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

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The updated edition of Surgical Pathology of the GI Tract, Liver, Biliary Tract and Pancreas is designed to act as a one-stop medical reference book for the entire gastrointestinal system, providing exhaustive coverage and equipping you with all of the necessary tools to make a comprehensive diagnostic workup. You'll access thousands of high-quality illustrations and eight brand-new chapters, so you can recognize and diagnose any pathological slide you encounter.

  • Consult this title on your favorite e-reader, conduct rapid searches, and adjust font sizes for optimal readability.
  • Make a comprehensive diagnostic workup with data from ancillary techniques and molecular findings whenever appropriate.
  • Effectively grasp complex topics and streamline decision-making by using extensive tables, graphs, and flowcharts.
  • Avoid diagnostic errors thanks to practical advice on pitfalls in differential diagnosis.
  • Navigate the book quickly with a "road map" featured at the beginning of each chapter.
  • Provide the clinician with the most accurate and up-to-date diagnostic and prognostic indicators, including key molecular aspects of tumor pathology, with access to the latest classification and staging systems available.
  • Evaluate diagnostically challenging cases using diagnostic algorithms.
  • Stay abreast of the latest advances with eight new chapters: Autoimmune Disorders of the GI Tract; Drug Induced Disorders of the GI Tract; Molecular Diagnostics of Tubal Gut Neoplasms; Molecular Diagnostics of the Gallbladder, Extrahepatic Biliary Tree, and Pancreatic Tumors; Tumors of the Ampulla; Molecular Diagnostics of Hepatocellular Neoplasms; Approach to the Liver Biopsy, and Approach to Gastrointestinal Tract Biopsies.
  • Remain at the forefront of your field with coverage of new molecular and genetic markers in GI neoplasms; updated knowledge on liver and biliary tree pathology; and expanded information on tumors of the ampulla.
  • Recognize and diagnose any tissue sample under the microscope with help from over 3000 high-quality color illustrations.

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Odze and Goldblum
Surgical Pathology of the
GI Tract, Liver, Biliary
Tract and Pancreas
THIRD EDITION
Robert D. Odze, MD, FRCP(C)
Professor of Pathology, Harvard Medical School, Chief, GI Pathology Service, Brigham and
Women’s Hospital, Boston, Massachusetts
John R. Goldblum, MD
Chairman of Pathology, Cleveland Clinic, Professor of Pathology, Cleveland Clinic Lerner
College of Medicine, Cleveland, OhioTable of Contents
Cover image
Title page
Copyright
Dedication
Contributors
Preface to the Third Edition
Acknowledgments
Part 1 Gastrointestinal Tract
Section I General Pathology of the Gastrointestinal Tract
Chapter 1 Gastrointestinal Tract Endoscopic and Tissue Processing Techniques and
Normal Histology
Introduction
Bowel Preparation
Methods for Obtaining Tissue Specimens
Methods of Processing Tissue for Pathologic Evaluation
Endoscopy-Induced Artifacts
Pathologic Features of a Healing Biopsy Site
Methods for Obtaining Cytology Specimens
Normal Histology of the Tubal Gut
Lymph Node Drainage and Lymphatics of the Tubal Gut
ReferencesChapter 2 Screening and Surveillance Guidelines in Gastroenterology
Introduction
Surveillance in Patients with Barrett Esophagus
Surveillance in Patients with Chronic Gastritis and Intestinal Metaplasia or Dysplasia
Surveillance for Colorectal Neoplasia in Patients with Inflammatory Bowel Disease
Screening and Surveillance Guidelines for Colon Polyps
Hyperplastic Polyposis Syndromes
Management of Large Pedunculated Polyps
Management of Large Sessile Polyps
Postpolypectomy Surveillance
Management of Malignant Polyps
Colonoscopic Surveillance after Colon Cancer Resection
Interaction of Gastrointestinal Endoscopists and Pathologists
References
Chapter 3 Diagnostic Cytology of the Gastrointestinal Tract
Introduction
Normal Morphology
Infections
Inflammatory, Reactive, and Metaplastic Changes
Neoplastic Lesions
References
Chapter 4 Infectious Disorders of the Gastrointestinal Tract
Introduction
Viral Infections of the GI Tract
Bacterial Infections of the Gastrointestinal Tract
Fungal Infections of the GI Tract
Parasitic Infections of the GI Tract
References
Chapter 5 Manifestations of Immunodeficiency in the Gastrointestinal TractPrimary Disorders of Immune Deficiency
Combined Cellular/Humoral Immunodeficiencies
Other Primary Immunodeficiencies
Graft-versus-Host Disease
Neutropenic Enterocolitis
The Gastrointestinal Tract in HIV Infection
References
Chapter 6 Systemic Illnesses Involving the Gastrointestinal Tract
Introduction
Cardiovascular Disorders
Dermatologic Disorders
Endocrine Disorders
Hematologic Disorders
Metabolic Disorders
Pulmonary Disorders
Reproductive Disorders
Rheumatologic Disorders
Urologic Disorders
Miscellaneous Disorders
References
Chapter 7 Neuromuscular Disorders of the Gastrointestinal Tract
Introduction
Esophagus
Stomach
Small and Large Intestine
Differential Diagnosis and Workup of Patients with Intestinal Dysmotility
Future Outlook
References
Chapter 8 Congenital and Developmental Disorders of the Gastrointestinal TractMolecular Mechanisms of Gastrointestinal Development
Embryology and Anatomic Development of the GI tract
Congenital Anomalies of the GI Tract
Anorectal Malformations
References
Chapter 9 Enteropathies Associated with Chronic Diarrhea and Malabsorption in
Childhood
Introduction
Biopsy Sampling and Indications In Children
Intestinal Development in Children
Congenital Disorders of Intestinal Digestion, Absorption, and Transport
Congenital Defects of Intestinal Epithelial Differentiation
Disorders of Immunomodulation
Necrotizing Enterocolitis
Lymphangiectasia
Metabolic Diseases
Neoplastic Disorders
References
Chapter 10 Vascular Disorders of the Gastrointestinal Tract
Introduction
Anatomy of the GI Vascular System
Upper GI Bleeding
Lower GI Bleeding
Upper GI Ischemia
Lower GI Ischemia
Vasculitis
Differential Diagnosis of Ischemia in Lower GI Biopsies
References
Chapter 11 Autoimmune Disorders of the Gastrointestinal TractIntroduction
Autoimmune Enteropathy
Immunoglobulin G4 (IgG4)–Related Disease of the Gastrointestinal Tract
References
Chapter 12 Drug-Induced Disorders of the Gastrointestinal Tract
Introduction
Nonspecific Injury Patterns
Specific Agents
References
Section II Inflammatory Disorders of the Gastrointestinal Tract
Chapter 13 Algorithmic Approach to Diagnosis of Inflammatory Disorders of the
Gastrointestinal Tract
Introduction
Esophagus
Gastroesophageal Junction
Stomach
Small Intestine
Colon
Chapter 14 Inflammatory Disorders of the Esophagus
Introduction
Esophagitis
Infectious Esophagitis
Pill-, Drug,- and Toxin-Related Esophagitis
Primary Eosinophilic Esophagitis
Lymphocytic Esophagitis
Mechanical Causes of Esophagitis
Congenital and Acquired Deformations
Esophageal Involvement in Systemic Disease
Barrett's EsophagusReferences
Chapter 15 Inflammatory Disorders of the Stomach
Historical Perspective
General Pathologic Features of Gastritis
Updated Sydney System
OLGA System
Acute Gastritis
Chronic Gastritis
Special Forms of Gastritis
Gastropathies
Gastric Cardia, Carditis, and Gastroesophageal Junction
Stomach in the Young and Elderly
Gastric Epithelial Dysplasia
References
Chapter 16 Inflammatory Disorders of the Small Intestine
Disorders of Malabsorption
Eosinophilic Gastroenteritis
Nutritional Deficiencies
Peptic Duodenitis and Duodenal Ulcer
Drug Injury of the Small Bowel
Inflammatory Bowel Disease
Ischemic Disorders of the Small Intestine
Cryptogenic Multifocal Ulcerating Stenosing Enteritis
Graft-versus-Host Disease
Intestinal Lymphangiectasia
Waldenström Macroglobulinemia
Pneumatosis Cystoides Intestinalis
References
Chapter 17 Inflammatory Disorders of the Large IntestineApproach to Evaluating Colitis
Ulcerative Colitis
Crohn's Colitis
Chronic Inflammatory Bowel Disease, Unknown Type (Indeterminate Colitis)
Dysplasia in Inflammatory Bowel Disease
Other Colitides
Mastocytic Disorders
Drug-Induced Colitis
Chemotherapy-Associated Colonic Injury
Effects of Bowel Preparation Agents
Mucosal Prolapse Syndrome
Behçet Syndrome
References
Chapter 18 Inflammatory Disorders of the Appendix
Normal Histology
Congenital, Developmental, and Acquired Anatomic Abnormalities
Acute Appendicitis and Associated Disorders
Chronic Appendicitis
Infectious Causes of Acute and Chronic Appendicitis
Miscellaneous Disorders of the Appendix
References
Section III Polyps of the Gastrointestinal Tract
Chapter 19 Polyps of the Esophagus
Introduction
Epithelial Polyps
Mesenchymal Polyps
Cystic and Diverticular Lesions
ReferencesChapter 20 Polyps of the Stomach
Introduction
Hyperplastic Polyps
Ménétrier Disease
Inflammatory Polyps
Hamartomatous Polyps
Embryonic Rests and Heterotopia
Epithelial Polyps
Nonepithelial Polyps
Lymphoid Polyps
Miscellaneous Rare Polyps and Polyp-like Lesions
References
Chapter 21 Polyps of the Small Intestine
Introduction
Inflammatory Lesions
Hyperplasia and Heterotopia
Hamartomatous Polyps
Benign Epithelial Neoplasms
Neuroendocrine Tumors
Mesenchymal Lesions
Lymphatic Lesions
Lymphoid Lesions
Metastases
References
Chapter 22 Polyps of the Large Intestine
Introduction
Inflammatory Polyps
Hamartomatous Polyps
Epithelial Polyps
Mesenchymal PolypsMiscellaneous Polypoid Lesions
References
Section IV Epithelial Neoplasms of the Gastrointestinal Tract
Chapter 23 Molecular Diagnostics of Tubal Gut Neoplasms
Introduction
Methodologies
Molecular Diagnostics of Hereditary Gastrointestinal Cancer
Molecular Diagnostics in Targeted Therapy
Molecular Diagnostics and Predictive Factors for Chemotherapy
Molecular Diagnostics of Hematologic Malignancies
Infectious Disease
References
Chapter 24 Epithelial Neoplasms of the Esophagus
Introduction
Benign Neoplasms and Tumor-Like Lesions
Malignant Neoplasms
References
Chapter 25 Epithelial Neoplasms of the Stomach
Introduction
Pathogenesis
Histologic Precursors of Gastric Cancer
Anatomic Distribution: Cardia Cancer
Early Gastric Cancer
Advanced Gastric Carcinoma
Morphologic Subtypes of Gastric Adenocarcinoma
Gastric Carcinoma in Special Clinical Circumstances
Natural History and Prognosis of Gastric Adenocarcinoma
Molecular Pathology of Gastric CancerReferences
Chapter 26 Epithelial Neoplasms of the Small Intestine
Introduction
Small-Intestinal Neoplasia in Polyposis and Hereditary Cancer Syndromes
Adenomatous Polyps
Preinvasive Ampullary Neoplasia
Small-Intestinal Adenocarcinoma
Crohn's Disease–Associated Adenocarcinoma
Celiac Disease–Associated Adenocarcinoma
Other Types of Carcinoma
Gangliocytic Paraganglioma
References
Chapter 27 Epithelial Neoplasms of the Large Intestine
Introduction
Special Studies
Prognostic Factors
Hereditary Nonpolyposis Colorectal Cancer and Lynch Syndrome
Colorectal Cancer in Serrated Polyposis Syndrome
Colitis-Associated Neoplasia
References
Chapter 28 Epithelial Neoplasms of the Appendix
Mucinous Epithelial Tumors
Neuroendocrine Tumors
Mixed Glandular and Endocrine Neoplasms
Secondary Tumors (Other Than Lymphoma)
References
Chapter 29 Neuroendocrine Tumors of the Gastrointestinal and Pancreatobiliary
Tracts
Neuroendocrine Cell System of the Gastrointestinal TractTrue Neuroendocrine Tumors
Mixed Tumors
Chimeric Tumors with Incomplete Neuroendocrine Differentiation
Other Tumors with Neuroendocrine Differentiation
Metastatic Tumors of Neuroendocrine Origin
Neuroendocrine Tumor Mimics
Acknowledgment
References
Section V Nonepithelial Neoplasms of the Gastrointestinal Tract
Chapter 30 Mesenchymal Tumors of the Gastrointestinal Tract
Introduction
Gastrointestinal Stromal Tumors (GISTs)
Tumors of Neural Origin
Tumors of Smooth Muscle Origin
Fibroblastic Tumors
Vascular Tumors
Tumors of Adipose Tissue
Rare but Noteworthy Entities
References
Chapter 31 Hematolymphoid Tumors of the Gastrointestinal Tract, Hepatobiliary
Tract, and Pancreas
Introduction
Gastric MALT Lymphoma
Intestinal MALT Lymphoma
Immunoproliferative Small-Intestinal Disease
Gastric Diffuse Large B-Cell Lymphoma
Intestinal Diffuse Large B-Cell Lymphoma
Mantle Cell Lymphoma
Follicular LymphomaBurkitt Lymphoma
Enteropathy-Associated T-Cell Lymphoma
Complicated Celiac Disease: Refractory Sprue and Ulcerative Jejunitis
Extranodal NK/T-Cell Lymphoma, Nasal Type
Other Gastrointestinal (GI)T-Cell Lymphomas
Appendiceal Lymphomas
Hodgkin Lymphoma of the GI Tract
GI Lymphoproliferative Disorders in Abnormal Immune States
Hepatic Lymphomas
Lymphomas of the Gallbladder
Lymphomas of the Extrahepatic Bile Ducts
Pancreatic Lymphomas
Proliferations of Histiocytes and Dendritic Cells in the GI Tract and Liver
Mastocytosis: Manifestations in the GI Tract and Liver
References
Section VI Anal Pathology
Chapter 32 Inflammatory and Neoplastic Disorders of the Anal Canal
Embryology and Anatomy of the Anal Canal
Embryologic Abnormalities of the Anus and Anal Canal
Benign Tumors and Tumor-like Lesions of the Anus and Anal Canal
Inflammatory Disorders of the Anal Canal
Benign Tumors of the Anal Canal
Squamous Neoplasms of the Anal Canal
Anal Adenocarcinoma
Paget Disease of the Anus
Anal Melanoma
Other Rare Neoplasms of the Anal Canal
References
Part 2 Gallbladder, Extrahepatic Biliary Tract, and PancreasChapter 33 Gallbladder, Extrahepatic Biliary Tract, and Pancreas Tissue Processing
Techniques and Normal Histology
Introduction
Normal Anatomy and Histology
Gallbladder
Extrahepatic Biliary Tract
Pancreas
Frozen Sections and Intraoperative Consultation
References
Chapter 34 Molecular Genetics of Pancreatobiliary Neoplasms
Introduction
Pancreatic Neoplasms
Biliary Neoplasms
Conclusion
References
Chapter 35 Diagnostic Cytology of the Biliary Tract and Pancreas
Introduction
Cytologic Sampling of the Pancreatobiliary Tract
Cytology of the Biliary Tract
Cytology of the Pancreas
References
Chapter 36 Developmental Disorders of the Gallbladder, Extrahepatic Biliary Tract,
and Pancreas
Introduction
Structural Development of the Gallbladder, Extrahepatic Biliary Tract, and Pancreas
Structural and Developmental Anomalies of the Gallbladder
Structural and Developmental Anomalies of the Extrahepatic Biliary Tract
Structural and Developmental Anomalies of the Pancreas
Acknowledgment
ReferencesChapter 37 Infectious and Inflammatory Disorders of the Gallbladder and
Extrahepatic Biliary Tract
Introduction
Gallstones
Cholecystitis
Acute Cholecystitis
Chronic Cholecystitis
Parasitic Infestation
Polyarteritis Nodosa and Other Types of Vasculitis
Cholesterolosis
Hydrops and Mucocele
Diverticular Disease
Ischemic Diseases
Traumatic Conditions and Chemical Cholecystitis
Biliary Fistulas
Metachromatic Leukodystrophy
Inflammatory Disorders of the Extrahepatic Bile Ducts
AIDS-Related Lesions
Cholangiopathy
References
Chapter 38 Benign and Malignant Tumors of the Gallbladder and Extrahepatic Biliary
Tract
Introduction
Sampling Gallbladder Specimens
Gallbladder
Extrahepatic Bile Ducts
Nonepithelial Tumors of the Gallbladder and Extrahepatic Bile Ducts
Secondary Tumors of the Gallbladder and Extrahepatic Bile Ducts
Acknowledgment
ReferencesChapter 39 Inflammatory and Other Nonneoplastic Disorders of the Pancreas
Introduction
Acute Pancreatitis
Chronic Pancreatitis
Alcoholic Pancreatitis
Genetics of Pancreatitis
Pancreatic Divisum
Autoimmune Pancreatitis
Paraduodenal Pancreatitis (“Groove” Pancreatitis)
Eosinophilic Pancreatitis
Tropical Pancreatitis
Obstructive Pancreatitis
Infectious Causes of Pancreatitis
Solid Non-neoplastic Lesions That Mimic Pancreatic Neoplasms
Non-neoplastic Cystic Lesions of the Pancreas
Congenital and Hereditary Abnormalities of the Exocrine Pancreas
References
Chapter 40 Tumors of the Pancreas
Introduction
Classification
Ductal Adenocarcinoma and Variants
Pancreatic Intraepithelial Neoplasia
Cystic Tumors
Intraductal Neoplasms
Differential Diagnosis of Cystic and Intraductal Lesions
Acinar Cell Carcinoma, Pancreatoblastoma, and Related Neoplasms
Pancreatic Neuroendocrine Neoplasms
Solid Pseudopapillary Neoplasms
Differential Diagnosis of Solid Cellular Tumors
Mesenchymal and Lymphoid NeoplasmsTumor-like Lesions
Secondary Tumors
References
Chapter 41 Tumors of Major and Minor Ampulla
Introduction
Anatomic and Histologic Considerations
Classification of Ampullary Tumors
Preinvasive Neoplasms
Invasive Adenocarcinomas
Uncommon Carcinomas
Staging of Ampullary Carcinomas
Neuroendocrine Neoplasms and Related Tumors
Mesenchymal Neoplasms
Tumor-like Lesions
Gross Evaluation and the Surgical Pathology Report
Acknowledgment
References
Part 3 Liver
Chapter 42 Algorithmic Approach to Diagnosis of Liver Disorders
Introduction
Helpful Diagnostic Tips
Identification of Major Pattern of Injury
References
Chapter 43 Liver Tissue Processing and Normal Histology
Liver Biopsy Specimens
Liver Resection Specimens
Routine and Special Stains
Immunohistochemistry
Electron MicroscopyMolecular Studies
Prognostic and Therapeutic Information from Liver Biopsies
References
Chapter 44 Molecular Pathogenesis and Diagnostics of Hepatocellular Tumors
Introduction
Benign Hepatocellular Tumors
Hepatocellular Carcinoma and Its Precursors
References
Chapter 45 Diagnostic Cytology of the Liver
Introduction
Use of Fine-Needle Aspiration Biopsy
Diagnostic Issues
Cystic Lesions of the Liver
Solid Lesions of the Liver
Combined Hepatocellular-Glandular Appearance
Nonhepatocellular Appearance
Metastatic Malignant Nonhepatocellular Lesions
References
Chapter 46 Acute and Chronic Infectious Hepatitis
Introduction
Viral Hepatitis
Other Viral Infections of the Liver
Bacterial Infections of the Liver
Fungal Infections of the Liver
Parasitic Infections of the Liver
References
Chapter 47 Autoimmune and Chronic Cholestatic Disorders of the Liver
Introduction
Autoimmune HepatitisPrimary Biliary Cirrhosis
Primary Sclerosing Cholangitis
Overlap Syndromes
Immunoglobulin G4–Associated Sclerosing Cholangitis
Secondary Sclerosing Cholangitis
Ischemic Cholangitis
Miscellaneous Ductopenic Syndromes
Obstructive Cholangitis
References
Chapter 48 Toxin- and Drug-Induced Disorders of the Liver
Introduction
Epidemiology
Clinical Assessment and Prediction of Hepatotoxicity
Prevention of Drug Hepatotoxicity
Treatment and Prognosis
Pathologic Patterns of Toxic Liver Injury
Examples of Common Offending Drugs
References
Chapter 49 Fatty Liver Disease
Introduction
Alcohol-Induced Liver Disease
Nonalcoholic Fatty Liver Disease
Fatty Liver Disease in Various Patient Groups
Differentiating Alcohol-Induced from Nonalcoholic Fatty Liver Disease
Grading and Staging of Fatty Liver Disease
Other Forms of Fatty Liver Disease
References
Chapter 50 Cirrhosis
IntroductionCollagen in the Liver
Hepatic Arterialization and Capillarization
Parenchymal Extinction
Shunt Formation
Congestive Hepatopathy
Vascular Thrombosis
Regeneration
Natural History and Reversibility of Cirrhosis
Anatomic Classification and Pathology
Etiology
Diagnosis
Diagnostic Pitfalls
Acknowledgment
References
Chapter 51 Vascular Disorders of the Liver
Introduction
Portal Vein Disease (Portal Vein Obstruction)
Arterial Disease
Sinusoidal Disease
Hepatic Vein Disease
Nodular Hyperplasia and Other Tumor-Like Conditions
Fibrotic Conditions with Vascular Pathophysiology
Acknowledgment
References
Chapter 52 Pathology of Liver and Hematopoietic Stem Cell Transplantation
Introduction
Donor Evaluation
Sources of Graft Dysfunction
Complications of Transplantation
Late Liver Allograft DysfunctionOther Transplantation Effects
Acknowledgement
References
Chapter 53 Liver Pathology in Pregnancy
Introduction
Laboratory and Histologic Changes of the Liver in Pregnancy
Intrahepatic Cholestasis of Pregnancy
Acute Fatty Liver of Pregnancy
Preeclampsia and Eclampsia
HELLP Syndrome
Hepatic Rupture
Hyperemesis Gravidarum
Hepatitis E Infection
Herpesvirus Infection
Budd-Chiari Syndrome
Conclusions
References
Chapter 54 Inherited Metabolic and Developmental Disorders of the Pediatric and
Adult Liver
Introduction
Pediatric Liver Biopsies
Approach to the Diagnosis of Pediatric Liver Disorders in Liver Biopsies
Liver Diseases of Infancy
Paucity of Intrahepatic Bile Ducts
Hereditary Disorders of Bilirubin Metabolism
Hereditary Disorders of Bile Acid Metabolism
Disorders of Carbohydrate Metabolism
Congenital Disorders of Glycosylation
Disorders of Amino Acid Metabolism
Disorders of Lipid MetabolismPeroxisomal Disorders
Urea Cycle Disorders
Inherited and Metabolic Diseases of Adolescents and Adults
Clinical Patients and Specific Types of Diseases
Abnormal Development of Liver Anatomy
Abnormal Development of the Biliary Tract
References
Chapter 55 Benign and Malignant Tumors of the Liver
Introduction
Specimen Analysis
Hepatocellular Tumors
Bile Duct Tumors
Mesenchymal Tumors
Pediatric Neoplasms
Hematopoietic Malignancies
Other Lesions Involving the Liver
Metastatic Neoplasms
References
IndexCopyright
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ODZE AND GOLDBLUM SURGICAL PATHOLOGY OF THE GI TRACT, LIVER,
BILIARY TRACT, AND PANCREAS, ED 3 ISBN: 978-1-4557-0747-8
Copyright © 2015, 2009, 2004 by Saunders, an imprint of Elsevier Inc.
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operation of any methods, products, instructions, or ideas contained in the material
herein.Library of Congress Cataloging-in-Publication Data
Surgical pathology of the GI tract, liver, biliary tract, and pancreas.
Odze and Goldblum surgical pathology of the GI tract, liver, biliary tract, and
pancreas / [edited by] Robert D. Odze, John R. Goldblum.—Third edition.
p. ; cm.
Preceded by Surgical pathology of the GI tract, liver, biliary tract, and pancreas /
[edited by] Robert D. Odze and John R. Goldblum. 2nd ed. c2009.
Includes bibliographical references and index.
ISBN 978-1-4557-0747-8 (hardcover : alk. paper)
I. Odze, Robert D., editor. II. Goldblum, John R., editor. III. Title.
[DNLM: 1. Digestive System Surgical Procedures. 2. Pathology, Surgical—
methods. 3. Digestive System—physiopathology. WI 900]
RD540
617.4'3—dc23
2014016499
Executive Content Strategist: William R. Schmitt
Content Development Specialist: Joanie Milnes
Publishing Services Manager: Patricia Tannian
Project Manager: Amanda Mincher
Senior Book Designer: Ellen Zanolle
Printed in China
Last digit is the print number: 9 8 7 6 5 4 3 2D e d i c a t i o n
This book is dedicated to my family, and particularly to my 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, and my late father, Raymond; and the rest of the Goldblum
and Shirali families, whom I also cherish.
John R. Goldblum MDContributors
DOUGLAS G. ADLER MD
Associate Professor of Medicine, Director of Therapeutic Endoscopy,
Gastroenterology and Hepatology, University of Utah School of Medicine, Salt Lake
City, Utah
Gastrointestinal Tract Endoscopic and Tissue Processing Techniques and Normal
Histology
N. VOLKAN ADSAY MD
Professor and Vice-Chair, Director of Anatomic Pathology, Emory University,
Department of Pathology, Atlanta, Georgia
Neuroendocrine Tumors of the Gastrointestinal Tract
Benign and Malignant Tumors of the Gallbladder and Extrahepatic Biliary Tract
Tumors of the Pancreas
Tumors of the Ampulla
GAMZE AYATA MD
Pathologist, Beth Israel Deaconess Medical Center, Boston, Massachusetts
Diagnostic Cytology of the Gastrointestinal Tract
KAMRAN BADIZADEGAN MD
Chair of Pathology, Nemours Children's Hospital; Professor of Pathology, University
of Florida College of Medicine, Orlando, Florida
Liver Pathology in Pregnancy
Charles Balabaud
Professor Emeritus of Hepatogastroenterology, Bordeaux University School of
Medicine, Bordeaux, France
Toxin- and Drug-Induced Disorders of the Liver
Olca Basturk MD
Assistant Attending Pathologist, Department of Pathology, Memorial Sloan Kettering
Cancer Center, New York, New York
Tumors of Major and Minor Ampulla
KENNETH P. BATTS MD
Hospital Pathology Associates, Abbott Northwestern Hospital, Minneapolis,
Minnesota
Autoimmune and Chronic Cholestatic Disorders of the Liver
ANA E. BENNETT MD
Subspecialty Director, Gastrointestinal Pathology, Anatomic Pathology and
Laboratory Medicine, Cleveland Clinic, Cleveland, Ohio
Inflammatory Disorders of the Esophagus
PAULETTE BIOULAC-SAGE
Professor Emeritus of Pathology, Senior Consultant, Department of Pathology,Pellegrin University Hospital and Bordeaux University School of Medicine, Bordeaux,
France
Molecular Pathogenesis and Diagnostics of Hepatocellular Tumors
Toxin- and Drug-Induced Disorders of the Liver
ELIZABETH M. BRUNT MD
Professor, Pathology and Immunology, Washington University School of Medicine, St.
Louis, Missouri
Fatty Liver Disease
BARBARA A. CENTENO MD
Senior Member and Director of Cytopathology, Anatomic Pathology, H. Lee Moffitt
Cancer Center and Research Institute; Professor, Oncologic Sciences and Pathology
and Cell Biology, University of South Florida College of Medicine, Tampa, Florida
Diagnostic Cytology of the Biliary Tract and Pancreas
JAMES M. CRAWFORD MD, PhD
Chair and Senior Vice President, Laboratory Services, Pathology and Laboratory
Medicine, Hofstra North Shore-LIJ School of Medicine, Manhasset, New York
Gastrointestinal Tract Endoscopic and Tissue Processing Techniques and Normal
Histology
Gallbladder, Extrahepatic Biliary Tract, and Pancreas Tissue Processing Techniques
and Normal Histology
Cirrhosis
Vascular Disorders of the Liver
Pathology of Liver and Hematopoietic Stem Cell Transplantation
Pediatric Liver Disease and Inherited Metabolic and Developmental Disorders of the
Pediatric and Adult Liver
ANTHONY J. DEMETRIS MD
Professor of Pathology, University of Pittsburgh; Director, Division of Liver and
Transplant Pathology, Department of Pathology, University of Pittsburgh Medical
Center, Pittsburgh, Pennsylvania
Pathology of Liver and Hematopoietic Stem Cell Transplantation
VIKRAM DESHPANDE MD
Associate Pathologist, Massachusetts General Hospital; Associate Professor of
Pathology, Harvard Medical School, Boston, Massachusetts
Autoimmune Disorders of the Gastrointestinal Tract
Inflammatory and Other Nonneoplastic Disorders of the Pancreas
ERINN DOWNS-KELLY DO, MS
Staff, Departments of Anatomic and Molecular Pathology, Cleveland Clinic,
Cleveland, Ohio
Mesenchymal Tumors of the Gastrointestinal Tract
LEONA A. DOYLE MD
Associate Pathologist, Instructor in Pathology, Department of Pathology, Brigham
and Women's Hospital and Harvard Medical School, Boston, Massachusetts
Inflammatory Disorders of the Appendix
DAVID K. DRIMAN MBCHB, FRCPC
Professor of Pathology, Schulich School of Medicine and Dentistry, Western
University; Pathologist, London Health Sciences Centre, London, Ontario, CanadaEpithelial Neoplasms of the Large Intestine
FRANCIS A. FARRAYE MD, MSC
Clinical Director, Section of Gastroenterology, Boston Medical Center; Professor of
Medicine, Boston University School of Medicine, Boston, Massachusetts
Gastrointestinal Tract Endoscopic and Tissue Processing Techniques and Normal
Histology
Screening and Surveillance Guidelines in Gastroenterology
LINDA D. FERRELL MD
Vice Chair and Distinguished Professor, Anatomic Pathology, University of California
San Francisco, San Francisco, California
Benign and Malignant Tumors of the Liver
JUDITH A. FERRY MD
Director of Hematopathology, Department of Pathology, Massachusetts General
Hospital; Associate Professor of Pathology, Harvard Medical School, Boston,
Massachusetts
Hematolymphoid Tumors of the GI Tract, Hepatobiliary Tract, and Pancreas
MILTON J. FINEGOLD MD
Professor, Pathology, Immunology, and Pediatrics, Baylor College of Medicine,
Houston, Texas
Inherited, Metabolic, and Developmental Disorders of the Pediatric and Adult Liver
ROBERT M. GENTA MD, DTM&H
Chief for Academic Affairs, Miraca Life Sciences Research Institute, Miraca Life
Sciences, Irving, Texas; Clinical Professor, Pathology and Medicine
(Gastroenterology), University of Texas Southwestern Medical Center at Dallas,
Dallas, Texas
Inflammatory Disorders of the Stomach
JOANNA A. GIBSON MD, PhD
Assistant Professor of Pathology, Yale School of Medicine, New Haven, Connecticut
Inflammatory Disorders of the Small Intestine
JONATHAN N. GLICKMAN MD, PhD
Director, Gastrointestinal Pathology, Miraca Life Sciences, Newton, Massachusetts;
Associate Clinical Professor, Department of Pathology, Harvard Medical School,
Boston, Massachusetts
Epithelial Neoplasms of the Esophagus
JOEL K. GREENSON MD
Professor of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
Inflammatory Disorders of the Large Intestine
JASON L. HORNICK MD, PhD
Director of Surgical Pathology, Department of Pathology, Brigham and Women's
Hospital; Director, Immunohistochemistry Laboratory, Associate Professor of
Pathology, Harvard Medical School, Boston, Massachusetts
Polyps of the Large Intestine
RALPH H. HRUBAN MD
Professor, Pathology and Oncology, The Johns Hopkins University School of
Medicine, Baltimore, Maryland
Molecular Genetics of Pancreatobiliary NeoplasmsDale Huff
Department of Pathology and Laboratory Medicine, The Children's Hospital of
Philadelphia, Philadelphia, Pennsylvania
Congenital and Developmental Disorders of the Gastrointestinal Tract
PRODROMOS HYTIROGLOU MD
Professor, Department of Pathology, Aristotle University Medical School,
Thessaloniki, Greece
Molecular Pathogenesis and Diagnostics of Hepatocellular Tumors
JOHN IAFRATE Molecular Diagnostics of Tubal Gut Neoplasms
Kumiko Isse MD, PhD
Research Instructor, Division of Transplant Pathology, Pittsburgh, Pennsylvania
Pathology of Liver and Hematopoietic Stem Cell Transplantation
DHANPAT JAIN MD, MBBS
Professor of Pathology, Director of Program in GI and Liver Pathology, Department of
Pathology, Yale University School of Medicine, New Haven, Connecticut
Neuromuscular Disorders of the Gastrointestinal Tract
JOSE JESSURUN MD
Professor of Pathology and Laboratory Medicine, New York Presbyterian Hospital,
Weill Cornell Medical College, New York, New York
Infectious and Inflammatory Disorders of the Gallbladder and Extrahepatic Biliary
Tract
DAVID S. KLIMSTRA MD
Attending Pathologist and Chairman, Department of Pathology, James Ewing Alumni
Chair in Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York
Neuroendocrine Tumors of the Gastrointestinal and Pancreatobiliary TractsBenign
and Malignant Tumors of the Gallbladder and Extrahepatic Biliary TractTumors of the
Pancreas
ALYSSA M. KRASINSKAS MD
Professor, Director of Surgical Pathology, Director of Gastrointestinal and Liver
Pathology, Department of Pathology and Laboratory Medicine, Emory University
Hospital, Atlanta, Georgia
Developmental Disorders of the Gallbladder, Extrahepatic Biliary Tract, and Pancreas
LAURA W. LAMPS MD
Professor and Vice-Chair for Academic Affairs, Department of Pathology, University
of Arkansas for Medical Sciences, Little Rock, Arkansas
Infectious Disorders of the Gastrointestinal Tract
Acute and Chronic Infectious Hepatitis
RICHARD H. LASH MD, FCAP, FACG
Chief Medical Officer and Group Head, Medical Practice, Gastrointestinal Pathology,
Miraca Life Sciences, Irving, Texas
Inflammatory Disorders of the Stomach
GREGORY Y. LAUWERS MD
Professor of Pathology, Harvard Medical School; Pathologist, Department of
Pathology, Massachusetts General Hospital, Boston, Massachusetts
Autoimmune Disorders of the Gastrointestinal Tract
Algorithmic Approach to Diagnosis of Inflammatory Disorders of theGastrointestinal Tract
Inflammatory Disorders of the Stomach
Epithelial Neoplasms of the Stomach
AUDREY LAZENBY MD
Professor, Pathology and Microbiology, Director, Anatomic Pathology, Pathology and
Microbiology, University of Nebraska Medical Center, Omaha, Nebraska
Polyps of the Esophagus
BRIGITTE LE BAIL MD, PhD
Professor of Pathology, Department of Pathology, Pellegrin University Hospital and
Bordeaux University School of Medicine, Bordeaux, France
Toxin- and Drug-Induced Disorders of the Liver
DAVID N.B. LEWIN MD
Professor, Department of Pathology and Laboratory Medicine, Medical University of
South Carolina, Charleston, South Carolina
Systemic Illnesses Involving the Gastrointestinal Tract
RICARD MASIA MD, PhD
Clinical Fellow in Gastrointestinal and Liver Pathology, Massachusetts General
Hospital; Research Fellow, Department of Neurobiology, Harvard Medical School,
Boston, Massachusetts
Autoimmune Disorders of the Gastrointestinal Tract
Marta I. Minervini MD
Assistant Professor of Pathology, Division of Transplantation Pathology, UPMC
Montefiore, Pittsburgh, Pennsylvania
Pathology of Liver and Hematopoietic Stem Cell Transplantation
JOSEPH MISDRAJI MD
Associate Professor, Department of Pathology, Massachusetts General Hospital,
Boston, Massachusetts
Drug-Induced Disorders of the Gastrointestinal Tract
Epithelial Neoplasms of the Appendix
KISHA A. MITCHELL MD
Assistant Professor, Department of Pathology, Yale University, New Haven,
Connecticut
Vascular Disorders of the Gastrointestinal Tract
Michael A. Nalesnik MD
Professor of Pathology, Division of Transplantation Pathology, UPMC Montefiore,
Pittsburgh, Pennsylvania
Pathology of Liver and Hematopoietic Stem Cell Transplantation
AMY E. NOFFSINGER MD
Gastrointestinal Pathologist, Miraca Life Sciences, Camp Dennison, Ohio
Epithelial Neoplasms of the Small Intestine
ANSU M. NORONHA MD
Assistant Professor, Section of Gastroenterology, Boston University School of
Medicine, Boston, Massachusetts
Screening and Surveillance Guidelines in Gastroenterology
SCOTT R. OWENS MDAssistant Professor, Department of Pathology, University of Michigan, Ann Arbor,
Michigan
Inflammatory and Neoplastic Disorders of the Anal Canal
REETESH K. PAI MD
Associate Professor, Pathology Department, UPMC Presbyterian Hospital, Pittsburgh,
Pennsylvania
Polyps of the Small Intestine
RISH K. PAI MD, PhD
Assistant Professor and Associate Staff, Department of Anatomic Pathology,
Cleveland Clinic, Cleveland, Ohio
Polyps of the Small Intestine
ST EPHA N PA MBU CCIA N I nfectious and I nflammatory D isorders of the
Gallbladder and Extrahepatic Biliary Tract
DEEPA T. PATIL MD
Assistant Professor and Staff, Department of Anatomic Pathology, Cleveland Clinic,
Cleveland, Ohio
Inflammatory Disorders of the Large Intestine
MARTHA BISHOP PITMAN MD
Associate Professor of Pathology, Harvard Medical School, Boston, Massachusetts
Diagnostic Cytology of the Liver
THOMAS P. PLESEC MD
Assistant Professor of Pathology, Cleveland Clinic Lerner College of Medicine; Staff
Pathologist, Cleveland Clinic, Cleveland, Ohio
Inflammatory and Neoplastic Disorders of the Anal Canal
Parmjeet S. Randhawa MD
Professor of Pathology, Division of Transplantation Pathology, UPMC Montefiore,
Pittsburgh, Pennsylvania
Pathology of Liver and Hematopoietic Stem Cell Transplantation
MARK REDSTON MD
Director, GI Molecular Diagnostics, Miraca Life Sciences, Newton, Massachusetts
Molecular Diagnostics of Tubal Gut Neoplasms
Epithelial Neoplasms of the Large Intestine
MARIE E. ROBERT MD
Professor of Pathology and Internal Medicine, Yale University School of Medicine,
New Haven, Connecticut
Inflammatory Disorders of the Small Intestine
ANGSHUMOY ROY MBBS, PhD
Assistant Professor, Departments of Pathology and Immunology and Pediatrics,
Baylor College of Medicine and Texas Children's Hospital
Pediatric Liver Disease and Inherited Metabolic and Developmental Disorders of the
Pediatric and Adult Liver
BRIAN RUBIN MD, PhD
Professor and Vice Chair of Research, Pathology and Laboratory Medicine Institute,
Cleveland Clinic, Cleveland, Ohio
Mesenchymal Tumors of the Gastrointestinal TractErin Rubin MD
Associate Professor, Department of Pathology and Immunology, Washington
University at St. Louis School of Medicine, St. Louis, Missouri
Pathology of Liver and Hematopoietic Stem Cell Transplantation
PIERRE RUSSO MD
Department of Pathology, The Children's Hospital of Philadelphia, Philadelphia,
Pennsylvania
Congenital and Developmental Disorders of the Gastrointestinal Tract
Enteropathies Associated with Chronic Diarrhea and Malabsorption in Childhood
Elizaburo Sasatomi MD
Assistant Professor of Pathology, Division of Transplantation Pathology, UPMC
Montefiore, Pittsburgh, Pennsylvania
Pathology of Liver and Hematopoietic Stem Cell Transplantation
ROMIL SAXENA MD, MBBS, FRCPath
Professor of Pathology and Laboratory Medicine, Professor of Medicine, Indiana
University School of Medicine, Indianapolis, Indiana
Algorithmic Approach to Diagnosis of Liver Disorders
CHANJUAN SHI MD, PhD
Assistant Professor, Department of Pathology, Microbiology, and Immunology,
Vanderbilt University, Nashville, Tennessee
Manifestations of Immunodeficiency in the Gastrointestinal Tract
AMITABH SRIVASTAVA MD
Assistant Professor, Department of Pathology, Brigham and Women's Hospital,
Boston, Massachusetts
Algorithmic Approach to Diagnosis of Inflammatory Disorders of the
Gastrointestinal Tract
ARIEF A. SURIAWINATA MD
NEIL D. THEISE MD
Professor, Departments of Pathology and Medicine (Digestive Diseases), Beth Israel
Medical Center of Albert Einstein College of Medicine, New York, New York
Algorithmic Approach to Diagnosis of Liver Disorders
SWAN N. THUNG MD
Professor of Pathology, Director of Liver Pathology Division, Icahn School of
Medicine at Mount Sinai, New York, New York
Liver Tissue Processing and Normal Histology
DINA G. TINIAKOS MD, PhD
Clinical Senior Lecturer/Honorary Consultant Histopathologist, Department of
Cellular Pathology, Royal Victoria Infirmary and Institute of Cellular Medicine,
Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United
Kingdom
Fatty Liver Disease
JERROLD R. TURNER MD, PhD
Professor and Associate Chair, Department of Pathology, The University of Chicago,
Chicago, Illinois
Polyps of the Stomach
HELEN H. WANG MD, DRPHProfessor of Pathology, Harvard Medical School; Director of Cytopathology,
Department of Pathology, Beth Israel Deaconess Medical Center, Boston,
Massachusetts
Diagnostic Cytology of the Gastrointestinal Tract
KAY WASHINGTON MD, PhD
Professor of Pathology, Vanderbilt University Medical Center, Nashville, Tennesee
Manifestations of Immunodeficiency in the Gastrointestinal Tract
AILEEN WEE MBBS, FRCPath, FRCPA
Professor and Senior Consultant, Department of Pathology, Yong Loo Lin School of
Medicine, National University of Singapore, National University Hospital, National
University Health System, Singapore
Diagnostic Cytology of the Liver
A. BRIAN WEST MD
Vice-Chair for Anatomic Pathology, Pathology, Yale University, New Haven,
Connecticut
Vascular Disorders of the Gastrointestinal Tract
JACQUELINE L. WOLF MD
Associate Professor of Medicine, Harvard Medical School and Beth Israel Deaconess
Medical Center, Department of Medicine, Division of Gastroenterology, Boston,
Massachusetts
Liver Pathology in Pregnancy
LA U RA D . WOOD MD , Ph D A ssistant Professor of Gastrointestinal and Liver
Pathology, Johns Hopkins Hospital, Baltimore, Maryland
MATTHEW M. YEH MD, PhD
Associate Professor, Director of Gastrointestinal and Hepatic Pathology, Department
of Pathology, University of Washington School of Medicine, Seattle, Washington
Vascular Disorders of the Liver
LISA M. YERIAN BS, MD
Director, Hepatopancreaticobiliary Pathology, Department of Anatomic Pathology,
Cleveland Clinic, Cleveland, Ohio
Acute and Chronic Infectious HepatitisPreface to the Third Edition
The current edition of Surgical Pathology of the GI Tract, Liver, Biliary Tract, and
Pancreas represents the most comprehensive textbook of gastrointestinal (and related
organs) pathology worldwide. We believe the third edition represents a significant
improvement over the second edition in a number of ways. The textbook contains six
new chapters. These include chapters on drug-induced disorders of the GI tract, an
algorithmic approach to the interpretation of tubal gut biopsies, molecular
diagnostics of tubal gut neoplasms, molecular diagnostics of the gallbladder,
extrahepatic biliary tree and pancreatic tumors, molecular diagnostics of
hepatocellular neoplasms, and an approach to the interpretation of liver biopsies. I n
this edition, we have separated and significantly expanded the discussion of
molecular features of tumors in both a clinically and a pathologically useful manner.
The chapters on an algorithmic approach to the interpretation of tubal gut and liver
biopsies provide diagnostic algorithms that we feel help pathologists navigate the
vast array of inflammatory disorders of these organs in an easy and accurate manner.
We have also greatly expanded all of the other chapters in this textbook by
updating current information, including references, and providing new and improved
tables that address difficult diagnostic issues and methods that can help pathologists
differentiate closely related disorders. S ome chapters have doubled in size, such as
the chapter on inflammatory disorders of the colon, providing a greatly expanded
discussion of pathogenesis and pathologic features. Furthermore, the editors have
paid closer a) ention to the quality of the images in this edition, which we believe
have been improved significantly from previous editions. We have greatly increased
the number of images as well. S imilar to the previous edition, the third edition
includes an online version that readers can access from any laptop computer
worldwide.
Consistent with our fundamental approach to GI pathology, we have produced this
textbook with the intent of providing the most relevant and up-to-date clinical,
etiologic, molecular, and therapeutic management information necessary for surgical
pathologists to make clinically relevant diagnoses. Ultimately, this is a
morphologybased textbook, with particular emphasis on histologic features that can differentiate
diseases based on evaluation of biopsy and resection specimens. However, this book
provides abundant clinical correlates and information that would be helpful to
gastroenterologists and surgeons as well.
The overall organization of the textbook is similar to the second edition. We believe
it allows readers to obtain information quickly and methodically, according to the
thinking process used by pathologists at the microscope. A ll of the chapters are
wri) en by pathologists who have a special interest and expertise in the topics covered
in their chapter. A s in the second edition, the editors have paid careful a) ention to
the writing, structure, and content of each chapter in order provide a consistent and
readable approach to GI pathology. We, the editors, have not left any stone unturnedin this third edition. A s a result, we believe the third edition is the most
comprehensive, state of the art textbook in pathology of the gastrointestinal tract,
liver, biliary tract, and pancreas. I t is a book we hope will be enjoyed by pathologists
and clinicians worldwide.
Robert D. Odze MD, FRCP(C)
John R. Goldblum MDAcknowledgments
A s in previous editions, many individuals, both medical and nonmedical, contributed
to the production of this textbook. We are most appreciative of all the technical,
administrative, and support staff involved, but particularly Kendra Glueck-A bramson
and Kathleen Ranney of the Brigham and Women's Hospital and Cleveland Clinic,
respectively. We would like to thank our fellows Cheryl A dackapara and Kyle Viani of
the Brigham and Women's Hospital and D rs. Homer Wiland, Kathryn Brown, and Lili
Lee of the Cleveland Clinic for their diligent proofreading of the chapters. We would
also like to thank Jonathan Alpert for his advice regarding the style of the book cover.
Professionally, I will always be greatly indebted to my longtime friends and
mentors, D r. D onald A ntonioli and D r. Harvey Goldman, for their lifelong support,
teaching, and guidance both in my personal life and particularly in gastrointestinal
pathology. D r. Goldblum would like to acknowledge his lifelong mentor in
gastrointestinal pathology, D r. Henry A ppelman. We would also like to thank D r.
J ames Crawford for his efforts in writing and editing several of the chapters related to
liver pathology. Finally, we would like to thank all of the authors of the third edition
for providing state-of-the-art, comprehensive discussions related to their fields of
interest, and for their patience required to labor through the long and sometimes
cumbersome editorial process.
Robert D. Odze MD, FRCP(C)
John R. Goldblum MDPA RT 1
Gastrointestinal Tract
OUT L INE
Section I General Pathology of the Gastrointestinal Tract
Section II Inflammatory Disorders of the Gastrointestinal Tract
Section III Polyps of the Gastrointestinal Tract
Section IV Epithelial Neoplasms of the Gastrointestinal Tract
Section V Nonepithelial Neoplasms of the Gastrointestinal Tract
Section VI Anal PathologyS E C T I O N I
General Pathology of the
Gastrointestinal Tract
OUT L INE
Chapter 1 Gastrointestinal Tract Endoscopic and Tissue Processing Techniques
and Normal Histology
Chapter 2 Screening and Surveillance Guidelines in Gastroenterology
Chapter 3 Diagnostic Cytology of the Gastrointestinal Tract
Chapter 4 Infectious Disorders of the Gastrointestinal Tract
Chapter 5 Manifestations of Immunodeficiency in the Gastrointestinal Tract
Chapter 6 Systemic Illnesses Involving the Gastrointestinal Tract
Chapter 7 Neuromuscular Disorders of the Gastrointestinal Tract
Chapter 8 Congenital and Developmental Disorders of the Gastrointestinal Tract
Chapter 9 Enteropathies Associated with Chronic Diarrhea and Malabsorption in
Childhood
Chapter 10 Vascular Disorders of the Gastrointestinal Tract
Chapter 11 Autoimmune Disorders of the Gastrointestinal Tract
Chapter 12 Drug-Induced Disorders of the Gastrointestinal TractC H A P T E R 1
Gastrointestinal Tract Endoscopic and
Tissue Processing Techniques and Normal
Histology
Douglas G. Adler
Francis A. Farraye
James M. Crawford
CHA P T E R OUT LINE
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
Optical Techniques
Normal Histology of the Tubal Gut
Esophagus
Stomach
Small Intestine
Colon
Appendix
Rectum and Anus
Lymph Node Drainage and Lymphatics of the Tubal Gut
Esophagus
Stomach
Small Intestine
Colon
Lymph Nodes
Introduction
Endoscopy provides a unique opportunity to visualize the mucosal surface of the gastrointestinal (GI ) tract as
well as a variety of extraluminal and extraintestinal organs and structures. When considered within the context
of a specific clinical picture, endoscopic images may be all that is needed to establish a specific diagnosis or
1provide sound clinical management. However, endoscopists often need to sample tissue. Examination by aqualified pathologist of specimens obtained at endoscopy is a routine and critical part of managing disorders of
the alimentary tract. The purpose of this 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 effectiveness of endoscopy often depends on the quality of the bowel preparation. Preparation of the
upper GI tract for endoscopy typically involves, at minimum, 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 2 days, followed by cleansing with oral polyethylene glycol
(PEG)electrolyte solution or other oral laxatives (e.g., magnesium citrate, senna) and rectal enemas (Table 1.1). I n
general, vomiting is reported more frequently with oral PEG-based high-volume lavage regimens than with
3,4 5,6other agents. PEG lavage regimens reportedly provide more consistent cleansing.
Table 1.1
Common Preparation Methods for Colonoscopy
48-hr clear liquid diet, 240-mL magnesium citrate PO, senna derivative laxative
48-hr clear liquid diet, senna derivative laxative, rectal enema
24-hr clear liquid diet, 240 mL magnesium citrate PO, or 4 L PEG-electrolyte lavage
24-hr clear liquid diet, 2 L PEG-electrolyte lavage, cascara-based laxative
24-hr clear liquid diet, 2 L sodium phosphate electrolyte lavage
PEG, Polyethylene glycol; PO, per os (by mouth).
Purgative- and laxative-based regimens are more likely to cause fla5 ening of surface epithelial cells, goblet
cell depletion, lamina propria edema, mucosal inflammation, and increased crypt cell proliferation, although
these effects occur infrequently. Osmotic electrolyte solutions, such as PEG-based solutions, are be5 er agents
7-10for preserving mucosal histology. I n the most severe form of mucosal damage due to purgatives such as
sodium phosphates, sloughing of the surface epithelium, neutrophilic infiltration of the lamina propria, and
hemorrhage may be encountered, and the changes may even resemble pseudomembranous colitis, nonsteroidal
11,12antiinflammatory drug-induced injury, or inflammatory bowel disease. Oral sodium phosphate bowel
preparations were removed from the market in 2008 after their use was associated with renal injury.
Chemicalinduced colitis, caused by inadequate cleaning of endoscopic instruments, also has been reported but is very
rare. S odium phosphate–based preparations may also cause endoscopically visible aphthoid-like erosions
13similar in appearance to Crohn's disease. Mucosal changes in this situation may also resemble
14pseudomembranous colitis, both endoscopically and microscopically.
Methods for Obtaining Tissue Specimens
There are a limited number of methods available for obtaining tissue via GI 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 common form of tissue
sampling; the biopsy site is usually fully visualized at the time of sampling. S uction capsule biopsy requires
fluoroscopic guidance to position a long tube with the biopsy apparatus and is done separately from endoscopy
without visualization. S uction capsule biopsy without bowel visualization is still performed in some centers, but
15it is less successful than endoscopy-guided biopsy in obtaining tissue and therefore has fallen out of favor.
Pinch biopsies may be small or large (the la5 er are referred to as “jumbo” biopsies) and can be obtained with or
without the use of electrocautery. Electrocautery has value for hemostasis and destruction of residual tissue but
introduces burn artifact into the harvested tissue.
A ll standard biopsy forceps have a similar design (Fig. 1.1). The sampling portion consists of a pair of small
cups that are in apposition when closed. I n this manner, they can be passed through the channel of a
gastroscope or colonoscope. S ome 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.
A fter insertion into the endoscope and emergence from the distal end, routine biopsy forceps can be opened
to a 4- to 8-mm width. The opened forceps is pressed against the mucosal surface for tissue sampling. Large-cup
(jumbo) biopsy forceps have jaws that open to a width of 7 to 9 mm. The biopsy forceps is closed against the
mucosal surface, and the endoscopist pulls the forceps away from the mucosa to remove the fragment of tissue.
This method often yields samples that include muscularis mucosae, except in regions such as the gastric body,
16where the mucosal folds are quite thick. The submucosa is sampled occasionally with either standard or
17jumbo forceps.
The sample size varies according to the amount of pressure the endoscopist applies to the forceps. I n
addition, application of a fully opened biopsy forceps flush against the mucosa before closure usually yields
larger pieces of tissue, compared with tissue obtained by tangential sampling or incomplete opening of the
18,19forceps. I n general, biopsy specimens are 4 to 8 mm in length. The forceps shape does not impart a
18significant difference in either size or adequacy of biopsy specimens. S ingle-use disposable biopsy forceps
20also have been shown to provide excellent samples. I n essence, there are no differences in the quality of tissue
samples obtained among the dozen or more biopsy forceps currently available, so the primary considerations in
21the selection of an endoscopic biopsy forceps are usually related to cost.
A fter the biopsy specimens have been obtained and the forceps have been removed from the endoscope, an
assistant dislodges the tissue fragments from the forceps with a toothpick or a similar small, sharp instrument.
The tissue is then placed into a container containing appropriate fixative and labeled according to instructions
provided by the endoscopist.
S pecimens obtained with a jumbo forceps often exceed 6 mm in maximum diameter, but these are not
necessarily deeper than standard biopsies. Rather, a jumbo forceps typically provides more mucosa for analysis.
This is particularly useful during surveillance tissue sampling, such as in patients with Barre5 's esophagus or
22ulcerative colitis. J umbo biopsy forceps are as safe as standard biopsy forceps. However, use of jumbo forceps
is limited by their diameter because the instrument cannot fit through a standard endoscope accessory channel.
J umbo forceps require a 3.2-mm-diameter channel, characteristic of therapeutic endoscopes, which may be less
comfortable for patients. I n addition, although jumbo biopsy specimens are larger than standard biopsy
23specimens, this does not necessarily mean that they are of greater diagnostic value.
Upper endoscopy or colonoscopy may be performed for clinical indications driven by symptomatology.
Colonoscopy, in particular, may also be performed for screening purposes in clinically asymptomatic
individuals. S election of a biopsy site at the time of endoscopy is driven by the need to assess visible mucosal
abnormalities. I n addition, it is advantageous to establish the inflammatory status of the “background” mucosa
by sampling normal-appearing mucosa during the evaluation of conditions such as gastroesophageal refluxdisease (GERD ), nonulcer dyspepsia, diarrhea, polyps, and nodules and for surveillance of premalignant
conditions, including Barre5 's esophagus and inflammatory bowel disease. For example, in patients with
inflammatory or dysplastic polyps of the stomach, it is essential to sample adjacent nonpolypoid mucosa to help
determine the background disorder in the stomach in which the polyp has developed. A s a second example, the
ampulla of Vater may be biopsied to exclude adenomatous change in patients with familial adenomatous
24polyposis, because the lifetime incidence of ampullary adenomas in these patients exceeds 50%.
Biopsy of biliary or pancreatic strictures may be carried out under fluoroscopic guidance during endoscopic
retrograde cholangiopancreatography (ERCP) with the use of either standard or specially designed biopsy
25forceps. Even gallbladder lesions observed on ERCP may be amenable to endoscopic biopsy, although this is
25rarely performed clinically. Endoscopy-directed diagnostic biopsies are extremely safe. I n one study of 50,833
22consecutive patients who underwent upper endoscopy, none had any biopsy-associated complications. The
26risk of perforation after diagnostic or therapeutic colonoscopy (with polypectomy) is extremely low.
Occasionally, an endoscopist uses a specialized insulated biopsy forceps to sample a small polyp (“hot
27biopsy”), after which remaining tissue is ablated in situ using electrocautery. Unfortunately, cautery artifact
16,28in such small tissue samples often makes histologic interpretation difficult (or impossible). In addition, the
electrocautery technique carries an excessive risk of perforation resulting from deep tissue burn, particularly in
29,30the cecum and ascending colon. Finally, destruction of residual dysplastic tissue by electrocautery may be
31incomplete in as many as 17% of cases. For these reasons, hot biopsies have been largely abandoned by most
endoscopists.
There is a limited literature available regarding the relatively new and controversial “resect and discard”
concept for diminutive colorectal polyps found during screening colonoscopy. This concept suggests that one
can safely perform endoscopic removal of diminutive colon polyps (usually by simple pinch biopsy removal
using cold forceps or cold snare polypectomy) without the need for pathologic analysis of the polyp. The
reasoning is that diminutive polyps have a very low likelihood of harboring either malignancy or advanced
adenomatous features such as high-grade dysplasia or villiform change. Therefore, discarding these lesions
32-34without histologic evaluation should be cost-effective and clinically efficacious, with an endoscopic
32sensitivity for correctly classifying adenomas of 94% and specificity of 89%. Furthermore, these polyps may be
35assessed by in situ optical scanning techniques that can help predict polyp histology. For instance, narrow
36band imaging has a reported negative predictive value of 95%, which further increases physician confidence
that the polyps can be discarded without pathologic examination.
Endoscopic Snare Polypectomy
D uring 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. D epending 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.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.
37,38Many endoscopists have reported successful removal of diminutive polyps (snare polypectomy. 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 larger than 0.5 cm 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).
A lternatively, large polyps can be removed in a piecemeal fashion and submi5 ed to pathology in several parts.
27This technique usually requires multiple transections of the lesion until the entire polyp has been removed.
One caveat with this technique is that identifiable tissue margins may be lost, so that the pathologist is often
unable to determine the status of the resection margins.
A hot snare allows the endoscopist to apply modulated electrosurgical current to a metal wire that cuts
through pedunculated polyps at the base. This assists tissue cu5 ing 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. I n 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. I nformation on the relative risk of clinically significant hemorrhage after hot polypectomy is
39,40limited, but the risk is generally considered to be low (0.4%). A large cross-sectional study from S outh
Korea established that loop polypectomy is only rarely performed without electrical current (i.e., cold
41polypectomy), but this is usually inadvertent, resulting from failure of application of the current. A bsence of
electrical current is associated with an increased risk of clinically significant postpolypectomy hemorrhage. A
higher risk of postpolypectomy hemorrhage also occurs in patients with pedunculated polyps larger than 1.7 cm
42or a stalk diameter larger than 0.5 cm, sessile polyps, or 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. A n artificial stalk can be
created when large sessile lesions are loop-excised. A true pedunculated polyp, with a stalk, has a narrow base
that persists after removal; the base of a sessile polyp is typically as wide as the mucosal surface that is sampled.
S nares are available in a variety of shapes and sizes. S ome snares can be rotated, which provides the
endoscopist with greater control of snare placement. The choice of snare size is usually based on the size of the
lesion being removed. The selection of a particular snare shape is a matter of personal choice.
S nare polypectomy is performed in a similar fashion regardless of whether colonic, esophageal, gastric, or
small bowel lesions are being removed. The ampulla of Vater may be resected by standard snare techniques if
43 44,45an ampullary lesion is discovered. The risk of perforation during snare polypectomy is less than 0.1%,
and perforation usually results from transmural burn secondary to cautery. One commonly used techniqueaimed 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.
46,47A nother commonly used method is saline-assisted polypectomy. A small needle is passed through the
endoscope and inserted into the gut wall adjacent to the polyp. A bolus of normal saline is then injected. Fluid
collects within the submucosal plane, 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
the electrical current. S aline-assisted polypectomy is usually reserved for large sessile polyps and ampullary
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
feature of endoscopic mucosal resection (EMR). This technique is commonly used to resect premalignant and
48malignant lesions confined to the mucosa. I n general, EMR requires some measure of confidence that a lesion
is, in fact, confined to the mucosa or submucosa. Many endoscopists now rely on endoscopic ultrasonography
(EUS ) to determine the depth of a particular lesion before EMR. The accuracy of high-frequency EUS (15 or
4820 MHz) may be as great as 95% for determining whether a lesion is limited to the mucosa.
S everal variations of the EMR technique are currently used. Many rely on submucosal injection of liquid, but
49there is no agreement regarding the type or quantity of liquid that should be injected. Most endoscopists
advocate the use of saline alone. Others add diluted epinephrine to saline in an a5 empt to constrict small blood
vessels at the base of the lesion. S ubmucosal fluid collections are absorbed in a relatively short time period,
which can limit their value. To lengthen the amount of time that the submucosal cushion may last, and thus
maximize the time available for performing a safe resection, investigators have used hypertonic solutions of
3.5% saline or 50% dextrose. Others advocate use of sodium hyaluronate instead of saline. N one of these agents
is used more often than simple saline. The quantity of liquid injected also varies. There is general agreement
that the selected lesion should appear, endoscopically, to be raised by the cushion of liquid before the EMR is
performed. Failure to lift the lesion despite generous use of submucosal saline (the so-called nonlifting sign)
50may be a sensitive indicator that a lesion has spread deeper 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 is passed through the second channel and
used to grab the lesion and pull the mucosa through the snare farther away from the muscularis propria. The
snare is then closed around the base of the tented lesion, and electrocautery is applied (Fig. 1.3). This method is
48,51referred to as the 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 (top left). The top of the mound
is pulled upward with forceps, and the snare is placed at the base of the lesion (top right
and bottom left). Electrosurgical current is applied through the snare to resect the mucosa,
and the lesion is removed (bottom right). B, EMR by aspiration: Saline is injected into the
submucosa, and the tissue is elevated (top left). The lesion is aspirated into a plastic cap at
the end of the endoscope, and the snare is closed around the lesion (top right). The
ensnared lesion is released from the cap (bottom left). Electrosurgical current is applied, and
the resected lesion is trapped within the cap by aspiration (bottom right). (A and B used 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. 1999;50:819-822.)
S uction methods of EMR incorporate the use of a cap fi5 ed onto the tip of an endoscope. The cap presents an
open surface to the mucosa and creates a short chamber into which the selected lesion may be aspirated and
held by suction, which is applied through a single-channel endoscope. A specialized snare is opened in the cap
before aspiration of the lesion. Once the mucosa has been drawn into the cap, the snare may be closed around
48the lesion and cautery applied in the usual fashion. This technique, also called aspiration mucosectomy, has
52been widely successful for removing lesions throughout the GI tract.
A newer EMR technique is similar to aspiration mucosectomy, but after the lesion has been 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 may be
removed by snare cautery. This is known as band-ligation EMR (Fig. 1.4).FIGURE 1.4 Band-ligation endoscopic mucosal resection. A, A region of endoscopically
visible high-grade dysplasia in the esophagus. B, A rubber band ligator has been applied to
the base of the lesion after aspiration of the mucosa and submucosa into a cap affixed to the
end of the endoscope. The result is a polypoid area containing the dysplastic tissue. C, The
pseudopolyp has been resected by snare cautery and can be retrieved for tissue
processing. D, The region where dysplasia was present has been removed, leaving a
cleanbased ulcer.
EMR allows the endoscopist to a5 empt an en bloc resection and thus, potentially, to completely resect an
51early malignant lesion. En bloc resection is limited, however, to small lesions (1.5 to 2 cm in largest diameter).
53I f deep margins are positive for neoplasia, surgical resection of the affected region is advocated. Current
indications for EMR include superficial carcinoma of the esophagus or stomach in patients who are not
candidates for surgery; unifocal high-grade (or low-grade) dysplasia in Barre5 's esophagus; and large, flat
colorectal adenomas (which might otherwise require piecemeal resection) regardless of the degree of dysplasia.
EMR as a form of primary therapy for small, superficial cancer has gained increasing popularity in the United
48,51,53S tates but is even more widely used in J apan, where early gastric cancer is more common. EMR is also
used as a form of primary therapy for small submucosal lesions such as rectal carcinoid tumors or leiomyomas.
54In 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 has 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 fewer than 1% to as many
48,51,53as 20% of cases, depending on the size of the lesion and its location. Clinically significant bleeding is
rare and usually is amenable to endoscopic hemostatic cauterization. Perforation rates are lower than 2% in the
55hands of experienced operators. A recent recommendation is that the endoscopist should immediately
inspect the underside of the resected specimen for the presence of a “target sign”: a pale ring of muscularis
mucosa resected with the mucosal lesion. A pplying endoscopic clips to the corresponding defect in the
resection site is purported to represent an effective method to mitigate against the risk of postprocedure
56bleeding. I n the hands of experienced operators, EMR results in large specimens for pathologic analysis, even
in the absence of complete resection. S uccess rates for en bloc resection of early gastric cancers by EMR range
51,53from 36% to 74%, greatly reducing the need for full-thickness surgical resection.
Methods of Processing Tissue for Pathologic Evaluation
A general framework for processing biopsy specimens is provided in Table 1.2.Table 1.2
Techniques of Processing Tissue Specimens Obtained by Endoscopy
Technique Comment
Formalin fixation Routine processing of all alimentary tract biopsies; immediate immersion in fixative.
Permits immunohistochemistry, molecular analysis.
Flow cytometry Suspected hematologic malignancy; fresh tissue in sterile culture medium
Electron Suspected poorly differentiated malignancy, infection (e.g., Whipple disease,
microscopy microsporidiosis); immediate immersion in electron microscopy fixative
Electron Suspected systemic mastocytosis, for which plastic-embedded thick sections with
microscopy toluidine blue staining may be used for identification of 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 fixatives used for human tissue, 10% buffered formalin remains the standard and is well
suited for mucosal biopsies of the GI tract. I t is inexpensive, is harmless to the tissue even after long periods,
and is compatible with most of the stains commonly used for morphologic assessment. Hollende solution, B5,
and Bouin fixative have been used for mucosal biopsies because of be5 er preservation of nuclear morphology
compared with formalin. However, the heavy metal content of these fixatives creates biohazard disposal
problems that are greater than those of formaldehyde-based fixatives. These fixatives also interfere with
isolation of nucleic acid from tissue; the search for substitute fixatives and new tissue processing techniques is
an active area of scientific investigation.
On occasion, the formaldehyde in formalin may be irritating to the eyes and upper respiratory tract of
personnel. The level at which formalin is considered carcinogenic is well above the level that causes sensory
57irritation, which has a threshold of 1.0 ppm. A ccordingly, in pathology suites, proper ventilation should be
used to maintain exposure below 1.0 ppm, the lowest concentration that may exert a cytotoxic effect in
58,59 60humans. A workplace surveillance program for formalin exposure is recommended. Typical occupational
exposure in endoscopy suites is exceedingly brief, so special ventilation is not usually required in that hospital
area.
A limentary tract biopsy specimens should be placed in a volume of formalin fixative that is at least 10 times
greater than that of the tissue, and the fixative should surround the specimen completely. These parameters are
usually easily met with small endoscopic tissue samples and even with those obtained by EMR, using small
tubes of fixative solution. For routine processing, it is a common mistake to place specimens on saline-soaked
gauze for delivery to the pathology suite: S evere drying may occur. Complete immersion of these biopsies in
formalin should always occur at the bedside. Formaldehyde diffuses into tissue at a rate of approximately
611.0 mm per hour at room temperature. Therefore, up to 1 hour is often needed to adequately fix a specimen
with a diameter greater than 1.0 mm, and more time is needed for larger specimens. Controlled microwave
62fixation at 63° to 65° 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 either a Crosby
63,64suction capsule or a Quinton hydraulic assembly. These two methods were performed fluoroscopically and
therefore did not permit direct visualization of the alimentary tract. Biopsies obtained by these methods were
carefully oriented under a dissecting microscope before fixation and embedding. By the late 1980s, the
fluoroscopy had been replaced by a suction capsule biopsy procedure in direct endoscopic biopsy of the small
65,66intestine. Biopsies obtained by this technique are not usually oriented before immersion in fixative,
processing, and embedding. Rather, microscopic examination of multiple tissue sections usually permits
identification of portions of the small intestinal mucosa that are well oriented and therefore can be assessed
satisfactorily for tissue architecture.I n contrast, processing of an endoscopic polypectomy specimen in the pathology suite requires diligent
67effort. The size and surface configuration (bosselated or villiform) of the polyp should be noted, and the base
of the polyp should be identified and described as to whether it is sessile or contains a cylindrical stalk.
Regardless of the configuration of the stalk, the base of the polyp should always be inked. I nk and cautery
artifact on a microscopic slide are valuable landmarks for locating the relevant resection margins. Small polyps (
S ection levels should be numbered consecutively; the first level is the one usually located closest to the
middle of the polyp stalk. Large polyps (≥1 cm in diameter) may be sectioned differently if the polyp head is too
wide to fit into a single casse5 e. First, the polyp should be bisected along its long axis and fixed overnight in
formalin. Once fixed, the sides of the polyp may be trimmed away from the stalk on a vertical axis and
submi5 ed in separate casse5 es that are labeled accordingly. The middle of the polyp, including the base,
should be sectioned vertically and submi5 ed in an appropriate number of casse5 es. I f a stalk is identified
histologically, the status of the margins should always be noted in the surgical pathology report.
I f the polyp has been excised in a piecemeal fashion, the size, color, surface configuration (bosselated or
villiform), and aggregate dimensions of the tissue fragments should be noted. I t is important to record the
number of tissue fragments received in the pathology suite.
Flow Cytometry
GI lesions suspected of representing a lymphoproliferative process are usually submi5 ed for histology but
68should also be processed for flow cytometry. Biopsy specimens intended for flow cytometric analysis, such as
gastric biopsies of a mass lesion or EUS -guided fine-needle aspiration (FN A) samples from concerning lymph
nodes, should be placed in sterile culture medium and delivered as rapidly as possible to the flow cytometry
laboratory. I deally, this should occur within several hours, but storage of specimens at 4°  C overnight is an
acceptable alternative.
On receipt in the laboratory, the tissue specimen is disaggregated, and a cell suspension is prepared.
Cocktails of fluorescently labeled antibodies appropriate to the diagnostic question are applied to the cell
suspension. Current flow cytometry machines can analyze 5000 to 10,000 cells per second, measuring multiple
wavelengths of laser-induced fluorescence simultaneously and thus permi5 ing rapid and highly efficient
analysis of cell populations. This technique cannot be performed on fixed tissue. I t is therefore incumbent on
the endoscopist to consider the possibility of a lymphoproliferative disorder at the time of endoscopy in order
to ensure that tissue is preserved in a fresh state. Communication between the endoscopist and the pathologist
before or immediately after the procedure increases the likelihood that the flow cytometry sample will be
received and processed in a timely fashion.
Electron Microscopy
For the rare instances in which electron microscopy of an alimentary tract biopsy is contemplated, tissue
samples should be placed directly into the appropriate fixative, which usually consists of a mixture of
paraformaldehyde and glutaraldehyde. Unlike formaldehyde-based fixatives, bifunctional glutaraldehyde
fixatives penetrate only approximately 0.5 mm into the tissue. Therefore, tissue fragments to be placed in
fixative for subsequent electron microscopy should, ideally, measure less than 1.0 mm in maximal dimension.
I ndications for electron microscopy of endoscopic biopsy specimens are now largely limited to examination of
69unusual tumors. However, this technique is also helpful in cases of unknown diarrhea in children and in
patients with the acquired immunodeficiency syndrome (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. S ome of these are listed in Table 1.3. Histologic features of artifacts are provided in
Table 1.4. The most common type of artifact (or effect) is lamina propria edema and intramucosal hemorrhage,
known as scope trauma (Fig. 1.6). Other effects include aggregation and clumping of inflammatory cells in the
lamina propria, surface fla5 ening, mucin depletion, and even erosion and influx of air into the tissue
70-72(pseudolipomatosis). The most common histologic artifacts include cautery and crush artifacts occurring
as a complication of tissue resection techniques. These may be difficult to avoid in clinical practice given the
nature of current endoscopic resection technologies (Fig. 1.7). Cautery artifact as a result of hot biopsy is a
normal and expected component of endoscopic polypectomy with electrocautery. S pecifically, 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” (caused by mechanical damage from the 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 of Hirschsprung disease)
sampling
Insufficient regional sampling (e.g., of “normal-appearing” mucosa)
location
Chemical colitis Inadequate rinsing of cleaning solution from the endoscope
Laxative-induced Edema, damage to surface epithelium from exposure to oral and rectal laxatives
changes
Air-drying Failure to immerse specimen promptly in fixative
Postbiopsy healing Sampling of a previous biopsy site during subsequent endoscopy
Wrong fixative Formalin rather than fixative for electron microscopy (suboptimal but not irretrievable)
No fresh tissue Failure to preserve fresh tissue; precludes flow cytometry, cytogenetics
Data from references 70-73.
Table 1.4
Histologic Artifacts Related to Endoscopy
Event Feature
“Scope trauma” Mucosal lamina propria hemorrhage or edema
Changes related to Clumping of inflammatory cells, mucin depletion, epithelial degenerative changes, focal
bowel neutrophilic infiltration, hemorrhage, edema, air in mucosa (pseudolipomatosis)
preparation
Insufflation of air Air spaces within mucosa or submucosa (pseudolipomatosis)
at endoscopy
Cautery artifact Coagulated, eosinophilic tissue without cellular or nuclear detail
Crush artifact Compressed tissue with markedly elongated, wavy nuclear remnants and no identifiable
architecture
Chemical colitis from inadequate cleaning of the endoscope
Degenerative damage to or sloughing of surface epithelium, intraepithelial neutrophils
and congestion, focal intramucosal hemorrhage
Laxative-induced Lamina propria edema and neutrophilic infiltration, flattening or sloughing of mucosal
changes 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 1.5FIGURE 1.6 Endoscopic appearance of “scope trauma.” A, A duodenal fold is swollen
because of lamina propria edema induced by passage of an endoscope; the region shows a
subtle ring of mucosal hemorrhage. B, The colonic mucosa demonstrates multifocal areas of
mucosal hemorrhage after withdrawal of the colonoscope; these were not present during
initial advancement of the colonoscope into the colon. (Photographs courtesy of Dirk Van
Leeuwen, Dartmouth Mary Hitchcock Medical Center, Lebanon, NH.)FIGURE 1.7 Histologic artifacts in endoscopic biopsies. A, Cautery artifact: Mucosal
architecture is obliterated, leaving a heat-induced coagulum with holes in the tissue and no
appreciable cellular architecture. Cautery artifact is an expected component of a hot biopsy
and is a useful guide for identifying the base of a polypectomy sample. B, Crush artifact: The
pinch site at the base of a biopsy is shown in the center of the image. All architectural details
are lost, and basophilic nuclear material is crushed against eosinophilic matrix and cellular
debris. C and D, Hemorrhage, edema, mucin depletion, and artificial shearing of the surface
epithelium as a result of bowel preparation procedures and endoscopic trauma. E,
Pseudolipomatosis of the colonic mucosa secondary to insufflation of air at the time of
endoscopy.
Pathologic Features of a Healing Biopsy Site
A fter endoscopic biopsy, the tissue healing process begins quickly (Table 1.5). A fter endoscopic polypectomy
involving removal of both mucosa and a portion of submucosa, granulation tissue forms during the first days
73after biopsy (Fig. 1.8, A and B). Routine superficial biopsies that involve only mucosa reepithelialize within 48
hours (see Fig. 1.8, C) and heal completely within a few weeks with only mild residual architectural distortion
(see Fig. 1.8, D). Ulcers that penetrate into the muscularis propria, such as those that form after aggressive
endoscopic mucosal resection, often take 3 to 6 days to reepithelialize (see Fig. 1.8, F and G ) and as long as a
month to heal completely.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 of the colon after endoscopic biopsy, based on examination of biopsy
sites in colonic segmental resections at known intervals after an endoscopic procedure. A,
Gross photograph of a resected colon specimen 2 days after endoscopic biopsy of a small
pedunculated adenoma. The large white arrow points to the original biopsy site. A small
defect is visible and has a protruding knob of granulation tissue. B, Photomicrograph of the
endoscopic polypectomy site shows ulceration, inflammation, and a granulation tissue
reaction. C, Two days after simple endoscopic pinch biopsy, there is a smaller mucosal
defect. An attenuated layer of epithelium already covers the healing biopsy site. D, One
month after endoscopic biopsy, mucosal integrity is restored, but budding (regenerative)
glands, an inflamed lamina propria and submucosa, and disorganized ingrowth of smooth
muscle cells in the region of the former muscularis mucosae are present. E, Two months
after endoscopic biopsy, the mucosa exhibits glandular architectural distortion, no discernible
muscularis mucosae, and scarring of the submucosa. F, One week after transanal
endoscopic mucosal resection that included a substantial sample of muscularis propria, the
residual defect is still ulcerated, and there is extensive mural scarring. G, High-power image
of the margin of the defect shows early reepithelialization of the ulcer from intact adjacent
mucosa.
A fter routine endoscopic mucosal biopsy during upper or lower endoscopy, there is no increased risk of
perforation because of subsequent insufflation (as from repeat endoscopy or from barium enema), even
immediately after the biopsy. The risk of perforation after a deep biopsy or endoscopic musocal resection that
73involves the muscularis propria returns to baseline within 3 to 6 days.
Pathologists should be aware of the changes associated with colonic biopsy site repair and not misinterpret
focal architectural distortion of the mucosa or focal submucosal scarring as evidence of inflammatory bowel
disease. I n addition, the finding of muscularis propria in a biopsy specimen in which this depth of sampling is
not expected (e.g., in an esophageal biopsy specimen) should be reported to alert the treating physician of the
potential risk of perforation.
Methods for Obtaining Cytology Specimens
See Chapters 3, 35, and 45.
Brush Cytology
74,75Brush cytology is a method used for broad sampling of the mucosal surface. Cytology brushes all have a
common design: Bristles, usually composed of nylon or metal fibers, branch off a thin metal shaft that runs
lengthwise within a protective plastic sheath. The various brushes that are currently available do not seem to
76vary in terms of performance characteristics. The cytology brush is passed through an accessory channel of anendoscope. 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 withdrawn from the endoscope, and the
brush is pushed out of the sheath, thus exposing the bristles. The bristle portion of the brush may be cut off,
placed into fixative, and sent in its entirety to the cytopathology laboratory. A lternatively, the bristles may be
rolled against a glass slide in the endoscopy suite. The slides should be immediately sprayed with fixative or
submerged within it and subsequently delivered to the cytopathologist. I f smears are made in the endoscopy
77suite, li5 le additional benefit is derived from inclusion of the bristles for cytopathologic analysis. Brush
cytology is most often used in the pancreaticobiliary tree to sample strictures in the pancreaticobiliary tract.
Another common use is sampling of esophageal plaques or lesions suspected to represent candidiasis.
Fluorescence in situ hybridization (FI S H) is an increasingly used technique that can be applied to biliary
brush cytology tissue specimens in patients with suspected pancreaticobiliary cancer and in those with primary
sclerosing cholangitis (who are by definition at increased risk for cholangiocarcinoma). FI S H relies on the fact
that a very high percentage of pancreaticobiliary malignancies show chromosomal aneuloploidy, typically with
chromosomal gains or additions. The presence of these polysomies is strongly associated with malignancy.
Commonly used and commercially available probes are used to target the pericentromeric regions of
chromosomes 3 (CEP 3), 7 (CEP 7), and 17 (CEP 17) and the chromosomal band 9p21 (LS I 9p21). FI S H can be
performed on biliary brush cytology specimens. A dedicated biliary brushing is often obtained for FI S H testing.
When FI S H results are combined with those of routine biliary cytology, the diagnostic yield is much
78-81higher.
Fine-Needle Aspiration
82-84FN A is another widely used method for obtaining tissue for cytology. FN A needles may be used during
standard endoscopy or EUS . EUS provides endoscopists with the ability to sample tissue from parenchymal
lesions and lymph nodes and fluid from cystic lesions. EUS provides real-time imaging to ensure that the
intended target is localized and sampled. The needles used for FN A during endoscopy areh ollow 19- to
25gauge needles and are often fi5 ed with a central stylet to avoid gathering of intervening tissue. S ome needles
can also obtain a “core” of tissue (which may be analyzed histologically) in addition to samples for cytologic
evaluation.
Once the lesion of interest has been identified, the sheath is pushed out of the endoscope, and the needle is
advanced into the target tissue under ultrasonographic guidance (during EUS ). I f a stylet is present, it is
removed, and suction is applied to a syringe at the proximal end of the needle. The endoscopist moves the
needle forward and backward within the lesion, filling the distal needle lumen with tissue. S ome endoscopists
85use suction during EUS FN A of solid lesions, whereas others do not. S uction is used to aspirate cysts for
86obvious reasons; there is some disagreement regarding the use of stylets in routine practice. The needle is
then withdrawn into the sheath, and the entire apparatus is removed from the endoscope. Complications from
FN A biopsy occur in fewer than 2% of cases; they include bleeding and, in the se5 ing of pancreatic mass FN A ,
acute pancreatitis.
Optical Techniques
I n recent years, there has been an increase in the use of optical techniques to assess in real time the pathologic
87status of patients with various disease states. N arrow band imaging (N BI ) is a technique in which a
highdefinition videoendoscope is used to allow evaluation of the GI mucosal surface without the use of dyes. N BI is
commercially available, and a high percentage of endoscopists have access to this technology. N BI uses
different types of optical filters to apply specific wavelengths of light that can achieve deep penetration of the
tissue. S pecifically, use of red light results in visualization of deeper tissue layers, because red light penetrates
more deeply into tissue than blue light does. N BI allows enhanced mucosal and vascular resolution, compared
with white light endoscopy. N BI also allows the endoscopist to evaluate large areas of the GI mucosa without
the use of vital dyes.
N BI has several clinical uses. I n Barre5 's esophagus, evaluation with N BI in which the vascular pa5 ern and
the mucosal regularity are assessed can be used to identify patients with dysplastic mucosa (Fig. 1.9, A and
88,89B). N BI has also been used to evaluate gastric and colonic lesions, in a5 empts to increase the polyp
detection rate during screening colonoscopy and to assess for dysplasia or malignancy in endoscopically visible
lesions. N BI does not appear to increase the adenoma or polyp detection rate during screening
90,91 92colonoscopy, but it does allow real-time detection of adenomas during colonoscopy. This technology
raises the possibility of performing an “optical biopsy” to identify adenomas during endoscopy. A s stated
earlier, whether diminutive, resected lesions optically identified as adenomas should still be sent for formal
pathologic evaluation or simply discarded remains a highly controversial issue.FIGURE 1.9 Optical imaging of the tubal gut. A, Standard white light image of a segment
of Barrett's esophagus. B, Narrow band image (NBI) of the same esophagus. C, White light
image of Barrett's esophagus and (D) confocal laser endomicroscopy (CLE) of the same
area. E, CLE image of intramucosal adenocarcinoma in Barrett's esophagus after
administration of intravenous fluorescein contrast. There is significant loss of glandular
architecture and leakage of fluorescein contrast. Large pleomorphic nuclei appear dark with
this imaging modality. F, Normal colonic mucosa is seen with CLE after intravenous
administration of fluorescein dye. Crypts are evenly spaced, and there is uniform distribution
of dye within colonocytes. (Images courtesy of Dr. Sharmila Anandasabapathy, Mount Sinai
School of Medicine, New York, NY.)
One other technique related to N BI is confocal laser endomicroscopy (CLE). This technique uses laser
technology to illuminate tissue and detect reflected fluorescent light. This technique allows cellular resolution
in vivo and in real time. The technique can be performed with special endoscopes (scope-based CLE) or with
standard endoscopes using specialized mini-probes that can be passed through the working channel of theendoscope (probe-based CLE). Probes are available for use in the esophagus, stomach, colon, and biliary tree.
This technique has not entered mainstream clinical practice but is currently an area of intense research because
there is a wide range of potential clinical applications, including the evaluation of Barre5 's esophagus, gastric
and colonic polypoid lesions, inflammatory bowel disease, and pancreaticobiliary strictures (see Fig. 1.9, C to
93F). Barre5 's esophagus may be the most promising area of interest given the desire to target dysplastic or
malignant tissue endoscopically for biopsy and potential ablation to facilitate targeted biopsies. I n this context
94-96the technique appears to be accurate and reproducible. However, it is unclear whether CLE will be used
routinely in clinical practice in the future.
Normal Histology of the Tubal Gut
Esophagus
The adult human esophagus measures approximately 25 cm in length. For the endoscopist, the length of the
esophagus is measured as the anatomic distance from the incisors. The esophagus usually begins at 15 cm, and
the gastroesophageal junction (GEJ ) is typically located at 40 cm. The 3-cm segment of proximal esophagus at
the level of the cricopharyngeus muscle (15 to 18 cm from the incisors) 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 universal anatomic landmarks that outline these high-pressure regions in relation to the underlying
esophageal musculature, although they can often be recognized during endoscopy by experienced clinicians.
I n keeping with the structural organization of the entire alimentary tract (Fig. 1.10), the wall of the esophagus
consists of mucosa, submucosa, muscularis propria, and adventitia. The mucosa has a smooth, glistening,
pinktan surface. I t has three components: a nonkeratinizing stratified squamous epithelial layer with an underlying
lamina propria and muscularis mucosae (Fig. 1.11). 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
97epithelium. The intraepithelial lymphocytes are mainly T cells. Melanocytes may be present in the esophagus
98,99in 3% to 8% of normal individuals. The lamina propria is the nonepithelial (mesenchymal) portion of the
mucosa and is located above the muscularis mucosae. I t consists of areolar connective tissue and contains
vascular and neural structures and sca5 ered inflammatory cells. Finger-like extensions of the lamina propria,
termed papillae, extend into the epithelial layer, usually to between one third to one half of its thickness. I n
esophagitis (e.g., reflux esophagitis), the papillae extend into the upper third of the epithelial layer. The
muscularis mucosae is a thick layer of longitudinally oriented smooth muscle bundles.FIGURE 1.10 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: Saunders; 2003:121-131.)
FIGURE 1.11 Normal histology of the esophageal mucosa. Stratified nonkeratinizing
squamous mucosa exhibits a basal zone of regenerating cells, rete pegs that extend partially
into the epithelial layer, and scattered intraepithelial lymphocytes.
T he submucosa consists of loose connective tissue containing blood vessels, a rich network of lymphatics,
inflammatory cells, lymphoid follicles, nerve fibers (including the ganglia of Meissner plexus), and submucosal
glands. S ubmucosal glands, which connect to the lumen of the esophagus by ducts lined with squamousepithelium, are sca5 ered along the entire esophagus but are more concentrated in the upper and lower
portions. S ubmucosal glands are suspended within the delicate mesenchyme of the submucosa. They have a
simple acinar structure and resemble salivary glands in that they contain mucous cells surrounding a central
lumen in a radial fashion. Their mucin-containing fluid secretions help lubricate the esophagus. S ubmucosal
100glands also secrete biologically active peptides such as those from the trefoil factor family 3 (TTF3) ; these
peptides play a role in mucosal protection and repair. Identification of a squamous duct and submucosal mucous
glands is considered a definitive anatomic landmark of the tubular esophagus. I n 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 surrounding the
gland ducts is commonly present.
Endoscopic biopsies of the esophagus usually yield squamous epithelium, lamina propria, and, occasionally,
the prominent underlying muscularis mucosae. S ampling of the submucosa is variable. The anatomic
landmarks change in patients with Barre5 's esophagus: The lamina propria no longer lies underneath the
epithelial layer only but is also located between the glands. A newly developed and more delicate muscularis
mucosae lies directly underneath the glands. This layer of muscularis mucosae represents the superficial layer
101of a “double muscularis” in patients with Barrett's esophagus (see Chapter 14 for more details).
Stomach
The stomach is a large, saccular organ with a volume of 1.2 to 1.5 L but a potential capacity of more than 3 L. I t
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 , which is generally considered to
represent the most proximal point of the gastric folds. I t 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 called the greater curvature. The angle along the lesser
curve, termed the incisura angularis, marks the approximate point at which the stomach narrows before its
junction with the duodenum.
The stomach is divided into five anatomic regions. The cardia is a narrow (0.1 to 0.4 cm in length), conical
portion of the stomach that is located immediately distal to the GEJ . I t has no anatomic landmarks and
therefore is defined by the presence of mucous glands or mixed mucous and oxyntic glands in the most
proximal gastric mucosa. The fundus is the dome-shaped portion of the proximal stomach that extends
superolateral to the GEJ and is composed exclusively of oxyntic glands. Theb ody, or corpus, comprises the
remainder of the stomach proximal to the incisura angularis. The stomach distal to the incisura, called the
antrum, contains simple mucous glands and is demarcated from the duodenum by the pylorus and its associated
sphincter.
The gastric wall consists of mucosa, submucosa, muscularis propria, and serosa. The interior surface of the
stomach exhibits coarse rugae (“folds”). The rugal folds of mucosa and submucosa extend longitudinally and are
most prominent in the proximal stomach. The rugae fla5 en when the stomach is distended. A finer, mosaic-like
pa5 ern is delineated by small furrows within the mucosa. Finally, the delicate texture of the mucosa is
punctuated by millions of gastric foveolae, or “pits,” which lead to the mucosal glands.
The normal gastric mucosa has two main epithelial compartments: the superficial foveolar (“leaf-like”)
compartment and the deeper glandular compartment. The foveolar compartment is relatively uniform
throughout the stomach. I n contrast, the glandular compartment exhibits major differences in thickness and
composition in different regions of the stomach (Fig. 1.12). The foveolar compartment consists of mucous cells,
which line the entire mucosal surface, and gastric pits ( foveolae). The tall, columnar, mucin-secreting foveolar
cells contain basal nuclei and crowded, small, relatively clear, mucin-containing 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 represent the cell progenitors of both the surface epithelium and the gastric
glands. Mitoses may be identified in this region, because the entire gastric mucosal surface is usually replaced
completely every 2 to 6 days.FIGURE 1.12 Normal histology of the stomach. A, High-power view of the distal esophagus
and proximal stomach (cardia) shows simple mucous glands (and some oxyntic glands)
underlying the surface and crypt epithelium. B, Low-power view of oxyntic mucosa shows
the thickness of the glandular mucosa. C, Low-power view of the antral mucosa shows a
slightly thinner mucosa, with mucous glands only.
The glandular compartment consists of gastric glands, which vary among the different anatomic regions of
the stomach.
• As noted earlier, in the cardia the mucosal 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 15). 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, meaning
“acidforming.”
• Antral and pyloric glands are identical and contain both mucus-secreting cells and endocrine cells. At the
junction of the antrum with the gastric body, 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 mucosaenters the proximal duodenum, the small intestinal mucosa (discussed 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 glands.
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
group 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 hematoxylin and eosin (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 within 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; ultrastructurally, they 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 29 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, via secretion directed into the local
tissue. In antral mucosa, most endocrine cells consist of gastrin-producing G cells. In the body, the endocrine
cells produce histamine, which binds the H receptor on parietal cells and leads to increased acid production.2
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, approximately 0.1 to 0.4 cm in length, which is located at the proximal cone of the gastric
cavity, just distal to the squamocolumnar mucosal boundary (Z-line) in normal individuals. Traditionally, the
gastric cardia is viewed as having “cardiac” mucosa, which is a mucinous, glandular mucosa typically lacking
the oxyntic glands that contain chief and parietal cells (see Fig. 1.12, A). However, some individuals show a
mixture of both types of glands (mucous and oxyntic) (see later discussion and Chapters 14 and 15).
The strict (physiologic) definition of the GEJ is actually manometric, in that the high-pressure zone of the
lower esophageal sphincter defines the true distal end of the esophagus. Because manometry is not a normal
part of routine endoscopy and the GEJ passes through the diaphragmatic orifice, the performance of endoscopy
on a live, breathing patient makes it difficult to identify precisely the true anatomic location of the GEJ region.
The point of flaring of the gastric cavity identified by retroflexion of the endoscope is considered to be a reliable
indicator of the beginning of the stomach. However, an axial hiatal hernia or proximal migration of the
squamocolumnar mucosal junction in the se5 ing of gastroesophageal reflux (whether physiologic or pathologic)
can makes it very difficult to identify the anatomic site of the most proximal stomach at the time of endoscopy.
The origin and nature of epithelium in the cardia region of the stomach is controversial. I n 1997, Öberg and
102colleagues found that 26% of endoscopic biopsies obtained at and below the GEJ in 334 patients showed
absence of cardia-type mucinous glands. Patients who had cardiac mucosa were also significantly more likely to
103have GERD . Chandrasoma and coworkers reported that the presence of cardia-type gastric mucosa or
“oxyntocardiac mucosa” (combined oxyntic and mucous glands) in the GEJ correlated with acid reflux. They
concluded that all cardia-type mucosa in the GEJ region represents metaplastic transformation of the squamous
104epithelium as a result of reflux. I n 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 in 10 (56%).
105These findings were contradicted by Kilgore and associates, who found cardia-type mucosa at the GEJ in all
autopsies of 30 pediatric patients, a population considered to be at low risk for GERD . Other investigators have
found either mucous glands or mixed mucous glands in most patients at the GEJ , even in those without any
history of GERD (Table 1.6).Table 1.6
The Gastric Cardiac Mucosa: Key Publications
Author Study Design Findings Conclusions
Öberg et al, Endoscopic No cardiac mucosa was Cardiac mucosa is the result of
1997102 biopsies; 334 detectable in 88 (26%). GERD.
patients
Chandrasoma Endoscopic Cardiac/oxyntocardiac mucosa Cardiac mucosa is not a normal
et al, 2000103 biopsies with was related to GERD in all anatomic structure.
acid reflux 71 patients.
measurement
Chandrasoma Autopsy study, Cardiac mucosa was absent in Cardiac mucosa is not a normal
et al, 2000104 adults 10 (56%) of 18 cases. anatomic structure.
Kilgore et al, Autopsy study, Cardiac mucosa was present in Cardiac mucosa is a normal
2000105 pediatric all 30 cases. anatomic structure.
Sarbia et al, Esophagogastric Cardiac mucosa or Cardiac and oxyntocardiac mucosa
2002106 resection oxyntocardiac mucosa is is a dynamic structure.
specimens present in all 20 cases.
Park et al, Autopsy study, Transitional zone was present Cardiac mucosa composed of pure
2003107 fetal and in the proximal fetal mucous cells is not a normal
pediatric stomach developmental structure.
Glickman et al, Biopsy study, 74 Pure mucous or mixed Cardiac mucosa is present in most
2002108 pediatric mucous/oxyntic glands pediatric patients and may
patients were present in 100% of increase in length with GERD.
patients
Chandrasoma Endoscopic Abnormal columnar A histologic system for classifying
et al, 2003109 biopsies, 959 epithelium was present in columnar mucosa of the cardiac
patients 811 (84.6%). region is proposed.
Marsman et al, Endoscopic Cardiac mucosa was present in Cardiac mucosa is uniformly
2004110 biopsies, 198 62% of patients, present adjacent to the
patients oxyntocardiac mucosa in squamous epithelium of the
38%. esophagogastric junction.
De Hertogh et al, Autopsy study, Simple columnar epithelium At least a part of the adult cardiac
2005111 fetal was identified in distal mucosa has a congenital origin.
esophagus of 48 fetal
autopsy specimens.
Lord et al, Endoscopic Cardiac mucosa was identified Cardiac mucosa can be acquired,
2004112 biopsies, after in 10 of 20 patients in likely related to reflux of acid
esophageal cervical esophagus. into remnant esophagus.
resection
GERD, Gastroesophageal reflux disease.
Data from Odze RD. Unraveling the mystery of the gastroesophageal junction: a pathologist's perspective. Am J
Gastroenterol. 2005;100:1853-1867.
A summary of the objective evidence and the controversies surrounding the nature of the cardia was reported
113by Odze in 2005. I n that evidence-based review, the preponderance of data indicates that the true gastric
cardia is an extremely short segment (Chapter 15.
Small Intestine
The adult small intestine is approximately 6 m in length. The colon (large intestine) is approximately 1.5 m in
length. The first 25 cm of small intestine, the duodenum, is retroperitoneal; the jejunum marks the entry of the
small intestine into the peritoneal cavity. The remainder of the small intestine is intraperitoneal until the point
at which it enters the colon at the ileocecal valve. The demarcation between the jejunum and ileum is not a
clearly defined landmark; the jejunum arbitrarily constitutes the proximal third of the intraperitoneal portion,
and the ileum the remainder.
The most distinctive feature of the small intestine is its mucosal lining, which is designed to provide maximalsurface area for the purpose of food absorption. The luminal area is enhanced by the presence of
circumferentially oriented plica circulares, which protrude into the lumen to impart a corrugated texture to the
intestinal surface. When cut in longitudinal section and examined histologically, the plica circulares are seen to
provide an undulating substrata for the mucosal lining (Fig. 1.13, A). At medium-power magnification, the
mucosa consists of innumerable villi, which extend into the lumen as finger-like projections covered by
epithelial lining cells (see Fig. 1.13, B). The central core of lamina propria contains blood vessels, lymphatics, a
small population of lymphocytes, eosinophils, mast cells, and sca5 ered fibroblasts and vertically oriented
smooth muscle cells. Between the bases of the villi are the pitlike crypts of Lieberkühn, which contain stem cells
that replenish and regenerate the epithelium. The crypts extend down to the muscularis mucosae. The
muscularis mucosae is a smooth, continuous sheet that serves to anchor the configuration of villi and crypts
alike. Villus height is greatest in the duodenum (except in the first portion) and in the proximal jejunum. Figure
1.13, C and D, represents a tissue sample obtained by a fluoroscopic suction-capsule biopsy technique. I n
normal individuals, the villus-to-crypt height ratio is between 4 : 1 and 5 : 1, but this is variable. I n the proximal
duodenum, which is exposed to gastric peptic juices to the highest degree, the villus-to-crypt height ratio may
reach only 2 : 1 to 3 : 1. Within the duodenum are abundant submucosal mucous glands, termed Brunner glands
(see Fig. 1.13, E). They are present immediately distal to the pyloric channel and extend into the second portion
of the duodenum. These glands secrete bicarbonate ions (which help neutralize peptic juice as it enters the
small intestine), glycoproteins, and pepsinogen I I . Except for their submucosal location, Brunner glands are
virtually indistinguishable from the mucous glands of the distal stomach.FIGURE 1.13 Normal histology of the small intestine. A, Low-power image of the distal
jejunum from a surgical specimen (longitudinal section). The mucosa rests on the plica
circulares; the muscular layer at the base of the image is the muscularis propria. B,
Mediumpower image shows mucosal villi and short crypts. C, Low-power image of a fluoroscopic
suction-capsule biopsy of the third portion of the duodenum shows tall villi and short crypts
resting on the muscularis mucosa. Vascular congestion is an occasional artefact of the
suction technique. D, High-power image of a villus shows the vascular stalk and an epithelial
layer resting on a basement membrane. Absorptive enterocytes exhibit basal nuclei and an
apical “brush border,” and there are interspersed goblet cells. Intraepithelial lymphocytes are
rare. E. Low-power image of the duodenum shows villiform mucosa, a submucosa occupied
by Brunner glands, and underlying muscularis propria.
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 by an
underlying mat of microfilaments (the “terminal web”) (see Fig. 1.13, D). I nterspersed regularly between
absorptive cells are mucin-secreting goblet cells and a few endocrine cells, described later. Goblet cells in the small
intestine contain mainly acidic sialated mucins, identifiable by the A lcian blue stain performed at pH 2.5
(acidic). Within the crypts reside stem cells, goblet cells, more abundant endocrine cells, and sca5 ered Paneth
cells. Paneth cells contain apically oriented, bright eosinophilic granules and help maintain intestinal
homeostasis through secretion of growth factors and a variety of antimicrobial proteins (e.g., defensins) that play
114,115a 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 proximalportion of the transverse colon. They normally are absent from the distal transverse, descending, and sigmoid
colon and the rectum.
Endocrine Cells
A diverse population of endocrine cells are sca5 ered among the epithelial cells that line the small intestinal villi
and small and large intestinal crypts (see also Chapter 29). Comparable cells are present in the epithelium
lining the pancreas, biliary tract, lung, thyroid, and urethra. Gut endocrine cells exhibit characteristic
morphologic features. I n most cells, the cytoplasm contains abundant fine eosinophilic granules that harbor
secretory products. The main portion of the cell is located at the base of the epithelium, and the nucleus resides
on the luminal side of the cytoplasmic granules. The number of endocrine cells in the small intestine is greater
than in the colon. The greatest diversity of endocrine cell types is in the duodenum and jejunum, and they
116become less diverse distally. 5-Hydroxytryptamine–containing endocrine cells are present in all regions of
the small and large intestine and comprise the single largest endocrine cell population. A minor proportion of
these cells contain substance P. The second largest cell population is that of glicentin cells, which are more
numerous in the ileum and colon. S omatostatin 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. Many
other peptides and bioactive compounds are released by endocrine cells in the small intestine and colon,
including β-endorphin, pro–γ-melanocyte-stimulating hormone (pro–γ-MS H), β-lipotropin, neurotensin,
glicentin, glucagon, and pancreatic polypeptide (see Chapter 29 for details).
Histologic distinction between endocrine cells and Paneth cells is based on the size and color of the
eosinophilic cytoplasmic granules. A lthough both cell types are pyramidal in shape, with broad bases that
narrow toward the crypt lumen, endocrine cells are small (approximately 8 µm in height), do not extend to the
surface of the epithelial layer, and contain abundant small, deeply eosinophilic granules. These granules may
have a basal orientation, with the nucleus displaced apically. 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. Paneth cell granules are always apical relative to the basally located cell nucleus.
The Intestinal Mucosal Immune System
Humans are exposed to an enormous load of environmental antigens through the GI tract, and the
ultrastructural surface area of the GI tract exposed to environmental antigens far exceeds that of the skin and
pulmonary tract. The immune system must balance antigenic tolerance against immune defense. The function
of the intestinal immune system is best addressed on the basis of its anatomy, almost all features of which can
be identified by routine light microscopy (Fig. 1.14; see also Chapter 31). Throughout the small intestine and
colon are nodules of lymphoid tissue, which lie either within the mucosa or within both the mucosa and the
submucosa. Lymphoid nodules distort the surface epithelium to produce broad domes rather than villi; within
the distal ileum, confluent areas of dense lymphoid tissue become macroscopically visible as Peyer patches. The
surface epithelium overlying lymphoid nodules contains both columnar absorptive cells and M (membranous)
cells, the la5 er found only in the small and large intestinal lymphoid sites. These cells cannot be readily
identified by light microscopy. M cells are capable of transporting antigenic macromolecules, intact, from the
lumen to the underlying lymphocytes, thus serving as an important afferent limb of the intestinal immune
system.FIGURE 1.14 Normal mucosa-associated lymphoid tissue (MALT) of the intestine.
Histologic sections from the jejunum show that the MALT may be confined to the mucosa
(A), rest astride the mucosa–submucosa interface (B), or reside predominantly in the
superficial submucosa (C). Peyer patches in the ileum are organized collections of MALT
(D). A focus of MALT in the colon also is shown (E).
Throughout the intestines, T lymphocytes are sca5 ered within the surface epithelium, usually at the base of
the epithelial layer. These T cells are referred to as intraepithelial lymphocytes (IELs), and are generally of the
cytotoxic CD 8+ phenotype. However, there is remarkable diversity of T-cell subtypes, some unique to the
117intestine. I n normal small intestinal villi, I ELs usually decrease in number from the base toward the tip. CD 3
immunohistochemistry can aid in detection of I ELs, particularly because some lymphocytes have irregular
118nuclear borders, which makes their identification on H&E stain more difficult. I n healthy individuals, the
duodenum usually contains less than 26 to 29 I ELs per 100 epithelial cell nuclei (mean, 11 per 100 in H&E–
119stained sections, 13 per 100 in CD 3-stained sections). The range of I EL counts among healthy individuals can
vary widely, from 1.8 to 26 per 100 epithelial nuclei, and there is no correlation between I EL counts and the
120villus-to-crypt height ratios. The mean number of I ELs decreases progressively in the distal small intestine
121,122and colon. N ormal villus I EL counts in the terminal ileum are in the range of 2 I ELs per 100 epithelial
123 124nuclei. A normal I EL count in the ileum does not preclude abnormality in the duodenum. A modest
125elevation in IEL counts accompanies many types of inflammatory conditions of the colon.
The lamina propria contains helper T cells (CD 4+), educated B cells, and plasma cells. The lamina propriaplasma cells secrete dimeric immunoglobulin A (I gA), I gG, and I gM, which enter into the splanchnic
circulation. I gA is transcytosed directly across enterocytes, or across hepatocytes, for secretion into bile; both
are mechanisms for delivering I gA 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 (MA LT). A lthough MA LT is most prominent in the small intestine, the
concept has relevance to both the stomach (as an acquired anatomic compartment) and the colon (in which it
also is normally present; see Chapter 31 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 a5 achment to the posterior abdomen are entirely
dictated by the mesentery, the anatomic locations of the colonic segments are established by other means. The
bulbous cecum and the ascending colon constitute the entire portion of the colon on the right side of the
abdomen and are fixed in location. A lthough peritoneal membrane covers their ventral surfaces, the dorsal
aspect of both the cecum and the ascending colon adheres 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
intraabdominal viscus, being entirely covered with peritoneum.) The transverse colon begins at the hepatic
flexure and swings across the most ventral aspect of the abdominal cavity to reach the splenic flexure. The
transverse colon is suspended by the lesser omentum, which reflects off the greater curvature of the stomach. I n
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 that is suspended entirely by mesentery. Therefore, it is subject to
redundancy that may, rarely, lead to volvulus. D istally, the colon is adherent to the posterior wall of the pelvis
beginning at the rectum, at approximately the level of the third sacral vertebra. Halfway along its 15-cm length,
the rectum passes between the crura of the peroneal muscles to exit the abdominal cavity.
I n normal adults, the length of the colon is quite variable but usually measures in the range of 0.8 to 1.1 m.
From the endoscopist's perspective, the rectal canal is approximately 15 cm in length, beginning at the anal
verge. The variable length of the sigmoid colon makes identification of further landmarks less reliable, but the
splenic flexure is located about 0.4 m proximal to the anal verge, and the hepatic flexure about 0.7 m proximal.
The anatomy of the wall of the colon is unique in that the external layer of the muscularis propria is
discontinuous. I nstead, 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 a5 achment of the mesentery to the colon. The second and third strips are located
equidistant at approximately 120 and 240 degrees around the circumference of the colon. Each strip is
approximately 0.5 cm in width, and they become 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 opposite sides of the cecal wall. N otably, throughout the entire length of colon, arteries and veins penetrate
through the continuous inner muscle layer at the edges of the tinea coli. These blood vessels constitute the
circumferential ramifications of the mesenteric vasculature. Hence, there are three double tracks of holes in the
inner muscle coat, owing to the orifices created by the penetrating vasculature. I t is through these holes that
diverticula usually protrude (see Chapter 7). S mall tags of adipose tissue, the epiploic appendages, also are
a5 ached to the colon, at the edges of the nonmesenteric tinea coli 120 and 240 degrees around the
circumference of the colon. I n this way, two double tracks of intermi5 ent epiploic appendages are created along
the entire length of the colon. Protruding diverticula can be difficult to identify because they are in the same
circumferential location as the epiploic appendages and may, in fact, protrude into epiploic appendages.
The cecum has the widest diameter of the colon, as well as the highest wall tension. N evertheless, the mural
thickness of the normal cecum is only approximately 0.2 cm. The mural thickness increases gradually over the
length of the colon and reaches approximately 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
approximately 2 to 4 cm in length. From the luminal aspect, the constrictions are termed haustral folds, and they
are prominent anatomic features notable during endoscopy.
The ileum inserts into the cecum at the ileocecal valve. This is a prominent circumferential lip of mucosa and
fa5 y submucosa that extends approximately 0.5 to 1 cm into the cecal lumen. The luminal opening may be
slitshaped or oval. The thickness of the “lip” is approximately 0.3 cm, but it may be thicker in some individuals.
The proximal aspect of the ileocecal valve contains small intestinal mucosa, and the distal aspect has colonic
mucosa. The mucosal transition occurs at the level of the abrupt luminal convexity of the valve. This structure
represents the mechanism that minimizes reflux of cecal contents into the ileum. Whether the “valve” restricts
flow of ileal contents into the cecum has never been established; it does not constitute a real muscular
sphincter.The function of the colon is to reclaim luminal water and electrolytes. Unlike the mucosa of the small
intestine, the colonic mucosa has no villi and is flat. The mucosa is punctuated by numerous straight,
nonbranching, tubular crypts that extend down and touch the muscularis mucosae (Fig. 1.15, A). 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
earlier discussion of small intestine), and undifferentiated crypt cells. Paneth cells are occasionally present at
the base of crypts in the cecum and the ascending and proximal transverse colon. I ELs are present throughout
122the colonic mucosal epithelium. Normal counts are less than 5 IELs per 100 epithelial nuclei.FIGURE 1.15 Normal histology of the colon. A, High-power view shows the characteristic
vertically oriented crypts resting on the muscularis mucosae. The delicate lamina propria
normally contains a modest population of mononuclear cells, predominantly lymphocytes.
BD, Medium-power images of normal colonic mucosa from different portions of the same
surgical resection specimen demonstrate variability in the contour of the mucosal surface. E,
Normal colonic mucosa may appear branched when located in the upper third of the mucosal
layer.
Two sources of potential diagnostic error arise from the normal variation in colonic mucosal microanatomy.
First, on occasion, the colonic mucosa exhibits undulation of the surface as a normal anatomic variant (see Fig.
1.15, B to D). A particular feature of this variant is that crypts that are located at the base of undulations appear
to branch in the upper third of the mucosa (see Fig. 1.15, E), akin to the type I I crypt branching evident on
125scanning electron microscopy. Confusion arises when these normal crypts are interpreted as evidence of
architectural distortion characteristic of chronic colitis. Crypt branching is considered abnormal only when it
occurs in the lower two thirds of the mucosal layer. S econd, in the immediate vicinity of a mucosal lymphoid
126nodule, the crypts are typically distorted. A lthough this may be obvious if the tissue section transects a
lymphoid nodule, a tissue section that passes near but not through a lymphoid nodule will reveal only
disorganized crypts. Scanning of 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 usually
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. I ts diameter is consistent and uniform along its length, approximately 0.3 to 0.5 cm. I t 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 layer 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 the submucosa (Fig. 1.16). The lymphoid tissue is particularly prominent in younger
individuals and dissipates gradually over a person's lifetime. The concept that the appendix undergoes normal
“fibrous obliteration” late in life has long been postulated. A n alternative proposal is that the fibrotically
obliterated lumen in resected appendices result from stromal proliferation in response to clinically silent
127mucosal or axial neuromas caused by repeated subclinical attacks of inflammation.
FIGURE 1.16 Normal histology of the appendix. In this low-power view,
mucosaassociated lymphoid tissue is visible in the mucosa and submucosa.Rectum and Anus
The rectum begins within the abdominal cavity and tapers rapidly to the base of the pelvis. The discontinuous
tinea coli converge and unite, again constituting 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.
128There are subtle differences 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.
1.17). Unlike the crypts in the rest of the colon, those in the rectum do not extend directly down to the
muscularis mucosae. The crypts may be slightly dilated or tortuous and are 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. S ca5 ered
muciphages are common in the lamina propria of the rectum, particularly in older adults. Presumably, they
represent the vestiges of previous mucosal injury. I t is important to recognize the simplified and somewhat
distorted mucosal architecture of the distal rectal columnar mucosa as normal and not as indicating true
architectural distortion characteristic of chronic inflammatory bowel disease.
FIGURE 1.17 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 in mucosal
128histology (see Chapter 32). First, it is critical to understand the macroscopic anatomy of the anal canal (Fig.
1.18). The rectal vault descends into the muscular anal canal, which is composed of the muscularis propria of the
anal canal (the internal anal sphincter) and the anorectal skeletal musculature (the external anal sphincter). The
external anal sphincter is a complex arrangement of perineal muscle fibers, the most proximal of which is the
puborectalis muscle (sling). The puborectalis muscle loops from the pubis bone around the upper portion of the
anal canal and back to the pubis, imparting a sharp mucosal angle to the posterior aspect of the rectal vault. A s
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.
A nal 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. I mmediately below the dentate line is a zone of smooth mucosa, which flares at the anal verge to become
anal skin, which is visible on external examination. The overall distance of the anal canal, in vivo, averages
4.2 cm in normal adults.FIGURE 1.18 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. N ext is the anal transitional zone, which spans the
distance of the anal columns down to the dentate line, approximately 1 cm. D istal to the dentate line is a
nonkeratinizing stratified squamous mucosa; at the anal verge, this becomes keratinized skin and contains
adnexal structures typical of perineal skin.
The mucosa of the anal transitional zone is the most variable (Fig. 1.19). I n some instances, nonkeratinizing
anal squamous mucosa extends up the anal columns and transitions directly into the columnar rectal mucosa at
its most proximal extent. However, in many individuals, a transitional mucosa is present that consists of four to
nine cell layers that are neither squamous nor columnar but rather stratified cuboidal or polygonal and overlie a
basal cell layer. Occasional mucin goblet cells may be present as well. Transitional mucosa may be present,
especially in the anal sinuses, extending proximal from the nonkeratinizing squamous mucosa of the lower anal
canal and transitioning to rectal columnar mucosa proximally. Regardless of whether the anal canal mucosa is
columnar, transitional, or nonkeratinizing squamous, this region retains the designation of the anal transitional
zone.FIGURE 1.19 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 Drainage and Lymphatics of the Tubal Gut
129General principles of lymphatic drainage are straightforward. : Lymphatics in the mucosa or submucosa
drain through the muscularis propria, then enter either into larger lymphatic channels located in the
perivisceral adventitia or into a pedicle or mesentery. However, there are key anatomic features in each segment
of the tubal gut, which have become increasingly important to understand because of the intraoperative use of
sentinel lymph node biopsy to identify lymph nodes that drain invasive carcinomas of the gut and potentially
130-132harbor metastatic cancer.
Esophagus
The mucosal anatomy of the esophagus bears one key difference from the remainder of the tubal gut: The
squamous mucosa overlies a definitive layer of lamina propria, which is supported by the muscularis mucosae
and submucosa. I n the stomach, small intestine, and colon, the lamina propria is intimately interdigitated with
the epithelium, so that the bases of epithelial glands or crypts lie directly on the muscularis mucosae. Hence,
unlike elsewhere, in the esophagus there is a rich mucosal plexus of lymphatics in the lamina propria oriented
133predominantly 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
I n the stomach, lymphatic channels are absent from the superficial lamina propria but are present in the
134interglandular 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 fibers to
form a polygonal meshwork. Valves are present in this intramural network. From there, larger lymphatic
channels track along the major arteries and veins into the gastric and colonic mesenteries.
Small Intestine
135The lymphatic drainage of the small intestine is distinct. I n the lamina propria of each villus are three or
more lymphatic channels that run parallel to one another along the long axis. Given the heavy flow of
chylomicrons and fa5 y droplets from the absorptive epithelium to the lymphatic space, the endothelial liningtypically contains numerous gaps. These lymphatic channels collect into central lacteals located within the
deeper part of the villi, which have a continuous endothelial lining and a reticulin fiber sheath to which smooth
muscle fibers a5 ach. The smooth muscle fibers are also oriented longitudinally in the villi, and they
intermi5 ently 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 la5 er
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
I n the colon, a lymphatic plexus lies just underneath the muscularis mucosae. This plexus sends small branches
into the deep mucosa at the level of the bases of the colonic crypts, to form a narrow lymphatic zone located
136immediately above the muscularis mucosae. The submucosal plexus drains to an intramural lymphatic
plexus located between the inner circular and outer discontinuous longitudinal layers of the muscularis propria
(Fig. 1.20). A s in the small intestine, lymphatic channels that exit the colonic wall enter the mesocolon in a radial
pa5 ern of drainage. I ntramucosal, submucosal, and mural lymphatic channels may be sites for microscopic
metastasis. However, in contrast to the esophagus, although there may be intramural lateral spread of invasive
137tumor as much as 2 cm from the primary tumor focus, microscopic evidence of colonic cancer more than
1382 cm proximal or distal to the macroscopic tumor mass is an exceedingly rare occurence.
FIGURE 1.20 Schematic diagram of the 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 there are plexuses within the
muscularis propria. Immediately adjacent to the muscularis propria are epicolic lymph nodes,
which drain toward 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: Saunders; 2003:121-131.)
The existence of lymphatic channels in the colorectal mucosa located immediately above the muscularis
mucosae is often overlooked by pathologists, particularly in light of the fact that lymphatic channels are very
difficult to identify on routine H&E-stained tissue sections (Fig. 1.21).FIGURE 1.21 Lymphatics in the colonic mucosa of a patient with angiodysplasia and
hemorrhage into the base of the mucosa. A, Low-power full-thickness image of the colon
demonstrates an intramucosal hematoma. Lightly eosinophilic-stained lymphatic channels are
visible immediately above the muscularis mucosa (hematoxylin and eosin stain). B,
Mediumpower image of the edge of the hematoma shows that the muscularis mucosae underlies
both hematoma and lymphatic channels (Trichrome stain). C, Higher-power image shows
two lymphatic channels containing rare lymphocytes and overlying mucosa-associated
lymphoid tissue (Trichrome stain). D, Factor VIII immunostain confirms the vascular origin of
these channels. Some lymphocyte nuclei are evident within the lymphatic space (hematoxylin
counterstain).
The number of intramucosal lymphatics does not increase in inflammatory conditions (e.g., ulcerative colitis)
but does increase in association with some pathologic changes such as widening of the muscularis mucosae,
139hyperplasia of the muscle fibers, filiform changes in the mucosa, and hyperplasia of the MA LT. I n colonic
specimens with epithelial dysplasia (adenomatous change), an association between dysplastic epithelium and
ectatic, and quantitatively increased, lymphatics may be present. However, in cases with carcinoma, no
relationship between malignant tumor and quantity of intramucosal lymphatics has been identified. D eposits of
carcinoma within intramucosal lymphatics typically occur only within the immediate vicinity of the primary
tumor mass. Whether intramucosal lymphatics are involved in clinically significant colorectal tumor metastasis
remains to be determined. A bundant data suggest that carcinomas confined to the mucosa (intramucosal) are
140not at significant risk of lymph node metastasis. I nvasion of carcinoma into the submucosa remains a
141biologic requisite for regional or distant cancer metastasis.
Lymph Nodes
The esophagus drains into numerous lymph node groups, including five directly adjacent to the esophagus in
paratracheal, parabronchial, paraesophageal, carinal, and posteriormediastinal locations; supraclavicular lymph
nodes may also exhibit drainage from the esophageal region (Fig. 1.22). The cervical esophagus also drains into
the internal jugular and cervical lymph nodes, the upper tracheal lymph nodes, and, potentially, the
supraclavicular lymph nodes. The infradiaphragmatic portion of the esophagus drains into the left gastric nodes
along the lesser curvature and into the ring of lymph nodes surrounding the cardia.FIGURE 1.22 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: Saunders; 2003:121-131.)
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. 1.23). A s detailed by Fenoglio-Preiser
133and 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: pancreaticosplenic 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 1.23 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 and 7)
pancreaticosplenic lymph nodes; (8) gastroepiploic lymph nodes in the greater omentum; (9)
pancreaticoduodenal lymph nodes; (10) paraaortic 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: Saunders; 2003:121-131.)
Effluents from all lymph node groups ultimately pass to the celiac nodes surrounding the main celiac axis.
There are approximately 200 mesenteric lymph nodes in the small and large intestinal mesentery. S mall
mesenteric lymph nodes lie along the radial and arcuate ramifications of the distal mesenteric vasculaturesubjacent to the bowel wall (Fig. 1.24). 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. 1.25). 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 the azygos vein and
receives lymphatic branches from the posterior mediastinal structures, the intercostals, and the jugular,
subclavian, and bronchomediastinal ducts before emptying into the angle between the left internal jugular and
left subclavian veins.
FIGURE 1.24 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
penetrate 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: Saunders; 2003:121-131.)FIGURE 1.25 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 and collect
into lymph nodes alongside the inferior vena cava. The liver capsule collects lymph from the
superficial portions of the liver corpus, draining anteroinferiorly toward the hilum and hepatic
artery lymph nodes and posterosuperiorly toward lymph nodes of the inferior vena cava,
mediastinum, and the paraesophageal/diaphragmatic region. (Reproduced with permission
from Crawford JM. Principles of anatomy. In: Rustgi AK, Crawford JM, eds. Gastrointestinal
Cancers: Biology and Clinical Management. Philadelphia: Saunders; 2003:121-131.)
D istal rectal lymphatics drain laterally along the course of the inferior hemorrhoidal vessels, and from there
into paraaortic lymph nodes to end in the hypogastric, obturator, and internal iliac nodes. A lternatively, they
follow the superior rectal artery to drain into lymph nodes in the sigmoid mesocolon near the origin of the
inferior mesenteric artery. Lymphatic fluid drains from the anus into the endopelvic fascia along the lateral
aspect of the ischiorectal space, to the genital femoral sulcus on either side, and ultimately to the inferomedial
group of superficial inguinal lymph nodes. S ome 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.
References
1. American Society for Gastrointestinal Endoscopy. Tissue sampling and analysis. Gastrointest Endoscopy.
1991;37:663–665.
2. Tooson JD, Gates LK Jr. Bowel preparation before colonoscopy: choosing the best lavage regimen.
Postgrad Med. 1996;100:203–214.
3. Hangartner PJ, Munch R, Meier J, et al. Comparison of three colon cleansing methods: evaluation of a
randomized clinical trial with 300 ambulatory patients. Endoscopy. 1989;21:272–275.
4. Lee J, McCallion K, Acheson AG, et al. A prospective randomised study comparing polyethylene glycol
and sodium phosphate bowel cleansing solutions for colonoscopy. Ulster Med J. 1999;68:68–72.
5. Borkje B, Pedersen R, Lund GM, et al. Effectiveness and acceptability of three bowel cleansing regimens.
Scand J Gastroenterol. 1991;26:162–166.
6. Dahshan A, Lin CH, Peters J, et al. A randomized, prospective study to evaluate the efficacy and
acceptance of three bowel preparations for colonoscopy in children. Am J Gastroenterol. 1999;94:3497–
3501.
7. Pockros PJ, Foroozan P. Golytely lavage versus a standard colonoscopy preparation: effect on normal
colonic mucosal histology. Gastroenterology. 1985;88:545–548.
8. Lawrance IC, Willert RP, Murray K. Bowel cleansing for colonoscopy: prospective randomized
assessment of efficacy and of induced mucosal abnormality with three preparation agents. Endoscopy.
2011;43:412–418.
9. Chlumská A, Benes Z, Mukensnabl P, Zámecnik M. Histologic findings after sodium phosphate bowel
preparation for colonoscopy: diagnostic pitfalls of colonoscopic biopsies. Cesk Patol. 2010;46:37–41.
10. Croucher LJ, Bury JP, Williams EA, Riley SA, Corfe BM. Commonly used bowel preparations have
significant and different effects upon cell proliferation in the colon: a pilot study. BMC Gastroenterol.
2008;8:54.
11. Meisel JL, Bergman D, Graney D, et al. Human rectal mucosa: proctoscopic and morphological changes
caused by laxatives. Gastroenterology. 1977;72:1274–1279.12. Rejchrt S, Bures J, Siroký M, et al. A prospective, observational study of colonic mucosal abnormalities
associated with orally administered sodium phosphate for colon cleansing before colonoscopy.
Gastrointest Endosc. 2004;59:651–654.
13. Zwas FR, Cirillo NW, el-Serag HB, Eisen RN. Colonic mucosal abnormalities associated with oral sodium
phosphate solution. Gastrointest Endosc. 1996;43:463–466.
14. Jonas G, Mahoney A, Murray J, et al. Chemical colitis due to endoscope cleaning solutions: a mimic of
pseudomembranous colitis. Gastroenterology. 1988;95:1403–1408.
15. Achkar E, Carey W, Petras R, et al. Comparison of suction capsule and endoscopic biopsy of small bowel
mucosa. Gastrointest Endosc. 1986;32:278–281.
16. Weinstein W. Mucosal biopsy techniques and interaction with the pathologist. Gastrointest Endosc Clin N
Am. 2000;10:555–572.
17. Bernstein D, Barkin J, Reiner D, et al. Standard biopsy forceps versus large-capacity forceps with and
without needle. Gastrointest Endosc. 1995;41:573–576.
18. Woods K, Anand B, Cole R, et al. Influence of endoscopic biopsy forceps characteristics on tissue
specimens: results of a prospective randomized study. Gastrointest Endosc. 1999;49:177–183.
19. Ladas S, Tsamouri M, Kouvidou C, et al. Effect of forceps size and mode of orientation on endoscopic
small bowel biopsy evaluation. Gastrointest Endosc. 1994;40:51–55.
20. Rizzo J, Bernstein D, Gress F. A performance, safety and cost comparison of reusable and disposable
endoscopic biopsy forceps: a prospective, randomized trial. Gastrointest Endosc. 2000;51:262–265.
21. Woods KL, Anand BS, Cole RA, et al. Influence of endoscopic biopsy forceps characteristics on tissue
specimens: results of a prospective randomized study. Gastrointest Endosc. 1999;49:177–183.
22. Levine D, Blount P, Rudolph R, et al. Safety of a systemic endoscopic biopsy protocol in patients with
Barrett's esophagus. Am J Gastroenterol. 2000;95:1152–1157.
23. Falk G, Rice T, Goldblum J, et al. Jumbo biopsy forceps protocol still misses unsuspected cancer in
Barrett's esophagus with high-grade dysplasia. Gastrointest Endosc. 1999;49:170–176.
24. Jailwala J, Fogel E, Sherman S, et al. Triple-tissue sampling at ERCP in malignant biliary obstruction.
Gastrointest Endosc. 2000;51:383–390.
25. Watanabe Y, Goto H, Hirooka Y, et al. Transpapillary biopsy in gallbladder disease. Gastrointest Endosc.
2000;51:76–79.
26. Fyock CJ, Draganov PV. Colonoscopic polypectomy and associated techniques. World J Gastroenterol.
2010;16:3630–3637.
27. Waye J. Techniques of polypectomy: hot biopsy forceps and snare polypectomy. Am J Gastroenterol.
1987;82:615–618.
28. Kimmey M, Silverstein F, Saunders D, et al. Endoscopic bipolar forceps: a potential treatment for the
diminutive polyp. Gastrointest Endosc. 1988;34:38–41.
29. Wadas D, Sanowski R. Complications of the hot biopsy forceps technique. Gastrointest Endosc. 1987;33:32–
37.
30. Gilbert D, DiMarino A, Jensen D, et al. Status evaluation: hot biopsy forceps. American Society for
Gastrointestinal Endoscopy Technology Assessment Committee. Gastrointest Endosc. 1992;38:753–756.
31. Peluso F, Goldner F. Follow-up of hot biopsy forceps treatment of diminutive colonic polyps. Gastrointest
Endosc. 1991;37:604–606.
32. Hassan C, Pickhardt PJ, Rex DK. A resect and discard strategy would improve cost-effectiveness of
colorectal cancer screening. Clin Gastroenterol Hepatol. 2010;8:865–869.
33. Hogan RB 3rd, Brill JV, Littenberg G, Demarco DC. Predict, resect, and discard … really? Gastrointest
Endosc. 2012;75:503–505.
34. Ignjatovic A, East JE, Suzuki N, et al. Optical diagnosis of small colorectal polyps at routine colonoscopy
(Detect InSpect ChAracterise Resect and Discard; DISCARD trial): a prospective cohort study. Lancet
Oncol. 2009;10:1171–1178.
35. Hogan RB 3rd, Brill JV, Littenberg G, Demarco DC. Predict, resect, and discard … .really? Gastrointest
Endosc. 2012;75:503–505.
36. Gupta N, Bansal A, Rao D, et al. Accuracy of in vivo optical diagnosis of colon polyp histology by
narrowband imaging in predicting colonoscopy surveillance intervals. Gastrointest Endosc. 2012;75:494–502.
37. McAfee J, Katon R. Tiny snares prove safe and effective for removal of diminutive colorectal polyps.
Gastrointest Endosc. 1994;40:301–303.
38. Tappero G, Gaia E, De Giuli P, et al. Cold snare excision of small colorectal polyps. Gastrointest Endosc.
1992;38:310–313.
39. Rathgaber SW, Wick TM. Colonoscopy completion and complication rates in a community
gastroenterology practice. Gastrointest Endosc. 2006;64:556–562.
40. Levin TR, Zhao W, Conell C, et al. Complications of colonoscopy in an integrated health care delivery
system. Ann Intern Med. 2006;145:880–886.
41. Kim HS, Kim TI, Kim WH, et al. Risk factors for immediate postpolypectomy bleeding of the colon: a
multicenter study. Am J Gastroenterol. 2006;101:1333–1341.
42. Dobrowski S, Dobosz M, Babicki A, et al. Blood supply of colorectal polyps correlates with risk ofbleeding after colonoscopic polypectomy. Gastrointest Endosc. 2006;63:1004–1009.
43. Binmoeller K, Boaventura S, Ramsperger K, et al. Endoscopic snare excision of benign adenomas of the
papilla of Vater. Gastrointest Endosc. 1993;39:205–207.
44. Lieberman D, Weiss D, Bond J, et al. Use of colonoscopy to screen asymptomatic adults for colorectal
cancer. N Engl J Med. 2000;343:162–168.
45. Macrae F, Tan K, Williams C. Towards safer colonoscopy: a report on the complications of 5000
diagnostic or therapeutic colonoscopies. Gut. 1983;24:376–383.
46. Rosenberg N. Submucosal saline wheal as safety factor in fulguration of rectal and sigmoidal polyps.
Arch Surg. 1955;70:120–123.
47. Deyhle P, Largiader F, More SJ, Fumagalli I. A method for endoscopic electroresection of sessile colonic
polyps. Endoscopy. 1973;5:38.
48. Soetikno R, Inoue H, Chang K. Endoscopic mucosal resection: current concepts. Gastrointest Endosc Clin
N Am. 2000;10:595–617.
49. Fleischer D. Endoscopic mucosal resection: (Not) made in the USA (so commonly). A dissection of the
definition, technique, use, and controversies. Gastrointest Endosc. 2000;52:440–444.
50. Uno Y, Munakata A. The non-lifting sign of invasive colon cancer. Gastrointest Endosc. 1994;40:485–489.
51. Tanabe S, Koizumi W, Kokutou M, et al. Usefulness of endoscopic aspiration mucosectomy as compared
with strip biopsy for the treatment of gastric mucosal cancer. Gastrointest Endosc. 1999;50:819–822.
52. Inoue H, Takeshita K, Hori H, et al. Endoscopic mucosal resection with a cap-fitted panendoscope for
esophagus, stomach, and colon mucosal lesions. Gastrointest Endosc. 1993;39:58–62.
53. Kojima T, Parra-Blanco A, Takahashi H, et al. Outcome of endoscopic mucosal resection for early gastric
cancer: review of the Japanese literature. Gastrointest Endosc. 1998;48:550–554.
54. Waxman I, Saitoh Y. Clinical outcome of endoscopic mucosal resection for superficial GI lesions and the
role of high-frequency ultrasound probe sonography in an American population. Gastrointest Endosc.
2000;52:322–327.
55. Oka S, Takanaka S, Kanao H, Ishikawa H, et al. Current status in the occurrence of postoperative
bleeding, perforation and residual/local recurrence during colonoscopic treatment in Japan. Dig Endosc.
2010;22:376–380.
56. Swan MP, Bourke MJ, Moss A, et al. The target sign: an endoscopic marker for the resection of
muscularis propria and potential perforation during colonic endoscopic mucosal resection. Gastrointest
Endosc. 2011;73:79–85.
57. Arts JH, Rennan MA, de Heer C. Inhaled formaldehyde: evaluation of sensory irritation in relation to
carcinogenicity. Regul Toxicol Pharmacol. 2006;44:144–160.
58. Bernstein S, Council on Scientific Affairs. Formaldehyde. JAMA. 1989;261:1183–1187.
59. Conolly RB, Kimbell JS, Janszen DB, et al. Dose response for formaldehyde-induced cytotoxicity in the
human respiratory tract. Regul Toxicol Pharmacol. 2002;35:32–43.
60. Hood J, Larrañaga M. Employee health surveillance in the health care industry. AAOHN J. 2007;55:423–
431.
61. Fox CH, Johnson FB, Whiting J, et al. Formaldehyde fixation. J Histochem Cytochem. 1985;33:845–853.
62. Login GR, Dvorak AM. Methods of microwave fixation for microscopy: a review of research and clinical
applications: 1970-1992. Prog Histochem Cytochem. 1994;27:1–127.
63. Crosby WH, Kugler HW. Intraluminal biopsy of the small intestine. Am J Dig Dis. 1957;2:236–249.
64. Flick AL, Quinton WE, Rubin CE. A peroral hydraulic biopsy tube for multiple sampling at any level of
the gastrointestinal tract. Gastroenterology. 1961;40:120–126.
65. Mee AS, Burke M, Vallon AG, et al. Small bowel biopsy for malabsorption: comparison of the diagnostic
accuracy of endoscopic forceps and capsule biopsy specimens. Br Med J. 1985;291:769–774.
66. Smith JA, Mayberry JF, Ansell ID, et al. Small bowel biopsy for disaccharidase levels: evidence that
endoscopic forceps biopsy can replace the Crosby capsule. Clin Chim Acta. 1989;183:317–326.
67. Lester SC. Manual of Surgical Pathology. Churchill-Livingstone: New York; 2001.
68. Stetler-Stevenson M, Braylan RC. Flow cytometric analysis of lymphomas and lymphoproliferative
disorders. Semin Hematol. 2001;38:111–123.
69. Varghese LR, Stanley MW, Lucido ML, et al. Esophageal carcinoma with a rhabdoid phenotype: a case
report of diagnosis by endoscopic ultrasound-guided fine-needle aspiration. Diagn Cytopathol.
2005;33:407–411.
70. Jonas G, Mahoney A, Murray J, et al. Chemical colitis due to endoscopic cleaning solutions: a mimic of
pseudomembranous colitis. Gastroenterology. 1988;95:1403–1408.
71. West AB, Kuan SF, Bennick M, et al. Glutaraldehyde colitis following endoscopy: clinical and
pathological features and investigation of an outbreak. Gastroenterology. 1995;108:1250–1255.
72. Meisel JL, Bergman D, Graney D, et al. Human rectal mucosa: proctoscopic and morphological changes
caused by laxatives. Gastroenterology. 1977;72:1274–1279.
73. Maglinte DDT, Strong RC, Strate RW, et al. Barium enema after colorectal biopsies: experimental data.
AJR Am J Roentgenol. 1982;139:693–697.
74. Baron T, Lee J, Wax T, et al. An in vitro, randomized, prospective study to maximize cellular yield duringbile duct brush cytology. Gastrointest Endosc. 1994;40:146–149.
75. Marshall J, Diaz-Arias A, Barthel J, et al. Prospective evaluation of optimal number of biopsy specimens
and brush cytology in the diagnosis of cancer of the colorectum. Am J Gastroenterol. 1993;88:1352–1354.
76. Camp R, Rutkowski M, Atkison K, et al. A prospective, randomized, blinded trial of cytological yield with
disposable cytology brushes in upper gastrointestinal tract lesions. Am J Gastroenterol. 1992;87:1439–
1442.
77. Ferrari A, Lichtenstein D, Slivka A, et al. Brush cytology during ERCP for the diagnosis of biliary and
pancreatic malignancies. Gastrointest Endosc. 1994;40:140–145.
78. Bangarulingam SY, Bjornsson E, Enders F, et al. Long-term outcomes of positive fluorescence in situ
hybridization tests in primary sclerosing cholangitis. Hepatology. 2010;51:174–180.
79. Boldorini R, Paganotti A, Sartori M, et al. Fluorescence in situ hybridisation in the cytological diagnosis
of pancreatobiliary tumours. Pathology. 2011;43:335–449.
80. Smoczynski M, Jablonska A, Matyskiel A, et al. Routine brush cytology and fluorescence in situ
hybridization for assessment of pancreatobiliary strictures. Gastrointest Endosc. 2012;75:65–73.
81. Athanassiadou P, Grapsa D. Value of endoscopic retrograde cholangiopancreatography-guided
brushings in preoperative assessment of pancreaticobiliary strictures: what's new? Acta Cytol.
2008;52:24–34.
82. Howell D, Beveridge R, Bosco J, et al. Endoscopic needle aspiration biopsy at ERCP in the diagnosis of
biliary strictures. Gastrointest Endosc. 1992;38:531–535.
83. Gress F, Hawes R, Savides T, et al. Endoscopic ultrasound-guided fine-needle aspiration biopsy using
linear array and radial scanning endosonography. Gastrointest Endosc. 1997;45:243–250.
84. Giovannini M, Seitz J-F, Monges G, et al. Fine-needle aspiration cytology guided by endoscopic
ultrasonography: results in 141 patients. Endoscopy. 1995;27:171–177.
85. Puri R, Vilmann P, Săftoiu A, et al. Randomized controlled trial of endoscopic ultrasound-guided
fineneedle sampling with or without suction for better cytological diagnosis. Scand J Gastroenterol.
2009;44:499–504.
86. Wani S, Gupta N, Gaddam S, et al. A comparative study of endoscopic ultrasound guided fine needle
aspiration with and without a stylet. Dig Dis Sci. 2011;56:2409–2414.
87. Vila PM, Thekkek N, Richards-Kortum R, Anandasabapathy S. The use of in vivo real-time optical
imaging for esophageal neoplasia. Mt Sinai J Med. 2011;78:894–904.
88. Kara MA, Ennahachi M, Fockens P, et al. Detection and classification of the mucosal and vascular
patterns (mucosal morphology) in Barrett's esophagus by using narrow band imaging. Gastrointest
Endosc. 2006;64:155.
89. Sharma P, Weston AP, Topalovski M, et al. Magnification chromoendoscopy for the detection of
intestinal metaplasia and dysplasia in Barrett's oesophagus. Gut. 2003;52:24–27.
90. Ikematsu H, Saito Y, Tanaka S, et al. The impact of narrow band imaging for colon polyp detection: a
multicenter randomized controlled trial by tandem colonoscopy. J Gastroenterol. 2012;47:1099–1107.
91. Rastogi A, Early DS, Gupta N, et al. Randomized, controlled trial of standard-definition white-light,
highdefinition white-light, and narrow-band imaging colonoscopy for the detection of colon polyps and
prediction of polyp histology. Gastrointest Endosc. 2011;74:593–602.
92. Rastogi A, Keighley J, Singh V, et al. High accuracy of narrow band imaging without magnification for
the real-time characterization of polyp histology and its comparison with high-definition white light
colonoscopy: a prospective study. Am J Gastroenterol. 2009;104:2422–2430.
93. Liu JTC, Loewke NO, Mandella MJ, et al. Point-of-care pathology with miniature microscopes. Anal Cell
Pathol. 2011;34:81–98.
94. Pohl H, Rösch T, Vieth M, et al. Miniprobe confocal laser microscopy for the detection of invisible
neoplasia in patients with Barrett's oesophagus. Gut. 2008;57:1648–1653.
95. Wallace MB, Sharma P, Lightdale C, et al. Preliminary accuracy and interobserver agreement for the
detection of intraepithelial neoplasia in Barrett's esophagus with probe-based confocal laser
endomicroscopy. Gastrointest Endosc. 2010;72:19–24.
96. Kiesslich R, Gossner L, Goetz M, et al. In vivo histology of Barrett's esophagus and associated neoplasia
by confocal laser endomicroscopy. Clin Gastroenterol Hepatol. 2006;4:979–987.
97. Wang HH, Mangano MM, Antonioli DA. Evaluation of T-lymphocytes in esophageal mucosal biopsies.
Mod Pathol. 1994;7:55–58.
98. De la Pava S, Nigogosyan G, Pickren JW, Cabrera A. “Melanosis” of the esophagus. Cancer. 1963;16:48–50.
99. Tateishi R, Taniguchi H, Wada A, et al. Argyrophil cells and melanocytes in esophageal mucosa. Arch
Pathol. 1974;98:87–89.
100. Kouznetsova I, Kalinski T, Peitz U, et al. Localization of TFF3 peptide in human esophageal submucosal
glands and gastric cardia: differentiation of two types of gastric pit cells along the rostro-caudal axis. Cell
Tissue Res. 2007;328:365–374.
101. Takubo K, Sasajima K, Yamashita K, et al. Double muscularis mucosae in Barrett's esophagus. Hum
Pathol. 1991;22:1158–1161.
102. Öberg S, Peters JH, DeMeester TR, et al. Inflammation and specialized intestinal metaplasia is amanifestation of gastroesophageal reflux disease. Ann Surg. 1997;226:522–532.
103. Chandrasoma PT, Lokuhetty DM, Demeester TR, et al. Definition of histopathologic changes in
gastroesophageal reflux disease. Am J Surg Pathol. 2000;24:344–351.
104. Chandrasoma PT, Der R, Ma Y, et al. Histology of the gastroesophageal junction. Am J Surg Pathol.
2000;24:402–409.
105. Kilgore SP, Ormsby AH, Gramlich TL, et al. The gastric cardia: fact or fiction? Am J Gastroenterol.
2000;95:921–924.
106. Sarbia M, Donner A, Gabbert HE. Histopathology of the gastroesophageal junction: a study on 36
operation specimens. Am J Surg Pathol. 2002;26:1207–1212.
107. Park YS, Park HJ, Kang GH, et al. Histology of gastroesophageal junction in fetal and pediatric autopsy.
Arch Pathol Lab Med. 2003;127:451–455.
108. Glickman JN, Fox V, Antonioli DA, et al. Morphology of the cardia and significance of carditis in
pediatric patients. Am J Surg Pathol. 2002;26:1032–1039.
109. Chandrasoma PT, Der R, Ma Y, et al. Histologic classification of patients based on mapping biopsies of
the gastroesophageal junction. Am J Surg Pathol. 2003;27:929–936.
110. Marsman WA, van Sandick JW, Tytgat GN, et al. The presence and mucin histochemistry of cardiac type
mucosa at the esophagogastric junction. Am J Gastroenterol. 2004;99:212–217.
111. De Hertogh G, Van Eyken P, Ectors N, Geboes K. On the origin of cardiac mucosa: a histological and
immunohistochemical study of cytokeratin expression patterns in the developing esophagogastric
junction region and stomach. World J Gastroenterol. 2005;11:4490–4496.
112. Lord RVN, Wickramasinghe K, Johansson JJ, et al. Cardiac mucosa in the remnant esophagus after
esophagectomy is an acquired epithelium with Barrett's-like features. Surgery. 2004;136:633–640.
113. Odze RD. Unraveling the mystery of the gastroesophageal junction: a pathologist's perspective. Am J
Gastroenterol. 2005;100:1853–1867.
114. Salzman NH, Underwood MA, Bevins CL. Paneth cells, defensins, and the commensal microbiota: a
hypothesis on intimate interplay at the intestinal mucosa. Semin Immunol. 2007;19:70–83.
115. Chu H, Pazgier M, Jung G, et al. Human α-defensin 6 promotes mucosal innate immunity through
selfassembled peptide nanonets. Science. 2012;337:477–481.
116. Sjölunk K, Sandén G, Håkanson R, Sundler F. Endocrine cells in human intestine: an
immunocytochemical study. Gastroenterology. 1983;85:1120–1130.
117. Lundqvist C, Baranov V, Hammarström S, et al. Intra-epithelial lymphocytes: evidence for regional
specialization and extrathymic T cell maturation in the human gut epithelium. Int Immunol. 1995;7:1473–
1479.
118. Brown I, Min-Kenudson M, Deshpande V, Lauwers GY. Intraepithelial lymphocytosis in architecturally
preserved proximal small intestinal mucosa: an increasing diagnostic problem with a wide differential
diagnosis. Arch Pathol Lab Med. 2006;130:1020–1025.
119. Veress B, Franzén L, Bodin L, Borch K. Duodenal intraepithelial lymphocyte-count, revisited. Scand J
Gastroenterol. 2004;39:138–144.
120. Hayat M, Cairns A, Dixon MF, O’Mahony S. Quantitation of intraepithelial lymphocytes in human
duodenum: what is normal? J Clin Pathol. 2002;55:393–394.
121. Ferguson A, Murray D. Quantitation of intraepithelial lymphocytes in human jejunum. Gut.
1971;32:1412–1414.
122. Dobbins WO. Human intestinal intraepithelial lymphocytes. Gut. 1986;27:972–985.
123. Sapp H, Ithamukkala S, Brien TP, et al. The terminal ileum is affected in patients with lymphocytic or
collagenous colitis. Am J Surg Pathol. 2002;26:1484–1492.
124. Dickey W, Hughes DF. Histology of the terminal ileum in coeliac disease. Scand J Gastroenterol.
2004;39:665–667.
125. Tamura S, Furuya Y, Tadokoro T, et al. Pit pattern and three-dimensional configuration of isolated crypts
from the patients with colorectal neoplasms. J Gastroenterol. 2002;37:798–806.
126. Flick AL, Voegtlin KF, Rubin CE. Clinical experience with suction biopsy of the rectal mucosa.
Gastroenterology. 1962;42:691–705.
127. Olsen BS, Holck S. Neurogenous hyperplasia leading to appendiceal obliteration: an
immunohistochemical study of 237 cases. Histopathology. 1987;11:843–849.
128. Fenger C. Histology of the anal canal. Am J Surg Pathol. 1988;12:41–55.
129. Crawford JM. Principles of anatomy. Rustgi AK, Crawford JM. Gastrointestinal Cancers: Biology and
Clinical Management. WB Saunders: Philadelphia; 2003:121–131.
130. Gretschel S, Schlag PM. Current status of sentinel lymph node biopsy in adenocarcinoma of the distal
esophagus, gastric cardia, and proximal stomach. Recent Results Cancer Res. 2010;182:107–114.
131. Wang YZ, Joseph S, Lindholm E, et al. Lymphatic mapping helps to define resection margins for midgut
carcinoids. Surgery. 2009;146:993–997.
132. Bianchi PP, Ceriani C, Rottoli M, et al. Laparoscopic lymphatic mapping and sentinel lymph node
detection in colon cancer: technical aspects and preliminary results. Surg Endosc. 2007;21:1567–1571.
133. Fenoglio-Preiser C, Noffsinger AE, Stemmermann GN, et al. Gastrointestinal Pathology: An Atlas andText. 2nd ed. Lippincott-Raven: Philadelphia; 1999.
134. Listrom MB, Fenoglio-Preiser CM. Gastric lymphatics. Am J Surg Pathol. 1987;11:156–157.
135. Lowden S, Heath T. Lymphatic drainage from the distal small intestine in the sheep. J Anat. 1993;183:13–
20.
136. Fenoglio CM, Kaye GI, Lane N. Distribution of human colonic lymphatics in normal, hyperplastic, and
adenomatous tissue: its relationship to metastasis from small carcinomas in pedunculated adenomas
with two case reports. Gastroenterology. 1973;64:51–66.
137. Hughes TG, Jenevein EP, Poulos E. Intramural spread of colon carcinoma: a pathologic study. Am J Surg.
1983;146:697–699.
138. Cross SS, Bull AD, Smith JHF. Is there any justification for the routine examination of bowel resection
margins in colorectal adenocarcinoma? J Clin Pathol. 1989;42:1040–1042.
139. Kaiserling E, Kröber S, Geleff S. Lymphatic vessels in the colonic mucosa in ulcerative colitis.
Lymphology. 2003;36:52–61.
140. Haggitt RC, Glotzbach RE, Soffer EE, Wruble LD. Prognostic factors in colorectal carcinomas arising in
adenomas: implications for lesions removed by endoscopic polypectomy. Gastroenterology. 1985;89:328–
336.
141. Nascimbeni R, Burgart LJ, Nivatvongs S, Larson DR. Risk of lymph node metastasis in T1 carcinoma of
the colon and rectum. Dis Colon Rectum. 2002;45:200–206.This page contains the following errors:
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C H A P T E R 2
Screening and Surveillance
Guidelines in Gastroenterology
Ansu M. Noronha
Francis A. Farraye
CHA P T E R OUT LINE
Introduction
Surveillance in Patients with Barrett Esophagus
Surveillance in Patients with Chronic Gastritis and Intestinal Metaplasia or
Dysplasia
Surveillance for Colorectal Neoplasia 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 Sessile Serrated Adenomas/Polyps
Hyperplastic Polyposis Syndromes
Management of Large Pedunculated Polyps
Management of Large Sessile Polyps
Postpolypectomy Surveillance
Management of Malignant Polyps
Colonoscopic Surveillance after Colon Cancer Resection
Interaction of Gastrointestinal Endoscopists and Pathologists
Introduction










This chapter focuses on clinical gastroenterology issues of interest to pathologists,
including endoscopic diagnosis and management of Barre esophagus, management of
intestinal metaplasia in the se ing of chronic gastritis, and surveillance in patients with
inflammatory bowel disease, colonic polyps, and colon cancer.
Surveillance in Patients with Barrett Esophagus
Most authorities recommend that patients with chronic reflux symptoms lasting 5 or
more years undergo an upper endoscopy to screen for Barre esophagus (Table 2.1). The
benefits of screening programs for Barre esophagus are controversial because of a lack
1of sufficient evidence that such programs improve survival rates or are cost-effective.
Furthermore, there is only indirect evidence to suggest that patients diagnosed with
adenocarcinoma while undergoing surveillance have an increased chance of survival.
N evertheless, the current standard of care dictates that if Barre esophagus is
diagnosed, the patient should be entered into an endoscopic surveillance program for
2early detection of dysplasia and adenocarcinoma.
Table 2.1
Screening and Surveillance Recommendations for Barrett Esophagus
Age 50 years or older
Male sex
White race
Chronic gastroesophageal reflux disease
Hiatal hernia
Elevated body mass index
Intraabdominal distribution of body fat
Data from Spechler SJ, Sharma P, Souza RF, et al. American Gastroenterological
Association medical position statement on the management of Barrett's esophagus.
Gastroenterology. 2011;140:1084-1091.
I n the past, endoscopic surveillance was undertaken only in patients who were
medically fit to undergo esophagectomy. However, with the advent of nonsurgical
ablative endoscopic techniques (e.g., photodynamic therapy, argon plasma coagulation,
cryotherapy) and endoscopic mucosal resection (EMR), the number of patients eligible
for surveillance has increased. Recent experience with EMR suggests that it may be the
treatment of choice in patients with high-grade dysplasia (HGD ) or intramucosal
adenocarcinoma in the se ing of Barre esophagus, given the opportunity for histologic
3-6assessment of the area.
A ggressive treatment of reflux with proton pump inhibitors is warranted before
surveillance endoscopy, because active inflammation with repair can mimic dysplasia.
Currently, endoscopic surveillance is performed by obtaining four-quadrant biopsies
at 2-cm intervals with the use of jumbo biopsy forceps. I n addition, specific a ention is
paid to mucosal abnormalities such as ulcers, irregular lesions, nodules, and polyps, and
these lesions should be submi ed separately. I n patients with known or suspected
dysplasia, biopsies should be obtained at 1-cm intervals instead of the standard 2 cm.
S tudies have shown that endoscopy with magnification and narrow band imaging (N BI )
allows for be er localization of HGD and may allow more targeted and fewer
7,8biopsies.
The recommended interval of surveillance for dysplasia in patients with Barreesophagus is determined by the presence and degree of dysplasia found (Table 2.2). I n
the absence of dysplasia, the surveillance interval is every 3 to 5 years with four-quadrant
biopsies every 2 cm. I f the pathology is indeterminate, the grade of dysplasia should be
clarified with an expert gastrointestinal pathologist. A ntisecretory medication should be
increased to reduce the presence of esophagitis, and upper endoscopy with biopsies
should be repeated. The presence of low-grade dysplasia (LGD ) should be confirmed
with endoscopy within 6 months, followed by surveillance every 12 months.
Table 2.2
Surveillance Guidelines for Barrett Esophagus
No dysplasia 3-5 years
Indeterminate for Consult expert gastrointestinal pathologist
dysplasia Increase antisecretory medications and repeat endoscopy
with biopsies
Low-grade 6-mo interval to confirm, then surveillance every 12 mo
dysplasia
High-grade 3 mo; consider endoscopic mucosal resection, radiofrequency
dysplasia ablation, or surgical resection
Data from Evans JA, Early DS, Fukami N, et al. The role of endoscopy in Barrett's
esophagus and other premalignant conditions of the esophagus. Gastrointest Endosc.
2012;76:1087-1094.
Patients with flat HGD confirmed by an expert gastrointestinal pathologist should
undergo a repeat endoscopy within 3 months with four-quadrant biopsies every 1 cm if
9an eradication method is not used. The prevalence of cancer in resection specimens
from patients who have undergone an esophagectomy for HGD ranges from 5% to 41%,
and the rate of progression to cancer in patients with HGD approaches 30% at 10 years.
Options for patients with flat HGD include intensive surveillance (every 3 months),
esophagectomy, and ablative therapies such as BA RRX or radiofrequency ablation.
Patients with HGD with mucosal irregularity should undergo endoscopic mucosal or
10surgical resection.
Surveillance in Patients with Chronic Gastritis and
Intestinal Metaplasia or Dysplasia
The most common causes of chronic gastritis are H elicobacter pylori infection,
environmental exposures including smoking, and autoimmune processes. Biopsies
obtained during endoscopy from patients with chronic gastritis may reveal intestinal
metaplasia (I M). A study from the United S tates demonstrated that 13% of patients at
low risk for gastric cancer, and 50% of patients at high risk, had I M on biopsies from
11normal-appearing gastric mucosa. A lthough gastric I M (incomplete type) is
considered a premalignant lesion, the overall risk of gastric cancer in patients with
gastric I M is very low. However, patients with I M and dysplasia have an approximately
11100-fold increased risk of gastric cancer.
I n the United S tates, where the incidence of gastric cancer is low, endoscopic
surveillance of patients with gastric I M is not recommended in patients who are at low
11risk for gastric cancer. Low-risk patients include those living in developed countries,whites without any family history of gastric cancer, and individuals without dysplasia on
gastric biopsy. The likelihood that endoscopic surveillance of low-risk patients with I M
will increase detection of curable gastric cancer is very low, and therefore it is not likely
to be cost-effective. Furthermore, I M is a histologic lesion that is not visible by the
endoscopist. This makes endoscopic surveillance difficult, because numerous biopsies
mapping the stomach would be needed to obtain a significant yield.
S urveillance in patients with I M who are at 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. N o formal
recommendations or data exist to support the implementation of an endoscopic
surveillance program in high-risk patients with gastric I M. The A merican S ociety of
Gastrointestinal Endoscopy (A S GE) concluded that patients who are at increased risk for
gastric cancer on the basis of ethnic background or family history may benefit from
surveillance, but there was no specific recommendation on the frequency of endoscopy.
I f surveillance is performed, the A S GE recommended that endoscopic surveillance with
gastric biopsies should incorporate a topographic mapping of the entire stomach
12histologically.
The location and type of dysplasia found determine the surveillance guidelines for
patients with I M. The histopathologic classification divides cases into the subtypes of
incomplete and complete I M, a distinction best determined after assessment for and
eradication of H . pylori infection. S tudies have suggested that if the patient has
incomplete or extensive I M, topographic mapping of the gastric mucosa should be
performed at 1 year, followed by repeated surveillance endoscopy every 3 years if
13extensive metaplasia persists. There is no consensus regarding surveillance in LGD ,
12but most studies suggest that surveillance is not warranted in average-risk patients.
The A S GE recommends that patients with confirmed HGD on gastric biopsies be
11considered for gastrectomy or EMR. We expect that further recommendations
regarding appropriate intervals for surveillance endoscopy and the use of new
techniques will be formalized in the near future.
Pernicious anemia, which can occur as a result of autoimmune chronic atrophic
gastritis, is another potential risk factor for gastric cancer and gastric carcinoid. A
twofold to threefold increased risk of gastric cancer has been seen, depending on the
14location and duration of disease. Clear guidelines for surveillance in atrophic gastritis
have not yet been established. Current guidelines from the A S GE advocate performance
of a screening upper endoscopy at the time of diagnosis of pernicious anemia to identify
lesions such a carcinoid or gastric cancer, but there are only weak data to support
12subsequent surveillance endoscopy if the initial test is negative.
Surveillance for Colorectal Neoplasia in Patients with
Inflammatory Bowel Disease
I nflammatory bowel disease (I BD ), which comprises ulcerative colitis (UC) and Crohn's
disease, is the second most common inflammatory disorder after rheumatoid arthritis.
14aThere are approximately 1.4 million patients with I BD in the United S tates. Each year,
between 20,000 and 25,000 new cases are diagnosed. The peak incidence occurs between
the ages of 15 to 35, with males and females equally affected.
The goal of colonoscopic surveillance is to minimize the morbidity and mortality from
colorectal cancer (CRC) with appropriate and timely referral for colectomy. Close
interaction between endoscopist and the pathologist is crucial in the management of15IBD. A lthough no prospective randomized studies have been performed to evaluate
the efficacy of surveillance colonoscopy to detect dysplasia or CRC in UC patients,
case16control studies suggest a reduction in mortality in those undergoing surveillance.
S urveillance colonoscopy should optimally be performed when the patient is in clinical
remission, because active inflammation may hinder the histologic diagnosis of dysplasia.
Biopsies taken during surveillance colonoscopy are graded as positive for dysplasia,
negative for dysplasia, or indefinite for dysplasia. D ysplasia is further classified as LGD ,
17HGD , or carcinoma. The greatest interobserver variability among pathologists lies in
the interpretation of the LGD and indefinite-for-dysplasia categories. Therefore, once
dysplasia is detected, a second pathologist with expertise in interpretation of
gastrointestinal biopsies should confirm the diagnosis. D ysplastic mucosa may be
characterized as either flat or raised. Flat dysplasia is generally considered to be
endoscopically undetectable, is identified by random biopsies, and can be further
classified as either multifocal or unifocal. Raised or polypoid dysplasia is referred to by
the acronym DALM: dysplasia-associated lesion or mass.
Current guidelines from the A merican College of Gastroenterology (A CG), the
A merican Gastroenterology A ssociation (A GA) T(able 2.3), and the British S ociety of
Gastroenterology(BS G) T( able 2.4) recommend that colonoscopic surveillance begin 8 to
10 years after the onset of symptoms of colitis in patients with UC or with Crohn's colitis
18-20involving at least one third of the colon. The results of the colonoscopy determine
the extent of disease, and appropriate patients are then entered into a surveillance
program. Repeated surveillance colonoscopy is performed every 1 to 3 years (A GA) or 1
18to 5 years (BS G). Patients with coexisting primary sclerosing cholangitis should begin
surveillance colonoscopy at the time of diagnosis of liver disease and continue annually
thereafter regardless of the extent of disease. Other risk factors associated with an
increased risk of developing colorectal neoplasia include CRC in a first-degree relative,
ongoing active endoscopic or histologic inflammation, and anatomic abnormalities such
as a foreshortened colon, stricture, or multiple inflammatory pseudopolyps. S everal
studies have correlated increased severity of colonoscopic macroscopic and histologic
21,22inflammation with a higher risk of CRC. Male gender has been identified as a risk
23,24factor for development of CRC. Patients with proctitis or distal proctosigmoiditis
are not at increased risk for the development of CRC and do not need to undergo
surveillance.Table 2.3
American Gastroenterology Association Surveillance Guidelines for CRC in Patients
with IBD
All patients, regardless of extent of disease at initial diagnosis, should undergo a
screening colonoscopy a maximum of 8 years after onset of symptoms, with
multiple biopsy specimens obtained throughout the entire colon, to assess the
true microscopic extent of inflammation.
Patients with ulcerative proctitis or ulcerative proctosigmoiditis are not considered
at increased risk for IBD-related CRC and thus may be managed on the basis of
average-risk recommendations.
Patients with extensive or left-sided colitis should begin surveillance within 1-2
years after the initial screening endoscopy.
After two negative examinations (no dysplasia or cancer), further surveillance
examinations should be performed every 1-3 years.
Patients with PSC should begin surveillance colonoscopy at the time of PSC
diagnosis and then yearly.
Patients with a history of CRC in a first-degree relative, ongoing active endoscopic
or histologic inflammation, or anatomic abnormalities (e.g., shortened colon,
multiple pseudopolyps, or stricture) may benefit from more frequent surveillance
colonoscopy.
Representative biopsy specimens from each anatomic section of the colon should
be obtained. Although no prospective trials have determined the optimal number
of biopsies to take, one study has recommended a minimum of 33 biopsy
specimens.
Surveillance colonoscopy should ideally be performed when the patient is in
remission.
These recommendations also apply to patients with Crohn's colitis involving at
least one third of the colon.
CRC, Colorectal cancer; IBD, inflammatory bowel disease; PSC, primary sclerosing
cholangitis.
From Farraye FA, Odze RD, Eaden J, Itzkowitz SH. AGA technical review on the diagnosis
and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology.
2010;138:746-774.e4.
Table 2.4
British Society of Gastroenterology Surveillance Colonoscopy Guidelines for
Patients with IBD
Low risk: colonoscopy Extensive colitis without evidence of endoscopic/microscopic
at 5-yr intervals inflammation at last colonoscopy, or left sided-colitis
Crohn's colitis affecting
Intermediate risk: Extensive colitis with mild endoscopic/microscopic
colonoscopy at 3-yr inflammation on previous colonoscopy
intervals
Family history of CRC in a first-degree relative
Higher risk: yearly Extensive colitis with moderate or severe
colonoscopy endoscopic/microscopic inflammation on previous
colonoscopy
Stricture within the past 5 years
Confirmed dysplasia within the past 5 years in a patient who
declines surgery
Primary sclerosing cholangitis
Family history of CRC in a first-degree relative before 50
years of age
CRC, Colorectal cancer; IBD, inflammatory bowel disease.
Reproduced from Cairns SR, Scholefield JH, Steele RJ, et al. Guidelines for colorectal
cancer screening and surveillance in moderate and high risk groups (update from 2002).
Gut. 2010;59:666-689, with permission from BMJ Publishing Group Ltd.
There is wide variability in the practice of surveillance by gastroenterologists as well as
25,26inconsistency in the management of patients with dysplasia. Current guidelines
recommend the use of chromoendoscopy and directed biopsies or four-quadrant random
biopsies every 10 cm for a minimum of 33 total colonic biopsies, or 6 biopsies in 6
20pathology specimen bo les. The recommendation for 33 biopsies is based on a
retrospective analysis that revealed a 90% positive predictive value for dysplasia with 33
27biopsy specimens and a 95% positive predictive value with greater than 56 specimens.
I t is also recommended that in patients with UC, four-quadrant biopsies should be taken
every 5 cm in the distal sigmoid and rectum, given the increased risk of carcinoma in
those areas. Other endoscopists obtain six specimens from each of the following
sections: cecum and ascending colon, transverse colon, descending colon, sigmoid,
rectosigmoid, and rectum. A dditional biopsies should be obtained from any suspicious
mucosal lesions. The BS G guidelines recommend pancolonic dye spraying and targeted
biopsies of abnormal mucosa. I f chromoendoscopy is not used, then two to four random
18biopsies every 10 cm should be taken.
28The A GA and BS G guidelines recommend proctocolectomy in cases of flat HGD .
Most authorities also recommend proctocolectomy in patients with multifocal flat LGD
or a single repetitive focus on more than one colonoscopy. Many authorities now
recommend proctocolectomy in patients with even a single focus of flat LGD because
this has been shown to be associated with concurrent adenocarcinoma in 20% of patients
28,29and to progress to higher grades of dysplasia in 50% of cases. A meta-analysis of 20studies found that when raised or flat LGD is detected at surveillance, there is a ninefold
30increased risk for CRC and a 12-fold increased risk for any advanced lesion. Patients
with LGD who elect against colectomy should undergo repeat surveillance colonoscopy
on a 3- to 6-month basis. For patients with indefinite dysplasia, colonoscopy should be
repeated at an interval of 3 to 6 months.
The management of a dysplastic “polyp” in patients with UC or Crohn's colitis has
similar guidelines. I f a well-circumscribed dysplastic polyp is found proximal to
histologically demonstrable colitis, it should be managed as a simple adenoma. D A LMs
were first identified by Blackstone and colleagues in 1981 and were associated with a
31high rate of CRC at colectomy. More recently, a raised dysplastic lesion with the
32appearance of sporadic adenoma has been termed an adenoma-like DALM. I n contrast,
poorly circumscribed lesions with indistinct borders and an irregular surface, or plaque
like lesions, have been termed nonadenoma-like D ALMs. A lternative terms are
endoscopically resectable and endoscopically nonresectable polypoid dysplasia,
respectively.
The endoscopist must make a distinction between an adenoma-like D A LM and a
nonadenoma-like D A LM, because these lesions overlap histologically. Patients with UC
who are found to have an area of endoscopically resectable dysplasia (adenoma-like
D A LM) may undergo polypectomy and continued endoscopic surveillance if no other
areas of flat dysplasia are detected in the adjacent mucosa or elsewhere in the
33-35colon. I t is recommended that additional biopsies be taken immediately adjacent to
the polyp and elsewhere in the colon to exclude flat dysplasia. I f no dysplasia is found,
repeat surveillance colonoscopy should be performed within 6 to 12 months. I n contrast,
patients with an area of nonresectable polypoid dysplasia (nonadenoma-like D A LM) are
usually referred for colectomy because of the high rate of association of these lesions
with synchronous or metachronous cancer. Recommendations for the management of
flat and polypoid dysplasia are presented in Figure 2.1.
FIGURE 2.1 Suggested surveillance strategy in patients with
inflammatory bowel disease and dysplasia. (From Farraye FA, Odze
RD, Eaden J, Itzkowitz SH. AGA technical review on the diagnosis
and management of colorectal neoplasia in inflammatory bowel
disease. Gastroenterology. 2010;138:746-774.)S tudies have demonstrated that the use of chromoendoscopy can greatly increase the
detection rate of dysplasia in patients with UC who have been enrolled in a surveillance
36program. Chromoendoscopy with targeted biopsies revealed significantly more
dysplastic lesions than conventional colonoscopy with random biopsies. The overall
37-39sensitivity of chromoendoscopy for predicting neoplasia was 93% to 97%. Given
these findings, consensus guidelines from several organizations have endorsed the use
18,20of chromoendoscopy in surveillance colonoscopy by trained endoscopists. A s more
data regarding chromoendoscopy become available and new imaging techniques are
developed, guidelines for surveillance endoscopy in patients with I BD will be refined to
reflect these advances. I t is also likely that molecular biology techniques will play a more
40important role in the future as an adjunct to endoscopic biopsy.
Screening and Surveillance Guidelines for Colon Polyps
The following is a review of the management of colonic polyps in patients who do not
41,42have I BD . This summary includes screening for colon polyps, surveillance after
polypectomy and resection for CRC, and the approach to the patient with a malignant
polyp.
CRC is the second most common cause of cancer death in the United S tates. The
overall mortality rate approaches 60%. A pproximately 5% to 6% of U.S .-born individuals
will develop colon cancer in their lifetime, and 2.5% will die of the disease. The incidence
does not vary significantly between men and women. I t is estimated that almost 143,000
new cases of CRC will be diagnosed and almost 51,000 deaths will occur from CRC in the
43United S tates in 2013. CRC is a suitable disease for screening because it is a common
malignancy with a long, asymptomatic preclinical phase and a high survival rate if
detected in its early stage. Prevention of CRC should be achievable by application of
screening programs to identify asymptomatic patients with adenomatous polyps and to
remove them. I n The N ational Polyp S tudy, colonoscopic polypectomy decreased the
44expected incidence of CRC by 53%. A n estimated 14.2 million colonoscopies and 2.8
45million flexible sigmoidoscopies were performed in 2002 in the United States.
Definition and Clinical Considerations
46S mall ( Advanced adenoma is defined as any polyp larger than 1 cm in diameter or any
polyp regardless of size that is villous or contains a focus of HGD. Efforts to reduce colon
cancer are now shifting mainly to strategies to reliably detect and resect advanced
adenomas before they become malignant rather than focusing on identifying small
tubular adenomas. I t should also be noted that interobserver variability with regard to
47diagnosis of villous components and HGD in an adenoma is high. Therefore,
reproducible histologic criteria must be developed by pathologists so that future
prospective outcome studies can accurately predict the fate of patients with advanced
adenomas. Currently, 70% of polyps removed at colonoscopy are adenomas. More than
80% of these are tubular, 5% to 15% are tubulovillous, and 5% to 15% are villous
48adenomas.
Initial Management of Polyps
Colonoscopy is the most accurate method for detecting polyps and allows immediate
biopsy and resection. I t has quickly replaced fecal occult blood testing (FOBT), flexible
sigmoidoscopy, and barium enema as the primary screening modality, although flexible
sigmoidoscopy and FOBT remain approved methods on screening for CRC in the
asymptomatic patient. Computed tomographic colonography, another option, is still
considered investigational as a screening modality. I t should be reserved for those
patients with incomplete optical colonoscopies, because the test has not been
determined to be cost-effective for routine screening and is not reimbursed by most
49insurance plans. A complete colonoscopy should be performed at the time of every
initial polypectomy to detect and resect all synchronous adenomas. A dditional
colonoscopic examinations may be required after resection of a large sessile adenoma, if
there were multiple adenomas, or if the quality of the colonic preparation was
suboptimal.
Management of Small Polyps
50S mall polyps (small polyps. A “resect and discard” policy is being discussed by
51gastroenterology societies as a method to lower the cost of colonoscopy. The first part
of this paradigm is applied to all diminutive polyps found during colonoscopy; a visual
assessment is made of the polyp during colonoscopy and after removal, and the tissue is
then discarded rather than submi ed for pathologic review. This approach allows for
reduction of costs as well as an immediate determination of the colonoscopy surveillance
interval. The second aspect of the paradigm proposes not resecting multiple
rectosigmoid hyperplastic polyps. This approach again leads to a reduction of costs and
52risks from polypectomy.
Management of Sessile Serrated Adenomas/Polyps
There is no evidence that small, distally located hyperplastic polyps carry an increased
risk for CRC, but it is now accepted that certain variants of hyperplastic-appearing or
serrated polyps are precursors to CRC. For example, serrated polyps have been linked to
the development of sporadic adenocarcinomas with high-level microsatellite instability
(MS I -H), which are associated with the development of “interval cancers” after
53colonoscopy. Hyperplastic-appearing polyps at risk for such progression are usually
large (>5 mm), sessile with a layer of yellow mucus, and found proximally in the colon on
colonoscopy. These have been called atypical hyperplastic polyps, sessile serrated polyps
(S S P), ors essile serrated adenomas (S S A) and sessile serrated adenomas/polyps (S S A /Ps).
These S S A /Ps tend to be found later in life (median age, 61 years), with a slight female
53predominance. I nitially, S S A s are not dysplastic, but over time, due to increased
microsatellite instability, they develop dysplasia and are precursors to CRC, accounting
54for approximately 15% to 20% of these cancers. D ysplastic serrated adenomas are
classified as sessile serrated adenomas with dysplasia (S S A D ) or traditional serrated
55adenomas (TSA), which tend histologically to appear more like traditional adenomas.
Because of their malignant potential, the most recent guidelines recommend that
large, proximally located, hyperplastic-appearing serrated polyps be managed in the
same way as adenomas of similar size. These guidelines recommend that serrated
lesions proximal to the sigmoid colon and all lesions larger than 5 mm be completely
53,55resected. When lesions are removed piecemeal, a follow-up colonoscopy should be
performed in 2 to 6 months to ensure that no residual polyp tissue has been left behind.
S S A s smaller than 10 mm should have repeat surveillance in 5 years, whereas larger
lesions and those containing any dysplasia should undergo surveillance in 3 years. S ee
Table 2.5 for a summary of recommendations for the colonoscopic surveillance of
serrated polyps.Table 2.5
Recommendations for Surveillance and Screening Intervals in Individuals with
Serrated Lesions
Baseline Colonoscopy: Most Advanced Recommended Surveillance Interval
Finding (Yr)
Sessile adenomas removed piecemeal 2-6 mo
Sessile serrated polyps 5
Sessile serrated polyp >10 mm 3
Sessile serrated polyp with dysplasia 3
Traditional serrated adenoma 3
Serrated polyposis syndrome 1
Data from Lieberman DA, Rex DK, Winawer SJ, et al. Guidelines for colonoscopy
surveillance after screening and polypectomy: a consensus update by the US Multi-Society
Task Force on Colorectal Cancer. Gastroenterology. 2012;143:844-857.
Hyperplastic Polyposis Syndromes
S errated polyposis syndrome (S PS ), formerly known ash yperplastic polyposis, is a
syndrome characterized by the presence of multiple serrated lesions, either serrated
adenomas or hyperplastic polyps. The World Health Organization has defined S PS as a
syndrome meeting one of the following criteria: (1) at least five serrated polyps proximal
to the sigmoid colon, with two or more being larger than 10 mm; (2) any serrated polyps
proximal to the sigmoid colon in any patient who has a first-degree relative with S PS ; (3)
56more than 20 serrated polyps of any size in any location throughout the colon. The risk
of cancer in S PS is unknown but is believed to be increased, and a retrospective study
57showed a 7% risk of cancer at 5 years in patients undergoing surveillance. S urveillance
colonoscopy is recommended at 1-year intervals to clear the proximal colon of lesions
larger than 5 mm; however, surgical resection is recommended if carcinoma is
discovered or the number of polyps is too great to be endoscopically managed. S urgery
should involve resection of the portion of the colon that contains the cancer as well as
that which has the largest polyps; usually, an extended right hemicolectomy or subtotal
colectomy is performed. Patients will then need annual surveillance of the remaining
colon and rectum.
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, EMR has been shown to be successful
58for large pedunculated 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
59polyps tend to recur locally after resection, and one study quoted a rate as high 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. A nother investigation
found that the use of EMR for resection of large sessile polyps was successful in 90% of
cases, with size larger than 40 mm and use of argon plasma coagulation leading to lower
59asuccess rates.
A ssessment of the adequacy of excision of a large sessile polyp (≥2 cm) is problematic
and depends on both the endoscopist's assessment of whether a residual lesion is
present and the pathologist's ability to identify resection margins with confidence. This
includes the issue of whether a large sessile polyp is resected intact or piecemeal. The
endoscopist may ta oo the polypectomy site with I ndia ink after endoscopic resection to
facilitate visualization during a subsequent endoscopic procedure. General practice has
suggested that a patient who has undergone colonoscopic excision of a large sessile
polyp in piecemeal fashion should have follow-up colonoscopy in 2 to 6 months to verify
complete removal. I f 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 is
recommended in 1 year. I f complete resection is not possible after two or three
41procedures, surgical resection should be considered.
Postpolypectomy Surveillance
Because a large number of patients with adenomas are being identified by colonoscopy,
the burden placed on medical resources (i.e., the timely availability of colonoscopy) is
60increasing dramatically. The U.S . Multi-S ociety Task Force on Colorectal Cancer and
the A merican Cancer S ociety recently revised the recommendations for surveillance
colonoscopy after polypectomy. Updated guidelines emphasize stratification of patients
into high- and low-risk groups (Table 2.6) and are based on the assumption that the
initial screening colonoscopy was of optimal quality. However, certain studies have
shown that approximately 17% of polyps larger than 10 mm are missed during optical
41colonoscopy and that these missed polyps account for the majority of interval cancers.
Table 2.6
Risk Factors for Metachronous Advanced Adenomas
High Risk Low Risk
• 3 to 10 adenomas • No adenomatous polyps
• Any adenoma >1 cm • 1 to 2 small (
• Adenoma with villous features
• High-grade dysplasia
• Serrated lesion
From Lieberman DA. Guidelines for colonoscopy surveillance after screening and
polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal
Cancer. Gastroenterology. 2012;143(3):844-857.
A fter an initial colonoscopy has been performed with complete polypectomy, patientswho are deemed to be at low risk for 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 (C H A P T E R 3
Diagnostic Cytology of the
Gastrointestinal Tract
Helen H. Wang
Gamze Ayata
CHA P T E R OUT LINE
Introduction
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, and Metaplastic Changes
Nonspecific Changes
Pemphigus
Barrett Esophagus
Neoplastic Lesions
Squamous Dysplasia or Carcinoma
Glandular Dysplasia or Carcinoma
Endocrine Tumors
Mesenchymal Tumors
Lymphoid Tumors+
+
Introduction
The popularity of gastrointestinal (GI ) cytology for the diagnosis of infection and
malignancy has waxed and waned during the past few decades. The ability to
distinguish between high-grade dysplasia or carcinoma in situ and invasive
carcinoma in biopsy specimens and the more prevalent expertise of surgical
pathology cause some to consider cytology an unnecessary duplication of GI mucosal
1,2biopsies. However, the combined use of endoscopy, ultrasound guidance, and
fine3needle aspiration (FNA) has expanded the horizons of GI cytology.
Specimen Types
Types of GI tract specimens commonly received in the cytology laboratory include
those obtained by endoscopic brushings and ultrasound-guided endoscopic FN A .
Endoscopic FN A has enabled endoscopists to reach farther than they can with biopsy
forceps to sample mural and extramural lesions, including lesions adjacent to the GI
tract. The nonendoscopic specimens obtained with balloon- or mesh-type samplers
have been evaluated in the research se ing to ascertain their usefulness in the
4-6surveillance of populations at high risk for esophageal carcinoma.
Specimen Preparations
D irect smears can be made from materials collected on the endoscopic brush, in the
needle, or on the balloon and mesh samplers; these can then be either fixed
immediately in 95% ethanol and stained with the Papanicolaou method or left to
airdry and stained with D iff-Quik (D ade-Behring, I nc., D eerfield, I L) or Wright-Giemsa
stain. A lternatively, the material can be rinsed into a medium such as CytoLyt,
CytoRich, or 50% ethanol for liquid-based preparations. The specimen can then be
processed by a concentration method, such as ThinPrep Processor (Hologic,
7,8Marlborough, MA) or Cytospin (ThermoFisher S cientific, Waltham, MA), to make
slides that are then stained with the Papanicolaou method. A ccording to a College of
A merican Pathologists I nterlaboratory Comparison Program in N ongynecologic
7Cytology, ThinPrep preparations performed be ert han non-ThinPrep preparations.
However, liquid-based preparations, including ThinPrep, involve altered morphology
and artifacts that require adjustment by cytopathologists, such as cleaner background
with altered or reduced background and extracellular elements, architectural changes
(smaller cell clusters and sheets and more three-dimensional clusters), altered cell
distribution (more dyshesion—dissociation of cells at the periphery of cell clusters or
as single cells), and changes in cytologic morphology (enhanced nuclear features and
9smaller cell size). Residual material from liquid-based preparations lends itself to
10cell block making with thromboplastin-plasma cell block technique, the Cellient
Automated Cell Block System (Hologic), or other techniques for ancillary studies.
Value and Accuracy of Specimens
Cytology specimens have some advantages over specimens obtained by endoscopic
biopsy. The brush can sample a wider area, and the fine needle can reach deeper
lesions than can be reached by biopsy forceps. A lso, both the brush and the fine
needle are less invasive than biopsy forceps and less likely to cause bleeding. I n
addition, cytology has a shorter turnaround time than histology. D irect smears can be
ready for review within minutes with no compromise of the quality of the preparation+
(unlike frozen sections of biopsy specimens, which compromise the quality of the
final or permanent preparation). However, as mentioned, cytology is limited in its
ability to distinguish between high-grade dysplasia or carcinoma in situ and invasive
carcinoma.
D espite the potential duplication of cytology and biopsy, the literature has
consistently shown that the highest diagnostic yield is obtained with the combined
11-13use of these specimens. The yield of cytology is significantly higher when the
14brushing is performed before rather than after the biopsy.
Normal Morphology
Esophagus
I ntermediate-type squamous cells with abundant cytoplasm and vesicular nuclei are
seen in the normal esophagus (Fig. 3.1). S uperficial-type squamous cells with
abundant cytoplasm and small pyknotic nuclei can also be seen in small numbers.
S ingle 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 is
composed predominantly of intermediate squamous cells
(Papanicolaou stain).
Stomach
Gastric surface foveolar cells can shed as single cells or in sheets. When in sheets, the
columnar cells exhibit abundant cytoplasm, regularly spaced nuclei, and open
chromatin arranged in a honeycomb or palisaded pa ern (Fig. 3.2), depending on the
orientation. When they are shed as single cells, they often lose their cytoplasm to
become naked nuclei. I n endoscopic FN A specimens, the sheets of foveolar cells can
mimic cells from a mucinous neoplasm, and the single naked nuclei, because of their
small, monomorphic appearance, can mimic cells from a pancreatic endocrine tumor.FIGURE 3.2 A sheet of benign gastric foveolar cells in a slightly
distorted honeycomb pattern with evident columnar cells in
palisading arrangement at the periphery is seen in a gastric
brushing specimen. The presence of small nucleoli in some of the
cells may indicate reactive change (Papanicolaou stain).
Small Intestine
The lining cells of the small intestine can be easily distinguished from gastric foveolar
cells by the presence of goblet cells. On low magnification, the specimen typically has
a S wiss cheese appearance, with the “holes” representing either goblet cells or gland
openings of the crypts (Fig. 3.3). On high magnification, the absorptive cells have
either finely granular or vacuolated cytoplasm, and the goblet cells have single large
mucin vacuoles and crescent-shaped nuclei with rounded contours. The striated
border of the absorptive cells may be seen at the periphery of the sheets.
FIGURE 3.3 A complex sheet of small intestinal–type epithelium
is seen in a duodenal brushing specimen. It has a Swiss cheese
appearance, with the “holes” representing either goblet cells or
gland openings of the crypts (Papanicolaou stain).
Large IntestineLarge Intestine
N ormal 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 a colonic brushing specimen. A gland opening is
seen in the left half of the field (Papanicolaou stain).
Infections
Most infectious agents that affect human hosts can infect the GI tract of
15immunocompetent and immunocompromised patients. S ome 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. Brushings
are more sensitive than biopsy specimens in the detection of esophageal
13candidiasis. 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 formations on Papanicolaou stain (Fig. 3.5).
Reactive squamous cells and inflammatory cells are often observed in the
background.FIGURE 3.5 Pseudohyphae and yeast forms from Candida
species are seen in an esophageal brushing specimen.
Inflammatory cells and debris are in the background
(Papanicolaou stain).
Herpes Simplex Virus
Herpes simplex virus infection can theoretically affect epithelial cells anywhere along
the GI tract, but it is most commonly seen in the esophagus. Multinucleation, nuclear
molding, ground-glass chromatin, and eosinophilic intranuclear inclusions are the
characteristic features of infected cells (Fig. 3.6).
FIGURE 3.6 A Cowdry type A inclusion characterized by an
eosinophilic intranuclear body surrounded by a halo is seen in the
center of the field in this specimen from an esophageal brushing
of herpetic esophagitis (Papanicolaou stain).
CytomegalovirusCytomegalovirus infection affects epithelial, stromal, and endothelial cells along the
GI tract and is characterized by large cells with a single large basophilic intranuclear
inclusion with a perinuclear halo (Fig. 3.7). I ntracytoplasmic textured inclusions can
occasionally be seen in the affected cells.
FIGURE 3.7 Both intranuclear and intracytoplasmic inclusions
are seen in this cytomegalovirus-infected cell from an esophageal
brushing. The intranuclear inclusion is a large amphophilic to
basophilic body surrounded by a halo, and the intracytoplasmic
inclusion is characterized by small, granular, basophilic to
amphophilic bodies (Papanicolaou stain).
Helicobacter pylori
Helicobacter pylori infection occurs exclusively in the stomach and is perhaps the most
common infection of the GI tract. These organisms can be demonstrated on imprint
16,17smears of gastric biopsies or on brush cytology specimens. Examination of
imprint and brushing cytology specimens is comparable, if not superior, in sensitivity
(88%) and specificity (61%) to histologic examination of sections stained with
16,17hematoxylin and eosin (H&E) and modified Giemsa stain. The benefits of
imprint and brushing cytology are rapid results, high specificity, and low cost.
However, the efficacy of cytologic detection depends on the extent of colonization by
these organisms. When present in large quantity, they are evident even at low
magnification, but they can be difficult to identify when present in small numbers.
On Papanicolaou stain, H . pylori organisms appear as faintly basophilic, S -shaped
rods admixed with mucus in the vicinity of glandular cell clusters (Fig. 3.8). S pecial
stains, such as a triple stain combining silver, H&E, and A lcian blue at pH 2.5, can
18enhance 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
preparation).
Giardia
Giardia affects the duodenum of both immunocompetent and immunocompromised
hosts. Brush cytology is a useful method for detecting Giardia because the organisms
are on the luminal surfaces of the intestinal epithelial cells. They are flat, gray,
pear19shaped, and binucleate, with four pairs of flagella (Fig. 3.9). Giardia lamblia
trophozoites have been found to be immunoreactive for the protooncogene KIT (C-kit,
20CD117), which may help to identify the organisms.FIGURE 3.9 A pear-shaped, gray, binucleate Giardia organism
is seen in the center of the field in this duodenal brushing
specimen (Papanicolaou stain).
Atypical Mycobacteria
Atypical mycobacteria accumulate within macrophages in the lamina propria, and
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). I n general, the
organisms are present in large numbers. On D iff-Quik–stained smears, the
mycobacteria form numerous rod-shaped negative images, either within the
21histiocytes or in the background (Fig. 3.11). S pecial 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 a man with
human immunodeficiency virus (HIV) infection. On special stain,
the cell is shown to be filled with acid-fast bacilli, consistent with
atypical mycobacteria (Papanicolaou stain).
FIGURE 3.11 Numerous negative images of rod-shaped
organisms are seen within and outside the histiocyte in the center
of the field (from the same case as in Fig. 3.10) (Diff-Quik
preparation).
Cryptosporidia
Cryptosporidia can involve any glandular epithelium of the GI tract in patients
infected with the human immunodeficiency virus (HI V) and can be detected by
22examination 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
methenaminesilver 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 stain).
Microsporidia
Microsporidia can be detected on cytologic specimens such as stool, nasal secretions,
duodenal aspirates, and bile, as well as on brushing specimens from the duodenum
23-25and 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 both epithelial cells and inflammatory cells. I n epithelial
cells, they are located in the supranuclear portion of the cytoplasm and therefore, 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
visible 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 stain).
Inflammatory, Reactive, and Metaplastic Changes
Nonspecific ChangesA ny injury to the mucosa can evoke a nonspecific inflammatory or reactive epithelial
change. When the injury is sufficient to result in ulceration, the change (i.e., the
epithelial repair) can become so extreme that it may mimic a malignancy. I t is often
difficult to determine whether the reparative epithelium is of glandular or squamous
origin. A lthough 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 appearance of atypical stromal cells or their stripped nuclei from granulation
tissue can also be quite alarming (Fig. 3.15). I n spite of striking nuclear enlargement
of such cells, hyperchromasia is absent. I nstead, they have fine, homogeneous
chromatin and thin, smooth nuclear membranes.
FIGURE 3.14 A sheet of reactive epithelial cells is seen in this
esophageal brushing specimen. The cells have sharp cellular
borders and are variably enlarged with prominent nucleoli. The
nuclear membranes in some cells appear wavy but without sharp
angles or indentations. A few inflammatory cells are
superimposed on or infiltrating this sheet. It is difficult to be
certain whether these cells are squamous or glandular
(Papanicolaou stain). (Courtesy of Dr. Mark Roth of the National
Cancer Institute, Rockville, Md.)FIGURE 3.15 A single, atypical, ovoid- to spindle-shaped cell
with an enlarged, smudged nucleus 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 stain).
Both cellular arrangements and the features of individual cells are useful in
distinguishing between severe reactive and neoplastic changes. Cells with reactive or
reparative changes are usually arranged in flat sheets without three-dimensionality or
prominent cell dyshesion. I n 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. I n addition, the enlarged nuclei in reactive or reparative changes
usually have uniform size and a similar number of small, prominent nucleoli, in
contrast to the variation in nuclear and nucleolar size and shape as well as the
chromatin pattern in the neoplastic lesions. Specific types of reactive cells may also be
seen, such as those with radiation-induced changes (Fig. 3.16). A s in other organs, the
cells are proportionally enlarged, with metachromatic cytoplasm and nuclear or
cytoplasmic vacuoles.+
FIGURE 3.16 A group of proportionally enlarged epithelial cells
showing prominent nucleoli and finely vacuolated cytoplasm is
seen on this esophageal brushing specimen from a patient with
previous radiation therapy for squamous cell carcinoma
(Papanicolaou stain).
Pemphigus
Rarely, pemphigus vulgaris, an autoimmune disease of the skin and mucous
membranes that a acks the intercellular junctions and causes a suprabasilar bleb or
blister as well as acantholysis, may affect the esophagus. N umerous acantholytic cells
are usually present. The characteristic cells are round to polygonal, uniform,
26,27parabasal-sized, and isolated. 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
28irregular, nucleoli (Fig. 3.17). A bar- or bullet-shaped nucleolus is characteristic.
However, the cells have smooth nuclear membranes, and the chromatin is pale, fine,
and even. N ormal mitotic figures can be seen. These atypical cells resemble those in
repair except for the increased number of single cells.+
+
+
+
FIGURE 3.17 A loose group of parabasal-sized squamous cells
with dense cytoplasm and prominent nucleoli can be seen in this
esophageal brushing specimen from a patient known to have
pemphigus vulgaris (Papanicolaou stain).
Barrett Esophagus
Cytology is not the optimal tool for the diagnosis of Barre esophagus. When
glandular epithelial cells are seen in a cytology specimen, it is difficult to be certain
whether they represent cells from the gastric side of the esophagogastric junction or
metaplastic glandular cells from the esophagus. I t has also been shown that cytology
29,30is neither sensitive nor specific for the detection of goblet cells, a hallmark of
this condition, in part because of the absence of a blue hue of acid mucin with the
Papanicolaou stain. However, a long segment of Barre esophagus is more readily
30appreciated by cytology because of the reduced probability of sampling error. I ts
appearance is similar to that of the lining epithelium of the small intestine, with a
S wiss cheese pa ern at low magnification and goblet cells with single, large
cytoplasmic vacuoles on high magnification (Fig. 3.18). The honeycomb arrangement
of the glandular cells in Barre esophagus 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 esophagus (Papanicolaou stain).
Neoplastic Lesions
Squamous Dysplasia or Carcinoma
S quamous dysplastic cells of the esophagus have morphology similar to that of the
dysplastic cells on cervicovaginal Papanicolaou smears (Box 3.1 and Figs. 3.19 and
313.20). The cellular features of squamous cell carcinoma vary with the degree of
differentiation (Box 3.2 and Fig. 3.21; Box 3.3 and Fig. 3.22).
Box 3.1
S qu a m ou s D yspla sia (F ig s. 3 .1 9 a n d 3 .2 0 )
• Some but not all of the malignant features to varying degrees, such as increased
nucleus-to-cytoplasm 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 reactive-appearing squamous cells. The dysplastic cell
shows mild hyperchromasia, nuclear membrane irregularity, and
chromatin aberration, but it still has a fair amount of cytoplasm.
Therefore, it is considered low grade (Papanicolaou
stain). (Courtesy of Dr. Mark Roth of the National Cancer
Institute, Rockville, Md.)
FIGURE 3.20 Compared with the dysplastic cell in Figure 3.19,
this dysplastic squamous cell has more pronounced nuclear
membrane irregularity and a much higher nucleus-to-cytoplasm
ratio. It is, therefore, considered high grade (Papanicolaou
stain). (Courtesy of Dr. Mark Roth of the National Cancer
Institute, Rockville, Md.)
Box 3.2
W e ll-D iffe re n tia te d S qu a m ou s C e ll C a rc in om a (F ig. 3 .2 1)
• 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
FIGURE 3.21 A keratinized squamous cell with a
hyperchromatic nucleus characteristic of well-differentiated
squamous cell carcinoma is present in this esophageal brushing
specimen along with nonkeratinized tumor cells (Papanicolaou
stain).
Box 3.3
M ode ra te ly a n d P oorly D iffe re n tia te d S qu a m ou s C e ll
C a rc in om a (F ig. 3 .2 2)
• Less striking keratinization of the cytoplasm
• Tumor cells in crowded, haphazardly arranged cell clusters with indistinct cell
borders
• Vesicular chromatin with prominent nucleoli+
+
FIGURE 3.22 In contrast to the cells seen in Figure 3.21, tumor
cells from a poorly differentiated squamous cell carcinoma have
vesicular chromatin and occasional prominent nucleoli. The
singlecell pattern, dense basophilic cytoplasm, and endoplasmic and
ectoplasmic demarcation in a cell close to the center of the field
suggest squamous differentiation (Papanicolaou stain).
Glandular Dysplasia or Carcinoma
Glandular dysplasia and carcinoma in the esophagus usually arise in the se ing of
Barre esophagus. The precursor lesions of adenocarcinoma in the stomach and in
the intestine can manifest as either polypoid or flat dysplastic lesions. A denomas of
the stomach and dysplasia of the esophagus or stomach are similar in cytologic
appearance. A lthough the few reported studies on this topic were based on very small
29,30,32,33numbers of cases and were insufficient to provide definitive conclusions on
34the usefulness of cytologic surveillance, the preliminary results appear promising.
Low-grade dysplasia may be difficult to distinguish from artifactual crowding,
whereas high-grade dysplasia may be confused with either severe reparative change
or invasive carcinoma (Box 3.4 and Fig. 3.23; Box 3.5 and Fig. 3.24; Box 3.6 and Fig.
3.25). A ncillary molecular studies may be helpful to identify dysplasia and carcinoma
35-37in esophageal brushing specimens from patients with Barrett esophagus.
Box 3.4
L ow -G ra de G la n du la r D yspla sia (F ig . 3 .2 3)
• 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 dyshesionFIGURE 3.23 A strip of stratified columnar cells with slightly
enlarged and elongated nuclei is seen in an esophageal brushing
specimen from a patient with biopsy-proven low-grade dysplasia
in Barrett esophagus (Papanicolaou stain).
Box 3.5
H igh -G ra de G la n du la r D yspla sia (F ig . 3 .2 4)
• 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
FIGURE 3.24 A sheet of haphazardly arranged and overlapped
atypical cells with granular cytoplasm on a clean background is
seen in an esophageal brushing specimen from a patient with
biopsy-proven high-grade dysplasia in Barrett esophagus. The
nuclei show chromatin aberration and occasional nucleoli, but the
cells do not appear to be malignant (Papanicolaou stain).+
Box 3.6
A de n oc a rc in om a (F ig . 3 .2 5)
• 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 3.25 Compared with the cells in Figure 3.24, the cells
in this gastric brushing from a well-differentiated adenocarcinoma
show significant three dimensionality and a more pronounced
haphazard arrangement. Cytoplasmic vacuolization as well as
polarization of cells indicates glandular differentiation. Red blood
cells are apparent in the background. The much increased
cellularity and marked architectural abnormality indicate an
invasive adenocarcinoma (Papanicolaou stain).
The amount and characteristics of the cytoplasm of the tumor cells depend on the
degree of differentiation. A ppearance varies from abundant vacuolated or granular
cytoplasm to scant dense cytoplasm that is difficult to distinguish from that of a
poorly differentiated squamous cell carcinoma.
S ignet ring cell carcinoma, a type of adenocarcinoma that occurs most commonly in
the stomach, is worthy of special consideration because it can be difficult to detect on
both cytologic and histologic preparations. Because the malignant cells infiltrate
predominantly the lamina propria, they are often not included in the brush cytology
sample unless mucosal ulceration is present. The reactive or reparative epithelial
changes associated with an ulcer can distract the pathologist from the real lesion. I n
addition, the numerous inflammatory cells from the ulcer can obscure the sca ered,
isolated tumor cells (Box 3.7 and Fig. 3.26). 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 CD68 (as detected by the KP1 antibody) and CD163.
Box 3.7
S ign e t R in g C e ll C a rc in om a (F ig . 3 .2 6)
• 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
• Crescent-shaped nucleus compressed against the cytoplasm with pointed ends
• 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 stain).
Endocrine Tumors
GI neuroendocrine neoplasms are classified into two main categories according to the
38latest classification from the World Health Organization : (1) neuroendocrine tumor
(N ET)—including grade 1 (carcinoid) and grade 2; and (2) neuroendocrine carcinoma
—both large cell and small cell. I n addition to morphology, the distinction between
39grade 1 and grade 2 N ET depends on mitoses and the Ki67 proliferation index,
which also distinguish NET from neuroendocrine carcinoma.
The prognosis of N ET depends on the grade and on features that cannot be
evaluated on cytologic preparations, including size and site of the lesion, presence of
40local invasion, angioinvasion, pa erns of hormone production, and metastases.+
Cytologic atypia, mitotic index, and the proliferative index obtained by Ki67
immunostaining can be evaluated to some extent on cytologic materials. A long the GI
tract, the small intestine is the most common site for such tumors, followed by the
41rectum and appendix, with the stomach a distant fourth. These tumors account for
42fewer than 1% of all gastric malignancies. However, cytologic specimens from the
appendix, ileum, and rectum are almost never seen. Our experience with cytology of
grade I N ET has primarily involved tumors in the stomach and duodenum B( ox 3.8
and Fig. 3.27).
Box 3.8
N e u roe n doc rin e T u m or (C a rc in oid) (F ig . 3 .2 7)
• 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 stain).
The tendency of N ET cells to lose their cytoplasm causes them to mimic
lymphomas with small cell morphology because of their small size and characteristic
monomorphism. S uch stripped nuclei can be distinguished from low-grade small cell
lymphoma by their complete absence of cytoplasm and their finely granular
(“saltand-pepper”) chromatin pa ern. Of course, one should always find intact cells to
confirm the diagnosis. S mall cell neuroendocrine carcinomas (small cell carcinomas)
of the GI tract are similar to those seen elsewhere and are characterized by small cells
with scant cytoplasm, showing nuclear molding and a finely dispersed chromatin
pattern. Mitoses and necrosis are also prominent features of these tumors.
Mesenchymal TumorsMesenchymal 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 usually accessible by endoscopic brush unless the tumor is ulcerated. Endoscopic
FN A with or without ultrasound guidance is the preferred method of sampling.
S pecimens from leiomyomas usually consist of sparse bland, cohesive spindle cells
arranged in parallel lines with evenly spaced nuclei and abundant intercellular
43fibrillary 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 and Fig. 3.28).
Box 3.9
G a stroin te stin a l S trom a l T u m or (F ig . 3 .2 8)
• Cellular specimen with fascicles, clusters, and sheets of spindle or epithelioid
cells or both
• Cell groups spread out thinly on the slide despite their large size
• Prominent small blood vessels
• Possibility of numerous single cells and naked nuclei
• Delicate fibrillary cytoplasm with wispy cytoplasmic extensions and indistinct
cell borders
• Ovoid- to spindle-shaped and occasional wavy nuclei
• Uncommon high-grade features, such as marked nuclear atypia, frequent
mitoses, and necrosis+
FIGURE 3.28 A, A hypercellular fascicle of spindle-shaped cells
is seen in this endoscopic gastric fine-needle aspiration specimen
of a gastrointestinal stromal tumor (Papanicolaou stain). B, On
higher magnification, the cells have fibrillary cytoplasm and
ovoidto spindle-shaped bland nuclei (Papanicolaou stain).
The individual cells of GI stromal tumors have a tendency to lose their cytoplasm to
44,45become stripped, spindle-shaped, or round to oval nuclei. Perinuclear or
paranuclear vacuoles are present in some cells. D elicate cytoplasm and prominent
46nuclear palisading have also been noted. The tumor cells may appear spindly or
47,48epithelioid. A lthough leiomyosarcomas tend to show more significant nuclear
pleomorphism and atypia as well as a less prominent vascular pa ern than GI
49,50stromal tumors, immunocytochemistry, polymerase chain reaction (PCR)
analysis of KIT, or both are needed to make the definitive distinction between the
two. Most GI stromal tumors show strong diffuse positivity for CD 117 and D OG1,
50,51whereas leiomyosarcomas are typically positive for desmin and actin and
negative for CD117 and DOG1.
A lthough immunocytochemical staining for CD 117 and D OG1 is useful in
confirming a cytologic diagnosis of GI stromal tumor, the diagnosis of malignancy
still depends on evaluation of the resected specimen. D etection of a KIT mutation in
an FN A specimen was found to be promising in predicting malignant behavior,52although absence of mutation does not preclude malignancy.
Lymphoid Tumors
The cytologic appearance of lymphoma of the GI tract depends on its subtype. With
adequate material and a combination of morphology and flow cytometry, a diagnosis
53of lymphoma can be established on the basis of a cytology specimen. The large cell
type usually does not pose any diagnostic difficulty on morphology, because large
malignant lymphoid cells are sufficiently atypical to raise the suspicion of a
malignancy (Fig. 3.29). The challenge is to recognize them as being lymphoid and to
distinguish them from poorly differentiated epithelial or mesenchymal tumors. Their
lymphoid nature may in fact be easier to identify on cytology than in a small biopsy
specimen. Large cell lymphoma cells shed as isolated, relatively monomorphic, large
atypical cells with scant cytoplasm, vesicular nuclei, and a single large nucleolus or
54multiple prominent nucleoli. The absence of any true cohesion is the principal
diagnostic feature of a lymphoma. A lthough a poorly differentiated carcinoma may
shed predominantly as single cells, cell clusters can usually be found after a careful
search. I n addition, a poorly differentiated carcinoma often has more abundant
cytoplasm, which may or may not be vacuolated, and a greater degree of nuclear
pleomorphism than a large cell lymphoma. I mmunocytochemical staining facilitates
the distinction between lymphoma and carcinoma.
FIGURE 3.29 Gastric brushing from a biopsy-proven large
Bcell lymphoma shows a monomorphic population of large atypical
cells with scant cytoplasm and central large prominent nucleoli.
Apoptotic bodies and a few inflammatory cells are noted in the
background (Papanicolaou stain).
A low-grade small cell lymphoma, such as a lymphoma of the mucosa-associated
lymphoid tissue (MA LT lymphoma or MA LToma), can be difficult to diagnose by
cytology. I t may be mistaken for an inflammatory process (Box 3.10 and Fig. 3.30),
because it may contain a polymorphous population of small, intermediate-sized, and
55-56large 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. These cells mayshow “plasmacytoid” morphology on air-dried preparations. D iagnosis of MA LToma
by cytology is challenging. A definitive diagnosis is usually made by cytology in only
55,5750% of the cases, and reactive follicular hyperplasia is often erroneously
56diagnosed. Whereas brushings may obtain limited materials, endoscopic
ultrasound-guided FN A has been shown to yield sufficient materials for
immunohistologic, flow cytometric, and cytogenetic assessments for diagnosis of
58lymphoproliferative disorders.
Box 3.10
L ym ph om a of th e M u c osa -A ssoc ia te d L ym ph oid T issu e
(M A L T om a ) (F ig . 3 .3 0)
• Predominance of small- to medium-sized lymphocytes in an apparently
inflammatory specimen
• Monomorphism and subtle atypia in the lymphoid population
FIGURE 3.30 Endoscopic fine-needle aspiration of a
biopsyproven gastric MALT lymphoma shows a monomorphic population
of medium-sized lymphoid cells with slightly irregular nuclear
membranes and occasional nucleoli. Each of these cells may be
mistaken for a reactive lymphocyte. The presence of many
similar-appearing lymphoid cells raises the suspicion of a
lymphoma (Papanicolaou stain). (Courtesy of Dr. Martha Pitman,
Massachusetts General Hospital, Boston, Mass.)
References
1. Cook IJ, de Carle DJ, Haneman B, et al. The role of brushing cytology in the
diagnosis of gastric malignancy. Acta Cytol. 1988;32:461–464.
2. Qizilbash AH, Castelli M, Kowalski MA, et al. Endoscopic brush cytology and
biopsy in the diagnosis of cancer of the upper gastrointestinal tract. Acta
Cytol. 1980;24:313–318.
3. Jhala N, Jhala D. Gastrointestinal tract cytology: advancing horizons. Adv Anat
Pathol. 2003;10:261–277.4. Falk GW, Chittajallu R, Goldblum JR, et al. Surveillance of patients with
Barrett's esophagus for dysplasia and cancer with balloon cytology [see
comments]. Gastroenterology. 1997;112:1787–1797.
5. Leoni-Parvex S, Mihaescu A, Pellanda A, et al. Esophageal cytology in the
follow-up of patients with treated upper aerodigestive tract malignancies.
Cancer. 2000;90:10–16.
6. Tsang TK, Hidvegi D, Horth K, et al. Reliability of balloon-mesh cytology in
detecting esophageal carcinoma in a population of US veterans. Cancer.
1987;59:556–559.
7. Clayton AC, Bentz JS, Wasserman PG, et al. Comparison of ThinPrep
preparations to other preparation types in gastrointestinal cytology:
observations from the College of American Pathologists Interlaboratory
Comparison Program in Nongynecologic Cytology. Arch Pathol Lab Med.
2010;134:1116–1120.
8. Smith GD, Chadwick BE, Adler DG, et al. Comparison of ThinPrep UroCyte
and Cytospin slide preparations for gastrointestinal specimens: evaluation
and retrospective performance review. Diagn Cytopathol. 2010;38:902–912.
9. Hoda RS. Non-gynecologic cytology on liquid-based preparations: a
morphologic review of facts and artifacts. Diagn Cytopathol. 2007;35:621–634.
10. Kulkarni MB, Desai SB, Ajit D, et al. Utility of the thromboplastin-plasma
cellblock technique for fine-needle aspiration and serous effusions. Diagn
Cytopathol. 2009;37:86–90.
11. Geisinger KR. Endoscopic biopsies and cytologic brushings of the esophagus
are diagnostically complementary. Am J Clin Pathol. 1995;103:295–299.
12. O'Donoghue JM, Horgan PG, O'Donohoe MK, et al. Adjunctive endoscopic
brush cytology in the detection of upper gastrointestinal malignancy. Acta
Cytol. 1995;39:28–34.
13. Wang HH, Jonasson JG, Ducatman BS. Brushing cytology of the upper
gastrointestinal tract: obsolete or not? Acta Cytol. 1991;35:195–198.
14. Zargar SA, Khuroo MS, Jan GM, et al. Prospective comparison of the value of
brushings before and after biopsy in the endoscopic diagnosis of
gastroesophageal malignancy. Acta Cytol. 1991;35:549–552.
15. Huppmann AR, Orenstein JM. Opportunistic disorders of the gastrointestinal
tract in the age of highly active antiretroviral therapy. Hum Pathol.
2010;41:1777–1787.
16. Mostaghni AA, Afarid M, Eghbali S, et al. Evaluation of brushing cytology in
the diagnosis of Helicobacter pylori gastritis. Acta Cytol. 2008;52:597–601.
17. Senturk O, Canturk Z, Ercin C, et al. Comparison of five detection methods for
Helicobacter pylori. Acta Cytol. 2000;44:1010–1014.
18. Ghoussoub RA, Lachman MF. A triple stain for the detection of Helicobacter
pylori in gastric brushing cytology. Acta Cytol. 1997;41:1178–1182.
19. Marshall JB, Kelley DH, Vogele KA. Giardiasis: diagnosis by endoscopic brush
cytology of the duodenum. Am J Gastroenterol. 1984;79:517–519.
20. Sinelnikov I, Sion-Vardy N, Shaco-Levy R. C-kit (CD117) immunostain is useful
for the diagnosis of Giardia lamblia in duodenal biopsies. Hum Pathol.
2009;40:323–325.
21. Maygarden SJ, Flanders EL. Mycobacteria can be seen as “negative images” in
cytology smears from patients with acquired immunodeficiency syndrome.
Mod Pathol. 1989;2:239–243.22. Clayton F, Heller T, Kotler DP. Variation in the enteric distribution of
cryptosporidia in acquired immunodeficiency syndrome. Am J Clin Pathol.
1994;102:420–425.
23. Chu P, West AB. Encephalitozoon (Septata) intestinalis: cytologic, histologic, and
electron microscopic features of a systemic intestinal pathogen. Am J Clin
Pathol. 1996;106:606–614.
24. Pol S, Romana CA, Richard S, et al. Microsporidia infection in patients with the
human immunodeficiency virus and unexplained cholangitis. N Engl J Med.
1993;328:95–99.
25. Weber R, Bryan RT, Owen RL, et al. Improved light-microscopical detection of
microsporidia spores in stool and duodenal aspirates. The Enteric
Opportunistic Infections Working Group. N Engl J Med. 1992;326:161–166.
26. Kobayashi TK, Ueda M, Nishino T, et al. Scrape cytology of pemphigus
vulgaris of the nipple, a mimicker of Paget's disease. Diagn Cytopathol.
1997;16:156–159.
27. Takahashi I, Kobayashi TK, Suzuki H, et al. Coexistence of pemphigus vulgaris
and herpes simplex virus infection in oral mucosa diagnosed by cytology,
immunohistochemistry, and polymerase chain reaction. Diagn Cytopathol.
1998;19:446–450.
28. DeMay RM. Intestinal tract. The Art and Science of Cytopathology. 2nd ed.
American Society of Clinical Pathologists: Chicago; 2012. DeMay RM. The Art
and Science of Cytopathology. Vol 1.
29. Saad RS, Mahood LK, Clary KM, et al. Role of cytology in the diagnosis of
Barrett's esophagus and associated neoplasia. Diagn Cytopathol. 2003;29:130–
135.
30. Wang HH, Sovie S, Zeroogian JM, et al. Value of cytology in detecting
intestinal metaplasia and associated dysplasia at the gastroesophageal
junction. Hum Pathol. 1997;28:465–471.
31. Roth MJ, Liu SF, Dawsey SM, et al. Cytologic detection of esophageal
squamous cell carcinoma and precursor lesions using balloon and sponge
samplers in asymptomatic adults in Linxian, China. Cancer. 1997;80:2047–2059.
32. Geisinger KR, Teot LA, Richter JE. A comparative cytopathologic and
histologic study of atypia, dysplasia, and adenocarcinoma in Barrett's
esophagus. Cancer. 1992;69:8–16.
33. Robey SS, Stanley RH, Gupta PK, et al. Diagnostic value of cytopathology in
Barrett esophagus and associated carcinoma. Am J Clin Pathol. 1988;89:493–
498.
34. Hughes JH, Cohen MB. Is the cytologic diagnosis of esophageal glandular
dysplasia feasible? [see comments]. Diagn Cytopathol. 1998;18:312–316.
35. Fritcher EG, Brankley SM, Kipp BR, et al. A comparison of conventional
cytology, DNA ploidy analysis, and fluorescence in situ hybridization for the
detection of dysplasia and adenocarcinoma in patients with Barrett's
esophagus. Hum Pathol. 2008;39:1128–1135.
36. Lin X, Finkelstein SD, Zhu B, et al. Loss of heterozygosities in Barrett
esophagus, dysplasia, and adenocarcinoma detected by esophageal brushing
cytology and gastroesophageal biopsy. Cancer Cytopathol. 2009;117:57–66.
37. Rygiel AM, van Baal JW, Milano F, et al. Efficient automated assessment of
genetic abnormalities detected by fluorescence in situ hybridization on brush
cytology in a Barrett esophagus surveillance population. Cancer.2007;109:1980–1988.
38. Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO Classification of Tumours
of the Digestive System. World Health Organizaton Press: Lyon; 2010.
39. Klimstra DS, Modlin IR, Coppola D, et al. The pathologic classification of
neuroendocrine tumors: a review of nomenclature, grading, and staging
systems. Pancreas. 2010;39:707–712.
40. Garcia-Carbonero R, Capdevila J, Crespo-Herrero G, et al. Incidence, patterns
of care and prognostic factors for outcome of gastroenteropancreatic
neuroendocrine tumors (GEP-NETs): results from the National Cancer
Registry of Spain (RGETNE). Ann Oncol. 2010;21:1794–1803.
41. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors.
Cancer. 2003;97:934–959.
42. Thomas RM, Sobin LH. Gastrointestinal cancer. Cancer. 1995;75:154–170.
43. Stelow EB, Stanley MW, Mallery S, et al. Endoscopic ultrasound-guided
fineneedle aspiration findings of gastrointestinal leiomyomas and
gastrointestinal stromal tumors. Am J Clin Pathol. 2003;119:703–708.
44. Dodd LG, Nelson RC, Mooney EE, et al. Fine-needle aspiration of
gastrointestinal stromal tumors. Am J Clin Pathol. 1998;109:439–443.
45. Rader AE, Avery A, Wait CL, et al. Fine-needle aspiration biopsy diagnosis of
gastrointestinal stromal tumors using morphology, immunocytochemistry,
and mutational analysis of c-kit. Cancer. 2001;93:269–275.
46. Boggino HE, Fernandez MP, Logrono R. Cytomorphology of gastrointestinal
stromal tumor: diagnostic role of aspiration cytology, core biopsy, and
immunochemistry. Diagn Cytopathol. 2000;23:156–160.
47. Dong Q, McKee G, Pitman M, et al. Epithelioid variant of gastrointestinal
stromal tumor: diagnosis by fine-needle aspiration. Diagn Cytopathol.
2003;29:55–60.
48. Elliott DD, Fanning CV, Caraway NP. The utility of fine-needle aspiration in
the diagnosis of gastrointestinal stromal tumors: a cytomorphologic and
immunohistochemical analysis with emphasis on malignant tumors. Cancer.
2005;108:49–55.
49. Seidal T, Edvardsson H. Diagnosis of gastrointestinal stromal tumor by
fineneedle aspiration biopsy: a cytological and immunocytochemical study. Diagn
Cytopathol. 2000;23:397–401.
50. Wieczorek TJ, Faquin WC, Rubin BP, et al. Cytologic diagnosis of
gastrointestinal stromal tumor with emphasis on the differential diagnosis
with leiomyosarcoma. Cancer. 2001;93:276–287.
51. Miettinen M, Sobin LH, Sarlomo-Rikala M. Immunohistochemical spectrum of
GISTs at different sites and their differential diagnosis with a reference to
CD117 (KIT). Mod Pathol. 2000;13:1134–1142.
52. Li SQ, O’Leary TJ, Sobin LH, et al. Analysis of KIT mutation and protein
expression in fine needle aspirates of gastrointestinal stromal/smooth muscle
tumors. Acta Cytol. 2000;44:981–986.
53. Zeppa P, Marino G, Troncone G, et al. Fine-needle cytology and flow cytometry
immunophenotyping and subclassification of non-Hodgkin lymphoma: a
critical review of 307 cases with technical suggestions. Cancer. 2004;102:55–65.
54. Sherman ME, Anderson C, Herman LM, et al. Utility of gastric brushing in the
diagnosis of malignant lymphoma. Acta Cytol. 1994;38:169–174.
55. Crapanzano JP, Lin O. Cytologic findings of marginal zone lymphoma. Cancer.2003;99:301–309.
56. Matsushima AY, Hamele-Bena D, Osborne BM. Fine-needle aspiration biopsy
findings in marginal zone B cell lymphoma. Diagn Cytopathol. 1999;20:190–198.
57. Chhieng DC, Cohen JM, Cangiarella JF. Cytology and immunophenotyping of
low- and intermediate-grade B-cell non-Hodgkin's lymphomas with a
predominant small-cell component: a study of 56 cases. Diagn Cytopathol.
2001;24:90–97.
58. Yasuda I, Goto N, Tsurumi H, et al. Endoscopic ultrasound-guided fine needle
aspiration biopsy for diagnosis of lymphoproliferative disorders: feasibility of
immunohistological, flow cytometric, and cytogenetic assessments. Am J
Gastroenterol. 2012;107:397–404.C H A P T E R 4
Infectious Disorders of the Gastrointestinal Tract
Laura W. Lamps
CHA P T E R OUT LINE
Introduction
Viral Infections of the GI Tract
Cytomegalovirus
Herpesvirus
Adenovirus
Other Enteric Viruses
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
Introduction
Gastrointestinal (GI ) infections are a major cause of morbidity and mortality worldwide. A s the number of transplant patients and those with
other immunocompromising conditions increases, and as global urbanization and transcontinental travel become more frequent, the surgical
pathologist must be familiar with infectious diseases that were once limited to tropical regions of the world or the realm of esoterica.
The goal of the surgical pathologist in evaluating GI specimens for infectious colitis is twofold. First, acute self-limited processes and
infectious processes must be differentiated from chronic idiopathic inflammatory bowel disease (I BD )—ulcerative colitis or Crohn's disease.
1S econd, dedicated a, empts must be made to identify the specific infecting organisms. I n 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,
and molecular analysis. A s these techniques have evolved, our knowledge of the specific histologic pa, erns of inflammation related to various
organisms has also increased.
Most enteric infections are self-limited. Patients who undergo endoscopic biopsies usually have chronic or debilitating diarrhea or systemic
symptoms, or they are immunocompromised. A discussion with the gastroenterologist regarding symptomatology and colonoscopic findings,
as well as knowledge of the patient's travel history, food intake (e.g., sushi, poorly cooked beef), sexual practices, and immune status can aid
immeasurably in the 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
Primary cytomegalovirus (CMV) infections in immunocompetent persons are usually asymptomatic. CMV infection may develop anywhere in
the GI tract, from mouth to anus, in both immunocompromised and immunocompetent persons. CMV is best known as an opportunistic
pathogen in patients with a suppressed immune system, most commonly in those with the acquired immunodeficiency syndrome (A I D S ) and
2in patients who have undergone solid organ or bone marrow transplantation. I n fact, CMV remains the most common GI pathogen overall in
patients with AIDS.
Primary infections in healthy persons are typically asymptomatic. When symptomatic disease does occur, it is usually self-limited and may
manifest as a mononucleosis-like syndrome. I n most of these cases, GI involvement is subclinical. S ymptomatic GI infection has been reported
3,4occasionally in immunocompetent patients, although many of these were elderly or were eventually found to have underlying malignancies
or hematologic disorders and therefore may not have had entirely competent immune systems.
Symptoms vary with site of infection. The most common clinical symptoms are diarrhea (either bloody or watery), abdominal pain, fever, and
2 5weight loss. Patients with esophageal infection often have dysphagia and odynophagia. A rare, but important, entity associated with
6,7pediatric CMV infection is hypertrophic gastropathy and protein-losing enteropathy resembling Ménétrier disease.
I n addition, secondary CMV infection may be superimposed on chronic GI diseases such as ulcerative colitis and Crohn's disease. I n such
cases, CMV superinfection is associated with exacerbations of the underlying disease, steroid-refractory disease, toxic megacolon, and a higher
mortality rate. S ome authorities recommend immunohistochemical evaluation for CMV as part of the routine evaluation of biopsies in patients
8,9with steroid-refractory ulcerative colitis.
Pathologic Features
2,10CMV causes a remarkable variety of gross lesions. Ulceration is the most common; the ulcers may be single or multiple, and superficial or
deep. They can be quite large (>10 cm), and often have a well-circumscribed, “punched-out” appearance. S egmental ulcerative lesions andlinear ulcers may mimic Crohn's disease. Other gross lesions include mucosal hemorrhage, pseudomembranes, and inflammatory polyps or
11,12masses.
The histologic spectrum of CMV infection is extremely variable, ranging from minimal inflammation to deep ulcers with prominent
granulation tissue and necrosis. Frequently observed histologic features include mucosal ulceration, a neutrophil-rich mixed inflammatory
2infiltrate, and cryptitis of glandular epithelium. Crypt abscesses, crypt atrophy and loss, and numerous apoptotic enterocytes may be seen as
10well. CMV may also cause a vasculitis featuring numerous endothelial viral inclusions with associated inflammation, necrosis, and
13thrombosis of the affected vessel and resultant mucosal ischemia.
I nfected cells show both nuclear and cytoplasmic enlargement (hence the name, “cytomegalovirus”) (Fig. 4.1, A). Characteristic “owl's-eye”
intranuclear viral inclusions and basophilic granular intracytoplasmic inclusions may be seen on routine hematoxylin and eosin (H&E)
preparations (see Fig. 4.1, B and C). I nclusions are preferentially found in endothelial cells, stromal cells, and macrophages, and, rarely, in
glandular epithelial cells. I n contrast to adenovirus or herpes, CMV inclusions are often found deep within ulcer bases rather than at the edges
of ulcers or in the superficial mucosa. A djacent nuclei may be enlarged, appear smudged, or have a “ground-glass” appearance, but they lack
typical inclusions. Characteristic inclusions with virtually no associated inflammatory reaction may occur in severely immunocompromised
patients.
FIGURE 4.1 A, Polyp removed from the gastric antrum contains innumerable cytomegalovirus (CMV) inclusions within
endothelial and stromal cells. CMV causes both nuclear enlargement and enlargement of the entire cell. B, Characteristic
“owl's-eye” nuclear inclusion is seen within an endothelial cell at the base of an ulcer. C, Granular, basophilic cytoplasmic
inclusions may also be seen.
I n biopsy specimens, the diagnosis are easily missed when only rare inclusions are present. Examination of multiple levels and use of
immunohistochemistry can be invaluable in detecting the rare cells containing an inclusion. Other diagnostic aids include viral culture,
polymerase chain reaction (PCR) assays, in situ hybridization, serologic studies, and antigen tests. S erologic studies often have limited
usefulness because of the persistence of latent CMV infection. I n addition, isolation of CMV in culture does not imply active infection, because
2the virus can be excreted for months to years after a primary infection.
Differential Diagnosis
5The differential diagnosis of CMV includes primarily other viral infections (Table 4.1), particularly adenovirus. A denovirus inclusions are
usually crescent shaped, located in surface epithelium, and only intranuclear in location. CMV inclusions typically have an owl's-eye
morphology, are typically 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.Table 4.1
Light Microscopic Comparison of CMV, Adenovirus, and HSV Infection
CMV Adenovirus HSV
Cell involved Stromal and endothelial Epithelial only—either surface epithelial Epithelial cells, usually squamous
cells; macrophages; cells or goblet cells in colon
rarely epithelial cells
Location of Nucleus and cytoplasm Exclusively intranuclear Intranuclear
inclusion
Characteristics of “Owl's-eye” morphology Basophilic “smudge cell” filling entire Homogeneous with “ground-glass” appearance
inclusion in nucleus; basophilic nucleus most common; rarely, or acidophilic with clear halo and peripheral
and granular in acidophilic inclusions with halos chromatin margination (Cowdry type A)
cytoplasm (Cowdry type A)
Associated Cellular enlargement Surface cell disorder, loss of orientation, Sloughing of epithelial cells, neutrophilic
changes Apoptosis apoptosis; cells not enlarged infiltrate; multinucleated cells common
Mixed inflammatory
infiltrate
Vasculitis
CMV, Cytomegalovirus; HSV, herpes simplex virus.
The distinction between CMV infection and graft-versus-host disease in bone marrow transplant recipients can be particularly difficult
because the clinical and histologic features are similar. I mmunohistochemistry or in situ hybridization studies should be used to rule out CMV
10infection in this se, ing, because failure to identify CMV infection could 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 se, ing of
minimal inflammation. The presence of viable nests of endocrine cells favors graft-versus-host disease.
Herpesvirus
Clinical Features
Herpetic infection can occur throughout the GI tract but is most common in the esophagus and anorectum. A lthough herpes infection of the
gut is often seen in immunocompromised patients and remains one of the most common infections in patients with human immunodeficiency
14virus (HI V), it is not limited to this group. I n immunocompetent patients, infection is often self-limited. I mmunocompromised patients,
however, are at risk for disseminated infection and life-threatening illness.
Patients with herpetic esophagitis are seen with odynophagia, dysphagia, chest pain, nausea, vomiting, fever, and GI bleeding. Many have
15disseminated herpes infection at the time of diagnosis. Herpetic proctitis is the most common cause of nongonococcal proctitis in
homosexual men. Patients typically are seen with severe anorectal pain, tenesmus, constipation, discharge, hematochezia, and fever.
Concomitant neurologic symptoms (difficulty in urination and paresthesias of the bu, ocks and upper thighs) are also well described, as is
15inguinal lymphadenopathy.
Pathologic Features
Ulcers are the most common gross finding in the esophagus, and these are usually associated with an exudate. The ulcers are often shallow and
well-circumscribed. S ome patients have vesicles surrounding the ulcers. Many patients have a nonspecific erosive esophagitis without discrete
ulcers, however. I n herpetic proctitis, the presence of perianal vesicles is common, often in association with pustules or shallow ulcers.
15,16Proctoscopic findings include ulceration and mucosal friability. Vesicles may extend into the rectum or anal canal.
Typical histologic findings, regardless of site, include ulceration, neutrophils in the lamina propria, and an inflammatory exudate that often
17contains sloughed epithelial cells (Fig. 4.2, A). Prominent aggregates of macrophages may also be present. I n the anorectum, perivascular
lymphocytic cuffing and crypt abscesses may be seen as well.FIGURE 4.2 A, Esophageal biopsy shows dyshesion and sloughing of squamous epithelial cells, intraepithelial neutrophils,
and herpetic inclusions within squamous cells. B, Higher-power view shows the homogeneous basophilic “ground-glass”
inclusions of herpes simplex virus with peripherally marginated chromatin. C, Multiple inclusions may be present within a
single cell, known as a polykaryon.
7Characteristic viral inclusions and multinucleate giant cells are present in only a minority of biopsy specimens (see Fig. 4.2, B and C). 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. Two types of
nuclear inclusions may be found: the homogeneous ground-glass inclusions and the acidophilic inclusions with a surrounding clear halo and
peripheral chromatin margination (Cowdry type A inclusions). I nclusions may be single or multinucleate. The histologic findings for herpes
simplex virus 1 (HSV-1) and HSV-2 are indistinguishable.
Differential Diagnosis
The differential diagnosis predominantly contains other viral infections, including CMV and varicella-zoster, that may infect the GI tract (see
18 18Table 4.1). Varicella produces histologic findings identical to those of HS V, but patients often have a rash. Mixed infections are common in
many situations in which herpetic infection is found. I mmunohistochemistry and in situ hybridization are very useful, and viral culture is a
valuable diagnostic aid as well. S erologic studies may be useful if there is a very high or rising antibody titer, but serologic testing has limited
use because latent infections can persist for years.
Adenovirus
A denovirus infection is second only to rotavirus as a cause of childhood diarrhea, and it is associated with a broad spectrum of diseases in both
children and adults. I t has gained more a, ention in recent years as a cause of diarrhea in immunocompromised patients, especially those with
19-21A I D S and those who have received bone marrow or solid organ transplants. Virtually all patients are seen with diarrhea, sometimes
accompanied by fever, weight loss, and abdominal pain. Characteristic inclusions may be seen, especially in immunocompromised patients, in
the nuclei of surface epithelial cells (particularly goblet cells); these are often accompanied by apoptotic epithelial cells and epithelial
19,24 22-24degenerative changes. A denovirus is also one of the associated with ileal and cecal intussusception in children. The characteristic
nuclear inclusions are known as “smudge cells” because of their enlarged, homogeneous, basophilic characteristics (Fig. 4.3; see Table 4.1).
Useful aids to help in the diagnosis of adenovirus infection include immunohistochemistry, stool examination by electron microscopy,
molecular studies, and viral culture. This entity is discussed further and illustrated in Chapter 5.
FIGURE 4.3 Multiple adenovirus inclusions, or “smudge cells,” are seen within the colonic epithelial cells in this biopsy from
a patient with AIDS.
Other Enteric Viruses
A cute viral gastroenteritis is one of the most common causes of illness worldwide. A lthough most infections are self-limited, viralgastroenteritis can cause severe dehydration (particularly when caused by rotavirus), as well as chronic diarrhea in children with
immunodeficiency syndromes such as severe combined immunodeficiency. Enteric viral infections are a significant cause of diarrhea in
patients with A I D S . Rotavirus and enterovirus, like adenovirus, are associated with intussusception in children. Many enteric viruses do not
cause disease in humans; others seldom cross the stage of the surgical pathologist because they are detected in stool samples rather than
biopsy specimens. Common enteric viruses known to cause diarrhea in humans include, but are not limited to, adenovirus, rotavirus,
25-30coronavirus, astrovirus, N orwalk virus and other enteric caliciviruses, and echovirus and other enteroviruses. Enteric involvement was
documented in the coronavirus-associated severe acute respiratory syndrome (S A RS ), and diarrhea was a common presenting symptom in that
25outbreak.
S mall bowel biopsy findings include villous fusion, broadening, and blunting; crypt hypertrophy; and an increased mononuclear cell
infiltrate within the lamina propria with variably present neutrophils (Fig. 4.4). There may also be an increase in intraepithelial lymphocytes.
Reactive and degenerative epithelial changes are usually present, particularly at the surface, including epithelial cell disarray and loss of
31,32nuclear polarity. I ncreased apoptosis may be seen in surface and glandular epithelium. I n the limited number of human studies available,
the severity of the histologic lesion does not appear to correlate with clinical severity of illness. Most human studies of the histopathology
associated with enteric viral infection are limited to the duodenum. The rare reports that have evaluated the large bowel have documented
histologic findings ranging from normal to focal cryptitis with increased apoptosis. With the exception of adenovirus infection, inclusions are
not seen on light microscopy.
FIGURE 4.4 Villous fusion, surface reactive and degenerative changes, and a mononuclear cell infiltrate are nonspecific
features that can be seen in biopsies from patients with gastroenteritis caused by enteric viruses.
33,34Other viruses that affect the GI tract include measles (rubeola), human herpesvirus 8 (HHV-8; also known asK aposi sarcoma–associated
35 36,37herpesvirus), HHV-6, and Epstein-Barr virus (EBV), which is associated with a wide variety of lymphoproliferative disorders.
Human Papillomaviruses
Human papillomavirus (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 19, 24, and 32.
Human Immunodeficiency Virus
GI disease is an important cause of morbidity and mortality in patients affected by HI V and in those with A I D S . A lthough opportunistic
pathogens are often found in these patients, there is a subgroup in whom no pathogens are found despite extensive clinical and pathologic
evaluation. The two major disease entities associated with HI V in the absence of other demonstrable pathogens are chronic idiopathic
esophageal ulcers and AIDS enterocolopathy.
38,39Chronic idiopathic esophageal ulcers reportedly cause 40% to 50% of ulcers found in HI V-infected patients. The ability of HI V to
directly cause these ulcers remains controversial, although evidence of HI V within the ulcerative lesions has been demonstrated by molecular
40analysis, immunohistochemical studies, and enzyme-linked immunosorbent assays (ELI S A). Patients are seen with severe odynophagia,
independent of food intake; chest pain; and weight loss. The middle esophagus is the most common location, followed by the distal esophagus.
Endoscopically, the ulcers consist of one or more well-circumscribed lesions of variable depth that can mimic ulcers caused by other infectious
agents, particularly viral pathogens. They can be quite large (>3.0 cm in greatest dimension) and deep, with irregular margins and overhanging,
edematous edges. Mucosal bridges and sinus tract formation may occur. Histologically, the ulcers contain granulation tissue with a mixed
acute and chronic inflammatory infiltrate that often contains eosinophils. By definition, special histochemical stains and immunohistochemical
stains for identifiable pathogens must be negative. This finding is especially important because these ulcers are sometimes treated with
41steroids. This entity is also discussed in Chapter 5.
HI V/A I D S enteropathy/colopathy is a somewhat controversial entity that has been loosely defined as the morphologic changes seen in the
gut of patients with HI V/A I D S and chronic diarrhea for which no other infectious cause has been identified. The controversy arises because
asymptomatic patients may have similar morphologic findings on biopsy and, conversely, severely symptomatic patients may have normal
42biopsies. I n addition, there is always the added concern that a causative pathogen simply has been missed. Because patients with HI V/A I D S
do have severe impairments of GI function including diarrhea, malabsoprtion, and weight loss, even in the absence of any demonstrable
pathogens, many authors support use of the term AIDS enteropathy (or colopathy) to describe the morphologic findings, provided that the bowel
43-45has been adequately sampled and all other infectious causes have been excluded. However, other authorities believe that this is a poorly
understood term that does not clearly represent a specific disease entity and therefore should be avoided.
Endoscopy and colonoscopy findings are usually normal. I n the small bowel, the histologic features include villous blunting and atrophy,
crypt hypertrophy, increased intraepithelial lymphocytes, variably increased mononuclear cells in the lamina propria, increased mitoses within
glandular epithelial cells, and increased numbers of apoptotic enterocytes at the surface and in the glands. I n the colon, inflammatory changes
are similar, but the apoptotic epithelial cells in the glandular epithelium are often very prominent (Fig. 4.5). The changes resemble those seen
43-45in mild graft-versus-host disease and chemotherapy-related mucosal injury. Other pathogens, particularly other viruses such as CMV and
adenovirus that can produce similar histologic features, must be rigorously excluded.FIGURE 4.5 Increased apoptotic cells in the glands are a prominent feature of HIV-associated enterocolopathy.
Bacterial Infections of the Gastrointestinal Tract
Bacterial diarrhea is a worldwide health problem. Many bacterial infections of the gut are related to ingestion of contaminated water or food or
to foreign travel, especially from an area of good sanitation to one of poor sanitation. A lthough bacterial pathogens are often recovered by
microbial culture, surgical pathologists may play a valuable role in diagnosis. D espite the dizzying array of bacterial infections that may affect
the GI tract, many produce a similar spectrum of histologic features and may be generally categorized as follows (Table 4.2):
1. Organisms that produce mild or no histologic changes, such as Vibrio cholerae and Neisseria gonorrhoeae
2. Organisms that produce the histologic features of acute infectious/self-limited colitis (ASLC) or focal active colitis (FAC), such as
Campylobacter, Aeromonas, and some Salmonella species
3. Organisms that produce specific or characteristic histologic features, such as pseudomembranes, granulomas, or viral inclusions
Table 4.2
Classification of Bacterial Infections of the Gastrointestinal Tract by Histologic Pattern
Acute
SelfMinimal or No
Limited Pseudomembranous Predominantly Predominantly ArchitecturalInflammatory Diffuse Histiocytic
Colitis Pattern Granulomatous Lymphohistiocytic Distortion
Change
Pattern
Toxogenic Vibrio Shigella Enterohemorrhagic E. Yersinia Rhodococcus equi Lymphogranuloma Salmonella
cholerae (O1 coli venereum
strain)
Enteropathogenic E. Campylobacter Clostridium difficile Mycobacterium Whipple disease Salmonella Shigella
coli tuberculosis typhimurium
Enteroadherent E. Aeromonas Occasionally Shigella Actinomycosis MAI Focal or mild:
coli (immunocompromised
patients)
Spirochetosis Occasionally MAI
Salmonella (immunocompetent
(especially patients)
other Vibrio
species
nontyphoid)
Neisseria spp. Occasionally
Clostridium
difficile
Syphilis (±
increased
plasma
cells)
E. coli, Escherichia coli; MAI, Mycobacterium avium-intracellulare.
Acute Self-Limited Colitis
The A S LC pa, ern is the most common pa, ern in enteric infections. Typical histologic features include neutrophils in the lamina propria, with
1,46-51or without crypt abscesses and cryptitis; preservation of crypt architecture; and lack of basal plasmacytosis. The acute inflammatory
component is often most prominent in the middle to upper levels of the crypts. Lack of crypt distortion, Paneth cell metaplasia, and basal
1,51lymphoplasmacytosis help to distinguish ASLC from IBD. The changes may be focal, as in focal active colitis, or diffuse.
S urgical pathologists should be aware of the infections that are most likely to mimic other I BD , particularly Crohn's disease, ulcerative
colitis, and ischemic colitis (see Table 4.2). Because most patients do not present for 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 because the
resolving phase of infectious colitis is more challenging to diagnose. At this stage, only occasional foci of neutrophilic cryptitis and only patchy
increases in lamina propria inflammation may be found, and these may, in fact, contain abundant plasma cells and increased intraepithelial
lymphocytes, features that are also seen in Crohn's disease or even lymphocytic colitis. I t is important to be aware of the patient's symptoms
(particularly acute versus chronic onset) and, ideally, the culture results, because the exact diagnosis may be difficult to resolve on histologicgrounds alone. The pathologic details of specific bacterial infections are discussed in the following sections.
Major Causes of Bacterial Enterocolitis
Vibrio cholerae and Related Species
V. cholerae (specifically the toxigenic O1 strain) is the causative agent of cholera, an important worldwide cause of watery diarrhea and
52,53dysentery that may lead to significant dehydration, electrolyte imbalance, and death within hours. Most infections result from
consumption of raw or undercooked seafood, especially shellfish. Other vibrios, including non-O1 strains of V. cholerae, Vibrio hollisae, and
54Vibrio parahaemolyticus, also can cause severe gastroenteritis. S ymptoms of cholera include the abrupt onset of diarrhea, usually profusely
watery and rarely bloody, accompanied by abdominal pain, vomiting, muscle cramps, and fever. D isseminated infection is a particularly
important risk with immunocompromised patients; patients with underlying liver disease, partial or total gastrectomy, and diseases of iron
metabolism are also at risk for more serious Vibrio infections.
Despite the severity of the illness, V. cholerae O1 is a noninvasive toxin-producing organism that cause minimal or no histologic change to the
intestinal mucosa. N onspecific findings such as small bowel mucin depletion, degenerative surface epithelial changes, and a mild increase in
55,56lamina propria mononuclear cells have been rarely reported. N on-toxigenic O1 and other non-cholerae Vibrio species may show an erosive
enterocolitis with active neutrophilic inflammation and associated hemorrhage. Useful ancillary diagnostic tests include culture, PCR, and
57serologic studies. A history of travel to or emigration from an endemic or epidemic area also can be invaluable.
Aeromonas and Related Species
I nitially believed to be nonpathogenic gram-negative bacteria, Aeromonas and related species are increasingly recognized as causes of
58-61gastroenteritis in both children and adults. Aeromonas hydrophila and Aeromonas sobria most often cause GI disease in humans. I nfection
usually is caused by exposure to untreated water but also may result from consumption of contaminated foods such as produce, meat, and
dairy products. I nfections most frequently occur in the late spring, summer, and early fall, and children are most commonly affected. A mild,
self-limited diarrheal illness is most common, sometimes accompanied by nausea, vomiting, and cramping abdominal pain. A more severe,
dysentery-like illness occurs in 15% to 25% of patients, featuring bloody or mucoid diarrhea and fecal leukocytes. This variant is most likely to
mimic chronic idiopathic IBD endoscopically.
Endoscopically, findings include mucosal edema, friability, erosions, exudates, and loss of vascular pa, ern. The distribution is often
62,63segmental, either right- or left-sided, and may mimic ischemic colitis, Crohn's disease, or ulcerative colitis macroscopically. A severe
pancolitis mimicking fulminant ulcerative colitis has also been described. The histologic features are usually those of A S LC, including
cryptitis, crypt abscesses, and a neutrophilic infiltrate in the lamina propria. However, ulceration and focal architectural distortion may be seen
in some cases (Fig. 4.6).
FIGURE 4.6 Focal cryptitis and architectural distortion are seen in a right colon biopsy specimen in a case of
cultureproven Aeromonas infection that was initially thought to be Crohn's disease based on the endoscopic appearance.
The differential diagnosis includes other infectious colitides, ischemic colitis, and chronic idiopathic I BD . When architectural distortion is
present in a patient with more chronic symptoms or macroscopic features mimicking chronic idiopathic I BD , it may be difficult to resolve the
issue of Aeromonas infection versus Crohn's disease or ulcerative colitis. A lthough there are no histologic features specific for Aeromonas
infection (as with many infections of the GI tract), it is important for the surgical pathologist to realize that this is one of the bacteria that can
most closely mimic chronic idiopathic IBD. Stool cultures are critical to diagnosis, and certain selective media may be required.
Escherichia coli
Escherichia coli is the most common gram-negative human pathogen. The diarrheogenic E. coli are classified into five groups, based primarily on
64,65serotyping. I f pathogenic E. coli is suspected, the clinical laboratory should be notified to search for it specifically, because it may be
missed on routine culture. I n addition, because pathogenic E. coli strains are often cleared rapidly from stool (often within 4 to 7 days), cultures
should be taken as early as possible.
Enterotoxigenic and Enteropathogenic E. coli
These noninvasive organisms cause nonbloody diarrhea. Enterotoxigenic E. coli (ETEC) is a major cause of traveler's diarrhea and of outbreaks
66-68within industrialized nations. Enteropathogenic E. coli (EPEC) is predominantly an infection of infants and neonates. The gross and
microscopic pathology of ETEC and EPEC have not been well described in humans.
Enteroinvasive E. coli
The pathology of enteroinvasive E. coli (EI EC) has not been well described in humans. These organisms are very similar toS higella genetically
69and in their clinical presentation and pathogenesis; therefore, the pathology could be expected to be similar as well. S ymptoms include
diarrhea (typically mucoid and watery but nonbloody), tenesmus, fever, malaise, and abdominal cramps. EI EC is transmi, ed via contaminatedcheese, water, and person-to-person contact; it is also a cause of traveler's diarrhea. The organisms produce a severe, dysentery-like illness as
70,71well as bacteremia; this can be a particular problem in AIDS patients.
Enteroadherent E. coli
This noninvasive strain of enteroadherent E. coli (EA EC) is similar to EPEC. Both have been increasingly recognized as causes of chronic
72-74diarrhea and wasting in A I D S patients. A lthough endoscopic findings are usually unremarkable, right colon biopsies more often yield
pathologic findings. Histologic examination shows degenerated surface epithelial cells with associated intraepithelial inflammatory cells. A
74coating of adherent bacteria at the surface epithelium is the most prominent feature (Fig. 4.7). The bacteria may be tightly or loosely
adherent. The histologic findings can be patchy and can resemble an exaggerated brush border; they may easily be missed at low power. I n
addition, specimens from infected patients may show no associated inflammatory reaction whatsoever. The main entities in the differential
diagnosis are normal mucosa and spirochetosis; the bacteria in EPEC and EA EC are not spirillar, in contrast to spirochetosis, and in general,
they stain gram negative.
FIGURE 4.7 Enteroadherent Escherichia coli in a patient with AIDS. A coating of gram-negative rods with little
inflammatory reaction is seen at the surface of the colonic mucosa (Gram stain). (Courtesy of Dr. Mary Bronner, University
of Utah School of Medicine.)
Enterohemorrhagic E. coli
75,76The most common strain of enterohemorrhagic E. coli (EHEC) is O157 : H7. This pathogen gained national a, ention in 1993 when a
massive outbreak in the western United S tates was linked to contaminated ground beef. A lthough contaminated meat is the most frequent
mode of transmission, infection may also occur through contaminated water, milk, and produce and through person-to-person contact. EHEC
produces a cytotoxin similar to that of Shigella dysenteriae, but there is no invasion. Hemolytic-uremic syndrome or thrombotic
thrombocytopenic purpura may develop in affected persons, and children and the elderly are at particular risk for grave illness. I n some
studies, the use of antibiotics to treat EHEC appears to increase the risk for hemolytic-uremic syndrome. S ymptoms usually consist of bloody
diarrhea with severe abdominal cramps and mild or no fever. N onbloody, watery diarrhea may occur, however. Only one third of patients have
fecal leukocytes.
Endoscopically, patients typically have severe mural edema with associated hemorrhage. The mucosa is eroded and ulcerated, and ulcers
often have an overlying purulent exudate. The edema may be so marked as to cause obstruction, and surgical resection may be required to
relieve this or to control bleeding. The right colon is usually most severely affected. The histologic features closely resemble ischemic colitis of
other causes, including marked edema and hemorrhage in the lamina propria and submucosa with associated mucosal acute inflammation,
crypt withering, and lamina propria hyalinization (Fig. 4.8). Microthrombi may be present within small-caliber blood vessels, and
pseudomembranes resembling antibiotic-associated pseudomembranous colitis (PMC) are occasionally present as well. Mucosal necrosis is
77,78frequently seen, often involving the upper portion of the mucosa but sparing the deeper crypts.
FIGURE 4.8 Enterohemorrhagic Escherichia coli. A, Transmural hemorrhagic necrosis and an acute inflammatory exudate
are seen in this right colon resection from a patient with E. coli O157 : H7 infection. B, The crypt withering and lamina propria
hyalinization are very similar to the features of ischemic colitis.
The differential diagnosis primarily includes Clostridium difficile–related PMC and ischemic colitis of other causes, from which EHEC may be
histologically indistinguishable. The clinical history, including the possibility of consumption of contaminated food, the age of the patient, and
macroscopic findings may aid in distinguishing ischemia from E. coli infection. The C. difficile antigen test or PCR assays, or both, may be veryhelpful in distinguishing C. difficile–related colitis from EHEC.
79A n antibiotic-associated hemorrhagic colitis has been reported in association with Klebsiella oxytoca. This colitis is hemorrhagic,
segmental, most common in the right and transverse colon, and lacks pseudomembranes. A history of antibiotic usage, especially penicillins,
may help distinguish this infection from EHEC. S tool culture is invaluable in making the diagnosis; however, routine stool cultures cannot
distinguish O157  :  H7 from normal intestinal flora, because microbiologic diagnosis requires screening on selective agar. A n
80immunohistochemical stain for the EHEC organism has been described, and molecular assays exist but are not widely available.
Salmonella
S almonellae are gram-negative bacilli that are transmi, ed through food and water and are prevalent where sanitation is poor. They are an
important cause of both food poisoning and traveler's diarrhea. The majority of medically important salmonellae are in the species Salmonella
enterica. They are differentiated by their serotyping, but the nomenclature has changed. For example, the bacterium Salmonella enteritidis is
now designated Salmonella enterica ser. Enteritidis, or simply S. enteritidis.
81D iscussion of Salmonella infection can generally be divided into infection by typhoid and nontyphoid species. Enteric (typhoid) fever is
usually caused by the serovar S. Typhi but may also be caused by S. paratyphi; the most common nontyphoid species include S. enteritidis, S.
typhimurium, S. muenchen, S. anatum, S. paratyphi,. and S. give. A lthough historically enteric fever was considered a much more severe disease
and nontyphoid salmonellosis a milder one, more recent literature suggests a greater degree of overlap (both clinically and pathologically) than
previously thought. Patients with low gastric acidity are at increased risk of salmonellosis, and patients with A I D S have a greater risk of
Salmonella infection as well as a greater likelihood of severe infection and septicemia.
Typhoid (Enteric) Fever
Typhoid fever typically manifests with abdominal pain, headache, an elevation in fever over several days, and occasionally constipation. A n
abdominal rash and leukopenia are often seen. D iarrhea, which begins in the second or third week of infection, is initially watery but may
81,82 82-85progress to severe GI bleeding. Perforation and toxic megacolon may complicate typhoid fever.
A ny level of the alimentary tract may be involved, but the characteristic pathology is associated with lymphoid aggregates and Peyer patches
and therefore is most prominent in the ileum, appendix, and colon. Grossly, the bowel wall is thickened, and raised nodules may be seen
corresponding to hyperplastic lymphoid tissue. A phthous ulcers overlying lymphoid aggregates, linear ulcers, discoid ulcers, and
fullthickness ulceration and necrosis are common as the disease progresses. A ssociated suppurative mesenteric lymphadenitis may occur.
82-85Occasionally, the mucosa is grossly normal or only mildly inflamed and edematous.
The histiocyte is the predominant inflammatory cell. Hyperplasia of Peyer patches leads to acute inflammation of the overlying epithelium
(Fig. 4.9, A and B). Eventually, macrophages, mixed with occasional lymphocytes and plasma cells, infiltrate and obliterate the lymphoid
82-85follicles; neutrophils are not prominent. N ecrosis then begins in the Peyer patch and spreads to the surrounding mucosa, which
eventually ulcerates. Ulcers are typically very deep. A rchitectural distortion that may mimic ulcerative colitis or Crohn's disease is well
described (see Fig. 4.9, C). Typhoid fever occasionally shows features more consistent with A S LC, including prominent neutrophils, cryptitis,
82-85crypt abscesses, and overlying fibrinous exudate. Granulomas are occasionally seen.
FIGURE 4.9 A, The typical histologic lesion of typhoid fever is ulceration overlying a lymphoid aggregate or Peyer patch.
(Courtesy of Dr. A. Brian West, Yale University.) B, The typical inflammatory infiltrate is predominantly mononuclear,
featuring plasma cells, lymphocytes, and histiocytes, with inconspicuous neutrophils. C, Architectural distortion can mimic
that of chronic idiopathic inflammatory bowel disease. D, Nontyphoid Salmonella infection often shows features of acute
infectious-type colitis but can also exhibit mild architectural disarray and gland loss.
Nontyphoid Salmonella Species
Nontyphoid Salmonella infection typically manifests as a self-limited gastroenteritis. Endoscopic findings include mucosal redness, ulceration,
and exudates; pathologic features are those of nonspecific A S LC. Occasionally, significant crypt distortion may be seen (seeF ig. 4.9,
82,83,86,87D).The differential diagnosis of typhoid fever includes other infections as well as chronic idiopathic I BD (Table 4.3), and there may be
82-85significant histologic overlap among these entities. A prominence of neutrophils and granulomas is rare in typhoid fever, and although
significant crypt distortion has been reported in some cases of salmonellosis, it is usually more pronounced in chronic idiopathic I BD . The
differential diagnosis of nontyphoid Salmonella infection includes other causes of infectious A S LC, and occasionally chronic idiopathic I BD as
well. Clinical presentation and blood and stool cultures can be invaluable to the pathologist in sorting out this differential diagnosis, and bone
marrow biopsy culture may be useful in establishing the diagnosis of typhoid fever. Of note, Salmonella infection may complicate preexisting
idiopathic IBD.
Table 4.3
Enteric Bacterial Infectious Mimics of Chronic Idiopathic Inflammatory Bowel Disease and Ischemic Colitis
Mimics of Crohn's Disease Mimics of Ulcerative Colitis Mimics of Ischemic Colitis
Salmonella typhimurium Shigella spp. Enterohemorrhagic Escherichia coli
Shigella spp. Nontyphoid Salmonella spp. Clostridium difficile (pseudomembranous colitis)
Yersinia Aeromonas spp. Clostridium perfringens
Mycobacterium tuberculosis Campylobacter (rarely)
Aeromonas spp. Lymphogranuloma venereum
Campylobacter (rarely)
Lymphogranuloma venereum
Shigella
Shigella species are virulent, invasive, gram-negative bacilli that cause severe watery and bloody diarrhea and are a major cause of infectious
52diarrhea worldwide. I nfection is transmi, ed by water contaminated with feces, and person-to-person transmission is also possible. I t has the
highest infectivity rate of the enteric gram-negative bacteria; symptoms may result from ingestion of a very low number of organisms. Children
younger than 6 years of age are commonly affected, as are homosexual men and malnourished or debilitated patients. Constitutional
symptoms are the earliest manifestation and include abdominal pain, malaise, and fever. The diarrhea is often watery initially; this is followed
by the onset of bloody diarrhea containing mucus or pus and accompanied by tenesmus. Complications include severe dehydration, sepsis,
perforation, toxic megacolon, reactive arthritis, Reiter syndrome, and hemolytic-uremic syndrome. Chronic disease is rare.
Grossly, the large bowel is typically affected (the left side usually more severely), but the ileum may be involved. The mucosa is hemorrhagic,
88-90with exudates that may form pseudomembranes. Ulcerations are variably present. Histologically, early disease has the features of A S LC
with cryptitis, crypt abscesses (often superficial), and ulceration (Fig. 4.10). Pseudomembranes similar to those of C. difficile infection may be
90seen, as may aphthous ulcers similar to those seen in Crohn's disease. A s the disease continues, increased mucosal destruction occurs with
many neutrophils and other inflammatory cells in the lamina propria. Marked architectural distortion mimicking idiopathic I BD is well
87,88,91described.
FIGURE 4.10 This biopsy from a patient with Shigella sonnei infection shows cryptitis, a crypt abscess, and a mucin
granuloma centered on a damaged gland. (Courtesy of Dr. Mary Bronner, University of Utah School of Medicine.)
The differential diagnosis of early shigellosis is primarily that of other infections, particularly EIEC and C. difficile. Shigellosis, especially later
in the disease course, can be extremely difficult to distinguish from Crohn's disease or ulcerative colitis, both endoscopically and histologically.
S tool cultures and clinical presentation may be helpful in this instance. Multiple stool cultures may be necessary, because the organism dies
rapidly and prolonged transit time may affect culture yield.
Campylobacter
Campylobacter (the name is derived from the Greek for “curved rod”) is a genus of gram-negative bacteria that are major causes of diarrhea
92-94worldwide and are the most common stool isolate in the United S tates. I nfection is most commonly associated with consumption of
93undercooked poultry, raw milk, or untreated water. Campylobacter jejuni is more frequently associated with food-borne gastroenteritis ;
Campylobacter fetus and the other, less common species are more often seen in immunosuppressed patients and homosexual men.
Campylobacter infects patients of all ages, but infants, children, and young adults are most often affected. The incidence in HI V-positive
patients is higher than in the general population, and severe, chronic, recurrent, or disseminated infections are more common in this group.
Campylobacter infection is associated with the subsequent development of several autoimmune disorders, including Guillain-Barré syndrome,
92,94Henoch-S chönlein purpura, and reactive arthropathy. Campylobacter infection may also cause exacerbations of underlying chronic
idiopathic I BD . Patients typically have fever, malaise, abdominal pain (often severe), and watery diarrhea that may contain blood and fecal
94,95leukocytes. N ausea, vomiting, tenesmus, myalgias, and headache are variably present. S ymptoms typically resolve within 1 to 2 weeks, but
relapse is common.
Endoscopic findings include friable colonic mucosa with associated erythema and hemorrhage. Histologic examination shows features of94,96,97ASLC. Mild crypt distortion may occasionally be seen, although the architecture overall is preserved (Fig. 4.11). The differential
diagnosis primarily includes other forms of infectious enterocolitis that produce the acute infectious-type colitis or focal active colitis pa, ern.
98Occasionally, when crypt distortion is seen, Campylobacter colitis can mimic chronic idiopathic I BD . Cultures are useful in resolving the
differential diagnosis.
FIGURE 4.11 This case of culture-proven Campylobacter jejuni colitis shows a neutrophilic infiltrate with overlying surface
mucosal erosion and hemorrhage. The architecture is largely preserved.
Yersinia
Yersinia are among the most common agents of bacterial enteritis in western and northern Europe, and the incidence is rising in both Europe
99-101and the United S tates. These gram-negative coccobacilli may cause appendicitis, ileitis, colitis, and mesenteric lymphadenitis. A lthough
yersiniosis is usually a self-limited process, chronic infections (including chronic colitis) have been well documented. I mmunocompromised
and debilitated patients, as well as patients who are taking desferrioxamine or have iron overload, are at risk for serious disease. Yersinia
102,103enterocolitica and Yersinia pseudotuberculosis are the species that cause human GI disease.
Yersinia organisms preferentially involve the ileum, right colon, and appendix and may cause a pseudoappendicular syndrome. I n addition,
104they are responsible for many cases of isolated granulomatous appendicitis. Grossly, the involved bowel has a thickened, edematous wall
105-107with nodular inflammatory masses centered on Peyer patches. A phthous and linear ulcers may be seen. I nvolved appendices are
enlarged and hyperemic, as in suppurative appendicitis; perforation is often seen. Involved lymph nodes may show gross foci of necrosis.
106Both suppurative and granulomatous pa, erns of inflammation are common, and these are often mixed. S ignificant overlap is seen
between the histologic features of infection with either species, and either may show epithelioid granulomas with prominent lymphoid cuffing
105(Fig. 4.12, A), lymphoid hyperplasia, transmural lymphoid aggregates, mucosal ulceration, and lymph node involvement. GI infection with
Y. pseudotuberculosis has characteristically been described as a granulomatous process with central microabscesses, almost always accompanied
107by mesenteric adenopathy (see Fig. 4.12, B). Gram stains are usually not helpful, but cultures, serologic studies, and PCR assays may be
useful in confirming the diagnosis.
FIGURE 4.12 A, Epithelioid granulomas with prominent lymphoid cuffs are typical of Yersinia enterocolitica infection. B,
Lymphoid hyperplasia with necrotizing granulomatous inflammation and prominent microabscess formation in a case of
appendicitis caused by Yersinia pseudotuberculosis.
The major differential diagnosis includes other infectious processes, particularly with mycobacteria and Salmonella species. A cid-fast stains
and culture results should help to distinguish mycobacterial infection; 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 difficult to distinguish from one another, and they have a long and complicated relationship (Table
4.4). They may show similar histologic features, including transmural lymphoid aggregates, skip lesions, and fissuring ulcers. I n fact, isolated
granulomatous appendicitis has in the past frequently been interpreted as primary Crohn's disease of the appendix. However, generalized I BD
104rarely develops in patients with granulomatous inflammation confined to the appendix. Features that favor a diagnosis of Crohn's disease
include cobblestoning of mucosa and creeping fat, grossly, and microscopic changes of chronicity, including crypt distortion, thickening of the
muscularis mucosae, and prominent neural hyperplasia. However, some cases are indistinguishable on histologic grounds alone.Table 4.4
Comparison of Histologic Features Useful in the Differential Diagnosis of Mycobacterium tuberculosis, Yersinia, and Crohn's disease
Histologic Feature M. tuberculosis Yersinia Crohn's Disease
Caseating granulomas Frequent Rare Absent
Confluent granulomas Frequent Frequent Absent
Numerous granulomas Common Common Rare
Prominent lymphoid cuff Frequent Frequent Uncommon
Lymphoid hyperplasia Common Very common Uncommon
Ulcers (both aphthous and deep) Common Common Common
Architectural distortion Common Common Common
Changes of chronicity unassociated with sites of granulomatous inflammation Absent Absent Common
Multiple sites of involvement Common Rare Common
Mucosal cobblestoning Uncommon Uncommon Common
Fistula formation Uncommon Rare Common
Anal/perianal disease Rare Absent Common
Clostridial Diseases of the Gut
Clostridial organisms are some of the most potent toxigenic bacteria in existence. Members of this group of bacteria are responsible for
PMC/antibiotic-associated colitis (usuallyC . difficile); necrotizing jejunitis (usually Clostridium perfringens [formerly Clostridium welchii]);
neutropenic enterocolitis or typhlitis (often Clostridium septicum), a serious complication of both chemotherapy-associated and primary
108neutropenia; and botulism (Clostridium botulinum).
Clostridium difficile–Related Colitis
C. difficile infection is most commonly related to prior antibiotic exposure (especially orally administered antibiotics), because the organism
cannot establish infection within the gut in the presence of normal flora. I t is the most common nosocomial GI pathogen. The majority of
patients are elderly, although infection is certainly not limited to this group. Recurrent disease is seen in as many as one half of cases, despite
successful treatment. Furthermore, the incidence of severe or life-threatening C. difficile colitis in N orth A merica has increased because of the
109,110hypervirulent BI /N A P1 strain. The range of clinical disease is highly variable, from mild diarrhea to fully developed PMC to fulminant
108,111,112disease 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. S ymptoms can occur as long as several weeks after
discontinuation of antibiotic therapy.
The entire colon is often involved, but the disease may be patchy or segmental, and any segment of the bowel may be affected, including the
small bowel and the appendix. Classic PMC shows yellow-white pseudomembranes, most commonly in the left side of the colon, that bleed
111when scraped. The distribution is often patchy, and the rectum may be spared. Atypical findings include mucosal erythema and friability
without pseudomembranes, and typical histologic findings may be seen in the absence of macroscopically evident pseudomembranes.
Histologically, classic PMC features “volcano” or “mushroom” lesions with intercrypt necrosis and ballooned crypts, giving rise to the
laminated pseudomembrane composed of fibrin, mucin, and neutrophils (Fig. 4.13, A and B). Ballooned glands are filled with neutrophils and
mucin, and the superficial epithelial cells are often lost. D egenerated goblet cells may slough and spill into the lumen of degenerated and
necrotic crypts (see Fig. 4.13, C); it is important to be aware of this reactive morphologic change in the context of PMC, because it can mimic
signet ring cell adenocarcinoma. S evere and prolonged PMC may lead to full-thickness mucosal necrosis. Less characteristic nonspecific
lesions, usually focal active colitis with occasional crypt abscesses but lacking the pseudomembranous feature, have been well described in
112association with a positive C. difficile toxin assay.
FIGURE 4.13 A, The classic “volcano” lesion of Clostridium difficile with a laminated pseudomembrane composed of fibrin,
mucin, and neutrophils. B, Higher-power view shows intercrypt necrosis and markedly dilated crypts giving rise to the
pseudomembrane. C, Sloughed epithelial cells within degenerated crypts may resemble signet ring cells.
I t is important to remember that the term “pseudomembranous colitis” is descriptive, not a specific diagnosis. A lthough most cases of PMC
are related to C. difficile, other infectious entities (especially Shigella and EHEC), as well as ischemic colitis, can have a similar appearance. A
hyalinized lamina propria favors the diagnosis of ischemia; other features, such as crypt withering, pseudomembranes, and mucosal necrosis,
113may be seen in either entity. Endoscopically, pseudomembrane formation is more frequent in PMC, although it can be seen in ischemia.
A history of antibiotic use may be important in making the diagnosis. C. difficile PCR assays are replacing theC . difficile enzyme-linked
immunosorbent assays (ELI S A) that detect toxins in many centers, owing to their superior sensitivity and specificity. A nother approach is toscreen stools by using enzyme immunoassays (EI A) that detect glutamate dehydrogenase derived from C. difficile. Unlike those that detect
114toxin, this immunoassay is highly sensitive, although positive results require confirmation (usually by PCR). S tudies comparing the
sensitivity and specificity of all of these ancillary diagnostic modalities are ongoing.
C. perfringens causes a segmental necrotizing enteritis (also termed enteritis necroticans or pigbel) related to food poisoning. This bacteria
115,116also causes diarrhea unrelated to food poisoning, which is often associated with antibiotic use and hospitalization in elderly patients.
Food-related infection is most common in S outheast A sia and N ew Guinea. The onset of disease usually follows a meal rich in infected meat
and occurs in persons with malnutrition and those in endemic areas who routinely eat very-low-protein diets and foods that are high in
117protease inhibitors. S imilar cases have been described after eating binges in Western countries. I nfection also has been associated with
118diabetes, possibly because of the delayed gastric emptying and reduced intestinal motility seen in these patients. S ymptoms include
abdominal pain, bloody diarrhea, and vomiting, often with abdominal distention. Complications include perforation, obstruction, bowel
gangrene, and septicemia with shock and rapid death. Mild or subacute forms have also been described. I nvolvement is predominantly seen in
the jejunum but is not limited to that site. The bowel is often dusky gray-green, as in ischemia. N ecrotic areas may be segmental and quite
focal, with intervening areas of normal mucosa. The mucosal exudate can be similar to that of PMC, but inflammation and necrosis often
become transmural and lead to perforation. Histologically, the mucosa is necrotic and ulcerated, with a heavy acute inflammatory infiltrate at
115,116the edges of ulcers (Fig. 4.14, A). S mall-vessel vasculitis and microthrombi may be seen. Pneumatosis may be present in severe cases,
particularly in the mucosa and submucosa (see Fig. 4.14, B). Gram-positive bacilli typical of Clostridium can be found in the necrotic exudate.
The major entities in the differential diagnosis of necrotizing enteritis include ischemia and other infections that cause an ischemic-type injury,
such as EHEC. The clinical history of consumption of large quantities of meat (especially pork or pork products) may be helpful, along with
exclusion of other possible causes of ischemia. Cultures can help to distinguish C. perfringens from other bacteria.
FIGURE 4.14 A, Mucosal hemorrhage, necrosis, ulceration, and crypt withering that mimic ischemia are seen in this case
of Clostridium perfringens infection. (Courtesy of Dr. Robert D. Odze, Brigham and Women’s Hospital.) B, Pneumatosis
may also be found in the submucosa.
Clostridium septicum is associated with neutropenic enterocolitis (typhlitis), a serious complication of both chemotherapy-related and primary
119neutropenia. Most patients have received chemotherapy within the month before the onset of colitis. A lthough C. septicum has been
frequently reported as a causative agent of typhlitis, especially in adults, other commonly implicated bacteria include other clostridial species,
120E. coli, Pseudomonas species, and enterococci. C. septicum infection is also associated with malignancies (particularly adenocarcinoma) in the
121colon and distal ileum, and infection may be the first indication of such a tumor. Patients usually are seen with the abrupt onset of GI
hemorrhage, accompanied by fever, abdominal pain and distention, and diarrhea. The pain often initially localizes to the right lower quadrant
but quickly progresses to peritonitis, shock, and sepsis. Perforation is a well-described complication, and infection is often fatal.
The right colon (especially the cecum) is preferentially involved, although the ileum and other sites in the colon may be affected. Gross
120findings include diffuse dilatation and edema of the bowel, with varying severity of ulceration and hemorrhage. Exudates and
pseudomembranes resembling C. difficile colitis are common. Microscopically, changes range from mild hemorrhage to prominent submucosal
edema, ulceration, marked hemorrhage, and focal necrosis, often with a striking absence of neutrophils (Fig. 4.15). However, neutrophils may
sometimes be found despite peripheral neutropenia. S ometimes organisms can be detected in the wall of the bowel on Gram staining. The
differential diagnosis includes ischemic colitis and PMC. The appropriate clinical se, ing and dearth of inflammatory cells should favor a
diagnosis of neutropenic enterocolitis. Culture is the most helpful technique for confirming the diagnosis of C. septicum infection, and isolation
of the organism from blood cultures may be helpful in septic patients.FIGURE 4.15 Typhlitis (neutropenic enterocolitis) in a chemotherapy patient features ulceration with hemorrhage,
prominent submucosal edema, mucosal ulceration and necrosis, and almost no neutrophils.
Mycobacterial Infections of the GI Tract
Mycobacterium tuberculosis
There has been a remarkable resurgence of tuberculosis in Western countries, due in large part to A I D S , but also to institutional overcrowding
and immigrant populations. Tuberculosis remains common in developing countries as well. GI tuberculosis may be acquired through several
mechanisms, including swallowing infected sputum in pulmonary tuberculosis; ingestion of contaminated milk (rare where pasteurization is
common); hematogenous spread from pulmonary or military disease; and direct extension from adjacent organs.
GI symptoms (rather than pulmonary) may be the initial presentation of disease, and extrapulmonary manifestations of tuberculosis are
more common in A I D S patients than in immunocompetent persons. I n addition, primary GI tuberculosis in the absence of pulmonary
infection has been well documented. S ymptoms and signs of GI tuberculosis vary with the site or sites of involvement. The ileocecal and
122-124jejunoileal areas are most commonly involved, probably because of the abundance of lymphoid tissue at those locations. A ssociated
mesenteric adenopathy is very common. I nvolvement of the ascending colon, duodenum, or rectum is less frequent. Gastroesophageal,
125-127appendiceal, or anal/perianal involvement is rare but is well documented in the literature. Peritoneal tuberculosis is slightly more
common than GI tuberculosis and may cause ascites as well as clinically significant adhesions.
Regardless of the site of involvement, patients often have nonspecific symptoms including weight loss, fever, abdominal pain, diarrhea, or a
122-124palpable abdominal mass. Other symptoms include night sweats, malaise, anorexia, GI bleeding, and signs of malabsorption.
Symptoms have often been present for months. Laboratory abnormalities include an elevated erythrocyte sedimentation rate and mild anemia.
S trictures and ulcers (often occurring together) are the most common endoscopic findings, along with thickened mucosal folds and
122inflammatory nodules. The ulcers are often circumferential and transverse. Multiple and segmental lesions with skip areas are common and
may mimic those of Crohn's disease (see Table 4.4). Large inflammatory masses (tuberculomas), usually involving the ileocecum, may be seen,
and well-described complications include obstruction, perforation, and hemorrhage. The wall of the bowel is often thickened and edematous,
with transmural inflammation, lymphoid hyperplasia, and fibrosis in later stages of the disease. Ulcers may be superficial or deep and may
overlie hyperplastic Peyer patches (aphthoid ulcers). The characteristic histologic lesion consists of caseating, often confluent, granulomas (Fig.
4.16, A) that may be present at any level of the gut wall but most commonly appear in the submucosa. A rim of lymphocytes is often present at
the periphery of the granulomas, and giant cells are variably present. Older lesions are frequently hyalinized and calcified, and well-formed
granulomas may be rare and difficult to find. I nflammation of submucosal vessels is common, and architectural distortion that mimics chronic
idiopathic I BD is frequently seen overlying areas of granulomatous inflammation. Characteristic granulomas are often present within involved
lymph nodes, with confluence and caseation.
FIGURE 4.16 A, Colonic Mycobacterium tuberculosis infection with mucosal and submucosal confluent, caseating
granulomas. B, Acid-fast organisms are seen in the necroinflammatory infiltrate (Ziehl-Neelsen stain).
A cid-fast stains sometimes demonstrate organisms (see Fig. 4.16, B), preferentially within necrotic areas or macrophages, but culture is
usually required for definitive diagnosis. The acid-fast bacilli of Mycobacterium tuberculosis are typically rod shaped and have a “beaded”
morphology. Organisms may be abundant in immunocompromised patients yet rare and difficult to detect in immunocompetent persons, and
the number of organisms may vary with the age of the lesion and previous antituberculosis therapy. PCR assays are becoming more widely
available, but sensitivity also suffers with this methodology if the number of organisms is very low. The purified protein derivative (PPD ) testsmay be helpful but are unreliable in immunocompromised or debilitated patients. S ome atypical mycobacteria, such as Mycobacterium kansasii
and Mycobacterium bovis, may cause similar pathologic findings.
The differential diagnosis includes other granulomatous infectious processes, especially yersiniosis and fungal disease, as well as
noninfectious processes such as sarcoidosis, Behçet disease, reaction to foreign material, and granulomatous changes secondary to a delayed or
interval appendectomy. The granulomas of yersiniosis are typically noncaseating with striking lymphoid cuffs, but there may be considerable
128histologic overlap. Crohn's disease may be difficult to distinguish from tuberculosis ; features favoring Crohn's disease are linear rather than
circumferential ulcers, transmural lymphoid aggregates, and deep fistulas and fissures. Tuberculosis also commonly lacks mucosal
cobblestoning. A further confounding factor is that tuberculosis has recently been associated with the use of infliximab, a tumor necrosis
factor-α neutralizing agent used in treating Crohn's disease and rheumatoid arthritis. The pattern of involvement in these patients is somewhat
129unusual, with most exhibiting extrapulmonary tuberculosis. The emergence of infection is often associated with initiation of treatment.
Mycobacterium avium-intracellulare Complex
Mycobacterium avium-intracellulare complex is the most common mycobacterium isolated from the GI tract. I t is typically found in patients with
130,131A I D S and other immunocompromising conditions, although it is occasionally seen in immunocompetent persons. S ymptoms include
diarrhea, abdominal pain, fever, and weight loss and often reflect systemic infection. Endoscopy findings are usually normal, although white
132nodules, small ulcers, or hemorrhages may be seen. The small bowel is preferentially involved, but colonic and gastroesophageal
133,134involvement may be present, as may mesenteric adenopathy.
Histologic manifestations vary with the site and the immune status of the patient. I mmunocompetent patients usually have a well-formed,
often epithelioid granulomatous response, either with or without necrosis. S mall bowel biopsies from immunocompromised patients typically
show villi distended by a diffuse infiltration of histiocytes containing bacilli (Fig. 4.17, A), with li, le inflammatory response other than
occasional poorly formed granulomas. The small bowel is most often involved, but similar histiocytic infiltrates may be seen in the colon and
other areas of the GI tract. Bacilli stain with acid-fast stains (seeF ig. 4.17, B), as well as periodic acid–S chiff (PA S ) and Gomori's methenamine
135silver (GMS ) stains. Mycobacteria (includingM . tuberculosis and Mycobacterium leprae) may also stain for desmin, actin, and keratin. Culture
and PCR assays can be extremely helpful in diagnosis. Organisms are usually abundant in the immunocompromised host but may be harder to
detect in healthy patients. The differential diagnosis includes Whipple disease and other infectious processes.
FIGURE 4.17 A, Small bowel villi are distended by clusters of histiocytes containing Mycobacterium avium-intracellulare,
with little associated inflammatory response. B, The histiocytes are packed with numerous acid-fast organisms typical of M.
avium-intracellulare (Ziehl-Neelsen stain).
Spirochetal Infections of the GI Tract
Syphilis
GI syphilis (Treponema pallidum infection) predominantly involves the anorectum, although other sites may be involved, particularly the
136stomach. Homosexual men are at particularly high risk of infection, and many authorities believe that syphilis, particularly anorectal
137syphilis, is markedly underdiagnosed because of the variability of the clinical findings. Patients are often asymptomatic, but pain (often
with defecation), constipation, bleeding, and discharge may be present in syphilitic proctitis. Luetic gastritis commonly manifests with upper
GI bleeding, which can occur early or late in the course of the disease. Melena and coffee-ground emesis may be present, along with nausea,
fever, malaise, anorexia, early satiety, and epigastric pain.
Gross findings in primary syphilis include anal chancres (indurated, circular lesions as large as 2 cm in diameter that may be single or
multiple, with variably present tenderness) that may be associated with a mild proctitis. S igns of secondary syphilis typically manifest 6 to 8
weeks later and include masses, a mucocutaneous rash, or condyloma lata (raised, moist, smooth warts that secrete mucus and are associated
138,139with itching and a foul odor). I nguinal adenopathy is typical. Gross signs of primary and secondary infection sometimes coexist. The
mass lesions of secondary syphilis may mimic malignancy, and surgical removal without a prior biopsy should be avoided. Gastric involvement
may be either an early or a late manifestation of syphilis. The most common presenting sign is upper GI bleeding, and patients typically have
136 140antral erosions, ulcers, or features of gastritis endoscopically. Ulcers may have irregular, heaped edges that mimic malignancy.
Histologically, anorectal syphilis features a dense mononuclear cell infiltrate with prominent plasma cells (Fig. 4.18, A). Cryptitis and crypt
abscesses are often present, along with gland destruction and reactive epithelial changes. Granulomas have been reported rarely; occasionally,
139,141prominent proliferative capillary endothelial cells may be observed (proliferative endarterteriologitis). S yphilitic proctitis may be very
nonspecific, showing features of A S LC or focal active colitis with or without an increase in plasma cells. S yphilitic gastritis often features a136dense plasmacytic infiltrate. The glands may be relatively spared by inflammation. Fibrosis may be prominent as the disease progresses.
FIGURE 4.18 A, Syphilitic proctitis featuring neutrophilic cryptitis, crypt abscesses, and a striking plasmacytic infiltrate in
the lamina propria. (Courtesy of Dr. Amy Hudson, Medical College of Wisconsin.) Numerous spirochetes can be detected
with (B) silver impregnation staining (Warthin-Starry stain) (Courtesy of Dr. Rodger Haggitt, University of Washington
Medical Center, and Dr. Mary Bronner, University of Utah School of Medicine.) and with (C) treponeme immunostaining.
The gross differential diagnosis of chancre includes anal fissures, fistulas, and traumatic lesions. I n general, condyloma acuminata are more
dry and more keratinized than condyloma lata. A s mentioned earlier, both anorectal and gastric syphilis can mimic malignancy. The histologic
differential diagnosis primarily includes other infectious processes, such as H . pylori infection in the stomach. I f the plasma cell infiltrate is
prominent and monomorphic and effaces the normal architecture, a hematopoietic neoplasm with plasmacytic differentiation should be
considered. T. pallidum staining with silver impregnation stains such as Warthin-S tarry (see Fig. 4.18, B), S teiner, and D ieterle stains is
available, as is immunohistochemistry (see Fig. 4.18, C). D arkfield examination of anorectal discharge may show organisms, although care must
be taken in interpretation, because spirochetes are also present in the normal gut flora as well as in intestinal spirochetosis. S erologic studies
such as the rapid plasma reagin (RPR), venereal disease research laboratory (VD RL), and fluorescent treponemal antibody absorption (FTA -
ABS) tests are extremely helpful in confirming the diagnosis.
Intestinal Spirochetosis
I ntestinal spirochetosis is a condition characterized by the presence of spirochetal microorganisms on the luminal surface of the large bowel
142mucosa. The prevalence of spirochetosis ranges from 2% to 16% in Western nations but is significantly higher in developing countries and
among homosexual and HI V-infected patients, in whom the prevalence is reportedly as high as 50% based on both biopsy findings and stool
culture. I t has also been described in association with a wide variety of conditions including diverticular disease, chronic idiopathic I BD ,
hyperplastic polyps, and adenomatous polyps. S pirochetosis represents infection by a heterogeneous group of related organisms, most
importantly Brachyspira aalborgi and Brachyspira pilosicoli, which are genetically unrelated to T. pallidum. Patients with spirochetosis may
142harbor one or both of these species.
A lthough patients with this histologic finding often have symptoms such as diarrhea or anal pain and discharge, it is not clear that
143,144spirochetosis causes these symptoms. Many patients have other infections (especially gonorrhea) complicating the clinical picture. A ny
level of the colon may be involved, as may the appendix. Typically, endoscopic abnormalities are mild or absent.
On H&E staining, spirochetosis resembles a fuzzy, “fringed” blue line at the luminal border of the colonic mucosa (Fig. 4.19, A). I nvasion is
not seen, and the changes can be focal. Most have no associated inflammatory infiltrate, although occasionally an associated cryptitis is seen.
The organisms stain intensely with Warthin-S tarry, D ieterle, or similar silver stains (seeF ig. 4.19, B). They also stain with A lcian blue (pH 2.5)
142,145and PA S . Currently there is an excellent immunohistochemical stain available, and many authorities argue that the immunostain is
superior, because the quality of silver impregnation stains varies widely depending on the freshness of the reagents and the ability of the
146,147technician. PCR and in situ hybridization assays also exist for identification of the organisms. The differential diagnosis consists
primarily of a prominent glycocalyx, which should not stain with silver impregnation stains. Occasionally, EA EC can give a similar appearance,
but E. coli should stain strongly gram negative and lack spirillar morphology.FIGURE 4.19 A, Spirochetosis is 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 stain).
Other Causes of Sexually Transmitted Bacterial Proctocolitis
Other causes of sexually transmi, ed bacterial proctocolitis include N eisseria gonorrhoeae, Calymmatobacterium granulomatis, and Chlamydia
species. Patients typically are seen with anal discharge, pain, diarrhea, constipation, bloody stools, and tenesmus. Proctoscopic findings range
138,139,148from normal to mucosal friability, erosions, and erythema.
Chlamydia trachomatis serotypes L1, L2, and L3 cause lymphogranuloma venereum (LGV). A nal pain is usually severe and accompanied by
139,149bloody discharge and tenesmus. The anorectum is the most common site, but LGV has been described in the ileum and colon as
149well. The inflammatory infiltrate is variable; most patients have a lymphoplasmacytic infiltrate in the mucosa and submucosa, but
neutrophils may be prominent. Granulomatous inflammation is sometimes present. Histologic features mimicking chronic idiopathic I BD
149-151have been described, including a striking “follicular” proctitis and significant architectural distortion that can mimic ulcerative colitis.
Culture, direct immunofluorescence studies, immunohistochemistry, and molecular tests may serve as valuable diagnostic aids. Granuloma
inguinale, caused by C. granulomatis, features anal and perianal disease that can appear similar to LGV, although extension into the rectum
148favors LGV. Warthin-S tarry or Giemsa stains may aid in visualization of the D onovan bodies typical of granuloma inguinale. A norectal
gonococcal infection is reportedly present in more than 40% of both women and men with uncomplicated gonorrhea. Proctoscopic examination
is usually unremarkable. Most biopsy findings in rectal gonorrhea are normal; some reveal a mild increase in neutrophils and mononuclear
152cells or focal cryptitis. Gram-negative cocci can occasionally be seen on Gram staining of anal discharge, and culture can be a valuable
diagnostic aid. N eisseria meningitidis has also been isolated from the anorectums of homosexual men, but it remains unclear whether this
represents colonization or an actual pathogen in this location.
Miscellaneous Bacterial Infections
Bacterial Esophagitis
Bacterial esophagitis is rare and usually is found in immunocompromised or debilitated patients. I mplicated bacteria include Staphylococcus
aureus, Lactobacillus acidophilus, and Klebsiella pneumoniae. Endoscopic findings include ulceration, pseudomembrane formation, and
hemorrhage. Histologic findings include acute inflammation and necrosis with bacteria demonstrable invading the wall of the esophagus (Fig.
1534.20).
FIGURE 4.20 A, Bacterial esophagitis is characterized by mucosal ulceration and necrosis, with clusters of bacteria at the
surface and invading into the wall. B, Gram staining highlights the clusters of bacteria within the esophageal wall.
Phlegmonous Gastritis and Enteritis
Phlegmonous enteritis, gastritis, and esophagitis have all been well documented. This is a suppurative, primarily submucosal inflammatory
process characterized by marked edema. The causative organisms vary and include E. coli, clostridia, Proteus species, staphylococci, and group
154,155 155A streptococci. Most patients are debilitated, and many have cirrhosis or alcoholic liver disease. A ffected patients may have
nonspecific GI or systemic symptoms, or phlegmonous disease may be found incidentally at autopsy. Patients typically develop an acute
abdomen, sometimes complicated by hematemesis or vomiting of purulent material. A ny 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. 4.21). A lthough the mucosa may be red and friable, discrete
ulceration is rarely present. Histologically, there is intense edema and acute inflammation located predominantly in the submucosa, and there
155may 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 staining may show organisms in the bowel wall, a finding that is diagnostic.FIGURE 4.21 Emphysematous (phlegmonous) enteritis caused by Clostridium perfringens. Notice the transmural necrosis
and mucosal sloughing with associated gas bubbles in the gut wall. (Courtesy of Dr. David Owen, University of British
Columbia.)
Actinomycosis
The filamentous, anaerobic, gram-positive bacterium Actinomyces israelii is a normal inhabitant of the oral cavity and the upper GI tract. Rarely,
156-158it produces a chronic, nonopportunistic GI infection. I nfection is usually in a solitary site, and it may occur at any level of the GI tract.
S ymptoms include fever, weight loss, abdominal pain, and, occasionally, a palpable mass. Perianal fistulas and chronic (often granulomatous)
appendicitis have been described. A ctinomycosis is sometimes associated with diverticular disease. Grossly, inflammation may produce a
157large, solitary mass, with or 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 (S plendore-Hoeppli
material). The inflammatory reaction is predominantly neutrophilic, with occasional abscess formation (Fig. 4.22, A). Palisading histiocytes and
giant cells, as well as frank granulomas, often surround the neutrophilic inflammation. There may be an associated fibrotic response. Gram
staining reveals the filamentous, gram-positive organisms (see Fig. 4.22, B). GMS and Warthin-S tarry stains are also used to show these
organisms. Commensal actinomyces may be present at the luminal surface, and these do not necessarily imply invasive infection, particularly if
there is no inflammatory response. I nvasive actinomycosis requires several weeks of intravenous antibiotic therapy; therefore, a definite
diagnosis of invasive actinomycosis (rather than the presence of commensals) is important and requires demonstration of the organisms
within the wall of the bowel with an associated inflammatory response. This may require multiple levels of lesional tissue sections.
FIGURE 4.22 A, Actinomycotic (“sulfur”) granule consisting of irregularly rounded clusters of bacteria bordered by
Splendore-Hoeppli material and an acute inflammatory exudate. B, Gram staining highlights the filamentous gram-positive
organisms.
The macroscopic differential diagnosis includes peptic ulcer, lymphoma, and carcinoma. The histologic differential diagnosis includes
primarily other infectious agents, particularly Nocardia. N ocardia are partially acid-fast and do not form the typical sulfur granules of
actinomycosis; however, cultures may be required to distinguish these two filamentous organisms. Even though actinomyces are GMS positive,
they have a more slender morphology than fungi and do not bud or produce hyphae. Care should be taken not to confuse actinomycosis with
other bacteria that form clusters and chains but are not truly filamentous, such as Pseudomonas and E. coli. Occasionally, the transmural
inflammation, fibrosis, and granulomatous inflammation produced by actinomycotic infection may mimic Crohn's disease.
Whipple Disease
Whipple disease typically occurs in middle-aged white men with chronic weight loss, arthritis, malabsorption, and lymphadenopathy. Many
159patients also have significant neuropsychiatric manifestations. The small bowel is most often affected, although colonic and appendiceal
involvement may be seen as well. Endoscopically, mucosal folds are thickened and coated with yellow-white plaques, often with surrounding
erythema and friability. Histologically, the characteristic lesion results from massive infiltration of the lamina propria and submucosa with
foamy macrophages (Fig. 4.23, A). The infiltrate often blunts and distends villi. I nvolvement may be diffuse or patchy. There is usually no
associated mononuclear inflammatory infiltrate, but varying numbers of neutrophils are present. The lamina propria may contain small foci of160fat, and overlying vacuolization of enterocytes may occur as well. Whipple bacillus was identified as Tropheryma whippelii, an
actinobacterium, 84 years after Whipple initially reported the disease. This bacillus is strongly PA S positive (seeF ig. 4.23, B); electron
microscopy and PCR assays may be diagnostic as well. The differential diagnosis includes predominantlyM . avium-intracellulare infection.
Infection by other intracellular organisms such as Histoplasma or Rhodococcus may rarely simulate Whipple disease.
FIGURE 4.23 Whipple disease. A, Villi are distended by an infiltrate of foamy macrophages with scattered fat cells and a
patchy neutrophilic infiltrate. B, The Whipple bacillus stains intensely with periodic acid–Schiff stain.
Rhodococcus equi
The gram-positive coccobacillus, Rhodococcus equi, may occasionally infect humans, particularly the immunocompromised. GI infection
manifests as chronic (often bloody) diarrhea and is usually a manifestation of systemic involvement. R. equi produces inflammatory polyps,
sometimes with associated mesenteric adenitis. Histologically, polyps consist of organism-laden macrophages that pack the mucosa and
submucosa, often with an associated granulomatous response. Organisms stain with PA S and Gram stains, and they may be partially acid-fast.
161The histologic features may mimic infection with M. avium-intracellulare or Whipple disease.
Rocky Mountain Spotted Fever
Rocky Mountain spo, ed fever is caused by Rickettsia rickettsii, which is transmi, ed by the bite of the common wood or dog tick. Many patients
have significant GI findings, including nausea, vomiting, diarrhea, pain, and GI bleeding. These manifestations may precede the rash.
162I nvolvement of every portion of the GI tract has been documented. Typical histologic findings include vasculitis, often with accompanying
nonocclusive microthrombi, and hemorrhage. The inflammatory infiltrate is composed of mononuclear cells with occasional lymphocytes,
macrophages, and neutrophils. Immunofluorescence staining demonstrates the organism, and serologic studies may also be of use.
Malakoplakia
163Malakoplakia is a rare disorder that can affect any portion of the GI tract. I t consists of soft, yellow plaques containing a dense histiocytic
infiltrate with characteristic Michaelis-Gutmann bodies (Fig. 4.24). Most cases are associated with colorectal adenocarcinoma or some other
immunocompromising condition. N umerous bacteria have been associated with GI malakoplakia, includingE . coli, Klebsiella, Yersinia,
mycobacterial organisms, and R. equi.
FIGURE 4.24 A, This colon biopsy shows the dense histiocytic infiltrate with admixed lymphocytes and plasma cells typical
of malakoplakia. B, Higher-power view highlights numerous Michaelis-Gutmann bodies. (Courtesy of Dr. Joel K. Greenson,
University of Michigan.)
Bacillary Angiomatosis
Bacillary angiomatosis comprises pyogenic granuloma-like lesions that occur in immunocompromised patients and mimic Kaposi sarcoma.
They are usually associated with Bartonella quintana.
Helicobacter pylori and Helicobacter heilmannii
These bacteria are discussed in detail in Chapter 15.Fungal Infections of the GI Tract
The incidence of invasive fungal infections, including fungal infections of the GI tract, has increased significantly
during the past 20 years with the rise in the number of patients with organ transplants, A I D S , other
164-166immunodeficiency states, or long-term chemotherapy. GI fungal infections occur most commonly in
immunocompromised patients, but virtually all have been described in immunocompetent persons as well.
Fungal infections of the GI tract can be roughly divided into two categories: those caused by transmucosal
invasion, and those that disseminate after primary infection of another site (usually pulmonary). I n addition,
invasive fungal infections are associated with repetitive abdominal surgeries, widespread use of antimicrobial
agents, intrusive vascular lines, diabetes, total parenteral nutrition, neonatal prematurity, and advancing age.
I n general, signs and symptoms of GI fungal infections are similar regardless of the type of fungus; they
include diarrhea, vomiting, melena, frank GI bleeding, abdominal pain, and fever. Esophageal fungal infections
usually manifest with odynophagia and dysphagia. Fungal infections of the GI tract are often part of a
disseminated disease process, but GI symptoms and signs may be the presenting manifestations.
Tissue biopsy remains one of the most important tools available in the diagnosis of fungal infections,
particularly because fungal cultures may require days to weeks for adequate growth and analysis. I n addition,
cultures frequently are not obtained as often as pathologists might wish or expect. A lthough organisms may be
identifiable on H&E-stained sections in cases of heavy infection, GMS and PA S stains remain invaluable
diagnostic aids. Fungi often can be correctly classified in tissue sections based on morphologic criteria (Table 4.5).
However, fungi exposed to antifungal therapy or ambient air may produce bizarre and unusual forms.
Microbiologic culture remains the gold standard for speciation, especially because antifungal therapy may vary
according to the specific type of fungus isolated. Helpful diagnostic aids, in addition to culture, include serologic
assays, antigen tests, immunohistochemistry, and molecular assays. Knowledge of the patient's geographic or
travel history can also be very helpful in diagnosing fungal infections.
Table 4.5
Morphologic Features of Fungi Involving the Gastrointestinal Tract
Primary Geographic Morphologic Major Differential
Organism Host Reaction
Distribution Features Diagnoses
Aspergillus Worldwide Hyphae-septate: Ischemic necrosis Zygomycetes
species uniform width with Fusarium
Branching- angioinvasion Pseudallescheria
regular: acute Acute boydii
angles inflammation
Conidial head Occasionally
formation in granulomatous
cavitary lesions
Blastomyces Similar to histoplasmosis; Large Mixed suppurative Histoplasma spp.
dermatitidis rare cases from Africa pleomorphic and Cryptococcus
(North and Central America (8-15 µm) granulomatous neoformans
American spherical to reaction (especially
blastomycosis) ovoid yeast
capsuleIntracellular or deficient)
extracellular Coccidioides
Broad-based immitis
buds
Multinucleate
Candida albicans Worldwide Mixture of Usually suppurative, Trichosporon
Candida budding yeast with variable
tropicalis and necrosis and
pseudohyphae; ulceration
occasional Occasionally
septate hyphae granulomatous
Occasional
angioinvasion
Candida Worldwide Budding yeast Similar to other Histoplasma
(Torulopsis) No hyphae Candida species Cryptococcus
glabrata No “halo”
effect
Cryptococcus Worldwide Highly Usually suppurative; Histoplasmosisneoformans pleomorphic may have BlastomycosisPrimary Geographic Morphologic Major DifferentialOrganism Host Reaction(4-7 µm) extnsive necrosis CandidaDistribution Features Diagnoses
Uninucleate Sometimes glabrata
Narrow-based granulomatous
buds
Usually
mucicarmine
positive
Histoplasma Worldwide, but endemic Uniform small (2- Lymphohistiocytic Cryptococcus
capsulatum in Ohio, Mississippi 5 µm), infiltrate with Penicillium
var. river basins; parts of uninucleate parasitized marneffei
capsulatum Central and South ovoid yeast histiocytes Candida
America; St. Lawrence Narrow-based Occasional glabrata
river basin in Canada buds granulomas Pneumocystis
Intracellular jiroveci
“Halo” effect Intracellular
around parasites
organism on
H&E
Pneumocystis Worldwide Ovoid Characteristic foamy Histoplasmosis
jiroveci Cup or casts Small parasites
crescent
shaped if
collapsed
No buds May have
Internal suppurative or
enhancing granulomatous
detail inflammation as
well
Zygomycetes Worldwide, associated Hyphae- Similar to Aspergillus Similar to
with diabetics more pauciseptate: Aspergillus
than any other ribbon-like,
mycosis thin
walls
Branchinghaphazard
H&E, Hematoxylin and eosin stain.
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, because Candida often superinfects ulcers that develop from other
causes. Candida albicans is the most common species, but Candida tropicalis and Candida (Torulopsis) glabrata can
167produce similar manifestations. I n addition, other non-albicans species (e.g., Candida krusei, Candida
parapsilosis) are emerging as important causes of invasive fungal infection.
Grossly, the esophagus typically contains white plaques that can be readily scraped off to reveal ulcerated
mucosa underneath. The gross features of candidiasis in the remainder of the GI tract are variable and include
ulceration, pseudomembrane formation, and inflammatory masses (Fig. 4.25, A). I f vascular invasion is
168prominent, the bowel may appear infarcted. I nvolvement may be diffuse or segmental. The associated
inflammatory response ranges from minimal (especially in immunocompromised patients) to marked with
prominent neutrophilic infiltrates, abscess formation, erosion or ulceration, and necrosis. Granulomas are
occasionally present as well. Fungi may invade any level of the gut wall. I nvasion of mucosal and submucosal
167,168blood vessels 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. 4.25, B). C. glabrata features tiny
164budding yeast forms (similar to those of Histoplasma) but does not produce hyphae or pseudohyphae. I t is
important to morphologically differentiate between invasive candidiasis and superficial colonization, because
Candida is capable of colonizing benign ulcers and mucosal surfaces without invasion.FIGURE 4.25 A, Colonic candidiasis featuring yellow-white plaques with associated marked
mucosal ulceration. (Courtesy of Dr. Cole Elliott, Pathology Associates of Albuquerque.) B,
GMS staining shows the mixture of budding yeast and pseudohyphae typical of Candida
species.
Aspergillus Species
Aspergillus infection of the GI tract occurs almost exclusively in immunocompromised patients and is much less
frequently seen in the esophagus than candidiasis. Gross findings are similar to those seen with Candida
166,168,169infection. Most patients with aspergillosis have coexistent lung lesions. The characteristic lesion of
aspergillosis is a nodular infarction consisting of a zone of ischemic necrosis centered on blood vessels containing
170fungal organisms (Fig. 4.26). Fungal hyphae often extend outward from the infarct, in parallel or radial arrays.
The inflammatory response ranges from minimal to marked, with a prominent neutrophilic infiltrate, and
164granulomatous inflammation 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 4.26 A, Typical macroscopic “target lesion” of aspergillosis, shown here in the
stomach, consisting of hemorrhagic infarction and necrosis centered on a blood vessel. B,
Histologically, this lesion corresponds to a nodular infarction of the mucosa and submucosa
caused by occlusion of the vessels by Aspergillus. C, Aspergillus organisms fill and penetrate
a vessel in the submucosa (GMS stain).
Fusarium is an emerging fungal infection in patients undergoing transplantation that may closely mimic
171,172aspergillosis morphologically. cultures are required to differentiate these fungi.
Mucormycosis
173The histologic lesions of mucormycosis are remarkably similar to those seen in aspergillosis. I n contrast toAspergillus, these organisms have broad, ribbon-like, pauciseptate hyphae that branch randomly at various angles
174(Fig. 4.27). Ulcers are the most common gross manifestation; they are often large with rolled, irregular edges
that may mimic malignancy. These fungi may also superinfect previously ulcerated tissues. Patients with diabetes
173,174or other causes of systemic acidosis are at increased risk for zygomycosis.
FIGURE 4.27 A, Mucormycosis of the stomach, featuring fungi within the mucosa with a
surrounding neutrophilic infiltrate and mucosal sloughing. (Courtesy Dr. Owen Middleton,
University of Alabama at Birmingham.) B, GMS stain shows typical broad, ribbon-like,
pauciseptate fungi with irregularly branching and optically clear centers.
Basdiobolomycosis, caused by Basidiobolus ranarum, is a related zygomycosis that was originally described in
S audi A rabia and is endemic in A rizona in the United S tates. GI cases can mimic malignancy and chronic
idiopathic I BD . The morphologic features of the fungus are similar to mucormycosis, but angioinvasion is rare,
eosinophils are prominent, and there is a marked S plendore-Hoeppli reaction to the organism (see Fig. 4.28). The
175-177inflammatory reaction may be suppurative or granulomatous, and necrosis is usually prominent.FIGURE 4.28 A, Basidiobolomycosis features prominent necrosis and numerous eosinophils,
as seen in this biopsy of a paracolonic mass. B, The organisms are broad, have optically clear
centers, and are surrounded by a striking Splendore-Hoeppli reaction. C, GMS staining shows
the optically clear centers and the characteristic “cellophane ball” crumpled appearance of the
fungi.
Histoplasmosis
Histoplasma capsulatum is endemic to the central United S tates but has been described in many nonendemic areas
as well. GI involvement occurs in more than 80% of patients with disseminated infection. Patients often present
initially with signs and symptoms of GI illness, but they do not always have concomitant pulmonary
178,179 177involvement. The ileum is the most common site, but any portion of the GI tract may be involved.
Gross lesions range from normal to ulcers, nodules, and obstructive masses. Often, a combination of these
lesions is present. Histologic findings include diffuse lymphohistiocytic infiltrates and nodules, usually involving
the mucosa and submucosa, with associated ulceration (Fig. 4.29). These lesions are usually located over Peyer
patches. D iscrete granulomas and giant cells are present in only a minority of cases. I n immunocompromised
178patients, large numbers of organisms may be seen with virtually no tissue reaction. Histoplasma organisms are
small, ovoid, usually intracellular yeast forms with small buds at the more pointed pole.FIGURE 4.29 A, A colon biopsy specimen shows numerous histiocytes within the lamina
propria in this case of histoplasmosis. B, Macrophages within the esophagus are packed with
Histoplasma with very little associated inflammatory reaction in this esophageal biopsy from
an immunocompromised patient (H&E/methenamine silver stain). C, On GMS staining,
numerous Histoplasma organisms are seen distending histiocytes in the lamina
propria. (Courtesy of Dr. Patrick J. Dean, GI Pathology, PLLC.)
Cryptococcus neoformans
The fungus Cryptococcus neoformans is an unusual but important cause of GI infection. A lmost all patients with GI
cryptococcosis have hematogenously disseminated disease with multisystem organ involvement, and most have
180,181associated pulmonary and meningeal disease. Grossly, cryptococcal infection may be located anywhere in
the GI tract. Endoscopic lesions include nodules and ulcers, sometimes associated with a thick white exudate.
180However, 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 effect can be seen with H&E staining, representing the capsule of the
organism. Both superficial and deep involvement may occur, and lymphatic involvement is not uncommon. The
inflammatory reaction is variable and depends on the immune status of the host, ranging from a suppurative,
necrotizing inflammatory reaction, often with granulomatous features (Fig. 4.30), to virtually no reaction (e.g., in
164,180anergic hosts). The mucopolysaccharide capsule stains with A lcian blue, mucicarmine, Fontana-Masson,
and colloidal iron; GMS stains are positive as well. Capsule-deficient cryptococci can pose a diagnostic challenge,
164,180but they are positive with Fontana-Masson staining.FIGURE 4.30 This case of gastric cryptococcosis features a granulomatous reaction with
associated giant cells and acute inflammation. A, A halo or “soap-bubble” effect can be seen
around the organisms. B, The round to oval yeast forms have a mucopolysaccharide capsule
that stains with mucicarmine. (Courtesy of Dr. Kay Washington, Vanderbilt University School
of Medicine.)
Pneumocystis jiroveci
A lthough the life cycle of Pneumocystis jiroveci (formerly P. carinii) more closely resembles that of a protozoan,
there is convincing molecular evidence that P. jiroveci has greater homology with fungi. P. jiroveci pneumonia is a
major cause of morbidity in the A I D S population, and extrapulmonary (including GI ) involvement is not
182uncommon. I n addition to patients with A I D S ,P neumocystis infection has been reported rarely in the context
of organ transplantation, hematologic malignancy, other immunodeficiency states, and steroid therapy.
Pneumocystis infection has also been reported in association with infliximab therapy, an immunosuppressive
183treatment for Crohn's disease and rheumatoid arthritis. Endoscopically, infection produces a nonspecific,
often erosive, esophagogastritis or colitis, sometimes with small polypoid nodules. Microscopically, granular,
foamy eosinophilic casts similar to those seen in pulmonary infection may be observed in mucosal vessels or in
182the lamina propria (Fig. 4.31, A). A s in the lung, a wide variety of inflammatory responses may occur,
including granulomatous inflammation, prominent macrophage infiltrates, and necrosis. The organisms are 5- to
7-µm spherules that have cup or crescent shapes when collapsed (see Fig. 4.31, B). Many contain characteristic,
single or paired, comma-shaped internal structures. Organisms stain with GMS and toluidine blue.FIGURE 4.31 A, Small bowel resection shows the characteristic foamy casts of
Pneumocystis jiroveci in the submucosa. B, GMS stain highlights numerous cyst forms with
central enhanced staining. (B, Courtesy of Dr. Henry Appelman, University of Michigan.)
Other fungal infections that occasionally involve the GI tract, but are not discussed in detail here, include
Blastomyces dermatididis and Paracoccidioides brasiliensis (S outh A merican blastomycosis), which can mimic chronic
184,185idiopathic IBD both clinically and radiographically.
Parasitic Infections of the GI Tract
Protozoal Infections
Protozoa are prevalent pathogens in tropical and subtropical countries, and they also cause some of the most
common intestinal infections in N orth A merica and Europe. I mmigration, increasing numbers of
immunocompromised patients, use of institutional child care facilities, and the development of improved
186-188diagnostic techniques have enhanced 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
A pproximately 10% of the world's population is infected with the Entamoeba histolytica parasite, predominantly in
tropical and subtropical regions. I n Western countries, this infection is most often seen in immigrants, overseas
travelers, male homosexuals, and institutionalized persons. I nfection is usually acquired through contaminated
water or food, and it also can be spread by the fecal-oral route. S exual transmission has been reported
occasionally. A lthough some patients suffer a severe, dysentery-like, fulminant colitis, many others are
189,190asymptomatic or show only vague GI symptoms. Complications include bleeding and dissemination to
190other sites, particularly the liver. Rarely, large inflammatory masses (amebomas) may form.
189,190Colonoscopy findings may be normal in asymptomatic patients and in those with mild disease. The
cecum is the most common site of involvement, followed by the right colon, rectum, sigmoid, and appendix.
Grossly, small ulcers are seen initially, but these may coalesce to form large, irregular, geographic or serpiginous
ulcers. Ulcers may undermine adjacent mucosa to produce classic “flask-shaped” lesions (Fig. 4.32, A), and there
may be associated inflammation or inflammatory polyps as well. The intervening mucosa is often normal.
Fulminant colitis, resembling ulcerative colitis; PMC, resembling that caused byC . difficile; and toxic megacolon
191have all been described in association with E. histolytica infection.FIGURE 4.32 A, This entamebic ulcer is deep and flask-shaped, undermining adjacent
normal mucosa. B, Amoebiasis is often associated with abundant debris that contains more
degenerated apoptotic material than intact inflammatory cells. C, Entamoeba histolytica have
pale, round nuclei with foamy cytoplasm and contain ingested erythrocytes.
Histologically, early lesions show a mild neutrophilic infiltrate. I n some cases, numerous organisms are present
at the luminal surface with liKle associated inflammation. I n more advanced disease, ulcers are often deep,
extending into the submucosa, with undermining of adjacent normal mucosa. There is usually abundant
necroinflammatory debris, which in many cases exceeds the amount of associated inflammation. The organisms
are usually found in the purulent material. I nvasive amebae are also occasionally present in the bowel wall.
A djacent mucosa is usually normal but may show gland distortion. The organisms may be few in number. They
resemble macrophages, with foamy cytoplasm and round, eccentric nuclei. The presence of ingested red blood
189,190cells (see Fig. 4.32, B and C) is pathognomonic of E. histolytica. I n asymptomatic patients and those with
only mild symptoms, histologic changes may range from normal to a heavy mixed inflammatory infiltrate.
Organisms may be difficult or impossible to detect in these patients. I nvasive amebiasis does not usually occur in
189,190patients who have only mild, or absent, symptoms.
I t may be difficult to distinguish amebae from macrophages in inflammatory exudates. However, amebae are
trichrome- and PA S -positive, and macrophages stain with immunostains such as CD 68 and CD 163. I n addition,
amoeba nuclei are usually more round and pale, with a more open nuclear chromatin paKern. The differential
diagnosis of amebiasis includes Crohn's disease, ulcerative colitis, and other types of infectious colitis,
particularly when gross skip lesions or significant architectural distortion is present. A lthough some features of
amebiasis may mimic idiopathic I BD , many of the other diagnostic features of Crohn's disease (e.g., transmural
lymphoid aggregates, mural fibrosis, granulomas, neural hyperplasia) and ulcerative colitis (e.g., basal
lymphoplasmacytosis, diffuse architectural distortion, pancolitis) are not typically present in amebiasis.
Flagellates
Giardia lamblia
Giardiasis (Giardia lamblia infection) is the leading GI protozoal disease in the United S tates and occurs
throughout temperate and tropical regions worldwide. The overall prevalence rate is 2% to 7% but reaches 35% in
day care centers. Patients often are seen with explosive, foul-smelling, watery diarrhea, abdominal pain and
distention, nausea, vomiting, malabsorption, and weight loss. The infection may resolve spontaneously, but often
it persists for weeks or months if left untreated. A significant percentage of patients go on to develop chronic
giardiasis, featuring diarrhea often accompanied by marked weight loss, signs of malabsorption, and anemia.
Complications include dehydration, especially in children, and failure to thrive among infants and small children.
192,193Many infections are asymptomatic, however. 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 inappearance. Rarely, biopsies may show mild to moderate villous blunting and increased lamina propria
inflammatory cells including neutrophils, plasma cells, and lymphocytes. Giardia trophozoites resemble pears
that are cut lengthwise and contain two ovoid nuclei with a central karyosome at the luminal surface (Fig.
1924.33). Tissue invasion is not a feature of this infection. A lthough Giardia is characteristically described as a
192small bowel inhabitant, colonization of the stomach and colon has also been reported. A bsence or a marked
decrease of plasma cells in the lamina propria in a patient with giardiasis should alert the pathologist to the
possibility of an underlying immunodeficiency disorder (see Chapter 5).
FIGURE 4.33 A, Duodenal mucosa with numerous Giardia trophozoites at the luminal
surface, illustrating the “falling leaves” pattern. B, Higher-power view shows the typical
pearshaped morphology with two prominent nuclei. (Courtesy of Dr. Rodger Haggitt, University of
Washington.)
Leishmania donovani and Related Species
194Leishmaniasis is endemic in more than 80 countries in A frica, A sia, S outh and Central A merica, and Europe.
Visceral leishmaniasis (or kala-azar) is emerging as an important opportunistic infection among HI V-infected
patients, particularly in southwestern Europe. In endemic areas, it often affects children and young adults.
GI involvement is rare and generally part of disseminated disease. A ny level of the GI tract may be affected. GI
195signs and symptoms include fever, abdominal pain, diarrhea, dysphagia, malabsorption, and weight loss. The
196spectrum of endoscopic findings includes normal mucosa, focal ulceration, and changes of enteritis.
Histologically, amastigote-containing macrophages are present in the lamina propria. I n large numbers,
macrophages may distend and blunt intestinal villi. A n associated inflammatory infiltrate is normally absent. The
amastigotes are rounded, 2- to 4-µm basophilic organisms with a round to oval central nucleus and a thin external
membrane (Fig. 4.34). The kinetoplast lies tangentially or at right angles to the nucleus, producing a characteristic
“double-knot” configuration. They are highlighted by Giemsa staining.FIGURE 4.34 Macrophages containing numerous Leishmania amastigotes. (Courtesy Dr.
Bruce Smoller, University of Arkansas for Medical Sciences.)
The differential diagnosis primarily includes other parasitic and fungal infections. Leishmania may be confused
with organisms such as Histoplasma and Trypanosoma cruzi. Leishmaniae are GMS negative, and they affect the
194,195lamina propria rather than the myenteric plexus. S erologic studies and immunohistochemistry may aid in
the diagnosis.
Chagas Disease
197,198Chagas disease is one of the most serious public health problems in S outh A merica. The prevalence in the
United S tates is unknown, and most infections diagnosed in the United S tates have been in immigrants from
endemic areas. Most acute infections go unrecognized. I nfected persons then enter the chronic phase, which in
the absence of effective therapy lasts for a lifetime. GI dysfunction is the second most common manifestation of
chronic Chagas disease (after cardiac involvement), and parasitic involvement of the enteric nervous system most
198frequently causes an achalasia-like megaesophagus (Fig. 4.35) or a megacolon or both. The stomach and small
bowel are more rarely affected. GI disease results from damage to intramural neurons. Upper GI symptoms
include dysphagia, odynophagia, reflux, aspiration, weight loss, cough, and regurgitation. I maging studies may
show a range of appearances from mild achalasia to megaesophagus. Lower GI symptoms include constipation,
stool impaction, and abdominal pain; imaging studies reveal a markedly dilated and elongated megacolon.
FIGURE 4.35 Elongated and markedly dilated esophagus, known as “megaesophagus,”
caused by Chagas disease. (Courtesy of Dr. Dennis Baroni-Cruz, University of Santa Cruz.)
Histologically, there is inflammatory destruction of the myenteric plexus, with eventual loss of as much as 95%
199of neurons. However, the parasite is rarely visible in myenteric plexuses. The inflammatory infiltrate is
primarily lymphocytic, with inflammation of the nerve fibers and ganglion cells that extends into the muscular
wall. A ccompanying findings include degenerative neuronal changes, loss of nerve fibers and ganglion cells, and
fibrosis. The differential diagnosis includes idiopathic primary achalasia as well as other visceral neuropathies.
However, many of these laKer disorders lack inflammation of the myenteric plexus. Unlike primary achalasia,Chagas disease usually involves other organ systems (especially the heart) or other areas of the GI tract.
N evertheless, often the differential diagnosis must be resolved clinically. Helpful laboratory tests include PCR
assays, serologic studies, and culture. N egative laboratory tests do not exclude infection, however, given the
frequently low levels of parasitemia.
Ciliates
Balantidium coli
The ciliate Balantidium coli produces 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
200,201course, the presence of cilia (Fig. 4.36).
FIGURE 4.36 Balantidium coli in the bowel wall. Notice the large size, kidney bean–shaped
nucleus, and cilia. (Courtesy of Dr. David Owen, University of Michigan.)
Coccidians
Coccidial infection is particularly important when considering the differential diagnosis of diarrhea in patients
202with A I D S , but it is also seen in healthy persons, including infants and children, in developing countries.
203Transmission is normally by the fecal-oral route, either directly or via contaminated food and water. A ll
coccidians are believed to also cause diarrhea (often prolonged) in healthy patients, especially infants and
children, travelers, and individuals who are institutionalized. D iarrhea may be accompanied by fever, weight loss,
abdominal pain, and malaise. S tool does not usually contain red blood cells or leukocytes. I n immunocompetent
persons, infection is usually self-limited, but immunocompromised patients are at risk for chronic, severe
203diarrhea with malabsorption, dehydration, and death. Many coccidial infections are asymptomatic. Endoscopic
findings are usually absent or mild and include mild erythema, mucosal granularity, mucosal atrophy, and
superficial erosions. A lthough 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. A comparison of the morphologic features of
the important GI coccidians is given in Table 4.6. ELI S A techniques, immunohistochemistry, and PCR studies are
202also available for diagnosis of these parasites.Table 4.6
Comparison of the Morphologic Features of Enteric Coccidians in Tissue Sections
Feature Microsporidia Cryptosporidia Cyclospora Isospora
Size 2-3 µm spores (smallest 2-5 µm 2-3 µm schizonts 15-20 µm (largest
coccidian) 5-6 µm coccidian)
merozoites
Location Epithelial cells; rarely Apical surface Upper third of Epithelial cells and
macrophages epithelial cell macrophages
Staining Modified trichrome, Giemsa, Acid-fast, auramine Giemsa, Gram, PAS
properties Giemsa, Gram, Gram stain positive positive positive
Warthin-Starry GMS, PAS,
positive Giemsa
negative
Other May be birefringent Organism bulges out of Parasitophorous Parasitophorous
under polarized light luminal surface of vacuole vacuole
enterocyte apex Eosinophilic
infiltrate
GMS, Grocott-Gomori methenamine–silver nitrate; PAS, periodic acid-Schiff.
Cryptosporidium parvum
Cryptosporidium parvum has a worldwide distribution. High-risk groups include children in day care centers,
patients in mental institutions, travelers to developing countries, immigrants, and immunocompromised
202,204patients, particularly A I D S patients. Transmission is through contaminated food and water, and
personto-person spread via the fecal-oral route is common. I t 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- to5 -µm, basophilic, spherical body
205that protrudes from the apex of the enterocyte (Fig. 4.37). The organisms have been referred to as “blue
beads” given their round, basophilic appearance. They are found in the crypts or in the surface epithelium.
Associated mucosal changes include villous atrophy (occasionally severe), crypt hyperplasia, mixed inflammation,
and crypt abscesses. Giemsa and Gram stains may aid in diagnosis, and immunohistochemical antibodies are
available. Cryptosporidia may be distinguished from most other coccidians by their size and unique apical
location (see Table 4.6).
FIGURE 4.37 Cryptosporidium parvum infection. The 2- to 5-µm, basophilic, spherical
bodies protrude from the apex of the enterocytes, giving a “blue bead” appearance.
Cyclospora cayetanensis
203,206Cyclospora is the most recently discovered enteric coccidian. I t has a worldwide distribution, and
transmission is through the fecal-oral route or by ingestion of contaminated water or food. I nfection may beasymptomatic, and Cyclospora can infect immunocompromised or immunocompetent patients. This organism
most commonly infects the small bowel. Histologic changes in mucosal biopsies are similar to those of other
206coccidians, including mild villous blunting, patchy lamina propria inflammation, and surface epithelial
206-208disarray. There are few detailed light microscopic descriptions of this parasite, and there is still some
disagreement regarding the spectrum of morphologic features in tissue sections. I ntracellular forms of Cyclospora
include 2- to 3-µm schizonts and 5- to 6-µm, banana-shaped merozoites located within enterocytes (Fig. 4.38).
207Organisms are often located within the upper third of the enterocyte, within a parasitophorous vacuole. The
organisms are acid-fast with modified Kinyoun or similar stains and are also positive with auramine. However,
they are GMS, PAS, Gram, and trichrome negative. They exhibit autofluorescence under epifluorescent light.
FIGURE 4.38 Both crescent-shaped merozoites and round schizonts are located within
surface enterocytes in this case of Cyclospora infection. Notice the small parasitophorous
vacuole. (From a case done by Dr. Rhonda Yantiss, Weill Cornell Medical Center.)
Isospora belli and Related Species
Isospora has a worldwide distribution but is more common in tropical and subtropical regions than temperate
climates. I t is transmiKed by ingestion of food or water contaminated with oocysts. Patients with isosporiasis are
more likely to have peripheral eosinophilia than those infected by other coccidians. I nfection may be severe and
debilitating in immunocompromised patients, and widespread dissemination has been reported rarely. The small
bowel is the most common site of Isospora infection, but the colon may also be involved. Histologic changes
include villous blunting, which may be severe; surface epithelial and nuclear disarray; crypt hyperplasia; mixed
100,101inflammation, often with prominent eosinophils; and, in chronic infections, fibrosis of the lamina propria.
Isospora is the largest coccidian (15 to 20 µm). I ntraepithelial inclusions are present in all stages of infection (Fig.
4.39), and can be found within both epithelial cells and macrophages in the lamina propria. I nclusions are both
perinuclear and subnuclear. S chizonts and merozoites (the asexual forms) are crescent or banana shaped; sexual
209-211forms are round with a prominent nucleus. The organisms often have an associated loose parsitophorous
vacuole. GMS and Giemsa stains are useful to highlight the organism. A lthough isospora are PA S positive, they
may be easily confused with goblet cells.FIGURE 4.39 Isospora belli infection. A small bowel villus has surface epithelial disarray and
large coccidians typical of Isospora within parasitophorous vacuoles. (Courtesy of Dr. Joel K.
Greenson, University of Michigan.)
Microsporidia
212,213Microsporidia have a worldwide distribution. They are present in many environmental water sources.
Human-to-human transmission and fecal-oral spread are common. This is the least likely coccidian to affect
214immunocompetent patients. Enterocytozoon bieneusi and Encephalitozoon intestinalis are the most common
human pathogens in this group. D issemination may occur, especially with E. intestinalis infection. The organisms
are usually present in the small bowel, but any level of the GI tract may be affected. Microsporidia are difficult to
detect in H&E-stained sections. The histologic features include patchy villous blunting, vacuolization and disarray
212,213of the surface epithelium, and patchy lymphoplasmacytic infiltrates in the lamina propria. A modified
trichrome stain can aid greatly in the diagnosis (Fig. 4.40), and the organisms also stain with Warthin-S tarry and
Brown-Brenn stains. Occasionally, microsporidial organisms in biopsy specimens demonstrate birefringence
under polarized light because of their chitin-rich internal polar filament. However, this method is unreliable,
because spore birefringence is unpredictable and because microscopes and light sources vary.FIGURE 4.40 A, Microsporidiosis featuring surface epithelial disarray and subtle
vacuolization with the surface enterocytes. B, Modified trichrome stain highlights the
organisms.
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. I mmunohistochemistry and PCR assays, as well as serologic tests,
215are useful diagnostic aids; however, serologies may be unreliable in severely immunocompromised patients.
Miscellaneous Protozoal Infections
D ientamoeba fragilis is an ameba of low pathogenicity that occasionally causes diarrhea in affected
216,217patients. A variety of other amebae are also occasionally associated with mild GI disease, including
Entamoeba hartmanni, Entamoeba coli, Entamoeba polecki, Iodamoeba buetschli,i and Endolimax nana. Blastocystis
hominis, another protozoan of low pathogenicity, may cause enteric disease when present in large
218,219numbers. However, these organisms are only rarely seen in tissue sections. I ndeed, when protozoa of low
pathogenicity are identified in tissue sections, symptomatic patients should be evaluated for alternative causes of
GI disease.
Helminthic Infections
A lthough 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
220(both Ascaris and Enterobius), and whipworms are the most common helminthic infections in humans. GI
helminths have a worldwide distribution, but their clinical importance varies with the geographic region. They
are more often a cause of serious disease in nations with deficient sanitation systems, poor socioeconomic status,
and hot, humid climates. However, helminthic infections are seen in immigrants and in patients who travel to
endemic areas, and they are an increasingly important problem in immunocompromised hosts. N utritional
220problems caused by helminths can be severe and even life-threatening, especially in children. The most
common site of anatomic infection is the small bowel, although the stomach and large bowel may also be
221involved.
Nematodes
Enterobius vermicularisPinworms (Enterobius vermicularis) 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 S tates 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. A lthough many infections are asymptomatic, appendicitis, vulvovaginitis,
222,223colitis, and peritoneal involvement have all been described. Heavy infections may cause abdominal pain,
nausea, and vomiting.
The etiologic role of Enterobius in appendicitis and colitis is controversial. A lthough pinworms are detected in
approximately 0.6% to 13% of resected appendices, their ability to cause mucosal damage has been a subject of
223debate. S ome believe that the lack of inflammation surrounding invasive pinworms indicates that the
223organism invades only after the appendix has been removed, to escape the decrease in oxygen tension.
222However, Enterobius 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 therefore may be seen with the naked eye (Fig. 4.41). A lthough the
mucosa of the GI tract often appears normal on examination, hemorrhage and ulceration may occur with tissue
invasion. I nvasive pinworms often incite liKle or no inflammatory reaction, but an inflammatory infiltrate
composed of neutrophils and eosinophils occurs uncommonly. Granulomas, sometimes with necrosis, may
develop as a reaction to degenerating worms or eggs. These have been described in the omentum and
223peritoneum, as well as in the appendix, anus, and colon in rare cases. Primary Enterobius infection may be
difficult to distinguish from infection complicating a preexisting inflammatory disorder such as an inflamed anal
fissure.
FIGURE 4.41 A, Appendix containing numerous pinworms. (Courtesy of Dr. George F. Gray,
Jr., Vanderbilt University Medical Center.) B, Numerous pinworms are present at the surface
of the appendix. C, Cross-section of worm showing cuticle, typical lateral ala, and numerous
eggs characteristic of Enterobius vermicularis.
Ascaris lumbricoides (Roundworm)
Ascaris is one of the most common parasites in humans. I t has a worldwide distribution but is most common in
tropical regions of the world. The worms are ingested from soil contaminated with feces. Clinical findings are
variable and include appendicitis, massive infection with obstruction and perforation, childhood growth
retardation, and pancreaticobiliary obstruction. Giant worms (as large as 20 cm in length) may be identified
endoscopically or in resection specimens (Fig. 4.42). Tissue damage occurs primarily at the anatomic sites of220,221attachment.
FIGURE 4.42 Ascaris atop colon cancer at resection. (Courtesy of Dr. George F. Gray, Jr.,
Vanderbilt University Medical Center.)
Ancylostomiasis (Hookworm)
Hookworm (N ecator americanus and Ancylostoma duodenale) is a common parasite in all tropical and subtropical
countries. The worms aKach 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
220,221eosinophilia when the worms migrate. A ny 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
224but may include villous blunting and eosinophilic infiltration. Pieces of worm are occasionally detected in
biopsy specimens.
Trichuris trichiura (Whipworm)
Whipworm (Trichuris trichiura) is a soil helminth with a worldwide distribution; it is most common in tropical
220,221,225climates. I n the United S tates, it is most often seen among immigrants and in the rural S outheast.
I nfection is acquired by ingesting contaminated water or food. A lthough most infections are asymptomatic, some
patients develop diarrhea, GI bleeding, malabsorption, anemia, and appendicitis. A n ulcerative inflammatory
220,221,226process similar to Crohn's disease and rectal prolapse have also been described. The worms can live
anywhere in the intestine but are most commonly found in the right colon and ileum. They thread their anterior
end under the epithelium, which may cause mucosal edema, erythema, hemorrhage, and ulceration at the
aKachment site. Histologically, enterocyte atrophy with an associated mixed inflammatory infiltrate (sometimes
220,227rich in eosinophils) and occasional crypt abscesses may be seen.
Strongyloides stercoralis
Strongyloides stercoralis is a nematode with a worldwide distribution. I n the United S tates, it is endemic in
southeastern urban areas with large immigrant populations and in mental institutions. Strongyloides occurs
primarily in adults, many of whom are hospitalized, suffer from chronic illnesses, or are
228,229immunocompromised. S teroids and human T-lymphotropic virus type I (HLTV-I ) infection are also
230associated with strongyloidiasis. S ymptoms and signs include diarrhea, abdominal pain and tenderness,
nausea, vomiting, weight loss, malabsorption, and GI bleeding. Mesenteric lymphadenopathy may also occur, and
231,232Strongyloides is a rare cause of appendicitis. GI manifestations may be accompanied by rash, eosinophilia,
221,228urticaria, pruritus, and pulmonary 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. I n addition, widespread
221,228dissemination may occur in 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 findings include
hypertrophic mucosal folds and ulcers. However, features typical of PMC have also been reported. Histologically,
both adult worms and larvae may be found in the crypts, but they can be difficult to detect. A dult worms typically
have sharply pointed tails that may be curved (Fig. 4.43). Other histologic features include villous blunting, ulcers
(which may be fissuring), edema, and a dense eosinophilic and neutrophilic infiltrate. Granulomas are
220,228occasionally present as well. The presence of larvae with sharply pointed, sometimes curved tails within
the glands of the GI mucosa is essentially diagnostic of strongyloidiasis. I n the proper clinical and geographic
seKing, however, Capillaria infection is also in the differential diagnosis. Rarely, fulminant intestinal233strongyloidiasis may mimic chronic idiopathic I BD . A ncillary diagnostic tests include stool examination for
larvae, worms, or eggs and serologic tests.
FIGURE 4.43 A, Numerous Strongyloides stercoralis are seen within the crypts in this case
of colonic Strongyloidiasi infection in the small bowel. B, Typical worms and larvae have
curved, sharply pointed tails.
Anisakis simplex and Related Species
The Anisakis simplex nematode parasitizes fish and sea mammals; humans ingest them by eating raw or pickled
fish. The most common clinical manifestations are those of acute gastric anisakiasis, which is characterized by
epigastric pain, nausea, and vomiting within 12 hours after ingestion of parasitized food. The symptoms may
220,233mimic peptic ulcer disease. The allergenic potential of Anisakis species has also been recognized, and
some patients with gastroallergic anisakiasis manifest both GI effects and hypersensitivity symptoms such as
234-236urticaria, 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 findings include mucosal edema, hemorrhage, erosions, ulcers, and thickened mucosal
folds. Occasionally, larvae may be identified and removed endoscopically. Histologic findings include an
inflammatory infiltrate that is rich in eosinophils and may extend transmurally into serosal and mesenteric
tissues (Fig. 4.44). Eosinophilic microabscesses, granulomas, and giant cells may also develop. I nflammatory
changes usually surround worms. Larvae (0.5 to 3.0 cm in length) are occasionally seen in tissue sections but very
234-236rarely in stool samples.FIGURE 4.44 Gastric anisakiasis. A, Areas of geographic necrosis and an inflammatory
infiltrate rich in eosinophils surrounds Anisakis larvae. (Courtesy of Dr. A. Morgan Wright and
Dr. Melissa Upton, University of Washington.) B, Large Anisakis worm in the center of a
submucosal eosinophilic and neutrophilic abscess. (Courtesy of Dr. David Owen, University of
Michigan.)
Capillaria Species (Intestinal Capillariasis)
Capillaria infection is most common in the Philippines, Thailand, and other parts of A sia, although cases have
been reported in nonendemic areas. The worms are ingested by eating infected raw fish. Clinical signs and
symptoms include malabsorption accompanied by diarrhea and abdominal pain. The worms measure 2 to 4 cm in
length and are most commonly found in the crypts of the small bowel, although they may also invade the lamina
propria. There usually is no inflammatory reaction, but villous blunting, mucosal sloughing, and mild
236-238inflammatory changes have been described.
Trematodes
Schistosomiasis
S chistosomiasis is one of the most common diseases in the world. A ll species of Schistosoma that infect humans
have the capability to cause significant GI disease, but the gut is a target organ for Schistosoma mansoni,
Schistosoma japonicum, Schistosoma mekongi, and Schistosoma intercalatum infections. These trematodes are endemic
in A frica, A sia, and parts of the A mericas. I n the United S tates, infected patients are often immigrants, travelers,
or persons who have worked abroad. Humans become infected by exposure to contaminated water. Patients
usually are seen 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,
221,239obstruction, perforation, intussusception, rectal prolapse, fistulae, and perianal abscesses. S chistosomes
240(most frequently Schistosoma haematobium) occasionally cause appendicitis.
A ny level of the GI tract may be affected. Endoscopically,S chistosoma can cause inflammatory polyposis
(particularly in the distal colon) with associated mucosal granularity, friability, punctate ulcers, and
241,242hemorrhages. Histologically, inflammatory polyps and mucosal ulcers with associated granulomatous
inflammation and an eosinophilic infiltrate are typical. Eggs may be detected in histologic specimens and are
221,239sometimes calcified. A s lesions progress, there is increased fibrosis, as well as an increase in macrophages
and multinucleated giant cells. Schistosome eggs are variably acid-fast; in H&E-stained sections, the calcified eggs
are typically dark blue or black and somewhat amorphous (Fig. 4.45). The worms themselves are slender and
241-243elongated, measuring approximately 0.5 to 2.5 cm in length, and are occasionally found within veins.FIGURE 4.45 A, A colon biopsy shows a small granuloma with associated eosinophils
centered on a calcified Schistosoma egg. (Courtesy of Dr. Rebecca Wheeler, University of
Arkansas for Medical Sciences.) B, Numerous calcified eggs are seen in the appendix in a
case of remote schistosomiasis. (Courtesy of Dr. Joseph Misdraji, Massachusetts General
Hospital.) C, Worms are occasionally seen in veins in the submucosa of the bowel.
Fasciolopsis buski and Related Species
More than 50 species of intestinal flukes have been described in humans, but most clinically significant infections
244-246are caused by Fasciolopsis buski, Echinostoma species, and Heterophyes species. These flukes are most
common in A sia. They are ingested with aquatic plants. A fter maturation, the adult worm aKaches to the
221,244proximal small bowel mucosa. The majority of infections are asymptomatic. S ymptoms, which usually
occur as a result of heavy infection, include diarrhea, often alternating with constipation; abdominal pain;
anorexia; nausea and vomiting; and malabsorption. I leus, obstruction, and GI bleeding have also been described.
The large worms (2 to 7.5 cm) may be seen endoscopically, and mucosal ulceration, inflammation, and abscess
formation may occur at sites of tissue attachment.
Cestodes
Taenia saginata (beef tapeworm), Taenia solium (pork tapeworm), and H ymenolepis nana (dwarf tapeworm) may
occasionally cause GI disease. D iphyllobothrium latum (fish tapeworm) is a rare cause of vitamin B12
221,236deficiency.
Other Helminthic Infections
The Central A merican nematode,A ngiostrongylus costaricensis, may cause dramatic, even fatal, ileocecal infection
characterized by the presence of large, obstructive inflammatory masses with perforation and mesenteric vessel
221,247 110thrombosis. Trichinella spiralis is a rare cause of diarrhea. Esophagostomiasis, a parasitic disease
usually seen in nonhuman primates, may form deep inflammatory masses, predominantly in the right colon and
221appendix.
The differential diagnosis of helminthic infections usually involves differentiation among the various types of
worms. However, other entities to be considered include causes of ulcerative inflammation, eosinophilic
infiltration, and granulomatous inflammation, such as tuberculosis, amebiasis, allergic enteritis, and Crohn's
disease.References
1. Surawicz CM. The role of rectal biopsy in infectious colitis. Am J Surg Pathol. 1988;12(suppl 1):82–88.
2. Chetty R, Roskell DE. Cytomegalovirus infection in the gastrointestinal tract. J Clin Pathol. 1994;47:968–
972.
3. Buckner FS, Pomery C. Cytomegalovirus disease of the gastrointestinal tract in patients without AIDS.
Clin Infect Dis. 1993;17:644–656.
4. Rafailidis PI, Mourtzoukou EG, Varbobitis IC, Falagas ME. Severe cytomegalovirus infection in apparently
immunocompetent patients: a systematic review. Virol J. 2008;5:47.
5. Wilcox CM, Diehl DL, Cello JP, et al. Cytomegalovirus esophagitis in patients with AIDS: a clinical,
endoscopic, and pathologic correlation. Ann Intern Med. 1990;113:589–593.
6. Cieslak TJ, Mullett CT, Puntel RA, et al. Menetrier's disease associated with cytomegalovirus infection in
children: report of two cases and review of the literature. Pediatr Infect Dis J. 1993;12:340–343.
7. Occena RO, Taylor SF, Robinson CC. Association of cytomegalovirus with Menetrier's disease in
childhood: report of two new cases with a review of literature. J Pediatr Gastroenterol Nutr. 1993;17:217–224.
8. Kambham N, Vig R, Cartwright CA, Longacre T. Cytomegalovirus infection in steroid-refractory
ulcerative colitis: a case-control study. Am J Surg Pathol. 2004;28:365–373.
9. Dimitroulia E, Spanakis N, Konstantinidou AE, et al. Frequent detection of cytomegalovirus in the
intestine of patients with inflammatory bowel disease. Infl Bowel Dis. 2006;12:879–884.
10. Kraus MD, Feran-Doza M, Garcia-Moliner ML, et al. Cytomegalovirus infection in the colon of bone
marrow transplant patients. Mod Pathol. 1998;11:29–36.
11. Laguna F, Garcia-Samaniego J, Alonso MJ, et al. Pseudotumoral appearance of cytomegalovirus
esophagitis and gastritis in AIDS patients. Am J Gastroenterol. 1993;88:1108–1111.
12. Rich JD, Crawford JM, Kazanjian SN, Kazanjian PH. Discrete gastrointestinal mass lesions caused by
cytomegalovirus in patients with AIDS: report of three cases and review. Clin Infect Dis. 1992;15:609–614.
13. Golden MP, Hammer SM, Wanke CA, Albrecht MA. Cytomegalovirus vasculitis: case reports and review of
the literature. Medicine (Baltimore). 1994;73:246–255.
14. Kato S, Yamamoto R, Yoshimitsu S, et al. Herpes simplex esophagitis in the immunocompetent host. Dis
Esophagus. 2005;18:340–344.
15. McBane RD, Gross JB. Herpes esophagitis: clinical syndrome, endoscopic appearance, and diagnosis in 23
patients. Gastrointest Endosc. 1991;37:600–603.
16. Goodell SE, Quinn TC, Mkrtichian E, et al. Herpes simplex virus proctitis in homosexual men: clinical,
sigmoidoscopic, and histopathological features. N Engl J Med. 1983;308:868–871.
17. Greenson JK, Beschorner WE, Boitnott JK, Yardley JH. Prominent mononuclear cell infiltrate is
characteristic of herpes esophagitis. Hum Pathol. 1991;22:541–549.
18. Mallet E, Maitre M, Mouterde O. Complications of the digestive tract in varicella infection including two
cases of erosive gastritis. Eur J Pediatr. 2006;165:64–65.
19. Yan Z, Nguyen S, Poles M, et al. Adenovirus colitis in human immunodeficiency virus infection: an
underdiagnosed entity. Am J Surg Pathol. 1998;22:1101–1106.
20. Ison MG. Adenovirus infections in transplant recipients. Clin Infect Dis. 2006;43:331–339.
21. Shayan K, Saunders F, Roberts E, Cutz E. Adenovirus enterocolitis in pediatric patients following bone
marrow transplantation: report of 2 cases and review of the literature. Arch Pathol Lab Med. 2003;127:1615–
1618.
22. Guarner J, de Leon-Bojorge B, Lopez-Corella E, et al. Intestinal intussusception associated with adenovirus
infection in Mexican children. Am J Clin Pathol. 2003;120:845–850.
23. Porter HJ, Padfield CJH, Peres LC, et al. Adenovirus and intranuclear inclusions in appendices in
intussusception. J Clin Pathol. 1993;46:154–158.
24. Janoff EN, Orenstein JM, Manischewitz JF, Smith PD. Adenovirus colitis in the acquired
immunodeficiency syndrome. Gastroenterology. 1991;100:976–979.
25. Leung WK, To KF, Chan PK, et al. Enteric involvement of severe acute respiratory syndrome-associated
coronavirus infection. Gastroenterology. 2003;125:1011–1017.
26. Walter JE, Mitchell DK. Astrovirus infection in children. Curr Opin Infect Dis. 2003;16:247–253.
27. Vernacchio L, Vezina RM, Michell AA, et al. Diarrhea in American infants and young children in the
community setting: incidence, clinical presentation and microbiology. Pediatr Infect Dis J. 2006;25:2–7.
28. Blacklow NR, Greenberg HB. Viral gastroenteritis. N Engl J Med. 1991;325:252–264.
29. Estes MK, Hardy ME. Norwalk virus and other enteric caliciviruses. Blaser MJ, Smith PD, Ravdin JI, et al.
Infections of the Gastrointestinal Tract. Raven Press: New York; 1995:1009–1034.
30. Saif LJ, Greenberg HG. Rotaviral gastroenteritis. Conner DH, Chandler FW. Pathology of Infectious Diseases.
Appleton and Lange: Stamford, CT; 1997:297–302.
31. Agus SG, Dolin R, Wyatt RG, et al. Acute infectious nonbacterial gastroenteritis: intestinal histopathology.
Ann Intern Med. 1973;79:18–25.
32. Barnes GL, Townley RRW. Duodenal mucosal damage in 31 infants with gastroenteritis. Arch Dis Child.
1973;48:343–349.
33. Paik SY, Oh JT, Choi YJ, et al. Measles-related appendicitis. Arch Pathol Lab Med. 2002;126:82–84.
34. Vieth M, Dirschmid K, Oehler U, et al. Acute measles gastric infection. Am J Surg Pathol. 2001;25:259–262.35. Kahl P, Buettner R, Friedrichs N, et al. Kaposi's sarcoma of the gastrointestinal tract: report of two cases
and review of the literature. Pathol Res Pract. 2007;203:227–231.
36. Halme L, Arola J, Hockerstedt K, Lautenschlager I. Human herpesvirus 6 infection of the gastroduodenal
mucosa. Clin Infect Dis. 2008;46:434–439.
37. Breddemann A, Laer S, Schmidt KG, et al. Case report: severe gastrointestinal inflammation and persistent
HHV-6B infection in a pediatric cancer patient. Herpes. 2007;14:41–44.
38. Kotler DP, Reka S, Orenstein JM, Fox CH. Chronic idiopathic esophageal ulceration in the acquired
immunodeficiency syndrome. J Clin Gastroenterol. 1992;15:284–290.
39. Wilcox CM, Schwartz DA. Endoscopic characterization of idiopathic esophageal ulceration associated with
human immunodeficiency virus infection. J Clin Gastroenterol. 1993;16:251–256.
40. Jalfon IM, Sitton JE, Hammer RA, et al. HIV-1 gp41 antigen demonstration in esophageal ulcers with
acquired immunodeficiency syndrome. J Clin Gastroenterol. 1991;13:644–648.
41. Dretler RH, Rausher DB. Giant esophageal ulcer healed with steroid therapy in an AIDS patient. Rev Infect
Dis. 1989;11:768–769.
42. Ehrenpreis ED, Patterson BK, Brainer JA, et al. Histopathologic findings of duodenal biopsy specimens in
HIV-infected patients with and without diarrhea and malabsorption. Am J Clin Pathol. 1992;97:21–28.
43. Bartlett JG, Belitsos PC, Sears CL. AIDS enteropathy. Clin Infect Dis. 1992;15:726–735.
44. Carlson S, Vokoo H, Craig RM. Small intestinal HIV-associated enteropathy: evidence for panintestinal
enterocyte dysfunction. J Lab Clin Med. 1994;124:652–659.
45. Greenson JK, Belitsos PC, Yardley JH, Bartlett JG. AIDS enteropathy: occult enteric infections and
duodenal mucosal alterations in chronic diarrhea. Ann Intern Med. 1991;114:366–372.
46. Abrams GD. Surgical pathology of the infected gut. Am J Surg Pathol. 1987;11(suppl 1):16–24.
47. Greenson JK, Stern RA, Carpenter SL, Barnett JL. The clinical significance of focal active colitis. Hum
Pathol. 1997;28:729–733.
48. Kumar NB, Nostrant TT, Appelman HD. The histopathologic spectrum of acute self-limited colitis (acute
infectious-type colitis). Am J Surg Pathol. 1982;6:523–529.
49. Volk EE, Shapiro BD, Easley KA, Goldblum JR. The clinical significance of a biopsy-based diagnosis of
focal active colitis: a clinicopathologic study of 31 cases. Mod Pathol. 1998;11:789–794.
50. Xin W, Brown PI, Greenson JK. The clinical significance of focal active colitis in pediatric patients. Am J
Surg Pathol. 2003;27:1134–1138.
51. Surawicz CM, Haggitt RC, Husseman M, McFarland LV. Mucosal biopsy diagnosis of colitis: acute
selflimited colitis and idiopathic inflammatory bowel disease. Gastroenterology. 1994;107:755–763.
52. Goldsweig CD, Pacheco PA. Infectious colitis excluding E. coli O157 : H7 and C. difficile. Gastroenterol Clin
N Am. 2001;30:709–733.
53. Piarroux R, Faucher B. Cholera epidemics in 2010: respective roles of environment, strain changes, and
human-driven dissemination. Clin Microbiol Infect. 2012;18:231–238.
54. Abbott SL, Janda JM. Severe gastroenteritis associated with Vibrio hollisae infection: report of two cases
and review. Clin Infect Dis. 1994;18:310–312.
55. Pastore G, Schiraldi G, Fera G, et al. A biopsy study of gastrointestinal mucosa in cholera patients during
an epidemic in southern Italy. Am J Dig Dis. 1976;21:613–617.
56. Shuangshoti S, Reinprayoon S. Pathologic changes of gut in non-O1 Vibrio cholerae infection. J Med Assn
Thailand. 1995;78:204–209.
57. Talkington D, Bopp C, Tarr C, et al. Characterization of toxigenic Vibrio cholerae from Haiti, 2010-2011.
Emerg Infect Dis. 2011;17:2122–2129.
58. George WL, Nakata MM, Thompson J, White ML. Aeromonas-related diarrhea in adults. Arch Intern Med.
1985;145:2207–2211.
59. Deutsch SF, Wedzina W. Aeromonas sobria associated left-sided segmental colitis. Am J Gastroenterol.
1997;92:2104–2106.
60. Merino S, Rubires X, Knochel S, Tomas JM. Emerging pathogens: Aeromonas spp. Int J Food Microbiol.
1995;28:157–168.
61. Travis LB, Washington JA. The clinical significance of stool isolates of Aeromonas. Am J Clin Pathol.
1986;85:330–336.
62. Farraye FA, Peppercorn MA, Ciano PS, Kavesh WN. Segmental colitis associated with Aeromonas
hydrophila. Am J Gastroenterol. 1989;84:436–438.
63. Yarze JC. Aeromonas as a cause of segmental colitis. Am J Gastroenterol. 1998;93:1012–1013.
64. Gilligan PH. Escherichia coli: EAEC, EHEC, EIEC, ETEC. Clin Lab Med. 1999;19:505–521.
65. Levine MM. Escherichia coli that cause diarrhea: enterotoxigenic, enteropathogenic, enteroinvasive,
enterohemorrhagic, and enteroadherent. J Infect Dis. 1987;155:377–389.
66. Beatty ME, Adcock PM, Smith SW, et al. Epidemic diarrhea due to enterotoxigenic E. coli. Clin Infect Dis.
2006;42:329–334.
67. Qadri F, Svennerholm AM, Faruque AS, Sack RB. Enterotoxigenic Escherichia coli in developing countries:
epidemiology, microbiology, clinical features, treatment, and prevention. Clin Microbiol Rev. 2005;18:465–
483.
68. Yoder JS, Cesario S, Plotkin V. Outbreak of enterotoxigenic Escherichia coli infection with an unusually longduration of illness. Clin Infect Dis. 2006;42:1513–1517.
69. Tulloch EF, Ryan EJ, Formal SB, Franklin FA. Invasive enteropathic E. coli dysentery. Ann Intern Med.
1973;79:13–17.
70. Bessesen MT, Wang E, Echeverria P, Blaser MJ. Enteroinvasive Escherichia coli: a cause of bacteremia in
patients with AIDS. J Clin Microbiol. 1991;29:2675–2677.
71. Wanger AR, Murray BE, Echeverria P, et al. Enteroinvasive E. coli in travelers with diarrhea. J Infect Dis.
1988;158:640–642.
72. Kotler DP, Giang TT, Thiim M, et al. Chronic bacterial enteropathy in a patient with AIDS. J Infect Dis.
1995;171:552–558.
73. Savarino SJ. Enteroadherent E. coli: a heterogeneous group of E. coli implicated as diarrhoeal pathogens.
Trans R Soc Trop Med Hyg. 1993;87(suppl 3):49–53.
74. Orenstein JM, Kotler DP. Diarrheogenic bacterial enteritis in acquired immune deficiency syndrome: a
light and electron microscopic study of 52 cases. Hum Pathol. 1995;26:481–492.
75. Tarr PI, Neill MA. Escherichia coli O157 : H7. Gastroenterol Clin N Am. 2001;30:735–751.
76. Welinder-Olsson C, Kaijser B. Enterohemorrhagic E. coli (EHEC). Scand J Infect Dis. 2005;37:405–416.
77. Griffin PM, Olmstead LC, Petras RE. Escherichia coli 0157:H7-associated colitis: a clinical and histological
study of 11 cases. Gastroenterology. 1990;99:142–149.
78. Kelly J, Oryshak A, Wenetsek M, et al. The colonic pathology of E. coli O157 : H7 infection. Am J Surg
Pathol. 1990;14:87–92.
79. Hogenauer C, Langner C, Beubler E, et al. Klebsiella oxytoca as a causative organism of antibiotic-associated
hemorrhagic colitis. N Engl J Med. 2006;355:2418–2426.
80. Su C, Brandt LJ, Sigal SH, et al. The immunohistological diagnosis of E. coli O157 : H7 colitis: possible
association with colonic ischemia. Am J Gastroenterol. 1998;93:1055–1059.
81. Edwards BH. Salmonella and Shigella species. Clin Lab Med. 1999;19:469–487.
82. Kraus MD, Amatya B, Kimula Y. Histopathology of typhoid enteritis: morphologic and immunophenotypic
findings. Mod Pathol. 1999;12:949–955.
83. Azad AK, Islam R, Salam MA, et al. Comparison of clinical features and pathologic findings in fatal cases
of typhoid fever during the initial and later stages of the disease. Am J Trop Med Hyg. 1997;56:490–493.
84. Boyd JF. Pathology of the alimentary tract in Salmonella typhimurium food poisoning. Gut. 1985;26:935–944.
85. McGovern VJ, Slavutin LJ. Pathology of Salmonella colitis. Am J Surg Pathol. 1979;3:483–490.
86. Scully RE, Mark EJ, NcNeely WF, et al. Case records of the Massachusetts General Hospital. N Engl J Med.
2001;345:201–205.
87. Sachdev HPS, Chadha V, Malhotra V, et al. Rectal histopathology in endemic Shigella and Salmonella
diarrhea. J Pediatr Gastroenterol Nutr. 1993;13:33–38.
88. Mathan MM, Mathan VI. Morphology of rectal mucosa of patients with shigellosis. Rev Infect Dis.
1991;4:S314–S318.
89. Khuroo MS, Mahajan R, Zargar SA, et al. The colon in shigellosis: serial colonoscopic appearances in
Shigella dysenteriae I. Endoscopy. 1990;22:35–38.
90. Kelber M, Ament ME. Shigella dysenteriae I: a forgotten cause of pseudomembranous colitis. J Pediatr.
1976;89:595–596.
91. Islam MM, Azad Ak, Bardhan PK, et al. Pathology of shigellosis and its complications. Histopathology.
1994;24:65–71.
92. Blaser MJ, Parsons RB, Wang WLL. Acute colitis caused by Campylobacter fetus ss. jejuni. Gastroenterology.
1980;78:448–453.
93. Blaser MJ, Berkowitz ID, LaForce FM, et al. Campylobacter enteritis: clinical and epidemiological features.
Ann Intern Med. 1979;91:179–185.
94. Fields PI, Swerdlow DL. Campylobacter jejuni. Clin Lab Med. 1999;19:489–503.
95. Price AB, Jewkes J, Sanderson PJ. Acute diarrhoea: Campylobacter colitis and the role of rectal biopsy. J Clin
Pathol. 1979;32:990–997.
96. Lambert ME, Schofield PF, Ironside AG, Mandal BK. Campylobacter colitis. Br Med J. 1976;1:857–859.
97. Schneider EN, Havens JM, Goldblum JR, et al. Molecular detection of Campylobacter infection in cases of
focal active colitis. Mod Pathol. 2004;17:129A.
98. Siegal D, Syed F, Hamid N, Cunha BA. Campylobacter jejuni pancolitis mimicking idiopathic ulcerative
colitis. Heart Lung. 2005;34:288–290.
99. Attwood SEA, Cafferkey MT, Keane FBV. Yersinia infections in surgical practice. Br J Surg. 1989;76:499–504.
100. Attwood SEA, Cafferkey MT, West AB, et al. Yersinia infection and acute abdominal pain. Lancet.
1987;1(8532):529–533.
101. Simmonds SD, Noble MA, Freeman HJ. Gastrointestinal features of culture-positive Yersinia enterocolitica
infection. Gastroenterology. 1987;92:112–117.
102. Natkin J, Beavis KG. Yersinia enterocolitica and Yersinia pseudotuberculosis. Clin Lab Med. 1999;19:523–536.
103. Saebo A, Lassen J. Acute and chronic gastrointestinal manifestations associated with Yersinia enterocolitica
infection: a Norwegian 10-year follow-up study on 458 hospitalized patients. Ann Surg. 1992;215:250–255.
104. Dudley TH, Dean PJ. Idiopathic granulomatous appendicitis, or Crohn's disease of the appendix revisited.
Hum Pathol. 1993;24:595–601.105. Lamps LW, Madhusudhan KT, Greenson JK, et al. The role of Y. enterocolitica and Y. pseudotuberculosis in
granulomatous appendicitis: a histologic and molecular study. Am J Surg Pathol. 2001;25:508–515.
106. Gleason TH, Patterson SD. The pathology of Yersinia enterocolitica ileocolitis. Am J Surg Pathol. 1982;6:347–
355.
107. El-Maraghi NRH, Mair N. The histopathology of enteric infection with Yersinia pseudotuberculosis. Am J
Clin Pathol. 1979;71:631–639.
108. Borriello SP. Clostridial disease of the gut. Clin Infect Dis. 1995;2:S242–S250.
109. Aslam S, Musher DM. An update on the diagnosis, treatment, and prevention of Clostridium
difficileassociated disease. Gastroenterol Clin N Amer. 2006;35:315–335.
110. Bartlett J. Narrative review: the new epidemic of Clostridium difficile-associated enteric disease. Ann Intern
Med. 2006;145:758–764.
111. Surawicz CM, McFarland LV. Pseudomembranous colitis: causes and cures. Digestion. 1999;60:91–100.
112. Nash SV, Bourgeault R, Sands M. Colonic disease associated with a positive assay for Clostridium difficile
toxin: a retrospective study. J Clin Gastroenterol. 1997;25:476–479.
113. Dignan CR, Greenson JK. Can ischemic colitis be differentiated from C. difficile colitis in biopsy
specimens? Am J Surg Pathol. 1997;21:706–710.
114. Selvaraju SB, Gripka M, Estes K, et al. Detection of toxigenic Clostridium difficile in pediatric stool samples:
an evaluation of Quik Check Complete Antigen assay, BD GeneOhm Cdiff PCR, and ProGastro Cd PCR
assays. Diagn Microbiol Infect Dis. 2011;71:224–229.
115. Murrell TGC, Roth L, Adelaide MB, et al. Pig-bel: Enteritis necroticans. Lancet. 1966;1(7431):217–222.
116. Gomez L, Martino R, Rolston KV. Necrotizing enterocolitis: spectrum of the disease and comparison of
definite and possible cases. Clin Infect Dis. 1998;27:695–699.
117. Lawrence G, Walker PD. Pathogenesis of enteritis necroticans in Papua New Guinea. Lancet.
1976;1(7951):125–126.
118. Gui L, Subramony C, Fratkin J, Hughson MD. Fatal enteritis necroticans (pigbel) in a diabetic adult. Mod
Pathol. 2002;15:66–70.
119. Al Otaibi A, Barker C, Anderson R, Sigalet DL. Neutropenic enterocolitis (typhlitis) after pediatric bone
marrow transplant. J Pediatr Surg. 2002;37:770–772.
120. Lev R, Sweeney KG. Neutropenic enterocolitis: two unusual cases with review of the literature. Arch Pathol
Lab Med. 1993;117:524–527.
121. Kirchner JT. Clostridium septicum infection: beware of associated cancer. Postgraduate Med. 1991;90:157–160.
122. Horvath KD, Whelan RL. Intestinal tuberculosis: return of an old disease. Am J Gastroenterol. 1998;93:692–
696.
123. Marshall JB. Tuberculosis of the gastrointestinal tract and peritoneum. Am J Gastroenterol. 1993;88:989–999.
124. Sharma MP, Bhatia V. Abdominal tuberculosis. Indian J Med Res. 2004;120:305–315.
125. Chung CC, Choi CL, Kwok SP, et al. Anal and perianal tuberculosis: a report of three cases in 10 years. J R
Coll Surg Edinb. 1997;42:189–190.
126. Singh MK, Arunabh, Kapoor VK. Tuberculosis of the appendix: a report of 17 cases and a suggested
aetiopathological classification. Post Med J. 1987;63:855–857.
127. Gordon AH, Marshall JB. Esophageal tuberculosis: definitive diagnosis by endoscopy. Am J Gastroenterol.
1990;85:174–177.
128. Pulimood AB, Peter S, Ramakrishna BS, et al. Segmental colonoscopic biopsies in the differentiation of
ileocolonic tuberculosis from Crohn's disease. J Gastroenterol Hepatol. 2005;20:688–696.
129. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor
alphaneutralizing agent. N Engl J Med. 2001;345:1098–1104.
130. Benson CA, Ellner JJ. Mycobacterium avium complex infection and AIDS: advances in theory and practice.
Clin Infect Dis. 1993;17:7–20.
131. Hellyer TJ, Brown IN, Taylor MB, et al. Gastrointestinal involvement in Mycobacterium avium-intracellulare
infection of patients with HIV. J Infect. 1993;26:55–66.
132. Monsour HP, Quigley EMM, Markin RS, et al. Endoscopy in the diagnosis of gastrointestinal
Mycobacterium avium-intracellulare infection. J Clin Gastroenterol. 1991;13:20–24.
133. Roth RI, Owen RL, Keren DF, et al. Intestinal infection with Mycobacterium avium-intracellulare in acquired
immune deficiency syndrome (AIDS): histological and clinical comparison with Whipple's disease. Dig
Dis Sci. 1985;5:497–504.
134. Farhi DC, Mason UG, Horsburgh CR. Pathologic findings in disseminated Mycobacterium
aviumintracellulare infection: a report of 11 cases. Am J Clin Pathol. 1986;85:67–72.
135. Umlas J, Federman M, Crawford C, et al. Spindle cell pseudotumor due to Mycobacterium
aviumintracellulare in patients with acquired immunodeficiency syndrome (AIDS). Am J Surg Pathol.
1991;15:1181–1187.
136. Fyfe B, Poppiti RJ, Lubin J, et al. Gastric syphilis: primary diagnosis by gastric biopsy. Arch Pathol Lab Med.
1993;117:820–823.
137. Quinn TC, Corey L, Chaffee RG, et al. The etiology of anorectal infections in homosexual men. Am J Med.
1981;71:395–406.
138. Wexner SD. Sexually transmitted diseases of the colon, rectum, and anus. Dis Colon Rectum. 1990;33:1048–1059.
139. Rompalo AM. Diagnosis and treatment of sexually acquired proctitis and proctocolitis. Clin Infect Dis.
1999;1:S84–S90.
140. Long BW, Johnston JH, Wetzel JH, et al. Gastric syphilis: endoscopic and histological features mimicking
lymphoma. Am J Gastroenterol. 1995;90:1504–1507.
141. Akdamar K, Martin RJ, Ichinose H. Syphilitic proctitis. Dig Dis Sci. 1977;22:701–704.
142. Esteve M, Salas A, Fernandez-Banares F, et al. Intestinal spirochetosis and chronic watery diarrhea:
clinical and histological response to treatment and long term follow up. J Gastroenterol Hepatol.
2006;21:1326–1333.
143. Koteish A, Kannangai R, Abraham S, Torbenson M. Colonic spirochetosis in children and adults. Am J
Clin Pathol. 2003;120:828–832.
144. Surawicz CM. Intestinal spirochetosis in homosexual men. Am J Med. 1988;82:587–592.
145. Weisheit B, Bethke B, Stolte M. Human intestinal spirochetosis: analysis of the symptoms of 209 patients.
Scand J Gastroenterol. 2007;42:1422–1427.
146. Rotterdam H. Intestinal spirochetosis. Connor DH, Chandler FW, et al. Pathology of Infectious Diseases.
Appleton and Lange: Stamford, CT; 1997:583–589.
147. Uhlemann ER, Fenoglio-Preiser C. Intestinal spirochetosis (letter). Am J Surg Pathol. 2005;29:982.
148. Baker RW, Peppercorn MA. Gastrointestinal ailments of homosexual men. Medicine (Baltimore).
1982;61:390–405.
149. de la Monte SM, Hutchins GM. Follicular proctocolitis and neuromatous hyperplasia with
lymphogranuloma venereum. Hum Pathol. 1985;16:1025–1032.
150. Geller SA, Zimmerman MJ, Cohen A. Rectal biopsy in early lymphogranuloma venereum proctitis. Am J
Gastroenterol. 1980;74:433–435.
151. Martin-Iguacel R, Llibre JM, Nielsen H, et al. Lymphogranuloma venereum proctocolitis: a silent endemic
disease in men who have sex with men in industrialised countries. Eur J Clin Microbiol Infect Dis.
2010;29:917–925.
152. McMillan A, McNeillage G, Gilmour HM, Lee FD. Histology of rectal gonorrhea in men, with a note on
anorectal infection with Neisseria meningitidis. J Clin Pathol. 1983;36:511–514.
153. Walsh TJ, Belitsos NJ, Hamilton SR. Bacterial esophagitis in immunocompromised patients. Arch Intern
Med. 1986;146:1345–1348.
154. Schultz MJ, van der Hulst RWM, Tytgat GNJ. Acute phlegmonous gastritis. Gastrointest Endosc. 1996;44:80–
83.
155. Rosen Y, Won OH. Phlegmonous enterocolitis. Am J Dig Dis. 1978;23:248–256.
156. Ferrari TC, Couto CA, Murta-Oliveira C, et al. Actinomycosis of the colon: a rare form of presentation.
Scand J Gastroenterol. 2000;35:108–109.
157. Skoutelis A, Panagopoulos C, Kalfarentzos F, Bassaris H. Intramural gastric actinomycosis. South Med J.
1995;88:647–650.
158. Mueller MC, Ihrler S, Degenhart C, Bogner JR. Abdominal actinomycosis. Infection. 2008;36:191.
159. Bai JC, Mazure RM, Vazquez H, et al. Whipple's disease. Clin Gastroenterol Hepatol. 2004;2:849–860.
160. Dobbins WO. Whipple's Disease. Charles C Thomas: Springfield, IL; 1987.
161. Hamrock D, Azmi F, O'Donnell E, et al. Infection by Rhodococcus equi in a patient with AIDS: histological
appearance mimicking Whipple's disease and MAI infection. J Clin Pathol. 1999;52:68–71.
162. Randall MB, Walker DH. Rocky mountain spotted fever: gastrointestinal and pancreatic lesions and
rickettsial infection. Arch Pathol Lab Med. 1984;108:963–967.
163. Mcclure J. Malakoplakia of the gastrointestinal tract. Post Med J. 1981;57:95–103.
164. Chandler FW, Watts JC. Pathologic Diagnosis of Fungal Infections. ASCP Press: Chicago; 1987.
165. Dictar MO, Maiolo E, Alexander B, et al. Mycoses in the transplanted patient. Med Mycol. 2000;38(suppl
1):251–258.
166. Ellis M. Invasive fungal infections: evolving challenges for diagnosis and therapeutics. Mol Immunol.
2001;38:947–957.
167. Walsh TJ, Merz WG. Pathologic features in the human alimentary tract associated with invasiveness of
Candida tropicalis. Am J Clin Pathol. 1986;85:498–502.
168. Prescott RJ, Harris M, Banerjee SS. Fungal infections of the small and large intestine. J Clin Pathol.
1992;45:806–811.
169. Schwesinger G, Junghans D, Schroder G, et al. Candidosis and aspergillosis as autopsy findings from 1994
to 2003. Mycoses. 2005;48:176–180.
170. Cohen R, Heffner JE. Bowel infarction as the initial manifestation of disseminated aspergillosis. Chest.
1992;101:877–879.
171. Fleming RV, Walsh TJ, Anaissie EJ. Emerging and less common fungal pathogens. Infect Dis Clin N Am.
2002;16:915–933.
172. Martino P, Gastaldi R, Raccah R, Girmenia C. Clinical patterns of Fusarium infections in
immunocompromised patients. J Infection. 1994;28(suppl 1):7–15.
173. Gonzalez CE, Rinaldi MG, Sugar AM. Zygomycosis. Infect Dis Clin N Am. 2002;16:895–914.
174. Thomson SR, Bade PG, Taams M, Chrystal V. Gastrointestinal mucormycosis. Br J Surg. 1991;78:952–954.175. Centers for Disease Control and Prevention (CDC). Gastrointestinal basidiobolomycosis—Arizona,
19941999. MMWR Morb Mortal Wkly Rep. 1999;48:710–713.
176. Lyon GM, Smilack JD, Komatsu KK, et al. Gastrointestinal basidiobolomycosis in Arizona: clinical and
epidemiological characteristics and review of the literature. Clin Infect Dis. 2001;32:1448–1455.
177. Nemenqani D, Yaqoob N, Khoja H, et al. Gastrointestinal basidiobolomycosis: an unusual fungal infection
mimicking colon cancer. Arch Pathol Lab Med. 2009;133:1938–1942.
178. Lamps LW, Molina CP, West AB, et al. The pathologic spectrum of gastrointestinal and hepatic
histoplasmosis. Am J Clin Pathol. 2000;113:64–72.
179. Cappell MS, Mandell W, Grimes MM, et al. Gastrointestinal histoplasmosis. Dig Dis Sci. 1988;33:353–360.
180. Washington K, Gottfried MR, Wilson ML. Gastrointestinal cryptococcosis. Mod Pathol. 1991;4:707–711.
181. Bonacini M, Nussbaum J, Ahluwalia C. Gastrointestinal, hepatic, and pancreatic involvement with
Cryptococcus neoformans in AIDS. J Clin Gastroenterol. 1990;12:295–297.
182. Dieterich DT, Lew EA, Bacon DJ, et al. Gastrointestinal pneumocystosis in HIV-infected patients on
aerosolized pentamidine: report of five cases and review of the literature. Am J Gastroenterol. 1992;87:1763–
1770.
183. Kaur N, Mahl TC. Pneumocystis jiroveci (carinii) pneumonia after infliximab therapy: a review of 84 cases.
Dig Dis Sci. 2007;52:1481–1484.
184. Penna FJ. Blastomycosis of the colon resembling clinically ulcerative colitis. Gut. 1979;20:896–899.
185. Goldani LZ. Gastrointestinal paracoccidioidomycosis: an overview. J Clin Gastroenterol. 2011;45:87–91.
186. Lewthwaite P, Gill GV, Hart CA, Beeching NJ. Gastrointestinal parasites in the immunocompromised.
Curr Opin Infect Dis. 2005;18:427–435.
187. Wiwanitkit V. Intestinal parasite infection in HIV infected patients. Curr HIV Res. 2006;4:87–96.
188. Stark D, Fotedar R, van Hal S, et al. Prevalence of enteric protozoa in human immunodeficiency virus
(HIV)-positive and HIV-negative men who have sex with men from Sydney, Australia. Am J Trop Med Hyg.
2007;76:549–552.
189. Variyam EP, Gogate P, Hassan M, et al. Nondysenteric intestinal amebiasis: colonic morphology and
search for Entamoeba histolytica adherence and invasion. Dig Dis Sci. 1989;34:732–740.
190. Brandt H, Tamayo P. Pathology of human amebiasis. Hum Pathol. 1970;1:351–385.
191. Hardin RE, Ferzli GS, Zenilman ME, et al. Invasive amebiasis and ameboma formation presenting as a
rectal mass: an uncommon case of malignant masquerade at a Western medical center. World J
Gastroenterol. 2007;13:5659–5661.
192. Oberhuber G, Kastner N, Stolte M. Giardiasis: a histologic analysis of 567 cases. Scand J Gastroenterol.
1997;32:48–51.
193. Ortega YR, Adam RD. Giardia: Overview and update. Clin Infect Dis. 1997;25:545–550.
194. Zimmer G, Guillou L, Gauthier T, et al. Digestive leishmaniasis in acquired immunodeficiency syndrome:
a light and electron microscopic study of two cases. Mod Pathol. 1996;9:966–969.
195. Baba CS, Makharia GK, Mathur P, et al. Chronic diarrhea and malabsoprtion caused by Leishmania
donovani. Indian J Gastroenterol. 2006;25:309–310.
196. Hofman V, Marty P, Perrin C, et al. The histological spectrum of visceral leishmaniasis caused by
Leishmania infantum MON-1 in acquired immune deficiency syndrome. Hum Pathol. 2000;31:75–84.
197. Bern C, Montgomery SP, Herwaldt BL, et al. Evaluation and treatment of Chagas disease in the United
States: a systematic review. JAMA. 2007;298:2171–2181.
198. de Oliveira RB, Troncon LEA, Dantas RO, Meneghelli UG. Gastrointestinal manifestations of Chagas’
disease. Am J Gastroenterol. 1998;93:884–889.
199. Krishnamurthy S, Schuffler MD. Pathology of neuromuscular disorders of the colon. Gastroenterology.
1987;93:610–639.
200. Schwartz DA, Mixon JP. Balantidiasis. Connor DH, Chandler FW, et al. Pathology of Infectious Diseases.
Appleton and Lange: Stamford, CT; 1997:1141–1145.
201. Schuster FL, Ramirez-Avila L. Current world status of Balantidium coli. Clin Microbiol Rev. 2008;21:626–638.
202. Huang DV, Chappell C, Okhuysen PC. Cryptosporidiosis in children. Semin Pediatr Infect Dis. 2004;15:253–
259.
203. Goodgame R. Understanding intestinal spore-forming protozoa: cryptosporidia, microsporidia, Isospora,
and Cyclospora. Ann Intern Med. 1996;124:429–441.
204. Cama VA, Ross JM, Crawford S, et al. Differences in clinical manifestations among Cryptosporidium
species and subtypes in HIV-infected persons. J Infect Dis. 2007;196:684–691.
205. Clayton F, Heller T, Kotler DP. Variation in the enteric distribution of cryptosporidia in acquired
immunodeficiency syndrome. Am J Clin Pathol. 1994;102:420–425.
206. Curry A, Smith HV. Emerging pathogens: Isospora, Cyclospora, and microsporidia. Parasitology.
1998;117:S143–S159.
207. Connor BA, Reidy J, Soave R. Cyclosporiasis: clinical and histopathologic correlates. Clin Infect Dis.
1999;28:1216–1221.
208. Sun T, Ilardi CF, Asnis D, et al. Light and electron microscopic identification of Cyclospora species in small
intestine: evidence of the presence of asexual life cycle in the human host. Am J Clin Pathol. 1996;105:216–
220.209. Orenstein JM. Isosporiasis. Connor DH, Chandler FW, et al. Pathology of Infectious Diseases. Appleton and
Lange: Stamford, CT; 1997:1185–1190.
210. Brandborg LL, Goldberg B, Breidenbach WC. Human coccidiosis: a possible cause of malabsorption. N
Engl J Med. 1970;283:1306–1313.
211. Velasquez JN, Carnevale S, Mariano M, et al. Isosporiasis and unizoite tissue cysts in patients with
acquired immunodeficiency syndrome. Hum Pathol. 2001;32:500–505.
212. Lamps LW, Bronner MP, Vnencak-Jones CL, et al. Optimal screening and diagnosis of microsporida in
tissue sections. Am J Clin Pathol. 1998;109:404–410.
213. Kotler DP, Giang TT, Garro ML, et al. Light microscopic diagnosis of microsporidiosis in patients with
AIDS. Am J Gastroenterol. 1994;89:540–544.
214. Wichro E, Hoelzl D, Krause R, et al. Microsporidiosis in travel-associated diarrhea in immune-competent
patients. Am J Trop Med Hyg. 2005;73:285–287.
215. Bertoli F, Espino M, Arosemena JR, et al. A spectrum in the pathology of toxoplasmosis in patients with
acquired immunodeficiency syndrome. Arch Pathol Lab Med. 1995;119:214–224.
216. Stark DJ, Beebe N, Marriott D, et al. Dientamoebiasis: clinical importance and recent advances. Trends
Parasitol. 2006;22:92–96.
217. Johnson EH, Windsor JJ, Clark CG. Emerging from obscurity: biological, clinical, and diagnostic aspects of
Dientamoeba fragilis. Clin Microbiol Rev. 2004;17:553–570.
218. Tungtrongchitr A, Manatsathit S, Kositchaiwat C, et al. Blastocystis hominis infection in irritable bowel
syndrome. Southeast Asian J Trop Med Public Health. 2004;35:705–710.
219. Tan KSW. Blastocystis in humans and animals: new insights using modern methodologies. Vet Parasitol.
2004;126:121–144.
220. Cooper ES, Whyte-Alleng CAM, Finzi-Smith JS, MacDonald TT. Intestinal nematode infections in
children: the pathophysiological price paid. Parasitology. 1992;104(suppl):S91–S103.
221. Cook GC. The clinical significance of gastrointestinal helminths: a review. Trans R Soc Trop Med Hyg.
1986;80:675–685.
222. Sinniah B, Leopairut RC, Connor DH, Voge M. Enterobiasis: a histopathological study of 259 patients. Ann
Trop Med Parasitol. 1991;85:625–635.
223. Wiebe BM. Appendicitis and Enterobius vermicularis. Scand J Gastroenterol. 1991;26:336–338.
224. Prociv P, Croese J. Human eosinophilic enteritis caused by dog hookworm Ancylostoma caninum. Lancet.
1990;335:1299–1303.
225. Elsayed S, Yilmaz A, Hershfield N. Trichuris trichiura worm infection. Gastrointest Endosc. 2004;60:990–991.
226. Sandler M. Whipworm infestation in the colon and rectum simulating Crohn's colitis. Lancet.
1981;2(8239):210.
227. Sinniah B. Trichuriasis. Connor DH, Chandler FW, et al. Pathology of Infectious Diseases. Appleton and
Lange: Stamford, CT; 1997:1585–1588.
228. Milder JE, Walzer PD, Kilgore G, et al. Clinical features of Strongyloides stercoralis infection in an endemic
area of the United States. Gastroenterology. 1981;80:1481–1488.
229. Concha R, Harrington W Jr, Rogers AI. Intestinal strongyloidiasis: recognition, management, and
determinants of outcome. J Clin Gastroenterol. 2005;39:203–211.
230. Keiser PB, Nutman TB. Strongyloides stercoralis in the immunocompromised population. Clin Microbiol
Rev. 2004;17:208–217.
231. Ramdial PK, Hlatshwayo NH, Singh B. Strongyloides stercoralis mesenteric lymphadenopathy: clue to the
etiopathogenesis of intestinal pseudo-obstruction in HIV-infected patients. Ann Diagn Pathol.
2006;10:209–214.
232. Nadler S, Cappell MS, Bhatt B, et al. Appendiceal infection by Entamoeba histolytica and Strongyloides
stercoralis presenting like acute appendicitis. Dig Dis Sci. 1990;35:603–608.
233. Weight SC, Barrie WW. Colonic strongyloides infection masquerading as ulcerative colitis. J R Coll Surg
Edinb. 1997;42:202–203.
234. Daschner A, Alonso-Gomez A, Cabanas R, et al. Gastroallergic anisakiasis: borderline between food
allergy and parasitic disease—clinical and allergologic evaluation of 20 patients with confirmed acute
parasitism. J Allergy Clin Immunol. 2000;105:176–181.
235. Gomez B, Tabar AI, Tunon T, et al. Eosinophilic gastroenteritis and Anisakis. Allergy. 1998;53:1148–1154.
236. Bruckner DA. Helminthic food-borne infections. Clin Lab Med. 1999;19:639–660.
237. Dronda F, Chaves F, Sanz A, Lopez-Velez R. Human intestinal capillariasis in an area of nonendemicity:
case report and review. Clin Infect Dis. 1993;17:909–912.
238. Grencis RK, Cooper ES. Enterobius, trichuris, capillaria, and hookworm including Ancyclostoma caninum.
Gastroenterol Clin N Am. 1996;25:579–597.
239. Gryseels B, Polman K, Clerinx J, Kestens L. Human schistosomiasis. Lancet. 2006;368:1106–1118.
240. Adebamowo CA, Akang EEU, Ladipo JK, et al. Schistosomiasis of the appendix. Br J Surg. 1991;78:1219–
1221.
241. Smith JH, Said MN, Kelada AS. Studies on schistosomal rectal and colonic polyposis. Am J Trop Med Hyg.
1977;26:80–84.
242. Strickland GT. Gastrointestinal manifestations of schistosomiasis. Gut. 1994;35:1334–1337.243. Smith JH, Christie JD. The pathobiology of Schistosoma haematobium infection in humans. Hum Pathol.
1986;17:333–345.
244. Liu LX, Harinasuta KT. Liver and intestinal flukes. Gastroenterol Clin N Am. 1996;25:627–636.
245. Chai JY, Darwin MK, Lymbery AJ. Fish-borne parasitic zoonoses: status and issues. Int J Parasitol.
2005;35:1233–1254.
246. Fried B, Graczyk TK, Tamang L. Food-borne intestinal trematodiases in humans. Parasitol Res.
2004;93:159–170.
247. Kramer MH, Greer GJ, Quinonez JF, et al. First reported outbreak of abdominal angiostrongyliasis. Clin
Infect Dis. 1998;26:365–372.C H A P T E R 5
Manifestations of Immunodeficiency in the
Gastrointestinal Tract
Kay Washington
Chanjuan Shi
CHA P T E R OUT LINE
Primary Disorders of Immune Deficiency
Humoral Immunodeficiencies
Common Variable Immunodeficiency
Combined Cellular/Humoral Immunodeficiencies
Severe Combined Immunodeficiency
Omenn Syndrome
Other Primary Immunodeficiencies
DiGeorge Syndrome
Chronic Mucocutaneous Candidiasis
Wiscott-Aldrich Syndrome
Chronic Granulomatous Disease
Miscellaneous Immune Deficiency Syndromes
Graft-versus-Host Disease (GVHD)
Acute GVHD
Chronic GVHD
Neutropenic Enterocolitis
The Gastrointestinal Tract in HIV Infection
Infections
HIV Enteropathy
Malignancy
Primary Disorders of Immune Deficiency
Many of the primary disorders of immune deficiency (Table 5.1) are associated with gastrointestinal (GI ) lesions.
Manifestations of immune deficiency in the GI tract may be broadly divided into three categories: (1) increased
susceptibility to infection, (2) idiopathic chronic inflammatory conditions, and (3) increased risk of neoplasia.
A lthough many GI lesions are infectious (Table 5.2), chronic inflammatory conditions resembling celiac disease and
inflammatory bowel disease (I BD ) (Table 5.3) are seen in many patients with antibody deficiencies and are probably
the result of the inability of dysfunctional mononuclear cells to suppress unwanted immune responses. A ll patients
1with primary immune deficiencies are at increased risk of neoplasia (Table 5.4), most commonly non-Hodgkin
2lymphoma (N HL), and the GI tract is often the primary site of involvement. I n addition to the risk of lymphoma,
3some of the primary immune deficiencies are associated with increased risk of gastric adenocarcinoma and
4,5colorectal carcinoma.Table 5.1
Molecular Basis of Primary Immunodeficiency Disorders
Disease Proposed Cause
Selective IgA deficiency Impaired IgA synthesis; molecular defect unknown in most cases; mutation in
TNFRSF13B in ~5%
Common variable Impaired B cell maturation; molecular defect unknown in most cases; mutation
immunodeficiency in TNFRSF13B in ~10-15%
X-linked agammaglobulinemia Mutation in BTK results in absence of BTK in B cells
Hyper-IgM syndrome Mutation in CD40L, leading to absence of CD40 ligand on T cells
Hyper-IgE syndrome Mutation in STAT3 in autosomal dominant form; mutation in DOCK8 in
autosomal recessive form.
Severe combined Multiple defects, most commonly in the common γ chain; others include
immunodeficiency adenosine deaminase deficiency, purine nucleoside deficiency, and T-cell
receptor deficiencies
Omenn syndrome Hypomorphic missense mutation in RAG1/2, IL7RA,RMRP, ADA, DNA ligase IV,
Artemis, γc
Immune dysregulation, Mutation in FOXP3
polyendocrinopathy,
enteropathy, X-linked
DiGeorge syndrome Thymic hypoplasia; microdeletion in 22q11.2
Chronic mucocutaneous Heterogeneous disorder; mutation in AIRE gene in some; mutation in STAT1 in
candidiasis autosomal dominant form
Wiskott-Aldrich syndrome Mutation in WASP gene involved in cell trafficking and motility
Chronic granulomatous disease Mutation in gene for component of NADPH oxidase; CYBB mutation in X-linked
form; mutation in CYBA, NCF1, NCF2, or NCF4 in autosomal recessive forms
Ig, Immunoglobulin; NADPH, reduced nicotinamide adenine dinucleotide phosphate.
From International Union of Immunological Societies Expert Committee on Primary Immunodeficiencies, Notarangelo LD,
Fischer A, et al. Primary immunodeficiencies: 2009 update. (Erratum appears in J Allergy Clin Immunol.
2010;125:771773.) J Allergy Clin Immunol. 2009;124:1161-1178.
Table 5.2
Gastrointestinal Infections in Primary Immunodeficiency
Disease Gastrointestinal Infections
Selective IgA deficiency Giardia intestinalis; strongyloidiasis
Common variable Giardia intestinalis; Cryptosporidium; CMV
immunodeficiency
X-linked agammaglobulinemia Giardia intestinalis; Cryptosporidium
Salmonella, Campylobacter
Rotavirus, coxsackievirus, poliovirus
Hyper-IgM syndrome Giardia intestinalis, Cryptosporidium, Entamoeba histolytica, Salmonella,
Histoplasma capsulatum
Severe combined Candida; Salmonella and other bacterial pathogens; CMV, rotavirus, Epstein-Barr
immunodeficiency virus
DiGeorge syndrome Candida
Chronic mucocutaneous Candida; Histoplasma capsulatum
candidiasis
CMV, Cytomegalovirus; Ig, Immunoglobulin.Table 5.3
Inflammatory Gastrointestinal 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 disease-like lesion
Granulomatous enteropathy
Colitis (ulcerative colitis–like; lymphocytic colitis)
X-linked agammaglobulinemia Crohn disease-like lesion
Perianal fistula and perianal abscess
Hyper-IgM syndrome Nodular lymphoid hyperplasia
Oral and perianal ulcers
Severe combined immunodeficiency GVHD-like lesion, small bowel and colon
Esophageal reflux
Omenn syndrome GVHD-like lesion, small bowel and colon
Chronic mucocutaneous candidiasis Atrophic gastritis
Immune dysregulation, Autoimmune enteropathy
polyendocrinopathy,
enteropathy, X-linked
Wiskott-Aldrich syndrome Crohn disease-like lesion involving colon
Chronic granulomatous disease Esophageal and gastric outlet obstruction; Crohn disease-like lesion in
small bowel; colitis (ulcerative colitis-like and Crohn disease-like)
Pigmented macrophages
GVHD, Graft-versus-host disease; Ig, immunoglobulin.
Table 5.4
Malignancies Involving the Gastrointestinal Tract in Primary Immunodeficiency
Disease Gastrointestinal Malignancy
Immunoglobulin A 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 lymphoma
Gastric adenocarcinoma
Colorectal adenocarcinoma
Hyperimmunoglobulin M Plasma cell proliferation
syndrome Colorectal carcinoma
High-grade neuroendocrine carcinomas of the gastrointestinal tract and
biliary tree
Wiskott-Aldrich syndrome Gastrointestinal lymphoma
Ataxia-telangectasia Gastric adenocarcinoma
Humoral Immunodeficiencies
Selective Immunoglobulin A Deficiency
D efined as a serum immunoglobulin A (I gA) concentration of less than 50 µg/mL, selective I gA deficiency is the
6 7most common primary immunodeficiency ; it occurs in 1 of every 600 people of N orthern European ancestry. Thedisorder is 20 times more common in white A mericans than in A frican A mericans. D efects in antibody production in
patients with I gA deficiency represent a continuum with those seen in common variable immunodeficiency (CVI D ), and
20% to 30% of I gA -deficient patients also have deficits in I gG subclasses. Mutations in the geneT NFRSF13B have
8-10been identified and associated with I gA deficiency, although the mutational defect remains unknown in many
cases. This gene encodes a member of the tumor necrosis factor-receptor (TN FR) superfamily, the transmembrane
activator and calcium-modulator and cyclophilin-ligand interactor (TA CI ), which mediates isotype switching in B
lymphocytes (see later discussion).
Clinical manifestations of I gA deficiency range from no symptoms to recurrent infections (typically involving
mucosal surfaces), autoimmune disorders, allergic diseases, and malignancy, but are typically milder than those seen
with CVI D . Recurrent upper and lower respiratory tracti nfections are common in both disorders. S imilarly, GI
manifestations of I gA deficiency are the same as those associated with CVI D . I nfections are less common than might
be expected, possibly because of compensation for lack of mucosal I gA by transport of I gM across the mucosa into
the gut lumen, but include acute diarrheal illnesses caused by bacterial enterocolitis and chronic diarrhea caused by
11persistent Giardia intestinalis infection. Chronic strongyloidiasis has also been reported.
S usceptibility to autoimmune disorders such as insulin-dependent diabetes mellitus and celiac disease may be
inherited together with I gA deficiency; all three conditions are linked to particular major histocompatibility
haplotypes and probably represent genetically linked susceptibilities in certain populations. The prevalence of celiac
disease, the most common noninfectious GI complication of I gA deficiency, is 7.7% in children with I gA deficiency,
12compared with 1 : 500 in the general population, and a novel shared risk locus, CTLA4/ICOS, has been described
13linking CVI D , I gA deficiency, and celiac disease. A ntigliadin I gA and endomysial I gA antibodies cannot be used
as screening tools in the I gA -deficient population, but the morphology of celiac disease occurring in the seKing of
I gA deficiency is similar to that seen in immunocompetent patients. I n addition, a sprue-like illness characterized by
chronic diarrhea with villous atrophy that does not respond to a gluten-free diet may be seen in I gA deficiency, as in
CVI D . Pernicious anemia complicating chronic atrophic autoimmune gastritis is seen more commonly in I gA
14deficiency than in CVI D , and nodular lymphoid hyperplasia (N LH) in the small bowel is only rarely reported. A s
with other B cell disorders, the incidence of Crohn disease and gastric adenocarcinoma appears to be increased in
15IgA deficiency.
X-Linked Agammaglobulinemia
The typical patient with X-linked agammaglobulinemia (XLA G) is susceptible to bacterial infections because of the
absence of all circulating immunoglobulin subtypes; mature circulating B cells are low to absent. This disorder is
characterized by an inability to make antibodies to virtually all antigens. The molecular basis of most cases of XLA G
37,38was elucidated in 1993, when a defect in the BTK (Bruton tyrosine kinase) gene was found ; subsequent studies
39-41have identified numerous deleterious mutations. The BTK 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 by which the defects in BTK lead to B-cell
maturation arrest remains unclear. XLA G may have more phenotypic diversity than has previously been recognized,
42-44because adults with mild or no clinical symptoms but with deficiencies in BTK have been described. A ge at
onset, disease severity, and genotype are roughly associated with mutation severity (as classified based on structural
39,40and functional consequences) in some but not all cohorts.
GI manifestations are less common in XLA G than in CVI D , perhaps because of preserved T-cell function in
45 39,46XLAG, although persistent or recurrent diarrhea is reported in 23% to 29% of patients. A ge at onset of GI
symptoms is younger than in CVI D patients, and autoimmune diseases are less common. S mall intestinal and
colonic mucosal biopsies in the XLA G patient without GI symptoms are notable only for the lack of plasma cells in
the lamina propria, giving the lamina propria an empty appearance. Mucosal architecture is unremarkable, and
villous blunting is not seen. A pproximately one third of patients are seen initially with GI complaints, most
commonly diarrhea or perirectal abscess, and 10% in one study had chronic GI symptoms, either from persistent
infection with G. intestinalis, Salmonella, or enteropathic Escherichia coli or secondary to bacterial overgrowth. N o
47cause for chronic diarrhea was found in half of these patients. Chronic infection with rotavirus is also reported in
48this population. Because biopsies are not routinely performed for this disorder, few descriptions of histopathologic
findings are available, but moderate blunting of duodenal villi with crypt hyperplasia and an increase in lamina
49propria inflammatory cells are reported in acute infections. D egenerative changes may be noted in epithelial cells
50on the surface of the villus with no increase in crypt apoptosis ; crypt cells are spared, and the crypt zone undergoes
a compensatory hyperplasia. The histologic changes of acute rotavirus infection are reported to resemble celiac
51disease but are patchier and quickly revert to normal with resolution of infection.
I n addition to GI infections, a chronic ulcerating inflammatory condition, clinically similar to Crohn disease, that is
manifested by recurrent diarrhea, malabsorption, ulcers, and small bowel strictures (Fig. 5.1). A prominent
23,52lymphocytic inflammatory infiltrate without plasma cells or granulomas is seen in the affected areas. I n one
case, enterovirus was found by polymerase chain reaction in inflamed ileum and adjacent mesenteric lymph nodes,
53suggesting that in some XLAG patients infection may be responsible for these lesions.FIGURE 5.1 A and B, A chronic inflammatory disorder with fissuring necrosis and small intestinal
ulcers resembling Crohn disease occurs in some patients with X-linked agammaglobulinemia.
Granulomas are typically absent. (H&E stain.)
Patients with XLA G are at increased risk for malignancy, even in childhood. The most common malignancy in this
group is N HL, which often involves the GI tract, and many of these cases occur in children younger than 10 years of
54 54 5age. There are rare reported cases of gastric adenocarcinoma and colorectal adenocarcinoma. The increased
5incidence of colorectal carcinoma for patients with XLA G was calculated as 30-fold in one study, although other
46,55registry studies have reported few or no colorectal cancers in their patients with XLA G. I n most of the reported
cases, XLA G patients with colorectal carcinoma are young adults in their 20s who are seen with advanced-stage
5tumors. In one reported case, multiple colorectal adenomas in addition to carcinoma were found.
X-Linked Hyperimmunoglobuin M Syndrome
X-linked hyperimmunoglobulin M syndrome (XHI M) results from a mutation in the gene for CD 40 ligand, which
leads to loss of isotype switching. T cells from patients with this disorder lack the CD 40 ligand and therefore do not
interact with CD 40 on the B-cell surface, an event necessary for immunoglobulin class switching. These patients have
56very low levels of I gG and I gA and normal or elevated levels of I gM. They are susceptible to pyogenic infections
similar to those encountered in XLA G, and in addition ares usceptible to Pneumocystis carinii pneumonia. A variety of
intracellular pathogens such as mycobacterial species, fungi, and viruses (e.g., CMV, adenovirus) are implicated in
causing disease in these patients. The most common site of infection is the upper or lower respiratory tract
56 57,58(approximately 50% and 80% of cases, respectively). D isseminated infection and esophageal infection with
Histoplasma capsulatum are also reported in XHIM.
56,59D iarrhea occurs in one third to one half of patients and follows a chronic course in most. Chronic watery
diarrhea may be caused by Cryptosporidium infection; G. intestinalis, Salmonella, and Entamoeba histolytica have also
56been implicated, although in most patients no pathogen is identified. N LH involving the GI tract is reported in
59approximately 5% of patients. Lymphoid hyperplasia may also result in hepatosplenomegaly, lymphadenopathy,
60and enlargement of the tonsils. I BD was reported in two patients with XHI M and chronic diarrhea; clinical details
59were not provided. S clerosing cholangitis is a common and serious complication (affecting about 20% of European
59patients) and is often related to chronic infection with Cryptosporidium; liver transplantation may be necessary. I n
59one European series, three of five patients infected with hepatitis B developed hepatocellular carcinoma.
Patients with XHI M are prone to autoimmune hematologic diseases, including cyclic or chronic neutropenia, and
59oral and perianal ulcers are common during neutropenic episodes. Massive proliferation of I gM-producing plasma
61cells may involve the GI tract, liver, and gallbladder, usually in the second decade of life, and may prove fatal.
62-64High-grade neuroendocrine carcinoma of the colon has been reported in this disorder, and there is an increased
63incidence of liver and biliary tract tumors.
Hyperimmunoglobulin E Syndrome
A lso known as J ob syndrome, hyperimmunoglobulin E syndrome is a rare, multisystem disorder characterized by
65recurrent elevated serum I gE, eczema, and sinopulmonary infections. Three genetic etiologies have been66identified: loss of function of DOCK8 in the autosomal recessive form of the disorder, mutations in STAT3 in the
67 68more common autosomal dominant form, and a single reported case of Tyk deficiency. I n addition to findings
related to the immune system, characteristic facial features and dental and skeletal abnormalities occur in the
65autosomal dominant form, and severe viral cutaneous infections are seen in the autosomal recessive form. Chronic
diarrhea and disorders resembling I BD are not reported in hyper-I gE syndrome. GI manifestations of the disease
appear limited to mucocutaneous candidiasis, tissue-invasive fungal infections with Cryptococcus (reported in the
69 70 71,72esophagus and colon ), and ileocecal histoplasmosis mimicking Crohn disease. Perforation of the colon,
73probably related to infection with staphylococcal species, has also been reported, as well as diverticulitis in a young
74patient. Patients with hyper-IgE syndrome do not appear to be at increased risk for primary GI malignancy.
Common Variable Immunodeficiency
A lthough CVI D is not a common disorder, it is probably the most common symptomatic primary immunodeficiency.
Clinical and immunologic features are heterogeneous, but most patients are seen with recurrent bacterial infections,
usually involving the upper and lower respiratory tracts and leading to chronic lung disease and bronchiectasis.
Patients may be seen with CVI D at any age from infancy to late adult life, and males and females are equally affected.
Autoimmune manifestations such as thyroid dysfunction, pernicious anemia, autoimmune hemolytic anemia,
autoimmune thrombocytopenia, and rheumatoid arthritis are common, and granulomatous involvement of skin and
16-18visceral organs mimicking sarcoidosis may be seen in CVI D . Chronic GI disorders resulting in malabsorption
and weight loss occur in approximately 20% of patients with CVID.
CVI D is characterized immunologically by hypogammaglobulinemia involving multiple antibody classes. T-cell
abnormalities are common; below-normal proliferative responses to mitogens are found in 40% of patients, and 20%
18have a relative lack of CD 4+ T cells. The common abnormality shared by I gA deficiency and CVI D is failure of
terminal maturation of B lymphocytes into plasma cells producing various I g subtypes. A primary B-cell defect is
favored in many patients, but in others defective antigen responsiveness in helper T cells may be the underlying
basis for the disorder.
A genetic basis has long been suspected, based on the observation that familial inheritance of CVI D occurs in 20%
19of cases and that CVI D and I gA deficiency tend to occur in the same family; individual family members may
gradually convert from one disorder to the other. I n multiple-case families, CVI D is often present in the parents and
I gA deficiency in the offspring, consistent with the hypothesis that CVI D may develop later in life as a more severe
manifestation of a common defect involving immunoglobulin class switching. S tudies of isotype switching led to the
discovery that the gene TNFRSF13B, which encodes the member of the TN FR family, TA CI , is mutated in
20approximately 10% to 15% of patients with CVI D and 5% of patients with I gA deficiency. TA CI has also been
shown to induce apoptosis in B cells, and this may be the basis for the susceptibility of patients with TA CI mutations
20to autoimmune and lymphoproliferative disorders. N ew gene defects in BAFFR (TNFRSF13C) , CD81, and CD20
21(now called MS4A1) resulting in a CVI D phenotype have been described in small numbers of patients,
underscoring the genetic heterogeneity of this disorder, and genome-wide association studies have identified
numerous candidate causative genes, as well as a strong association of CVI D with the major histocompatibility
22region.
Patients with CVI D are at particular risk for chronic inflammatory disorders and malignancies affecting the GI
tract. The inflammatory disorders may represent a response to acute or chronic infection, but in some patients the GI
23lesions are probably a manifestation of autoimmunity and are associated with other disorders of autoimmunity. I n
one large clinical study of patients with CVI D , 22% had one or more autoimmune diseases, most commonly
18idiopathic thrombocytopenia purpura (6%) and autoimmune hemolytic anemia (5%).
Infections in CVID
Chronic infection with G. intestinalis is a common problem in patients with CVI D and may or may not cause clinical
symptoms. I n some cases, malabsorption, steatorrhea, and villous abnormalities can be reversed if Giardia is
eradicated. S mall bowel mucosal abnormalities in giardiasis include villous blunting, increased intraepithelial
lymphocytes, and N LH. The trophozoite form of the organism can be identified on small bowel biopsy F( ig. 5.2). The
prevalence of Giardia infection in this population appears to be decreasing, but giardiasis remains a significant cause
15of chronic diarrhea in CVID.FIGURE 5.2 Giardiasis. Numerous trophozoites in varying orientations are closely associated
with the surface of this small bowel biopsy specimen from a patient with common variable
immunodeficiency. The underlying epithelium is normal. (Hematoxylin and eosin [H&E] stain.)
Other GI infections are less common in CVI D . Cryptosporidiosis is occasionally found. The prevalence of common
bacterial intestinal infections (e.g., Salmonella, Campylobacter) does not appear to be increased. A lthough prolonged
15antibiotic use is common in these patients, an increase in pseudomembranous colitis has not been reported. On
occasion, viral and fungal organisms infect the GI tract in CVI D patients, but such infections are less common in
CVI D than in acquired immunodeficiency syndrome (A I D S ). Cytomegalovirus (CMV) infection involving the
esophagus, stomach, jejunum, and ileocecal area and resulting in multiple ulcers and obstructing strictures has been
15reported in a patient with CVID.
Inflammatory Disorders and Malignancy in CVID
Stomach
I n the stomach, a nonspecific increase in lamina propria lymphocytes is seen in some patients with CVI D F( ig. 5.3,
23,24A); increased apoptosis of gastric epithelial cells is present in some cases (see Fig. 5.3, B). I n a study of gastric
biopsies from 34 patients with CVI D and dyspepsia, 41% of patients were infected withH elicobacter pylori. A ll H.
pylori–positive patients and 20% of H . pylori–negative patients had chronic gastritis, and 50% of those infected with
H . pylori had multifocal atrophic gastritis. Ten percent of H . pylori–negative patients had multifocal atrophic
25gastritis. Atrophic gastritis resembling autoimmune atrophic gastritis on clinical and morphologic grounds (see
Fig. 5.3, C) and resulting in pernicious anemia may occur in the absence of demonstrable anti–parietal cell antibodies
in these patents. Atrophic gastritis may develop at a very young age in patients with CVI D , and it has been reported
26in a 6-year-old who developed multifocal gastric adenocarcinoma at age 11.FIGURE 5.3 A, In common variable immunodeficiency (CVID), the gastric mucosa often contains
a nonspecific mononuclear cell infiltrate. B, Notice the apoptotic body (arrow) and the absence of
plasma cells. C, Loss of gastric glands leads to atrophic gastritis at a young age in patients with
CVID. Loss of parietal cells results in pernicious anemia and may occur in the absence of
antiparietal cell antibodies. (H&E stain.)
A dults with CVI D are also at increased risk for gastric adenocarcinoma. I t has been estimated that patients with
27CVI D have a 47-fold increase in gastric carcinoma compared with the general population of Great Britain, and
gastric carcinoma ultimately develops in 5% to 10% of CVI D patients, usually many years after the onset of
hypogammaglobulinemia.
Small Bowel
I n the small bowel, a sprue like lesion with villous blunting occurs in some patients with CVI D and is associated with
severe malabsorption, often requiring parenteral nutrition. Villous atrophy associated with CVI D generally lacks the
degree of crypt hyperplasia seen in celiac disease (Fig. 5.4, A), but may be indistinguishable on biopsy. I n general, the
lamina propria inflammatory infiltrate is not as prominent as in celiac disease, and enterocyte maturation is normal,
23with preservation of the brush border. Most CVI D patients with this small bowel lesion do not respond to a
gluten28free diet, although an elemental diet may be beneficial, and most respond to corticosteroids, at least initially.
Plasma cells are absent or are found only in very small numbers in the lamina propria. S urface intraepithelial
lymphocytes are often markedly increased (see Fig. 5.4, B), even in the absence of villous atrophy. I n some cases, an
increase in apoptotic bodies is found in crypt epithelial cells (see Fig. 5.4, C). Clinical autoimmune enteritis with loss
24of goblet cells has also been reported.FIGURE 5.4 A, Villous atrophy associated with common variable immunodeficiency (CVID) may
be severe and may lead to profound malabsorption. Notice the relatively sparse inflammatory
infiltrate. 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. (H&E stain.)
Granulomatous enteropathy has also been reported in patients with CVI D and may be associated with protracted
diarrhea unresponsive to antibiotic therapy. Poorly formed non-necrotizing granulomas are found in the lamina
24,29propria in multiple sites in the GI tract, including the stomach, small intestine, and colon ; the diarrhea usually
resolves with intravenous immunoglobulin therapy.
N LH in the GI tract is characterized by multiple discrete hyperplastic lymphoid nodules in the lamina propria and
submucosa of the small intestine (Fig. 5.5), 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 scaKered tingible body
macrophages; the mantle zones contain mature and immature B cells, and the extramantle zones contain a mixture of
cell types including B cells, T cells, and macrophages. N LH is found in as many as 60% of patients with CVI D but
may be seen in the seKing of giardiasis without antibody deficiency. I n contrast to N LH in CVI D patients, plasma
cells are present in the extramantle zones in nonimmunodeficient patients. N LH is not considered a malignant
disorder. However, malignant lymphomas of the GI tract in patients with immunodeficiencies often arise in a
background of N LH, and clonal immunoglobulin gene rearrangement has been demonstrated in N LH in the GI tract
30of a child with CVI D . Consistent with these observations, the most common malignancy in CVI D is N HL, which
18affects approximately 8% of patients ; these lymphomas often originate in extranodal sites, with small bowel the
most common GI site. Most of these lymphomas are of B-cell origin; they include diffuse large B-cell lymphoma
18(DLBCL) and follicular lymphoma.FIGURE 5.5 A, Nodular lymphoid hyperplasia in common variable immunodeficiency. Numerous
small mucosal and submucosal nodules are present. B, Most of the lymphoid nodules contain
enlarged germinal centers. Overlying villi are slightly distorted. (H&E stain.)
Chronic inflammatory processes involving small or large bowel that are clinically similar to I BD develop in some
patients with CVI D . I n some patients, the small bowel is the primary site of involvement and the lesions resemble
Crohn disease, with transmural inflammation and small bowel obstruction. Granulomas usually are not present in
31these Crohn disease-like disorders.
Large Bowel
The colitis occurring in CVI D is variable in morphology. I n some patients, the inflammatory process is limited to the
colon and clinically mimics ulcerative colitis. Mucosal architectural distortion with crypt destruction is present,
although crypt distortion is less pronounced than in most cases of ulcerative colitis, with less crypt branching (Fig.
5.6, A). N eutrophils are present in the lamina propria and crypt epithelium (see Fig. 5.6, B). I n contrast to ulcerative
colitis, plasma cells are not present in the lamina propria in CVI D -associated colitis, and an increase in CD 8+ T cells
32(compared with normal controls and those with I BD ) has been reported in the colon of CVI D patients. I n some
cases, the crypt destruction and mucosal distortion is accompanied by increased apoptosis, and the histology is
23,24similar to that of colonic graft-versus-host disease (GVHD ). Milder cases of colitis in CVI D may resemble
33lymphocytic colitis, characterized by increased intraepithelial lymphocytes and minimal mucosal distortion, and an
34atypical form of collagenous colitis with pseudomembranes has been reported in one patient. The etiology and
pathogenesis of colitis in these patients remain largely unknown. The association of chronic GI inflammatory
disorders and autoimmune disorders in these patients, and the resemblance of the lesions to other disorders of
immune dysregulation, imply that the colitis of CVID may be autoimmune in origin.FIGURE 5.6 Colitis in common variable immunodeficiency may mimic inflammatory bowel
disease, with crypt distortion and loss. A, The inflammatory infiltrate is relatively sparse in some
cases, compared with ulcerative colitis, and plasma cells are not present. B, Notice crypt shortfall
and infiltration of crypts by acute inflammatory cells (acute cryptitis).
A denocarcinoma of the colon is reported in young patients with CVI D . S mall cell neuroendocrine carcinoma of the
35cecum was reported in a 16-year-old boy, who died of liver metastases 5 months after diagnosis. I n another case, 9
36adenocarcinomas and 20 adenomas were present synchronously in the colon of a 22-year-old man with CVID.
Combined Cellular/Humoral Immunodeficiencies
Severe Combined Immunodeficiency
S evere combined immunodeficiency (S CI D ) is a heterogeneous group of congenital disorders characterized by
defects in both B- and T-cell function. Children with S CI D typically are seen in the first year of life with severe
recurrent bacterial or viral infections. A number of molecular defects may result in S CI D . Most are autosomal
recessive, including adenosine deaminase deficiency, which accounts for 50% of autosomal recessive S CI D ; purine
75nucleoside deficiency; T-cell receptor deficiencies; Zap70 deficiency; J A K3 deficiency; and I L-7 receptor deficiency.
However, X-linked S CI D , resulting from a defect in the common γ chain, is the single most common type of S CI D in
76the United States. I t has a characteristic phenotype of absence of T cells and natural killer (N K) cells but normal
Bcell numbers, although the B cells are dysfunctional.
GI disorders in S CI D are caused by a variety of infectious pathogens. Oral, esophageal, and perianal candidiasis is
common, and profound diarrhea may develop in children with S CI D early in life. I n general, GI biopsy specimens
from these patients show a 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. I n particular, rotavirus,
normally a self-limited infection, may cause chronic diarrhea in these children. A lthough villous blunting has been
51 77described in acute rotavirus infection in normal children and in animal models, the intestinal pathology of
chronic rotavirus infection has not been described in S CI D patients. Cytopathic viral infections that may be
identified on GI biopsy include CMV and adenovirus F( ig. 5.7). Salmonella may also cause chronic GI infection in
S CI D patients. Patients receiving nonirradiated blood products or allogeneic bone marrow transplants are
susceptible to GVHD . Furthermore, a GVHD -like process affecting the colon and small intestine has beedne scribed
78,79in patients with S CI D who had not undergone bone marrow transplantation. Children with S CI D may be a
80greater risk for reflux esophagitis than the normal population.FIGURE 5.7 A, Disseminated adenovirus may involve the gastrointestinal tract in patients with
severe combined immunodeficiency. Here, the small bowel crypts are involved; in less severe
cases, inclusions may be identified only in surface mucosa. B, With adenovirus, infected cells are
typically not enlarged. Classic “smudge cells” with homogeneous nuclear staining are shown.
(H&E stain.)
Omenn Syndrome
Omenn syndrome is an autosomal recessive type of S CI D with clinical and pathologic features of GVHD . The
immunologic hallmark of the disease is expansion of an oligoclonal population of T cells and a near absence of B
76cells. I nfants with Omenn syndrome are seen with diffuse erythroderma, hepatosplenomegaly, lymphadenopathy,
81and failure to thrive ; chronic diarrhea and alopecia are common. Hypereosinophilia and hypogammaglobulinemia
are characteristic. Paradoxically, serum I gE levels are increased, although B lymphocytes are not detectable in the
circulation, lymph nodes, or skin. A ctivated circulating T cells are normal to increased in number but constitute an
oligoclonal population. The underlying basis for these findings in Omenn syndrome is impairment but not complete
loss of the V(D )J recombination process as a result of mutations inR AG1 or RAG2, the recombination activating
76 − −genes. Mutations in these genes were first identified in a subset of S CI D patients with TB S CI D . The occurrence
of this type of S CI D and Omenn syndrome in the same kindred furnished the clue that Omenn syndrome was caused
− −by mutations in the same genes. D ifferences between T B S CI D and Omenn syndrome can be explained by the
presence of two entirely defective alleles in S CI D and the presence of one marginally functional allele that is capable
of establishing the oligoclonal T-cell population in patients with Omenn syndrome. I nfants with S CI D with maternal
82T-cell engraftment may exhibit GVHD symptoms indistinguishable on clinical grounds from Omenn syndrome,
and a diagnosis of Omenn syndrome depends on excluding this possibility by appropriate human leukocyte antigen
typing or molecular analysis. Published accounts of the histopathologic changes in Omenn syndrome are scant, but
83,84skin changes resemble those of GVHD , and numerous apoptotic crypt cells are found in colonic biopsies in a
paKern similar to that of GVHD (unpublished observations). Crypt injury and an increase in lamina propria
eosinophils may also be seen (Fig. 5.8).FIGURE 5.8 Omenn syndrome. Focal crypt destruction with a localized increase in lamina
propria eosinophils is seen. (H&E stain.)
Other Primary Immunodeficiencies
DiGeorge Syndrome
D iGeorge 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
85 86common microdeletion syndrome in humans, and is estimated to affect 1 of every 4000 live births. T cells are
markedly reduced in number, but B cells are normal in number and functionality. Midline anomalies affecting the GI
tract (e.g., esophageal atresia, imperforate anus) are seen in some cases in association with D iGeorge syndrome, and
87water diarrhea and malabsorption have been described but not well characterized. Oral candidiasis is common.
88Dysphagia and feeding difficulties have been reported in infants with 22q11.2 deletion.
Chronic Mucocutaneous Candidiasis
Chronic mucocutaneous candidiasis is a heterogeneous 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 more than 50% of patients. There is a high
89frequency of association with thymoma and systemic lupus erythematosus. Mutations in STAT1 have been
90,91identified in the autosomal dominant form of the disease, and the autosomal recessive form has been linked to
92deficiency in interleukin-17 receptor A . I mmune defects include disorders of T-cell immunity with variable B-cell
involvement. The most common GI manifestation is esophageal candidiasis. A lthough superficial infection with
93Candida is a defining characteristic, infections with other fungi (e.g., H. capsulatum) and bacteria are common.
Wiscott-Aldrich Syndrome
WiskoK-A ldrich syndrome, characterized by early onset of profound thrombocytopenia with small platelets, eczema,
and recurrent infections, is inherited as an X-linked recessive disease. Platelets and T cells are most severely affected.
The genetic basis of WiskoK-A ldrich syndrome, described in 1994, is a mutation of the WASP gene, which encodes an
94intracellular protein expressed exclusively in hematopoietic cells. This protein is involved in transduction of signals
from cell surface receptors to the actin cytoskeleton and is important in cytoskeletal architecture and cell trafficking
87and motility. D iarrhea is reported in patients with this disorder but has been poorly characterized. Bloody diarrhea
in these patients is often aKributed to thrombocytopenia, and biopsies may not be performed because of the risk of
hemorrhage. A Crohn's disease-like inflammatory process with cobblestone appearance and inflammatory
95pseudopolyps involving the descending and transverse colon has been reported in WiskoK-A ldrich syndrome.
96Massive hemorrhage from aneurysms involving the liver, small bowel mesentery, and kidney has been reported.
Chronic Granulomatous Disease
I n 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 reduced nicotinamide
adenine dinucleotide phosphate (N A D PH) oxidase. The most common form of the disease, accounting for 70% of
97cases, is X-linked recessive; four other forms are autosomal recessive. A s a result of this defect, patients with CGD
suffer from recurrent bacterial and fungal infections; abscesses in a variety of sites and pneumonia are common.
They are also prone to develop inflammatory and rheumatic diseases, such as an I BD -like condition and a lupus-like
syndrome. GI manifestations are relatively rare in CGD , but reported cases can be broadly grouped into obstructive
and inflammatory categories.
Obstruction can occur in patients with CGD at a number of levels of the GI tract, from esophagus to small bowel.
97Gastric outlet obstruction is more common in the X-linked form of the disease. I n some cases, the obstruction is
caused by infiltration of the viscus wall by pigment-laden macrophages (the histologic hallmark of CGD ) or bygranulomatous inflammation. I n other cases, the obstruction is reportedly secondary to a functional disturbance in
GI motility, although infiltration of the deep layers of the organ by macrophages often cannot be excluded.
97Esophageal obstruction occurs in 1% of CGD patients ; biopsies of the esophageal mucosa usually show nonspecific
98findings or reflux esophagitis but may demonstrate pigmented macrophages. I nvolvement of the gastric antrum
and pylorus is somewhat more common, occurring in 16% of patients, and gastric outlet obstruction may be the first
manifestation of CGD . Granulomas, giant cells, and macrophages laden with brown-yellow fine pigment are
99 100commonly present in gastric biopsy specimens, but in some cases only nonspecific inflammation is seen. S mall
101bowel obstruction is relatively rare in CGD but is occasionally reported in the context of an inflammatory process.
I n a review of small bowel and rectal biopsies from nine patients with CGD , pigment-laden macrophages were found
in the lamina propria at both sites. I n the small bowel, the macrophages were located deep in the mucosa adjacent to
crypts, but when numerous, they also extended into the villus core (Fig. 5.9). I n rectal biopsies, the number of
pigmented histiocytes was quite variable, ranging from rare scaKed cells to large numbers of histiocytes
accumulating between the base of the crypts and the muscularis mucosae. Granulomas with giant cells were also
present in rectal biopsies from some patients. I n one of eight cases, distortion of crypt architecture without crypt
102abscesses was seen.
FIGURE 5.9 Chronic granulomatous disease. Accumulation of pigmented macrophages
containing light brown, dusky material in the small intestinal mucosa is seen. (H&E stain.)
Chronic inflammatory processes that are indistinguishable from I BD affecting the small and large bowel may
103occur in CGD patients ; as with obstructive lesions of the GI tract, these lesions are more common in the X-linked
97form of the disease. Polymorphisms in genes unrelated to N A D PH oxidase may modify the clinical phenotype in
CGD ; certain polymorphisms in the genes for myeloperoxidase and Fcγ receptors are strongly associated with GI
104complications. I nvolvement of the small bowel in CGD may produce fistulas, longitudinal ulcers, stenosis, and
105non-necrotizing granulomatous inflammation that can be mistaken for Crohn disease ; discontinuous
106inflammation and perianal disease may also contribute to the difficulty in distinguishing the two entities. The
granulomas seen in intestinal lesions in CGD are often more florid than is usually seen in Crohn disease, but
granulomas are not present in all cases. I n a study of colitis in one CGD patient, the presence of an acute and chronic
inflammatory infiltrate confined to the colonic mucosa, crypt abscesses, and lack of granulomas were more
suggestive of ulcerative colitis than Crohn disease. Mucosal architectural distortion and ulceration were not as
prominent as is usually the case in ulcerative colitis, however, and pigmented macrophages were present in the
103lamina propria.
Miscellaneous Immune Deficiency Syndromes
Other rare disorders of immunity occasionally associated with GI manifestations includel eukocyte adhesion deficiency,
in which delayed wound healing and susceptibility to bacterial and fungal infection lead to necrotizing
107enterocolitis. A chronic inflammatory process with multiple aphthous ulcers involving the gastric antrum,
terminal ileum, cecum, and right colon, which resolved with bone marrow transplantation, has also been reported in
108leukocyte adhesion deficiency, and a case of rectal ulcer resembling Crohn disease has been reported in a109pediatric patient.
I mmune dysregulation, polyendocrinopathy, and enteropathy, X-linked (I PEX) syndrome, caused by mutations in
FOXP3, usually manifests in affected males with severe watery diarrhea early in life. The entire GI tract may be
involved and primarily shows GVHD -like histologic changes with prominent crypt apoptosis F( ig. 5.10). S mall bowel
110,111disease with villous atrophy mimicking celiac disease has also been reported in IPEX.
FIGURE 5.10 The GI tract in immune dysregulation, polyendocrinopathy, and enteropathy,
Xlinked syndrome shows graft-versus-host disease–like changes with villous injury (A), and
prominent apoptotic bodies (B, arrow). (H&E stain.)
Graft-versus-Host Disease
GVHD , most commonly involving GI tract, skin, or liver, develops in as many as 50% of allogeneic bone marrow
112transplant recipients. I ndeed, the most common cause of persistent nausea and anorexia in patients beyond day
11320 after transplantation is acute GVHD . Changes identical to those seen in GVHD after allogeneic transplantation
may be seen in the GI tract and liver after autologous stem cell transplantation and are considered to be a form of
GVHD resulting from a lack of regulation of immune mechanisms by the reconstituting immune system. This
syndrome of acute GVHD –like changes in the GI tract after autologous transplantation is rare, occurring in gastric
114biopsies in only 4% of patients with upper GI tract symptoms and approximately 5% of all autologous
115 116transplantation patients. Rarely, GVHD occurs after solid organ transplantation or blood transfusion.
S ymptoms indicative of GI tract involvement by GVHD include profuse diarrhea, crampy abdominal pain, GI
117hemorrhage, anorexia, nausea, and vomiting. Severe GI bleeding and peritonitis are also reported.
Historically, acute GVHD has been defined as occurring less than 100 days after myeloablative stem cell
transplantation. However, current clinical practices in stem cell transplantation have rendered this classification
inadequate, because the use of reduced-intensity regimens, for instance, has led to late occurrence of otherwise
typical acute GVHD . A ccordingly, recommendations for classification of GVHD as acute or chronic have been
118developed by an expert panel convened by the N ational I nstitutes of Health (Table 5.5). Characteristic skin, GI
tract, or liver abnormalities are now classified as acute GVH D regardless of time after transplantation. D iagnosis of
chronic GVH D requires the presence of at least one diagnostic clinical sign or distinctive clinical manifestation
confirmed by biopsy or other relevant tests in the same or another organ. I n the GI tract, the presence of an
esophageal web, stricture, or concentric rings documented by endoscopy or barium contrast radiography is sufficient
to establish the diagnosis of chronic GVHD . D istinctive criteria that are, by themselves, insufficient to establish a
diagnosis of chronic GI GVHD include pancreatic exocrine insufficiency, anorexia, nausea, vomiting, diarrhea, weight
118loss, and wasting syndrome.Table 5.5
Classification of Graft-versus-Host Disease
Time ofClassification Features
Onset
“Classic” acute GVHD ≤100 days Maculopapular rash, nausea, vomiting, anorexia, profuse diarrhea, ileus, or
after cholestatic hepatitis
HSCT
Persistent, recurrent, >100 days Same as “classic” acute GVHD, without diagnostic or distinctive
or late acute GVHD after manifestations of chronic GVHD; often seen after withdrawal of
HSCT immunosuppression
“Classic” chronic No time At least one diagnostic or distinctive manifestation of chronic GVHD without
GVHD limit features characteristic of acute GVHD
Overlap syndrome of No time Features of acute and chronic GVHD appear together
acute and chronic limit
GVHD
GVHD, Graft-versus-host disease; HSCT, hematopoietic stem cell transplantation.
Acute GVHD
On endoscopic examination, the appearance of the GI mucosa in acute GVHD is variable, ranging from only mucosal
119edema and erythema to more severe changes such as ulcers and mucosal sloughing. The major histologic features
of GVHD in the GI tract are epithelial cell apoptosis and a relatively sparse mononuclear inflammatory cell infiltrate
(Fig. 5.11, A). A poptotic epithelial cells are found primarily in the regenerative compartment of the mucosa, such as
the crypt in the colon and small intestine and the neck area of gastric glands. I n the colon, the apoptotic cells are
particularly conspicuous and are termed “exploding crypt cells”; these cells contain intracytoplasmic vacuoles filled
with karyorrhectic nuclear debris (see Fig. 5.11B). A poptotic cells are smaller and less conspicuous in the gastric
mucosa (Fig. 5.12). I n more severe cases of acute GVHD , crypt abscesses may be seen, and destruction and loss of
crypts is seen. I n the most severe cases, mucosal sloughing and extensive ulceration occur. I n the stomach, granular
120eosinophilic necrotic cellular debris without neutrophils may be present in the lumina of injured gastric glands.
Villous blunting is commonly seen in small bowel GVHD . A grading system for acute GVHD affecting the colon has
121been proposed (Fig. 5.13 and Table 5.6); however, correlations with clinical symptoms and patient outcome are
weak.
FIGURE 5.11 Acute graft-versus-host disease (GVHD) involving colon. A, The lamina propria
inflammatory infiltrate is relatively sparse; no crypt loss is seen in this example, although crypts
are slightly distorted. B, Large apoptotic bodies known as “exploding crypt cells” are typical of
colonic GVHD.FIGURE 5.12 A, In the gastric body, dilated glands containing granular eosinophilic debris are
sometimes found in acute graft-versus-host-disease (GVHD). B, As in the colon, the inflammatory
infiltrate is relatively sparse. C, Apoptotic bodies in glandular epithelium are often small and
inconspicuous in acute GVHD in the stomach. (H&E stain.)
FIGURE 5.13 A, An example of grade I acute graft-versus-host-disease (GVHD) in the colon,
consisting of scattered single-cell apoptotic epithelial cells. B, Grade II acute GVHD showing
epithelial apoptosis, crypt atrophy, and crypt abscesses. C, Grade III acute GVHD with loss of
contiguous crypts. D, Grade IV acute GVHD with replacement of mucosa by loose granulation
tissue. (H&E stain.)Table 5.6
Grading of Acute Graft-versus-Host Disease of the Colon
Grade Histologic Features
I Rare apoptotic cells, without crypt loss
II Loss of individual crypts
III Loss of two or more contiguous crypts
IV No identifiable crypts (mucosal ulceration)
Data from Villa A, Notarangelo LD, Roifman CM. Omenn syndrome: inflammation in leaky severe combined
immunodeficiency. J Allergy Clin Immunol. 2008;122:1082-1086.
The changes that occur in the GI tract in acute GVHD are not entirely specific. The differential diagnosis includes
drug-related injury, infection, recurrent hematologic malignancy, and other causes of immune activation (Table 5.7).
I n particular, mycophenolate mofetil (MMF) treatment may cause active colitis with ulcers, marked crypt cell
122apoptosis, and a mixed lamina propria inflammatory infiltrate that can mimic GVHD (Fig. 5.14). Other reported
123paKerns of injury include I BD -like changes and, more rarely, ischemic colitis. N ormal biopsy findings in sites
124distant from these GVHD -like lesions should raise the question of MMF-associated colitis rather than GVHD ;
improvement after discontinuation of MMF is also good evidencet hat the injury was drug related. Use of proton
pump inhibitor (PPI ) therapy has been associated with an increase in apoptotic epithelial cells in the gastric mucosa
125(Fig. 5.15), mimicking the histologic changes seen in GVHD.
Table 5.7
Differential Diagnosis of Graft-versus-Host Disease
Diagnosis (Ref. No.) Features Comments
Conditioning Epithelial cell apoptosis; Found in early period after transplantation (up to day 20);
regimen158 increased mitotic activity; severe injury at day 20 likely represents GVHD, because
crypt cell regeneration effects of chemotherapy and radiation are typically
improving by then
Cytomegalovirus159 Increased epithelial cell May occur concomitantly with gastrointestinal GVHD
apoptosis; nuclear
inclusions may be sparse
160 Increased epithelial cell Rarely encountered in biopsies in HSCT populationCryptosporidium
apoptosis
Mycophenolate Colitis with increased crypt cell Apoptotic bodies in sites other than colon are suggestive of
mofetil161 apoptosis, focal ulcers, GVHD
mixed lamina propria
inflammatory infiltrate
Proton pump Increased epithelial cell Biopsy of oxyntic mucosa may be more informative than
inhibitors162 apoptosis in gastric antral antral mucosa in patients receiving PPI therapy
mucosa, without
inflammation
Cord colitis Chronic active colitis with crypt Described in patients undergoing umbilical cord blood
syndrome131 distortion; granulomas in stem cell transplantation; response to antibiotics
some cases suggests infectious etiology
GVHD, Graft-versus-host disease; HSCT, hematopoietic stem cell transplantation; PPI, proton pump inhibitor.FIGURE 5.14 Mycophenolate mofetil–induced colitis. Prominent crypt cell apoptosis and
relatively sparse mononuclear inflammatory infiltrate in the lamina propria may mimic
graft-versushost-disease (GVHD). (H&E stain.)
FIGURE 5.15 Increased gastric epithelial cell apoptosis (arrow) has been associated with
proton pump inhibitor (PPI) use. Notice the apical cytoplasmic protrusions in parietal cells, typical
of the PPI effect. (H&E stain.)
79Changes similar to GVHD are reported in colonic biopsies from patients with severe T-cell deficiencies,
126 23,24malignant thymoma, and primary immune disorders such as CVI D . I n the patient who has undergone bone
marrow transplantation, the effects of cytoreductive therapy (Fig. 5.16) may resemble changes of GI GVHD in the
early posKransplantation period; therefore, a diagnosis of GVHD must be made with caution before day 21 after
transplantation. Recurrence of hematologic malignancies, particularly acute lymphoblastic leukemia, may also mimic
127acute GVHD. CMV infection may produce mucosal damage characterized by apoptotic epithelial cells, mimicking
120GVHD ; differentiation from GVHD relies on the demonstration of viral inclusions. GVHD and CMV infection may
occur simultaneously, making it difficult to separate the effects of each process on the GI tract. I nfection with
Clostridium difficile has also been reported to be associated with GI GVHD and a high nonrelapse mortality rate in
128this group; it is postulated that C. difficile toxin may predispose to increased severity of GVHD.
FIGURE 5.16 Pretransplantation cytoreductive therapies can injure gastrointestinal mucosa,
resulting in increased apoptotic bodies, seen here in the colon, that mimic graft-versus-host
disease. (H&E stain.)Chronic GVHD
Chronic GVHD is clinically similar in many ways to some of the collagen vascular diseases and has been compared to
autoimmune disorders such as scleroderma, S jögren syndrome, and primary biliary cirrhosis. Chronic GVHD
involves multiple organs, such as salivary gland, mouth, eye, and upper respiratory tract, that are not involved by
120acute GVHD.
I n chronic GVHD , skin changes of dermal fibrosis may resemble scleroderma, and involvement of the oral
squamous mucosa leads to painful ulcers and submucosal fibrosis. I nvolvement of minor salivary glands results in
an oral sicca syndrome. I n advanced cases, ulcers and submucosal fibrosis occur in the esophagus (Fig. 5.17), the
124most commonly affected site in the GI tract. S mall bowel involvement is less common; when present, it is
associated with diarrhea. Focal fibrosis of the lamina propria and segmental submucosal fibrosis, with minimal
129mucosal changes, has been reported. I n colonic biopsies, chronic colitis similar to that seen in ulcerative colitis
130has also been reported in allogeneic bone marrow transplant recipients. These changes consist of mild to
moderate crypt distortion and crypt atrophy, and it is unclear whether the mucosal architectural distortion is caused
by chronic GVHD or by other factors. I n one study, similar findings of mild chronic active colitis, with granulomas in
some cases (Fig. 5.18), were reported in 10% of patients undergoing umbilical cord blood stem cell transplantation,
occurring 88 to 314 days after transplantation. A lthough patients were culture negative, this “cord colitis syndrome”
131responded to antibiotic therapy, suggesting an infectious etiology.
FIGURE 5.17 Nonspecific ulcers with submucosal fibrosis may be seen in the esophagus in
patients with chronic graft-versus-host syndrome. (H&E stain.)
FIGURE 5.18 Increased crypt cell apoptosis (A) and loose non-necrotizing granulomas (B) may
be seen in “cord colitis syndrome” occurring after umbilical cord blood stem cell transplantation.
(H&E stain.) (Courtesy of Dr. Jason Hornick, Brigham and Women's Hospital, Boston, Mass.)
Neutropenic Enterocolitis
N eutropenic enterocolitis (N EC) is a necrotizing inflammatory process that predominantly affects the cecum,
terminal ileum, and ascending colon and occurs most commonly in the seKing of neutropenia. Hemorrhagic necrosis
of the cecum in this seKing has also been termed typhlitis. Historically, most patients with N EC have had acute
leukemia, although N EC is has also been reported in patients undergoing stem cell or autologous bone marrow
132transplantation for solid malignancies. N EC also occurs in patients with aplastic anemia, renal transplant
recipients, and those with other hematologic malignancies. I ncidence varies from less than 1% to almost 7% in
133,134 132children with cancer, with a pooled incidence of about 5% in adult patients. Most patients have received135 3chemotherapy in the previous 30 days, and absolute neutrophil counts of less than 1500 cells/mm are associated
with the disease. Patients may be seen with clinical features suggestive of acute appendicitis, such as fever and right
136 135lower quadrant pain. One third are seen with GI hemorrhage, and rarely a palpable right lower quadrant mass
is present. The combination of abdominal pain, diarrhea, and fever is the most common presentation; diagnosis is
often established by radiographic studies showing a fluid-filled, dilated cecum and inflammatory changes in the
136abdomen.
On gross examination, the cecum and other affected portions of the GI tract are dilated, edematous, and congested
or hemorrhagic. Pneumatosis intestinalis (Fig. 5.19, A) may be seen but is relatively rare. The mucosa is hemorrhagic,
often necrotic, and covered with granular eosinophilic debris; no significant inflammatory reaction is present (see
Fig. 5.19, B). The pathogenesis of this disorder is initiated with mucosal injury, primarily related to recent
administration of chemotherapeutic agents and augmented by neutropenia. Bacterial invasion of the injured mucosa
then occurs, with Clostridium spp. implicated as major offenders; fungi such as Candida spp. have also been
implicated as causative or contributing agents. Toxins produced by organisms invading the gut wall lead to edema
and necrosis. D istention of the bowel wall leads to decreased blood flow, adding an element of ischemic injury. Most
patients become septicemic. I f N EC is left untreated, the prognosis is grave, but patients may survive with optimal
medical and surgical management; recovery depends on the restoration of adequate neutrophil counts.
FIGURE 5.19 Neutropenic enterocolitis. A, Clear spaces in the bowel wall represent
pneumatosis coli. The mucosa is necrotic, hemorrhagic, and lacks a significant inflammatory
response. B, Sloughed epithelium is seen in the lumen. (H&E stain.)
The Gastrointestinal Tract in HIV Infection
GI illnesses are common in human immunodeficiency virus (HI V)-infected patients, with diarrhea, nausea, vomiting,
anorexia, and abdominal pain as presenting symptoms. Before the use of new, highly active antiretroviral therapy
(HA A RT), opportunistic infections with such pathogens asI sospora, Mycobacterium avium-intracellulare complex
(MA C), microsporidia,C ryptosporidium, and CMV were frequent causes of diarrhea, malabsorption, and wasting
(Table 5.8). A lthough the prevalence of intestinal pathogens has dramatically decreased since then, from a reported
85% (in men with A I D S and diarrhea) to 12% (found almost exclusively in homosexual men), current studies
continue to show a high prevalence of GI dysfunction in HI V-infected patients. Chronic diarrhea is reported in
137approximately 25% of HIV patients and was not associated with degree of immune suppression in one cohort.Table 5.8
HIV-Associated Gastrointestinal Diseases
Infection Neoplasia
Giardia intestinalis Kaposi sarcoma
Cryptosporidium parvum Burkitt lymphoma
Isospora belli Diffuse large B-cell lymphoma
Microsporidia Plasmablastic lymphoma
Cytomegalovirus Anal squamous cell carcinoma
Candida albicans Hodgkin lymphoma
Listeria monocytogenes
Strongyloides stercoralis
Human herpesvirus 8
Epstein-Barr virus
HIV, Human immunodeficiency virus.
Infections
CMV remains the most common pathogen in HI V-infected patients, and CMV infection can involve any segment of
the GI tract, most commonly the esophagus and colon. CMV esophagitis often manifests with distal esophageal
ulceration. CMV primarily infects endothelial cells, followed by macrophages; biopsy specimens obtained from the
ulcer bed are, therefore, more likely to demonstrate characteristic CMV cytopathic effects. Endoscopic features in
CMV gastritis include patchy erythema, erosions, or multiple small ulcers. Unlike other sites in the GI tract, in the
stomach the epithelial cells are preferentially infected. CMV colitis can manifest as colitis with or without ulcers. A s
in the esophagus, characteristic CMV inclusions can be seen in stromal and endothelial cells.
A lthough GI herpes simplex virus (HS V) infection occurs less frequently than CMV infection, approximately 5% of
138esophageal ulcerative lesions in HI V-infected patients are caused by HS V infection. HS V esophagitis can manifest
as either vesicular or ulcerative lesions. Unlike CMV esophagitis, HSV characteristically infects squamous epithelium.
One of the important differential diagnoses for CMV and HS V esophagitis in HI V-infected patients is idiopathic
esophageal ulcer. HI V patients with idiopathic esophageal ulcer always are seen with severe odynophagia and weight
139loss, which often respond to therapy with corticosteroid or thalidomide or both. Endoscopically, HI V-associated
idiopathic esophageal ulceration appears as large, irregular ulcers in the middle or distal esophagus. To diagnose
idiopathic esophageal ulcer, exclusion of infectious etiologies is required.
Bacterial pathogens involving the GI tract in the HI V-positive population includeC . difficile, mycobacteria, and
spirochetes. C. difficile–associated colitis is the most common cause of bacterial diarrhea in HI V-infected patients
140after HA A RT. GI MA C infection can be seen in severely immunocompromised patients, involving the stomach,
the small intestine (Fig. 5.20, A), and, rarely, the colon. Endoscopic presentations include normal-appearing mucosa,
friability, multiple raised nodules, or ulceration. Microscopically, the lamina propria of the intestinal mucosa may be
stuffed with distended macrophages containing the organisms, which can be confirmed by a special stain for
acidfast bacilli (see Fig. 5.20, B). Periodic acid–S chiff (PA S ) stain characteristically reveals abundant delicate bacilli in
macrophages (see Fig. 5.20, C).FIGURE 5.20 A, Mycobacterium avium-intracellulare complex involving the duodenum in HIV
infection is manifested as accumulation of macrophages with foamy cytoplasm in the lamina
propria. B, Acid-fast stain reveals numerous organisms. C, Periodic acid–Schiff stain shows
abundant delicate bacilli in macrophages.
Human intestinal spirochetosis is a common cause of diarrhea in HI V patients and preferentially infects the
surface epithelium of the distal colon and rectum. I n addition to HI V-infected individuals, intestinal spirochetosis is
141also diagnosed in general population without HI V infection. The prevalence of intestinal spirochetosis varies
considerably from region to region. For example, in the Western countries, the prevalence of intestinal spirochetosis
in rectal biopsies is 2% to 7%, whereas in developing countries it is much higher, ranging from 11.4% to 32.6%.
A mong homosexual and HI V-infected men, the rate is even higher, up to 54%. I ntestinal spirochetosis is much more
common in men than in women. Two strains of Bachyspira have been identified as being responsible for intestinal
spirochetosis—Brachyspira aalborgi and Brachyspira pilosicoli—with B, aalborgi being the major causative agent in
Western countries.
Because many cases of intestinal spirochetosis are asymptomatic, there is much debate as to whether intestinal
spirochetosis is a pathogen or a commensal. However, accumulating evidence supports the notion that intestinal
spirochetosis can be the cause of GI symptoms in a subset of patients, especially in homosexual men, HI V patients,
142-146and children. A ssociation of intestinal spirochetosis with invasive colitis and hepatitis, rectal discharge, rectal
bleeding, and even spirochetemia has been reported. I mprovement of symptoms after eradication of the spirochetes
is seen in individuals with symptomatic intestinal spirochetosis.
147For a long time, intestinal spirochetes have been described as noninvasive. However, some studies have
148demonstrated invasion of spirochetes beyond the surface epithelium. The presence of spirochetes in epithelial
cells, lamina propria, macrophages, and even S chwann cells has been reported. I n addition, invasive intestinal
spirochetosis is associated with immediate-type immune reaction of the host, featured by a marked increase of I
gEproducing plasma cells in the lamina propria and intraepithelial mast cells. S tunting, destruction, and loss of
microvilli are seen in invasive cases and can result in reduction of the resorptive surface, leading to diarrhea. I nvasive
intestinal spirochetosis has been correlated to GI symptoms in the general population, whereas homosexual and
HIV-infected men are more likely to be symptomatic regardless of invasion, for unclear reasons.
The most common symptoms associated with intestinal spirochetosis include diarrhea, abdominal pain, altered
142-145bowel movement habits, and rectal bleeding. I ntestinal spirochetosis can affect the rectum, the colon, or both,
with the rectum the most severely involved area. Colonization of appendiceal epithelium by intestinal spirochetosis
141occurs frequently. I n one study, spirochetes were found in 7.8% of appendectomy specimens. The endoscopic
appearance of the colon is largely normal; however, some subtle changes (e.g., erythema) may be present. Biopsy
reveals long, undulating bacteria vertically aKached to the brush border, forming a blue bushy layer on hemotoxylin
and eosin (H&E) staining (Fig. 5.21, A). The organisms stain dark black with the Warthin-Starry stain (see Fig. 5.21, B).
The colonic mucosa is always unremarkable, with no increase in chronic inflammation and no active colitis. However,
in a small subset of patients, mild inflammatory changes such as increased intraepithelial lymphoctyes can be seen.A severe acute inflammatory reaction with crypt abscesses and ulcers was reported in two patients with advanced
148HIV infection.
FIGURE 5.21 A, Intestinal spirochetosis involving the colon in human immunodeficiency virus
infection is characterized by long, undulating bacteria vertically attached to the brush border,
forming a bushy layer (H&E stain). B, A Warthin-Starry stain reveals dark-brown to black
spirochetes.
I n general, no treatment is needed for asymptomatic cases. I f intestinal spirochetosis is identified as the sole
intestinal pathology in a symptomatic patient, it should be treated with antibiotics to eradicate the spirochetes.
Metronidazole is the drug of choice for the treatment of intestinal spirochetosis. Most cases treated with
142,144metronidazole show symptom improvement with eradication of the bacteria in follow-up biopsies.
Candida is the most common HI V-associated fungal pathogen, with the esophagus the site most often involved.
Esophageal candidiasis is characterized by white or yellow plaques with surrounding mucosal erythema
endoscopically. Biopsy of the plaques reveals necroinflammatory exudates, budding yeast forms, and pseudohyphae.
I n HI V-infected patients, histoplasmosis is most likely to involve the ileocecal region, occasionally leading to GI
bleeding, obstruction, perforation, and stricture. I ntestinal mucosal biopsies reveal marked infiltration of the lamina
propria by macrophages containing budding yeasts.
GI parasitic infections are relatively uncommon in HI V-infected patients after HA A RT. They mainly occur in the
small intestine. I nfecting agents include Cryptosporidium, Microsporidium, Isospora, and Giardia. I n cryptosporidiosis,
the parasite inhabits the microvillous brush border of the intestinal epithelium, causing enfacement of the brush
border. The intestinal epithelium may be atrophic and in disarray. A relatively mild active colitis may be seen in the
colon, with cryptitis and a few crypt abscesses (Fig. 5.22) . Microsporidium is difficult to identify on H&E-stained
sections; special stains such as Giemsa may be beneficial, and electron microscopy is the gold standard for
confirming the presence of the organism in the surface epithelial cells.
FIGURE 5.22 A, Cryptosporidial infection in the colon in HIV infection may produce a relatively
mild acute inflammatory infiltrate, with mild cryptitis and a few crypt abscesses. B, The organism
may be visualized on H&E-stained slides as spherical basophilic forms adherent to the luminal
surface of crypt epithelial cells.
HIV Enteropathy
GI dysfunction, as manifested by d-xylose malabsorption, is common, even in early HI V disease. I t may be a
manifestation of HI V enteropathy, defined as a reduction in small bowel villous surface area associated with chronic
diarrhea in the absence of enteric pathogens. The pathogenesis of HI V enteropathy is not well understood. The
chronic diarrhea may be caused by an unidentified pathogen, but there is evidence that diarrhea is directly related tolocal infection by the virus. S tudies have shown that HI V-infected patients show improvement in clinical symptoms
after initiation of HA A RT. S tudies of intestinal permeability, epithelial cell barrier function, and cytoskeletal
149integrity have demonstrated changes in HI V-infected subjects after administration of antiviral agents alone.
These studies indicate that medications should also be considered as a cause of diarrhea in these patients, and they
150may account for up to 45% of noninfectious cases ; commonly implicated medications are nelfinavir, ritonavir,
saquinavir, indinavir, and didanosine.
I n small bowel biopsies, HI V enteropathy is characterized by relatively mild villous blunting without
well151developed crypt hyperplasia. The degree of villous atrophy is typically less than that seen in celiac disease. The
histology of the colon in HI V enteropathy is less well understood. I ncreased epithelial cell apoptosis has been
152reported in association with HI V infection ; however, it is unclear whether this is related to the presence of the
virus, other immune mediators, or antiretroviral therapy. The presence of an opportunistic pathogen, especially
Cryptosporidium, Microsporidium, Isospora, or Giardia in the small intestine and Salmonella, Shigella, Mycobacterium,
Cryptosporidium, E. histolytica, and CMV in the colon, must always be ruled out in these patients.
Malignancy
The effective use of HA A RT in the treatment of HI V has led to a gradual decline in infectious diseases and an
increase in HI V-associated malignancies (seeT able 5.6). The most prevalent cancers in this population are Kaposi
sarcoma and A I D S -related N HL. Kaposi sarcoma is still the most common HI V-associated malignancy, despite a
decline in incidence since advent of HA A RT. S tudies have reported GI involvement in 40% of cases at initial
153presentation and in as much as 80% at autopsy. Endoscopically, Kaposi sarcoma appears as flat to raised, purple
plaques. Microscopically, the lesion is composed of plump spindle cells, which often form fine vascular lumina
containing red blood cells (Fig. 5.23). Hemosiderin and eosinophilic hyaline droplets may be present. Kaposi sarcoma
is caused by human herpes virus 8 (HHV-8). I mmunohistochemical stain for HHV-8 is useful in confirming the
diagnosis.
FIGURE 5.23 Kaposi sarcoma of the colon. A, A proliferation of spindled cells in the mucosa is
seen replacing the colonic crypts and muscularis mucosa. B, Slit like spaces containing
erythrocytes are present.
The A I D S -related N HL lymphomas are predominantly of B-cell lineage and include BurkiK lymphomaF (ig. 5.24),
DLBCL (immunoblastic, centroblastic, and anaplastic variants), primary effusion lymphoma (PEL), and plasmablastic
153,154lymphoma. The GI tract is the most common site of extranodal N HL, including BurkiK lymphoma and
155,156DLBCL. Classic PEL affects the peritoneal cavity, whereas solid PEL may be seen in extraserous sites such as
large intestine and lymph nodes. Plasmablastic lymphoma has been documented in the oral cavity and
153anorectum. The development of these HI V-associated malignancies is often aKributable to coinfection by viruses
such as HHV-8 (also called Kaposi sarcoma–associated herpesvirus) and Epstein-Barr virus. I n addition to these more
common HI V-associated cancers, large database studies have shown an association of HI V infection with other
malignancies. This list includes Hodgkin lymphoma, multiple myeloma, leukemia, anal squamous cell carcinoma,
153,157head and neck squamous cell carcinoma, esophageal carcinoma, and gastric carcinoma.FIGURE 5.24 A-C, Burkitt lymphoma in the rectum in an HIV-infected individual. Diffusely
infiltrative, atypical lymphocytes with scattered tingible body macrophages result in the
characteristic “starry-sky” appearance. (H&E stain.)
References
1. Salavoura K, Kolialexi A, Tsangaris G, Mavrou A. Development of cancer in patients with primary
immunodeficiencies. Anticancer Res. 2008;28:1263–1269.
2. Cunningham-Rundles C, Cooper DL, Duffy TP, Strauchen J. Lymphomas of mucosal-associated lymphoid
tissue in common variable immunodeficiency. Am J Hematol. 2002;69:171–178.
3. Dhalla F, da Silva SP, Lucas M, et al. Review of gastric cancer risk factors in patients with common variable
immunodeficiency disorders, resulting in a proposal for a surveillance programme. Clin Exp Immunol.
2011;165:1–7.
4. Brosens LAA, Tytgat KMAJ, Morsink FHM, et al. Multiple colorectal neoplasms in X-linked
agammaglobulinemia. Clin Gastroenterol Hepatol. 2008;6:115–119.
5. van der Meer JW, Weening RS, Schellekens PT, et al. Colorectal cancer in patients with X-linked
agammaglobulinaemia. Lancet. 1993;341:1439–1440.
6. Yel L. Selective IgA deficiency. J Clin Immunol. 2010;30:10–16.
7. Burrows PD, Cooper MD. IgA deficiency. Adv Immunol. 1997;65:245–276.
8. Castigli E, Wilson SA, Garibyan L, et al. TACI is mutant in common variable immunodeficiency and IgA
deficiency. Nat Genet. 2005;37:829–834.
9. Rachid R, Castigli E, Geha RS, Bonilla FA. TACI mutation in common variable immunodeficiency and IgA
deficiency. Curr Allergy Asthma Rep. 2006;6:357–362.
10. Salzer U, Chapel HM, Webster AD, et al. Mutations in TNFRSF13B encoding TACI are associated with
common variable immunodeficiency in humans. Nat Genet. 2005;37:820–828.
11. Leung VK, Liew CT, Sung JJ. Strongyloidiasis in a patient with IgA deficiency. Trop Gastroenterol. 1995;16:27–
30.
12. Meini A, Pillan NM, Villanacci V, et al. Prevalence and diagnosis of celiac disease in IgA-deficient children.
Ann Allergy Asthma Immunol. 1996;77:333–336.
13. Haimila K, Einarsdottir E, de Kauwe A, et al. The shared CTLA4-ICOS risk locus in celiac disease, IgA
deficiency and common variable immunodeficiency. Genes Immun. 2009;10:151–161.
14. Joo M, Shim SH, Chang SH, et al. Nodular lymphoid hyperplasia and histologic changes mimicking celiac
disease, collagenous sprue, and lymphocytic colitis in a patient with selective IgA deficiency. Pathol Res Pract.
2009;205:876–880.
15. Lai Ping So A, Mayer L. Gastrointestinal manifestations of primary immunodeficiency disorders. Semin
Gastrointest Dis. 1997;8:22–32.
16. Ardeniz O, Cunningham-Rundles C. Granulomatous disease in common variable immunodeficiency. Clin
Immunol. 2009;133:198–207.
17. Artac H, Bozkurt B, Talim B, Reisli I. Sarcoid-like granulomas in common variable immunodeficiency.
Rheumatol Int. 2009;30:109–112.18. Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features
of 248 patients. Clin Immunol. 1999;92:34–48.
19. Hammarstrom L, Vorechovsky I, Webster D. Selective IgA deficiency (SIgAD) and common variable
immunodeficiency (CVID). Clin Exp Immunol. 2000;120:225–231.
20. Castigli E, Geha RS. Molecular basis of common variable immunodeficiency. J Allergy Clin Immunol.
2006;117:740–746.
21. Eibel H, Salzer U, Warnatz K. Common variable immunodeficiency at the end of a prospering decade: towards
novel gene defects and beyond. Curr Opin Allergy Clin Immunol. 2010;10:526–533.
22. Orange JS, Glessner JT, Resnick E, et al. Genome-wide association identifies diverse causes of common
variable immunodeficiency. J Allergy Clin Immunol. 2011;127:1360–1367.
23. Washington K, Stenzel TT, Buckley RH, Gottfried MR. Gastrointestinal pathology in patients with common
variable immunodeficiency and X-linked agammaglobulinemia. Am J Surg Pathol. 1996;20:1240–1252.
24. Daniels JA, Lederman HM, Maitra A, Montgomery EA. Gastrointestinal tract pathology in patients with
common variable immunodeficiency (CVID): a clinicopathologic study and review. Am J Surg Pathol.
2007;31:1800–1812.
25. Zullo A, Romiti A, Rinaldi V, et al. Gastric pathology in patients with common variable immunodeficiency.
Gut. 1999;45:77–81.
26. Conley ME, Ziegler MM, Borden St, et al. Multifocal adenocarcinoma of the stomach in a child with common
variable immunodeficiency. J Pediatr Gastroenterol Nutr. 1988;7:456–460.
27. Cunningham-Rundles C, Siegal FP, Cunningham-Rundles S, Lieberman P. Incidence of cancer in 98 patients
with common varied immunodeficiency. J Clin Immunol. 1987;7:294–299.
28. Malamut G, Verkarre V, Suarez F, et al. The enteropathy associated with common variable immunodeficiency:
the delineated frontiers with celiac disease. Am J Gastroenterol. 2010;105:2262–2275.
29. Mike N, Hansel TT, Newman J, Asquith P. Granulomatous enteropathy in common variable
immunodeficiency: a cause of chronic diarrhoea. Postgrad Med J. 1991;67:446–449.
30. Laszewski MJ, Kemp JD, Goeken JA, et al. Clonal immunoglobulin gene rearrangement in nodular lymphoid
hyperplasia of the gastrointestinal tract associated with common variable immunodeficiency. Am J Clin
Pathol. 1990;94:338–343.
31. Hermaszewski RA, Webster AD. Primary hypogammaglobulinaemia: a survey of clinical manifestations and
complications. Q J Med. 1993;86:31–42.
32. Agarwal S, Smereka P, Harpaz N, et al. Characterization of immunologic defects in patients with common
variable immunodeficiency (CVID) with intestinal disease. Inflamm Bowel Dis. 2011;17:251–259.
33. Teahon K, Webster AD, Price AB, et al. Studies on the enteropathy associated with primary
hypogammaglobulinaemia. Gut. 1994;35:1244–1249.
34. Byrne MF, Royston D, Patchett SE. Association of common variable immunodeficiency with atypical
collagenous colitis. Eur J Gastroenterol Hepatol. 2003;15:1051–1053.
35. de Bruin NC, de Groot R, den Hollander JC, et al. Small-cell undifferentiated (neuroendocrine) carcinoma of
the cecum in a child with common variable immunodeficiency. Am J Pediatr Hematol Oncol. 1993;15:258–261.
36. Adachi Y, Mori M, Kido A, et al. Multiple colorectal neoplasms in a young adult with
hypogammaglobulinemia: report of a case. Dis Colon Rectum. 1992;35:197–200.
37. Tsukada S, Saffran DC, Rawlings DJ, et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in
human X-linked agammaglobulinemia. Cell. 1993;72:279–290.
38. Vetrie D, Vorechovsky I, Sideras P, et al. The gene involved in X-linked agammaglobulinaemia is a member of
the src family of protein-tyrosine kinases. Nature. 1993;361:226–233.
39. Lee PPW, Chen T-X, Jiang L-P, et al. Clinical characteristics and genotype-phenotype correlation in 62 patients
with X-linked agammaglobulinemia. J Clin Immunol. 2010;30:121–131.
40. Teimourian S, Nasseri S, Pouladi N, et al. Genotype-phenotype correlation in Bruton's tyrosine kinase
deficiency. J Pediatr Hematol Oncol. 2008;30:679–683.
41. Wang Y, Kanegane H, Wang X, et al. Mutation of the BTK gene and clinical feature of X-linked
agammaglobulinemia in mainland China. J Clin Immunol. 2009;29:352–356.
42. Hashimoto S, Miyawaki T, Futatani T, et al. Atypical X-linked agammaglobulinemia diagnosed in three adults.
Intern Med. 1999;38:722–725.
43. Mitsui T, Tsukamoto N, Kanegane H, et al. X-linked agammaglobulinemia diagnosed in adulthood: a case
report. Int J Hematol. 2006;84:154–157.
44. Valiaho J, Smith CI, Vihinen M. BTKbase: the mutation database for X-linked agammaglobulinemia. Hum
Mutat. 2006;27:1209–1217.
45. Agarwal S, Mayer L. Gastrointestinal manifestations in primary immune disorders. Inflamm Bowel Dis.
2010;16:703–711.
46. Winkelstein JA, Marino MC, Lederman HM, et al. X-linked agammaglobulinemia: report on a United States
registry of 201 patients. Medicine (Baltimore). 2006;85:193–202.
47. Lederman HM, Winkelstein JA. X-linked agammaglobulinemia: an analysis of 96 patients. Medicine
(Baltimore). 1985;64:145–156.
48. Saulsbury FT, Winkelstein JA, Yolken RH. Chronic rotavirus infection in immunodeficiency. J Pediatr.
1980;97:61–65.
49. Davidson GP, Barnes GL. Structural and functional abnormalities of the small intestine in infants and young
children with rotavirus enteritis. Acta Paediatr Scand. 1979;8:181–186.50. Eisengart LJ, Chou PM, Iyer K, et al. Rotavirus infection in small bowel transplant: a histologic comparison
with acute cellular rejection. Pediatr Develop Pathol. 2009;12:85–88.
51. Moon HW. Comparative histopathology of intestinal infections. Adv Exp Med Biol. 1997;412:1–19.
52. Abramowsky CR, Sorensen RU. Regional enteritis-like enteropathy in a patient with agammaglobulinemia:
histologic and immunocytologic studies. Hum Pathol. 1988;19:483–486.
53. Cellier C, Foray S, Hermine O. Regional enteritis associated with enterovirus in a patient with X-linked
agammaglobulinemia. N Engl J Med. 2000;342:1611–1612.
54. Lavilla P, Gil A, Rodriguez MC, et al. X-linked agammaglobulinemia and gastric adenocarcinoma. Cancer.
1993;72:1528–1531.
55. Plebani A, Soresina A, Rondelli R, et al. Clinical, immunological, and molecular analysis in a large cohort of
patients with X-linked agammaglobulinemia: an Italian multicenter study. Clin Immunol. 2002;104:221–230.
56. Winkelstein JA, Marino MC, Ochs H, et al. The X-linked hyper-IgM syndrome: clinical and immunologic
features of 79 patients. Medicine (Baltimore). 2003;82:373–384.
57. Hostoffer RW, Berger M, Clark HT, Schreiber JR. Disseminated Histoplasma capsulatum in a patient with hyper
IgM immunodeficiency. Pediatrics. 1994;94(2 Pt 1):234–236.
58. Tu RK, Peters ME, Gourley GR, Hong R. Esophageal histoplasmosis in a child with immunodeficiency with
hyper-IgM. AJR Am J Roentgenol. 1991;157:381–382.
59. Levy J, Espanol-Boren T, Thomas C, et al. Clinical spectrum of X-linked hyper-IgM syndrome. J Pediatr.
1997;131(1 Pt 1):47–54.
60. Ramesh N, Seki M, Notarangelo LD, Geha RS. The hyper-IgM (HIM) syndrome. Springer Semin Immunopathol.
1998;19:383–399.
61. Rosen FS, Cooper MD, Wedgwood RJ. The primary immunodeficiencies. N Engl J Med. 1995;333:431–440.
62. Erdos M, Garami M, Rakoczi E, et al. Neuroendocrine carcinoma associated with X-linked
hyperimmunoglobulin M syndrome: report of four cases and review of the literature. Clin Immunol. 2008;129:455–
461.
63. Hayward AR, Levy J, Facchetti F, et al. Cholangiopathy and tumors of the pancreas, liver, and biliary tree in
boys with X-linked immunodeficiency with hyper-IgM. J Immunol. 1997;158:977–983.
64. Zirkin HJ, Levy J, Katchko L. Small cell undifferentiated carcinoma of the colon associated with hepatocellular
carcinoma in an immunodeficient patient. Hum Pathol. 1996;27:992–996.
65. Freeman AF, Holland SM. Clinical manifestations of hyper IgE syndromes. Dis Markers. 2010;29:123–130.
66. Dasouki M, Okonkwo KC, Ray A, et al. Deficient T cell receptor excision circles (TRECs) in autosomal
recessive hyper IgE syndrome caused by DOCK8 mutation: implications for pathogenesis and potential
detection by newborn screening. Clin Immunol. 2011;141:128–132.
67. Holland SM, DeLeo FR, Elloumi HZ, et al. Mutations in the hyper-IgE syndrome. N Engl J Med. 2007;357:1608–
1619.
68. Minegishi Y, Saito M, Morio T, et al. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple
cytokine signals involved in innate and acquired immunity. Immunity. 2006;25:745–755.
69. Jacobs DH, Macher AM, Handler R, et al. Esophageal cryptococcosis in a patient with the
hyperimmunoglobulin E-recurrent infection (Job's) syndrome. Gastroenterology. 1984;87:201–203.
70. Hutto JO, Bryan CS, Greene FL, et al. Cryptococcosis of the colon resembling Crohn's disease in a patient with
the hyperimmunoglobulinemia E-recurrent infection (Job's) syndrome. Gastroenterology. 1988;94:808–812.
71. Alberti-Flor JJ, Granda A. Ileocecal histoplasmosis mimicking Crohn's disease in a patient with Job's
syndrome. Digestion. 1986;33:176–180.
72. Steiner SJ, Kleiman MB, Corkins MR, et al. Ileocecal histoplasmosis simulating Crohn disease in a patient with
hyperimmunoglobulin E syndrome. Pediatr Infect Dis J. 2009;28:744–746.
73. Hwang EH, Oh JT, Han SJ, Kim H. Colon perforation in hyperimmunoglobulin E syndrome. J Pediatr Surg.
1998;33:1420–1422.
74. Stover DG, Freeman AF, Wright PW, et al. Diverticulitis in a young man with hyper-IgE syndrome. South Med
J. 2010;103:1261–1263.
75. International Union of Immunological Societies Expert Committee on Primary Immunodeficiencies,
Notarangelo LD, Fischer A, et al. Primary immunodeficiencies: 2009 update. [[Erratum appears in J Allergy
Clin Immunol. 2010;125:771-773]] J Allergy Clin Immunol. 2009;124:1161–1178.
76. Cossu F. Genetics of SCID. Ital J Pediatr. 2010;36:76.
77. Salim AF, Phillips AD, Walker-Smith JA, Farthing MJ. Sequential changes in small intestinal structure and
function during rotavirus infection in neonatal rats. Gut. 1995;36:231–238.
78. Lee EY, Clouse RE, Aliperti G, DeSchryver-Kecskemeti K. Small intestinal lesion resembling graft-vs-host
disease: a case report in immunodeficiency and review of the literature. Arch Pathol Lab Med. 1991;115:529–
532.
79. Snover DC, Filipovich AH, Ramsay NK, et al. Graft-versus-host-disease-like histopathological findings in
prebone-marrow transplantation biopsies of patients with severe T cell deficiency. Transplantation. 1985;39:95–97.
80. Boeck A, Buckley RH, Schiff RI. Gastroesophageal reflux and severe combined immunodeficiency. J Allergy
Clin Immunol. 1997;99:420–424.
81. Villa A, Notarangelo LD, Roifman CM. Omenn syndrome: inflammation in leaky severe combined
immunodeficiency. J Allergy Clin Immunol. 2008;122:1082–1086.
82. Muller SM, Ege M, Pottharst A, et al. Transplacentally acquired maternal T lymphocytes in severe combined
immunodeficiency: a study of 121 patients. Blood. 2001;98:1847–1851.83. Jouan H, Le Deist F, Nezelof C. Omenn's syndrome—pathologic arguments in favor of a graft versus host
pathogenesis: a report of nine cases. Hum Pathol. 1987;18:1101–1108.
84. Scheimberg I, Hoeger PH, Harper JI, et al. Omenn's syndrome: differential diagnosis in infants with
erythroderma and immunodeficiency. Pediatr Dev Pathol. 2001;4:237–245.
85. Fomin ABF, Pastorino AC, Kim CA, et al. DiGeorge syndrome: a not so rare disease. Clinics (São Paulo, Brazil).
2010;65:865–869.
86. Wurdak H, Ittner LM, Sommer L. DiGeorge syndrome and pharyngeal apparatus development. Bioessays.
2006;28:1078–1086.
87. Ament ME. Immunodeficiency syndromes and the gut. Scand J Gastroenterol Suppl. 1985;114:127–135.
88. Eicher PS, McDonald-Mcginn DM, Fox CA, et al. Dysphagia in children with a 22q11.2 deletion: unusual
pattern found on modified barium swallow. J Pediatr. 2000;137:158–164.
89. San Filippo J. Chronic mucocutaneous candidiasis associated with malignant thymoma and systemic lupus
erythematosus with hypergammaglobulinemia: a case report and literature review. Cutis. 2006;78:57–60.
90. Liu L, Okada S, Kong X-F, et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and
underlie chronic mucocutaneous candidiasis. J Exp Med. 2011;208:1635–1648.
91. van de Veerdonk FL, Plantinga TS, Hoischen A, et al. STAT1 mutations in autosomal dominant chronic
mucocutaneous candidiasis. N Engl J Med. 2011;365:54–61.
92. Puel A, Cypowyj S, Bustamante J, et al. Chronic mucocutaneous candidiasis in humans with inborn errors of
interleukin-17 immunity. Science. 2011;332:65–68.
93. Herrod HG. Chronic mucocutaneous candidiasis in childhood and complications of non-Candida infection: a
report of the Pediatric Immunodeficiency Collaborative Study Group. J Pediatr. 1990;116:377–382.
94. Derry JM, Ochs H, Francke U. Isolarion of a novel gene mutated in Wiskott-Aldrich syndrome. Cell.
1994;78:635–644.
95. Hsieh KH, Chang MH, Lee CY, Wang CY. Wiskott-Aldrich syndrome and inflammatory bowel disease. Ann
Allergy. 1988;60:429–431.
96. Loan W, McCune K, Kelly B, Maxwell R. Wiskott-Aldrich syndrome: life-threatening haemorrhage from
aneurysms within the liver, small bowel mesentery and kidney, requiring both surgical and radiological
intervention. J R Coll Surg Edinb. 2000;45:326–328.
97. Winkelstein JA, Marino MC, Johnston RB Jr, et al. Chronic granulomatous disease: report on a national
registry of 368 patients. Medicine (Baltimore). 2000;79:155–169.
98. al-Tawil YS, Abramson SL, Gilger MA, Paul ME. Steroid-responsive esophageal obstruction in a child with
chronic granulomatous disease (CGD). J Pediatr Gastroenterol Nutr. 1996;23:182–185.
99. Dickerman JD, Colletti RB, Tampas JP. Gastric outlet obstruction in chronic granulomatous disease of
childhood. Am J Dis Child. 1986;140:567–570.
100. Stopyrowa J, Fyderek K, Sikorska B, et al. Chronic granulomatous disease of childhood: gastric manifestation
and response to salazosulfapyridine therapy. Eur J Pediatr. 1989;149:28–30.
101. Lindahl JA, Williams FH, Newman SL. Small bowel obstruction in chronic granulomatous disease. J Pediatr
Gastroenterol Nutr. 1984;3:637–640.
102. Ament ME, Ochs HD. Gastrointestinal manifestations of chronic granulomatous disease. N Engl J Med.
1973;288:382–387.
103. Sloan JM, Cameron CH, Maxwell RJ, et al. Colitis complicating chronic granulomatous disease: a
clinicopathological case report. Gut. 1996;38:619–622.
104. Foster CB, Lehrnbecher T, Mol F, et al. Host defense molecule polymorphisms influence the risk for
immunemediated complications in chronic granulomatous disease. J Clin Invest. 1998;102:2146–2155.
105. Mitomi H, Mikami T, Takahashi H, et al. Colitis in chronic granulomatous disease resembling Crohn's
disease: comparative analysis of CD68-positive cells between two disease entities. Digest Dis Sci. 1999;44:452–
456.
106. Marks DJ, Miyagi K, Rahman FZ, et al. Inflammatory bowel disease in CGD reproduces the
clinicopathological features of Crohn's disease. Am J Gastroenterol. 2009;104:117–124.
107. D’Agata ID, Paradis K, Chad Z, et al. Leucocyte adhesion deficiency presenting as a chronic ileocolitis. Gut.
1996;39:605–608.
108. Hawkins HK, Heffelfinger SC, Anderson DC. Leukocyte adhesion deficiency: clinical and postmortem
observations. Pediatr Pathol. 1992;12:119–130.
109. Jain AK, Motil KJ, Abramson SL, et al. Rectal ulcer with an elusive diagnosis: all that ulcers is not Crohn
disease. J Pediatr Gastroenterol Nutrit. 2010;51:367–369.
110. Guerrerio AL, Frischmeyer-Guerrerio PA, Lederman HM, Oliva-Hemker M. Recognizing gastrointestinal and
hepatic manifestations of primary immunodeficiency diseases. J Pediatr Gastroenterol Nutrit. 2010;51:548–555.
111. Patey-Mariaud de Serre N, Canioni D, Ganousse S, et al. Digestive histopathological presentation of IPEX
syndrome. Mod Pathol. 2009;22:95–102.
112. Mastaglio S, Stanghellini MTL, Bordignon C, et al. Progress and prospects: graft-versus-host disease. Gene
Ther. 2010;17:1309–1317.
113. Ferrara JLM, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet. 2009;373:1550–1561.
114. Tzung SP, Hackman RC, Hockenbery DM, et al. Lymphocytic gastritis resembling graft-vs.-host disease
following autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant. 1998;4:43–48.
115. Cogbill CH, Drobyski WR, Komorowski RA. Gastrointestinal pathology of autologous graft-versus-host
disease following hematopoietic stem cell transplantation: a clinicopathological study of 17 cases. Mod Pathol.2011;24:117–125.
116. Zhang Y, Ruiz P. Solid organ transplant-associated acute graft-versus-host disease. Arch Pathol Lab Med.
2010;134:1220–1224.
117. Chirletti P, Caronna R, Arcese W, et al. Gastrointestinal emergencies in patients with acute intestinal
graftversus-host disease. Leuk Lymphoma. 1998;29:129–137.
118. Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on
criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and Staging Working Group report.
Biol Blood Marrow Transplant. 2005;11:945–956.
119. Ponec RJ, Hackman RC, McDonald GB. Endoscopic and histologic diagnosis of intestinal graft-versus-host
disease after marrow transplantation. Gastrointest Endosc. 1999;49:612–621.
120. Washington K, Jagasia M. Pathology of graft-versus-host disease in the gastrointestinal tract. Hum Pathol.
2009;40:909–917.
121. 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. 1979;3:291–299.
122. Papadimitriou JC, Drachenberg CB, Beskow CO, et al. Graft-versus-host disease-like features in
mycophenolate mofetil-related colitis. Transplant Proc. 2001;33:2237–2238.
123. Selbst MK, Ahrens WA, Robert ME, et al. Spectrum of histologic changes in colonic biopsies in patients
treated with mycophenolate mofetil. Mod Pathol. 2009;22:737–743.
124. Shulman HM, Kleiner D, Lee SJ, et al. Histopathologic diagnosis of chronic graft-versus-host disease:
National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic
Graftversus-Host Disease. II: Pathology Working Group Report. Biol Blood Marrow Transplant. 2006;12:31–47.
125. Welch DC, Wirth PS, Washington K, et al. Gastric graft-versus-host disease revisited: does proton pump
inhibitor therapy affect endoscopic gastric biopsy interpretation? Am J Surg Pathol. 2006;30:444–459.
126. Wang MH, Wong JM, Wang CY. Graft-versus-host disease-like syndrome in malignant thymoma. Scand J
Gastroenterol. 2000;35:667–670.
127. Weisdorf D, Arthur D, Rank J, et al. Gastric recurrence of acute lymphoblastic leukaemia mimicking
graftversus-host disease. Br J Haematol. 1989;71:559–561.
128. Chakrabarti S, Lees A, Jones SG, Milligan DW. Clostridium difficile infection in allogeneic stem cell transplant
recipients is associated with severe graft-versus-host disease and non-relapse mortality. Bone Marrow
Transplant. 2000;26:871–876.
129. Shulman HM, Sullivan KM, Weiden PL, et al. Chronic graft-versus-host syndrome in man: a long-term
clinicopathologic study of 20 Seattle patients. Am J Med. 1980;69:204–217.
130. Asplund S, Gramlich TL. Chronic mucosal changes of the colon in graft-versus-host disease. Mod Pathol.
1998;11:513–515.
131. Herrera AF, Soriano G, Hornick JL, et al. Cord colitis syndrome in cord-blood stem-cell transplantation. N
Engl J Med. 2011;365:815–824.
132. Gorschluter M, Mey U, Strehl J, et al. Neutropenic enterocolitis in adults: systematic analysis of evidence
quality. Eur J Haematol. 2005;75:1–13.
133. Fike FB, Mortellaro V, Juang D, et al. Neutropenic colitis in children. J Surg Res. 2011;170:73–76.
134. Mullassery D, Bader A, Battersby AJ, et al. Diagnosis, incidence, and outcomes of suspected typhlitis in
oncology patients: experience in a tertiary pediatric surgical center in the United Kingdom. J Pediatr Surg.
2009;44:381–385.
135. Katz JA, Wagner ML, Gresik MV, et al. Typhlitis: an 18-year experience and postmortem review. Cancer.
1990;65:1041–1047.
136. Shafi MA, Bresalier RS. The gastrointestinal complications of oncologic therapy. Gastroenterol Clin N Am.
2010;39:629–647.
137. Knox TA, Spiegelman D, Skinner SC, Gorbach S. Diarrhea and abnormalities of gastrointestinal function in a
cohort of men and women with HIV infection. Am J Gastroenterol. 2000;95:3482–3489.
138. Wallace MR, Brann OS. Gastrointestinal manifestations of HIV infection. Curr Gastroenterol Rep. 2000;2:283–
293.
139. Wilcox CM, Schwartz DA. Endoscopic characterization of idiopathic esophageal ulceration associated with
human immunodeficiency virus infection. J Clin Gastroenterol. 1993;16:251–256.
140. Sanchez TH, Brooks JT, Sullivan PS, et al. Bacterial diarrhea in persons with HIV infection, United States,
1992-2002. Clin Infect Dis. 2005;41:1621–1627.
141. Tsinganou E, Gebbers JO. Human intestinal spirochetosis: a review. Ger Med Sci. 2010.
142. Weisheit B, Bethke B, Stolte M. Human intestinal spirochetosis: analysis of the symptoms of 209 patients.
Scand J Gastroenterol. 2007;42:1422–1427.
143. Koteish A, Kannangai R, Abraham SC, Torbenson M. Colonic spirochetosis in children and adults. Am J Clin
Pathol. 2003;120:828–832.
144. Esteve M, Salas A, Fernandez-Banares F, et al. Intestinal spirochetosis and chronic watery diarrhea: clinical
and histological response to treatment and long-term follow up. J Gastroenterol Hepatol. 2006;21:1326–1333.
145. Anthony NE, Blackwell J, Ahrens W, et al. Intestinal spirochetosis: an enigmatic disease. Digest Dis Sci.
2012;58:202–208.
146. Calderaro A, Bommezzadri S, Gorrini C, et al. Infective colitis associated with human intestinal spirochetosis.
J Gastroenterol Hepatol. 2007;22:1772–1779.
147. van Mook WN, Koek GH, van der Ven AJ, et al. Human intestinal spirochaetosis: any clinical significance? EurJ Gastroenterol Hepatol. 2004;16:83–87.
148. Korner M, Gebbers JO. Clinical significance of human intestinal spirochetosis: a morphologic approach.
Infection. 2003;31:341–349.
149. Kotler DP. HIV infection and the gastrointestinal tract. AIDS. 2005;19:107–117.
150. Call SA, Heudebert G, Saag M, Wilcox CM. The changing etiology of chronic diarrhea in HIV-infected patients
3with CD4 cell counts less than 200 cells/mm . Am J Gastroenterol. 2000;95:3142–3146.
151. Cummins AG, LaBrooy JT, Stanley DP, et al. Quantitative histological study of enteropathy associated with
HIV infection. Gut. 1990;31:317–321.
152. Kotler DP, Weaver SC, Terzakis JA. Ultrastructural features of epithelial cell degeneration in rectal crypts of
patients with AIDS. Am J Surg Pathol. 1986;10:531–538.
153. Cheung MC, Pantanowitz L, Dezube BJ. AIDS-related malignancies: emerging challenges in the era of highly
active antiretroviral therapy. Oncologist. 2005;10:412–426.
154. Carbone A, Gloghini A. AIDS-related lymphomas: from pathogenesis to pathology. Br J Haematol.
2005;130:662–670.
155. Crump M, Gospodarowicz M, Shepherd FA. Lymphoma of the gastrointestinal tract. Semin Oncol. 1999;26:324–
337.
156. Sharma A, Raina V, Gujral S, et al. Burkitt's lymphoma of stomach: a case report and review of literature. Am J
Hematol. 2001;67:48–50.
157. Koshy M, Kauh J, Gunthel C, et al. State of the art: gastrointestinal malignancies in the human
immunodeficiency virus (HIV) population. Int J Gastrointest Cancer. 2005;36:1–14.
158. Epstein RJ, McDonald GB, Sale GE, et al. The diagnostic accuracy of the rectal biopsy in acute
graft-versushost disease: a prospective study of thirteen patients. Gastroenterol. 1980;78:764–771.
159. Snover DC. Mucosal damage simulating acute graft-versus-host reaction in cytomegalovirus colitis.
Transplantation. 1985;39:669–670.
160. Lumadue JA, Manabe YC, Moore RD, et al. A clinicopathologic analysis of AIDS-related cryptosporidiosis.
AIDS. 1998;12:2459–2466.
161. Papadimitriou JC, Drachenberg CB, Beskow CO, et al. Graft-versus-host disease-like features in
mycophenolate mofetil-related colitis. Transplant Proc. 2001;33:2237–2238.
162. Welch DC, Wirth PS, Washington K, et al. Gastric graft-versus-host disease revisited: does proton pump
inhibitor therapy affect endoscopic gastric biopsy interpretation? Am J Surg Pathol. 2006;30:444–449.C H A P T E R 6
Systemic Illnesses Involving the Gastrointestinal Tract
David N.B. Lewin
CHA P T E R OUT LINE
Introduction
Cardiovascular Disorders
Cardiac Surgery and Heart Transplantation
Ischemic Disease
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
Decidualization of the Peritoneum
Endometriosis
Rheumatologic Disorders
Scleroderma
Dermatomyositis and Polymyositis
Systemic Lupus Erythematosus
Mixed Connective Tissue Disease
Rheumatoid Arthritis
Reactive Arthritis
Sjögren 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
S ystemic illnesses commonly affect the gastrointestinal (GI ) tract. GI symptoms and morphologic changes can result from several different
pathogenetic mechanisms, such as nonspecific or constitutional symptoms, pathologic changes common to intestinal and extraintestinal
organs, secondary changes such as opportunistic infections or drug reactions, and metastatic disease. This chapter focuses on morphologic
alterations in the GI tract resulting from disorders that primarily affect other organ systems.
Cardiovascular Disorders
Cardiac Surgery and Heart TransplantationGI complications after open heart surgery are uncommon, occurring in approximately 1% of cases; however, the mortality rate is high
1,2(approximately 30%). Clinical features typically consist of GI hemorrhage secondary to stress ulceration, vascular insufficiency with
ischemic necrosis of bowel, and acute diverticulitis. A dditional risk factors for ischemia include end-stage renal disease, female sex, non–
2coronary artery bypass graft, and long pump times.
I n contrast to GI complications after open heart surgery, GI complications after cardiac transplantation have been reported in as many as
3,420% of patients. Complications include all of the hemorrhagic conditions mentioned previously. I n addition, the use of steroids and
immunosuppressive agents increases the risks of intestinal perforation, fistula formation, and infectious GI diseases. These patients are also at
5risk for posttransplantation lymphoproliferative disorders (see Chapter 52).
Ischemic Disease
Intestinal ischemic disease can be divided into two major subsets: nonthrombotic (approximately 60% of cases) and thrombotic (approximately
640% of cases). N onthrombotic causes of ischemic disease include decreased mesenteric blood flow secondary to cardiac failure, shock,
atherosclerotic vascular disease, disseminated intravascular coagulation, vasculitis, and fibromuscular dysplasia. Thrombotic causes can be
divided into arterial embolism, arterial thrombosis, and venous thrombosis. These are a heterogeneous group of disorders usually seen in
7elderly individuals. Colonic ischemia, the most common disorder (typically nonthrombotic), has a favorable prognosis. A cute mesenteric
6ischemia, in contrast, has a poor prognosis, with a survival rate of only 50%. Histologically, resultant lesions range from epithelial and
8lymphocytic apoptosis to mucosal necrosis and transmural infarction of the bowel (Fig. 6.1). S pecifics concerning histology and pathology are
discussed in Chapter 10.
FIGURE 6.1 Early ischemia of the colon. Intermediate magnification reveals atrophy and mucin depletion of the epithelium.
A mild acute inflammatory infiltrate is present, as is epithelial apoptosis. The lamina propria has a characteristic light pink,
homogeneous appearance.
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 (Box 6.1). These lesions are discussed in this section.
Box 6.1
P rim a ry D e rm a tologic D ise a se s I n volvin g th e G a stroin te stin a l T ra c t
Bullous diseases
Epidermolysis bullosa
Pemphigus vulgaris
Bullous pemphigoid
Erythema multiforme
Stevens-Johnson syndrome
Hailey-Hailey and Darier diseases
Dermatitis herpetiformis
Dermatogenic enteropathy
Eczema
Psoriasis
2. Systemic disorders involving both the skin and the GI tract (Box 6.2). These lesions are discussed in other areas of this chapter.
Box 6.2
S yste m ic D ise a se s I n volv in g th e S kin a n d G a stroin te stin a l T ra c t
Vascular disorders
Hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease)
Kaposi sarcoma
Blue rubber bleb nevus syndrome
Necrotizing angiitis
Degos disease (malignant atrophic papulosis)
Metabolic disorders
Acrodermatitis enteropathica
Fabry disease (angiokeratoma corporis diffusum)
Plummer-Vinson syndrome
Rheumatologic and connective tissue disorders
Scleroderma
Dermatomyositis
Systemic lupus erythematosusPolyarteritis nodosa
Pseudoxanthoma elasticum
Ehlers-Danlos syndrome
Miscellaneous disorders
Amyloidosis
Familial Mediterranean fever
Mastocytosis
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.
Bullous Diseases
The majority of primary dermatologic bullous disorders that involve the GI tract occur in conjunction with a skin disorder (excluding
dermatitis herpetiformis). These diseases typically involve the upper portion of the esophagus. Patients are seen with symptoms of dysphagia
and odynophagia. Histologically, the lesions in esophageal squamous mucosa appear similar to those in the skin. The key distinguishing
morphologic features are the level of the plane of separation (vesicle formation), the type of inflammatory infiltrate, and the presence or
9absence of acantholysis. Because the bullae rarely remain intact, 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. I n the esophagus,
lesions often rupture and produce erosions; occasionally, fibrosis and stricture formation are also seen.
Epidermolysis Bullosa
10Epidermolysis bullosa, a group of more than 12 genetically determined disorders that involve all organs lined by squamous 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). I nvolvement of the
11GI tract occurs in 50% of patients with the dystrophic form and in 33% of those with the junctional or simplex form. S tricture and esophageal
12webs occur most frequently in the dystrophic form but can also be seen rarely in the junctional or simplex form. I n 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.
Epidermolysis bullosa aquisita is a rare acquired disorder with clinical characteristics similar to those of epidermolysis bullosa except for
adult onset, milder skin disease, and lack of family history. I t may be associated with systemic diseases such as amyloidosis, multiple
myeloma, diabetes mellitus, and inflammatory bowel disease (I BD ). A subset of patients have circulating immunoglobulin G (I gG) that
recognizes collagen IV. Endoscopic biopsy may show linear deposition of IgG in the basement membrane.
Pemphigus Vulgaris
Pemphigus vulgaris is a bullous disorder that affects middle-aged and older individuals. The bullae are superficial and flaccid. The lesion is an
intraepidermal bulla formed by acantholysis (loss of intracellular bridges). Histologically, the cells lose their normal angular contours and
become rounded. Basal keratinocytes typically remain aGached to the epidermal basement membrane. The inflammatory infiltrate is variable;
eosinophils and lymphocytes are the cells most commonly present in the epidermis, both surrounding and within the bullae and within the
13subjacent lamina propria. S tandard biopsy forceps may provide only superficial specimens that are inadequate for diagnosis. D irect
14immunofluorescence for immunoglobulins and complement component C3 is positive in the epidermal intercellular spaces. The incidence
15,16of esophageal involvement is unclear. S ome studies report endoscopic lesions in as much as 80% of patients. I n addition,
17immunofluorescence 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 involvement of the GI tract
18is much less common than in pemphigus vulgaris, although one report described esophageal blisters in 4% of patients with typical bullous
19pemphigoid. The histology of the bullous lesion has not been described. However, linear deposits of I gG and complement in the basement
18membrane of the esophagus and occasionally in the stomach, similar to those found in the skin, have been described. A single case of bullae
20in the colon has also been reported.
Cicatricial pemphigoid (benign mucous membrane pemphigoid) is an autoimmune bullous disease related to bullous pemphigoid. I t has
similar immunohistochemical linear deposition of C3 and I gG. The circulating autoantibodies recognize bullous pemphigoid antigen 2
21(BPAC2). Esophageal involvement has been reported in approximately 4% of patients with the disease.
Erythema Multiforme
Erythema multiforme, as the name implies, is a cutaneous reaction paGern characterized by a combination of skin and mucosal lesions. The
mucosal lesions usually occur on the lips or in the oral cavity and conjunctiva. However, the esophagus and, rarely, other regions of the GI tract
22 23may be involved. I ncluded in this group of disorders is the S tevens-J ohnson syndrome (macular trunk lesions with mucosal involvement).
Many of these lesions occur secondary to drug reactions (type I V hypersensitivity reactions) or, occasionally, reactions to infectious agents
such as mycoplasmae. I n the esophagus, lesions have been described as small white patches similar to those caused by Candida spp. infection.
Histologically, superficial ulceration and marked intraepithelial lymphocytosis are often observed. I ndividual squamous cell necrosis most
often involves the basal cells but may also include the entire thickness of the epithelium. Lesions typically regress; therefore, GI complications
usually are not sampled for biopsy.
Hailey-Hailey and Darier Diseases
Hailey-Hailey disease, also known as benign familial pemphigus, is a rare disorder with an autosomal dominant inheritance paGern. Patients
typically are seen in the fourth to fifth decade of life with blistering and crusting skin lesions in intertriginous zones. Mucous membrane
involvement is rare but may occur. D arier disease is similar to Hailey-Hailey disease, but its onset is typically in the first to second decade of
life. Histologic features of both include dyskeratosis, suprabasal acantholysis, papillomatosis, and suprabasal separation with loss of
24intracellular bridges. Darier disease more commonly involves the esophagus.
Dermatitis Herpetiformis
D ermatitis herpetiformis is a pruritic vesicular dermatitis with a symmetric distribution on the skin. Unlike the previously discussed bullous
disorders of the skin, this disease does not produce bullous lesions in the GI tract. D ermatitis herpetiformis is strongly associated with celiac
25disease. A pproximately 70% of patients with dermatitis herpetiformis show evidence of villous atrophy on small bowel biopsy. However,
26most patients are asymptomatic. Of patients with dermatitis herpetiformis, 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 skin27disease and the GI symptoms can be controlled by a gluten-free diet.
Dermatogenic Enteropathy
Many GI symptoms and histologic findings have been described in patients with active psoriasis and eczema. S teatorrhea and malabsorption
28,29are not uncommon, and the terms dermatogenic enteropathy and psoriatic enteropathy have been applied to these syndromes. Histologically,
the duodenal mucosa shows an increase in the numbers of mast cells and eosinophils. A subset of patients have increased numbers of
30duodenal intraepithelial lymphocytes and antibodies to gliadin (suggestive of latent celiac sprue). I n addition, the colon may show increased
lamina propria cellularity, active inflammation, and occasional gland atrophy in mucosal biopsy specimens from patients who have psoriasis
31without bowel symptoms.
Dermatologic Disorders Associated with Malignancies of the GI Tract
Acanthosis Nigricans
A canthosis nigricans consists of numerous brown, hyperpigmented, velvety skin plaques located in the axillae, groin, and flexural areas. The
lesion has two major forms—one associated with internal malignancies and the other associated with insulin resistance. Microscopically,
dermal lesions are characterized by diffuse hyperkeratosis and papillomatosis. Epithelial hyperplasia of the esophagus also has been
described.
When present, this lesion is usually associated with adenocarcinomas of the stomach and colon. At least one report has suggested that it is
32caused 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. I t is strongly
33associated with the development of squamous cell carcinoma of the esophagus, with tumors appearing in 95% of patients. The skin lesion is
characterized by thickening of the stratum corneum of the palms and soles. The esophageal mucosa in tylosis is typically affected by
papillomatosis, which appears as multiple small protrusions, some with spines due to acanthosis. Molecular studies have mapped the
34,35defective gene to a small region on chromosome 17q25. The same region has been implicated in the development of sporadic squamous
cell carcinoma and Barrett esophagus–associated adenocarcinoma.
Miscellaneous Disorders
36S everal other nonspecific skin diseases are associated with GI neoplasms. These diseases include generalized dermal pigmentation,
37migratory thrombophlebitis, and seborrheic keratosis (Leser-Trélat sign).
Endocrine Disorders
A lterations in the secretion of endocrine hormones in endocrine disorders may have a variety of GI effects. Most of these produce functional
GI symptoms such as vomiting, diarrhea, constipation, and abdominal pain secondary to changes in GI motility T( able 6.1). Most of these
diseases do not cause significant morphologic or histologic abnormalities and are described only briefly here.
Table 6.1
Gastrointestinal Manifestations of Endocrine Disorders
Organ Endocrine Disorder Gastrointestinal Manifestation
Adrenal Addison 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
A ddison disease (primary chronic adrenocortical insufficiency) may cause common GI disturbances such as anorexia, nausea, vomiting, and
38diarrhea. Pheochromocytomas are characterized by hypertension due to high catecholamine levels. I ntestinal pseudo-obstruction,
megacolon, and even bowel ischemia have also been described and are thought to be secondary to the vasoconstrictive action of excess
39catecholamine levels.
Hypothalamus and Pituitary
The hypothalamus and pituitary function as a unit. D isorders of either one infrequently affect the GI tract. Hypopituitarism affects intestinal
motility, as does hypothyroidism. Pituitary adenomas are part of the multiple endocrine neoplasia (MEN ) syndrome, discussed later in this
chapter. Of the hyperpituitary lesions, acromegaly is of interest with respect to GI neoplasia. A cromegaly is characterized by chronic
hypersecretion of growth hormone and insulin-like growth factor, usually due to a pituitary adenoma. I t is associated with overgrowth of the
musculoskeletal system and all organs, including the GI tract. A cromegaly has been shown to increase epithelial cell proliferation in the
40 41colon, and an increased prevalence of colonic adenomas and colonic carcinoma has been observed. A n increased risk of gastric carcinoma42has also been suggested but is less well established.
Pancreas
D iseases of the exocrine and endocrine pancreas commonly affect the GI tract. These include pancreatic exocrine insufficiency, diabetes, and
hormonal effects of functional pancreatic endocrine neoplasms. Pancreatic exocrine insufficiency typically gives rise to steatorrhea and
malabsorption and is discussed further in Chapter 39.
43D iabetes can involve significant 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 vomiting. A bdominal bloating appears to correlate best
44with 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 malabsorption. Patients are also at increased risk
45 46for Candida infection of the esophagus. Histologic features are nonspecific. Neuropathic findings with silver stains have been described, as
47have periodic acid–Schiff (PAS)-positive vascular deposits in the vessels of the submucosa.
Excess hormonal production from the pancreatic islets of Langerhans can be a result of diffuse hyperplasia (nesidioblastosis) or pancreatic
endocrine tumors. Many hormones, such as insulin, glucagon, somatostatin, pancreatic polypeptide, gastrin, adrenocorticotropic hormone,
calcitonin, parathormone, and serotonin, can be produced by these lesions. A ll GI manifestations reflect altered digestive function and
48motility.
Parathyroid
Both hyperparathyroidism and hypoparathyroidism can cause GI symptoms. GI symptoms occur in half of patients with hyperparathyroidism
49and 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 be due to hypercalcemia, which results in altered neuronal transmission and neuromuscular
50excitability. Hypoparathyroidism can be associated with malabsorption and steatorrhea. The small intestinal mucosa is typically
51histologically normal, but rare associations with celiac sprue have been reported.
Thyroid
Both hyperthyroidism and hypothyroidism can cause GI symptoms. Hyperthyroidism produces hypermotility of the gut, and hypothyroidism
52causes hypomotility. Hyperthyroidism can result in rapid gastric emptying, watery diarrhea, and steatorrhea. N o 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,
52ileus, volvulus, constipation, and megacolon. I n patients with marked myxedema, dilation and thickening of the bowel wall with microscopic
53accumulation of mucopolysaccharide substances in the submucosa, muscularis propria, and serosa have been described.
Thyroid neoplasms may also produce GI effects. Medullary carcinoma of the thyroid is a tumor of the calcitonin-producing endocrine C cells
54of the thyroid. Patients may have prominent “explosive” watery diarrhea as the result of ectopic hormone production. Papillary carcinoma of
55the thyroid also can be associated with Gardner 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 I I a, and MEN I I b (or I I I ). GI manifestations are caused by the products
56of endocrine proliferations. Each of these syndromes is associated with a mutant gene locus—MEN I with theM EN1 gene locus, and MEN
I I a and I I b with theR ET gene locus. MEN I is associated with pancreatic endocrine tumors (often gastrinomas) and with the Zollinger-Ellison
syndrome, which is associated with gastric and duodenal disease. MEN I I b may be associated with ganglioneuromatosis, ganglion cell
hyperplasia, and hypertrophy of the plexuses of Meissner and Auerbach in the GI tract. Chronic constipation, diarrhea, or both may be
57associated with MEN IIb.
Hematologic Disorders
Hemorrhagic Disorders
Patients with bleeding disorders may develop spontaneous hemorrhage in any part of the GI tract. Between 10% and2 5% of patients with
58 59hemophilia suffer from GI hemorrhage. Von Willebrand disease, heparin or warfarin overdose, vitamin K deficiencies, platelet deficiency,
thrombotic thrombocytopenic purpura, and hemolytic-uremic syndrome (HUS ) 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. I t can be severe enough to involve the entire thickness
60of the bowel wall and give rise to an intramural hematoma. More severe lesions can cause luminal narrowing, rigidity with obstruction, and,
58rarely, intussusception.
Thrombotic Disorders
61 62 63S ickle cell anemia, polycythemia rubra vera, and other thrombotic disorders can produce thrombosis, leading to infarction and
hemorrhage of the intestines. S ickle cell anemia causes sickling of red blood cells and hyperviscosity of the blood and typically produces
61arterial and capillary obstruction. I t involves the watershed areas of the distal transverse colon and splenic flexure, which have the lowest
oxygen tension. S ickled 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. D iagnosis is based on the finding
of venous thrombi in the mesenteric and mesocolic tissues not in the field of infarction, which occur in conjunction with appropriate clinical
history.
Megaloblastic Anemia
Megaloblastic anemias are associated with deficiencies of folic acid and vitamin B . These anemias are characterized by megaloblastic12
proliferation of actively growing cells, as is typically described in bone marrow aspirations but is also seen in the epithelial cells of the GI tract.
Owing to impaired D N A synthesis, actively dividing cells in the gastric pits, small bowel, and colonic crypts typically show enlarged,
immature-appearing nuclei (Fig. 6.2). The nucleus-to-cytoplasm ratio is decreased. The overall numbers of mitotic figures are also reduced. I n
64addition, PA S -negative, A lcian 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 6.2 Nucleomegaly in megaloblastic anemia; in this high-power view, actively dividing cells are 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
I nvolvement 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 31 for details).
65Autopsy studies have revealed GI involvement in 50% of patients with leukemia. I n secondary involvement of the GI tract by either
66leukemia or lymphoma, tumor infiltrates are often multifocal and may be present anywhere from the esophagus to the rectum. These
infiltrates can cause aphthous-type ulcers (typical of leukemic infiltrations) or can result in polypoid, masslike, or large ulcers (typical of
67 68lymphomatous involvement). The larger mass lesions can occasionally cause obstruction or intussusception. Histologic features are those
typical of the particular type of leukemia or lymphoma. Malignant cells are typically found in the mucosal and submucosal tissue. Tissue
should be collected for molecular and cytogenetic analysis, because many leukemias and lymphomas include diagnostic and clinically
69important changes. Primary lymphomas of the GI tract are often solitary lesions, although diffuse forms do occur (usually in the small
bowel).
S econdary effects of tumor overgrowth, or of chemotherapy, resulting in decreased numbers of platelets and inflammatory cells can lead to
hemorrhagic lesions of the GI tract and opportunistic infections. I n addition, neutropenic colitis, which is a necrotizing inflammatory disorder
70of the colon that occurs in neutropenic patients, can occur 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. I t typically manifests with diarrhea. Histologically, it is characterized by apoptosis of the epithelial
71cells, followed by crypt and gland loss and, ultimately, mucosal erosion and ulceration.
Metabolic Disorders
Acrodermatitis Enteropathica
A crodermatitis enteropathica is a systemic disorder that occurs secondary to zinc deficiency resulting from a congenital defect in absorption of
72dietary zinc. This disorder has been localized to a gene (SLC39A4) that codes for a transmembrane zinc uptake protein (hZI P4). I t typically
73manifests after infancy and weaning (although rare cases have been described in adulthood ). I t is characterized by chronic diarrhea
associated with failure to thrive, periorofacial dermatitis, paronychia, nail dystrophy, alopecia, susceptibility to infection, and behavioral
change. S erum zinc levels are typically decreased. Treatment is provided in the form of oral zinc. Mucosal biopsy of the small bowel can be
74normal or can show mild, patchy villous lesions. A bnormal inclusion bodies have been described in Paneth cells on electron microscopy.
75 76Acrodermatitis may also be caused by zinc deficiency secondary to Crohn's disease or malnutrition.
Plummer-Vinson Syndrome (Paterson–Brown Kelly Syndrome)
77The unusual Plummer-Vinson syndrome has shown a recent decrease in incidence. I t is characterized by iron deficiency (its presumed
78cause), dysphagia, and esophageal webs. D ermatologic findings of angular stomatitis, atrophic tongue, and briGle nails are also seen.
Longstanding disease is associated with an increased incidence of postcricoid carcinoma. Iron repletion improves all lesions.
Vitamin Disorders
I n general, vitamin disorders are not associated with specific GI symptoms or lesions. Exceptions are brown bowel syndrome, which is thought
to be caused by a deficiency of vitamin E (discussed later), and pellagra, which is associated with niacin deficiency (discussed in this section).
Multiple vitamin deficiencies are often noted in malabsorptive disorders. Vitamins, macronutrients, and minerals are thought to have a
79,80 81protective effect with respect to neoplasia of the GI tract, especially for esophageal and gastric malignancies. D eficiency in vitamin K or
82anticoagulation therapy leads to a decrease in coagulation factors and can result in hemorrhagic lesions throughout the body. I n the GI tract,
these range from focal petechial hemorrhages to frank exsanguination. N o specific histologic features are associated with these lesions.
S imilarly, vitamin C deficiency (scurvy) can lead to hemorrhage and delayed wound healing. D eficiencies of folic acid and vitamin B are12
83associated with megaloblastic anemia and megaloblastic changes in the epithelial cells of the stomach and small intestine. Olestra (a
84nonabsorbed fat replacement) may decrease the absorption of fat-soluble vitamins.
Pellagra
Pellagra is a vitamin deficiency that has major GI effects. I t is caused by a deficiency of niacin, either dietary (deficiency found in developing
85 86countries, alcoholics, and the elderly) or secondary to impaired absorption (e.g., Crohn's disease, amyloidosis ). I t is characterized clinically
87by diarrhea, dermatitis, and dementia. D iarrhea is often bloody. However, patients can have steatorrhea. The vitamin deficiency interferes
with the normal renewal of epithelial tissue; hence, the effects on the skin and GI tract. Endoscopically, approximately half of patients have
lesions. However, all have microscopic inflammation. Endoscopic lesions range from redness and granularity to focal ulceration and more88extensive confluent lesions. Microscopically, the inflammatory infiltrate is nonspecific. I n the esophagus, mild to severe esophagitis is seen.
89The small bowel may be normal or may show mild villous blunting and increased inflammatory cells in the lamina propria. I n the large
bowel, a mild to moderate inflammatory infiltrate with features of colitis cystica superficialis (cystic dilation of the crypts and crypt abscess
formation) has been described. Patients usually respond to niacin replacement therapy.
Lipoprotein Disorders
Abetalipoproteinemia
A betalipoproteinemia (discussed further in Chapter 9) 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
90disturbance in gait and balance and fatigue. On peripheral smear, acanthocytes are usually prominent (in 50% of red blood cells). Laboratory
findings show an absence of very-low-density lipoproteins, the presence of chylomicrons, and a reduction in triglycerides and other lipids. The
91defect occurs in a microsomal triglyceride transfer protein required for the secretion of plasma lipoproteins containing apolipoprotein B.
N ormal intraluminal digestion of lipids occurs, along with transport of triglycerides and monoglycerides and their reesterification in
enterocytes. However, lipids cannot be excreted on the basal lateral membrane of the enterocytes into blood and lymphatics. Histologically,
this translates into prominent accumulation of fine lipid droplets within the basal aspect of the enterocytes (Fig. 6.3). These can be stained
with Oil Red O on frozen-section tissue or seen by electron microscopic examination. The overall architecture of the small bowel is normally
well maintained. One pitfall in diagnosis is the similar appearance of lipid droplets identified in normal individuals after a recent lipid-rich
meal; therefore, the diagnosis should be made only in fasting patients.
FIGURE 6.3 Abetalipoproteinemia. A, High-power view shows vacuolated epithelial cells that are clear-staining. B, Fat
stain highlights 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; 2003:742.)
Tangier Disease
Tangier disease is an autosomal recessive disorder characterized by deposition of cholesteryl esters in the reticuloendothelial system, almost
92complete absence of high-density lipoprotein in the plasma, and aberrant cellular lipid trafficking. Clinically, patients present with
hepatosplenomegaly, enlarged tonsils, peripheral neuropathy, and, occasionally, diarrhea. Laboratory studies reveal low blood levels of
highdensity lipoprotein and cholesterol (due to lack of apoprotein A) and high levels of triglycerides. Endoscopically, the lesions are described as
93tiny yellow nodules or orange-brown spots. Microscopic examination reveals clusters of foamy histiocytes in the lamina propria (Fig. 6.4).
94Electron microscopic findings include intracytoplasmic vacuoles unbounded by membranes; these are often confluent in appearance (see
Chapter 9 for details).
FIGURE 6.4 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. S ubstances typically accumulate within cells at the site where most of the degraded material is found; degradation
typically occurs at this location.
S torage disorders can be divided based on the biochemical nature of the accumulated metabolite into glycogenoses, sphingolipidoses(lipidoses), mucopolysaccharidoses, mucolipidoses, and others. Most of these diseases have prominent central or peripheral nervous system
95 96effects. Except for Fabry disease, they do not have significant GI effects. Case reports of malabsorption in GM1 gangliosidosis, diarrhea in
97 98Niemann-Pick disease, and diarrhea and vomiting in Wolman disease have been described.
The importance of these diseases is that depositions can be identified in a variety of cells in the GI tract (Table 6.2), 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 S udan black on frozen-section tissue or PA S stain, depending on
the particular substance that has accumulated. Electron microscopic examination typically reveals enlarged, unusually shaped lysosomes.
Historically, many of these diagnoses have been made on rectal biopsy with histochemical stains and subsequent electron microscopic
99-101examination. This technique has largely been supplanted by specific enzyme content analysis of circulating lymphocytes or biopsy
material. Differentiation among the common mimics of storage disorders is described in the next section.
Table 6.2
Lysosomal Storage Diseases
ElectronMajor Accumulating
MicroscopicDisease Enzyme Deficiency GI Symptoms Affected Cells Histologic FeaturesMetabolite
Features
Glycogenoses
Type 2 Pompe α-1,4-Glucosidase Glycogen None Hepatocytes, Glycogen within Glycogen
disease cardiac and sarcoplasm, PAS
skeletal positive
muscle cells
Sphingolipidoses
GM1 GM1 ganglioside β- GM1 ganglioside Malabsorption Neurons Ballooned neurons, Whorled
gangliosidosis galactosidase fat stain positive configurations
GM2 Gangliosidosis
Tay-Sachs disease Hexosaminidase α GM2 ganglioside None Neurons Ballooned neurons, Whorled
subunit fat stain positive configurations
Sandhoff disease Hexosaminidase β GM2 ganglioside None Neurons Ballooned neurons, Whorled
subunit fat stain positive configurations
Variant AB Ganglioside activator GM2 ganglioside None Neurons Ballooned neurons, Whorled
protein fat stain positive configurations
Sulfatidoses
Metachromatic Arylsulfatase A Sulfatide None Phagocytic cells Inclusions stain Free lipid bodies
leukodystrophy with toluidine without
blue or other cytosomes
metachromatic
stains
Multiple sulfatase Arylsulfatases A, B, Sulfatide, heparan None Phagocytic cells Inclusions stain Zebra bodies
deficiency C sulfate, dermatan with toluidine
sulfate blue and other
metachromatic
stains
Krabbe disease Galactosylceramidase Galactocerebroside None Phagocytic cells Globoid PAS- Curved tubular
positive cells inclusions
Fabry disease α-Galactosidase A Ceramide trihexoside Delayed Phagocytic, Vacuolization, fat Zebra bodies
gastric ganglion, stain positive
emptying endothelial
cells,
smooth
muscle
fibers
Gaucher disease Glucocerebrosidase Glucocerebroside None Phagocytic cells Fibrillary cytoplasm Elongated
(tissue paper– lysosomes,
like), PAS stacks of
positive bilayers
Niemann-Pick Sphingomyelinase Sphingomyelin Diarrhea Phagocytic Innumerable small, Zebra bodies
disease cells, axons, uniform
Schwann vacuoles, PAS
cells positive
Mucopolysaccharidoses (MPS)
Hurler syndrome α-l-Iduronidase Dermatan sulfate, None Phagocytic Balloon cells, PAS Lamellated zebra
(MPS I) heparan sulfate cells, positive bodies
endothelial
cells
fibroblasts
Hunter syndrome l-Iduronidase Dermatan sulfate, None Phagocytic Balloon cells, PAS Lamellated zebra
(MPS II) sulfatase heparan sulfate cells, positive bodiesendothelial ElectronMajor Accumulating cells, intimal MicroscopicDisease Enzyme Deficiency GI Symptoms Affected Cells Histologic FeaturesMetabolite cells, Features
fibroblasts
Mucolipidoses (ML)
I-cell disease Mannose-6- Mucopolysaccharide, None Gastric chief Vacuolated cells, Enlarged
(ML2) phosphate glycolipid cells, PAS and fat lysosomes
phosphorylating enterocytes stain positive
enzyme
Other
Cystinosis Cystine Cystine transported None Phagocytic cells Polarizable crystals,
Membraneunfixed bound
specimen crystals
Mannosidosis Oligosaccharides Mannosidase None Phagocytic Small vacuoles, PAS Small
membranecells, nerve positive on bound bodies
and muscle frozen section with fibrillar
cells, only material
fibroblasts
Neuronal ceroid Unknown Ceroid or lipofuscin-like None Phagocytic Large, coarse, Globules with a
lipofuscinosis protein cells, some granular granular
(Batten disease muscle and pigment, matrix,
and Kufs Schwann positive for “Finnish
disease) cells, Sudan black, snowballs”
endothelial PAS, acid-fast,
cells yellow
autofluorescence
Wolman disease Acid lipase Cholesterol esters, Diarrhea, Phagocytic cells Large lipid
Membranetriglycerides vomiting vacuoles, fat bound lipid
stain positive droplets
GI, Gastrointestinal; PAS, periodic acid–Schiff stain.
Fabry Disease
Fabry disease is a rare, X-linked lipid storage disorder that is caused by a deficiency of lysosomal α -galactosidase A and results in cellular
deposition of glycolipids in many tissues. Clinically, these patients have involvement of multiple organ systems. S ymptoms include
excruciating pain in the extremities (acroparesthesia), skin vessel ectasia (angiokeratoma), corneal and lenticular opacity, cardiovascular
102 103disease, stroke, and renal failure. GI symptoms are seen in 62% of male and 29% of female heterozygotes. Features include vascular
104 105 106ectasia, delayed gastric emptying, diarrhea, and, rarely, ischemic bowel disease with perforation. Histologically, glycolipid deposition
is identified in vacuolated ganglion cells in the Meissner plexus and in small blood vessels. By electron microscopy, laminated and amorphous
103intralysosomal, “zebra-like,” osmiophilic deposits occur in ganglion cells, smooth muscle fibers, and endothelial cells.
Common Mimics of Lysosomal Storage Diseases
Common mimics of lysosomal storage diseases are summarized in Table 6.3. These are divided into two general categories—pigmented and
nonpigmented. The majority of lesions result from a proliferation of histiocytes with either engulfed infectious organisms or cellular or
extracellular material. Pigmented lesions, which are in the differential diagnosis of neuronal ceroid lipofuscinosis, include melanosis,
pseudomelanosis, brown bowel syndrome, hemosiderosis, and barium granuloma. N onpigmented lesions are in the differential diagnosis of
all of the rest of the lysosomal storage diseases and include xanthoma, muciphages, Whipple disease, Mycobacterium avium-intracellulare
complex (MAC) infection, pseudolipomatosis, malakoplakia, granular cell tumors, signet ring adenocarcinoma, and malignant histiocytosis.Table 6.3
Macrophage Infiltrates in the Lamina Propria
Diagnosis Histology Histochemical Immunohistochemical
Pigmented
Melanosis Dark brown, granular macrophages PAS and acid-fast positive CD 68 positive (must bleach pigment)
Pseudomelanosis Black, subepithelial macrophages Iron positive CD 68 positive
Brown bowel Brown smooth muscle cells PAS, acid-fast positive N/A
syndrome Yellow autofluorescence
Hemosiderosis/ Finely granular, brown to black particles in Iron positive N/A
hemochromatosis epithelial cells
Barium granuloma Gray, finely granular refractile pigment PAS negative N/A
Chronic Golden-brown macrophages Fat stain and PAS positive N/A
granulomatous
disease
Nonpigmented
Xanthoma Clear, foamy macrophages Fat stain positive on unfixed α -Antitrypsin, monocyte chemotactic1
tissue and activating factor positive
Muciphages Clear, foamy macrophages d-PAS, Alcian blue positive CD 68 and lysozyme positive
Pseudolipomatosis Clear open space with no cell lining Negative for all stains Negative for all immunostains
Whipple disease Pink, foamy macrophages d-PAS granular positive FISH for rRNA positive
Mycobacterium avium Pink, foamy macrophages Acid-fast or Fite positive CD 68 positive
d-PAS diffuse positive
Malakoplakia Pink, foamy macrophages with nuclear d-PAS positive CD 68 positive
grooves MGB positive for calcium
Michaelis-Gutmann bodies (MGB) and iron
Granular cell tumor Pink, granular histiocytic cells d-PAS positive S100 positive
Signet ring cell Clear cytoplasm with displaced nucleus d-PAS-, Alcian blue-, and Cytokeratin positive
adenocarcinoma mucin-positive globules
Clear cell carcinoid Clear cells with foamy cytoplasm d-PAS and mucin negative Chromogranin positive
tumor
Malignant Granular Langerhans cells with irregular d-PAS and mucin negative S100 and CD1a positive
histiocytosis elongate nuclei and nuclear grooves
d-PAS, Periodic acid–Schiff with diastase; FISH, Fluorescence in situ hybridization; PAS, periodic acid–Schiff; rRNA, ribosomal ribonucleic acid.
Pigmented Lesions
Melanosis.
Melanosis coli is characterized by pigment deposition in macrophages in the lamina propria. Endoscopically, the bowel mucosa can appear
normal or brownish in color, depending on the amount of pigment present. Occasionally, the pigment is so prominent that the mucosa shows
multiple foci of tiny white polypoid lesions on a brown background. The white lesions represent normal or hyperplastic lymphoid aggregates
107that do not contain pigment. Histologically, the pigment in macrophages has a dark brown, granular appearance, and these cells may be
108located anywhere in the lamina propria (Fig. 6.5, A). I t contains polymerized glycolipids, glycoproteins, and melanin (“melanized ceroid”)
and is typically associated with anthraquinone laxative use. However, a number of studies have shown an association with increased apoptosis
108,109 110 111 112of epithelial cells (caused by laxatives as well as chronic colitis, chronic granulomatous disease, and bamboo leaf extract ) and
have suggested that melanosis is a nonspecific marker of increased apoptosis.FIGURE 6.5 Pigmented cells mimicking lysosomal storage disease. A, Melanosis coli. Colonic mucosa contains lamina
propria macrophages with dark brown, granular appearance. B, Pseudomelanosis. Duodenal mucosa contains
macrophages with a black pigment. C, Barium. Colonic mucosa contains a gray, finely granular material in the lamina
propria.
Pseudomelanosis.
This is a rare benign condition characterized by the presence of discrete, flat, small, brown-black spots located typically in duodenal mucosa
113(speckled duodenum) but also reported in gastric mucosa. I t occurs in any age group and appears to be associated with upper GI bleeding,
114chronic renal failure, hypertension, or diabetes mellitus. Unlike melanosis coli, it is not associated with use of anthraquinone laxatives.
Microscopically, the black pigment is located subepithelially in mucosal macrophages, often at the tips of the villi (see Fig. 6.5, B).
Histochemical studies have revealed that the pigment represents a mixture of iron sulfide, hemosiderin, lipomelanin, and ceroid. I t 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 that is associated with malabsorptive states and vitamin E deficiency. I t 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. I t occurs most
often in the small bowel but can involve the colon or stomach as well. Vitamin E (α-tocopherol) is an antioxidant that prevents peroxidation of
unsaturated faGy acids. I t is postulated that a deficiency in this vitamin may result in oxidized lipids, which polymerize with polysaccharides
to form the brown pigment. Histologically, the pigment is most prominent in the smooth muscle cells of the muscularis mucosae and propria.
115S ome pigmentation of macrophages, nerves, ganglia, and vascular smooth muscle also is usually observed. The distribution of the pigment
in conjunction with an appropriate clinical history often helps in differentiation of this lesion from those described earlier. The pigment, which
stains positive with PAS, acid-fast, and fat stains on unfixed tissues, also shows the typical bright yellow autofluorescence pattern of lipofuscin.
116Electron microscopic examination usually reveals mitochondrial damage as well as pigment concentrated in the perinuclear Golgi region.
117 118Clinically, the pigment does not have any direct effect on the bowel, although defects in contractility, intussusception, and toxic
119megacolon have been reported.
Hemosiderosis/Hemochromatosis.
I n advanced iron overload disorders such as hemosiderosis or hemochromatosis, iron is deposited in parenchymal cells throughout the body.
I n the GI tract, deposits are found most commonly in the parietal cells of the stomach, the Brunner glands in the duodenum, and the epithelial
120,121cells of the gut. S ome minor amounts of pigment can also be seen in macrophages. The pigment appears as finely granular, dark brownto black particles. I t 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 occurs secondary to extravasation of barium into the wall of the bowel as
122a result of mucosal injury, overinflation of the rectal balloon, or intrinsic inflammatory disease. Endoscopically, it may manifest as a
polypoid lesion and may mimic an adenoma or carcinoma. Histologically, one sees a granulomatous reaction surrounding gray, finely granular,
refractile, PA S -negative material located in the cytoplasm of histiocytes and in the lamina propria (see Fig. 6.5, C). The material is not
123birefringent. Radiographs 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 termsx anthoma, xanthelasma, lipid island, and
xanthogranulomatous inflammation are used synonymously. Endoscopically, xanthomas appear as small yellow nodules or streaks on the
mucosa. They represent an accumulation of lipid and cholesterol within macrophages. Microscopically, one sees a collection of macrophages
containing foamy cytoplasm positive for fat stains on unfixed tissue (Fig. 6.6, A). I mmunohistochemical stains for α -antitrypsin and monocyte1
124chemotactic and activating factor are also typically positive, whereas cytokeratin and mucin stains are negative. The lesions are typically
125 124associated with chronic inflammatory states but can be seen with malignancies.FIGURE 6.6 Nonpigmented cells mimicking lysosomal storage disease. A, Xanthoma. A gastric biopsy specimen with
abundant macrophages in the lamina propria is shown. The macrophages have a bland central nucleus with foamy
cytoplasm. B, Muciphages in the rectum. Rectal biopsy specimen contains foamy macrophages with coarse, large
cytoplasmic vacuoles in the superficial lamina propria. C, Pseudolipomatosis. Colonic biopsy specimen shows clear, unlined
spaces in the lamina propria. D, Whipple disease. A small bowel biopsy specimen 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-intracellulare complex infection. A small bowel biopsy specimen with marked expansion of the lamina
propria of the villi by pink, homogeneous macrophages is shown. F, Malakoplakia. Colonic biopsy specimen shows
infiltration of the lamina propria with macrophages. A marked acute inflammatory infiltrate is also seen. The macrophages
contain small blue inclusions (Michaelis-Gutmann bodies). G, Granular cell tumor. An esophageal biopsy specimen with
infiltration of large granular cells in the lamina propria below the squamous epithelium is shown. H, Signet ring cell
adenocarcinoma. Gastric biopsy specimen shows infiltration of single cells in the lamina propria. Signet ring cells can be
identified in the center of the photograph, just under the surface epithelium. They contain eccentrically located, enlarged,
atypical nuclei.
Muciphages.
These are mucin-rich phagocytes that accumulate as a result of mucosal damage. They are most common in the rectum (as many as 40% of all
126 127rectal biopsies contain muciphages) and are also commonly found in the lamina propria and in the stalk of adenomatous polyps.
Endoscopically, muciphages can appear as polyps or nodules. Histologically, foamy histiocytes containing coarse cytoplasmic vacuoles are
present in the superficial lamina propria (see Fig. 6.6, B). Mild fibrosis and architectural distortion may occur in cases associated with a
128previous injury. Histochemical stains with d-PA S (PA S with diastase digestion) and A lcian blue at pH 2.5 and with immunohistochemical
stains for CD68 and lysozyme are positive in muciphages.
Pseudolipomatosis.
This is a common iatrogenic lesion caused by influx of air into the mucosa secondary to endoscopy-related trauma. I t is a benign, transient
129lesion that is characterized histologically by clear open spaces in the lamina propria or submucosa, representing trapped gas, without an
130epithelial or endothelial cell lining (see Fig. 6.6, C). These clear spaces do not stain with any specific immunohistochemical or histochemical
reaction.
Whipple Disease.
This is a systemic infection that is caused by a cultivation-resistant bacterium, Tropheryma whippelii. I n the GI tract, it is primarily found in the
131 132small bowel; however, it can involve the stomach, esophagus, and colon as well. Histologically, one sees characteristic abundant,
pinkcolored, foamy macrophages filling the lamina propria. These macrophages may contain small granules that are positive for d-PA S .
Extracellular lipid is often present as well (see Fig. 6.6, D). Electron microscopic examination reveals intracellular and extracellular bacterial
133rods in various stages of disintegration. These bacteria are also found within I gA -positive plasma cells. With the use of fluorescence in situ
hybridization (FI S H) for ribosomal RN A , the active organism appears to be most prevalent near the tips of intestinal villi in the lamina
134propria.
Mycobacterium avium-intracellulare Complex Infection.135This is a common pathogen in A I D S that may also bes een in other immunocompromised patients. I t typically affects the small bowel and
136colon. Endoscopically, the mucosa can appear normal or coarsely granular. Histologically, abundant, variably sized sheets of foamy
macrophages are seen in the lamina propria and cause widening of the villi (see Fig. 6.6, E). D iagnosis is made with acid-fast or Fite stain
positivity; numerous elongated organisms are revealed within the macrophages. PA S stain typically reveals a relatively diffuse fibrillary
staining paGern in macrophages, as opposed to the granular staining characteristic of Whipple disease. The organisms are typically intact,
unlike the various stages of disintegration that are seen in Whipple disease.
Malakoplakia.
This is a rare bacterial infection that affects patients with an underlying macrophage phagolysosome defect (not typically seen in patients with
137 138AIDS). I t is usually caused by Escherichia coli or Klebsiella spp. and 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, there is infiltration of the lamina propria by neutrophils and abundant macrophages; the
laGer often contain nuclear grooves (see Fig. 6.6, F). Michaelis-Gutmann bodies, which are small, pale, intracytoplasmic concretions that stain
for calcium and iron, are diagnostic. Macrophages also stain with d-PA S . Electron microscopic examination reveals degenerated bacilli in
139phagolysosomes, similar to those seen in Whipple disease.
Granular Cell Tumor.
140These tumors are believed to be of neurogenic origin and are typically found in the esophagus, but they can occur anywhere in the GI tract.
141,142Rare cases have been described in the small bowel and colon. They are mostly benign, but malignant tumors have rarely been
described. The tumors typically manifest as nodules in patients with nonspecific GI symptoms. Histologically, these tumors include abundant
epithelioid or histiocytic cells with distinct pink granular cytoplasm in the lamina propria or submucosa (see Fig. 6.6, G). The cells are positive
for d-PA S and are strongly S 100 positive. Electron microscopic examination reveals cells filled with giant autophagic vacuoles (lysosomes) that
contain myelin-like debris of giant lysosomes.
Signet Ring Cell Adenocarcinoma.
This tumor (described in detail in Chapters 25 and 27) shows an infiltration of malignant cells with clear cytoplasm and an eccentrically placed
hyperchromatic nucleus (see Fig. 6.6, H). I t is differentiated from other lesions by the presence of highly atypical nuclear features and by
143positivity with mucin and cytokeratin stains.
Clear Cell Carcinoid Tumor.
144A rare case has been reported of a gastric carcinoid composed entirely of clear cells with foamy cytoplasm. I mmunopositivity 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.
I nvolved areas may manifest as a polypoid or mass lesion. Histologically, one sees a mucosal infiltrate composed of Langerhans cells that have
irregular, elongated nuclei and prominent nuclear grooves and folds. The cytoplasm of the tumor cells is abundant and finely granular. These
tumors are usually associated with a prominent eosinophilic infiltrate as well. A s with mucosa-associated lymphoid tissue (MA LT) lymphoma,
145invasion and destruction of the epithelium are common. I mmunohistochemical stains for S 100 and CD 1a are intensely positive in tumor
146cells. Electron microscopic examination reveals Birbeck granules in the cytoplasm of tumor cells.
Amyloidosis
A myloidosis is not a single disease but the product of a variety of diseases. The common feature of these diseases is extracellular deposition of
amyloid proteins that stain with Congo red and show apple-green birefringence under polarized light. The proteins have a typical fibrillary
appearance on electron microscopy. A ll amyloid fibrils are protein complexes with a common tertiary molecular structure, referred to as a
twisted β-pleated sheet pattern.
Classification
Historically, amyloidosis was classified according to its clinical presentation (localized versus diffuse) or its underlying cause (primary,
secondary, hereditary, or endocrine related); now, the classification is determined on the basis of the biochemical composition of the amyloid
fibrils (Table 6.4). The most common types that involve the GI tract are A A , A L, and A β 2M. I n addition to the more common proteins listed in
the table, a number of other types of amyloid proteins have been described, such as A β (β protein precursor), A A poA 1 (apolipoprotein A 1),
ALys (lysozyme), ACys (cystatin C), and AGel (gelsolin).
Table 6.4
Amyloidosis
Amyloid Precursor
Etiology Type Disease
Protein
Primary AL Myeloma, Waldenström, plasma cell dyscrasias B-cell malignancies Light chains
AH Heavy chain disease Immunoglobulin G1
Secondary AA Chronic inflammatory lesions: inflammatory bowel disease, rheumatoid arthritis, chronic Serum amyloid A
infections, familial Mediterranean fever
Rare malignancies: gastric and renal carcinoma
Aβ2M Long-term kidney dialysis β -Microglobulin2
Hereditary ATTR Familial amyloid polyneuropathy Transthyretin
(prealbumin)
AFib Fibrinogen A
αchain
Endocrine AIAAP Endocrine associated Islet amyloid
polypeptide
Clinical Features147-149GI involvement is common in all types of systemic amyloidosis (primary and secondary), ranging from 85% to 100%. I n most cases
associated with systemic amyloidosis, patchy involvement of the GI tract is seen without associated symptoms. However, a variety of GI
150 151 152 153symptoms may occur, including bleeding, pseudo-obstruction, decreased motility, and, rarely, perforation. The greater the
number of deposits and the more widespread the involvement, the higher the likelihood of clinical symptoms. Vascular involvement by
amyloid produces fragility and rupture of affected vessels, which can lead to the development of petechial hemorrhage of the mucosa and
154ischemic disease and its manifestations. In fact, ulcerating lesions may mimic IBD grossly.
155 156A myloid infiltration within nerve and muscle fibers can cause motility disorders. Malabsorption may result from stasis and bacterial
157overgrowth. Finally, amyloidosis can occasionally manifest as a solitary mass lesion or polyp that mimics a malignant tumor.
Endoscopically, the mucosa may appear normal or may show a fine granular appearance with erosions, friability, and thickening of the
158,159valvulae conniventes.
Pathologic Features
Microscopically, amyloid deposits are extracellular and have a classic waxy, homogeneous appearance (Fig. 6.7, A). Pink hyaline amyloid may
contain small, slitlike spaces caused by cracking during tissue processing. Histochemical stains for Congo red (the most specific), toluidine
blue, crystal violet, fluorochrome, and thioflavine are usually positive with all types of amyloid (see Fig. 6.7, B). A myloid also stains positive
with the PA S reaction and negative with lipid and mineral stains. I n general, A A amyloid seems to localize to capillaries, small arterioles, and
the mucosa. A L amyloid is often found in the muscularis propria and in medium-sized to large vessels. A β2M amyloid is found mainly in the
160muscularis propria and in small arterioles and venules, forming subendothelial nodular lesions. A L and A A forms also can be
distinguished by pretreatment with potassium permanganate. This pretreatment abolishes the Congo red affinity of the AA fibrils but not that
161of the A L fibrils. I mmunohistochemical stains with antibodies to amyloid A , immunoglobulins λ and κ light chain amyloid fibril proteins,
162β -microglobulin, and transthyretin characterize the majority of amyloid deposits. Electron microscopy reveals an interlocking meshwork2
of fibrils that measure 7.5 to 10 nm in diameter with variable length.
FIGURE 6.7 Amyloidosis. A, Intermediate-power view of a colonic mucosal biopsy specimen. Homogeneous material is
present in the vessels in the submucosa and as extracellular deposits. The overlying colonic mucosa is unremarkable. B,
Same section stained with Congo red. The amyloid deposits have a bright orange-red appearance.
A myloidosis should be differentiated from arteriosclerosis in blood vessels and from collagen in the lamina propria, submucosa, and
muscularis (in systemic sclerosis). Congo red stains can help with this differential diagnosis in that neither arteriosclerosis nor collagen stains
with Congo red. One study suggested that Congo red stain may not be sensitive enough in patients with early amyloidosis in minute
163amounts.
GI biopsy is a procedure commonly used to diagnosis amyloidosis. Rectal biopsies have a sensitivity of 85%, compared with a sensitivity of
14754% for fat biopsies. I n 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. S ome studies have suggested that gastric or small bowel biopsies have a
156,164sensitivity as high as 100% for the diagnosis of amyloidosis.
Familial Mediterranean Fever (Familial Paroxysmal Polyserositis, Recurring Polyserositis)
Familial Mediterranean fever is an inherited autosomal recessive disorder seen almost exclusively in S ephardic J ews, A rabs, A rmenians, and
people of Turkish descent. I t is characterized by recurring and self-limited aGacks of fevers and serosal inflammation involving the peritoneal,
synovial, and pleural membranes. This disease typically begins in childhood or adolescence and recurs at irregular intervals throughout
165life. GI involvement consists of acute inflammation limited to the serosal surfaces of the bowel (peritonitis). Repeated episodes can result
in the formation of peritoneal adhesions that may cause obstruction. S ystemic amyloidosis may also occur in untreated patients. The A A
amyloid type is believed to develop as a consequence of recurrent inflammation. Furthermore, amyloid deposits in the lamina propria and the
submucosal vessels may occur without symptoms. The disease is often treated with colchicine.
Pulmonary Disorders
Hypoxia-producing pulmonary disorders can lead to ischemic injury of the GI tract. A n increased incidence of peptic ulcer disease has also
166been described in patients with chronic obstructive pulmonary disease. This is thought to be the result of hypercapnia, which stimulates
gastric acid secretion. Pneumonia, bronchitis, asthma, and idiopathic pulmonary fibrosis are all associated with gastroesophageal reflux
167disease (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. N ausea, vomiting, and heartburn are common in the first trimester. S ome studies168suggest that these effects are secondary to human chorionic gonadotropin or estrogen secretion, which leads to abnormalities in gastric
169myoelectrical activity and contractility. S econdary esophagitis may develop as a result of severe vomiting. Reflux, peptic ulcers, Helicobacter
pylori infection, and cholecystitis are also increased. I n addition, constipation is a frequent problem during the late stages of pregnancy.
170Thrombosed external hemorrhoids, anal fissures, and rectal wall prolapse can occur secondary to vaginal delivery.
Pregnancy outcomes are generally good in patients with I BD . Population studies suggest that maternal I BD is associated with increased
odds of preterm delivery, low birth weight, smallness for gestational age (Crohn's disease), and congenital malformations (ulcerative
171-173colitis). The risk of pregnancy-related complications and the disease behavior during pregnancy depend mainly on disease activity at
the time of conception. However, pregnancy does not seem to influence the course of I BD . Most drugs used to treat I BD are safe to use in
pregnancy and breast feeding. Biologic agents do cross the placenta (mainly in the third trimester) and are often held after 30 weeks' gestation
174and restarted after delivery.
Oral contraceptive pills and exogenous estrogens are associated with nausea and vomiting. They also are associated with thrombosis and,
175consequently, an increased risk for ischemia of the small bowel and colon.
Decidualization of the Peritoneum
Ectopic decidualization of the peritoneum is a rare lesion. I t can yield macroscopic nodules (peritoneal deciduosis or deciduosis peritonei) that
176mimic peritoneal carcinomatosis. Grossly, multiple light-tan peritoneal masses or nodules typically are identified at the time of caesarean
section. Microscopically, plump pink (decidualized) cells are present between the mesothelial cells and muscularis propria (Fig. 6.8). This is a
physiologic reaction with an excellent prognosis and spontaneous resolution after delivery.
FIGURE 6.8 Decidualization of the peritoneum. A, Low-power view of the serosal aspect of a colonic resection specimen.
Muscularis propria is present at the superior portion of the image with marked thickening and decidualization of the
subserosal tissue. B, High-power view of the plump pink (decidualized) cells present between the muscularis propria
(superior) and mesothelial cells (inferior).
Endometriosis
Clinical Features
Endometriosis is a condition characterized by the presence of endometrial glands or stroma outside of the uterus. I t can involve any portion of
the GI tract. The most common sites of involvement are organs in the pelvis such as the rectosigmoid colon, appendix, and small bowel. The GI
177tract is involved in 12% to 37% of cases. I ntestinal endometriosis is usually asymptomatic. However, when symptomatic, it typically causes
177obstructive symptoms as a result of adhesions. Complete obstruction of the bowel lumen occurs in fewer 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 manifest 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 a 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. 6.9). At least two of these three findings should be present for a diagnosis of
endometriosis to be established with certainty. I n addition, fibrosis and prominent smooth muscle proliferation may surround foci of
endometriosis. Fresh hemorrhage may occur. I mmunohistochemical staining for estrogen receptors is usually positive in both the glands and
178stromal cells.