the process and is useful for rapid processing of specimens.
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
49 50either a Crosby suction capsule or a Quinton hydraulic assembly. , These two methods were
performed 0uoroscopically and therefore did not permit direct visualization of the alimentary tract.
Biopsies obtained by these methods were carefully oriented under a dissecting microscope before
xation and em-bedding. Direct endoscopic biopsy of the small intestine replaced the 0uoroscopy with
51 52suction capsule biopsy procedure by the late 1980s , ; biopsies obtained by this technique are not
usually oriented before immersion in xative, processing, and embedding. Rather, microscopic
examination of multiple tissue sections usually permits identi cation 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
53diligent e%ort. The size and surface con guration (bosselated or villiform) of the polyp should be
noted, and the base of the polyp should be identi ed and described as to whether it is sessile or contains
a cylindrical stalk. Regardless of the con guration 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="" _diameter29_="" should="" be="" bisected=""
along="" the="" vertical="" plane="" of="" stalk="" so="" that="" surgical="" margin="" is=""
included.="" both="" halves="" specimen="" can="" then="" submitted="" one="">
Section levels should be numbered consecutively; the rst level is the one normally located closest to
the middle of the polyp stalk. Large polyps (≥1 cm in diameter) may be sectioned di%erently if the
polyp head is too wide to t into a single cassette. First, the polyp should be bisected along its long axis
and xed overnight in formalin. Once xed, 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 identi ed 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 con guration (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
54for histology, but should also be processed for 0ow cytometry. Biopsy specimens intended for 0ow
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 0ow 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 0uorescently labeled antibodies appropriate to the diagnostic question are applied to the
cell suspension. Current 0ow cytometry machines can analyze 5000 to 10,000 cells per second,
measuring multiple wavelengths of laser-induced 0uorescence simultaneously, thus permitting rapid
and highly eK cient analysis of cell populations. This technique cannot be performed on xed 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 xative, which usually
consists of a mixture of paraformaldehyde and glutaraldehyde. Unlike formaldehyde-based xatives,
bifunctional glutaraldehyde xatives penetrate only about 0.5 mm into the tissue. Thus, tissue
fragments to be placed in xative for subsequent electron microscopy should, ideally, measure less than
31.0 × 1.0 × 1.0 mm in maximal dimension. Indications for electron microscopy of endoscopic biopsy
55specimens are now largely limited to examination of unusual tumors. 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 e%ect) is lamina propria
edema and intramucosal hemorrhage (“scope trauma”), as illustrated in Figure 1-6. Other e%ects
include aggregation and clumping of in0ammatory cells in the lamina propria, surface 0attening,
56-58mucin depletion, and even erosion and in0ux of air into the tissue (pseudolipomatosis). 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. Speci cally, 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 “Scope trauma” (due to mechanical damage from endoscope) or excessive
hemorrhage) 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 Absence of submucosa (e.g., evaluate submucosal lesion, rule out amyloid)
sampling depth
Inadequate Absence of muscularis mucosa (for evaluation for Hirschsprung’s disease)
sampling location
Insufficient regional sampling (e.g., of “normal-appearing” mucosa)
Chemical Inadequate rinsing of cleaning solution from the endoscope
colitis56, 57
Laxative-induced Edema, damage to surface epithelium from exposure to oral and rectal laxatives
changes58
Air-drying Failure to immerse specimen promptly in fixative
Postbiopsy
Sampling of a previous biopsy site during subsequent endoscopy
healing
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 Clumping of inflammatory cells, mucin depletion, epithelial degenerative
changes changes, focal neutrophilic infiltration, hemorrhage, edema, air in mucosa
(pseudolipomatosis)
Insufflation of air at Air spaces within mucosa or submucosa (pseudolipomatosis)
endoscopy
Cautery artifact Coagulated, eosinophilic tissue without cellular or nuclear detailCrush artifact Compressed tissue with markedly elongated, wavy nuclear remnants and
no identifiable architecture
Chemical colitis from Degenerative damage to, or sloughing of, surface epithelium,
inadequate cleaning of intraepithelial neutrophils and congestion, focal intramucosal hemorrhage
the endoscope
Laxative-induced Lamina propria edema and neutrophilic infiltration, flattening or
changes 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 arti cial shearing of the surface epithelium as a result of bowel preparation procedures and
endoscopic trauma. E, Pseudolipomatosis of the colonic mucosa secondary to insuX ation 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).
59Blood clot and granulation tissue form within several hours after biopsy, as illustrated in Figure 1-8A
and B. Routine super cial 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 super cial biopsy, there is no increased risk
of perforation during subsequent insuX ation (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
59muscularis propria, returns to baseline after 3 to 6 days. 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, in0ammation, 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
60 61Brush cytology is a method used for broad sampling of the mucosal surface. , Cytology brushes,
whether reusable or disposable, have a common design. A cytology brush consists of bristles, usually
composed of nylon bers, that branch o% 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
62performance characteristics. 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 o%, placed into xative, 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 xative immediately, or submerged within it, and subsequently delivered
to the cytopathologist. If smears are made in the endoscopy suite, little additional bene t is derived
63from inclusion of the bristles for cytopathologic analysis.
FINE-NEEDLE ASPIRATION
64-66Fine-needle aspiration (FNA) is another method used for obtaining tissue for cytology. 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 0uid 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 tted with a central stylet to avoid
gathering of intervening tissue. Once the lesion of interest has been identi ed, the sheath is pushed out
of the endoscope, and the needle is advanced into the target tissue either under 0uoroscopic 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 lling 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
highpressure 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 strati ed 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
67 68 69T cells. Melanocytes may be present in the esophagus in 3% to 8% of normal individuals. ,
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. Strati ed 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 in0ammatory 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., re0ux 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 in0ammatory cells, with occasional lymphoid follicles, nerve bers (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 0uid secretions help lubricate the esophagus. Submucosal glands also
70secrete biologically active peptides, such as those from the trefoil factor family 3 (TTF3) ; these
peptides play a role in mucosal protection and repair. Identi cation of a squamous duct and submucosal
mucous glands is considered a de nitive 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 super cial layer of a “double muscularis” in patients
71with Barrett’s esophagus.
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 ve 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 0atten when the stomach is
distended. A ner, 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 super cial 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
di%erences in thickness and composition in di%erent 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 identi ed 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 di%erent 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,
lowpower 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 H2
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) de nition of the GEJ is actually manometric, in that the high-pressure zone of
the lower esophageal sphincter de nes the true distal end of the esophagus. Because manometry is not a
normal part of routine endoscopy and the GEJ passes through the diaphragmatic ori ce, the
performance of endoscopy on a live, breathing patient makes it diK cult to identify precisely the true
anatomic location of the GEJ region. The 0aring of the gastric cavity on retro0exion 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 re0ux
(whether physiologic or pathologic), also makes it very diK cult 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,
72Öberg and colleagues 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 signi cantly more likely to have gastroesophageal re0ux disease. Chandrasoma and
73coworkers reported that the presence of cardia-type gastric mucosa or “oxyntocardiac mucosa”
(combined oxyntic and mucous glands) in the GEJ correlated with acid re0ux. These authors concluded
that all cardia-type mucosa in the GEJ region represents metaplastic transformation of the squamous
74epithelium as a result of re0ux. In another autopsy study by the same group, the entire circumference
of the GEJ was examined histologically in 18 patients, and cardia-type mucosa was completely absent
75in 10 (56%). These ndings were contradicted by Kilgore and associates, who found cardia-type
mucosa at the GEJ in all 30 pediatric autopsies examined, a population considered to be at low risk for
gastroesophageal re0ux 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
83reported by Odze in 2005. In that evidence-based review, the preponderance of evidence indicates
that the true gastric cardia is an extremely short segment (<0.4 _cm29_="" of="" mucosa="" that=""
is="" typically="" composed="" pure="" mucous="" _glands2c_="" or="" mixed=""
_mucous2f_oxyntic="" glands.="" _notably2c_="" these="" glands="" are="" histologically=""
indistinguishable="" from="" metaplastic="" mucinous="" columnar="" epithelium="" the=""
distal="" esophagus="" characteristic="" _barrette28099_s="" esophagus.="" in="" patients=""
with="" gastroesophageal="" re0ux="" _disease2c_="" length="" 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 rst 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 de ned 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.
112A,B). These extend into the lumen as nger-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 broblasts 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 con guration 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 micro laments (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, identi able 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
84called defensins) which play a role in mucosal innate immunity against bacterial infection. 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 ne
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
85cell types is in the duodenum and jejunum, becoming less diverse distally. 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 identi ed 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 con0uent 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 identi ed 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 con0uent 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,
86some unique to the intestine. In normal small intestinal villi, IELs normally decrease in number from
13the base toward the tip. CD3 immunohistochemistry can aid in the detection of IELs, particularly
because some lymphocytes have irregular nuclear borders, which makes their identi cation on H&E
87stain more diK cult. 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
88CD3-stained sections, respectively. 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
89the villus-to-crypt height ratios. The mean number of IELs decreases progressively in the distal small
90 91intestine and colon. , Normal villus IEL counts in the terminal ileum are in the range of 2 IELs per
92100 epithelial nuclei. A normal IEL count in the ileum does not preclude abnormality in the
93duodenum. A modest elevation in IEL counts accompanies many types of in0ammatory conditions of
92the colon.
+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 xed 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 0exure, and swings across the most ventral aspect of the


abdominal cavity to reach the splenic 0exure. The transverse colon is suspended by the lesser omentum,
which re0ects o% 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 identi cation of further
landmarks less reliable, but the splenic 0exure 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 rami cations of the mesenteric vasculature.
Hence, there are three double tracks of holes in the inner muscle coat, owing to the ori ces 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 diK cult 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 re0ux of cecal contents
into the ileum. Whether the “valve” restricts 0ow 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 0at. 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 undi%erentiated 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
91than 5 IELs per 100 epithelial nuclei.
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 0at 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,
socalled 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 de nitive only when it
occurs in the lower third of the mucosal layer. Second, in the immediate vicinity of a mucosal lymphoid
94nodule, the crypts are typicallydistorted. 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 “ brous obliteration” late in life has long been postulated. More likely,
alterations to the lumen of the appendix re0ect a life of clinically silent in0ammatory 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.
94There are subtle di%erences in the normal histology of the distal rectal mucosa. 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
simpli ed and somewhat distorted mucosal architecture of the distal rectal columnar mucosa as normal,
and not indicative of true “architectural distortion” characteristic of chronic in0ammatory 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
95mucosal histology (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 bers, 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 0ares 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 strati ed 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 strati ed 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
96General principles of lymphatic drainage are straight-forward : 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 di%erence from the remainder of the tubal gut, in
that the squamous mucosa overlies a de nitive 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
97plexus of lymphatics in the lamina propria oriented predominantly in a longitudinal direction. 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 super cial lamina propria but are present in
98the interglandular region of the deeper portions of the mucosa. 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 bers 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
99The lymphatic drainage of the small intestine is distinct. 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 0ow
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 ber sheath to which smooth muscle bers attach. The smooth muscle bers 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
100branches into the deep mucosa at the level of the bases of the colonic crypts. 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
101mass. 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 con ned to the mucosa (intramucosal) are not at signi cant risk of lymphatic
102metastasis. Indeed, these lymphatic channels are very diK cult 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 o% 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: ve directly adjacent to the esophagus in
paratracheal, parabronchial, paraesophageal, pericardial, and posterior mediastinal locations (Fig.
121). 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
97Fenoglio-Preiser and colleagues, 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.)
EX uents 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 rami cations 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 super cial 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 super cial 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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1985;89:328336.

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 in ammatory bowel disease, colonic
polyps, and colon cancer.
Surveillance in Patients with Barrett’s Esophagus
Most authorities recommend that patients with chronic re ux symptoms of 5 years
or longer undergo an upper endoscopy to screen for Barrett’s esophagus. The
bene ts of screening programs for Barrett’s esophagus are controversial because of



$
a lack of su" cient evidence to support an improvement in survival rates or
cost1e ectiveness of such programs. 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
2and adenocarcinoma. In the recent past, endoscopic surveillance was undertaken
only in patients medically t 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
3-5intramucosal adenocarcinoma in the setting of Barrett’s esophagus. Aggressive
treatment of re ux with proton pump inhibitors is warranted prior to surveillance
endoscopy because active in ammation 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, speci c 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
6 7chromoendoscopy, may also allow more targeted biopsies. ,
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 at
high grade dysplasia con rmed 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
at 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-upNone Two EGDs with biopsy Endoscopy every 3 yr
within 1 yr
Low 1 yr interval until no dysplasia × 2
• Highest grade on repeat
Grade
EGD with biopsies within 6
mo
• Expert pathologist
confirmation
High
• Mucosal irregularity ER
Grade
• Repeat EGD with biopsies Continued 3 mo surveillance or
to rule out EAC within 3 mo intervention based on results and
patient
• Expert pathologist
confirmation
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
8meta-plasia on biopsies from normal-appearing gastric mucosa. 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
8of gastric cancer.
Currently, in the United States where the incidence of gastric cancer is low,
endoscopic surveillance of patients with gastric intestinal metaplasia is not
9recommended in those at low risk for gastric cancer. 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
coste ective. Furthermore, intestinal metaplasia is a histologic lesion, not visible
endoscopically. This makes endoscopic surveillance di" cult, 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 bene t from surveillance, although there was no
9speci c recommendation on the frequency of endoscopy. If surveillance is
performed, the American Society of Gastrointestinal Endoscopy recommends that
endoscopic surveillance with gastric biopsies should incorporate a topographic
9mapping of the entire stomach histologically.
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 con rmed high-grade dysplasia on gastric biopsies be considered
9for gastrectomy or endoscopic mucosal resection. Recent studies using
magni cation chromoendoscopy have shown that this technique is useful in
10identifying precancerous gastric lesions. 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
e" cacy of surveillance colonoscopy to detect dysplasia or colorectal cancer in
in ammatory bowel disease, it has become the standard of care to o er
colonoscopy to these patients. The available data suggest a reduction in mortality
from colorectal cancer in patients with in ammatory bowel disease who are
11undergoing surveillance. Surveillance colonoscopy should optimally be
performed when the patient is in remission, because active in ammation 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
1to 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,
12-15colonoscopy should again be performed at 1- to 2-year intervals. 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 in ammation and the risk of
16colorectal cancer. Patients with coexisting primary sclerosing cholangitis should
begin surveillance colonoscopy at the time of diagnosis of liver disease, and then
13 15annually thereafter regardless of the extent of disease. , 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,
17-20strictures, and stulas involving the colon. 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
18colonoscopy. 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
13colitis.
There is wide variability in the practice of surveillance by gastroenterologists as
21 22well as inconsistency in the management of patients with dysplasia. , 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
23with greater than 56 specimens. In practice, most endoscopists obtain
fourquadrant biopsies at 10-cm intervals from the cecum to the rectum. It is also
recommended that in patients with ulcerative colitis, fourquadrant biopsies should
13be taken every 5 cm in the distal sigmoid and rectum. 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,
24or masses) in ulcerative colitis was visible to the endoscopist. The nding of
dysplasia of any grade needs to be con rmed by a pathologist with special
expertise in GI pathology. For patients with inde nite dysplasia, colonoscopy


13should be repeated at a shorter interval of 3 to 6 months. 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
22proctocolectomy for patients with low-grade dysplasia. 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
25in 50% of cases. 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 rst identi ed by Blackstone and colleagues in 1981 and were associated with
26a high rate of colorectal cancer at colectomy. More recently, a raised dysplastic
lesion with the appearance of sporadic adenoma has been termed an adenoma-like
27DALM. 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 at dysplasia are
detected in the adjacent mucosa or elsewhere in the colon, because the risk of
13 28 29adenocarcinoma is negligible. , , It is recommended that at least four
biopsies be taken immediately adjacent to the polyp to appropriately exclude at
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 at and polypoid dysplasia are shown in
Figure 2-1.



FIGURE 2-1 Suggested surveillance strategy in patients with in ammatory 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 signi cantly more dysplastic lesions than conventional
colonoscopy with random biopsies. The overall sensitivity of chromoendoscopy for
30-32predicting neoplasia was 93% to 97%. Given these ndings, the Crohn’s and
Colitis Foundation consensus guideline has endorsed the use of chromoendoscopy
13in surveillance colonoscopy by trained endoscopists. As more data regarding
chromoendoscopy become available and new techniques are developed, guidelines
for surveillance endoscopy in patients with in ammatory bowel disease will no
27 33doubt be re ned to re ect these advances. , It is also likely that molecular
biology techniques may play a more important role in the future as an adjunct to
34endoscopic biopsy.
Screening and Surveillance Guidelines for Colon Polyps
The following is a review of the management of colonic polyps in patients who do
35 36not have in ammatory bowel disease. , 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 _cm29_="" tubular="" adenomas="" are="" extremely="" common=""
and="" have="" a="" low="" risk="" of="" becoming="" malignant.="" only=""
small="" proportion="" these="" develop="" histologic="" features=""
highgrade="" dysplasia="" or="" cancer.="" advanced="" de ned="" as="" any=""
polyp="" greater="" than="" 1="" cm="" in="" _diameter2c_="" regardless=""
size="" that="" is="" villous="" contains="" focus="" dysplasia.="" e orts=""
to="" reduce="" colon="" cancer="" now="" shifting="" mainly="" strategies=""
reliably="" detect="" resect="" before="" they="" become="" malignant=""
rather="" focusing="" on="" identifying="" adenomas.="" _currently2c_=""
_7025_="" polyps="" removed="" at="" colonoscopy="" approximately=""
_8525_="" _tubular2c_="" _1025_="" _2525_="" _tubulovillous2c_="" less=""
37_525_="">
INITIAL MANAGEMENT OF POLYPS
Colonoscopy is the most accurate method for detecting polyps and allows
38immediate biopsy and resection. It has quickly replaced fecal occult blood
testing, exible 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 exible 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="" _pedunculated29_=""
can="" be="" resected="" by="" a="" number="" of="" di erent=""
_techniques2c_="" both="" with="" without="" electrocautery.=""
_however2c_="" the="" monopolar="" hot="" biopsy="" forceps="" has=""
limitations="" _risks2c_="" including="" bleeding="" _perforation2c_="" that=""
need="" to="" carefully="" considered.="" considering="" small="" adenoma=""
is="" dysplastic="" _lesion2c_="" resection="" any="" polyp="" justi ed.=""
_currently2c_="" there="" no="" evidence="" _small2c_="" distally="" located=""
hyperplastic="" polyps="" carry="" an="" increased="" risk="" for=""
colorectal="" cancer.="" _thus2c_="" traditional="" found="" during=""


exible="" sigmoidoscopy="" _not2c_="" _itself2c_="" indication=""
colonoscopy.="" accumulating="" certain="" variants=""
hyperplasticappearing="" serrated="" may="" indeed="" precursor="" _example2c_=""
adenomas="" have="" recently="" been="" linked="" development=""
sporadic="" microsatellite="" unstable="" adenocarcinomas.="" at="" such=""
progression="" are="" usually="" _large2c_="" _sessile2c_="" proximally="" in=""
colon.="" these="" called="" atypical="" _polyps2c_="" _adenomas2c_=""
among="" other="" terms="" _28_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
39 40adenomas. , Data also con ict as to whether small distal adenomas predict the
presence of proximal, clinically signi cant adenomas. Recent studies seem to
indicate that there is no increased risk of proximal adenomas or neoplasia in
41 42patients with small distal adenomas found on exible sigmoidoscopy. ,
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
43pedunculated polyps with flat broad stalks.
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
44high as 46%. 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
45removed piecemeal.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 con dence. 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
46considered for surgical resection.
Postpolypectomy Surveillance
Because a large number of patients with adenomas are being identi ed by
colonoscopy, the burden placed on medical resources (i.e., the timely availability of
47colo-noscopy) is increasing dramatically. 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 strati cation 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 de ned as one that
reaches the cecum, has an excellent colonic preparation, and has a withdrawal
46time from the cecum to the anus of at least 6 minutes.
TABLE 2-2 Risk Factors for Development of Metachronous Advanced Adenomas
High Risk Low Risk
• 3 to 10 adenomas • No adenomatous polyps
• Any adenoma • 1 to 2 small (<1 _cm29_="" tubular="" adenomas=""
greater than 1 cm with="" low-grade="">
• Adenoma with
villous features
• High-grade dysplasiaAfter 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 _cm29_=""
tubular="" adenomas="" with="" only="" low-grade="" dysplasia.=""
patients="" at="" high="" risk="" for="" developing="" advanced="" 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 insu" cient to include these two variables as
possible risk factors, and thus they were not included in the formulation of the
48 49Multi-Society Task Force guidelines. , However, family history of colon cancer
in a rst-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
high50grade dysplasia in an adenoma is high. 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 Follow-up colonoscopy in 5 to 10 yr. Precise timing should be
patients based on clinical judgment, patient comfort, and family history.
High-risk Follow-up colonoscopy in 3 yr, provided that piecemeal
patients 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 Repeat colonoscopy in 10 yr, as in average risk guidelines.
hyperplastic (exception: patients with hyperplastic polyposis syndrome)
rectal
polyps
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 ColorectalCancer and the American Cancer Society. CA Cancer J Clin 56:153-159; quiz 184-185,
2006.
Management of Malignant Polyps
A malignant polyp is de ned as an adenomatous polyp with cancer invading the
submucosa; favorable and unfavorable histologic features are reviewed in Table
24. Guidelines from the American College of Gastroenterology for the management
36of malignant polyps are reviewed in Table 2-5.
TABLE 2-4 Malignant Colonic Polyps: Favorable and Unfavorable Features
Favorable Unfavorable
Cancer is well differentiated to moderately Cancer is poorly
differentiated (grade I or II) differentiated (grade III)
Absence of lymphovascular invasion Lymphovascular invasion is
present
Carcinoma is ≥2 mm from deep margin Cancer is <2 mm=""
from="" deep="">
TABLE 2-5 Malignant Colonic Polyps: Management
Findings Management
Pedunculated polyp with No change in surveillance regimen
favorable histology
Sessile polyp with favorable Follow-up colonoscopy in 3 to 6 mo; if no
histology evidence of residual adenoma or cancer on
followup, return to regular surveillance.
Pedunculated or sessile Consider surgical resection.
polyp; at least one
unfavorable histologic
feature
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 ful lled.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 justi ed. 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.
51A recent study 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
52initial diagnosis. It has also been shown that in surveillance groups after cancerresection there is an annual incidence for metachronous cancers of 0.35% per
52year.
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 rst 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
MultiSociety 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, usuallyperformed 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
53pathologist and GI endoscopist in the management of patients. 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
Reports using the terms carcinoma in situ or intramucosal adenocarcinoma None
Designation of the degree of dysplasia in adenomas as low grade or high 100%
grade
Use of the terms mild, moderate, or severe to describe dysplasia and None
adenomas
Adequate characterization of malignant polyps (resection line “margin,” 100%
degree of differentiation, presence or absence of vascular [or lymphatic]
invasion)
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
Gastroenterol 97:1296-1308, 2002.
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Recommendations of the U.S. Multi-Society Task Force on Colorectal Cancer. Am J
Gastroenterol. 2002;97:1296-1308.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
1 2consider cytology an unnecessary duplication of GI mucosal biopsies. , However,
the combined use of endoscopy, ultrasound guidance, and ne-needle aspiration
3has expanded the horizons of GI cytology.
SPECIMEN TYPES
Types of GI tract specimens commonly received in the cytology laboratory include
endoscopic brushings and ultrasound-guided endoscopic ne-needle aspirations.
Endoscopic ne-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
4-6carcinoma.
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 xed
immediately in 95% ethanol and stained with the Papanicolaou method or left to
air-dry and stained with Di/ -Quik (Dade-Behring, Inc., Deer eld, IL) or
WrightGiemsa 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 ne needle can reach deeper
lesions than can be reached by biopsy forceps. Also, both the brush and the ne
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 nal 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>
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!
consistently shown that the highest diagnostic yield is obtained with the combined
7-9use of these specimens. The yield of cytology is signi cantly higher when the
10brushing is performed before rather than after the biopsy.
Normal Morphology
ESOPHAGUS
Intermediate-type squamous cells with abundant cytoplasm and vesicular nuclei
are seen in the normal eso-phagus (Fig. 3-1). Super cial-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 in ammatory 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 ne-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.!
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!
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 magni cation, 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 magni cation, the
absorptive cells have either nely 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 eld
(Papanicolaou).
Infections
Most infectious agents that a/ ect 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
7candidiasis. 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 in ammatory cells are often noted in the
background.>
!
FIGURE 3-5 Pseudohyphae and yeast forms from Candida species are seen in this
esophageal brushing specimen. In ammatory cells and debris are in the
background (Papanicolaou).
HERPES SIMPLEX VIRUS
Herpes simplex virus infection can theoretically a/ ect 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 eld, from an
esophageal brushing of herpetic esophagitis (Papanicolaou).
CYTOMEGALOVIRUS
Cytomegalovirus infection a/ ects 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.!
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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
11either on imprint smears of gastric biopsies or on brush cytology specimens.
Imprint and brushing cytology specimens are comparable in sensitivity (88%) and
speci city (61%) with histologic examination of sections stained with hematoxylin
11and eosin and modi ed Giemsa. The bene ts of imprint and brushing cytology
are the rapid results, high speci city, and low cost. However, the eF cacy 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
magni cation, but they can be diF cult 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
12alcian blue at pH 2.5, can enhance their detection by cytology.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).
G I A R D I A
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,
13gray, pear shaped, and binucleate, with four pairs of flagella (Fig. 3-9).
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 Di/
-Quikstained smears, the mycobacteria form numerous rod-shaped negative images,!
!
14either within the histiocytes or in the background (Fig. 3-11). 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 lled 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 eld (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
15patients and can be detected by examination of stool and cytology specimens.
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
16-18duodenum and biliary tract. 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
in ammatory 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>
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Any injury to the mucosa can evoke a nonspeci c in ammatory or reactive
epithelial change. When the injury is suF cient to result in ulceration, the change
(i.e., the epithelial repair) can become so extreme that it may mimic a malignancy.
It is often diF cult 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 in ammatory cells are superimposed
on or in ltrating this sheet. It is diF cult 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 at sheets without
threedimensionality 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
threedimensionality. 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. Speci c 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 nely 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 a/ ect the esophagus. Numerous acantholytic
cells are usually present. The characteristic cells are round to polygonal, uniform,
19 20parabasal-sized isolated cells. , 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!
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21characteristic. However, the cells have smooth nuclear membranes and pale,
ne, and even chromatin. Normal mitotic gures 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 diF cult 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
22 23cytology is neither sensitive nor speci c for the detection of goblet cells, , 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
22probability of sampling error. Its appearance is similar to that of the lining
epithelium of the small intestine, with a Swiss cheese pattern at low magni cation
and goblet cells with single, large cytoplasmic vacuoles on high magni cation (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
24dysplastic cells on cervicovaginal Pap smears (Box 3-1). The cellular features of
squamous cell carcinoma vary with the degree of di/ erentiation (Boxes 3-2 and
33).
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 diathesisFIGURE 3-19 A dysplastic squamous cell is surrounded by a few
reactiveappearing 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-di/ erentiated 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 di/ erentiated 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 at 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
22 23 25 26numbers of cases , , , and were insuF cient to provide de nitive
27conclusions on the usefulness of cytologic surveillance, the preliminary results
appear promising. Low-grade dysplasia may be diF cult 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-tocytoplasm 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 strati ed 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).!
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!
FIGURE 3-25 Compared with the cells in Figure 3-21, the cells in this gastric
brushing from a well-di/ erentiated adenocarcinoma show signi cant 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 di/ erentiation. Appearance varies from abundant vacuolated or
granular cytoplasm to scant dense cytoplasm that is diF cult 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
diF cult to detect on both cytologic and histologic preparations. Because the
malignant cells in ltrate 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
in ammatory 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 classi ed into three major categories: (1)
welldi/ erentiated endocrine tumors, (2) welldi/ erentiated endocrine carcinomas, and
28(3) poorly di/ erentiated endocrine (small cell) carcinomas. The distinction of
well-di/ erentiated endocrine tumors from well-di/ erentiated 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
classi cation 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
29tumors, followed by the rectum and appendix, with the stomach a distant fourth.
30These tumors account for less than 1% of all gastric malignancies. 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).!
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>
BOX 3-8 Well-Di erentiated 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 welldi/ erentiated endocrine tumors
31and carcinomas. 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 nely granular
(“saltand-pepper”) chromatin pattern. Of course, one should always nd intact cells to
con rm the diagnosis. Poorly di/ erentiated 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
nely 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 ne-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
32nuclei and abundant intercellular brillary matrix. 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!
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FIGURE 3-28 A, A hypercellular fascicle of spindle-shaped cells is seen in this
endoscopic gastric ne-needle aspiration specimen of a GI stromal tumor
(Papanicolaou). B, On higher magni cation, the cells have brillary cytoplasm and
ovoid to spindle-shaped bland nuclei (Papanicolaou).
The individual cells of GI stromal tumors have a tendency to lose their cytoplasm
33 34to become stripped, spindle-shaped or round to oval nuclei. , Perinuclear or
paranuclear vacuoles are present in some cells. Delicate cytoplasm and prominent
35nuclear palisading have also been noted. The tumor cells may appear spindly or
36 37epithelioid. , Although leiomyosarcomas tend to show more signi cant nuclear
pleomorphism and atypia as well as a less prominent vascular pattern than GI
38 39stromal tumors, , immunocytochemistry or polymerase chain reaction analysis
of c-kit (or both) is needed to make the de nitive distinction between the two. A
majority of GI stromal tumors show strong di/ use positivity for CD117 (c-kit),
38 40whereas leiomyosarcomas are typically positive for desmin and actin , and
negative for CD117.
Although immunocytochemical staining for CD117 is useful in con rming 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 ne-needle aspiration specimen was found to be promising in predicting>
>
malignant behavior, although absence of mutation does not preclude
41malignancy.
LYMPHOID TUMORS
The cytologic appearance of lymphoma of the GI tract depends on its subtype.
With adequate material and a combination of morphology and ow cytometry, a
42diagnosis of lymphoma can be established on the basis of a cytology specimen.
The large cell type usually does not pose any diagnostic diF culty on morphology
because large malignant lymphoid cells are suF ciently 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 di/ erentiated 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,
43vesicular nuclei, and a single large nucleolus or multiple prominent nucleoli. 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
di/ erentiated 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 in ammatory 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 diF cult to diagnose by cytology because it
may be mistaken for an in ammatory process (Box 3-10), as it may contain a
44 45polymorphous population of small, intermediate-sized, and large cells. , 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 de nitive diagnosis is usually made by
44 46cytology in only 50% of the cases, , and reactive follicular hyperplasia is often
45erroneously diagnosed.
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 ne 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
similarappearing lymphoid cells raises the suspicion of a lymphoma (Papanicolaou).
(Courtesy of Dr. Martha Pitman, Massachusetts General Hospital, Boston.)
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41 Li SQ, O’Leary TJ, Sobin LH, et al. Analysis of KIT mutation and protein expression
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42 Zeppa P, Marino G, Troncone G, et al. Fine-needle cytology and flow cytometry
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45 Matsushima AY, Hamele-Bena D, Osborne BM. Fine-needle aspiration biopsy
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46 Chhieng DC, Cohen JM, Cangiarella JF. Cytology and immunophenotyping of
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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
selflimited processes and infectious processes must be di erentiated from chronic idiopathic in ammatory bowel disease
(ulcerative colitis or Crohn’s disease). Second, dedicated attempts must be made to identify the speci) c infecting
1organisms. 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 speci) c
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 ) ndings, 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
2with a suppressed immune system, including those with AIDS, and after solid organ or bone marrow transplantation.
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,
2fever, and weight loss. 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,
steroidrefractory 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
steroid3refractory ulcerative colitis.
Pathologic Features
CMV causes a remarkable variety of gross lesions. Ulceration is the most common. Ulcers may be single or multiple,
and either super) cial 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 in ammation 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 super) cial
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 in ammatory in) ltrate usually including numerous
2neutrophils, and mucosal ulceration. Crypt abscesses, crypt atrophy and loss, and numerous apoptotic enterocytes
4may be seen as well. Character-istic inclusions, with virtually no associated in ammatory 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
2months to years after a primary infection."
#
Differential Diagnosis
5The di erential diagnosis of CMV includes primarily other viral infections, particularly adenovirus. 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 di? cult, 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
4could result in delay of antiviral therapy. 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
6bleeding. Many have disseminated herpes infection at the time of diagnosis. 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 (di? culty in urination and
6paresthesias of the buttocks and upper thighs) are also well described, as is inguinal lymphadenopathy.
Pathologic Features
Ulcers are the most common gross ) nding in the esophagus, and these are usually associated with an exudate.
However, many patients have a nonspeci) c erosive esophagitis. In herpetic proctitis, the presence of perianal vesicles
is common. Proctoscopic ) ndings include ulceration and mucosal friability. Vesicles are occasionally seen in the
6 7rectum or anal canal. ,
Typical histologic ) ndings, regardless of site, include focal ulceration, neutrophils in the lamina propria, and an
in ammatory exudate that often contains sloughed epithelial cells (Fig. 4-2A). In the anorectum, perivascular
lymphocytic cu? ng and crypt abscesses may be seen as well. Characteristic viral inclusions and multinucleate giant
7cells are present in only a minority of biopsy specimens (Fig. 4-2B). 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 di erential diagnosis predominantly includes other viral infections including CMV and varicella-zoster, which
8may also infect the GI tract. 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,
9-11coronavirus, echovirus, enterovirus, astrovirus, and Norwalk virus. 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,
nonspeci) c biopsy ) ndings 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 in) ltrate 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
5 12cells), sometimes accompanied by epithelial degenerative changes. , 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.
13The changes resemble those seen in mild graft-versus-host disease and chemotherapy-related mucosal injury. Many
patients have chronic diarrhea, but some are asympto-matic. Some authors support use of the term AIDS enteropathy
to describe these morphologic ) ndings, provided that the bowel has been adequately sampled and all other infectious
13causes have been excluded. Others believe that this is a poorly understood term that does not clearly represent a
speci) c 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 a ect 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 a ect 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#
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the lamina propria, with or without crypt abscesses and cryptitis, preservation of crypt architecture, and lack of basal
1 14plasmacytosis. , The acute in ammatory 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 in ammation 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 di? cult 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 signi) cant 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 nonspeci) c ) ndings such as small bowel
15mucin depletion and a mild increase in lamina propria mononuclear cells have been reported. 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 classi) ed into ) ve groups,
based primarily on serotyping. If pathogenic E. coli are suspected, the clinical laboratory should be noti) ed 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
16well as food-borne outbreaks in industrialized nations. 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.
17These organisms are a cause of traveler’s diarrhea. 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 ) ndings are usually unremarkable, right
colon biopsies more often yield pathologic ) ndings. Histologic examination shows degenerated surface epithelial cells
with associated intraepithelial in ammatory cells. A coating of adherent bacteria on the surface epithelium is the most
18prominent feature, which may stain gram-negative (Fig. 4-4)."
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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. A ected persons may develop hemolytic-uremic syndrome or
19thrombotic thrombocytopenic purpura. Children and older adults are at particular risk for grave illness.
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 a ected. 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 in ammation and necrosis (Fig. 4-5). Microthrombi may be present in small-caliber
20 21blood vessels, and pseudomembranes may occasionally be present as well. ,
FIGURE 4-5 Enterohemorrhagic Escherichia coli. The hemorrhagic necrosis, acute in ammatory exudates, and crypt
withering are very similar to the features of ischemic colitis.
Routine stool cultures cannot distinguish O157:H7 from normal intestinal ora, because microbiologic diagnosis
requires screening on selective agar. An immunohistochemical stain for this organism has recently been described.
The di erential diagnosis includes Clostridium di. cile-related colitis, idiopathic in ammatory bowel disease, and
especially ischemic colitis, from which enterohemorrhagic E. coli may be histologically indistinguishable. In cases of"
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the latter, knowledge about the speci) c 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
22third week of infection, is initially watery but may progress to severe GI bleeding.
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
22-24suppurative mesenteric lymphadenitis. Perforation and toxic megacolon may complicate typhoid fever.
24 25Occasionally, the mucosa is grossly normal or only mildly inflamed and edematous. ,
Histiocytes are the predominant in ammatory cell. Following hyperplasia of Peyer’s patches, acute in ammation of
the overlying epithelium develops. Eventually, macrophages, mixed with occasional lymphocytes and plasma cells,
23in) ltrate and obliterate the lymphoid follicles; neutrophils are not prominent. 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
self24 25limited colitis, including prominent neutrophils, cryptitis, crypt abscesses, and overlying ) brinous exudate. ,
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 ) ndings include mucosal redness, ulceration, and exudates; the pathologic features are
25those of nonspecific ASLC. Occasionally, significant crypt distortion is seen.
The di erential diagnosis of typhoid fever includes yersiniosis and other infectious processes, as well as Crohn’s
23 25disease, and there may be signi) cant histologic overlap between them (Table 4-2). , Neutrophils and granulomas
are often more prominent in Crohn’s disease and in yersiniosis. The di erential diagnosis of nontyphoid Salmonella
17includes other causes of acute self-limited infectious colitis, as well as ulcerative colitis. In addition, Salmonella
infection may complicate preexisting idiopathic in ammatory bowel disease. Although signi) cant 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#
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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 a ected. 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 a ected (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
super) cial), 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 in ammatory cells in the lamina propria. Marked architectural distortion mimicking idiopathic
26inflammatory bowel disease is well described.
The di erential diagnosis of early shigellosis includes primarily other enteroinvasive infections, particularly those
caused by E. coli and C. di. cile. Shigellosis, particularly later in the course of the disease, may be extremely di? cult
1to distinguish from Crohn’s disease or ulcerative colitis, both endoscopically and histologically. 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
27United States. 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
19less common species are more often seen in immunosuppressed patients and homosexual men. Patients typically
28have fever, malaise, abdominal pain (often severe), and watery diarrhea, which may contain blood and leukocytes.
Most infections are self-limited, especially in healthy patients. Of note, Guillain-Barré syndrome and reactive
27arthropathy are associated with Campylobacter infection.
Endoscopic ) ndings 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
29methods in almost 20% of patients who have the focal active colitis pattern of in ammation on colon biopsy. Mild
28crypt distortion may occasionally be seen, although crypt architecture is normally well preserved.
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
30syndrome. In addition, it is responsible for many isolated cases of granulomatous appendicitis. Grossly, involved
bowel has a thickened, edematous wall with nodular in ammatory 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 in ammation 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
31patches with overlying ulceration, acute in ammation, hemorrhagic necrosis, and palisading histiocytes. GI
infection with Y. pseudotuberculosis has characteristically been described as a granulomatous process with central
32microabscesses, almost always accompanied by mesenteric adenopathy (Fig. 4-6A). There is signi) cant overlap
between the histologic features of Y. enterocolitica and Y. pseudotuberculosis infection, however, and either species#
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may show epithelioid granulomas with prominent lymphoid cu? ng (see Fig. 4-6B), lymphoid hyperplasia, transmural
30lymphoid aggregates, mucosal ulceration, and lymph node involvement. 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 in ammation and prominent microabscess
formation in appendicitis caused by Yersinia pseudotuberculosis. B, Epithelioid granulomas with prominent lymphoid
cuffs in Yersinia enterocolitica infection.
The major di erential diagnosis includes other infectious processes, particularly those caused by mycobacteria and
Salmonella. Acid-fast stains and culture results help distinguish mycobacterial infection. The speci) c 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 di? cult 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 ) ssuring 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
33granulomatous in ammation con) ned to the appendix rarely develop generalized in ammatory bowel disease.
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
34-38widely, ranging from a few days to several years, indicating that Aeromonas infection can cause chronic colitis.
Endoscopically, signs of colitis, including edema, friability, erosions, exudates, and loss of vascular pattern, may be#
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34seen. The features are often segmental and may mimic ischemic colitis or Crohn’s disease. Pancolitis mimicking
ulcerative colitis has also been described. The histologic features are usually those of acute self-limited colitis.
34-38However, ulceration and focal architectural distortion may be seen in some instances (Fig. 4-7).
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 di erential diagnosis includes other infectious processes, ischemic colitis,
and chronic idiopathic in ammatory bowel disease. Culture helps to exclude other infections, but when architectural
distortion is present in a patient with chronic symptoms, it may be di? cult 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
39Clostridium septicum), and botulism (Clostridium botulinum).
C. difficile-related colitis
C. difficile infection is most commonly related to prior antibiotic exposure (especially orally administered), because the
39organisms cannot infect in the presence of normal ora. 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 signi) cantly in patients with chronic idiopathic in ammatory bowel disease, and it
40 41negatively affects clinical outcome in terms of hospitalization and need for colectomy. ,
The range of disease is variable, from mild diarrhea to fully developed pseudomembranous colitis to fulminant
42 43disease with perforation or toxic megacolon. , Watery diarrhea is almost always present initially and may be
accompanied by abdominal pain, cramping, fever, and leukocytosis. Bloody diarrhea is sometimes seen. Symptoms
42can occur up to several weeks after discontinuation of antibiotic therapy.
Endoscopically, classic pseudomembranous colitis shows yellow-white pseudomembranes, most commonly in the
42left colon, that bleed when scraped. The distribution is often patchy, and the rectum may be spared. Atypical
) ndings include mucosal erythema and friability without pseudomembranes. Typical histologic ) ndings 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 ) brin, mucin, and neutrophils (Fig. 4-8A-C). The ballooned glands are ) lled with neutrophils and mucin,
43and they often lose the super) cial epithelial cells. 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
43in association with a positive C. difficile toxin assay.
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 speci) c diagnosis. Although
most cases of pseudomembranous colitis are related to C. di. cile, other infectious entities, as well as ischemic colitis,
may have a similar endoscopic and histologic appearance. A hyalinized lamina propria favors the diagnosis of
ischemia; other features, such as crypt withering, pseudomembranes, and mucosal necrosis, may be seen in either
44entity. 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. di. cile 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
45have also been described.
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 in ammation and"
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necrosis often become transmural and lead to perforation. Histologically, the mucosa is edematous, necrotic, and
ulcerated, with a heavy acute in ammatory in) ltrate at the edges of ulcers. Pneumatosis may be present in severe
45cases, particularly in the mucosa and submucosa. Small vessel vasculitis and microthrombi may be seen.
Grampositive 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
46 47clostridial species, E. coli, Pseudomonas, and Enterococcus. , An association with CMV has also been noted.
46Patients usually present with GI hemorrhage, fever, abdominal pain and dis-tension, and diarrhea. Perforation is a
well-described complication.
The right colon is preferentially involved, although the ileum and other sites in the colon may be a ected as well.
Gross ) ndings include di use dilation and marked edema of the bowel, with varying severity of ulceration and
46hemorrhage. Exudates and pseudomembranes resembling C. di. cile colitis are common. Microscopically, changes
range from mild hemorrhage to prominent submucosal edema, ulceration, marked hemorrhage, and necrosis, typically
with a striking absence of in ammatory 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 di erential 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 nonspeci) c and include weight loss,
48 49fever, abdominal pain, diarrhea, and a palpable abdominal mass. , Mesenteric adenopathy is common.
Grossly, the ileocecal and jejunoileal areas are most commonly involved, followed by the appendix and as-cending
48 49colon , ; 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 ) ndings, along with thickened mucosal folds and in ammatory nodules. The ulcers are
often circumferential and transverse. Multiple and segmental lesions with skip areas are common. Large in ammatory
masses, usually involving the ileocecum, may be seen, and well-described complications include obstruction,
48-50 51perforation, and hemorrhage. Anal and perianal disease have also been reported, but rarely.
The characteristic histologic lesion consists of caseating, often con uent, 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 calci) cation. Aphthous ulcers, as well as in ammation of submucosal vessels, may"
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be present. Acid-fast stains sometimes demonstrate organisms in granulomas or necrotic areas (see Fig. 4-10B), but
culture is usually required for de) nitive diagnosis. In addition, PCR assays are available. Skin tests with puri) ed
protein derivative are unreliable in immunocompromised or debilitated patients.
FIGURE 4-10 A, Colonic Mycobacterium tuberculosis with mucosal and submucosal con uent, caseating granulomas.
B, Rare acid-fast organisms are seen in the necroinflammatory infiltrate (Ziehl-Neelsen).
The di erential diagnosis includes other granuloma-tous infectious processes, especially yersiniosis and fungal
30,52-54disease (Table 4-3). The granulomas of yersiniosis are typically noncaseating, with striking lymphoid cu s,
but there may be considerable histologic overlap. Crohn’s disease may be very di? cult to distinguish from
tuberculosis. Features favoring Crohn’s disease are the presence of linear rather than circumferential ulcers, transmural
lymphoid aggregates, deep ) stulas and ) ssures, and mucosal changes of chronicity that are present away from areas
52of granulomatous in ammation. 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"
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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 re ect 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
55 56gastroesophageal involvement may be present, as well as mesenteric adenopathy. ,
Immunocompetent patients typically manifest a granulomatous response, with or without necrosis.
Immunocompromised patients generally have villi distended by a di use in) ltration of histiocytes containing bacilli
55(Fig. 4-11A), with little in ammatory response other than occasional poorly formed granulomas. The bacilli stain
with acid-fast stains, as well as periodic acid-Schi (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 di erential diagnosis includes Whipple’s disease and other infectious
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FIGURE 4-11 A, Small bowel villi are distended by clusters of histiocytes containing Mycobacterium
aviumintracellulare, with little associated in ammatory 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
56 57 56-58stomach. , Patients are often asymptomatic, but pain, constipation, bleeding, and discharge may be present.
Gross ) ndings 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,
56 58smooth warts that secrete mucus and are associated with itching and a foul odor). , 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
57upper GI bleeding, and patients typically have antral erosions, ulcers, or features of gastritis endoscopically. Ulcers
may have irregular, heaped-up edges that mimic malignancy.
Histologically, syphilitic chancres typically contain a dense mononuclear cell in) ltrate with prominent plasma cells.
Syphilitic proctitis is very nonspeci) c, 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
57infiltrate. However, the glands may be relatively spared by in ammation. Granulomas have been reported, and
59 60occasion-ally prominent, proliferative capillary endothelial cells are noted. , Dark) eld examination, silver
impregnation stains (see Fig. 4-12B), serologic studies, and immunohistochemistry may be helpful diagnostic aids."
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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 di erential diagnosis of chancre includes anal ) ssures, ) stulas, or traumatic lesions. In general,
condyloma acuminata are more dry and keratinized than condyloma lata. The histologic di erential 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
61infection by a group of related organisms. Patients with this histologic ) nding 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.
61-63However, symptomatic patients do appear to respond to antimicrobial therapy. 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.
413A). Tissue invasion by organisms is not seen, and the changes can be very focal. Most cases show no associated
in ammatory in) ltrate, although occasionally an associated cryptitis is present. The organisms stain intensely with
64Warthin-Starry or similar silver stains (see Fig. 4-13B). They also stain with alcian blue (pH 2.5) and PAS.#
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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 di erential 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 ) ndings range from normal to erythema,
58mucosal friability, and surface erosions.
Chlamydia trachomatis.
Serotypes L1, L2, and L3 cause lymphogranuloma venereum (LGV). Anal pain is usually severe and accompanied by
59-65bloody discharge and tenesmus. The anorectum is the most common site, but LGV has been described in the
65ileum and colon as well. The in ammatory in) ltrate is variable; most patients have a lymphoplasmacytic in) ltrate
in the mucosa and submucosa, but neutrophils may be prominent as well. Granulomatous in ammation is sometimes
65 66present. Histologic features mimicking Crohn’s disease have been described. , In addition, LGV may produce a
65striking “follicular” proctitis. Culture, direct immuno uorescence studies, and immunohistochemistry may serve as
valuable diagnostic aids.
Granuloma inguinale.
Calymmatobacterium granuloma-tis (recently reclassi) ed as Klebsiella granulomatis) causes anal and perianal disease
66that may resemble LGV, although extension into the rectum favors a diagnosis of LGV. Warthin-Starry or Giemsa
stain aids in visualizing the Donovan bodies typical of granuloma inguinale.#
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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
67rectal gonorrhea are normal; some reveal a mild increase in neutrophils and mononuclear cells, or focal cryptitis.
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 ) ndings include ulceration,
pseudomembrane formation, and hemorrhage. Histologic ) ndings include acute in ammation and necrosis, with
68bacteria demonstrable in the wall of the esophagus.
Phlegmonous gastritis and enteritis.
Phlegmonous enteritis, gastritis, and esophagitis have all been well documented. This is a suppurative, primarily
submucosal in ammatory process, characterized by marked edema. The causative organisms vary and include E. coli,
69 70clostridial organisms, Proteus, staphylococci, and group A streptococci. , Most patients are debilitated, and many
70have cirrhosis or alcoholic liver disease. A ected patients may have nonspeci) c 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 in ammation located predominantly in the
70submucosa, and there may be transmural involvement as well. 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)."
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This ) lamentous anaerobic gram-positive bacterium is a normal inhabitant of the oral cavity and the upper GI tract.
71Rarely, it produces a chronic, nonopportunistic GI infection. 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 ) stulas and chronic (often granulomatous) appendicitis have both been described. In fact, sometimes
actinomycosis is associated with diverticular disease. Grossly, in ammation may produce a large, solitary mass, with
72or without ulceration, and infiltration into surrounding structures.
The organism typically produces actinomycotic (“sulfur”) granules, consisting of irregular round clusters of bacteria
rimmed by eosinophilic, clublike projections (Splendore-Hoeppli material). The in ammatory 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 in ammation. There may be an associated ) brotic response.
Gram stain reveals the ) lamentous, 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 di erential diagnosis includes peptic ulcer, lymphoma, and carcinoma. The histologic di erential
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
73lym-phadenopathy. Many patients also have significant neuropsychiatric manifestations.
The small bowel is most often a ected, 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 in) ltration of the lamina propria and
submucosa with foamy macrophages (Fig. 4-16A). The in) ltrate often blunts and distends villi. Involvement may be
di use or patchy. There is usually no associated mononuclear in ammatory in) ltrate, but varying numbers of
neutrophils may be present. The lamina propria may contain small foci of fat, and overlying vacuolization of
74enterocytes may occur as well.#
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FIGURE 4-16 Whipple’s disease. A, Villi are distended by an in) ltrate 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 identi) ed 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 di erential 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
in ammatory 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
75M. avium-intracellulare or Whipple’s disease.
Rocky Mountain spotted fever (Rickettsia rickettsii).
This disease is transmitted by bites of the common wood or dog tick. Many patients have signi) cant GI ) ndings,
including nausea, vomiting, diarrhea, pain, and GI bleeding. These manifestations may precede the rash. Involvement
76of every portion of the GI tract has been documented. Typical histologic ) ndings include vasculitis, often with
accom-panying nonocclusive microthrombi, and hemorrhage. The in ammatory in) ltrate is composed of
mononuclear cells with occasional lymphocytes, macrophages, and neutrophils. Immuno uorescence staining
demonstrates the organism, and serologic studies may also be of use.
Malakoplakia.
This rare disorder may a ect any portion of the GI tract. It consists of soft, yellow plaques containing a dense#
"
histiocytic in) ltrate 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 in) ltrate
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 immunode) ciency 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
77manifestations.
Grossly, the esophagus typically contains white plaques that can be readily scraped o 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 in ammatory masses (Fig. 4-18A). If vascular invasion is prominent, the bowel may
78appear infarcted. 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 in ammatory response ranges from minimal (especially in immunocompromised patients) to marked
with prominent neutrophilic in) ltrates, 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
77 78vessels is sometimes a prominent feature in invasive Candida infection. , 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
79forms (similar to those of Histoplasma) but does not produce hyphae or pseudohyphae.
Aspergillus species
Aspergillus infection of the GI tract occurs almost exclusively in immunocompromised patients and is much less
78frequently seen in the esophagus than is candidiasis. Gross ) ndings are similar to those seen with Candida infection.
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 in ammatory response ranges from minimal to marked, with a
79prominent neutrophilic in) ltrate, and granulomatous in ammation may develop as well. 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
79various angles. 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
80causes of systemic acidosis, are at increased risk for developing zygomycosis.
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
81with signs and symptoms of GI illness, but they do not always have concomitant pulmonary involvement.
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 ) ndings
include di use lymphohistiocytic in) ltrates 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
81be seen with virtually no tissue reaction. 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
82meningeal disease.
Grossly, cryptococcal infection may be located anywhere in the GI tract. Endoscopic lesions include nodules and
82ulcers, sometimes associated with a thick white exu-date. However, the mucosa is normal in many cases.
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 e ect can be
seen with H&E staining, representing the capsule of the organism. Both super) cial and deep involvement may occur,
and lymphatic involvement is not uncommon. The in ammatory reaction is variable and depends on the immune
status of the host, ranging from a suppurative, necrotizing in ammatory reaction, often with granulomatous features
79 82(Fig. 4-22A), to virtually no reaction such as in anergic hosts. , The mucopolysaccharide capsule stains with
alcian blue, mucicarmine (see Fig. 4-22B), and colloidal iron; GMS stains are positive as well. Unfortunately,
capsulede) cient cryptococci can pose a diagnostic challenge, but most have su? cient capsular material left to be seen with
79 82mucin stains. ,
FIGURE 4-22 This case of gastric cryptococcosis features a granulomatous reaction with associated giant cells and
acute in ammation. A, A halo e ect 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
83in the AIDS population, and extrapulmonary (including GI) involvement is not uncommon.
Endoscopically, P. carinii infection resembles a nonspeci) c, often erosive, esophagogastritis or colitis, sometimes
with small polypoid nodules. Microscopically, granular, foamy eosinophilic casts common to pulmonary infection may
83be seen in mucosal vessels or in the lamina propria (Fig. 4-23). As in the lung, a wide variety of in ammatory
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 identi) ed in tissue sections on the basis of morphologic criteria (Table 4-4).
Although organisms may be identi) able 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 speci) c 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 di erential 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
84 85enhanced our understanding and recognition of these protozoa. , 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 su er a severe, dysentery-like, fulminant colitis, many others are asymptomatic or show only vague GI
86symptoms. 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 “ ask-shaped” lesions (Fig. 4-24A), and there may
be associated in ammation or in ammatory 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. di. cile; and toxic megacolon
87have all been described in association with E. histolytica infection. Colonoscopy may be normal in asymptomatic
86patients or in those with mild disease."
#
"
#
#
#
#
#
#
FIGURE 4-24 A, This entamebic ulcer is deep and ask-shaped, undermining adjacent normal mucosa. B, Entamoeba
histolytica in the inflammatory exudates, containing ingested erythrocytes.
Histologically, early lesions show a mild neutrophilic in) ltrate. 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 necroin ammatory 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
in ammation. The organisms may be few in number. They resemble macrophages, with foamy cytoplasm and round,
87eccentric nuclei. The presence of ingested red blood cells (see Fig. 4-24B) is pathognomonic of E. histolytica. In
asymptomatic patients or those with only mild symptoms, histologic changes may range from normal to a heavy
mixed in ammatory in) ltrate. Organisms may be particularly di? cult (if not impossible) to detect in these patients.
86Invasive amebiasis does not generally occur in patients who have only mild, or absent, symptoms.
Distinction of amebae from macrophages in in ammatory exudates may be di? cult. 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 di erential diagnosis of amebiasis also includes Crohn’s disease, ulcerative colitis, and other types
of infectious colitis. Although some features of amebiasis may mimic idiopathic in ammatory bowel disease, many of
the other diagnostic features of Crohn’s disease (e.g., transmural lymphoid aggregates, mural ) brosis, granulomas,
neural hyperplasia) and ulcerative colitis (e.g., basal lymphoplasmacytosis, di use 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
88 89persists for weeks or months if left untreated. , 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 in ammatory
cells including neutrophils, plasma cells, and lymphocytes. Giardia trophozoites resemble pears that are cut lengthwise
88and contain two ovoid nuclei with a central karyosome at the luminal surface (Fig. 4-25). Tissue invasion is not a
feature of this infection. Although Giardia is characteristically described as a small bowel inhabitant, colonization of
88the stomach and colon has also been reported. 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 immunode) ciency disorder
(see Chapter 5).#
#
"
"
#
#
"
FIGURE 4-25 Duodenal mucosa with numerous Giardia trophozoites at the luminal surface, without signi) cant
mucosal inflammation.
(Courtesy of Dr. Rodger Haggitt.)
Leishmania donovani and related species
90Leishmaniasis is endemic in over 80 countries in Africa, Asia, South and Central America, and Europe. 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
91tract. The spectrum of endoscopic findings includes normal mucosa, focal ulceration, and changes of enteritis.
Histologically, amastigote-containing macrophages are present in the lamina propria. In large numbers,
macrophages may distend and blunt intestinal villi. An associated in ammatory in) ltrate is normally absent.
Amastigotes are round to oval, tiny organisms with a nucleus and kinetoplast in a “double-knot” con) guration; they
do not have typical agella. They are highlighted by Giemsa staining. The di erential 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 a ect the lamina propria rather than the myenteric
90 91plexus. , 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
92frequent manifestations. Histologically, there is in ammatory destruction of the myenteric plexus, with loss of up to
9395% of neurons. However, the parasite is rarely visible in myenteric plexuses. The di erential diagnosis includes
idiopathic primary achalasia as well as other visceral neuropathies. However, many of these latter disorders lack
in ammation 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
94of cilia (Fig. 4-26)."
#
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 di erential diagnosis of diarrhea in patients with
95AIDS, but it is also seen in healthy persons, including infants and children, in developing countries. Transmission is
96normally via the fecal-oral route, either directly or via contaminated food and water. 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
96risk for chronic, severe diarrhea, with malabsorption, dehydration, and death. Many coccidial infections are
asymptomatic. Endoscopic ) ndings 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,
95and PCR studies are also available for diagnosis of these parasites.
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
97(Fig. 4-27). The organisms are found in the crypts or in the surface epithelium. Associated mucosal changes include
villous atrophy (occasionally severe), crypt hyperplasia, mixed in ammation, 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-m μ 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
98coccidians. 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
99parasitophorous vacuole. The organisms are acid-fast with modi) ed Kinyoun or similar stains, and they are positive
with auramine. However, they are GMS negative. The major di erential diagnosis is with Cryptosporidium, but
98Cyclospora organisms are much larger (Fig. 4-28), and they exhibit auto uorescence under epi uorescent light.
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 m μ
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 m μ).#
"
"
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
in ammation, often with prominent eosinophils, and, in chronic infections, ) brosis of the lamina propria.
Intraepithelial inclusions, both perinuclear and subnuclear, may be present at all stages of infection. Rarely, organisms
100 101are also present in the lamina propria or in macrophages. , When motile, these parasites are large and
bananashaped, 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 di erentiated 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 a ected. Microsporidia are di? cult to
detect in H&E-stained sections. The histologic features include patchy villous blunting, vacuolization of the surface
102 103epithelium, and patchy lymphoplasmacytic in) ltrates in the lamina propria. , A modi) ed 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 ) lament. 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
104aids.
Miscellaneous Protozoal Infections
105 106Dientamoeba fragilis is an ameba of low pathogenicity that occasionally causes diarrhea in a ected patients. , 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
107 108of low pathogenicity, may cause enteric disease when present in large numbers. , However, these organisms are
only rarely seen in tissue sections. Indeed, when protozoa of low pathogenicity are identi) ed 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
109and Enterobius), and whipworms are the most common helminthic infections in man. 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 de) cient 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
109severe and even life-threatening, especially in children. The most common site of anatomic infection is the small
110bowel, although the stomach and large bowel may also be involved.
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
110 111described. , 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
112debate. Some believe that the lack of in ammation surrounding invasive pinworms indicates that the organism
111invades only after the appendix has been removed, thus to escape the decrease in oxygen tension. However,
111Enterobius organisms are, in fact, capable of mucosal invasion, 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 in ammatory reaction, but an in ammatory in) ltrate 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,
111anus, and colon in rare cases. Primary Enterobius infection may be di? cult 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 ) ndings 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 identi) ed endoscopically or in resection
110specimens (Fig. 4-32). Tissue damage occurs primarily at the anatomic sites of attachment.
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
109when the worms migrate. 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
110blunting and eosinophilic infiltration. 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 in ammatory process similar
109 110to Crohn’s disease and rectal prolapse have also been described. , 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
110 113inflammatory infiltrate. Crypt abscesses may also be present. ,
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
114 115whom are hospitalized, su er from chronic illnesses, or are immunocompromised. , Steroids and human T
116lymphotropic virus type-1 infection are also associated with strongyloidiasis. Symptoms and signs include diarrhea,
abdominal pain and tenderness, nausea, vomiting, weight loss, malabsorption, and GI bleeding. Mesenteric
lymphade117nopathy may also occur. GI manifestations may be accompanied by rash, eosinophilia, urticaria, pruritus, and
110 114pulmonary symptoms. , 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
110 114in immunocompromised patients, causing severe and even fatal illness. ,
Lesions may be seen in the stomach, as well as in the small and large intestine. Endoscopic ) ndings 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 di? cult 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 ) ssuring), edema, and a dense eosinophilic and neutrophilic in) ltrate.
110 114Granulomas are occasionally present as well. ,
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 ) sh and sea mammals, so humans ingest them by eating raw or pickled ) sh. The most
common clinical manifestations are those of acute gastric anisakiasis, characterized by epigastric pain, nausea, and
110 118vomiting within 12 hours of ingestion of parasitized food. The symptoms may mimic peptic ulcer disease. , The
allergenic potential of Anisakis species has also been recognized, and some patients with gastroallergic anisakiasis
118manifest both GI and hypersensitivity symptoms such as urticaria, angioedema, eosinophilia, and anaphylaxis.
The stomach is the most frequent site of involvement, although the small bowel, colon, and appendix may also be
involved. Endoscopic ) ndings include mucosal edema, hemorrhage, erosions, ulcers, and thickened mucosal folds.#
"
#
#
#
#
#
#
Occasionally, larvae may be identi) ed, and removed, endoscopically. Histologic ) ndings include an in ammatory
in) ltrate rich in eosinophils, which may extend transmurally into serosal and mesenteric tissues (Fig. 4-34).
Eosinophilic microabscesses, granulomas, and giant cells may also develop. In ammatory 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
119 120samples. ,
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 ) sh. 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 in ammatory reaction, villous blunting, mucosal sloughing, and mild in ammatory
109 121changes have been described. ,
Trematodes
Schistosomiasis.
All Schistosoma species have the capability to cause signi) cant 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
110 122prolapse, ) stulae, and perianal abscesses. , Any level of the GI tract may be a ected. Endoscopically,
Schistosoma can be seen to cause in ammatory polyposis (particularly in the distal colon) with associated mucosal
granularity, friability, punctate ulcers, and hemorrhages. Histologically, in ammatory polyps and mucosal ulcers,
with associated granulomatous in ammation and an eosinophilic in) ltrate, are typical. Eggs may be detected in
110 123histologic specimens and are sometimes calcified. , 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, Calci) ed 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 ukes have been described in humans, but most clinically signi) cant infections are
124-126caused by F. buski, Echinostoma species, and Heterophyes species. These ukes are most common in Asia. They
are ingested with aquatic plants, and after maturation, the adult worm attaches to the proximal small bowel
110 124mucosa. , 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, in ammation, 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
12 110occasionally cause GI disease. Diphyllobothrium latum () sh tapeworm) is a rare cause of vitamin B de) ciency. ,
120
Other Helminthic Infections
The Central American nematode, Angiostrongylus costaricensis may cause dramatic, even fatal, ileocecal infection
characterized by the presence of large obstructive in ammatory masses with perforation and mesenteric vessel
110 110thrombosis. Trichinella spiralis is a rare cause of diarrhea. Esophagostomiasis, a parasitic disease generally seen
110in nonhuman primates, may form deep inflammatory masses, predominantly in the right colon and appendix.
The di erential diagnosis of helminthic infections usually involves di erentiation between the various types of
worms. However, other entities to be considered include causes of ulcerative in ammation, eosinophilic in) ltration,
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 de ciency (Table 5-1) are associated with GI
pathology. Manifestations of immune de ciency in the GI tract can be broadly divided
into three categories: (1) increased susceptibility to infection, (2) idiopathic chronic
in%ammatory conditions, and (3) increased risk for neoplasia. Although many GI
disorders are infectious (Table 5-2), chronic in%ammatory conditions resembling celiac
disease and in%ammatory bowel disease (Table 5-3) are seen in patients with various
types of antibody de ciencies. 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 de ciencies are also at increased risk for neoplasia
(Table 5-4), most commonly non-Hodgkin’s lymphoma. In fact, the GI tract is often the
1-3primary site of involvement. In addition to an increased risk for lymphoma, some of
the primary immune de ciencies are associated with an increased risk for gastric
4 5adenocarcinoma and colorectal carcinoma.
Molecular Basis of Primary Immunodeficiency Disorders*TABLE 5-1
Disease Proposed Cause
IgA deficiency Impaired IgA synthesis; mutation in TNFRSF13B in some cases
Common variable Impaired B-cell maturation; mutations in TNFRSF13B in 10%-immunodeficiency 15%
X-linked Mutation in Btk results in absence of Btk in B cells
agammaglobulinemia
Hyper-IgM syndrome Absence of CD40 ligand on T cells
Hyper-IgE syndrome Defect on chromosome 4; exact defect unknown
Severe combined Multiple defects; most common results from defect in common
immunodeficiency γ chain; others include adenosine deaminase deficiency, purine
nucleoside deficiency, and T-cell receptor deficiencies
Omenn’s syndrome Missense mutation in Rag1, Rag2
DiGeorge syndrome Thymic hypoplasia; deletion in chromosome 22q11.2
Chronic Heterogeneous disorder; mutation in gene in some*AIRE
mucocutaneous
candidiasis
Wiskott-Aldrich Mutation in WASP gene involved in cell trafficking and
syndrome motility
Chronic Mutation in gene for component of NADPH oxidase
granulomatous
disease
* From Tzung SP, Hackman RC, Hockenbery DM, et al: Lymphocytic gastritis resembling
graftvs.-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 G. intestinalis, Cryptosporidium, cytomegalovirus
immunodeficiency
X-linked G. intestinalis, Cryptosporidium, Salmonella, Campylobacter,
agammaglobulinemia rotavirus, coxsackievirus, poliovirus
Hyper-IgM syndrome G. intestinalis, Cryptosporidium, Entamoeba histolytica,
Salmonella, Histoplasma capsulatum
Severe combined Candida, Salmonella and other bacterial pathogens,
immunodeficiency cytomegalovirus, rotavirus, Epstein-Barr virus
DiGeorge syndrome CandidaChronic Candida, H. capsulatum
mucocutaneous
candidiasis
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
Multifocal atrophic gastritis ± intestinal metaplasia
immunodeficiency
Villous atrophy
Nodular lymphoid hyperplasia
Crohn’s disease–like lesion
Granulomatous enteropathy
Colitis (ulcerative colitis–like; lymphocytic colitis)
X-linked
Crohn’s disease–like lesion
agammaglobulinemia
Perianal fistula and perianal abscess
Hyper-IgM syndrome
Nodular lymphoid hyperplasia
Oral and perianal ulcers
Severe combined
Graft-versus-host disease–like lesion, small bowel and colon
immunodeficiency
Esophageal reflux
Omenn’s syndrome Graft-versus-host disease–like lesion, small bowel and colon
Chronic Atrophic gastritis
mucocutaneous
candidiasis
Wiskott-Aldrich Crohn’s disease–like lesion involving colon
syndrome








Chronic Esophageal and gastric outlet obstruction; Crohn’s disease–like
granulomatous lesion in small bowel; colitis (ulcerative colitis–like and
disease 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
Gastric adenocarcinoma
immunodeficiency
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 de ciency, de ned as a serum IgA concentration of less than 50 μg/mL, is
the most common type of primary immunode ciency, occurring in 1 in 600 individuals
6of northern European ancestry. This disorder is 20 times more common in white
6Americans than in African Americans. Defects in antibody production in patients with
IgA de ciency represent a continuum with those seen in common variable
immunode ciency (CVID). In fact, 20% to 30% of IgA-de cient patients also have
de cits in subclasses of IgG antibodies. Recently, mutations in the gene TNFRSF13B have
7-9been identi ed and shown to be associated with IgA de ciency. 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 de ciency
range from absence of symptoms to multiple recurrent infections, generally involving
mucosal surfaces; autoimmune disorders; allergic diseases; and malignancy. The clinical
manifestations of IgA de ciency 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 de ciency 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
10been reported.
Susceptibility to insulin-dependent diabetes mellitus and celiac disease may be
inherited together with IgA de ciency; 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 de ciency, is 7.7% in children with IgA de ciency, compared with 1
11in 500 in the general population. 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 de ciency, and similarly it may occur in patients with CVID.
The morphology of celiac disease that develops in the setting of IgA de ciency is similar
to that in immunocompetent patients. Pernicious anemia complicating chronic atrophic
autoimmune gastritis is associated with IgA de ciency more commonly than with CVID.
As with other B-cell disorders, the incidence of Crohn’s disease and gastric
12adenocarcinoma appears to be increased in IgA deficiency.
Common Variable Immunodeficiency
Common variable immunode ciency is not a common disorder despite its name.
However, it is probably the most common symptomatic type of primary
immunode ciency. Clinical and immunologic features diKer, 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 aKects 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
13 14sarcoidosis may also occur. , 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



1320%. The common abnormality shared by IgA de ciency 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
15the underlying basis for the disorder.
A genetic basis for CVID has long been suspected because of the observation that
16familial inheritance of CVID occurs in 20% of cases and CVID and IgA de ciency 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 de ciency occurring in the oKspring, 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
17deficiency. 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
17autoimmune and lymphoproliferative disorders.
Patients with CVID are at particular risk for chronic in%ammatory disorders and
malignancies of the GI tract. Development of in%ammatory 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
18autoimmunity. In one large clinical study of patients with CVID, 22% had at least one
autoimmune disease. The most common were idiopathic thrombocytopenia purpura (6%)
13and autoimmune hemolytic anemia (5%).
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 identi ed on small bowel biopsy (Fig. 5-1). The prevalence of
Giardia infections in this population appears to be decreasing, but giardiasis remains a
12significant cause of chronic diarrhea in patients with CVID.
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
12pseudomembranous colitis has not been reported. 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
19strictures, has also been reported in a patient with CVID.
INFLAMMATORY DISORDERS AND MALIGNANCY IN CVID
Stomach.
In the stomach, a nonspeci c increase in lamina propria lymphocytes may be detected in
some patients with CVID (Fig. 5-2A); increased apoptosis of gastric epithelial cells is
18present in some cases. 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.
pylori20negative patients, 10% had multifocal atrophic gastritis. 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 aKected patents. Atrophic gastritis may develop at a very young age in
patients with CVID. One child developed multifocal gastric adenocarcinoma at 11 years
21 14of age. Adults with CVID are also at increased risk for gastric adenocarcinoma. It has
been estimated that patients with CVID have a 47-fold increased incidence of gastric
22carcinoma compared with the general population of Great Britain, 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 immunode ciency, the gastric mucosa often
contains a nonspeci c mononuclear cell in ltrate. Note the absence of plasma cells. B,
Loss of gastric glands leads to atrophic gastritis at a young age in patients with common
variable immunode ciency. 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 in%ammatory in ltrate is not
as prominent as in celiac disease, and enterocyte maturation is normal, with preservation
18of the brush border. Most CVID patients with this type of small bowel pathology do not
respond to a gluten-free diet, although an elemental diet may be bene cial. 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 immunode ciency
(CVID) may be severe and lead to profound malabsorption. Note the relatively sparse
in%ammatory in ltrate 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
23the GI tract, including the stomach, small intestine, and colon. 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
24CVID, but it may also be seen in giardiasis, without antibody de ciency. In contrast to
NLH in CVID patients, plasma cells in nonimmunode cient patients are present in the
extramantle zones. NLH is not considered a malignant disorder. However, malignant
lymphomas of the GI tract in patients with immunode ciencies often arise in a
background of NLH. In a child with CVID, clonal immunoglobulin gene rearrangements
25have been demonstrated in NLH in the GI tract. Consistent with these observations, the
most common malignancy in CVID is non-Hodgkin’s lymphoma, which aKects
13approximately 8% of patients. 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
14origin, and include diffuse large B-cell lymphoma and follicular lymphoma.
FIGURE 5-4 A, Nodular lymphoid hyperplasia in common variable immunode ciency.
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 in%ammatory processes involving the small
or large bowel that clinically resemble in%ammatory bowel disease. In some patients, the
small bowel is the primary site of involvement, and the lesions resemble Crohn’s disease
with transmural in%ammation and small bowel obstruction. However, granulomas are

26generally not present in CVID-related Crohn’s disease-like disorders.
Large bowel.
Colitides that occur in CVID are quite variable in morphology. In some patients, the
in%ammatory 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
18resemble colonic graft-versus-host disease. Milder cases of colitis in CVID may resemble
lymphocytic colitis, characterized by increased intraepithelial lymphocytes with minimal
27crypt distortion. The etiology and pathogenesis of colitis in CVID patients remain
largely unknown. The association of chronic GI in%ammatory 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 immunode ciency may mimic in%ammatory
bowel disease, with crypt distortion and loss. The in%ammatory in ltrate 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-year28old boy who died of liver metastases 5 months after diagnosis. In another case, nine
adenocarcinomas and 20 adenomas were present, synchronously, in the colon of a
2229year-old man with CVID.
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
30 31tyrosine kinase) gene was rst detected. , 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 de ciencies in Btk, have been
32-34described.
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.
35In this study, the etiology of chronic diarrhea was found in only half of the patients.
36Chronic infection with rotavirus was also previously reported in this patient population.
Since biopsies are not routinely performed for this disorder, few descriptions of
histopathologic ndings are available. However, a moderate degree of villous blunting
with crypt hyperplasia, and an increase in lamina propria in%ammatory cells have been
37reported in the duodenum in acute infections. 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
38disease and quick reversion to normal after resolution of infection.
In addition to GI infections, patients with XLAG may develop a chronic ulcerating
in%ammatory condition similar to Crohn’s disease, manifested by recurrent diarrhea,
malabsorption, ulcers, and small bowel strictures (Fig. 5-6). The inflammatory infiltrate is
18 39characterized by prominent lymphocytes, without plasma cells or granulomas. , In
one case, enterovirus was detected by polymerase chain reaction in in%amed ileum and
adjacent mesenteric lymph nodes, suggesting that infection may be responsible for the
40inflammatory disorder in some patients.
FIGURE 5-6 A chronic in%ammatory disorder, with ssuring 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
41cases occur in children under the age of 10 years. In fact, there are rare reported cases
41 5of gastric adenocarcinoma and colorectal adenocarcinoma. The incidence of
colorectal carcinomas in patients with XLAG is increased 30-fold. The mortality is 59-fold
5greater than in the normal European population. 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
5present.
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

42are the upper (approximately 88%) and lower respiratory tracts (approximately 83%),
43 44followed by disseminated infection and esophageal infection with Histoplasma
capsulatum.
Diarrhea occurs in over half of aKected patients, and it often follows a chronic
42course. Chronic watery diar-rhea may be caused by Cryptosporidium, G. intestinalis,
Salmonella, or Entamoeba histolytica infection. Nodular lymphoid hyperplasia involving
42the GI tract has been reported in about 5% of patients. Lymphoid hyperplasia may also
45result in hepatosplenomegaly, lymphadenopathy, and tonsillar enlargement. In fact,
in%ammatory bowel disease has also been reported in two patients with XHIM and
42chronic diarrhea. Sclerosing cholangitis is a common (approximately 20% of European
patients) and serious complication of XHIM, which is often related to chronic infection
42with Cryptosporidium. Some cases require liver transplantation. In one European series,
42three of five patients infected with hepatitis B developed hepatocellular carcinoma.
Patients with XHIM are prone to autoimmune hematologic diseases, including cyclical
42or chronic neutropenia with simultaneous oral and perianal ulcers. Some patients
develop a marked proliferation of IgM-producing plasma cells in the GI tract, liver, and
46gallbladder, usually in the second decade of life, which often proves fatal. Small cell
47carcinoma of the colon has also been reported in this disorder, and an increased
48incidence of liver and biliary tract tumors occurs as well.
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
49pneumatocele, elevated serum IgE, eczema, candidiasis, and eosinophilia. The exact
genetic defect has not been elucidated, but the disease locus has been mapped to
50chromosome 4. In addition to ndings related to the immune system, characteristic
facial features, and dental and skeletal abnormalities have been reported in a cohort of
4930 patients who were followed for a long period of time. However, chronic diarrhea,
and disorders resembling in%ammatory bowel disease have not been reported in
hyperIgE syndrome. GI manifestations of this disease are usually limited to mucocutaneous
candidiasis and tissue-invasive fungal infections with Cryptococcus that invade the
51 52esophagus and colon. Ileocecal histoplasmosis mimicking Crohn’s disease has been
53reported. Perforation of the colon, probably related to infection with staphylococcal
54species, may develop as well, but this is rare. Patients with hyper-IgE syndrome do not
appear to be at increased risk for primary GI malignancies. However, associations with
55 56lymphomas of both B- and T-cell derivation have been reported. ,
COMBINED CELLULAR AND HUMORAL IMMUNODEFICIENCIES
Severe Combined Immunodeficiency
Severe combined immunode ciency (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 rst 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 de ciency, accounting for 50% of autosomal recessive
SCID; purine nucleoside de ciency; T-cell receptor de ciencies; Zap70 de ciency; JAK3
57de ciency; and IL-7 receptor de ciency. X-linked SCID resulting from a defect in the
58common gamma chain is the single most common type of SCID. This type of SCID has
a characteristic phenotype of absence of T and natural killer cells but normal B cell
57numbers, although the B cells are dysfunctional.
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 aKected children. Although villous blunting has been described in acute
38 59rotavirus infection in normal children and in animal models, the intestinal pathology
of chronic rotavirus infection in SCID patients has not been described. Cytopathic viral
infections, including cytomegalovirus and adenovirus infection, may be identi ed 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 aKecting the colon and small intestine has also
been described in SCID patients who have not undergone bone marrow
60 61transplantation. , Children with SCID may be at greater risk for re%ux esophagitis
62than the normal population.





FIGURE 5-7 A, Disseminated adenovirus may involve the GI tract in patients with
severe combined immunode ciency. In this case, the small bowel crypts are involved; in
less severe cases, inclusions may be identi ed only in surface epithelium. B,
Adenovirusinfected 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 immunode ciency
disorder with clinical and pathologic features of GVHD. The immunologic hallmark of the
63disease is expansion of an oligoclonal population of T cells combined with a near
64absence of B cells. Infants with Omenn’s syndrome present with diKuse 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 ndings in Omenn’s
syndrome is the impairment of the V(D)J recombination process as a result of mutations
64 65in Rag1 or Rag2, the recombination-activation genes. , Mutations in these genes were
−rst identi ed 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. DiKerences 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 of65establishing the oligoclonal T cell population in patients with Omenn’s syndrome.
Infants with SCID and with maternal T-cell engraftment may exhibit GVHD symptoms
66indistinguishable on clinical grounds from symptoms of Omenn’s syndrome. 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
67 68Omenn’s syndrome are scant, but skin changes may resemble those of GVHD. ,
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
69humans and is estimated to affect 1 in 4000 live births. T cells are markedly reduced in
number, but B cells are normal in number and functionality. Midline anomalies aKecting
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
70described but not well characterized. Oral candidiasis is common. Dysphagia and
71feeding difficulties have been reported in infants with 22q11.2 deletion as well.
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
72association with thymoma and systemic lupus erythematosus. Immune defects include
disorders of T-cell immunity with variable B-cell involvement. The most common GI






manifestation is esophageal candidiasis. Although super cial infection with Candida is a
de ning characteristic, infections with other fungi (e.g., H. capsulatum) and bacteria are
73common.
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 aKected. The genetic basis of
Wiskott-Aldrich syndrome, rst described in 1994, is mutation of the WASP gene, which
74encodes an intracellular protein expressed exclusively in hematopoietic cells. This
protein is involved in transduction of signals from cell surface receptors to the actin
75cytoskeleton and is important in cytoskeletal architecture, cell traQ cking, and
76motility. Diarrhea is reported in patients with this disorder but has been poorly
70characterized. 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 in%ammatory process, with a cobblestone appearance
and in%ammatory pseudopolyps of the mucosa involving the descending and transverse
77colon, has been reported in Wiskott-Aldrich syndrome. Massive hemorrhage from
aneurysms involving the liver, small bowel mesentery, and kidney has also been
78reported.
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
79other forms are autosomal recessive. As a result of this defect, patients with CGD suKer
from recurrent bacterial and fungal infections. Abscesses may occur in a variety of sites,
and pneumonia is also common. AKected patients are also prone to develop a variety of
in%ammatory and rheumatic diseases, such as an in%ammatory 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
79obstruction is more common in the X-linked form of the disease. In some cases,
obstruction is caused by in ltration of the viscus wall by pigment-laden macrophages
(the histologic hallmark of CGD) or to granulomatous in%ammation. In other cases,
obstruction is reportedly secondary to a functional disturbance in GI motility, although in
these cases, in ltration of the deep layers of the organ by macrophages was not
79completely excluded. Esophageal obstruction occurs in 1% of patients with CGD.
Biopsies of the esophageal mucosa generally show nonspeci c ndings or histologic


80evidence of re%ux esophagitis 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 rst manifestation of
CGD. Granulomas, giant cells, and macrophages laden with brown-yellow ne pigment
81are commonly present in gastric biopsies, but in some cases, only nonspeci c
82in%ammation is present. Small bowel obstruction is relatively rare in CGD, but it is
83occasionally reported in the context of an in%ammatory process. 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
84cases, distortion of crypt architecture, without crypt abscesses, was also seen.
FIGURE 5-9 Chronic granulomatous disease. Accumulation of pigmented macrophages
containing light brown dusky material in the small intestinal mucosa.
Chronic in%ammatory processes indistinguishable from in%ammatory bowel disease,
85aKecting the small and large bowel, may also occur in patients with CGD. As with
obstructive lesions of the GI tract, these manifestations are more common in the X-linked
79form of the disease. Polymorphisms in genes unrelated to NADPH oxidase may modify
the clinical phenotype of CGD; certain polymorphisms in the genes for myeloperoxidase





86and Fc γ receptors are strongly associated with GI complications. Involve-ment of the
small bowel in CGD may produce stulae, longitudinal ulcers, stenosis, and
non87 88necrotizing granulomatous in%ammation that may be mistaken for Crohn’s disease. ,
Granulomas in intestinal lesions in CGD are often more %orid than typically seen in
87Crohn’s disease, but granulomas are not present in all cases. In a CGD patient with
colitis, the presence of an acute and chronic in%ammatory in ltrate con ned 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,
85pigmented macrophages were present in the lamina propria.
Miscellaneous Immune Deficiency Syndromes
Other rare disorders of immunity occasionally associated with GI manifestations include
leukocyte adhesion de ciency, in which delayed wound healing and susceptibility to
89bacterial and fungal infection lead to necrotizing enterocolitis. A chronic in%ammatory
process with multiple aphthous ulcers involving the gastric antrum, terminal ileum,
cecum, and right colon, which resolved with bone marrow transplantation, has also been
90reported in leu-kocyte adhesion de ciency. Ataxia-telangiectasia, a chromosomal
breakage syndrome, is associated with an increased risk for gastric adenocarcinoma. Bare
lymphocyte syndrome (a de ciency 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
91transplant recipients. Skin and liver are the most common organs involved. Indeed, the
most common cause of persistent nausea and anorexia in patients beyond post-transplant
92day 20 is acute GVHD. 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
93of regulation of immune mechanisms by the reconstituting immune system. Acute
GVHD-like changes in the GI tract after autologous transplantation are rare, occurring in
94gastric biopsies in only 4% of patients with upper GI tract symptoms. 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
91also been reported. Involvement of the upper GI tract is slightly more common than
involvement of the large bowel, although simultaneous involvement of both the upper
95and lower GI tract is common.
On endoscopic examination, the appearance of GI mucosa in acute GVHD is variable,
96ranging from mucosal edema and erythema, to ulceration and mucosal sloughing. The


major and most characteristic histologic features of GVHD in the GI tract are epithelial
cell apoptosis combined with a relatively sparse mononuclear in%ammatory cell in ltrate
(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
97intracytoplasmic vacuoles lled with karyorrhectic nuclear debris (see Fig. 5-10B).
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
98present in the lumen of injured gastric glands (see Fig. 5-11B). Villous blunting is
usually present in the small bowel with GVHD. A grading system for acute GVHD of the
97colon has been proposed (Table 5-5). 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 in%ammatory in ltrate 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
speci c. For example, similar changes have been reported in colonic biopsies from
61 99 18patients with severe T-cell de ciencies, malignant thymoma, and CVID. In bone
marrow transplantation patients, the eKects 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,
100particularly acute lymphoblastic leukemia, may also mimic acute GVHD.






Cytomegalovirus infection may produce mucosal damage characterized by apoptotic
101epithelial cells, also mimicking acute GVHD. Of course, diKerentiation of
102cytomegalovirus infection from GVHD relies on demonstration of viral inclusions.
Furthermore, because GVHD and cytomegalovirus infection may occur simultaneously, it
may be diQ cult to separate the eKects 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 in%ammation, 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 eKects 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 di7 cile infection has also been associated with GVHD and has been
associated with a high nonrelapse mortality rate. It has been postulated that C. di7 cile
103toxin may predispose patients to more severe degrees of GVHD. Use of proton pump
inhibitor therapy has also been associated with the development of apoptotic cells in the
104gastric antrum, which may mimic the histologic changes seen in GVHD. 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,
bowelpreparation eKect is often more prominent in the right colon than in the left colon and
rectum. Finally, as indicated later, patients with AIDS often show nonspeci c 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 de ned 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
105Chapters 14 and 44). 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 brosis 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 brosis may also occur in the esophagus, which is the most
106commonly aKected site in the GI tract. Altered transit may lead to secondary
re%uxrelated changes in the overlying mucosa. Small bowel involvement is less common and,
when present, is usually associated with diarrhea. Patchy brosis of the lamina propria
106and submucosal brosis, with minimal mucosal changes, are characteristic ndings.

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
107architectural distortion results from chronic GVHD or other factors. Otherwise,
expression of chronic GVHD in colonic biopsies may be completely normal, or it may
reveal crypt disorder with brosis, crypt abscesses, or other features of in%ammatory
bowel disease.
Neutropenic Enterocolitis
Neutropenic enterocolitis (NEC) is a necrotizing in%ammatory process predominantly
aKecting 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,
3has also been termed typhlitis. Absolute neutrophil counts of less than 1500/mm 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
108 109marrow transplantation for solid malignancies. , 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
110of chemotherapy in the previous 30 days. Patients may present with clinical features
suggestive of acute appendicitis, such as fever and right lower quadrant pain, but up to
110one third present with overt GI hemorrhage. Rarely, a right lower quadrant mass may
be palpable. The combination of abdominal pain, diarrhea, and fever is the most
109common presentation in the acute phase of NEC.
On gross examination, the cecum, as well as any other aKected 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 nding 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 in%ammation,
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 oKend-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 eKects 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 %ow, which also adds an element of
ischemictype 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 eKective antiretroviral agents, opportunistic infections caused by pathogens such
a s 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
111almost exclusively in homosexual men, 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
111the degree of immune suppression.

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
de ned 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,
112which can occur after administration of antiviral agents. Thus, some authors have
suggested that medications should also be considered as a possible etiologic factor in the
113development of diarrhea and may even account for up to 45% of noninfectious cases.
Commonly implicated medications are nel navir, ritonavir, saquinavir, indinavir, and
didanosine. In small bowel biopsies, HIV enteropathy is characterized by mild villous
114blunting but without crypt hyperplasia. The degree of villous atrophy is typically less
than that seen in celiac disease.
The eKective 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
HIVassociated 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
2involvement in 40% of cases at initial presentation and up to 80% at autopsy. AIDS-related non-Hodgkin’s lymphomas are predominantly of B-cell lineage and include
Burkitt’s lymphoma (Fig. 5-14), diKuse large B-cell lymphoma (immunoblastic,
centroblastic, and anaplastic variants), primary eKusion lymphoma, and plasmablastic
2 3lymphoma. , The GI tract is the most common site of extranodal non-Hodgkin’s
1 117lymphomas, including Burkitt’s lymphoma and diKuse large B-cell lymphoma. ,
Classic primary eKusion lymphoma aKects the peritoneal cavity, whereas solid primary
eKusion lymphoma may be seen in extraserous sites such as the large intestine and lymph
2nodes. Plasmablastic lymphoma has been documented in the oral cavity and anorectum.
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
2 116 117carcinoma, and gastric carcinoma. , ,
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.
DiKusely in ltrative 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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human immunodeficiency virus (HIV) population. Int J Gastrointest Cancer. 2005;36:1-14.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 a ect the GI tract. GI symptoms and morphologic changes can result from several
di erent pathogenetic mechanisms, such as nonspeci c 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
1 2mortality rate is high (approximately 30%). , Clinical features typically consist of GI hemorrhage secondary to stress
ulceration, vascular insu( ciency with ischemic necrosis of bowel, and acute diverticulitis. Additional risk factors for
2ischemia include end-stage renal disease, female sex, non-coronary artery bypass graft, and long pump times.
In contrast to GI complications after open heart surgery, GI complications after cardiac transplantation have been
3 4reported in a much greater proportion of patients (up to 20%). , Complications include all of the hemorrhagic
conditions mentioned previously. In addition, the use of steroids and immunosuppressive agents increases the risk of
intestinal perforation, stula formation, and infectious GI diseases. Finally, these patients are also at risk for
post5transplantation lymphoproliferative disorders (see Chapter 44).
ISCHEMIC DISEASE
Intestinal ischemic disease can be divided into two major subsets: nonthrombotic (approximately 60% of cases) and
6thrombotic (approximately 40% of cases). Nonthrombotic causes of ischemic disease include decreased mesenteric
blood 4ow secondary to cardiac failure, shock, atherosclerotic vascular disease, disseminated intravascular
coagulation, vasculitis, and bromuscular dysplasia. Thrombotic causes can be divided into arterial embolism, arterial
7thrombosis, and venous thrombosis. These are a heterogeneous group of disorders usually seen in elderly individuals.
Colonic ischemia, the most common disorder (typically nonthrombotic), has a favorable prognosis. Acute mesenteric
6ischemia, in contrast, has a poor prognosis, with a survival rate of only 50%. Histologically, resultant lesions range
8from epithelial and lymphocytic apoptosis 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 magni cation reveals atrophy and mucin depletion of the
epithelium. A mild acute in4ammatory in ltrate 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 a ect 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%
9of patients with this condition present with repeated bleeding episodes and iron de ciency anemia, typically after the
fourth decade of life. The lesions can be identi ed 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
10then subsequently re ll. The GI lesions are similar; thus, patients often present with bleeding or anemia.
Histologically, the lesions in both the skin and the GI tract are cavernous hemangiomas. Polypoid lesions include large,
11dilated vascular spaces in the submucosa. Conservative excision is the treatment of choice.
Kaposi’s Sarcoma
Kaposi’s sarcoma is a relatively common finding in the GI tract of patients with HIV infection with severe immunologic
12impairment. Among patients with established skin or lymph node disease, 50% have GI lesions; however, a majority
13of these (80%) are clinically silent. The newer, highly active antiretroviral therapies have made GI lesions less
14frequent. 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 a ected by systemic in4ammatory vasculitides. Solitary GI
15tract involvement may occur, but only rarely. Classi cation is based on the size of the involved blood vessels, the
16anatomic site, and the histologic characteristics of the lesions and the clinical manifestations of the patients.
Vasculitides may cause local or di use pathologic changes such as nonspeci c 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 in4ammation of the inner half of the media, centered on the internal elastic membrane. Intestinal
17involvement is unusual, but some patients may present with intestinal perforation. Takayasu’s arteritis occurs rarely
18in the GI tract. In contrast to giant cell arteritis, this disorder a ects 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 in4ammation of small and medium-sized
19arteries, often in a segmental manner. Acute abdominal syndromes may be present in 30% of patients. 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 in4ammatory in ltrate within the vessel wall, and a marked in ltrate of
neutrophils, eosinophils, and mononuclear cells. Commonly, brinoid 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 in ltrate 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 in4ammatory vascular disorder that typically a ects the lung and kidney, and
involves small to medium-sized blood vessels. A ected patients usually have a positive antineutrophil cytoplasmic
20antibody (c-ANCA). Rare presentations include abdominal pain, which results from GI involvement. Granulomatous
21inflammation in these cases can be confused with Crohn’s disease.
CHURG-STRAUSS SYNDROME
This syndrome is characterized by the presence of small vessel vasculitis, extravascular granulomas, asthma, and
22eosinophilia. GI manifestations occur in at least 30% of patients, but are inaugural in only 16%. Typical GI
23symptoms include abdominal pain, diarrhea, and bleeding. Ulceration and frank perforation may occur. These
patients also have a positive c-ANCA. Granulomatous in4ammation 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 in4ammatory
in ltrate, 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
24been reported.
BEHÇET’S DISEASE
This is a form of chronic relapsing vasculitis, characterized by aphthous ulceration of the mouth, in4ammatory 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 in4ammatory in ltrate of medium-to small-sized arteries and veins is typically present.
25Occasionally, brinoid necrosis is also noted. 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 a ected.
Segmental brinoid 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
26may occur in the kidney and lung. However, GI involvement may occur in some cases.
HENOCH-SCHÖNLEIN PURPURA
This is a small vessel vasculitis that primarily a ects 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
27 28bleeding is present in 33%. Endoscopic and histologic duodenitis have been described.




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
29infection with the hepatitis C virus. GI involvement often includes the liver and spleen. The intestinal tract is
30involved less commonly.
DEGOS’ DISEASE
Malignant atrophic papulosis (Degos’ disease) is a rare vascular disorder characterized by distinctive skin lesions
31associated with multiple GI infarctions. Skin lesions typically consist of red papules that become umbilicated in the
32center. 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 di use or localized pain; eventually,
33 34intestinal infarction and perforation, with peritonitis, occur. , The condition is often fatal. Histologically, the basic
pathologic process is endovasculitis, characterized by endothelial cell swelling and proliferation, sometimes with
brinoid necrosis within the intima of the blood vessel. The intima is the primary site of involvement. Typically, there
is an absence of signi cant in4ammation and necrosis in the media and adventitia. Organized thrombi are often
35present in the vessel lumen. Necrosis of the bowel wall is common.
DIFFUSE HEMORRHAGIC GASTROENTEROPATHY
This is an unusual disorder characterized by di use 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
36fibrin thrombi, are always present. 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 in4ammatory
veno37occlusive disease, intramural mesenteric venulitis, and idiopathic colonic phlebitis. All of these disorders are
characterized by the presence of a lymphocyte-rich phlebitis with thrombotic obstruction of the veins (Fig. 6-4). At
38later stages of disease, myointimal occlusive proliferation, without the in4ammation, is typically seen.
Granulomatous and necrotizing in4ammation 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 in4ammatory
in ltrate 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 in4ammatory in ltrate, 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
39squamous epithelium, 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
40the dystrophic form and in 33% of patients with the junctional or simplex form. Stricture and esophageal webs
occur most frequently in the dystrophic form. However, they can also be seen rarely in the junctional or simplex
41form. 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 a ects middle-aged and older individuals. The bullae are super cial and
4accid. 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 in4ammatory in ltrate 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
42propria. Standard biopsy forceps may provide only super cial biopsies that are inadequate for diagnosis. Direct
43immuno4uorescence for immunoglobulins is positive in the epidermal intercellular spaces. The incidence of
44 45esophageal involvement is unclear. Some studies report endoscopic lesions in up to 80% of patients. , In addition,
46immunofluorescence performed on esophageal mucosa is usually positive in all patients with active disease.
Bullous Pemphigoid
Bullous pemphigoid is a subepidermal bullous disorder characterized by large, tense blisters on the skin. Mucosal
47involvement of the GI tract is much less common than in pemphigus vulgaris, although one report described
48esophageal blisters in 4% of patients with typical bullous pemphigoid. 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
48occasionally in the stomach, similar to those found in the skin, have been described. A single case of bullae in the
49colon has also been reported.
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
50esophagus and, rarely, other regions of the GI tract may be involved. Included in this group of disorders is the
51Stevens-Johnson syndrome (macular trunk lesions with mucosal involvement). 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, super cial
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
52atrophy on small bowel biopsy. However, most patients are asymptomatic. Of patients with dermatitis
53herpetiformis, 90% are positive for endomysial autoantibodies (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
54the GI symptoms can be controlled by a gluten-free diet.
DERMATOGENIC ENTEROPATHY
Many GI symptoms and histologic ndings have been described in patients with active psoriasis and eczema.
Steatorrhea and malabsorption are not uncommon, and the terms dermatogenic enteropathy and psoriatic enteropathy



55 56have been applied to these syndromes. , 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
57antibodies to gliadin (suggestive of latent celiac sprue). In addition, the colon may show increased lamina propria
cellularity, active in4ammation, and occasional gland atrophy in mucosal biopsies of patients with psoriasis without
58bowel symptoms.
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
4exural 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 di use 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
59suggests that it is caused by the production of transforming growth factor-α by tumor cells.
Tylosis
Focal nonepidermolytic palmoplantar keratoderma (tylosis) is a rare autosomal dominant inherited defect of
keratinization. It is strongly associated with the development of squamous cell carcinoma of the esophagus, with tumors
60appearing in 95% of patients. The skin lesion is characterized by thickening of the stratum corneum of the palms
61 62and soles. Molecular studies have mapped the defective gene to a small region on chromosome 17q25. , The same
region has been implicated in the development of sporadic squamous cell carcinoma and Barrett’s
esophagusassociated adenocarcinoma.
Miscellaneous Disorders
63Several other nonspeci c skin diseases are associated with GI neoplasms. These include generalized dermal
64pigmentation, migratory thrombophlebitis, and seborrheic keratosis (Leser-Trélat sign).
Endocrine Disorders
Alterations in the secretion of endocrine hormones in endocrine disorders may have a variety of GI e ects. 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 signi cant 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 insu( ciency) may cause common GI disturbances, including
65anorexia, nausea, vomiting, and diarrhea. Pheochromocytomas are characterized by hypertension due to high
catecholamine levels. Intestinal pseudo-obstruction, megacolon, and even bowel ischemia have also been described
66and are thought to be secondary to the vasoconstrictive action of excess catecholamine levels.
HYPOTHALAMUS AND PITUITARY
The hypothalamus and pituitary function as a unit. Disorders of either one infrequently a ect the GI tract.
Hypopituitarism a ects 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
67system and all organs, including the GI tract. It has been shown to increase epithelial cell proliferation in the colon,
68and an increased prevalence of colonic adenomas and colonic carcinoma has been noted. A less well-established
69increased risk of gastric carcinoma has also been suggested.
PANCREAS
Diseases of the exocrine and endocrine pancreas commonly a ect the GI tract. These include pancreatic exocrine
insu( ciency, diabetes, and hormonal e ects of functional pancreatic endocrine neoplasms. Pancreatic exocrine
insufficiency typically gives rise to steatorrhea and malabsorption and is discussed further in Chapter 34.
70Diabetes can involve signi cant GI symptoms. These result from decreased motility secondary to autonomic
nervous system dysfunction. Patients have symptoms such as abdominal pain, bloating, early satiety, nausea, and
71vomiting. Abdominal bloating appears to correlate best with decreased gastric emptying. 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
72increased risk for Candida infection of the esophagus. Histologic features are nonspeci c. Neuropathic ndings with
73 74silver stains have been described, as have PAS-positive vascular deposits in the vessels of the submucosa.
Excess hormonal production from the pancreatic islets of Langerhans can be a result of di use 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
75lesions. All GI manifestations reflect altered digestive function and motility.
PARATHYROID
Both hyperparathyroidism and hypoparathyroidism can cause GI symptoms. GI symptoms are common in
76hyperparathyroidism; they occur in half of patients and may be the presenting symptom in 15% of cases. These
patients typically have abdominal pain, nausea, vomiting, and constipation. Many of these symptoms are thought to
77be due to hypercalcemia, which results in altered neuronal transmission and neuromuscular excitability.
Hypoparathyroidism can be associated with malabsorption and steatorrhea. The small intestinal mucosa is typically
78histologically normal, but rare associations with celiac sprue have been reported.
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
79diarrhea, and steatorrhea. 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,
79and megacolon. 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
80described.







Thyroid neoplasms may also produce GI e ects. Medullary carcinoma of the thyroid is a tumor of the
calcitoninproducing endocrine C cells of the thyroid. Patients may have prominent “explosive” watery diarrhea as the result of
81 82ectopic hormone production. Papillary carcinoma of the thyroid also can be associated with Gardner’s syndrome.
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
83manifestations are caused by the products of endocrine proliferations. 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,
84or both may be associated with MEN IIb.
Hematologic Disorders
HEMORRHAGIC DISORDERS
Patients with bleeding disorders may develop spontaneous hemorrhage in any part of the GI tract. Ten to 25% of
85 86patients with hemophilia su er from GI hemorrhage. Von Willebrand’s disease, heparin or warfarin overdose,
vitamin K de ciencies, platelet de ciency, 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
87an intramural hematoma. More severe lesions can cause luminal narrowing, rigidity with obstruction, and, rarely,
85intussusception.
THROMBOTIC DISORDERS
88 89 90Sickle cell anemia, polycythemia rubra vera, and other thrombotic disorders can produce thrombosis, leading
to infarction and hemorrhage of the intestines. Sickle cell anemia causes sickling of red blood cells and hyperviscosity
88of the blood and typically produces arterial/capillary obstruction. It involves the watershed areas of the distal
transverse colon and splenic 4exure, 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 nding of venous
thrombi in the mesenteric and mesocolic tissues not in the eld of infarction that occur in conjunction with
appropriate clinical history.
MEGALOBLASTIC ANEMIA
12Megaloblastic anemias are associated with de ciencies of folic acid and vitamin B . 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-tocytoplasm ratio3 is decreased. The overall numbers of mitotic gures are also reduced. In addition, PAS-negative,
91Alcian blue-negative cytoplasmic vacuoles have been described in duodenal enterocytes. 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).
92Autopsy studies have revealed GI involvement in 50% of patients with leukemia. In secondary involvement of the
GI tract by either leukemia or lymphoma, tumor in ltrates are often multifocal and may be present anywhere from
93the esophagus to the rectum. These can cause aphthous-type ulcers (typical of leukemic infiltrations) or can result in
94polypoid, masslike, or large ulcers (typical of lymphomatous involvement). The larger mass lesions can occasionally
95cause obstruction or intussusception. 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
96cytogenetic analysis because many leukemias and lymphomas include diagnostic and clinically important changes.
Primary lymphomas of the GI tract are often solitary lesions, although di use forms do occur (typically in the small
bowel).
Secondary e ects of tumor overgrowth, or of chemotherapy, resulting in decreased numbers of platelets and
in4ammatory cells can lead to hemorrhagic lesions of the GI tract and opportunistic infections. In addition,
neutropenic colitis, which is a necrotizing in4ammatory disorder of the colon that occurs in neutropenic patients, can
97occur with chemotherapy and, rarely, as a complication of acute leukemia. 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
98of the epithelial cells, followed by crypt and gland loss and, ultimately, mucosal erosion and ulceration.
Metabolic Disorders
ACRODERMATITIS ENTEROPATHICA
This systemic disorder occurs secondary to zinc de ciency, 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
99uptake protein (hZIP4). It typically presents after infancy and weaning (although rare cases have been described in
100adulthood ). 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
101 102microscopy. Acrodermatitis may also be due to zinc de ciency secondary to Crohn’s disease and
103malnutrition.
PLUMMER-VINSON SYNDROME (PATERSON-BROWN KELLY SYNDROME)
























104This unusual syndrome has shown a recent decrease in incidence. It is characterized by iron de ciency (its
105presumed cause), dysphagia, and esophageal webs. Dermatologic ndings 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 speci c GI symptoms or lesions. Exceptions are
brown bowel syndrome, thought to be due to a de ciency of vitamin E (discussed later), and pellagra associated with
niacin de ciency. Multiple vitamin de ciencies are often noted in malabsorptive disorders. Vitamins, macronutrients,
and minerals are thought to have a protective e ect with respect to neoplasia of the GI tract, especially for
106 107 108esophageal , and gastric malignancies. De ciency in vitamin K or anticoagulation therapy leads to a
109decrease in coagulation factors and can result in hemorrhagic lesions throughout the body.
In the GI tract, these range from focal petechial hemorrhages to frank exsanguination. No speci c histologic features
are associated with these lesions. Similarly, vitamin C de ciency (scurvy) can lead to hemorrhage and delayed wound
12healing. De ciencies of folic acid and vitamin B are associated with megaloblastic anemia and megaloblastic
110changes in the epithelial cells of the stomach and small intestine. Also of interest, Olestra (a nonabsorbed fat
111replacement) may decrease the absorption of fat-soluble vitamins.
Pellagra
Pellagra is a vitamin de ciency that has major GI e ects. It is due to a de ciency of niacin, either dietary (de ciency
found in developing countries, alcoholics, and the elderly) or secondary to impaired absorption (such as with Crohn’s
112 113disease or amyloidosis ). It is characterized clinically by diarrhea, dermatitis, and dementia. Diarrhea is often
114bloody. However, patients can have steatorrhea. The vitamin de ciency interferes with the normal renewal of
epithelial tissue, hence the e ects on the skin and GI tract. Endoscopically, approximately half of patients have
lesions. However, all have microscopic in4ammation. Endoscopic lesions range from redness and granularity to focal
ulceration and more extensive con4uent lesions. Microscopically, the in4ammatory in ltrate is nonspeci c. In the
115esophagus, mild to severe esophagitis is seen. The small bowel may be normal or may show mild villous blunting
116and increased in4ammatory cells in the lamina propria. In the large bowel, a mild to moderate in4ammatory
in ltrate with features of colitis cystica super cialis (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
117disturbance in gait and balance and fatigue. On peripheral smear, acanthocytes are usually prominent (in 50% of
red blood cells). Laboratory ndings 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
118required for the secretion of plasma lipoproteins containing apolipoprotein B. Normal intraluminal digestion of
lipids occurs, along with transport of triglycerides and monoglycerides and their reesteri cation 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 ne 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 identi ed 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
119lipid tra( cking. 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
t o lack of apoprotein A) and high levels of triglycerides. Endoscopically, the lesions are described as tiny yellow
120nodules or orange-brown spots. Microscopic examination reveals clusters of foamy histiocytes in the lamina propria
(Fig. 6-7). Electron microscopic ndings include intracytoplasmic vacuoles unbounded by membranes; these are often
121confluent in appearance (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
122central or peripheral nervous system e ects. In general, except for Fabry’s disease, these diseases do not have
123 124signi cant GI e ects. Case reports of malabsorption in GM1 gangliosidosis, diarrhea in Niemann-Pick disease,
125and diarrhea and vomiting in Wolman’s disease have been described. The importance of these diseases is that
depositions can be identi ed 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
126-128with histochemical stains and subsequent electron microscopic examination. This technique has largely been
supplanted by speci c enzyme content analysis of circulating lymphocytes or biopsy material. Di erentiation 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 de ciency 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
129and lenticular opacity, cardiovascular disease, stroke, and renal failure. GI symptoms are seen in 62% of male and
130 131 13229% of female heterozygotes. Features include vascular ectasia, delayed gastric emptying, diarrhea, and,
133rarely, ischemic bowel disease with perforation. Histologically, glycolipid deposition is identi ed 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 bers, and endothelial
130cells.
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 di erential
diagnosis of neuronal ceroid lipofuscinosis, include melanosis, pseudomelanosis, brown bowel syndrome,
hemosiderosis, and barium granuloma. Nonpigmented lesions are in the di erential 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
134background. The white lesions represent normal or hyperplastic lymphoid aggregates that do not contain pigment.
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
135(“melanized ceroid”) and is typically associated with anthraquinone laxative use. However, a number of studies
135 136have shown an association with increased apoptosis of epithelial cells , (caused by laxatives as well as chronic
137 138 139colitis, chronic granulomatous disease, and bamboo leaf extract ) and suggest that melanosis is a nonspeci c
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, nely granular material in the
lamina propria.
Pseudomelanosis.
This is a rare benign condition characterized by the presence of discrete, 4at, small, brown-black spots typically in
140duodenal mucosa (speckled duodenum) but also reported in gastric mucosa. It occurs in any age group and
141appears to be associated with upper GI bleeding, chronic renal failure, hypertension, or diabetes mellitus. 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 sul de, 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 de ciency. 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 de ciency 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
142smooth muscle also is usually noted. The distribution of the pigment in conjunction with an appropriate clinical
history often helps in di erentiation of this lesion from the others described earlier. The pigment, which stains positive
for PAS, acid-fast, and fat stains on un xed tissues, also shows the typical bright yellow auto4uorescence pattern of
lipofuscin. Electron microscopic examination usually reveals mitochondrial damage as well as pigment concentrated
143in the perinuclear Golgi region. Clinically, the pigment does not have any direct e ect on the bowel, although
144 145 146defects in contractility, intussusception, and toxic megacolon have been reported.
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
147 148epithelial cells of the gut. , Some minor amounts of pigment can also be seen in macrophages. The pigment
appears as nely 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, overin4ation of the rectal balloon, or intrinsic in4ammatory
149disease. Endoscopically, it may present as a polypoid lesion and may mimic an adenoma or carcinoma.
Histologically, one sees a granulomatous reaction surrounding gray, nely 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.
150Radiographs of the paraffin block can help reveal the presence of radiopaque material.
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 un xed tissue (Fig. 6-9A). Immunohistochemical stains for α -antitrypsin and monocyte chemotactic and1
151activating factor are also typically positive, whereas cytokeratin and mucin stains are negative. The lesions are
152 151typically associated with chronic inflammatory states, but can be seen with malignancies.








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
super cial 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 in ltration of the lamina propria with macrophages. A marked acute in4ammatory
in ltrate is also seen. The macrophages contain small blue inclusions (Michaelis-Gutmann bodies). G, Granular cell
tumor. Esophageal biopsy with in ltration of large granular cells in the lamina propria below the squamous
epithelium. H, Signet ring cell adenocarcinoma. Gastric biopsy with in ltration of single cells in the lamina propria.
Signet ring cells can be identi ed 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
153rectum (up to 40% of all rectal biopsies contain muciphages) and are also commonly found in the lamina propria
154and in the stalk of adenomatous polyps. Endoscopically, muciphages can present as polyps or nodules.
Histologically, foamy histiocytes containing coarse cytoplasmic vacuoles are present in the super cial lamina propria
155(see Fig. 6-9B). Mild brosis and architectural distortion may occur in cases associated with a previous injury.
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 in4ux of air into the mucosa secondary to endoscopy-related trauma. It
156is a benign, transient lesion that is characterized histologically by clear open spaces in the lamina propria or











157submucosa, representing trapped gas, without an epithelial or endothelial cell lining (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
158 159primarily found in the small bowel; however, it can involve the stomach, esophagus, and colon as well.
Histologically, one sees characteristic abundant, pink-colored, foamy macrophages lling 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
160disintegration. These bacteria are also found within IgA-positive plasma cells. With the use of 4uorescence in situ
hybridization for ribosomal RNA, the active organism appears to be most prevalent near the tips of intestinal villi in
161the lamina propria.
Mycobacterium avium complex infection
162This is a common pathogen in AIDS that may also be seen in other immunocompromised patients. It typically
163a ects the small bowel and colon. Endoscopically, the mucosa can appear normal or coarsely granular.
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 di use brillary 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 a ects patients with an underlying macrophage phagolysosome defect (not
164 165typically seen in patients with AIDS). It is usually caused by Escherichia coli or Klebsiella species. 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 in ltration 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
166examination reveals degenerated bacilli in phagolysosomes, similar to those seen in Whipple’s disease.
Granular cell tumor.
These tumors are believed to be of neurogenic origin and are typically found in the esophagus, but they can occur
167 168 169anywhere in the GI tract. Rare cases have been described in the small bowel and colon. , They are mostly
benign, but malignant tumors have been described as well. The tumors typically present as nodules in patients with
nonspeci c 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 lled 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 in ltration of malig-nant cells with clear cytoplasm
and an eccentrically placed hyperchromatic nucleus (see Fig. 6-9H). It is di erentiated from other lesions by the
170presence of highly atypical nuclear features and by positivity with mucin and cytokeratin stains.
Clear cell carcinoid tumor.
171A rare case has been reported of a gastric carcinoid composed entirely of clear cells with foamy cytoplasm.
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
in ltrate composed of Langerhans’ cells that have irregular, elongated nuclei and prominent nuclear grooves and
folds. The cytoplasm of the tumor cells is abundant and nely granular. These tumors are usually associated with a












prominent eosinophilic in ltrate as well. Similar to mucosa-associated lymphoid tissue (MALT) lymphoma, invasion
172and destruction of the epithelium are common. Immunohistochemical stains for S100 and CD1a are intensely
173positive in tumor cells. Electron microscopic examination reveals Birbeck granules in the cytoplasm of tumor cells.
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 brillary appearance under electron microscopy. All amyloid brils are
protein complexes with a common tertiary molecular structure, referred to as a twisted β-pleated sheet pattern.
Classification
Historically, amyloidosis has been classi ed according to its clinical presentation (localized versus di use) or its
underlying cause (primary, secondary, hereditary, or endocrine related); more recently, the classi cation is
determined on the basis of the biochemical composition of the amyloid brils (Table 6-6). The most common types
that involve the GI tract are AA, AL, and A β 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 A β ( β protein precursor), AapoA1
(apolipoprotein A1), ALys (lysozyme), ACys (cystatin C), and AGel (gelsolin). Finally, a novel and common amyloid
174 175protein, called portal amyloid, has also been described. , 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
176-178100%. In addition, autopsy studies in the elderly (those older than 80 years of age) have identi ed GI amyloid
174 175deposits (portal amyloid) in 35% to 57% 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
179 180seen without associated symptoms. However, a variety of GI symptoms, such as bleeding, pseudo-obstruction,
181 182decreased motility, and, rarely, perforation, 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 a ected 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 in4ammatory bowel disease
183grossly.
184 185Amyloid in ltration within nerve and muscle bers can cause motility disorders. Malabsorption may result
from stasis and bacterial overgrowth. Finally, amyloidosis can occasionally present as a solitary mass lesion or polyp
186that mimics a malignant tumor. Endoscopically, the mucosa may appear normal, or show a ne granular
187 188appearance with erosions, friability, and thickening of the valvulae conniventes. ,
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 speci c), toluidine blue, crystal violet, 4uorochrome, and thio4avine 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. A β 2M amyloid is found mainly in the
189muscularis propria and in small arterioles and venules, forming subendothelial nodular lesions. Portal amyloid is
usually limited to mesenteric veins as small dotlike or comma-like deposits in close proximity to elastic bers. AL and
AA forms also can be distinguished by pretreatment with potassium permanganate. This pretreatment abolishes the
190Congo red a( nity of the AA brils but not that of the AL brils. Immunohistochemical stains with antibodies to
amyloid A, immunoglobulins lambda and kappa light chain amyloid bril proteins, β2-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
orangered appearance.
Amyloidosis should be di erentiated 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 di erential diagnosis in that
neither arteriosclerosis nor collagen stains with Congo red. One study suggests that Congo red stain may not be
191sensitive enough in patients with early amyloidosis in minute amounts.
GI biopsy is a procedure commonly used to diagnosis amyloidosis. Rectal biopsies have a sensitivity of 85%,
176compared with a sensitivity of 54% for fat biopsies. 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
187 192the diagnosis of amyloidosis. ,
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 in4ammation involving the peritoneal, synovial, and pleural membranes. This disease typically begins in
193childhood or adolescence and recurs at irregular intervals throughout life. GI involvement consists of acute
in4ammation 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 in4ammation. 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




194ulcer disease has also been described in patients with chronic obstructive pulmonary disease. This is thought to be
due to hypercapnia, which stimulates gas-tric acid secretion. Pneumonia, bronchitis, asthma, and idiopathic
195pulmonary brosis are all associated with gastroesophageal re4ux disease (GERD). 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 rst
196trimester. Some studies suggest that this is secondary to human chorionic gonadotropin or estrogen secretion,
197which leads to abnormalities in gastric myoelectrical activity and contractility. Secondary esophagitis may develop
as a result of severe vomiting. Re4ux, 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 ssures, and rectal wall prolapse are all complications that can occur secondary to vaginal
198delivery. Population studies suggest that maternal in4ammatory bowel disease is associated with increased odds of
preterm delivery, low birthweight, smallness for gestational age (Crohn’s disease), and congenital malformations
199-201(ulcerative colitis). Pregnancy, however, does not seem to in4uence the course of in4ammatory bowel
202disease.
Oral contraceptive pills and exogenous estrogens are associated with nausea and vomiting. They also are associated
203with thrombosis and, thus, an increased risk for is-chemia of the small bowel and colon.
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
204rectosigmoid colon, appendix, and small bowel. The GI tract is involved in 12% to 37% of cases. Intestinal
endometriosis is usually asymptomatic. However, when symptomatic, it typically presents with obstructive symptoms
204as a result of adhesions. Complete obstruction of the bowel lumen occurs in less than 1% of cases. 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 ndings should be present for a diagnosis
of endometriosis to be established with certainty. In addition, brosis and prominent smooth muscle proliferation may
surround foci of endometriosis. Fresh hemorrhage may occur. Immunohistochemical staining for estrogen receptors is
205usually positive in both the glands and stromal cells.











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 identi ed in the muscularis propria of the colon. Marked
muscular hypertrophy is also seen. B, High-power view of in ltrating, bland, well-formed glands with characteristic
stroma.
Differential Diagnosis
Most important, the di erential diagnosis includes invasive adenocarcinoma. This may be extremely problematic to
di erentiate on ne-needle aspiration specimens. On ne-needle aspiration, the glandular epithelium is preferentially
aspirated and may show nuclear atypia, mimicking an adenocarcinoma. The nding of hemorrhage,
hemosiderinladen macrophages, and stromal cells helps establish a correct diagnosis. On histologic section, di erentiation from
adenocarcinoma depends on the nding of characteristic stroma and hemosiderin-laden macrophages, in addition to
206glandular epithelium. Endometriosis may occasionally be present in mucosal biopsies, and can resemble colitis
cystica profunda. If smooth muscle proliferation is prominent, di erentiation from a leiomyoma can be achieved by
deeper sectioning of the tissue to look for glandular epithelium. In di( cult cases, colonic glands are positive for
207carcinoembryonic antigen, whereas endometrial glands are negative for this peptide.
Rheumatologic Disorders
Connective tissue disorders may a ect the GI tract in a variety of ways. They can cause hypomotility secondary to
muscle in4ammation 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-in4ammatory drugs that can have major GI e ects. 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 in4ammation,






brosis, upregulated collagen production, and vasculitis. GI involvement is common and is typically characterized by
hypomotility. Scleroderma can be part of the CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal
involvement, sclerodactyly, and telangiectases). Scleroderma most commonly involves the esophagus; manometric
208abnormalities are seen in up to 90% of patients. However, abnormalities of the entire GI tract can be noted as well.
209Colonic dysfunction has been reported in up to 20% of patients.
In the esophagus, lower esophageal sphincter pressure is reduced and gastric emptying of the stomach is
210delayed. Both of these factors increase the incidence of GERD, erosive esophagitis, and stricture formation. The
211small and large intestine may also be involved. Typical features include scattered wide-mouthed diverticula,
212 213pseudo-obstruction, and intestinal perforation.
Pathologically, scleroderma is characterized by smooth muscle atrophy and replacement by collagenized brous
tissue (Fig. 6-12). The lesion most commonly a ects 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
214loss of muscle tissue. Fibrosis may also involve the submucosa to a variable degree. Muscular atrophy results in
atony and dilation and produces wide-mouthed pseudodiverticula that can be identi ed radiographically. In addition,
215the small vessels of the bowel may show a proliferative endarteritis and mucinous changes of the media. 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 in4ammatory myopathies that primarily involve skeletal muscle. However, skin involvement occurs also in
216dermatomyositis. These disorders may be associated with motor dysfunction of the GI tract. The striated muscle of
217the cervical esophagus is most frequently a ected when delayed esophageal emptying is common. Histologic
changes include chronic in4ammation, edema, and muscle atrophy. Features can mimic scleroderma, but brosis is
not prominent in these disorders.
SYSTEMIC LUPUS ERYTHEMATOSUS
This systemic multisystem autoimmune disease a ects the GI tract in approximately 20% of patients. The
218development of vasculitis can lead to ischemia and perforation in the GI tract. It also has been associated with
219 220malabsorption, protein-losing enteropathy, and amyloidosis.
MIXED CONNECTIVE TISSUE DISEASE
This is a disease with features of scleroderma, systemic lupus erythematosus, and polymyositis. GI abnormalities are
221 222common. GI features are similar to those of scleroderma, with motility dysfunction and vasculitis being the
most common complications.





RHEUMATOID ARTHRITIS
223GI involvement occurs in 25% of patients with long-standing rheumatoid arthritis. Notably, this occurs in the form
of a necrotizing vasculitis that a ects small to medium-sized arteries, similar to polyarteritis nodosa. The condition is
224usually asymptomatic. However, hemorrhage or even perforation may occur. 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 in4ammatory disorders associated with arthritis (spondyloarthropathy). It includes psoriatic
arthritis, Reiter’s syndrome, ankylosing spondylitis, and arthritis associated with in4ammatory bowel disease. Most
225a ected individuals (70%) have chronic active colitis. Interestingly, clinical remission is always associated with
226normal gut histology.
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 ssuring and ulceration of the pharynx and esophagus.
Esophageal webs have been noted in up to 10% of patients. Atrophic gastritis, atrophy, and chronic in4ammation of
227the esophageal glands have been noted as well. 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
228defect in collagen synthesis or structure. These defects result in thinning of the bowel wall and vascular structures ;
229as a result, these patients are at increased risk for GI hemorrhage and perforation. Patients with Ehlers-Danlos
syndrome also have diaphragmatic hernias and GI diverticula. Upper GI tract hemorrhage occurs in 13% of patients
230with pseudoxanthoma elasticum. In these cases, submucosal, yellowish, nodular lesions, similar to xanthoma-like
231skin lesions, may be noted. Histologic examination typically reveals super cial 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
232hemorrhage secondary to hypotension, stress, and multiorgan failure.
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 di( cult to
233 234di erentiate histologically from an acute colitis. Presentations mimicking intestinal intussusception and
235ulcerative colitis have also been described. During HUS, an associated colitis is seen in most patients, and there is a
2361% to 2% incidence of colonic perforation. Marked mucosal and submucosal edema and hemorrhage of the colon
can occur, but in4ammation is not usually signi cant (Fig. 6-13). Microvascular angiopathy with endothelial cell
237damage and overt thrombosis may also be noted.


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
238GI symptoms that are common among patients with uremia include gastroesophageal re4ux, 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
239signi cantly di erent from that in the general population. 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
240ulceration and occur in 60% of patients who die from uremia. 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 identi ed in patients with chronic renal failure or
241uremia, and in patients after renal transplantation. Microscopically, calcinosis appears as small, white, 4at
plaques, or nodules, that contain amorphous basophilic deposits within the subepithelial compartment of the
superficial lamina propria.
Long-Term Hemodialysis
242 243Acute 4uid loss during the process of dialysis can lead to hypotension and nonocclusive mesenteric ischemia. ,
Peritonitis secondary to bacterial infection and acute bowel obstruction secondary to incarcerated hernia into the
244catheter tract can also develop in patients on peritoneal dialysis. Patients on dialysis are also susceptible to
245 246Salmonella species enteritis and dialysis-associated β2-microglobulin amyloidosis.
Kidney Transplantation
247GI complications are an important cause of morbidity and mortality in kidney transplant recipients. 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
248increased risk for exacerbation of diverticulitis, for reasons unknown.
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
249increased risk for colonic neoplasia at, or near, the site of anastomosis. 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
250adenocarcinomas. Endoscopic surveillance biopsies are recommended to screen for epithelial dysplasia. In addition
249 251to dysplasia, one may see inflammatory polyps, edema, crypt branching, and Paneth cell metaplasia. ,








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 rst year) include
252shortening of villi with loss of microvilli and decreased numbers of goblet cells. Late changes (after 4 years) consist
253of marked 4attening of the epithelium with epithelial strati cation, similar to urothelium. Dysplasia has not been
described.
Antire4uxing 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
254details). It is characterized by recurrent infection in infants and children. A ected children su er from chronic
infections, often with abscess formation, in many organs. The GI system is involved in approximately 25% of
255 12patients. Patients may present with vitamin B de ciency 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 nding 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
255 256 257 258gastric outlet obstruction, , perineal abscess, di use colitis, or even esophageal narrowing.
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 100 μm 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 in4ammatory 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 di erential diagnosis includes other granulomatous disorders, such as mycobacterial and fungal infections,
sarcoidosis, and in4ammatory 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 super cial lamina propria and
not usually present in the small intestine.
SARCOIDOSIS
259Sarcoidosis rarely involves the GI tract. The stomach is the most common site of sarcoidosis, 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 rst 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
260serum angiotensin-converting enzyme activity. 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)
261is seen. 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
262a linitis plastica-like appearance of the stomach. 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 di erential 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 puri ed protein derivative skin test may also help to
di erentiate 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
263symptoms when a careful history is obtained. Abnormalities include diarrhea, peptic ulcer pain, GI bleeding,
264nondyspeptic abdominal pain, urgency, and fecal incontinence. 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 brosis, and portal hypertension can
263cause GI hemorrhage.
265The stomach and duodenum are most commonly involved. 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
in ltrate is usually seen throughout the GI tract but predominantly in the mucosa and submucosa (Fig 6-16A). It is
often associated with other in4ammatory cells such as eosinophils (see Fig. 6-16B). The in ltrate 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
266cell numbers do not correlate with elevated skin mast cell counts in this condition.




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 eld (normal being 13 to 15 ± 3 per high-power eld) indicates a pathologically increased mast cell
267-270number.
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
269 270metastasize to the bowel. , 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 di use linitis plastica variant of gastric
271carcinoma. Metastatic breast carcinoma, particularly the lobular type, can mimic primary signet ring cell
272carcinoma and may even have a linitis plastica appearance (Fig. 6-17). Immunohistochemical stains for estrogen
and progesterone receptors, gross cystic 4uid protein, and cytokeratin 5/6 are often positive in breast carcinoma,
273whereas cytokeratin 20, DAS-1, MUC5AC, and MUC6 are often positive in gastric carcinoma. Epithelial
malignancies that metastasize to the GI tract are typically di erentiated 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 nding 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
274often cytokeratin 7 positive and cytokeratin 20 variable.

FIGURE 6-17 Metastatic lobular carcinoma of the stomach. Intermediate-power view of a gastric biopsy shows an
in ltrate of numerous small cells in the lamina propria. There is the suggestion of single-cell ling 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
275lung. The syndrome is caused by the release of serotonin, which causes hypermotility of the gut. Oat cell
276carcinoma can also lead to gastroparesis secondary to antibody (anti-Hu) production by the tumor. Another
example is Zollinger-Ellison syndrome caused by excessive gastrin production from gastrinomas. These patients often
277present with multiple duodenal ulcers secondary to gastrin-induced acid hypersecretion.
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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
1remains much the same throughout the GI tract, with some minor variations. The
smooth muscle forms a super cial 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. Identi cation of these two
distinct layers is often di cult 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 ( oor. The longitudinal muscles of the rectum continue between the
two anal sphincters and nally 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 bers 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 bers, which eventually
culminate on the intrinsic neural plexuses. The sympathetic bers originate in the
prevertebral ganglia and run along the superior and inferior mesenteric arteries. The
parasympathetic bers 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 identi ed 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 identi ed 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
2 3meshwork (Fig. 7-2). ,



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
welloriented section.
In addition to muscle bers 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
4 5cells of bowel peristalsis. , 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
6-8painstaking ultrastructural studies. Ultrastructurally, these cells show partial basal
lamina, many intermediate laments, darkly staining cytoplasm, abundant rough
endoplasmic reticulum, sublamellar caveolae, oval indented nuclei, and lack of myosin
laments. Many of these features overlap with the features of smooth muscle cells. It has
9been shown that these cells express c-kit, a tyrosine kinase receptor.
Immunohistochemical stains using antibodies against c-kit have been used to visualize
10-12these cells. ICC have an intricate network and form a close liaison between smooth
muscle cells and nerve endings. They are most easily identi ed 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 diBerences in the regional
13distribution within each segment have been described.
$

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
welloriented sections, this morphology is di cult 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 nonspeci c manifestations. The
pathogenesis of many of these conditions is still very poorly understood, and many
disorders lack speci c 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
14 15esophageal sphincter to relax in response to swallowing. , It is an uncommon
5disorder: the overall prevalence has been estimated to be less than 10 cases/10
16population. Its incidence has been fairly static over the past 50 years. It involves both
sexes equally and is primarily a disease of adults, predominantly aBecting 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
17cells, but the inciting events remain unknown. 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
18 19(Allgrove’s, or triple-A, syndrome). , 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 identi ed, 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,
20and the identification of anti-myenteric neuronal antibodies in some patients. 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
21achalasia. It has been speculated that a factor in the serum other than antineuronal
21antibody may be responsible for this phenomenon. Varicella-zoster viral DNA has been
22shown in the myenteric plexus in rare cases by in situ hybridization.
The pathogenesis of this condition is also poorly understood. Progressive in( ammatory
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
23swallowing. 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
24 25decrease in VIP-containing neurons in the distal esophagus. , 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
26 27loss of VIP ganglion cells is synonymous with loss of nitrergic ganglion cells. , Most
earlier studies evaluated specimens at the time of autopsy or esophagectomy; thus the
end stage of the disease was re( ected. Study of esophagomyomectomy specimens lends
some insight into the earlier sequence of events, although very early changes during the
28asympto-matic stages of the disease are largely unknown. As the disease progresses,
however, the in( ammatory in ltrate decreases in intensity as the ganglionic cell loss and
myenteric plexus degeneration become more prominent.
Clinical Features



Younger children (<5 _years29_="" and="" infants="" present="" with="" feeding=""
_aversion2c_="" failure="" to="" _thrive2c_="" _choking2c_="" recurrent=""
_pneumonia2c_="" nocturnal="" _cough2c_="" _aspiration2c_="" or="" nonspeci c=""
regurgitation.="" older="" children="" adults="" _vomiting2c_="" chest="" _pain2c_=""
dysphagia="" for="" solids="" liquids.="" heartburn="" is="" a="" common=""
symptom="" even="" in="" untreated="" patients="" _28_about="" _5025_29_2c_=""
but="" only="" minority="" of="" these="" have="" documented=""
29gastroesophageal="" re( ux=""> Diagnosis is con rmed 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 in( ammatory cells are seen in and
around a brotic 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
14proximal part of the esophagus. A variable amount of chronic lymphocytic in ltrate
admixed with eosinophils, plasma cells, and mast cells is often seen around the myenteric



28nerves and residual ganglion cells (see Fig. 7-4B). Occasionally, lymphocytes may be
seen in ltrating the cytoplasm of ganglion cells (ganglionitis). A majority of chronic
in( ammatory cells are CD3-positive T cells, most of which are CD8-positive (see Fig.
7234C), although the relative percentage of these cells decreases with disease progression. ,
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
calci cation. 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
15vagus nerve and its dorsal motor nucleus have been described. It has been postulated
that these may be caused by a neurotrophic viral infection; however, no speci c virus has
31been identified. The mucosa also shows secondary changes, including diffuse squamous
hyperplasia, increased intraepithelial lymphocytes (lymphocytic esophagitis),
32papillomatosis, basal cell hyperplasia, and nonspeci c lamina propria in( ammation.
Some of these changes mimic re( ux esophagitis, although sustained lower esophageal
33pressure does not allow regurgitation of gastric contents in untreated cases. After
esophagomyotomy, gastroesophageal re( ux develops in up to 50% of patients and can
34 35even lead to Barrett’s esophagus in some cases. ,
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
34 36esophagus , (the risk is estimated to be 33 times higher than in the general
37population).
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
38 39invades the myenteric plexus or that occurs as a paraneoplastic phenomenon. , 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
40 41protozoan Trypanosoma cruzi. , The infection is acquired through the bite of
bloodsucking 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
aBected, 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 signi cance. Most cases are diagnosed at autopsy,
although the condition can be diagnosed clinically with current imaging techniques and
42esophageal motility studies. Some patients are symptomatic, with dysphagia, chest
43pain, vomiting, and weight loss, but many are asymptomatic. 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
44cataracts and Alport-like nephropathy. Squamous cell carcinoma has also been
45described in some cases. Pathologically, the muscularis propria appears markedly
43thickened, particularly toward the lower end (Fig. 7-5). Some cases show mild
lymphocytic in ltration in the myenteric plexus. The majority of cases lack any evidence
of muscle ber degeneration, brosis, ganglion cell abnormalities, or neural plexus
abnormalities. Clinically and pathologically, this disorder needs to be diBerentiated 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 in( ammation, brosis, muscle
degeneration, or myenteric plexus abnormalities.
Stomach
PYLORIC STENOSIS
Infantile and adult forms of this disorder are recognized. Infants present with projectile
46 47vomiting, usually within 2 to 4 weeks after birth. , It occurs in approximately 1 in
1000 live births, has a high familial incidence and a strong male preponderance, and
classically occurs in the rst 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
48 49Denmark). The etiology remains unclear. 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
50 51been implicated as a risk factor; however, the evidence is not conclusive. ,
The pathogenesis of this condition also remains unclear. No evidence of a mechanical
52obstruction has been found, and the pylorus can be easily intubated. 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
53-58synthase. Homozygous transgenic mice carrying inactivating genes for nitric oxide
59synthase develop hypertrophy of the pylorus.
Clinical Features
Infants present with progressive nonbilious vomiting, which gradually assumes a more
characteristic projectile pattern. The hypertrophied pylorus can be palpated as an
olivesized epigastric mass, and gastric peristalsis may be visible. Some patients also have a
congenital diaphragmatic hernia. Idiopathic hypertrophic pyloric stenosis is uncommon
60in adults ; 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 bers are disorganized, with
increased intercellular collagen, sometimes associated with a mild lymphocytic in ltrate.
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
53longitudinal muscle, as shown by c-kit immunostains and ultrastructure. Only the inner
layer of the circular muscle shows somewhat preserved ICC.
Treatment and Follow-Up
Surgical myotomy is the de nitive treatment, and pyloric hypertrophy disappears within
61a few months after the procedure. Pyloric biopsy specimens studied several months
after myotomy reveal restoration of abnormalities of the nerve bers, glial cells, ICC, and
62 63neuronal nitric oxide synthase. Long-term outcome is excellent.
Small and Large Intestine
HIRSCHSPRUNG’S DISEASE
General Comments
Hirschsprung’s disease is a heterogeneous group of disorders characterized by lack of
64 65ganglion cells resulting in bowel obstruction. , 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 ( exure (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
66may fail.
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 :
671). Rare acquired forms, as well as adult cases, have also been described.
Longsegment disease and total bowel aganglionosis show familial aggregation. However,
classic Hirschsprung’s disease usually occurs as a sporadic anomaly. A large number of
associated conditions have been reported, including Down syndrome, cardiovascular
malformations, neuro bromatosis, Waardenburg’s syndrome, Laurence-Moon or
BardetBiedl syndrome, Ondine’s curse (Haddad syndrome), multiple endocrine neoplasia, and
neuroblastoma, many of them belonging to the group of neural crest disorders
65(“neurocristopathies”).
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 diBerent genes that play a role in various stages of
development and migration of the enteric ganglion cells have been
64,65,68-73recognized. Mutations of the RET proto-oncogene, which are the most
frequent, have been identi ed 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
$
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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
74and occasionally life-threatening complication. 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 ve
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 identi cation sometimes di cult.
Their arrangement in clusters and their association with nerves facilitates recognition.
Immuno-staining has been recommended in di cult cases using antibodies for
neuronspeci c enolase, RET oncoprotein, BCL-2, cathepsin D, PGP 9.5, or other neuronal
65 75 76markers, but in practice they are seldom useful. , , In routine clinical practice,
none of the generic neuronal markers oBers a signi cant advantage over thorough
histologic examination of H&E-stained preparations, and they need to be used with
77extreme caution.

$
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 bers in the submucosa, muscularis mucosae, and lamina propria. The presence of
acetylcholinesterase-positive bers in the muscularis mucosae and lamina propria
supports the diagnosis of Hirschsprung’s disease.
Although a full-thickness transmural biopsy specimen oBers 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
65more than 2 cm above the pectinate line is diagnostic of Hirschsprung’s disease.
Although hypertrophy of nerves, by itself, should not be considered su cient 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
78acetylcholinesterase. In classic cases, acetylcholinesterase-positive nerve bers 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 bers are few and di cult 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
79 80change is the result of the absence of ganglion cells and is of little diagnostic use. ,
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 de nitive diagnosis is
65rendered. 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 bers, 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
65this epithelium should be specifically mentioned in the pathology report.
In addition, speci c attention should be given to the presence or absence of mucosal
in( ammation 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
74 81 82colitis (Fig. 7-8). , , Severe cases with transmural necrotizing in( ammation may
progress to perforation.
FIGURE 7-8 A, Mild colitis in a patient with Hirschsprung’s disease showing a mild
increase in lamina propria in( ammatory 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 de nitive anastomosis is performed
65after initial colostomy. Seromuscular biopsy specimens (full-thickness biopsy) need to
be obtained for intraoperative frozen section evaluation to detect ganglion cells in
speci c segments before completion of the anastomosis, and also to con rm the lack of
ganglion cells in the aBected segment. However, frozen sections obtained for evaluation
of ganglion cells are not without problems and should not replace a preoperative suction
83mucosal biopsy before the corrective procedure is attempted. When the frozen section
is obtained, a toluidine blue, Giemsa, or DiB-Quick stain, in addition to routine stains,
may aid in identi cation 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 diBerentiation 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 de ne and
diagnose other enteric dysganglionoses are poorly established and often impractical to
84-87apply. This has resulted in the use of many diBerent 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
88decreased number of ganglion cells per ganglion, and a smaller size of ganglia. 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
88millimeter constitutes hypoganglionosis. These criteria have been established from
15μm-thick frozen sections stained with lactate dehydrogenase and cannot be readily
88applied to paraffin-embedded sections with a different neuronal marker or H&E stain.
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 diBuse condition (ganglioneuromatosis). The
presence of isolated ganglion cells in deep lamina propria, by itself, is not considered
89pathologic. DiBuse 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
90intestinal neuronal dysplasia (IND), and two forms, IND-A and IND-B, are recognized.
IND-A is extremely rare and is characterized by sympathetic aplasia, myenteric
91hyperplasia, and colonic in( ammation. 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
85 92number of large ganglion cells in the neural plexuses. , The diagnostic criteria for
IND-B have changed over time, and the diagnosis currently requires the presence of giant
submucosal ganglia, de ned as more than eight ganglion-cell cross sections per
submucosal ganglion. These giant ganglia should constitute greater than 20% of all
87ganglia, and at least 25 submucosal ganglia should be evaluated. 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
87only in children older than 1 year and younger than 4 years.
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


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followed by degeneration of ganglion cells (hypoganglionosis), enteric plexus, and ICC,
93resulting from a mechanical obstruction caused by a Ladd’s band. Such an adaptive
response and neuronal plasticity have also been shown in animal models of mechanical
94 95bowel obstruction. , Despite several reports of IND-B and hypoganglionosis and
87 96 97many attempts to reach a consensus regarding diagnostic criteria, , , these entities
remain controversial, their clinical signi cance 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 di cult even on conventionally oriented
transmural biopsies. Alterations in speci c subtypes of ganglion cells can be resolved only
3with special staining and electrophysiologic studies. 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
98synthase-producing ganglion cells in cases of IND. 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 de ned 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
99occurs after abdominal surgery, abdominal trauma, or peritonitis. The entire bowel
becomes paralyzed and distended. The diagnosis is made on clinical grounds and
99treatment is supportive. 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
100recently undergone surgery or are ill from other causes. The etiopathogenesis is poorly
understood, although temporary autonomic dysfunction is suspected. Patients
demonstrate bowel dilation, most often con ned to the right colon, which may lead to
transmural ischemia and perforation, most frequently in the cecum. Histopathologic
changes are nonspeci c 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 aBect
101 102various components of the bowel neuromuscular apparatus. , 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-ObstructionTABLE 7-2 Secondary Chronic Intestinal Pseudo-ObstructionA. 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
103these patients. 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
101Both sporadic and familial myopathic forms are recognized. 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 di cult to elicit. Familial visceral
myopathy may also involve other organs (urinary bladder or biliary tract), and it has
104 105been called hollow visceral myopathy. , 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,
106normal esophagus, and normal colon. 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
107cardiac abnormalities have also been described.
Although smooth muscle degeneration is thought to be responsible for bowel
dysmotility, the etiopathogenesis for most of these cases remains obscure. Rare cases with
108 109actin or desmin abnormalities have been described. , In cases of “desmin
myopathy,” systemic skeletal and cardiac muscle involvement is also commonly noted.
Rare cases show a T-cell-rich in( ammatory leiomyositis and are possibly autoimmune in
110nature. A distinctive type of nonfamilial visceral myopathy has been described in
young children from southern, central, and eastern Africa (African visceral
111leiomyopathy). In some cases, absence of c-kit-positive ICC has been thought to be the
112underlying mechanism (see later). 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, in( ammation, ulceration, and ischemia may supervene
101secondary to stasis and extensive dilation.






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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 brous replacement of the smooth muscle.
Degenerative changes are most prominent in the muscularis propria, but they also aBect
113the muscularis mucosae and thus may be identi ed in mucosal biopsy specimens. The
longitudinal layer tends to be more severely involved. However, rarely, only the inner
101 105circular layer is involved. , In these cases, distinction from scleroderma may be
di cult. Muscle degeneration results in brosis, cytoplasmic vacuolation, variation in
muscle ber size, and thinning of the bowel wall (Fig. 7-10A,C). Fibrosis may be subtle
101and may require a trichrome stain to be fully appreciated (see Fig. 7-10B,D). Other
changes include nuclear atypia, increased mitotic activity, and periodic acid-SchiB
114(PAS)-positive intracytoplasmic inclusions. Ultrastructurally, cytoplasmic inclusions
114represent aggregates of degenerated myo brils. However, potential artifactual
changes in the muscle are not uncommonly seen in surgical specimens (Fig. 7-11). Rare
cases with de cient smooth muscle α -actin show an absence of staining with smooth
109 115muscle actin antibodies, particularly in the inner circular muscle layer, , but the
signi cance of this nding has recently been questioned and caution is warranted in
116interpreting this nding in clinical practice (Fig. 7-12). Electron microscopy shows
nonspeci c degenerative changes, which include mitochondrial vacuolation and may be
101 105 111the only diagnostic evidence of myopathy when light microscopy is normal. , , ,





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 brosis (trichrome stain). C, Higher magni cation of the smooth muscle in the
muscularis propria shows degenerative changes. D, Moderate interstitial brosis
(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 ndings associated with myopathic changes (e.g., nuclear
pleomorphism, ber size variation, interstitial brosis, 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
101 118of the bowel, in both sporadic and familial forms. , 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 calci cation. The autosomal dominant variant does
not show extraintestinal manifestations. The X-linked form is associated with a short
119small intestine, malrotation, and pyloric hypertrophy.
The etiopathogenesis of the neurodegenerative changes remains obscure. Pathogenetic
mechanisms that may be involved include altered calcium signaling, mitochondrial
120dysfunction, and free-radical injury. Patients with rare autosomal recessive forms
present with a progressive multisystem neurodegenerative disorder and abnormalities in
121mitochondrial DNA. Many genes have been identi ed 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
122transcription factor SOX10. 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
123 124leukoencephalopathy. , Decreased ganglion cell survival may be a factor in some




125cases, as suggested by decreased BCL2 gene product in the enteric ganglion cells.
Some cases reveal in( ammatory neuronal degeneration, which suggests an autoimmune
126 127or infectious etiology. Neuronal autoantibodies are detected in some patients.
Some of these cases represent a paraneoplastic manifestation, and some remain
128idiopathic.
Pathologic features.
Gross ndings are similar to those of other forms of intestinal pseudo-obstruction and do
not help diBerentiate the various subtypes. Examination of routine sections is often
unrevealing except in cases where neurons are markedly decreased in number, or when
118 129 130cytomegalovirus-like intranuclear inclusions can be identi ed in neurons. , ,
Electron microscopy has revealed these inclusions to be proteinaceous material composed
of curving laments, and not viral particles. Some cases tend to show lymphocytic
128in( ammation of the ganglions and myenteric plexus. In addition, subtle degenerative
101changes in neurons and abnormal dendritic processes are also identi ed. 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 speci city and fail to
103 128diBerentiate primary from secondary changes. , Of these BCL2 has been more
widely used as a marker of increased neuronal apoptosis and supports the idea of
125neuropathic changes. 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.
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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
131 132constipation and features suggestive of chronic intestinal pseudo-obstruction. ,
133Also, blockade of the c-kit receptor results in severe disturbance of bowel motility.
Piebaldism in humans, a condition associated with inactivating c-kit mutations, is
134 135associated with life-long constipation. , It has recently been shown that some cases
of intestinal pseudo-obstruction show near-total to total loss of c-kit-positive
112,136-138ICC. A rare case of ICC hyperplasia without underlying germline c-kit
mutation and appearing as chronic idiopathic intestinal pseudo-obstruction in a pediatric
139patient has also been reported.
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
140abnormalities are di cult to appreciate on routine formalin- xed tissues. 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
139cells stain strongly with c-kit antibody, which makes their recognition as ICC easier.




FIGURE 7-14 Chronic idiopathic intestinal pseudo-obstruction. There are no signi cant
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-de ned group includes cases of neuroblastoma and ganglioneuroblastoma
141 142associated with chronic intestinal pseudo-obstruction. , 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
143associated with intestinal pseudo-obstruction has also been reported.
Secondary Chronic Intestinal Pseudo-Obstruction
SYSTEMIC DISORDERS
Patients with scleroderma or progressive systemic sclerosis may have signi cant
involvement of the bowel, resulting in a severe motility disorder that often requires
144surgical resection. Clinically, esophageal involvement usually predominates. The
inner circular layer is often preferentially involved, in contrast to primary visceral
101 145myopathy, which involves the outer longitudinal muscle layer preferentially. , In
scleroderma, collagenous replacement of the muscle layer tends to be nearly complete,
which is unlike the delicate form of interstitial brosis 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 nonspeci c and secondary to
the underlying motility problem (e.g., re( ux 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 brosis. The inner circular layer here, unlike in most cases of
scleroderma, is relatively well preserved. B, Extensive and coarse brosis 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
144,146-148muscular dystrophy. 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
149AL-type amyloid is more often deposited in the muscularis propria.
Parkinson’s disease, familial autonomic dysfunction, and Shy-Drager syndrome may be
associated with dysmotility, but no speci c pathologic changes are identi ed in these
conditions. DiBuse polyclonal lymphoid in ltration of the small intestine is another rare
150condition of un-certain etiopathogenesis. 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
151-153other tumors as well. 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
154 155dysmotility of the stomach, small intestine, colon, and anus. , Bowel dysfunction
resolves with improvement of the cutaneous disease. Cytomegalovirus infection has also
been implicated in intestinal pseudo-obstruction, especially in immunocompromised
156 157individuals. , In some cases, evidence of Epstein-Barr virus infection has been
demonstrated by polymerase chain reaction and in situ hybridization studies of the
158myenteric plexus. Histologically, the only clues may be the presence of in( ammatory
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),
41 159 160resulting in intestinal pseudo-obstruction. , ,
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
161 162both) of any bowel segment (Fig. 7-16). , Ultrastructurally, the granular
electrondense material contains myelin gures 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 de ciency has also been
implicated as an underlying factor. It is unclear whether this is a purely nonspeci c
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 magni cation. At higher magni cation
(inset), the cytoplasmic pigment appears granular, light brown, and lipofuscin-like. No
other abnormalities of the smooth muscle cells or muscularis propria are seen.




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(Courtesy of Dr. Thomas Smyrk.)
Irritable Bowel Syndrome
Irritable bowel syndrome is a common disorder of uncertain etiopathogenesis that most
commonly aBects 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
163number of lymphocytes, mast cells, and enterochroma n cells. 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
164abnormalities. Diverticula result from mucosal outpouchings secondary to
brosisinduced 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
165 166reduced colonic propulsive capacity, , and it most commonly aBects 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 nding. 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
165 167ganglion cells, intraganglionic neuro laments, and ICC have been described. , ,
168 Amphophilic, hyaline, and round to ovoid (4 to 22 μm) cytoplasmic inclusions of
169unclear composition may be found in smooth muscle cells. These inclusions are
nonspeci c and can be identi ed 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

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to 30 years; infants and children tend to have a poorer prognosis and die at a young
103age. Treatment is symptomatic and supportive, as no speci c and eBective 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
170intractable cases. The main causes of death in these patients are related to surgery, to
103total parenteral nutrition, or to transplantation complications.
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 speci c 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
171toxins, imaging and physical ndings, and pathologic features. 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 di cult
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
154 155postinfectious cause of pseudo-obstruction. , In select cases, serology for
110 122circulating antineuronal and anti-smooth muscle antibodies may be helpful. ,
Endoscopy, laparotomy, and radiology may help exclude mechanical causes of





intestinal obstruction. GI ma-nometry, although not essential, also helps diBerentiate
122 171mechanical from functional obstruction. , It also helps diBerentiate 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 ndings and use of
a systematic approach to the histologic examination of tissue specimens are essential
(Table 7-3). Mucosal biopsies often show nonspeci c ndings. 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
xed 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 brosis, 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 in( ammation involving the neuromuscular
apparatus. In( ammation surrounding the neural plexus, and ganglionitis, may point
toward an infectious, paraneoplastic, or autoimmune neuropathy, whereas dense
lymphocytic in( ammation limited to the muscular layers may suggest autoimmune
110 126leiomyositis. , However, one should be cautious when evaluating in( ammation
within the neuromuscular apparatus, because secondary involvement with in( ammatory
disorders (e.g., in( ammatory bowel disease) is more common than primary involvement.
Neural hypertrophy and atrophy, although nonspeci c, 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
Evaluate pattern of fibrosis
Trichrome
Periodic Evaluate cytoplasmic inclusions in smooth muscle fibers
acid–Schiff
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Congo red Rule out amyloidosis
Immunohistochemical stains
S100 Evaluate neural plexuses
C-kit Evaluate interstitial cells of Cajal
(CD117)
Smooth Decreased or absent staining in myopathic cases
muscle
actin
Desmin Decreased or absent staining in myopathic cases
BCL2 Decreased staining in neuropathic cases
Electron
Evaluate degenerative changes in muscle fibers and ganglion cells, or
microscopy
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, nonspeci c, or
nondiagnostic. ICC are di cult to appreciate on H&E-stained tissue sections and need
immunohistochemical analysis with c-kit antibody. ICC abnormalities should always be
considered in the diBerential 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
140better evaluated in frozen tissue. Quantitation of ICC and evaluation of their network
2 168are also di cult on routine tissue sections. , 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
generelated 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.
REFERENCES
1 Sternberg S. Histology for Pathologists, ed 2, New York: Lippincott-Raven; 1997:461--571.
2 Nemeth L, Yoneda A, Kader M, et al. Three-dimensional morphology of gut innervation in