Atlas of Gastrointestinal Pathology: A Pattern Based Approach to Non-Neoplastic Biopsies [1 ed.] 1451188102, 9781451188103

Table of contents :
Title
Copyright
Contributors
Preface
Acknowledgments
Contents
ESOPHAGUS
THE UNREMARKABLE ESOPHAGUS
ACUTE ESOPHAGITIS PATTERN
EOSINOPHILIC PATTERN
PARAKERATOTIC PATTERN
ESOPHAGEAL LYMPHOCYTOSIS PATTERN
PIGMENTS
NEAR MISSES
STOMACH
THE UNREMARKABLE STOMACH
REACTIVE GASTRITIS/GASTROPATHY PATTERN
ACUTE GASTRITIS PATTERN
CHRONIC GASTRITIS PATTERN
LYMPHOCYTIC GASTRITIS PATTERN
COLLAGENOUS GASTRITIS PATTERN
GASTRIC EOSINOPHILIA PATTERN
HYPERPLASTIC PATTERN
GRANULOMATOUS GASTRITIS PATTERN
VASCULAR AND HEMORRHAGIC CHANGES PATTERN
PIGMENTS AND EXTRAS
NEAR MISSES
SMALL BOWEL
THE UNREMARKABLE SMALL BOWEL
ACUTE DUODENITIS PATTERN
ACUTE ILEITIS PATTERN
CHRONIC INFLAMMATION PATTERN
CRYPT ARCHITECTURAL DISTURBANCE PATTERN
EOSINOPHILIA PATTERN
MALABSORTION PATTERN
FOAMY MACROPHAGE PATTERN
DILATED LACTEAL PATTERN
METAPLASIA AND HETEROTOPIA
PIGMENTS AND EXTRAS
NEAR MISSES
COLON
THE UNREMARKABLE COLON
FOCAL ACTIVE COLITIS PATTERN
ACUTE COLITIS PATTERN
ISCHEMIC COLITIS PATTERN
PSEUDOMEMBRANOUS PATTERN
CHRONIC COLITIS PATTERN
LYMPHOCYTIC PATTERN
EOSINOPHILIA PATTERN
GRANULOMATOUS PATTERN
PIGMENTS AND EXTRAS
NEAR MISSES
INDEX

Citation preview

Atlas of Gastrointestinal Pathology A Pattern Based Approach to Non-Neoplastic Biopsies

CHRISTINA A. ARNOLD, MD

Assi stant Professor Department of Pathology Division of Gastrointestinal and Liver Pathology Division of Bone and Soft Tissue Pathology The Ohio State University Wexner Medical Center Columbus , Ohio DORA M. LAM-HIMLlN, MD

Assistant Professor Department of Laboratory Medicine and Pathology Mayo Clinic Scottsdale , Arizona ELIZABETH A. MONTGOMERY, MD

Professor of Pathology, Oncology, and Orthopedic Surgery Department of Pathology Division of Gastrointestinal and Liver Pathology Johns Hopkins Medical Institutions Baltimore , Maryland

®

Wolters Kluwer Philadelphia· Baltimore· New York· London Buenos Aires· Hong Kong· Sydney· Tokyo

Acquisitions Editor: Ryan Shaw Product Development Editor: Kate Marshall Marketing Manager: Dan Dressler Production Project Manager: Joan Sinclair Design Coordinator: Teresa Mallon Manufacturing Coordinator: Beth Welsh Prepress Vendor: Aptara, Inc. Copyright © 2015 Wolters Kluwer All rights reserved. This book is protected by copyright. No part of this book may be reproduced or transmitted in any form or by any means, including as photocopies or scanned-in or other electronic copies, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews. Materials appearing in this book prepared by individuals as part of their official duties as U.s.

government employees are not covered by the above-mentioned copyright. To request permission, please contact Wolters Kluwer at Two Commerce Square, 2001 Market Street, Philadelphia, PA 19103, via email at [email protected]. or via our website at Iww.com (products and services). 9 8 7 6 5 4 3 2 Printed in China.

Library of Congress Cataloging-in-Publication Data Arnold, Christina A., author.

Atlas of Gastrointestinal Pathology: A Pattern Based Approach to Non-Neoplastic Biopsies I Christina A. Arnold, Dora

M. Lam-Himlin, Elizabeth A. Montgomery p. ;cm. Includes bibliographical references. ISBN 978-1-4511-8810-3 (hardback) I. Lam-Himlin, Dora M., author. II. Montgomery, Elizabeth (Elizabeth A.), 1958- author. Ill. Title. [DNLM: 1. Gastrointestinal Diseases-pathology-Atlases. 2. Gastrointestinal Tract-pathology-Atlases. WI 171 RC802.9 616.3'307-dc23 2014017635 This work is provided "as is," and the publisher disclaims any and all warranties, express or implied, including any war­ ranties as to accuracy, comprehensiveness, or currency of the content of this work. This work is no substitute for individual patient assessment based upon healthcare professionals' examination of each pa­ tient and consideration of, among other things, age, weight, gender, current or prior medical conditions, medication his­ tory, laboratory data and other factors unique to the patient. T he publisher does not provide medical advice or guidance and this work is merely a reference tool. Healthcare professionals, and not the publisher, are solely responsible for the use of this work including all medical judgments and for any resulting diagnosis and treatments. Given continuous, rapid advances in medical science and health information, independent professional verification of medical diagnoses, indications, appropriate pharmaceutical selections and dosages, and treatment options should be made and healthcare professionals should consult a variety of sources. W hen prescribing medication, healthcare professionals are advised to consult the product information sheet (the manufacturer's package insert) accompanying each drug to ver­ ify, among other things, conditions of use, warnings and side effects and identify any changes in dosage schedule or con­ tradictions, particularly if the medication to be administered is new, infrequently used or has a narrow therapeutic range. To the maximum extent permitted under applicable law, no responSibility is assumed by the publisher for any injury and! or damage to persons or property, as a matter of products liability, negligence law or otherwise, or from any reference to or use by any person of this work. LWWcom

ex> o ' pancreas) , oxyntic gland hyperplasia , and gastric and small bowel ulcerations . Secondary to tumor-mediated hypergastrinemia . Most are sporadic . Thirty percent are familial due to MENl tumor suppressor mutation.

Chapter 2

Fig u re 2 . 1 76 Oxyntic g l a n d hyperp l a s i a patte rn . This biopsy was of n o n polypoid m u cosa a n d sh ows s l i g ht oxyntic g l a n d d i l atation with m i l d l u m i n a l snouti n g . This n o n specifi c patte rn can be seen with a n y p rocess that i nterferes with gastric acid p roductio n ; it is n ot specific fo r p roton p u m p i n h i bitor usage.

FAQ: If the biopsy i s of flat m ucosa and s l i g ht oxyntic g l a n d d i l atation is see n , is

" p roto n- p u m p i n h i bitor c h a n g e " a p p ropriate ( F i g . 2 . 1 76)? Answer: P roba b l y n ot. In the spora d i c sett i n g , oxyntic g l a n d hyperp l a s i a is seen with a n y eti o l ogy ch a rac­ terized by l ow g a stric acid p rod u ct i o n a n d , con seq uently, hyperg a stri n e m i a . Reca l l , g a stric acid i n h i b its G -ce l l m e d i ated p ro d u ction of g a strin a n d , converse ly g a s­ tric a c i d d e p l etion rel i eves th i s negative i n h i bition a n d resu lts i n e n h a n ced G - ce l l m e d i ated re l ease o f g a stri n , i n attem pts t o restore a c i d p ro d u ction ( F i g . 2 . 80) . H ig h g a stri n l eve l s sti m u l ate t h e oxyntic m u cosa t o p rod uce a c i d a n d i n d uce oxyn­ tic gland hyperp l a s i a , resu l t i n g i n d i l ated oxyntic g l a n d s and hypertro p h i c oxy n ­ tic e p i th e l i u m w i t h p rotu bera nt l u m i n a l " snouts " . Th i s n o n specific m o rphology i s see n w i t h a n y p rocess that i nterferes w i t h g a stric a c i d p rod u cti o n , such as p ro­ ton p u m p i n h i bitors, a u to i m m u n e m eta p l a stic atro p h i c g a stritis, a n d l ate e n v i ron­ m e nta l m eta p l a stic atro p h i c g a striti s (He/icoba cter, m e d i cations, rea ctive g a striti s/ g astropathy, etc . ) . To fu rth e r e m p h a size t h i s poi nt, Helicobacter i nfect i o n s were recently fou n d to p rod uce identical h i sto l o g i c fi n d i n g s i n oxyntic m u cosa as those seen with P P I S . 1 50 As a res u l t , descri b i n g the h i sto l o g i c featu res of oxyntic hyperp l a ­ s i a w i t h o u t p resu m i n g the c h a n g es a re l i n ked t o a part i c u l a r m e d i cation i s advised .

FOVEO LAR HYP E RP LAS IA Hyperplasia of the superficial gastric foveolar epithelium can result i n either discreet gastric hyperplastic polyps or giant gastric folds . Because superficial gastric foveolar epithelium lines the entire stomach, this hyperplastic pattern can be seen in any stomach compartment. Gastric hyperplastic polyps are the second most common stomach polyp , comprising 1 7% of all stomach polyps 1 4 3 They are seen in any compartment of the stomach : antral ( 5 6 % ) , oxyntic (60 % ) , and transitional (60%) . 1 5 1 Earlier work found up t o 85% were associated with background inflammatory injury, such as Helicobacter (2 5 % ) , reactive gastritis/gastropathy (2 1 % ) , autoimmune metaplastic atrophic gastritis ( 1 2 %) , and environmental metaplastic atrophic gastritis (8 % ) , suggesting gastric hyperplastic polyps are a marker for nonspecific gastric mucosal injury, unlike their colonic counterparts . 1 5 2 As a result, gastric hyperplastic polyps can be an important red flag for one to consider other speCific etiologic agents of mucosal injury (Figs . 2 . 1 7 7 and 2 . 1 78) Histologically, gastric hyperplastic polyps are benign neoplasms defined by polypoid foveolar hyperplasia, cystic dilatation of antral and pyloric

STO MACH

1 41

1 42

AT LAS

0 F

GASTR0 I NT EST I N A L

PAT H O LOGY

F i g u re 2 . 1 7 7 Foveo l a r hyperp l a s i a patter n , g a stric hyperp l a st i c p o l y p w i t h i ro n deposition . U n l ike colon hyperplastic p o l y p s , g a stric hyperp l a stic po lyps a re a result of m u cosal inju ry. Ca refu l i nspection wi l l occasio n a l ly u n cover the potentia l i nj u rious a gent. I n this case, i ro n d e position was fou n d (arrowhead), a potenti a l contri butor to this i nj u ry pattern .

F i g u re 2 . 1 78 Fove o l a r hyperp l a s i a patter n , g a stric hyperp l a stic polyp with i ron depositi o n . Higher power of previous fig u re .

Figure 2 . 1 7 9 Fove o l ar hyperplasia pattern, sporadic gastric hyper­ p l a stic polyp. This a ntra l gastric hyperp l a stic polyp appears polyp­ oid at sca n n i n g m a g n ificatio n . The cha racteristic h isto l o g i c features i n c l u d e p ro m i n e n t fove o l a r hyperp l a s i a and a n infl a m m a to ry rich stro m a . Foca l i ntest i n a l m eta plasia is a lso seen (arrowhead).

Figure 2 . 1 80 Foveolar hyperplasia pattern, sporadic gastric hyper­ p l a stic polyp. H i g h e r power of previous case (Fi g . 2 . 1 7 9) sh ows the foca l intesti n a l m eta p l a s i a .

glands, and increased lamina propria acute and chronic inflammation . Ulcerations , erosions , increased lamina propria acute and chronic inflammation, and fibromuscular hyperplasia! prolapse change are common (Figs . 2 . 1 79-2 . 1 84) . Lam-Himlin and colleagues found sporadic gastric hyperplastiC polyps defied reliable dis­ tinction from syndromic gastric juvenile polyps (Figs . 2 . 1 85-2 . 1 89) and syndromic gastric Peutz-Jeghers polyps (Figs . 2 . 1 90 and 2 . 1 9 1 ) , despite the latter two polyps' more character­ istic histology when seen in the small and large bowel . 1 5 1 Similarly, nearly indistinguishable morphology is seen in polyps of Cronkhite-Canada syndrome (Figs . 2 . 1 92-2 . 1 94) and PTEN-associated hamartomatous polyps (Cowden syndrome , Bannayan-Riley-Ruvalcaba syndrome, Adult Lhermitte-Duclos disease) (Figs. 2 . 1 9 5 and 2 . 1 96) . Although gastric pol­ yps are themselves benign, if they are linked to a polyposis syndrome associated with an increased risk of neoplasia or mortality, then they become important red flags for close clini­ cal follow-up . Since the histologiC features of sporadic and syndromic gastric hyperplastic

C h a pte r 2

5TOMAC H

1 43

Figure 2 . 1 8 1 Fove o l a r hyperplasia pattern , spora d i c gastric hyper­ p l a stic polyp. I n this polyp, fove o l a r hyperplasia a n d i n fl a m m atory strom a is seen . The fove o l a r epith e l i u m is mucin de p l eted, a m a n i ­ festation o f foca l l y rea ctive a n d regenerative c h a n g e typical o f th i s injury patte rn .

F i g u re 2 . 1 8 2 Fove o l a r h y p e rp l a s i a patte rn , spora d i c gastric hyperpl astic polyp. G a stris hyperplastic polyps a re often eroded a n d u l ce rated with a cute and c h ro n i ca l l y i nfl a m ed l a m i n a propri a , as i n t h i s case.

Figure 2 . 1 83 Foveol a r hyperplasia pattern , spora d i c gastric hyper­ p lastic polyp. H ig h e r power. The inta ct epith e l i u m shows fove o l a r hyperp l a s i a a n d cysti c d i l atation of the a ntra l/py l o ri c g l a n d s .

Figure 2 . 1 84 Foveol a r hyperp l a s i a pattern, spora d i c gastric hyper­ p l a stic polyp. N ote the pro m i nent fove o l a r hyperp l a s i a a n d cystic d i l atation of the a ntra l/pyloric g l a n d s .

Figure 2 . 1 85 Fove o l a r hyperp l as i a pattern, j uve n i l e polyposis syn­ d rome, g a stric resectio n . This p a rtia l gastric resection was for gastric o bstruction seco n d a ry to i n n u m e ra b l e g a stric polyps i n a patient with esta b l ished juve n i l e polyposis synd ro m e .

Figure 2 . 1 86 Fove o l a r hyperp l a s i a pattern, juve n i l e polyposis syn­ d ro m e , g a stric resect i o n . J u ve n i l e polyposis synd rome is chara cter­ ized by SMAD4 and BMPR 1 A m utations.

1 44

ATLAS

O F

GASTRO I N TESTI N A L

PAT H O LOGY

Figure 2 . 1 87 Foveo l a r hyperplasia pattern, juve n i l e polyposis syn­ d ro m e . Correspo n d i n g h isto l o g i c sections of the polyps s h ow i n d is­ t i n g u i s h a b l e morp h o l ogy from sporadic g a stric hyperpl astic polyps: fove o l a r hyperp l a s i a , cystic d i l atation of the a ntra l/py l o ri c g l a nds, a n d a n i nfl amed lamina p ropri a .

Figure 2 . 1 88 Foveo l a r hyperp l a s i a pattern, juve n i l e polyposis syn­ d ro m e . Alternate fie l d .

Fig u re 2 . 1 89 Foveol a r hyperplasia pattern, juve n i l e polyposis syn­ d ro m e . H i g h e r power. Foveo l a r hyperplasia, cystic d i l atation of the a ntra l/pylori c g l a nds, and a n i nfl amed l a m i n a propria is see n . This g a stric j u ve n i l e polyp is i n d istin g u i s h a b l e fro m a spora d i c g a stric hyperp l a stic polyp.

Figure 2 . 1 90 Fove o l a r hyperp l asia patte rn, Peutz-J e g h e rs polyp. This gastric polyp features fove o l a r hyperp l a s i a , cystic d i l atation of the a ntra l/pyl oric g l a n ds, and a n i nfl a m ed l a m i n a propri a . Scattered sm ooth b u n d l es a re seen (arrowh eads), a feature wh ich can be seen as a m a n ifestation of p ro l a pse i nj u ry i n l a rg e polyps of any sort, a n d a lso i n g a stric Peutz-J e g h e rs polyps. I n the s m a l l bowel a n d col o n , these lesions a re m o re e a s i l y reco g n ized based on the prom in en t a rborizi n g sm ooth m uscle fi bers enve l o p i n g l a rge g ro u ps of u n re­ m a rka b l e m u cosa . Ana l og o u s fi n d i n g s i n the stomach a re m i n i m a l a n d nonspecific.

Figure 2 . 1 9 1 Fove o lar hyperplasia patte rn, Peutz-J e g h e rs polyp. H igher powerofprevious case (Fig. 2 . 1 90). Patients with syndromic Peutz­ J e g h e rs have germ l i n e STK1 11LKB l m utations a n d a 93% lifeti m e risk for m a l i g n a ncy, i n c l u d i n g ca rci nomas o f t h e gastroi ntesti n a l tract, breast, ova ry, and testis. Sporadic Peutz-Jeghers polyps h ave a s i m i l a r l ifetim e risk o f m a l i g n a n cy, and req u i re s i m i l a rly cl ose surve i l lance.

Figure 2. 1 92 Foveol a r hyperplasia pattern , Cronkh ite-Ca nada syn­ d rome. In Cronkh ite-Canada synd rome, both the polyp and interven­ i n g non polypoid m u cosa show similar features to a sporadic gastric hyperplastic polyp, as seen here . N ote the foveolar hyperplasia, cystic d i l atation of the antra l/pyloric g l ands, and the i nfla m ed l a m i n a propri a .

C h a pte r 2

STOM AC H

1 45

F i g u re 2 . 1 93 Foveo l a r hyperp l a s i a patte r n , Cro n k h ite-Ca n a d a syn d ro m e . Cro n kh ite-Ca n a d a i s a n o n i n h e rited c l i n i ca l condition c h a ra cterized by g a stro i n testi n a l h a m a rtomatous polyposis, d i a r­ rhea, a n d dermato l o g i c abnormal ities (a lopecia, onychodystrophy, a n d hyperp i g m e ntation).

Figure 2 . 1 94 Fove o l a r hyperp l a s i a patte rn , Cro n kh ite-Ca n a d a syn d rome. Despite this b l a n d a p pe a ra n ce, o n l y 55% o f patients a re a l ive at 5 yea rs after d i a g nosis; accu rate, t i m e l y d i a g n osis is critica l to ensure a p p ropriate supportive thera py. I n isolation, these features a re i n d isti n g u is h a b l e fro m a gastris hyperp l a stic polyp.

Fig u re 2 . 1 95 Foveo l a r hyperp l a s i a patte r n , Cowde n syn d ro m e . G a stric polyps o f PTEN synd romes a re i n d isti n g u is h a b l e from those of spora d i c g astric hyperplastic polyps. PTEN syn d romes of i nterest i n c l u d e Cowden synd rome, B a n n a yan-R i l ey-Ruva lcaba syn d ro m e , a n d a d u l t Lherm itte-Duclos disease.

Figure 2 . 1 96 Fove o l a r hyperp l a s i a patte rn, Cowden synd ro m e . H i g h e r power. The PTEN pathway negative ly reg u l ates the ph os­ p h atidyl i n ositol 3 - k i n a se-AKT a n d m a m m a l i a n target of ra pamy­ c i n (mTOR) sig n a l i n g pathways, thereby, l e a d i n g to tum origenesis t h ro u g h i n terferi n g with cel l prol iferation, ce l l cyc l e p rogression, and apoptosis.

polyps are indistinguishable , awareness of these clinical syndromes and diagnostic criteria is important to assure appropriate clinical follow-up (Table 2 . 3 ) . 153,15 4 In challenging cases, cor­ relation with endoscopic evaluation of the small and large bowel can be helpful to highlight the syndromic polyps' more characteristic features, as is molecular correlation (syndromic juvenile polyposis is characterized by SMAD4, BMPRl A mutations ; syndromic Peutz-Jeghers is characterized by STKl l lLKBl germline mutations; Cowden syndrome , Bannayan-Riley­ Ruvalcaba syndrome , Adult Lhermitte-Duclos disease have PTEN mutations) . If diffuse changes are seen involving both the polypoid and nonpolypoid mucosa , Cronkhite-Canada should be considered. It is an exceptionally rare , non familial syndrome characterized by the triad of alopecia , onychodystrophy, and hyperpigmentation . 155 , 156 Patients present with altered taste , diarrhea , nutritional defiCiency, and generalized edema . Histologic sections of both the polyp , and , importantly, the nonpolypoid mucosa show features indistinguishable from gastric hyperplastic polyps with foveolar hyperplasia , cystic dilatation of antral and pyloric glands, increased lamina propria acute and chronic inflammation, and fibromuscular hyperplasia/prolapse change (Figs . 2 . 1 92-2 . 1 94) . The 5-year mortality rate is 5 5 % , underscoring the importance of recognizing this pattern so that appropriate supportive measures can be taken with electrolyte stabilization and immunosuppression.

1 46

ATLAS

O F

GASTRO I N T E S T I N A L

PAT H O LOGY

Figure 2 . 1 97 Foveo l a r hyperp l a s i a patter n , M e netri e r disease. N ote t h e p ro m i nent fove o l a r hyperp l a s i a and cystic d i l atatio n of the superfi c i a l g l a n ds. The oxyntic g l a nds a re re latively atten u ated (bracket). S u perficial biopsy of this lesion wou l d be i n d isti n g u ishable from a spora d i c g a stric hyperp l a stic polyp. Another consideration for massive foveolar hyperplasia is Menetrier disease . I t is another rare syndrome (so an extremely popular subj ect for examinations ! ) seen in the foveolar hyperplasia pattern . In biopsy material , it is indistinguishable from sporadic gastric hyperplastic polyp s , but clinically it is characterized by gigantic gastric folds that histologically consist of dramatic foveolar hyperplasia and oxyntic gland loss (Fig. 2 . 1 9 7) . Clinically, patients have protein losing enteropathy, peripheral edema , and hypochlor­ hydria (increased pH) secondary to the massive mucus secretion that impairs normal absorption and alters the local microenvironment. 1 57 In adults , the disease is chroni c , progressive , and associated with TGFa overexpression. 1 58 Transgenic mice with TGFa over­ expression show Menetrier disease-like findings , suggesting this molecule may be play a central role in Menetrier disease , at least in the adult setting. 159 In children, Menetrier disease is associated with CMV infection and can spontaneously regress . 1 60 Treatment is generally supportive with a high-protein die t , although some patients ultimately require gastrectomies for intractable Symptoms . Newer studies show promising success with EGF receptor inhibitors , which competitively inhibit TGFa binding and activation of the EGF receptor. 161-163 KEY F EATU R E S of t h e Fove o l a r Hype r p l a si a Patter n : •

Discrete gastric polyps •

Sporadic gastric hyperplastic polyps indicate background mucosal injury.

•

They can be seen in any gastric compartment .

•

•

•

Sporadic gastric hyperplastic polyps are histologically indistinguishable from the syndromic counterparts (Gastric Juvenile Polyp , Gastric Peutz-Jeghers Polyp , Cronkhite-Canada Syndrome , PTEN syndromes (Cowden syndrome , Bannayan­ Riley-Ruvalcaba syndrome , Adult Lhermitte-Duclos disease) , and Menetrier diseas e . Awareness of the syndromic associations i s critical because of the increased risk of neoplasia and mortality

Giant gastric folds •

Cronkhite-Canada is characterized by the triad of alopecia , onychodystrophy, and hyperpigmentation. •

•

Patients present with altered taste , diarrhea , nutritional deficiency, and general­ ized edema . Histologic sections of both the polyp and nonpolypoid mucosa show features indistinguishable from gastric hyperplastic polyps.

C h a pter 2

•

•

The 5-year mortality rate is 55%.

•

Treatment is supportive.

Menetrier disease is characterized by protein losing enteropathy, peripheral edema , and hypochlorhydria (increased pH) . •

•

Biopsy is indistinguishable from gastric hyperplastic polyp but the clinical presen­ tation consists of dramatic, giant gastric folds . Associated with TGFa overexpression in adults , and CMV in children.

PEARLS & PITFALLS

Patients with syn d ro m i c Peutz-J e g h e rs h a ve g e rm l i n e STK 1 1 1LKB 1 m utatio n s a n d a 9 3 % l ifet i m e r i s k fo r m a l i g n a n cy, i n c l u d i n g ca rc i n o m a s o f t h e g a stro i ntesti n a l tract, b rea st, ova ry, a n d test i s . Sporadic Peutz-J e g h e rs po l yps have a s i m i l a r l ife­ t i m e risk of m a l i g n a n cy, a n d req u i re s i m i l a rl y c l ose s u rvei l l a n c e . 1 64

G RAN U LO MATOUS GASTRITIS PATTERN

Figu re 2 . 1 98 G ra n u l o m atous g a stritis pattern. The g ra n u l o m atous g a stritis pattern is best a p p reciated at low power. I n th i s specta c u l a r exa m p l e , n u m erous l a rge g ra n u l om ata a re seen d e e p i n t h e m u cosa (arrowheads) . Th is patient had a h i story of sa rco idosis, was status post pancreatoduodenectom y for pancreatic adenocarci n o m a , a n d was on c h e m othera py. Conseq u e n tl y, this patient h a d n u m e rous potentia l causes fo r this no nspecific i nj u ry pattern .

C H E C K L I ST: Eti o l o g i c C o n s i d e rati o n s for t h e G r a n u l o matous G a stritis Pattern o

Cro h n D i sease

o

Sarcoidosis

o

I nfect i o n (Helicobacter, Myco b a cter i a l , F u n g a l)

o

M ed i cation

o

Fore i g n Body R e a ct i o n

o

N e a r by N e o p l a s m

o

Va scu l itis (B est Assessed o n Resection Speci m e n s)

o

Com m o n Var i a b l e I m m u n odefi c i e n cy

o

Chro n i c Gra n u l om ato u s D i sease

STO MACH

1 47

1 48

ATLAS

O F

GASTRO I N TE ST I N A L

PAT H O LOGY

Granulomata are collections of epithelioid histiocytes admixed with lymphocytes and plasma cells (Fig. 2 . 1 98) . They are occasionally accompanied by foreign body-type giant cells (Figs . 2 . 1 99-2 . 2 05) . The morphology of the granulomata can offer some clues to a specific etiology based on subtle histologic features: poorly formed granulomata are com­ monly seen in Crohn disease , tight granulomata are common in sarcoidosis , and uniformly sized granulomata with caseating necrosis suggest an infection . Unfortunately, these sub­ tle histologic clues are not reliable enough for a confident etiologic diagnosis . Indee d , the granulomatous gastritis pattern may be one of the best examples of a patterns based approach because the identical inj ury pattern can be seen with an expansive list of varied

Figure 2 . 1 99 G ra n u l om ata . H i g h e r power of the p revious case ( F i g . 2 . 1 98). A g ra n u l o m a is a co l l ecti o n of epith e l io i d h i stiocytes a d m ixed with lymphocytes a n d p l a s m a ce l ls . As seen h e re, epith e l i ­ o i d h i stiocytes a re cha racterized b y " s l i pper-sha ped " n u clei o r nuclei with oblong, thin n u clei (arrowheads) . Speci a l sta i n s for Helicobacter, fu n g i (G M S) , and mycobacteria (AFB) were negative.

F i g u re 2 . 200 G ra n u l o m ata , fo re i g n body rea ct i o n . I n t h i s c l a s­ s i c exa m p l e of a g ra n u l o m a , t h e epith e l ioid h i stiocyte co l l e ction is s u rrou nded by lym ph ocytes, p l a s m a cells, a n d scattered fo re i g n body-type g i a n t ce l l s (arrowheads) . Th is patient h a d a h isto ry o f a gastrostomy tube p l a cement a n d m u cosa l erythema was e ndoscopi­ ca l ly identified i n association with the i n stru ment ti p . I n the a bsence of oth er contri buti n g factors, iatrog e n i c i nj u ry was the l i ke l y n i d u s fo r t h e associ ated g ra n u l o m atous infl a m mati o n . Specia l sta i n s for m i croo rg a n isms were negative .

Fig u re 2 . 2 0 1 G ra n u l o m atous g a stritis patte r n , sa rcoidosis. This case o ri g i n ated fro m a patient with sa rcoidosis. Speci a l sta i n s fo r m icroorg a n isms were negative .

F i g u re 2 . 20 2 G ra n u l o m atous g a stritis patte rn, C ro h n d is e a s e . Alth o u g h the prior c a s e s fea t u re spectac u l a r tea c h i n g exa m p l e s of the g ra n u l o m ato us gastritis pattern, i n a ctua l ity, g a stric g ra n u lo­ m ata a re u su a l ly m uch h a rd e r to identify. This m o re typical exa m p l e o ri g i n ated from a patient with a l o n g -sta n d i n g h i story o f u pp e r­ tract Cro h n d i sease. A sma l l , poorly formed g ra n u l o m a is i d entified (arrowh ead) i n a backgro u n d of a ctive chro n i c gastritis .

C h a pte r 2

Figure 2 . 203 G ra n u l o m atous gastritis pattern , Cro h n d isease. O n h i g h e r power, t h e epith e l ioid appeara n ce o f t h e h i stiocytes is better appreciated (arrowhead), as is the backg ro u n d a ctive c h ro n i c i nfl a m ­ mati o n . Speci a l sta i n s for m i croorg a n isms were negative, suggest­ i n g this i nj u ry pattern was m ost l i ke l y a m a n ifestation of upper-tract Cro h n d isease.

ST O M AC H

1 49

Figure 2.204 G ra n u lo m atous gastritis pattern , Cro h n d isease. This case features a n other sneaky g ra n u loma (arrowhead) i n a patient with a h i story of u pper-tract Cro h n d isease. This type of subtle g ra n u l o m a is best appreciated on sca n n i n g magnificatio n : at low power, a " h o l e " ­ l i ke appeara n ce is d u e to loca l displacement o f the neighboring gas­ tric pits. A backg ro u n d of a ctive chronic infl a mmation is a l so see n .

Figure 2 . 205 G ra n u l o matous g a stritis patter n , Cro h n d isease. I t wo u l d be e a sy to m iss this tiny g ra n u l o m a (arrowh ea d) w i t h such p ro m i n ent backgro u n d a ctive c h ro n i c infl a m m ation : g ra n u l o m ata a re typi ca l l y best seen at l ower power (co m p a re to previous fig u re). Speci a l sta i n s for m icroorg a n isms were negative.

clinical settings . In the largest series of the granulomatous gastritis pattern ( n = 71 patients) , most cases showed a single granuloma and most granulomas (64%) were located in the antrum. Careful clinical correlation determined an association with Helicobacter (92 % , n = 64) , Crohn disease (52 % , n = 3 7) , foreign body reaction ( 1 0 % , n = 7) , neoplasms (7% , n = 4) , sarcoidosis ( 1 % , n = 1 ) , Whipple disease ( 1 % , n = 1 ) , and vasculitis ( 1 % , n = 1 ) 165 . Similar associations have been reported by others . 166 167 The granulomatous gastritis pattern can also be a red flag to consider rare immune-mediated diseases such as common vari­ able immunodeficiency (CVID) 98 and chronic granulomatous disease (CGD) / 68 making it worthwhile to evaluate for apoptotic body prominence and paucity of plasma cells (CVID) and a careful chart review for clinical stigmata of CGD, particularly in the p ediatric setting. Some suggest that idiopathic granulomatous gastritis is rare, if it exists at all, and should be surmised only if a thorough and exhaustive exclusion of all possible diagnoses have been confidently excluded . 166 This leaves the pathologist with a fair amount of detective work, including careful scrutiny of the background mucosa , a detailed clinical chart review, and

1 50

ATLAS

O F

GASTRO I N T E ST I N A L

P AT H O LO G Y

often a conversation with the clinician to frame this peculiar finding in its appropriate clinicopathologic context . Acid fast bacillus (AFB) and Gomori methenamine silver (GMS) special stains are worthwhile to exclude mycobacteria and fungal organisms , respectively, in all cases of granulomatous gastritis , although most are negative .

FAQ: What is the significance of an isolated foreign body g i a nt ce l l in the stom­ ach (Fig. 2 . 206)? Answer: An i so lated fore i g n body g i a nt cell is a b n o rm a l but this fi n d i n g is etiologi­ ca l ly nonspecific. Deeper sections may be worthwh i l e to see if the fore i g n body g i a nt cel l is pa rt of a deeper g ra n u l o m a . S u c h cases a re signed out descri ptive ly with a n ote a d d ress i n g the m ost l i kely possi b i l ities after ca refu l c h a rt revi ew ; for exa m ple, i n the context of a patient with esta b l i shed sa rco idosis, th i s isol ated fi n d i n g is m ost l i kely com patib l e with the h i story of sa rcoidosis, whereas in patient status post che­ m othe ra py for widely m etastatic c a rci noma , a m ed i cation i nj u ry wou l d be favored, a ssu m i n g i nfection h a s been exc l u d e d . For the c l i n i c i a n , a n isol ated fore i g n body g i a nt cel l ca n someti mes ra ise concerns for Cro h n d isease, in w h i c h case corre l ation with the c l i n i ca l h i story and biopsies of the terrn i n a l i l e u m , rig h t col o n , l eft co l o n , a n d recta l biopsies may be worthwh i l e , i n the appropri ate c l i n icopath o l o g i c setti n g .

Fig u re 2 . 206 A n isolated fore i g n body-type g i a n t ce l l i n a back­ g ro u n d of active chro n i c g a stritis (arro w) . Alth o u g h an isolated for­ eign body g i a nt cel l is abnorm a l , it does n ot imply a specific etiology.

FAQ: What is the best a p p roach for a case wit h a vag uely g r a n u l o m a - l i ke focus t h at is exh austed on deeper sections? Answer: Bewa re of crushed g a stric e p i th e l i u m , ca uterized m uscu l a ri s m u cosae,

and scattered h i sti o cytes that ca n l oo k vag ue l y l i ke epith e l i o i d g ra n u l om ata i n s u b­ opti m a l speci m e n s . I n q uesti o n a b l e cases, deeper sectio n s a n d a C D 6 8 i m m u n o s­ ta i n ca n be h e l pfu l , if t h e i n d i cated foc u s is p resent on deeper sect i o n s . I n cases i n w h i c h col l e ctions o f h i sti o cytes a re s e e n but/the h i stiocytes l a c k both the epithe­ l io i d m o rp h o l ogy a n d g ra n u l o m a type a rc h i tectu re , " foca l h isti ocyte a g g regates" o r " foca l h isti o cyte co l l e cti o n s " a re satisfa cto ry to docu m e n t t h e fi n d i n g s without g l o rifyi n g these a m b i g u o u s fi n d i n g s with the c l i n i ca l ly c h a rged term " g ra n u l o m a " .

C h a pt e r 2

VASCU LAR AN D H E M ORRHAG I C CHAN G ES PATTERN

Figure 2 . 207 Vascu l a r changes, porta l hyperten sive g a stropathy (PHG). This exa m p l e i l l u strates a vascu l a r pattern of i nj u ry: a n u m be r of congested m u cosa l vessel s a re s e e n i n a backgro u n d of rea ctive gastritis/g astropathy. This patient was known to have cirrhosis a n d porta l hyperte n s i o n ; these h isto l o g i c fi n d i n g s s u p p o rt t h e c l i n i co­ path o l o g i c d i a g nosis of P H G .

A prominent vascular and or hemorrhagic pattern of gastric injury can be seen with a variety of entities (Fig. 2 . 2 07) . In especially satisfying cases, the underlying etiology can be established such as the identification of amyloid deposits in systemic amyloidosis or 9 Gyttrium-labeled microspheres in radiation gastritis; however, more common is the sce­ nario in which identification of this inj ury pattern prompts a careful examination of the background mucosa and chart review. Portal hypertensive gastropathy, for example , is a diagnosis seen with some regularity and yet the characteristic features can be subtle , requir­ ing a careful chart review for the requisite history of portal hypertension. Similarly, the characteristic features of GAVE can be almost miss-able in mild cases, requiring correla­ tion with the clinical history and the characteristic endoscopic image showing a striped watermelon-like pattern. This section discusses the most common causes of vascular and hemorrhagic pattern of gastric inj ury C H E C K L I ST: Eti o l o g i c C o n s i d e rations fo r Vascu l a r a n d or H e m o r r h a g i c Pattern o

Porta l Hyperte n sive Gastropathy

o

Gastr i c Antra l Vasc u l ar Ectas i a

o

Amy l o i d

o

R a d i a t i o n Gastritis Patter n

PO RTAL HYP E RT E N S IVE GASTRO PATHY Portal hypertension is a n increase i n the pressure o f the venous system , seen most commonly in cirrhotic patients . In healthy patients , the veins that drain the stomach , intestines, spleen , and p ancreas merge into the p ortal vein , which then drains into the liver. In cirrhotic patients , the advanced liver fibrosis creates a high-resistanc e , high­ pressure venous system, also termed "portal hypertension . " As a resul t , blood backs up into the low-resistance , low-pressure system o f the collateral circulation , mani­ festing as esophageal varices (or collateral circulation through the esophageal veins) ,

STO MACH

1 51

1 52

AT LAS

0 F

GAST R0 I N T E S T I N A L

PAT H O LOGY

caput medusa (or collateral circulation through the periumbilical and abdominal wall veins) , and hemorrhoids (or collateral circulation through the perirectal veins) . These congested, engorged vessels are prone to significant clinical bleeding with up to 2 5 % o f cirrhotic patients succumbing t o a fatal gastrointestinal hemorrhage . 1 69 After vari­ ceal bleeding, portal hypertensive gastropathy (PHG) and peptic ulcer disease are the next commonest causes of gastrointestinal blee ding in cirrhotic patients 1 70, 1 7 1 PHG is seen in 2 0 % to 9 8 % of cirrhotic patients . 1 7 2 - 1 74 Endoscopically, PHG consists of a snake skin mosaic-like pattern (as seen in mild cases) or bulging red or brown marks (as seen in marke d cases) that predominantly affects the body and fundus (Figs . 2 . 2 0 8 and 2 . 2 09) 1 69, 1 7 2 Histologically, variably prominent congested vessels are seen (Figs . 2 . 2 1 0-2 . 2 1 3 ) . The findings can be very subtle and easy to miss , but care­ ful attention to the requisition often uncovers the red flags of "esophageal varices" or "cirrhotic patient with upper gastrointestinal bleeding . " Treatment efforts are aimed at reducing the portal hypertenSion with medications , such as beta-blockers .

Figure 2 . 208 P H G , endoscopic a ppeara n ce . P H G sh ows a s n a ke ski n , mosaic-like pattern on endoscopy.

Figure 2 . 209 S n a ke ski n . This p h otog ra ph of a sna ke's skin sh ows sm ooth sca les positioned i n an a l m ost perfect geometric confi g u ra­ tion, features sim i l a r to those seen endoscopica l l y i n P H G .

Figure 2 . 2 1 0 P H G . At low power, the p red o m i n a n t fi n d i n g is that of rea ctive g a stritis/g a stropathy pattern of i nj u ry: g a stric foveo l a r m u c i n ce l l d e p l etio n , a co rkscrew- l i ke a ppearance o f t h e fove o l a r epith e l i u m , l a m i n a p ropria edema , a n d l ittle t o no infl a m m ation . The rea ctive g a stritis/gastropathy patte rn can be a red fl a g to a va riety of additi o n a l d i a g n oses. In this case, scattered congested vessels a re seen (arrowheads) .

Figure 2 . 2 1 1 P H G . On h i g h e r power, t h e congested vesse l s a re m o re easily seen . A chart review revea led a h i story of porta l hyper­ te n s i o n , a n d a d i a g n osis of porta l hyperte n s ive g a stropathy was rendered. This case is a n exce l l e n t exa m p l e of push i n g th ro u g h the fi rst obvious d i a g nosis (reactive g a stritis/gastropathy patte rn) a n d thoro u g h l y sea rch i n g fo r oth er i m porta nt d i a g n oses (porta l hyper­ tensive gastropathy) .

C h a pte r 2

Fig u re 2 . 2 1 2 P H G .

•

Clinical red flags include cirrhosis , portal hypertension, and esophageal varices .

•

Endoscopically, a snake-skin mosaic-like pattern or red marks are seen.

•

1 53

Fig u re 2 . 2 1 3 P H G . T h i s case was subm itted t o us i n consultation with a concern fo r dys p l a s i a . The req u isition deta i l ed a h i story of porta l hyperte n s i o n and the bio psy sh ows reactive g a stritis/g as­ tropathy and con gested m u cosal vesse ls, supporti n g a diag nosis of porta l hypertensive gastropathy. Although the epith e l i u m i n reactive gastritis/gastropathy can be atypica l , it is i m porta nt to i nterpret the changes in the context of the c l i n i copath ologic setti n g . In this case, the rea ctive epith e l i a l c h a n g es (a bit of hyperchromasia and n u c l e a r e n l a rgem ent) a re d iffuse, a fi n d i n g t h a t supports the d i a g n osis o f a rea ctive c h a n g e . I n contrast, dysp lasia has a brupt a n d d iscreet tra n ­ sitions. T h i s case w a s sig ned o u t as " porta l hypertensive gastropathy with rea ctive epith e l i a l change, negative fo r dysplasia . "

KEY F EATU R ES of P o rt a l Hypert e n sive G ast ropathy:

•

5T O M AC H

Histologically, the mucosa shows variably prominent congested vessels in the body and fundus . Treatment efforts are aimed at redUCing portal hypertension with beta-blockers .

GASTRI C ANTRAL VASC U LAR ECTAS IA GAVE shares many important clinical features with PHG (Table 2 . 4) . Both entities can occur in patients with background liver disease and chronic gastrointestinal bleeding, and whose gastric endoscopic images show red spots . 1 75 Distinction is important, however, since the treatments are unique: GAVE is treated with endoscopic techniques, whereas PHG is predominantly treated with medications to reduce the portal hypertension, such as beta-blockers . Distinguishing features of GAVE include that it is much less common, has a less stringent association with portal hypertension , and , instead, has associations with chronic renal failure , autoimmune connective tissue diseases, and bone marrow transplantation. 1 7 6- 1 78 In addition , GAVE is typically antral predominant, unlike PHG which is claSSically described as bodylfundus predominant. OccaSionally GAVE diffusely involves the stomach, in which case the preferred terminology is diffuse gastric vascu­ lar ectasia . Although both entities can have similar endoscopic images with gastric red spots, in GAVE , the red spots coalesce , imparting a striped watermelon-like appearance (Figs . 2 . 2 1 4 and 2 . 2 1 5) . Histologically, GAVE and PHG can both show a background of reactive gastritis/gastropathy and prominent ectatic, congested vessels . GAVE , however, also shows prominent mucosal thrombi (Figs . 2 . 2 1 6_2 . 2 2 0) 1 79 , 1 8 0 Endoscopic therapy remains the mainstay of GAVE treatment with argon plasma coagulation being the most common thermoablative based techniqu e . Unfortunately, some GAVE cases are refrac­ tory to standard endoscopic intervention and , consequently, (partial) gastric resection is sometimes require d .

1 54

AT LAS

0 F

GASTR0 I N TE STI N AL

PAT H O LOGY

TABLE 2.4: Gastric Antral Vascu lar Ectasia versus Portal Hypertensive Gastropathy Porta l Hypertensive Gastric Antra l Vascu l a r Ectasia

C l i n i ca l featu res

Gastropathy

Patie nts with l iver d i sease

+

C h ro n i c g a stro i n testi n a l

+

+

P o rta l hy p e rte n s i o n

+/-

+

Oth e r associati o n s

C h ro n i c re n a l fa i l u re, a u to i m m u n e

+

b l ee d i n g

m ixed c o n n ective tissue d i s o r­ d e rs, b o n e m a rrow tra n s p l a n t E n d o s co p i c featu res

Red o r b rown s p ots Oth e r

+

+

Str i p e d waterm e l o n - l i ke

S n a ke-ski n m o s a i c o r red/b rown s p ots

H i sto l o g i c featu res

D i stri b u t i o n C o n g ested ectatic vesse l s B a c k g ro u n d reactive g astritis / g a stropathy M u cosa l t h r o m b i

Antra l + +

+

+

+

E n d oscopy

Treatment

Body/F u n d u s

M ed ication

C R F, chro n i c ren a l fa i l u re; M CT, m ixed connective tissue d isease; B M T, bone m a rrow tra n s p l a nt.

KEY F EATU R E S of G a st r i c Antra l Vascu l a r Ect a s i a : •

•

•

•

Associations include patients with liver disease , chronic renal failure , autoimmune con­ nective tissue diseases , and bone marrow transplantations . Endoscopic images include gastric red spots which can coalesce into a striped water­ melon-like appearance . Histologically, a background of reactive gastritis/gastropathy, congested, ectatic ves­ sels , and prominent mucosal vascular thrombi are characteristic and most typically seen in the antrum. Treatment includes endoscopic therapy such as argon plasma coagulation and surgical resection in cases refractory to endoscopic management .

Figure 2 . 2 1 4 G a stric Antra l Vasc u l a r Ecta sia (GAVE). This endo­ scopic i m a g e sh ows a stri pped waterm e l o n - l i ke a p p e a ra n ce c h a r­ acteristic of GAVE.

F i g u re 2 . 2 1 5 Waterm e l o n . The waterm e l o n 's a lternating ye l l ow a n d g reen stri pes decorate the stem rem n a nt, a n d m i rror the m uco­ sal changes seen in GAVE.

C

h a pte

r

2

STOMAC H

1 55

F i g u re 2 . 2 1 6 GAV E . I n this rem a rka b l e case, a p a rti a l g a stric resection was perfo rmed fo r GAVE refra ctory to en dosco p i c m a n ­ a g e m ent. N u m e rous foci o f he mo rrhage a n d thro m b i a re seen a t sca n n i n g m a g n ificatio n (brackets) .

Figure 2 . 2 1 7 GAVE. O n h i g h e r power, i ntravascu l a r t h ro m b i a re seen a l o n g with pools of h e m orrh a g e . The correspon d i n g e n d o­ scop i c i m a g e s h owed t h e c h a ra cteristi c stri ped waterm e l o n- l i ke a ppeara n ce consistent with the c l i n i copathologic d i a g n osis of GAVE.

Figure 2 . 2 1 8 GAVE. T h i s s pecta c u l a r exa m p l e of GAVE sh ows a n u m ber of i ntravasc u l a r thro m b i (arrowh eads) . N ote, fi brin is h ot­ p i n k with a h o m og e n o u s a ppeara n c e . I n contrast, the nea rby con­ g ested vesse l s a re e n go rged with red blood cells (not thro m b i) a n d appear a bolder s h a d e o f red (arrows).

Figure 2 . 2 1 9 GAVE. The d i a g n osis of GAVE can be easy to m i ss at l ow power, u n l ess the m u cosa l vesse ls a re d i l i g ently i n s pected i n e a c h sto m a c h b i o psy. Often times, t h e m u cosa l thro m b i a re best a p p reciated on h i g h e r power, as in this case (arrowhead).

Fig u re 2 . 2 2 0 GAV E . T h i s case o ri g i n ated fro m a 5 5 -yea r-o l d w o m e n with a m ixed c o n n e ctive tissue disease, e m p h asizi n g t h e known association o f GAVE with a utoi m m u n e d i seases.

1 56

ATLAS

O F

GAST R O I N T E ST I N A L

PAT H O LO G Y

F i g u re 2 . 2 2 1 Amyloidosis. T h i s stom a c h b i opsy sh ows a pro m i ­ nent p i n k i nfi ltrate t h a t d i s p l a ces the n o rm a l back-to-back pit pat­ tern (arrowheads).

F i g u re 2 . 2 2 2 Amyloidosis. O n h i g h e r power, the p i n k materi a l is seen between stro m a l ce l ls .

F i g u r e 2 . 2 2 3 Amyloidosis (Con g o R e d ) . A C o n g o R e d confirms the p resence of amyloid, which is ora n g e o n d i rect l ight a n d bright g reen under p o l a rized l ight (not shown). This patient was seen for worku p of g a stro i ntesti n a l b l e e d i n g a n d was fo u n d to have a m y­ l o idosis i nvolving a l l G I biopsies (eso p h a g u s , sto m a c h , a n d colon).

AMYLO I D A hemorrhagic gastritis pattern can also be seen in the setting o f systemic amyloidosis . On mucosal biopsies , the deposition is most commonly seen within the lamina propria , muscularis mucosa e , or vascular walls . Deposition within vascular walls compromises the vessel's structural integrity and can result in hemorrhage and or ischemia to the downstream mucos a . Unfortunately, the deposition can be fo cal and subtle, and so requires diligent inspection . On H&E , amylOid appears glassy and amorphous with a characteristic cracking or "chatter" artifact (Figs . 2 . 2 2 1 -2 . 2 2 3 ) . The amylOid appears orange under direct light on a C ongo red speCial stain and bright-apple green under polarized ligh t .

RAD I ATION GASTRITIS PATT E R N Radiation gastritis pattern i s similar t o radiation injury seen elsewhere i n the gastrointes­ tinal tract . 1 8 U 82 Endoscopically, erythema , erosions , ulcerations , and friability can be seen (Fig. 2 . 224) . Histologically, lamina propria hyalinization, atypical stromal , endothe­ lial , and epithelial cells , and prominence of ectatic , and damaged vessels are seen (Figs . 2 . 2 2 5-2 . 2 2 7) . OccaSionally the radiation damage is seen in association with radia­ tion microspheres , such as 9 Clyttrium-labeled microspheres . See also Pigments & Extras

Ch a pter 2

Figu re 2 . 224 Radiation gastritis patte rn. This pati ent had a h i story of rad i ation for esoph ageal adenocarci n o m a . The endoscopic i m a g e is d ra m atic w i t h erosive c h a n ges, e ryth e m a , s u p e rfi c i a l u l cerati o n , m u cosa l s l o u g h i n g , a n d fri a b i l ity.

,', -="'� .........." ,..

"

1 57

Figure 2 . 22 5 Radiation gastritis pattern . The correspo n d i n g stom­ ach biopsy h a s m o re s u btle fi n d i n g s than the e n dosco p i c i m a g e . The ra diation g a stritis pattern refers t o t h e l a m i n a p ropria hya l i n iza­ tion and scattered ectatic vessels that a re para l l e l to the s u rface epi­ thel i u m (arrowheads) . I n a ctive c h ronic gastritis, i n c l u d i n g increased eosi n o p h i l s , and g l a n d u l a r atrophy a re a lso seen .

,-

:.4.

'f .' .

ST O M AC H

.- . ...

. .

, ,'

•

,

..

,

• •

. .

',

.

t

1'

-

. •

...

"

� ..,.

.

.

.

,

.p

..s · • .

...

.

;

J,

1

,

' .

\� . •

.

. \

.. \

•

.. ! , • ..

-

' III>' / 4

,

\

",

j

•

"

.

Figure 2 . 226 Radiation g a stritis patter n . On h i g h e r power, scat­ tered atypi c a l stro m a l ce l l s a re seen that a re hyperch romatic a n d a b i t p l e o m o r p h i c (a rrow) . The backg ro u n d s h ows scatte red, t h i n wa l l ed ectatic vess e l s (arrowhead) a n d stro m a l hya l i n izati o n t h a t appears p i n k . Occasi o n a l l y stro m a l hya l i n ization ra ises concerns for a myloidosis, but a m y l oidosis wo u l d n ot h ave atypical stro m a l ce l l s n o r th i n w a l l e d ectatic vessel s (reca l l a m y l oidosis typ i ca l l y i nfi ltrates the vessel w a l l s , resu lting in a th i ck, s m u d gy, vascu l a r wa l l ) . In c h a l ­ l e n g i n g cases, a C o n g o R e d spec i a l sta i n t o eva l u ate fo r amyloid is worthwh i l e . A CMV i m m u n osta i n was n e gative .

..

. � ., 4

·

� .

�

.,

'

.

.

. • - ....

Figure 2 . 227 Radiation gastritis pattern . This a lternate fie l d sh ows stro m a l h ya l i n ization (or l a m i n a p ropria expanded by p i n k m ate­ ri a l ) , scattered ectatic vessel s which that para l l e l to the s u rfa ce, a n d c h ro n i c infl a m m ation, i n c l u d i n g i n creased eosi n o p h i l s .

subsection, this chapter. Radiation gastritis has some overlap with CMV infections , making routine CMV immunostains worthwhile in these cases . The atypical stromal cells character­ istic of radiation gastritis can also raise concern for infiltrating carcinoma . In such cases a cytokeratin and smooth muscle actin stain can be reassuring (the atypical stromal cells are cytokeratin negative and sometimes smooth muscle actin positive) . P EA R LS & PITFALLS

S i nce rad iation i s a d m i n i ste red to m a n a g e n e o p l a s m s , recog n it i o n of th i s i nj u ry patte rn i s a n i m po rtant red fl a g to l o o k ca refu l l y fo r res i d u a l/recu rrent n e o p l a s m s .

1 58

ATLAS

0 F

GAST R0 I N TE S TI N A L

PAT H O LOGY

P IG M E NTS AN D EXTRAS

F i g u re 2 . 228 I ro n pattern Bl" i ro n p i l l g a stritis " . P i g m e n t in the sto m a c h c a n h e ra l d a variety of eti o l o g i e s and cons u m a b l es . I n this exa m pl e , t h e golden p i g m e n t o f i ro n i s seen e m bedded i n the superfi c i a l m u cosa and with i n the l u m i n a l debris. This case was s u b­ m itted as " ru l e-out ca rc i n o ma " based on the o m i n ou s e ndoscopic i m pressi o n .

C H E C KLI ST: Etio l o g ic C o n s i derat i o n s fo r P i g m e nts a n d Ext r as o

Iron

o

Gastr i c pseudom e l a n os i s

o

Ca l c i n os i s

o

Res i n s

o

9Dyttri u m (9Dy)-l a be l ed m i crosph eres

I RO N Gastric iron deposition is seen in u p t o 3 . 8 % o f upper tract biopsies (Fig. 2 . 228) . 23 , 2 4, 183-185 In a study of 500 gastric biopsies , the deposition was demonstrated in three generalized patterns . Pattern A (also referred to as "nonspecific gastric siderosis") was the most common subpattern and involved 2 . 2 % of specimens (Figs . 2 . 22 9 and 2 . 230) . This subpattern was associated with prior mucosal microhemorrhages, and the subtle depositions were predom­ inantly identified within macrophages and stromal cells of the lamina propria . Pattern B (also referred to as "iron pill gastritis") was seen in 0 . 8 % of the biopsies and was consis­ tently associated with ferrous sulfate therapy This deposition was coarse and crystalline and predominantly identified in the extracellular and most superficial aspect of the biopsy (Figs . 2 . 23 1-2 . 234) . In this subpattern, the background mucosa had a reactive gastritis/ gastropathy pattern with erosions , ulcerations, and fibrino-inflammatory exudate common. In a separate study of 1 ,300 gastric biopsies, a similar "iron pill gastritis" inj u ry pattern was detailed . 184 This latter group reproduced the identical iron deposits in the laboratory by oxidizing ferrous sulfate tablets , providing clear evidence for the iron origin of these deposits . The mechanism of injury is a bit unclear in this subpattern. Some speculate that the iron pill has a direct caustic effect on the adj acent mucosa , whereas others suggest that the iron deposits may simply colonize previously inj ured mucosa. Pattern C (also referred to as "gastric glandular siderosis") was the least common pattern, involving 0 . 6 % of the specimens . This subpattern was associated with iron overload settings , such as hereditary

Ch a pte r 2

.

'I! f�'f "' .

::.

�

I.

I, '

.

. , , . "

.

.

. : . l.

.

.... ,

;

, , \.

(

� . ,' . '

.

. ' \ :.� \ I \� .

-_�'"

l

" ,10 ; 1,

....

'. � 't,;: .

,

•

.

. . •

; �. , �

· ,. ;r. , . , ,,,. : I'! ..

: .

, ,' I 1\\ ' . '

•

•

"

' t-

I.

"

-

.. ... /

.

,

,

.

"

'-

. .

,

,

'.

.

� ,. ,

_ ..

"

-

. .�

1" : .�

' .1

�.' ( ,.�

J

,

"' -

, �l :

'-

,

.'( . � '"

r

.f

•

:'

.

, .....

.

"

e.

,r

'

.. '

/

�

�

.,

.. .-

'\

.

c.

;

:

•

.

,

... .

•

.

"

':

,

1 59

STO MAC H

.

.

, , ; \' ' .". , ..... _ ,. -.

�.. " .. ." ,

I

-'

./

.

� ., ulcerative colitis) . This inj ury pattern ranges from mild acute ileitis to erosions , deep-penetrating ulcer­ ations , perforations , and necrosis. Diaphragm disease is a rare consequence of chronic NSAID usage and refers to muco­ sal strictures that concentrically involve the bowel wall , narrowing the lumen to a pin­ hole size , resulting in obstruction . Assess the background mucosa for clues such as aphthoid lesions , granulomata, fea­ tures of chronic mucosal injury, radiation inj ury, amyloidosis , and neoplasia, in attempts to uncover the etiology.

Figure 3.56 Acute i l eitis pattern , ba ckwash i leitis, u l cerative col i ­ t i s . T h i s i l e a l biopsy w a s taken from a patient with we l l-esta b l ished u l cerative colitis.

Figure 3.57 Acute i l e itis pattern, backwash i l e itis, u l ce rative co l itis. H ig h e r m a g n ifi cation of the previous fi g u re reve a l s mild focal a cute i n fl a m m ation (arrowheads) that s h o u l d n ot be m i staken fo r C ro h n d isease.

Ch a pter 3

5 M ALL

BOWE L

203

Figure 3 . 5 8 G ra n u l om atous pattern (brackets), term i n a l i l e u m , sa r­ coidosis. Th is term i n a l i l e u m resection o ri g i n ated from a 58-ye a r-o ld wom a n with a n exten sive h i story of sa rcoidosis who presented with a sma l l bowel obstru cti o n . The backgro u n d m u cosa was u n re m a rk­ a b l e . AFB a n d G M S speci a l sta i n s were negative.

Figure 3.59 Acute i l eitis patte rn, g ra n u l o m a , Cro h n d i sease. This snea ky g ra n u l o m a is a l m ost m iss-a ble on l ow power (arrowhead) . This biopsy orig i n ated from a patient with a history of Cro h n disease a n d scattered m u cosa l g ra n u l om ata were seen thro u g hout re p re­ sentative upper a n d lower gastrointesti n a l tract biopsies.

Figure 3 . 60 Acute i l eitis pattern , g ra n u l o m a , Cro h n d isease. On higher power, the g ra n u l oma is more easily spotted (arrowhead) as is the foca l a cute infl a m mation i n the adj o i n i n g epith e l i u m (bracket) . AFB a n d G M S speci a l sta i n s we re negative .

Figure 3.61 Acute i l eitis pattern , erosive active c h ro n i c g ra n u l o­ matous i l eitis, Cro h n d i sease. Active chro n i c infl a m mation refe rs to a cute i nj u ry ( i . e . , a cute infl a m m ation in the epith e l i u m or crypt l u mens, erosions, a n d o r u lcerations) and c h ron i c inju ry. In this case, a n e rosion is seen (arrowhead) a long with a n expa nsion of the l a m ­ i n a propria b y a Iym p h o h i stiocytic infl a m mation (brackets) .

F i g u re 3.62 Acute i l e itis patte rn , e rosive a ctive c h ro n i c g ra n u ­ l o m ato us i l e itis, Cro h n d isease. On i nterm e d i ate power, a fo re i g n b o d y g i a nt cel l i s m o re easily s e e n (arrowhead) i n add ition t o va g u e g ra n u l omatou s infl a m m ation (brackets) . G ra n u l o m ata i n Cro h n d i s­ ease a re often poorly fo rmed, as in th is case.

F i g u r e 3.63 Acute i l e itis patte rn, erosive a ctive c h ro n i c g ra n u ­ l o m atous i l e itis, Cro h n d isease. On h i g h est power, t h e epith e l i o i d m o rp h o l ogy c h a ra cteristic o f g ra n u lomatous i n fl a m m ation is seen (bracket). AFB and G M S specia l sta ins were neg ative .

204

ATLAS

O F

GAST R O I N T E ST I N A L

PAT H O LO G Y

F i g u r e 3 .64 Acute i l e itis pattern , a ctive c h ro n i c g ra n u l omatous i l e­ itis, Cro h n d isease. At low power, crypt shortfa l l with basa l Iympho­ plasmacytosis i s see n : note that the crypts fa l l short of the m uscu l a ris m u cosae (arrowheads) beca use of a basa l layer of Iym p h o p l a s m a ­ cytic infl a m mation (bracket) . G ra n u l om ata i n Cro h n d i sease (aster­ isk) can be n otoriously difficult to a p p reciate in i ntensely i nfl a m ed speci mens, as in this case. In contrast to norm a l term i n a l i l e u m a rch i­ tectu re, n ote that it wou l d be i m poss i b l e to stri p off the overlying epith e l i u m i n this case s i n ce the epith e l i u m is inseparably melded to the associ ated a ctive c h ro n i c i n fl a m m atory i n j u ry. Contrast this i m a g e with n o rm a l a rch itectu re (Figs. 3 . 20-3 .25).

F i g u r e 3 . 65 Acute i l e itis patte rn , a ctive c h ro n i c g ra n u l om a tous i l e itis, Cro h n d isease. On higher power a g ra n u l o m a with fo re i g n body g i a n t ce l l s is m o re e a s i l y appreciated (bracket). AFB a n d G M S speci a l sta i n s were negative.

F i g u r e 3.66 Acute i l eitis pattern , a ctive c h ro n i c i l eitis, Cro h n d i s­ ease. Active c h ro n i c i nj u ry i m p l ies both a cute a n d c h ro n i c i n fl a m ­ m atory i nj u ry. Alth o u g h a cute infl a m mation is n ot a p p a rent at t h i s m a g n ificati o n , featu res o f esta b l ishe d c h ro n i c i nj u ry (ch ro n i city) i n c l u d e pyloric g l a n d m eta p l asia (best a p p reciated at h i g h e r power) and a rch itectu ra l d i stortion (n ote the vari a b l y sized crypts with vari­ able i nterve n i n g l a m i n a propria). Also n ote the tra n s m u ra l fi brosi s a n d c h ro n i c i n fl a m m a ti o n , a n d s u bsero s a l l y m p h o i d a g g re gates (brackets), features compatible with the h i story of esta b l ished Cro h n disease.

F i g u re 3.67 Acute i l eitis patte rn , u lcerative a ctive c h ro n i c i l e itis, Cro h n d i sease. This resection is from a patient with a h i story of ter­ m i n a l i l eu m - restricted Cro h n disease. The i m a g e featu res both acute i nj u ry (u l ceration (arrowhead) a n d a c ute i n fl a m m ation in the e p i ­ th e l i u m (not sh own)) a n d chro n i c i nj u ry (ga stric fove o l a r m eta p l asia [bra ckets] , pyloric gland m eta p l a s i a [asterisks] , a n d s l i g ht a rch itec­ tu ra l d i stortion with va ri a b l y sized crypts, vari a b l e interve n i n g l a m ­ i n a propri a , m i n i m a l crypt shortfa l l , a n d basa l lym phopla smacytosis [arrows]) .

C h a pte r 3

S M ALL

BOWE L

205

Figure 3.68 Acute i l e itis pattern, u l ce rative a ctive chro n i c i l eitis, Cro h n disease. Alternate fi e l d . Lu m i n a l u l cer de bris is seen a l o n g with features o f c h ro n i c m u cosal injury (gastric fove o l a r m eta p l asia a n d a rch itectura l d istortion) .

Figure 3 . 69 Acute i l eitis patte rn , active chron i c i l eitis, Cro h n d is­ ease. Alternate fie l d . Arc h itectu ra l distortion is often best seen at low power: note the vari a bly sized crypts with vari a b l e i nterve n i n g l a m i n a propri a .

Fig u re 3 . 7 0 Acute i l e itis patte rn , active c h ro n i c i l e itis, Cro h n d is­ ease. Arch itectura l distortion can a lso be a pp reciated on s m a l l bits of b i opsy m ateri a l , as this case. N ote the centra l biza rre l y sha ped crypt with g reater than seven bra n ches, and the va ri a b l e a m o u nt of i nterve n i n g l a m i n a p ropria thro u g h o ut, both features of chro n i c m u cosa l inju ry. Acute i l e itis w a s a l so s e e n (not shown).

F i g u re 3 . 7 1 Acute i l eitis patte rn, a ctive (arrow) c h ro n i c (arrow­ heads) i l e itis, Cro h n disease.

F i g u re 3 . 7 2 Acute i l e itis patte r n , a ctive c h ro n i c i l eitis, Cro h n d isease. Pyl oric g l a n d m eta p l a s i a is evi d e n ce o f c h ro n i c m u cosa l i nj u ry (brackets). Pyloric g la n d meta p l a s i a of the i l e u m is h isto l o g i ­ ca l l y identica l to the pyloric-type g l a n d s of the gastric c a rd i a a n d antrum a n d to B ru n n e r g l a n ds of the d u o d en u m . These g l a n d s a re com posed o f m u cus secret i n g ce l l s w i t h a b u n d a n t c l e a r foa my cytoplasm a n d basa l ly l o cated n u c l e i . A PAS/AB speci a l sta i n wou l d h i g h l ight eos i n o p h i l i c n eutra l m u c i n (not shown).

Figure 3 . 7 3 Acute i l e itis pattern, active chro n i c i l eitis, Cro h n dis­ ease. H ig h e r power of p revious case .

206

ATLAS

0 F

GAST R0 I N T EST I N A L

PAT H O LOGY

C H RO N I C I N F LAM MATION PATTERN

Fi g u re 3.74 C h ro n i c infl a m m at i o n , n o n s pecific. N ot u n co m m o n ly, s m a l l bowel b i o psies s h ow a c h ro n i c i n fl a m m atory i nfi ltrate with­ out oth e r specific features. F o l l o w i n g syste m atic review of a l l tis­ sue com p a rtments fo r c l u es, and c h a rt review for c l i n ica l corre l ates, some cases j u st rem a i n " n onspecifi c . "

CH ECKLI ST: Eti o l o g i c C o n s i derations fo r t h e C h ro n i c I nfl a m m at i o n Pattern o

Reactive D u o d e n o pathy

o

I nfl a m m atory Bowel D i sease

o

I nfect i o n

o

I nfl a m m atory or I m m u n e-Reg u l ated D i sord ers (i . e . , Psor i a s i s)

The chronic inflammation pattern is defined by mild expansion of the lamina propria with mononuclear cells or lymphoid aggregates in the absence of villous blunting or intraepi­ thelia I lymphocytosis (Fig. 3 . 74) . This is the most nonspecific of the small bowel patterns , but also among the most common . Etiologic considerations include reactive duodenopa­ thy (see Malabsorption Pattern , this chapter) , infection , and upper tract involvement by IBD (Figs . 3 . 75 and 3 . 7 6) . Up to 4 0 % of patients with Crohn disease may show active , chronic, and granulomatous inflammation in varying proportions . 14 By comparison, ulcer­ ative colitis is typically limited to the lower gastrointestinal tract , although up to 1 0 % of ulcerative colitis patients may demonstrate a diffuse chronic duodenitis . I S Keep in mind, however, that IBD is a primary consideration only when the changes are " focally enhanced" (Figs . 3 . 7 7 and 3 . 78) (See Focally Enhanced Gastritis , Stomach Chapter) or are accompa­ nied by mucosal granulomata , or if lower gastrointestinal tract disease is present . Sampling error in the duodenum may result in the lack of specific features, and this can raise a host of other differential diagnoses , such as medication-induced changes, upstream gastric disease , and other inflammatory or immune-regulated disorders . One such example is psoriasis , 16-18 It is perhaps , which may show mild duodenal inflammation and mast cell infiltration . therefore , best not to speculate on the etiology of a mild nonspeCific duodenitis in the absence of clinical information. Rather, simple documentation of the mild abnormality and acknowledgement of pertinent negatives are sufficient.

C h a pter 3

S M AL L

B OWE L

207

Fig u re 3 . 7 5 C h ro n i c infl a m mati o n , n o nspecific, d u o d e n a l g i a rdia­ sis. C h ro n i c infl a m m ation i n the s m a l l bowel i s often n o nspecific, but routi n e carefu l exa m i nation of a l l the tissue compartments may yield d i a g nostic fi n d i ngs. This exa m p l e sh ows a pro m i n ent lymphoid a g g regate a n d some d i lated l a ctea ls (arrow) i n this duoden a l biopsy. The tissue fi n d i n g s a re n o nspecific, but the d i a g n osis resides in the space between the vi l l i (arrowhead) .

Fig u re 3.76 C h ro n i c infl a m m ation, nonspecific, d u oden a l g i a rd i a ­ sis H i g h e r m a g n ification of the i n d i cated a rea i n the previous fig u re reve a l s the protozoa G iardia .

Fig ure 3 . 7 7 C h ro n i c i nfl a m m at i o n , foca l l y e n h a nced, d u od e n a l Cro h n d i sease. T h i s bio psy sh ows a patte rn of foca l ly e n h a n ced infl a m mation i n a patient with duodenal Cro h n d i sease. The fin d i n g s a re n o n s pecific a n d consist o f loca l ized infl a m mati o n , which s h o u l d be i nterpreted i n the proper c l i n i c a l setti n g .

Fi g u re 3 . 7 8 C h ro n i c infl a m mati o n , n o nspecific, duoden a l Cro h n d isease. H ig h e r m a g n ification o f t h e previous fi g u re sh ows cryptitis (arrowheads) consistent with the patient's known h i story of duoden a l i nvolvement b y Cro h n d i sease.

SAM P L E N OT E : S MA L L BOWE L WITH M I LD C H RO N I C I N F LAM MATION. B U T N O OTH E R S P E C I F I C F EATU R E S :

Small Bowel, Biopsy: •

•

Small intestinal mucosa with mildly increased lamina propria chronic inflammation , nonspecific . Negative for intraepithelial lymphocytosis or villous blunting.

208

ATLAS

0 F

GAST R0 I N TEST I N A L

PAT H O LOGY

CRYPT ARCH ITECTU RAL D I STU RBAN CE PATTE RN

Figure 3 . 7 9 Crypt a rchitectu ra l d istu rba n ce pattern . This pattern encompasses the g enera l features of " ch ro n i city" i n c l u d i n g crypt d i stortion and bra n c h i n g (pictu red h e re), crypt d ropout, crypt short­ fa l l , a n d pyloric m eta p l a s i a .

CH ECKLI ST: Eti o l o g i c C o n s i d e r at i o n s for t h e Arch itect u r a l D i st u r b a n ce Pattern o

I nf l a m m atory Bowe l Disease

o

D i a p h ra g m D i sease

o

I sc h e m i a

o

Graft Ve rsu s Host D i sease

o

Acute M ed i cation R e a cti o n ( M yco p h e n o l ate M ofeti l and Myco p h e n o l i c Acid)

o

Al l o g raft Rej ecti o n

o

R a d i a t i o n D u o d e n itis

o

Pouch itis and P o u c h - R e l ated C h a n g es

At scanning magnification , the appearance of crypt architectural disturbance can be seen as: crypt distortion, crypt dropout, crypt shortfall with or without basal lymphoplasma­ cytosis, or microcrypt formation (Fig. 3 . 79) . Note that this pattern is exclusive of villous architectural changes (i. e . , villous blunting) , which , instead, is a feature of malabsorption pattern and confers a different group of differential diagnoses. Although some might con­ sider villous blunting a feature of chronic inj ury, isolated architectural disturbances of the villi should be investigated as a malabsorption pattern. Furthermore , although many of these features indicate chronic inj ury, this pattern spans a histologic spectrum from subtle to striking, encompassing features from the earliest crypt disturbance (a Single withered crypt) to marked crypt distortion. Crypt architectural disturbance is a nonspecific pattern of inj ury, the etiology of which encompasses IBD, mesenteric ischemia , graft versus host disease , allograft rej ection , short gut syndrome , radiation duodenitis , and (ileal) pouchitis . Incisive readers will note that crypt disturbances are a minor histologic pattern in many of these entities , and indicate chronic injury. Accordingly, examination for other primary fea­ tures (e .g. , increased apoptotic bodies in graft vs . host disease) and correlation with clinical circumstances are required to arrive at an etiology.

I N F LA M MATO RY BOW E L D I S EAS E Crohn disease is a chronic idiopathic inflammatory disorder characteristically involving the distal 1 5 to 25 cm of the terminal ileum; however the gastrointestinal manifestations of Crohn disease are remarkably diverse and may include variations such as ileocolic Crohn disease (30%

Ch a pte r 3

5 M A L L

BOWE L

209

to 50% of patients with Crohn disease) , localized or extensive disease of the small bowel (2 5 % t o 50%), isolated Crohn colitis ( 1 5 % t o 3 0 % ) , anorectal Crohn disease (5% t o 1 9 % ) , o r gastric, esophageal and duodenal Crohn disease (5% to 30%). 19-22 Histologically, the disease manifests in a patchy distribution with a combination of activity (cryptitis, crypt abscess, erosion, and ulceration) and chronicity (villous blunting, crypt architectural distortion, crypt dropout, crypt shortfall, basal lymphoplasmacytosis, increased lamina propria chronic inflammation, pylOriC metaplaSia , transmural lymphoid aggregates, and neuromuscular hyperplasia-with or with­ out granulomata) . For an expanded discussion on the general features of Crohn disease, see also Inflammatory Bowel Disease , Chronic Colitis Pattern, Colon Chapter. In the duodenum, Crohn disease produces typical lesions in approximately 0 . 5 % to 4% of patients 23 These lesions usually coexist with ileal involvement, and may extend proximally and distally to involve the stomach or j ejunum. By comparison, "regional j ejunitis" rarely coexists with duodenal disease and may locally or diffusely involve the j ejunum. Progressive transmural inflammation with scarring and deep ulceration may ultimately lead to symp­ toms associated with intestinal obstruction, perforation, bleeding, or fistula formation. When obstruction develops , it usually does so in the distal ileum, and deep linear ulcers or fistu­ lae may give rise to profound gastrointestinal bleeding. Gross and full-thickness microscopic examination of the small bowel are considered the gold standard for diagnosis. Gross pathol­ ogy shows thickening of the bowel wall, fistula formation, strictures, serpiginous ulcers, aph­ thous ulcers , and creeping mesenteric fat. The corresponding histology shows a combination of variable activity (cryptitis , villitis, crypt abscess, erosion, and ulcer) and chronicity (villous blunting, crypt architectural distortion, crypt dropout, crypt shortfall, basal lymphoplasmacy­ tosis, increased lamina propria chronic inflammation, pylOriC metaplaSia, transmural lymphoid aggregates, and neuromuscular hyperplasia-with or without granulomata) (Figs. 3 . 80-3 . 87) . FAQ: What is " cree p i n g fat ? " A n swer: The a nti mesenteric serosa l s u rfa ce o f the sma l l bowe l a n d c o l o n is usu­

a l ly s m o oth a n d devo i d of a d i pose tiss u e . In Cro h n d i sease, re peated cycl e s of tra n s m u ra l d a m a g e ca n res u l t i n a n i rreg u l a r a nti mesenteric serosa l s u rfa ce com­ posed of p ro m i n ent fi b rosis and fat ( " creepi n g fat " ) . Th is c reep i n g fat i s u sed by s u rg e o n s to i d e n tify the exte nt of affected bowe l fo r resect i o n . In a d d i t i o n , this fi n d i n g sh o u l d be docu m ented at the g ross i n g bench a s it c a n h e l p d iffe renti ate Cro h n d i sease fro m u l ce rative c o l itis.

F i g u r e 3.80 Crypt a rch itectu ra l d istu rba nce, Cro h n d isease. The crypt a rchitectu ra l d istu rba n ces a re evident at low m a g n ifi cati o n . N o r m a l ly, t h e crypts rest d i rectly on t h e m u scu l a ris m u cosae. I n th is exa m p l e , the base of a crypt fa l l s short of touch i n g the m uscu l a ris m u cosa e . This g a p betwee n the m u scu l a ris m u cosae a n d the crypt is c a l l e d " crypt shortfa l l " (a rrow) . Also, n ote the i rregu l a rly sha ped crypts, or a b n o r m a l crypt confi g u rati o n , i n add ition to a reas of tota l g l a n d u l a r l oss, or " crypt d ropout . "

F i g u re 3 . 8 1 Crypt a rchitectu ra l distu rba nce, Cro h n d i sease. Crypt a rc h itectu ra l d i stu rba n ces a re seen with i rreg u l a rl y s h a ped crypts a n d bifid bra n c h i n g crypts (arrowhead). N ote a l so the p resence of cryptitis with i n this same crypt a n d the loosely-formed g ra n u l oma (arrow) .

21 0

AT LAS

0 F

GAST R0 I N TESTI N A L

PAT H O LOGY

F i g u re 3.82 Crypt a rch itectu ra l d istu rba nce, Cro h n d i sease. Resid­ u a l v i l l o u s p roj ecti o n s a re p resent, but the m aj o r patte rn h e re is crypt a rch itectu ra l d i stu rba n ces, i n c l u d i n g crypt d i storti o n , crypt shortfa l l , and crypt d ropout. The l a m i n a propria is expanded with i n creased chro n i c i n fl a m m ation a n d p ro m i nent pyloric m eta p lasia (arrowheads) is present.

F i g u r e 3 . 8 3 Crypt a rch itectu ra l d istu rba nce, pyloric m eta p l a s i a . Pyloric-type g l a n d s a re n o rm a l l y l i m ited t o the pylorus at the j u n c­ tion of the sto m a c h a n d sma l l bowe l . When seen in the term i n a l i l e u m , these m eta p l a stic g l a nds i n d i cate c h ro n icity.

Fi g u re 3 . 84 Crypt a rch itectu ra l d istu rba nce, pyloric m eta p l a s i a . These pyloric g l a n d s h ave a b u n d a nt foa my-to-cl e a r cytoplasm a n d sm a l l , rou n d or ovo id n u c l e i t h a t may b e fl attened a g a i n st t h e base­ ment m e m bra n e .

F i g u r e 3 . 8 5 Crypt a rch itectu ra l d istu rba nce, pyloric meta p l as i a . Alth o u g h pyloric m eta p lasia (arrowhead) i n d i cates c h ro n i c ity, it i s n o t specifi c fo r Cro h n d isease, a n d can be fo u n d i n oth e r c h ro n i c conditions, s u ch a s d i a p h ra g m disease o f t h e term i n a l i l e u m .

F i g u re 3.86 Crypt a rch itectu ra l d i stu rba n ce , Cro h n d isease. T h i s exa m p l e sh ows crypt d i stortion a n d expansion of the l a m i n a propria with a n infl a m matory infi ltrate . Areas of pyloric m eta p l a s i a (arrow) a re a l so p resent.

F i g u re 3 . 8 7 C rypt a rch itectu ra l d i stu rba n c e , C ro h n d is e a s e . Alth o u g h c h ro n i c i nj u ry features a re evident at low power, h i g h e r m a g n ification is req u i red t o s e e a reas o f active i n fl a m mation (activ­ ity) i n d i cated by n e utro p h i l s . Seen h e re a re cryptitis (a rrow) a n d l a m i n a p ropria a cute infl a m m ation (arrowhead) .

Ch a pte r 3

5 M ALL

B OWE L

21 1

FAG: Does i nvo lvement of resection m a r g i n s by C ro h n disease h ave p rog nostic s i g n ifica n ce? A n swe r : N o . T h e status o f resect i o n m a rg i n s i s n o t p red i ctive o f d i sease recu rre n c e . 24 Post­ operative recu rre n ce of C ro h n d i sease is m o re c o m m o n in patients with g reater d i sease exte nt, perfo rati n g d i sease, and m ed i ca l ly refra ctory Cro h n d i sease. 2 5

D IAPH RAG M D I S EAS E NSAIDs cause a wide spectrum of histologic changes in the small bowel , some of which are segment specific, such as diaphragm disease of the terminal ileum . Mild lesions consist of superficial erosions with nonspecific neutrophilic, eosinophilic and plasmacytic infil­ trates . These erosions may be multiple , can coalesce forming deep ulcers , and may result in hemorrhage . Repeat cycles of ulceration and healing can cause submucosal scarring and web-like mucosal septa that proj ect into the lumen . These resulting circumferential stenos­ ing lesions appear as multiple diaphragm-like narrowings and are more commonly seen in the distal small bowel , particularly the terminal ileum (Figs . 3 . 88 and 3 . 89) . Accordingly, the patients often present with a surgically emergent obstruction . This so-called diaphragm disease can be accompanied by a wide array of additional abnormalities , including crypt architectural disturbances mimicking IBD , eosinophilic enteritis, enteritis cystica profunda , and neuromuscular and vascular hamartoma-like changes (Figs . 3 . 9 0-3 . 92) 26 By com­ parison , NSAID inj ury in the proximal small bowel often results in subtle and nonspeCific reactive duodenopathy-type changes , rather than chronic architectural changes. See also Malabsorption Pattern , this chapter. A diagnosis of diaphragm disease can be suggested by the endoscopic or pathologic findings but requires correlation with the patient's medica­ tion list for definitive diagnosis . Distinction from ileal Crohn disease can be particularly challenging if a history of NSAID use cannot be documented ; in general , there is minimal chronic inflammation in NSAID-associated inj ury, whereas it is abundant in Crohn enteri­ tis . Anecdotally, we have seen surreptitious N SAID abuse lead to segmental resection of obstructing diaphragms ; family members of the patients may be able to provide the clinical correlation in these cases .

F i g u re 3 . 8 8 D i a p h ra g m d i sease, endosco pic view. C h ro n i c N SAI D i nj u ry in the d i sta l sma l l bowel ca u ses cycl es of u l ce ration a n d h e a l ­ i n g that res u l t i n c i rcu mfe renti a l stenosing lesions ( " d i a p h ra g m s " ) a n d can l e a d t o obstru ctio n .

F i g u re 3 . 8 9 Crypt a rchitectu ra l d i sturba nce, d i a p h ra g m disease. Low power m a g n ification of the d i a p h ra g m sh ows ra ised m u cosa pushed u pward by a thi ckened and fi brotic s u b m u cosa.

21 2

AT LAS

0 F

GAST R0 I N T E ST I NA L

PAT H O LOGY

Figure 3 . 90 Crypt a rch itectu ra l d i stu rba nce, d i a p h ra g m disease, s u b m u cosa l fi brosis. Dense co l l a g e n re p l a ces the n o rm a l ly l oose s u b m u cosa l tissues after repeat cycles of u l ceration and h ea l i n g .

Fig u re 3 . 9 1 Crypt a rch itectu ra l d i stu rba nce, d i a p h ra g m d isease, pyloric m eta p l as i a . D i a p h ra g m d isease i s fou n d a l m ost excl usive l y i n the i l e u m a n d can d e m o n strate c h ro n i c i nj u ry fea t u res such a s crypt a rc h i tectu ra l d i stortion a n d p y l o r i c meta p l asia (arrowheads) . The m a i n d iffe rential d i a g nosis is with i n fl a m m atory bowel d isease.

Figure 3.92 Crypt a rch itectura l d istu rba nce, d i a p h ra g m d i sease. Lon gsta n d i n g d i a phragm d isease can show m u cosa l a b n o rm a l ities s i m i l a r to those seen i n infl a m m atory bowel d isease, and ca n be a d i a g n osti c pitfa l l . KEY F EATU R E S o f D i a p h r a g m Disease: •

•

Caused by chronic NSAID use or abuse . Repeat cycles of ulceration and submucosal scarring result in diaphragm-like nar­ rowing of the terminal ileum.

•

Features can mimic lED , with ileal stricturing and histologic features of chronicity.

•

Correlation with clinical use of NSAlDs is required.

ISCH E M IA Acute insufficiency of mesenteric arterial blood flow accounts for 6 0 % to 7 0 % of cases of mesenteric ischemia , and results in mortality rates exceeding 60% 2 7 Severe pain is a common presentation of small bowel ischemia compared with ischemia of the colon, in which extreme pain is usually not as prominent a feature . Specific risk factors include advanced age , atherosclerosis , low cardiac output states , cardiac arrhythmias , severe car­ diac valvular diseas e , recent myocardial infarction , and intra-abdominal malignancy. 2 7

C h a pte r 3

TABLE 3 . 2 : C a u ses of I ntesti n a l I s c h e m i a Acute vascu l a r occ l u s i o n •

•

A rte r i a l o r ve n o u s t h rom bosis Embolus

Low flow states • • •

Low c a rd i a c output Hypote n s i o n/shock S p l a n c h n i c s h u nt i n g , s u c h as i n extre m e ath l eticism ( m a rath o n r u n n e rs)

Ath e rosc l e rosis Mechanical •

•

•

I ntussu sception Vo lvu l u s Hernia

N ecroti z i n g e nteroco l itis Vas c u l itides and vasc u l opathies H y p e rcoa g u l a b l e states Drugs •

O r a l contraceptives

•

Coca i n e

•

•

D i g ita l is a n d vaso p ressors Potass i u m c h l o r i d e

Vas c u l a r co m p ress i o n of ce l i a c a x i s Amyl o i d os i s C o l l a g e n vasc u l a r d isease Rad iation damage

The causes of intestinal ischemia are many (Table 3 . 2) , but can be classified into four maj or categories 28 , 29 : •

Superior mesenteric artery (SMA) embolism (5 0%): This is most frequently due to a dislodged thrombus from the left atrium, left ventricle , or cardiac valves. The SMA is anatomically most susceptible to embolism due to its large caliber and narrow take-off angle from the aorta 29 The embolus usually lodges 3 to 1 0 cm distal to the origin of the SMA, in a tapered segment distal to the take-off of the middle colic artery Concomitant arteriolar vasoconstriction usually occurs , further impairing splanchnic blood flow and exacerbating ischemia, The middle segment of the j ej unum is most often involved in the ischemic process , as it is most distant from the collateral circulation of the celiac and inferior mesenteric arteries.

•

Superior mesenteric artery thrombosis 0 5 % t o 2 5 %) : Acute thrombosis of the mesenteric circulation usually occurs as a superimposed phe­ nomenon in patients with a history of chronic intestinal ischemia from progressive atherosclerotic stenosis , but may also happen in the setting of abdominal trauma or infection. There does not appear to be a Significant association between inherited coagu­ lation defects and mesenteric arterial thrombosis 30 , 3 1

•

Mesenteric venous thrombosis (5%): Risk factors include hypercoagulable states , p ortal hypertension, abdominal infec­ tions , blunt abdominal trauma , pancreatitis , splenectomy, and malignancy in the portal region 32 Ischemia is due to the resistance in mesenteric venous blood flow, which sub­ sequently causes diminished arterial flow. 2 7

•

N onocclusive ischemia (20 % to 3 0 %): This is thought to be caused by splanchnic hypoperfusion and vasoconstriction, 33 and it occurs most frequently in patients with atherosclerotic vascular disease . Inciting

5 M A L L

B OWE L

21 3

214

ATLAS

O F

GAST R O I N T E ST I N A L

PAT H O LO G Y

events include aortic insufficiency, sepsis , cardiac arrhythmias , and medications such as digoxin and alpha-adrenergic agonists . Ischemia secondary to cocaine use has also been described. 34,35 Mesenteric angiography remains the gold standard diagnostic study, and most patients do not receive endoscopic examination due to the risk of bowel perforation. As such , it is quite rare to diagnose small bowel ischemia by endoscopic biopsy. Naturally, the histologic findings are similar to those seen in the colon, namely mucosal coagulative necrosis . Early and minimal injury occurs first at the villous tips due to splanchnic shunting of blood away from the mucosa . This is noted as degeneration and sloughing of superfiCial epithelial cells , edema , and vascular congestion (Fig. 3 . 9 3 ) . Later, the epithelial cells become markedly attenuated and the crypts appear compressed and atrophiC ("micro crypts") as the lamina propria swells and hemorrhages (Fig. 3 . 94) . Within 5 hours of total acute occlusion , almost the entire intestinal wall appears necrotic (Fig. 3 . 9 5 ) . These changes are all devoid of acute inflammation (Fig. 3 . 96) until reperfusion occurs . And , paradoxically, reperfusion further inj ures the tissues by introdUCing oxygen free radical formation, 36 the severity of which is dependent upon the duration of the preceding hypoxia (Figs . 3 . 9 7-3 . 1 00)

F i g u re 3 . 9 3 Crypt a rch itectu ra l d i stu rba nce, isch e m i c enteritis, e a r l i est s i g n s . M a rked congesti o n of ca p i l l a ries with s l o u g h i n g of epith e l i a l cells a long the v i l l o u s s u rface a re p resent i n the a bsence of a n infl a m m atory i nfi ltrate . At these earliest sta ges, the crypts rem a i n i ntact.

Figu re 3.94 Crypt a rch itectu ra l disturba nce, isch e m i c enteritis. The l a m i n a p ropria h a s become h e m orrh a g i c a n d the crypt a rch itect u re is a b n o rm a l with a reas of crypt d ropout a n d m i rocrypt formati o n .

Figure 3 . 95 Crypt a rch itectu ra l d istu rbance . End sta g e isch e m i c bowel with n ecrosis.

F i g u re 3 . 96 C rypt a rch itectu ra l d istu rba nce, isch e m i c enteritis. This exa m p l e l acks the stri king hemorrh a g e seen previously, but the epith e l i a l cel l s h ave s l o u g h ed off, l eavi n g s l i g htly necrotic v i l l o u s tips a n d res id u a l m icrocrypts (arrowheads) at the base.

C h a pte r 3

Figure 3 . 9 7 Crypt a rch itectu ra l d istu rba n ce , isch e m i c enteritis. Th is exa m p l e sh ows the m a rked crypt a rch itectura l d i sturbance that c a n acco m p a n y isch e m i c enteritis . The l a m i n a p ropria h a s h e m o r­ rhage a n d h ya l i n izati o n , y i e l d i n g an eosi n o p h i l i c a p peara n ce . The crypt l u m i n a h ave s l o u g h ed degenerated epith e l i a l ce l l s that m i m i c crypt a bscesses (arrowhead).

F i g u re 3 . 99 C rypt a rchitectu ra l d i st u rba nce, isch e m i c enteritis. There i s m a rked crypt a rch itectu ra l d i stortio n at low power, a n d the l a m i n a propria appears h e m orrh a g i c a n d hya l i n ized .

•

•

•

•

BOWE L

21 5

Fig u re 3 . 9 8 Crypt a rch itect u ra l d istu rba n c e , ischemic enteritis. H i g h e r m a g n ification of the crypts shows that they a re fi l led with ka ryorrh ectic debris from sloughed e p ith e l i a l c e l l s and not neutro­ phils.

F i g u re 3 . 1 00 Crypt a rchitectu ra l d isturba nce, ische m i c enteritis . H i g h er m a g n ificatio n o f t h e previo u s fig u re revea l s focal m icrocrypt fo rmati o n . The a b u n da n t fi brin deposition in the l a m i n a propria i m p a rts a homogenous eosi n o p h i l i C/hya l i n ized a ppeara nce.

KEY F EATU R E S of I sc h e m i a : •

5 MA L L

Mesenteric ischemia can be clinically categorized as SMA embolism, SMA thrombosis , mesenteric venous thrombosis , and nonocclusive ischemia . Severe pain is a common presentation in mesenteric ischemia, but not colonic ischemia. Early histologic findings include sloughing of superficial epithelial cells, edema, and vascular congestion. Later stages include lamina propria hemorrhage , hyalinization, microcrypt formation, followed by coagulative necrosis . Acute inflammation is absent unless reperfusion has occurred.

•

Beware not to overcall crush artifact from biopsy forceps as ischemic change .

•

Inflammatory changes can mimic vasculitis .

21 6

AT LAS

0 F

GAST R0 I N T E S T I N A L

PAT H O LOGY

PEARLS & PITFALLS

Crush Art ifact from B i o p sy Forceps Can M i m i c I schemic I nj u ry

B i o psy fo rceps m a y stri p epith e l i a l ce l l s from v i l l i a n d ca u se crushed g l a nd s that ca n be m i staken fo r atro p h i c m icrocrypts . Tru e i sc he m i c i nj u ry sh ows l a m i n a pro­ p r i a h e m o rrh a g e a n d d e g e n e rative cel l u l a r c h a n g es , s u c h a s l oss of t h e a p ic a l b r u s h bord e r a n d g h ostl i ke n uc l e i ( F i g s . 3 . 1 0 1 -3 . 1 03).

Figure 3 . 1 0 1 Crypt a rch itectu ra l d istu rba nce, isch e m i c e nteritis m i m ic, crush a rtifact. Forceps biopsies can sometimes cause crush a rtifact that m i m ics isch e m i c i nj u ry. These crypt epith e l i a l ce l l s have " popped " out of their ri g h tfu l p l a ce (a rrows) a s a resu lt of crush i nj u ry. N ote h ow the deta ched epith e l i a l ce l l s lack degenerative fea­ tures, a n d how the l a m i n a propria l ooks inta ct, without h e m o rrhage, fi brin depositi o n , hya l i n izatio n , or fi brosis.

Figure 3 . 1 02 C rypt a rch itectu ra l d isturba nce, isch e m i c enteritis m i mic, crush a rtifa ct. The s l o u g h i n g epithel i a l ce l l s l eave some vi l l i without inta ct epith e l i u m ; h owever o n e c a n b e reassu red this i s the resu lt of en dosco p i c (or laboratory) m a n i p u lation because the epi­ the l i a l ce l l s l a c k d e g e n e rative c h a n ges, a n d the lamina p ropria of the vi l l i (arrowh eads) l a c k e d e m a , h e m o rrh a g e , fi brin de positi o n , hya l i n izati o n , a n d fi b rosis.

Figure 3 . 1 03 Crypt a rch itectu ra l distu rba nce, ische m i c enteritis. A row of microcrypts is present in a fi brotic l a m i n a propri a . M icrocrypts a re h i g h l y specific for isch e m i c i n j u ry. C o m p a re this Fig u re to t h e m i m ics a bove. P E A R LS & PITFALLS

Eva l uation for U nd e r l y i n g Vascu l it i s

I sc h e m i c d a m a g e ca n cause vascu l a r th ro m b i , a n d rep e rfu s i o n i nj u ry may c a u s e i nfl a m m atory c h a n g es , n e i t h e r of w h i c h s h o u l d be confused for a n u n d e rl y i n g ca u s a l vascu l it i s . P ri m a ry vascu l a r i nj u ry s h o u l d o n l y b e eva l u ated i n a re a s n ot d i rectly s u bj a ce n t to ische m i a or u l ce rati o n ( F i g s . 3 . 1 04 a n d 3 . 1 05).

C h a pte r

Figure 3 . 1 04 Crypt a rch itectural dist u rba nce, isch e m i c enteritis, adjacent vasc u l itis m i m ic. When e n co u nteri n g isch e m i c enteritis, it is prudent to search for vasc u l itis as a poss i b l e u nderlyi n g etio l ogy; h oweve r bewa re as vesse ls that a re d i rectly s u bjacent to isch e m i c a reas may s h o w infl a m m ation a n d occlusion secondary t o t h e m u co­ sa l d a m a g e (as o pposed to the cause of the m u cosal i nj u ry) . T h i s m uscu l a r a rtery i s i n vo lved b y m a rked a cute infl a m m ation a n d fi brin depositi o n .

5 M ALL

BOWE L

217

Figure 3 . 1 05 Crypt a rch itectu ra l d istu rba n ce , isch e m i c enteritis, adjacent vascu l itis m i m i c . This h i g h e r m a g n ification of the previ­ ous Fig u re sh ows ka ryo rrh ectic debris (arrowhead) and n eutro p h i l s with i n t h e sm ooth m u s c l e wa l l o f the a rte ry. Overinterpretation a s vascu l itis is a p itfa l l . Vascul itis assessment i s best performed in a reas away from the a cute i nj u ry.

PEARLS & PITFALLS

D i st i n ct i o n fro m I nfect i o u s E nteritides

There a re n o re l ia b l e h i sto l o g i c featu res to d i sti n g u i s h isch e m i c enteriti s from i n fec­ t i o u s enteritis; corre l at i o n with e n dosco p i c i m p ress i o n , c l i n i ca l i nfo rm a t i o n a n d m i cro b i o l o g i c stu d i e s i s i m perative. I nfect i o u s enteritides t h a t a re tox i n m e d i ated , s u c h a s Escherich ia coli 0 1 5 7 : H 7 ca n ca u se h e m o rrh a g i c e n te riti s . I n a d d i t i o n , wh i l e the pse u d o m e m bra n e of Clostridium difficile c o l itis i s h i g h ly c h a racte ristic, pse u d o m e m b ra n e s a re a l so fre q u e n t l y seen i n i sch e m i c enteritis (Fi g . 3 . 1 06) .

Figure 3 . 1 06 Crypt a rch itectu ra l d i stu rba nce, isch e m i c enteritis, pse u d o m e m bra n e fo rm ati o n . Com p a re the isch e m i c right side of this F i g u re with the i n ta ct m u cosa on the left. N ote the crypt a rch i­ tectu ra l d i stu rba n ces on the right, i n addition to the h e m orrh a g i c a n d h ya l i n ized a ppeara n ce o f t h e l a m i n a p ro p ri a . The s u rfa ce i s covered w i t h a pseudomem bra n e , s i m i l a r t o that s e e n i n C . dif{icile col itis.

3

218

AT LAS

0 F

GASTR0 I N TEST I N A L

PAT H O LOGY

G RAFT V E RS U S H OST D I S EAS E Graft versus host disease (GVHD) is the donor T lymphocyte mediated destruction of host tissues that occurs following allogeneic transplant. Although allogeneic bone mar­ row and stem cell transplantation has the highest frequency of GVHD (40% to 80% of patients) , GVHD can also occur in donor lymphocyt e , whole blo o d , and solid organ transplantation . 37-39 Although in mild cases apoptotic bodies may be the only morpho­ logic clue to GVHD , in more severe cases cystic dilatation of glands or crypts lined by regenerative epithelium, crypt abscesses, and frank epithelial destruction are seen . Thu s , scanning magnification view of t h e biopsies will show architectural disturbance a n d loss of crypts that correlates with severity of histologic grade (Figs . 3 . 1 0 7 and 3 . 1 08) . Histo­ logic grading of GVHD is not performed in all transplantation centers , some preferring to use a qualitative approach by reporting "mil d , moderate , or severe" GVHD, but when used, a modification of the system for colonic GVHD described by Lerner40 is most com­ mon (Figs . 3 . 1 09-3 . 1 1 3 ) : Grade 1 : Isolated apoptotic epithelial cells Grade 2 : Loss or damage of isolated crypts with or without crypt abscesses Grade 3 : Loss of 2 or more contiguous crypts Grade 4: Extensive crypt loss with mucosal denudation See also GVHD , Lymphocytic Pattern, Esophagus Chapter. KEY F EATU R E S of G raft Ve rsus H ost Disease: •

•

•

•

•

•

GVHD is an immune-mediated destruction of host tissue following bone marrow and stem cell transplantation . GVHD may also follow solid organ transplantation , donor T lymphocyte transfusion , and whole blood transfusion . Grading of GVHD may be done based on histologiC findings (Lerner system) or on diag­ nostic confidence (NIH system) . Crypt architectural disturbance in GVHD indicates at least moderate GVHD (grade 2 and higher by the Lerner system) . Crypt apoptotic activity is the histologiC hallmark of GVHD , but is nonspeCific . The differential diagnosis for apoptotic inj ury includes infection, chemotherapeutic con­ dition regimen , and the immunosuppressant medication mycophenolate mofetil .

Figure 3. 1 07 Crypt a rch itectura l distu rba n ce, g raft versus h ost d is­ ease. Crypt a rch itectura l d i stu rba n ce is present in the form of m i l d crypt distortion a n d crypt shortfa l l (arrowhead) involving at least two contiguous crypts (Lerner g rade 2 of 4) . In addition, the prol iferative compartment of the crypts a p p e a rs expanded and hyperc h romatic.

F i g u re 3 . 1 08 C rypt a rch itectu ra l d istu rba nce, g raft versus h ost disease (GVHD). T h i s d u o d e n a l biopsy sh ows m a rked crypt d ropout i n this patient with GVH D . The villous a rch itectu re rem a i n s rel ative ly inta ct.

C h a pter

Figure 3 . 1 09 Crypt a rch itectu ra l disturbance, g raft versus host d is­

3

S M A L L

BOWEL

21 9

ease. M a rked g l a n d u l a r i nj u ry and d ropout h ave occu rred as a resu l t o f GVH D i n t h i s pati ent with a b o n e m a rrow tra n s p l a nt.

Figure 3 . 1 1 0 Crypt a rchitectu ra l d i stu rba n ce, g raft versus host dis­ ease. Res i d u a l crypt bases a re see n . N ote the re l ative abu ndance of entero-e ndocri n e c e l l s (arrowheads) , w h i ch a re not as affected by apoptotic injury.

Figure 3 . 1 1 1 Crypt a rch itect u ra l d istu rba nce, g raft versus h ost d i sease. Th i s bio psy sh ows m a rked crypt a rch itectura l c h a n ges d u e to g raft versus h ost d isease. A t this power, it m ight be easy t o m is­ d i a g n ose a crypt a bscesses.

Figure 3 . 1 1 2 Crypt a rch itectura l d i sturbance, g raft versus host d i s­ ease. H ig h e r m a g n ification of the p revious fig u re shows s l o u g h ed epith e l i a l cel l s in the crypt l u m e n (n ot acute infl a m mation as wou l d be expected i n a crypt a bscess) .

Fig u re 3 . 1 1 3 Crypt a rc h i tectural d istu rba nce, g raft versus h ost d i sease. Co m p l ete loss of epith e l i u m a n d crypts a re seen in t h i s exa m p l e o f seve re GVH D (Lerner g rade 4 of 4) .

220

AT LAS

0 F

GAST R0 I NT EST I N A L

PAT H O LOGY

P EARLS & PITFALLS

A p o ptosis i s a N o n s pecific Pattern of I nj u ry, a n d N ot S i n g u l a rly D i a g n osti c fo r GVH D

F a l se positive i nterpretati o n s m a y be d u e to effects of c h e m othera peutic con d i ­ tion i n g reg i m e n s , concom ita nt i n fectio n s , a n d m e d i cati o n s . A s a res u l t o f i n d uc­ tion c h e m ot h e ra py, an a po ptoti c pattern of i nj u ry ca n be seen with i n the fi rst 20 days of b o n e m a rrow a b l ation ,41 ren d e ri n g t h e d i a g n o s i s of a cute GVH D d i f­ fi c u l t . I n a d d i ti o n , a p o ptoses a re com m o n l y seen i n cyto m e g a l ov i ru s i nfection42 a n d c ryptospori d i osis,4 3 w h i c h a re p reva l e n t i n th i s i m m u n ocom p ro m i sed popu l a ­ ti on . F u rt h e r com p l i cati n g the p i ct u re m a y be t h e u se of the i m m u n os u p p ressa nt myco p h e n o l ate m ofet i l posttra n s p l a ntatio n , which c a n cause acute m u cosa l i nj u ry with foca l u l ce ratio n a n d m a rked crypt ce l l a popto s i s (see bel ow) . 44 FAQ: How m a n y a p o ptot i c bodies a re req u i re d for a d i a g n osis of GVHD? A n s w e r : Adva n ces i n h e a l t h ca re a l l ow c l i n i c i a n s to s u spect GVH D at much e a rl i e r

sta g e s , a n d m o rp h o l o g i c featu res m a y be m o re s u bt l e t h a n re p o rted i n e a r l i e r stu d i e s . Co rrespo n d i n g l y, m i n i m u m th resh o l d s h ave not been esta b l i s h e d , b u t m a n y path o l o g i sts req u i re the fi n d i n g o f at l e a st o n e a po ptotic b o d y per b i o psy tissue fra g m ent to s u g g est the d i a g nosis of G V H D . 45.46 Oth e r p u b l i shed thres h o l d s i n c l u d e ( 1 ) the tota l n u m be r o f a po ptotic bod ies at l e a st eq u a l to the n u m ber o f p i eces, or ( 2 ) scatte red a po ptotic b o d i e s i n m o re t h a n o n e c rypt.40.45.47 Ta ke n ote , h owever, that s u rfa ce epith e l i a l apoptoses m a y occ u r as the res u l t of bowel pre­ pa ratory reg i m e n s , and t h e refo re s h o u l d not be c o n s i d e red d ia g nostic for GVH D .

FAQ: H ow can I t e l l i f t h is a n apoptotic b o d y o r a l y m p hocyte? Answer: Apoptotic ce l l s conta i n i ntra cyto p l a s m i c vacu o l es fi l l ed with n u c l e a r d u st

a n d oth e r ka ryorrhectic debris. These a po ptotic fra g m e nts a ppea r as s m a l l , d a rk, ro u n d bodies s u rro u n d e d by a wh ite h a l o . S i m i l a rly, I E Ls m a y have a clear h a l o ; h owever b y c o m p a ri so n , l y m p h o cytes reta i n a u n ifo r m size o f a bo u t 1 0 m i crons i n d i a m eter. To d i ffere n ti ate the two, simply i d e n t ify a l y m p h ocyte o r plasma ce l l n u cl e u s i n the l a m i n a p ropria a n d use t h i s a s y o u r b e n c h m a rk fo r size co m pa ri so n . Because o f t h e i r fra g m e nted n a tu re , a poptotic b o d i e s a re typ i ca l l y m u ch sm a l l e r a n d va ri a b l y sized ( F i g . 3 . 1 1 4) .

Fi g u re 3 . 1 1 4 C rypt a rch itectura l d i sturbance, g raft vers u s h ost disease. At the crypt bases, n u m erous apoptotic bodies (circled) a re see n . N ote how the n u c l e a r fra g m e nts h ave a m uch s m a l l e r d i a m ­ eter a n d a re more vari a b l y sized than t h e m o n o n u c l e a r ce l l s i n t h e l a m i n a propri a .

C h a pte r 3

S M A LL

B OWE L

221

M E D I CATI O N S (MYCO P H E N O LATE M O F ETI L AN D MYCO P H E N O LI C ACI D) Mycophenolate mofetil and mycophenolic acid are immunosuppressants commonly pre­ scribed to transplant recipients and are used in the treatment of some autoimmune diseases . This reversible inhibitor of inosine monophosphate dehydrogenase results in inhibition of purine synthesis and causes a reduction in B and T lymphocytes . At high dosages, epi­ thelial cell damage can also occur, which leads to clinical diarrhea and histologic findings of prominent apoptotic inj ury with crypt damage and distortion (Figs . 3 . 1 1 5_3 . 1 2 1 ) 44 , 4 8 These changes overlap with Crohn disease , GVHD , and ischemia. 44 , 48-5 1 Further compli­ cating the picture , dual pathology is frequently present in patients prescribed mycopheno­ late 50 Fortunately, a reduction in dosage or discontinuation of the medication yields rapid clinical response. In difficult cases, a note suggesting modification of the medication list may be helpful to clinicians .

Fig u re 3 . 1 1 5 Crypt a rc h i te ct u ra l d istu rba nce, myco p h e n o l ate­ i n d u ced i nj u ry. This low m a g n ification view of the duoden u m , from a patient with u n expl a i n ed d i a rrh ea, sh ows very m i l d crypt a rch itec­ t u ra l d i sturbance with very foca l crypt d ropout (arrows) . Alth o u g h the v i l l o u s a rchitectu re is p reserved , isol ated d istu rb a n ces o f the crypts s h o u l d p ro m pt further investigati o n .

F i g u re 3 . 1 1 7 C rypt a rch itectur al d i stu rba n c e , myco p h e n o l ate­ i n d u ced i nj u ry. Additio n a l c rypts fro m the p revi o u s case s h o w n u m e ro u s a p o ptotic bodies (arrowh eads) . I nvestigation i nto the patient's medical record reve a l ed use of myco p h e n o l ate m ofetil fo r i m m u n osuppression in the setting of card i a c tra n s p l a ntati o n .

Fig u re 3 . 1 1 6 Crypt a rc h i tectu ra l d istu rba nce, myco p h e n o l ate­ i n d u ced i nj u ry. An a rea of c rypt d ropout fro m the p revious case is sh own at h i g h e r m a g n ification and featu res a p o ptotic activity (arrowheads) . Alth o u g h up to 4 a po ptoses per 1 0 duodenal crypts may be considered n o rm a l , the presence of apoptoses in confl uent crypts is a b n o rm a l .

Fig u re 3 . 1 1 8 C rypt a rch itectu ra l d istu rbance, myco p h e n o l ate­ i n d u ced i nj u ry. Additi o n a l c rypts from the previous case show conti g u o u s crypts, each conta i n i n g a po ptotic bodies. This fi n d i n g s h o u l d pro m pt fu rth e r i n vestigati o n .

222

AT LAS

0 F

GAST R0 I N TEST I NA L

PAT H O LOGY

Fig u re 3 . 1 1 9 Crypt a rch itectu ra l d i stu rba n c e , myco p h e n o l ate­ i n d u ced i nj u ry. This biopsy of the duoden u m is from a kidney tra ns­ p l a n t patient experiencing u nexp l a i ned d i a rrhea . Very foca l d ropout of the crypts, crypt s h o rtfa l l a n d basa l ly mp ho p lasmacytosis (bra ck­ ets), a n d a possible crypt a bscess (arrow) a re visi b l e at low m a g n ifi­ cati o n . N ote that the d i sturbances in this biopsy a re l i m ited to the crypts, while the vi l l i a p p e a r i ntact. These mild d i sturban ces of the crypt a rch itectu re at low m a g n ifi cation should pro m pt h i g h e r mag­ n ification exa m i n ation .

Fig u re 3 . 1 20 Crypt a rch itect u ra l d i sturbance, myco p h e n o l ate­ i n d u ced i nj u ry. H i g h e r power m a g n ification of the previo u s case reve a l s m a rked apoptotic d estru cti o n of the crypts (arrowh eads) rath e r than crypt a bscesses. T h i s fi n d i n g s h o u l d p ro m pt review of the medication l i st in a n y tra ns p l a n t patient.

Figure 3 . 1 2 1 Crypt a rch itect u ra l d i sturbance, myco p h e n o l ate­ i n d u ced i nj u ry. H i g h e r m a g n ification of oth er crypts from those in the p revious fig u res revea l s confl uent apoptotic a ctivity (arrowhead) with n u m e rous apoptoti c bodies i n the p ro l iferative co m p a rtment ( i . e . , base) of the crypts. Cessati o n of mycoph e n o l ate use i n this patient resu lted i n d ra m atic c l i n ic a l i m p rovement with i n 48 h o u rs .

ALLOG RAFT R EJ E CTI O N , S MALL BOW E L Small bowel transplantation i s increasingly performed t o treat patients with irreversible intestinal failure . Because the intestine is a lymphoid-rich organ , intestinal transplanta­ tion requires complex immunologic events to occur for the graft to function; for example , the donor mucosal immune system must be replaced by the host, and a chimeric state is essential for allograft function. 52 Clinical features of acute rej e ction include fever, nausea and vomiting, diarrhea , and abdominal pain and distension. Severe cases may be accom­ panied by septic shock, metabolic acidosis , hypotension , and adult respiratory distress syndrome . Surveillance endoscopy can be performed through the ileostomy stoma , and endoscopists should be encouraged to biopsy away from the stoma since stoma sites contain inflammatory and regenerative changes. In addition, since features of acute cellular rej ection

C h a pte r 3

S M ALL

BOWE L

223

TABLE 3.3: G ra d i n g S c h e m a for S m a l l Bowel Al l og raft Acute Ce l l u l a r Rejections2 G rade

H istologic F i n d i ngs

I n d ete r m i n ate fo r a c ute

- Foca l a n d va r i a b l e prese n c e of th ree main featu res of

rej e ct i o n

a c ute rej e cti o n - M i n i m a l i n fi ltrate - 6 a p o ptotic bodies p e r 1 0 c rypts - Va ri a b ly s h o rtened vi l l i - S l i g ht a rch itect u r a l d istort i o n

M o d e rate acute rej e ct i o n

- W i d e l y d i s persed i n fl a m m atory i n fi ltrate - D iffuse crypt i nj u ry a n d cryptitis - Vi l l o u s fl atte n i n g - Foca l " co n fl u ent a popto s i s " - M i l d to m o d e rate i n ti m a l a rteritis may be s e e n - I ntact m u cosa with s u p e rfi c i a l e ros i o n , b u t n o u l ce rati o n

Severe a cute rej e ct i o n

- M a rked crypt d a m a g e a n d u l ceration - Adjacent viable m u cosa s h ows rej e ct i o n -associated changes

may be patchy, multiple biopsies should be obtained from both endoscopically normal and abnormal areas. Diagnosis of acute cellular rej ection requires clinicopathologic correlation, and requires immediate aggressive immunosuppressive therapy, since progression of allograft rej ection can advance to graft loss or mortality. The histologiC diagnosis of acute intestinal rej ection is similar to that of GVHD and is based on a varying combination of three main fea­ tures which can be used to determine a rej ection grade (Table 3 . 3) (Figs . 3 . 1 22_3 . 1 2 8) 52-55 : 1 . Infiltration by a mixed but primarily mononuclear inflammatory population , including immunoblasts or activated lymphocytes 2 . Crypt inflammation and inj ury, characterized by cytoplasmic basophilia, nuclear enlarge­ ment and hyperchromasia , decreased cell height and mucin depletion 3 . Increase in crypt apoptotic bodies

Fig u re 3 . 1 22 Crypt a rc h itectu ra l d i stu rba nce, sma l l bowel a l l og raft rej ection . This exa m p l e of s m a l l bowel a l l o g raft rej e ction sh ows m a rked crypt a rch itectu ra l d i stu rba n ces, such as crypt d i stortio n a n d b ra n c h i n g with a reas o f crypt d ropout. The l a m i n a propria is m a rk­ edly expa n d ed by c h ro n i c i nfl a m m atory ce l l s .

F i g u re 3 . 1 23 Crypt a rch itectura l d i stu rbance, sma l l bowe l a l lograft rejecti o n . H i g h e r m a g n ification of the previous fi g u re shows a b u n ­ d a n t a po ptotic bodies (circled) with i n the crypt epith e l i u m . N ote how the n u c l e a r debris i s sma l l er a n d more i rreg u l a r than the m o n o­ n u c l e a r ce l l s in the adjacent l a m i n a propri a .

224

ATLAS

0 F

GAST R0 I N TEST I N A L

PAT H O LOGY

S:� :. � .'" � Figu re 3 . 1 24 Crypt a rch itectu ra l d i stu rba nce, sma l l bowel a l l og raft rej e cti o n . This sma l l bowel a l l o g raft sh ows c rypt d ropout. S o m e a re a s w i t h resi d u a l crypt p rofi les show s l o u g h ed epith e l i a l ce l l s with i n th e i r l u men (arrowhead).

Figure 3 . 1 25 Crypt a rch itectu ra l d i sturbance, sma l l bowel a l lograft rejecti o n , moderate to severe . Alth o u g h the v i l lous a rch itectu re is re latively i ntact, there i s only o n e res i d u a l crypt (bottom right). The m a rked crypt loss i n d i cates m o d e rate to seve re a l lo g raft rejection.

F i g u re 3 . 1 26 Crypt a rch itectu ra l d i stu rba nce, i n d eterm i n ate for s m a l l bowe l a l l o g raft rej ecti o n . T h e re a re very m i l d a rch itectu ra l c h a n g es i n t h i s biopsy, but the crypt epith e l i u m a n d vi l l i a ppear intact.

F i g u re 3 . 1 27 Crypt a rch itect u ra l d istu rba nce, i n d eterm i n ate fo r s m a l l bowel a l l o g raft rej ectio n . H i g h e r m a g n ification of the p revi­ ous fi g u re shows m u lti p l e a p o ptotic bodies (arrowheads) with i n the crypt epith e l i u m . I n this sett i n g , the b i o psy is best considered inde­ term i n ate for a cute ce l l u l a r rejectio n and cl ose c l i n i ca l fo l l ow-u p is reco m m ended. Compa rison of these bodies to a m o n o n u c l ea r ce l l (arrow) i n the l a m i n a propria e m p h asizes their s m a l l size a n d h e l ps d ifferentiate them from I E Ls.

F i g u re 3 . 1 2 8 Crypt a rch itectu ra l d istu rba nce, i n d eterm i n ate fo r sm a l l bowe l a l l o g raft reject i o n . Additi o n a l apoptotic body exa m p l es (arrowheads) .

C h a pter 3

5 M ALL

BOWE L

225

KEY F EATU R E S of A l l og raft Rejectio n : •

•

•

•

•

Surveillance of small bowel allografts can be performed endoscopically through the stoma site . Biopsies should be taken away from the stoma to avoid chronic and regenerative changes . Histologic features are similar to GVHD and include increased chronic inflammation, crypt inflammation and injury, and apoptotic activity. The presence of crypt injury and crypt architectural disturbance indicates at least moder­ ate acute rej ection . Immediate and aggressive immunosuppressive therapy is required for small b owel allograft rej ection to prevent graft loss and mortality. FAQ: H ow many a p o ptotic bodies a re req u i red to esta b l i s h a d i a g n osis of acute a l l og raft rejection? Answer: As many a s o r m o re t h a n six a poptot i c bod i e s per 1 0 crypts i n addition

to c rypt i nj u ry a n d l y m p h ocytic infi ltrati o n . If a l l th ree of the criteria a re n ot m et, t h e case i s best co n s i d e red as i n dete r m i nate fo r a cute rej ect i o n .

RADIATION E NTERITIS Advances i n technology allow more precise delivery of radiation dosage and result i n less side scatter damage ; however the small bowel remains more susceptible to radiation inj ury than the large bowel , and a number of factors enhance radiation inj ury, particularly the presence of other diseases such as diabetes , hypertension, atherosclerosis , prior intestinal inj ury, and cardiovascular disease . 56 The mechanism of inj ury is similar to that of ischemic enteritis whereby endothelial cell damage results in edema , fibrin deposition, and increases in vascular permeability 56 Correspondingly, the histologic features are similar to those seen in ischemic mesenteritis and include epithelial degeneration, mucosal denudation , crypt disintegration , mucosal edema , and necrosis (Figs . 3 . 1 2 9 and 3 . 1 3 0) . Features indicating that tissues were within a radiation field include hyaline sclerosis of small vessels , intimal thickening and fibrosis of muscular arteries , endarteritis obliterans , and enlarged bizarre nuclei of endothelial cells and fibroblasts (Figs . 3 . 1 3 1 and 3 1 3 2 ) .

F i g u re 3 . 1 29 C rypt a rch itectu ra l distu rba nce, radiation enteritis . L o w m a g n ification sh ows c rypt a rch itectu ra l d i sturban ces i n c l u d i n g m i l d crypt disto rtion a n d l o s s o f crypts (arrow) . The l a m i n a p ropria conta i n s hemorrh age a n d m uscu l a r a rteries show congestion (arrow­ heads) . Surfa ce fove o l a r g a stric meta p l asia is a lso p resent, but may be u n rel ated to the radiation c h a n ges.

Figure 3 . 1 30 Crypt a rch itectu ra l d istu rba nce, radiation enteritis. H i g h e r m a g n ification of the p revious fig u re h i g h l i g hts congested m uscu l a r a rteries (arrowh ead) and ectatic ca p i l l a ries i n the l a m i n a p ropria (arrows) .

226

ATLAS

0 F

GAST R0 I N T EST I N A L

PAT H O LOGY

Figure 3 . 1 3 1 Crypt a rch itectura l d i stu rba n ce , radiation enteritis. H i g h e r m a g n ification of the p revious fig u res sh ows a n a b n o rm a l l y p ro m i n e n t m u scu l a r a rtery. A l s o n ote t h e l a m i n a p ropria h e m o r­ rh a g e a n d ea rly hya l i n izati o n .

Figure 3 . 1 32 Crypt a rch itect u ra l d i sturbance, rad iation enteritis. H i g h e r m a g n ification of the a rtery in the p revious fi g u res shows e n l a rged endoth e l i a l ce l l s with m i l d n u c l e a r atypi a .

POUCH ITIS AN D P O U C H - R E LATE D CHAN G ES Ileal pouch anal anastomosis (rPM) is a procedure that consists of a total colectomy with stripping of the rectal mucosa and preservation of the anal sphincter. An ileal reservoir/ pouch is constructed (sometimes termed 'J-pouch") and anastomosed either to the residual rectal cuff at the anus or directly to the anus itself (Fig. 3 . 1 3 3 ) . This procedure is favored

J-pouch

�

ileum

---- a n u s Figure 3 . 1 33 I l ea l-pouch a n a l a n a stomosis (I PAA) . Closure o f a tota l p rocto­ colectomy req u i res either an ostom y/stom a site o r a n I PAA (in th i s i l l u stration the colon is " g reyed out" to represent rem ova l). I PAA i s the p referred s u rg i ­ cal a p p roach beca u se it m a i nta i n s G IT conti n u ity a n d avoids the need for a perm a n ent enterostom y b a g . I PAA i nvo lves a n a stomosis of the i l e u m either to the recta l cuff at the anus o r d i rectly to the anus itself. A reservoi r is created by stitc h i n g two loops of i l e u m togeth e r and removing the i ntern a l wa l l s . The resu lti n g reservoi r is i n the s h a pe of a "J" a n d often termed a "J-pouch . " H is­ torica l ly, I PAA was the sta n d a rd of ca re for u l cerative col itis patients but was genera l l y contra i n d i cated in Cro h n cases beca use of i n creased risks of d isease fl a res, a view that h a s evo lved .

C h a pter 3

S M A LL

BOWE L

227

over total proctocolectomy with permanent ileostomy because it allows patients to retain sphincter function and intestinal continuity; it has been most often employed in patients with ulcerative colitis and familial adenomatous polyposis (FAP) . Traditionally, the diag­ nosis of Crohn disease was an absolute contraindication for an IPAA because of high rates of pouch complications and failure ; however recent studies have demonstrated good func­ tional outcomes in the maj ority of Crohn disease patients , and suggest that trial IPAA may be offered to highly motivated patients wishing to avoid a permanent stoma 57-5 9 The most frequently observed long-term complication of IPAA is "pouchitis , " an acute and/or chronic inflammation of the ileal reservoir that remains poorly defined in regards to its true prevalence (reported as 7% to 44 % ) , 60-64 etiology, and natural history. Five to 1 0 % of patient with IPAA develop chronic antibiotic-refractory pouchitis o r Crohn disease o f the pouch, both of which are leading causes of permanent diversion o r pouch failure 65 ,66 Preoperative risk factors for pouchitis include use of steroids prior to colectomy, s evere pancolitis , appendiceal involvement , extraintestinal manifestations of colitis and primary scleroSing cholangitis 61 ,67-69 Postoperative risk factors include bacterial overgrowth due to stasis , closure of ileostomy site , nonsteroidal anti-inflammatory drug use , and lack of short chain fatty acids in diet. 70 ,7 1 SerologiC markers show increased risk for pouchitis in patients with perinuclear anti cytoplasmic antibodies (ANCA) , whereas positive antibodies to anti­ Saccharomyces cerevisiae (ASCA) have been linked to developing postoperative fistulas and a change in diagnosis to from ulcerative colitis to Crohn disease in patients with an IPAA n Clinical manifestations of pouchitis include increased stool frequency, urgency, hemato­ chezia, abdominal pain , and fever. These symptoms trigger biopsy of the pouch to exclude specific infection (such as cytomegalovirus) and other etiologies . If histologic changes sup­ port pouchitis , antibiotic therapy is instituted (Figs , 3 , 1 3 4 and 3 . 1 3 5) . It should be noted, however, that histologic changes in the pouch are nonspecific . For example , long-standing pouches invariably contain chronic inflammation , villous blunting, crypt architectural disturbance and colonic metaplasia (Figs . 3 . 1 3 6 and 3. 1 3 7) ?3 , 74 Moreover, while acute inflammation can support a clinical impression of pouchitis, neutrophils could also indicate residuaVrecurrent IBD , the histologic distinction of which should not be attempted without strong clinical correlation. IBD may be a consideration in the following scenarios: •

•

Biopsies of the rectal cuff show active chronic features discordant with those o f the pouch proper; consider residuaVrecurrent ulcerative colitis (also referred to as "cuffitis") (Figs . 3 . 1 3 8-3 1 43) Pouchitis has been refractory to multiple rounds of antibiotic therapy; consider p ouch involvement of Crohn disease .

Fig u re 3 , 1 34 Crypt a rch itectura l d i stu rba n ce, pouchitis. Pouch itis refers to a cute a n d/or c h ro n i c infl a m m ation of the i l e a l rese rvo i r or " pouch " a s a resu l t of an i l e a l pouch a n a l a n a stomosis (I PAA) , At low m a g n ification, the m i l d crypt distorti o n , crypt d ropout, expa n­ sion of the l a m i n a p ropria with c h ro n i c infl a m m ation and loss of vi l l i a re a p p a rent,

F i g u re 3 , 1 35 C rypt a rch itect u r a l d istu rba n c e , m o d e rate a cute pouch itis, The p rese n c e of cryptitis and crypt a bscesses (arrow) a re consistent with m o d e rate a cute pouch itis, i n the p roper c l i n i ­ c a l sett i n g .

228

AT LAS

0 F

GASTR0 I N T ESTI N A L

PAT H O LOGY

F i g u re 3 . 1 36 C rypt a rch itect u ra l d i st u r b a n c e , c h ro n i c p o u c h ch a n g e s . O v e r t i m e , a l l p o u c h e s show c h ro n i c i nj u ry fea t u res, reg a rd l ess of whether there i s a h i story of acute pouch itis. Th i s exa m p l e l acks a cute infl a m mation, b u t shows s o m e m i l d crypt d i s­ tortion a n d v i l l o u s b l u nt i n g .

F i g u re 3 . 1 37 Crypt a rch itect u ra l d istu rba n c e , c h ro n i c p o u c h chan ges m i m icki n g co l o n i c m u cosa . This b i opsy o f a lon g-sta n d i n g p o u c h shows res i d u a l Paneth ce l l s (arrowheads) b u t no i ntact vi l l i . I d e ntica l fi n d i n g s cou l d b e seen with cuffitis o r i n fl a m m atory bowel disease i nvolvi n g the resid u a l colon m u cosa . U nfortu n ate ly, there a re no re l i a b l e h i stologic featu res to d i sti n g u ish pouchitis from cuffitis. I n such cases, i t is best that the endoscopist separate l y submit biopsies of the pouch and the rectal cuff i n sepa rate j a rs .

F i g u re 3 . 1 3 8 C rypt a rc h itect u ra l d i st u r b a n c e , c h ro n i c p o u c h c h a n g es m i m i c k i n g rect a l cuff. It can be d i ffi c u l t to d iffe rentiate c h ro n i c pouch itis changes from rect a l cuff tiss u e . H isto l o g i c a l l y, this biopsy cou l d rep resent a pouch with c h ro n i c changes or recta l cuffitis. S a m p l es from both the pouch a n d the recta l cuff sent i n separate j a rs a re m ost h e l pfu l i n t h i s d i st i n ctio n .

Figure 3 . 1 39 Crypt a rch itect u ra l d i stu rb a n ce , recta l cuffitis. This biopsy was taken from the recta l cuff a n d shows conti n ued i nvolve­ ment by u l cerative col itis. There is crypt d i stortion and cryptitis pres­ ent in a backg ro u n d of m a rked c h ro n i c i n fl a m m a ti o n .

Figure 3 . 1 40 P a i red intact pouch. T h i s pouch biopsy is p a i red with the previous cuffitis. The pouch shows intact a rch itecture and long vi l l i , with only m i l d expansion of the l a m i n a p ropria. The sta rk contrast between the cuff a n d the pouch a l l ows for easier distinction of which disease state is p resent -pouch itis or cuffitis. Based on sepa rate s u b­ m ission of the pouch and cuff, this case featu res cuffitis, or infl a m m a ­ tory bowel d isease changes involving t h e residual recta l cuff.

F i g u re 3 . 1 4 1 Crypt a rch itectu ra I d i stu rba n ce , recta l cuffi t i s . Anoth er exa m p l e of rectal cuffitis d e m o n strates a ctive a n d c h ro n i c featu res o f u l cerative col itis, with c rypt d i stortion a n d bra n c h i n g , crypt s h o rtfa l l/ba s a l Iym p h o p l a s m a cytosi s (arrow), crypt d ropo ut, and m a rked l a m i n a p ropria c h ron ic infl a m m at i o n . Moderate a ctive and c h ro n i c pouch itis can look s i m i l a r.

Ch a pter 3

Figure 3 . 1 42 Crypt a rch itectura l disturbance, recta l cuffitis . H i g h e r m a g n ification o f the p revious fi g u re sh ows cryptitis (a rrowh ead). Paneth ce l l m eta p l a s i a i s a lso seen i n the l ower l eft crypt.

•

Extraintestinal and intestinal manifestations of Crohn disease become apparent (i . e . , muco­ sal granulomata , uveitis , arthritis, small bowel stricture or fistula , perianal disease, etc . ) .

Ileal pouch anal anastomosis (IPAA) is a sphincter-sparing proctocolectomy that results in a small bowel reservoir (or "pouch") attached to either the residual rectal cuff or directly to the anus.

•

Pouchitis is a poorly defined inflammatory complication of this procedure .

•

Symptoms include : stool frequency, urgency, hematochezia, abdominal pain , and fever.

•

•

Biopsies of the pouch are sent to exclude specific infection (e.g. , cytomegalovirus) and confirm active and chronic inflammation Histologic features of activity and chronicity support a clinical impression of pouchitis, but are nonspecific .

•

There are no reliable histologic features to distinguish IBD from pouchitis.

•

Residual or recurrent IBD involving the rectal cuff is known as "cuffitis . "

•

Crohn disease should only b e suggested i f strong clinical correlation i s available , such as: •

Antibiotic-refractory pouchitis

•

Extraintestinal manifestations of Crohn disease

•

Perianal disease

•

Small bowel strictures or fistulas

BOWE L

229

Figure 3 . 1 43 P a i red intact pouch . This pouch biopsy is p a i red with the previous cuffitis. The i ntact and n o n i nfl amed pouch is a stri k i n g comparison t o the cuffitis s e e n previously, a l lowi n g for confident d if­ ferentiation between cuffitis and pouchitis. This case featu res cuffitis, or infl a m matory bowel disease changes i nvolvi n g the residual recta l cuff.

K E Y F EATU R E S o f Pouchitis: •

S M A LL

PEARLS & PITFALLS

Reca l l that a res i d u a l cuff of recta l m u cosa ca n rem a i n d i sta l to the p o u c h i n con­ stru ct i o n of an I PAA. Detect i o n of res id u a l l B D i n th i s recta l cuff ( " c uff iti s " ) i s i m por­ ta nt fo r p ro g n ostic a n d treatm e n t p u rposes; h oweve r take cauti o n , as meta p l a stic c h a n g e s in the pouch ca n ca u se it to a pp e a r c o l o n i c and th u s m i staken fo r cuffitis. Li kewise, the c h ro n i c c h a n ges of I B D (i . e . , P a n eth ce l l m eta p l a s i a) i n t h e recta l cuff ca n m i m i c s m a l l bowe l m u cosa a n d be m i staken for p o u c h i t i s ; t h u s , i d e a l ly recta l cuff a n d pouch b i o ps i e s s h o u l d be s u b m i tted sepa rate l y by the endoscopist, a n d c l ea rly l a be l e d . I B D m i g h t be s u g g ested by the path o l og i st w h e n t h e re i s m ajor h i sto l o g i c d i sc o rd a n ce a m o n g b i opsy sa m p l e s (i . e . , one t i s s u e fra g m e nt sh ows m a rked a ctive a n d c h ro n i c c h a n g es, w h i l e the re m a i n i n g fra g m e nts a re u n re m a rk­ a b l e ) ; see sa m p l e n ote b e l ow ( F i g s . 3 . 1 3 9 a n d 3 . 1 40) .

230

AT LAS

0 F

GAST R0 I NT EST I N A L

PAT H O LOGY

Fig u re 3 . 1 44 Crypt a rc h itectu ra l d i stu rba n ce , p repouch b i o psy with chro n i c changes. This prepouch biopsy sh ows m a rked l a m i n a p ropria c h ro n i c i n fl a m m at i o n , i n c l u d i n g l y m p h o i d a g g regate fo r­ matio n . Findings such as this may be fou n d in the prepouch sma l l bowe l a n d s h o u l d n ot b e over- i nterpreted as Cro h n d i sease.

Figure 3 . 1 45 Crypt a rch itectura l d i stu rba n c e , p repouch b i o psy with chro n i c c h a n ges. An other exa m p l e of a p repouch biopsy sh ow­ i n g c h ro n i c featu res (crypt d i stortion, d ropo ut, a n d s h o rtfa l l/bas a l Iymphoplasmacytosis) . C h ro n i c c h a n g e s such a s this may be fou n d i n p repouch biopsies a n d do not i n d i cate Cro h n d isease.

FAQ: Does a ctive and chronic i nfl a m m at i o n i n the p repouch b i opsy i n d i cate the p resence of C ro h n d i sease? Answe r : N o .

I nfl a m m ation p roxi m a l t o t h e pouch, o r " prepouch i l e itis, " i s com mo n i n patients with pouch itis ( 1 3%) a n d does not i m p l y m i ssed Cro h n d i sease or p red i ct pouch fa i l u re l5 The majority of patients (86%) with p re pouch i leitis respond to antibiotic treatment, fu rthe r supporti n g that p repouch i l eitis is not a m a n ifestation of Cro h n d i sease. 76 A d i a g n osis o f Cro h n d i sease ca n o n l y be made i n the p roper c l i n ica l con­ text; for exa m p l e , if the patient demonstrates extra intesti n a l m a n ifestati o n s of Cro h n d i sease, peria n a l d i sease, o r sma l l bowe l strictu res o r fistu l a s ( F i g s . 3 . 1 44 a n d 3 . 1 45) . FAQ: I s pyloric g l a n d meta p l a s i a i n i l e a l pouch biopsies a defi n itive m a rker for C ro h n d isease? Answe r : N o .

Pyl o ri c g l a n d m eta p l a s i a ( F i g . 3 . 1 46) i s m o re com m o n i n pat i e n ts w h o expe rience com p l i cation fo l l owi n g a n I PAA ( 5 5 %) a s c o m p a red to those w h o fo l l ow a n o rm a l postoperative c o u rse ( 1 2%) . T h e p rev a l e n ce i s h i g h e r i n patients with C ro h n d i s­ ease of the pouch (7 7 %) as co m pa red to u l cerative co l itis patients with c h ro n i c po u c h itis (22%), but ca n n ot be u sed a s a defi n itive m a rke r fo r C ro h n d i sease. 77

Fi g u re 3 . 1 46 Pyloric m eta p l as i a (arrowh eads) i n c h ro n i c pouch c h a nges does n ot necessa ri ly i m p l i cate Cro h n d isease. It is a non­ specific sign of chro n i c m u cosa l i nj u ry.

C h a pte r 3

5 M ALL

BOWE L

231

FAQ: C a n p o u c h itis be d isti n g uished from I B D h i stologica l ly? Answe r : N o . T h e h i st o l o g i c c h a n ges o f a ctive a n d c h ro n i c p o u c h i t i s a re n o n specific a n d ca n n ot be d i sti n g u i s h e d from the a ctive a n d ch ro n i c c h a n ges seen i n I B D . The fu n cti o n of pouch b i o ps i e s i s to exc l u d e oth e r eti o l og i es (e . g . , cyto m eg a l ov i r u s i nfection) a n d t o confi rm t h e c l i n i c a l i m p ress i o n o f p o u c h i t i s . A d i a g n o s i s o f Cro h n d i sease c a n o n l y b e m a d e i n t h e pro pe r c l i n i c a l co ntext ( F i g s . 3 . 1 47-3 . 1 5 2 ) .

F i g u re 3 . 1 47 An a l tra n sition . A h e l pfu l t i p can s o m eti mes b e fou n d i n the biopsy. If biopsies conta i n the a n a l tra n sition (a rrow­ head) of co l u m n a r m u cosa to sq u a m o u s , the biopsy is from the rec­ tal cuff a n d n ot the pouch.

Figure 3 . 1 48 Crypt a rch itectu ra l d istu rba n ce , pouch with Cro h n disease. T h i s p o u c h sh ows n o nspecific features o f chro n i city, i n c l u d ­ i n g crypt bra n c h i n g a n d d i stortion a n d i n creased c h ro n i c infl a m ­ m at i o n . Fo l l ow i n g a n I PAA proce d u re , t h i s patient deve loped extra i ntesti n a l m a n ifestations of Cro h n d isease, i n c l u d i n g uve itis, i ritis, a n d a rth ritis. This case i l l ustrates that, unfo rtu nately, there a re no re l i a b l e h isto l o g i c features to d i sti n g u ish pouch itis from infl a m ­ matory bowe l d isease: identica l fi n d i n g s can be s e e n i n both set­ tings. Corre l ation with the c l i n ical setting offers the best means to disti n g u ish pouch itis from infl a m matory bowel d isea se.

Fig u re 3 . 1 49 Crypt a rch itectu ra l d i stu rba n ce , pouch with Cro h n d isease. Add iti o n a l b i o p s i e s o f the pouch from the s a m e patient show m a rked crypt shortfa l i/basa l lym p h o p l a s m a cytosis a n d c h ro n i c infl a m m atio n .

Figure 3 . 1 5 0 Crypt a rch itectu ra l d i stu rba nce, p repouch biopsies i n patient with Cro h n d i sease. Biopsies of the prepouch sma l l bowe l in the sa m e patients show crypt d i stortion a n d crypt a bscesses (arrowhead) .

232

AT LAS

0 F

GAST R0 I N TE S T I N A L

PAT H O LOGY

F i g u re 3 . 1 5 1 Crypt a bscess i n p repouch b i o psy fro m p revious case.

Figure 3 . 1 5 2 Crypt a rch itectura l disturba nce, p repouch biopsies i n patient with Cro h n d isease. Additi o n a l p repouch b iopsies show features of ch ro n i c ity. In the a bsence of perti nent c l i n ical i nforma­ tion, the fi n d i n g s a re nonspecific.

SAM P LE N OTE: U NCOM PL I CATE D PO UCH B I O PSY WITH ACUTE I N F LAM M AT I O N AN D CH RON I C CHAN G ES F O R " S U S P E CT PO U C H ITIS"

Ileum, Pouch, Biopsy: •

Mild acute inflammation with chronic mucosal changes , consistent with clinical impres­ sion of mild active chronic pouchitis .

SAM PL E N OT E : PO U C H B I O PSY S E NT FOR " R U L E O U T C RO H N D I S EAS E "

Ileoanal Pouch, Biopsy: •

Small intestinal mucosa with moderate acute inflammation and chronic mucosal inj ury changes.

Note: The histologic sections show small intestinal mucosa with crypt abscesses and chronic changes (marked villous blunting and increased lamina propria chronic inflam­ mation) without granulomata . The features are nonspecific and are compatible with active chronic pouchitis in the proper clinical setting. Involvement by Crohn disease can show similar changes and this possibility cannot be entirely excluded. Correlation with clinical information is recommended.

SAM PL E N OT E : D ISTA L POUCH O R R ECTAL C U F F B I O PSY WITH F EATU R ES S U S PI C I O U S FOR I N F LA M M ATO RY BOW E L D I S EAS E

Ileum, Distal, and Postpouch Biopsies: •

Intestinal-type mucosa with moderately active chronic inflammatory disease and patchy ulceration.

Note: Long-standing chronic pouchitis may show metaplastic changes that mimic colonic mucosa; however, it is suspected this biopsy was taken from the rectal cuff and the findings represent active IBD ("cuffitis") . Correlation with endoscopic and clinical findings is sug­ gested . No dysplasia identified .

Ch a pter 3

E OS I N O P H I LIA PATTERN

F i g u re 3 . 1 5 3 Eosi n o p h i l s i n t h e l a m i n a p ropri a . Eosi n o p h i l s a re b i -I obed l e u kocytes with a b u n d a n t brightly eosi n o p h i l i c g ra n u les that m a ke t h e m easily identifi a b l e at low m a g n ificati o n . They a re a n o r m a l i n h a bitant of the s m a l l bowel l a m i n a propria, but a reas of i ntense c l u steri n g , i ntra epith e l i a l eosi n o p h i ls, o r eosi n o p h i l i c a bscesses m a y i n d icate a n u n derlying disease state .

C H ECKLI ST: Eti o l o g ic Considerat i o n s for t h e Eos i n o p h i l i a Pattern o

I d io path i c Eosi n o ph i l i c Enter itis

o

M e d icati o n s

o

Al l ergy

o

Parasitic I nfect i o n

o

I nf l a m m a tory B o w e l D i sease

o

Co n n ective Tiss u e D i sord ers and Va scu l itis

The eosinophilia pattern is broadly defined as excessive numbers of eosinophils in a normal location (i . e . , lamina propria) or any eosinophils in an abnormal location (i . e . , epithelium or muscularis mucosae) (Fig. 3 . 1 5 3) . Eosinophil numbers show an upward gradient from the esophagus to the small bowel. 7 8 Currently, there are no vigorous standards for the threshold of increased eosinophils in the small bowel, although some studies employ >20 eosinophils in one high powered field 79 Low-level eosinophilia is relatively common in routine biopsies and studies have shown an association with allergy and hypersensitivity in patients 7 8-8 4 Nonetheless , compared to other gastrointestinal sites, there is a relative pau­ city of information regarding eosinophilia in the small bowel, and diagnoses are frequently descriptive and operator-dependent (Figs . 3 . 1 54-3 . 1 5 7) . Until further study clarifies the significance of small bowel eosinophilia, the differential diagnosis broadly overlaps with that of gastric eosinophilia. For this reason, readers are referred to the Eosinophilia Pattern , Stomach Chapter.

5 M ALL

BOWE L

233

234

ATLAS

0 F

GAST R0 I N TE ST I N A L

PAT H O LOGY

Fig u re 3 . 1 5 4 M u cosa l eosi n o p h i l i a , m e d i cation -re l ated (arrow­ head) . Review of a patient's med ication l i st m a y p rovide eti o l o g i c c l u es for m u cosal eosi n o p h i l i a . I n this exa m p l e , the patient w a s tak­ i n g the i m m u n osu p p ressa nt myco p h e n o l ate m ofeti l , w h i ch h a s a known association with m u cosa l eosi n o p h i l i a .

F i g u re 3 . 1 5 5 M u cosa l eosi n o p h i l i a , m e d i cati o n -re l ated (arrow­ heads) . M u cosa l eosi n o ph i l i a is n o nspecific with out c l i n ic a l context. This exa m p l e is from a patient on a chemothera peutic reg i m e n fo r c h ro n i c l y m p h o cyti c l e u ke m i a who presented with a skin rash a n d gastrointesti n a l symptoms. The fi ndings l i kely represent m e d i cation­ re l ated m u cosa l eosi n o p h i l i a .

Figure 3 . 1 56 Duodenal eosi noph i l i a i n a patient with eosinop h i l i c esophag itis. Th is duoden a l biopsy shows m i l d vi l l o u s b l u nting a n d m a rked expansion o f t h e l a m i n a propria b y a n infl a m m atory i nfi ltrate .

Fig u re 3 . 1 57 Duoden a l eosi noph i l ia i n a patient with eosi n o p h i l i c eso p h a g itis (EoE). H i g h e r m a g n ification o f t h e previous fig u re shows a b u n d a n t m u cosa l eosi n o p h i l s in the l a m i n a propria (arrows) . The patient h a s a n esta b l ished d i a g n osis of EoE, a n d the d u o d en a l fi nd­ i n g s ra ise the poss i b i l ity of a m o re genera l ized i d i opath i c eosi no­ p h i l i c enteritis.

SAM P L E N OT E : D U O D E NA L EOS I N O PH I LIA PATT E R N O F I NJ U RY, M I LD, N O S

Duodenum, Biopsy: •

Duodenal mucosa with increased eosinophils .

Note: The presence of eosinophils in the gastrointestinal tract is a nonspecific finding and has been associated with food allergy, medication reaction , parasitic infection, Crohn dis­ ease , hematologic or lymphoid disorders , and connective tissue disorders . Some cases remain idiopathic , and exclusion of involvement of other sites in the gastrointestinal tract (i . e . , stomach and colon) may be of interest . Correlation with clinical and serologiC infor­ mation is recommended .

C h a pter 3

MALABSORTION PATTE RN

F i g u re 3 . 1 58 M a l a bso rptio n pattern of i nj u ry in the sma l l i ntesti n e . This s m a l l bowe l b i o psy sh ows n e a r-co m p l ete atrophy o f the vi l l i , associ ated c rypt hyperp l a s i a , a n d m a rked i ntraepith e l i a l lymph ocy­ tosis. These three fi n d i n g s may be seen in vari a b l e com b i n ation i n t h e m a l a bsorption patter n , b u t n ote the i ntact crypt a rch itecture; crypt a rch itectura l d i stortion i s n ot a p ro m i n ent featu re of the m a l ­ a bsorption pattern.

CH ECKLIST: Et i o l o g i c Considerations for t h e M a l a bsorpt i o n Pattern o

M e d i ca t i o n s

o

R e a ctive D u o d e n o pathy

o

S m a l l I ntesti n a l B a cteri a l Ove rg rowth

o

Gl uten Sen sitive Enteropathy (Ce l i a c D i se a se) a n d Refra cto ry S p ru e .

o

N o n g l uten P rote i n S e n sitivity

o

Tro p i ca l S p r u e

o

Co m m o n Va ri able I m m u nodefi c i e n cy

o

Auto i m m u n e Enteropathy

o

Co l l a g e n o u s D u o d e n itis (Co l l a g e n o u s S p ru e)

The malabsorption pattern of injury refers to a combination of intraepithelial lymphocyto­ sis , crypt hyperplasia , and villous blunting (Fig. 3 . 1 5 8) . This triad is the histologic hallmark of malabsorption in the small bowel and is frequently accompanied by the clinical symptom of diarrhea . These features can manifest singly or in combination along a wide histologic spectrum.

Intraepithelial Lymphocytosis Intraepithelial lymphocytosis represents an immunologic process of crosstalk between luminal antigens and mucosal lymphocytes. The number of IELs in the normal small intes­ tine has been reported as 1 1 to 23 IELs per 1 0 0 enterocytes 85-87 Except in the case of gluten sensitive enteropathy (celiac disease) , there are currently no speCific cut-off points for any the various disease entities . As such , the number of IELs does not need to be assessed in all cases ; however if a reliable obj ective measure is needed, a rapid method of counting IELs can be performed by counting 20 epithelial cells at the distal apex (tip) of each of 5 villi (Fig. 3 . 1 5 9) 85 . 8 7 ,88 This number can be expressed as IELs per 1 00 enterocytes .

Villous Blunting and Crypt Hyperplasia Crypt hyperplasia is ambiguously defined as the elongation of the crypt compartment and is difficult to quantify. As such , crypt hyperplasia and villous blunting are frequently assessed together and can be expressed as a crypt-to-villous ratio. When the crypt compartment elongates and blunting of the villi occurs , the normal crypt-to-villous ratio 0 : 3 to 1 : 5) increases (Fig, 3 . 1 60) 89

S M A LL

BOWE L

235

236

ATLAS

0 F

GAST R0 I N T EST I N A L

PAT H O LOG Y

Fig u re 3 . 1 59 Cou nti n g I E Ls . O n e ra pid m ethod of counting I E Ls can be perfo rmed by selecti n g a n enterocyte at o n e v i l l o u s tip (cen­ ter arrow) and cou nti n g 1 0 epith e l i a l ce l l s to either side. This brack­ ets off 20 epith e l i a l ce l ls (latera l arrows). Count the I E Ls (arrowheads) in this a re a . When this m ethod is performed a cross five vi l l ou s ti ps, the n u m ber of I E Ls can be q u a ntifi ed per 1 00 enterocytes.

Figure 3 . 1 60 M a l a bsorption pattern, abnormal crypt to vi l lous ratio. This biopsy from the second portio n of the duoden u m has a crypt depth to v i l l o u s height ratio of approximately 1 : 1 which is the resu l t o f both crypt hyperplasia a n d v i l l o u s b l u nting. Norm a l crypt t o v i l l o u s ratios ran g e from 1 :3 t o 1 : 5 . Com pare this fig u re t o fig u re 3 . 3 , w h i c h has a normal crypt t o villous ratio. Care should be taken n ot t o over­ ca l l villous b l u nting i n the bu l b, as vi l l i in the b u l b a re natu ra l l y shorter.

The severity of features , whether manifested singly or in combinatibn , can serve as diagnostic clues ; however the features are nonspecific , and they may be seen in an ever­ increasing list of conditions that require clinical correlation, as discussed below.

SAM P L E N OT E : I NTRA E PITH E LIAL LYM PH OCYTOS I S I N TH E ABS E N C E O F VI L LO U S ATRO PHY

Duodenum, Biopsy: •

Duo denal mucosa with mild intraepithelial lympho cytosis and preserved villous architecture .

Note: The duodenal biopsy shows mild histologic changes including mild intraepithelial lymphocytosis in the setting of preserved crypt and villous architecture . The findings are nonspeCific and raise a differential diagnosis including small intestinal bacterial overgrowth (SIBO) , medication-induced inj ury (NSAIDs and olmesartan) , peptic injury, celiac disease , and sensitivity to nongluten proteins , among others . Correlation with clinical information is recommended . A similar approach would be recommended in the case of mild villous atrophy.

SAM P L E N OT E : MALABS O R PTIO N PATT E R N O F I NJ U RY, S EV E R E

Duodenum, Biopsy: •

Duodenal mucosa with near-total villous atrophy, crypt hyperplasi a , and marked intra epithelial lymphocytosis .

Note: Duodenal biopsies show a marked malabsorption pattern of inj ury including near­ total villous atrophy, crypt hyperplasia , marked intraepithelial lymphocytosis , and expan­ sion of the lamina propria by chronic inflammation. The findings are nonspeCific , but raise a differential diagnosis including celiac disease, hypersensitivity reaction to nongluten proteins , severe bacterial overgrowth, chronic malnutrition , and immune dysregulation disorders (e.g, common variable immunodefiCiency [ CVID ] , and autoimmune enteropa­ thy [AlE ] ) . Of note , the normal expected constituents are present (i . e . , plasma cells , gob­ let cells , Paneth cells , and enteroendocrine cells) . Correlation with clinical, serologic and microbiologic information is necessary.

C h a pter

3

5 M ALL

BOWE L

237

M E D I CATI O N NSAIDs cause a wide spectrum of histologic changes in the small bowel , some of which are segment specific. The frequency of injury is likely underappreciated, with one study demonstrating 5 5 % to 7 5 % of healthy volunteers showing small bowel damage after 2 weeks of treatment 90 Mechanistically, the prostaglandin reduction from both selective and nonselective COX inhibitors alters mucus and bicarbonate secretions , reduces mucosal blood flow, affects neutrophilic function and alters endothelial function . Selective COX2 inhibitors reduce, but do not completely eliminate side effects . Mild lesions may occur along the length of the small intestine and consist of superficial erosions with nonspe­ cific neutrophilic , eosinophilic and plasmacytic infiltrates . These erosions may be multiple, coalesce forming deep ulcers , and result in hemorrhage . Repeat cycles may result in chronic inj ury, such as diaphragm disease in the terminal ileum . See also Diaphragm Disease , Crypt Architectural Disturbance Pattern , this chapter; however NSAID inj ury in the proximal small bowel is typically mild and results in subtle and nonspecific malabsorption-type changes, such as mild villous blunting and intra epithelial lymphocytosis (Figs . 3 . 1 6 1 and 3 . 1 62 ) . These cases require correlation with the patient's medication list to exclude NSAID injury Note that severe diffuse villous blunting has not been reported in association with NSAIDs. In the absence of a definitive etiology for a mild malabsorption pattern of inj ury, a descriptive report listing the differential diagnoses should suffice (see sample note above) . The antihypertensive medication olmesartan (Benicar) , an angiotensin II receptor inhibi­ tor, is associated with lymphocytiC gastritis , collagenous gastritis , and collagenous enteri­ tis 9 ! These patterns of inj ury may occur singly or in combination , and have been described as "sprue-like . " Patients often present with clinically significant diarrhea and weight loss and the biopsies can be indistinguishable from those of celiac disease . Interestingly, these patients do not respond to a gluten-free diet (GFD ) , celiac serologies are typically negative , and the histology and symptomatology reverse upon olmesartan cessation. As such, this pattern of inj ury is histologically indistinguishable from celiac disease or other non-drug­ related conditions , making review of the patient's medication list an important effort during biopsy review. See also Malabsorption Pattern , Collagenous Enteritis, this chapter. KEY F EATU R E S of M e d i cation I nj u ry: •

•

•

NSAIDs are the most common culprits . Repeat cycles of ulceration and submucosal scarring can result in "diaphragm disease" of the terminal ileum. The proximal small bowel can show a nonspecific mild malabsorption pattern of injury

•

Severe diffuse villous blunting is not seen in NSAID-induced injury.

•

Correlation with clinical use of NSAIDs is reqUired.

Figure 3 . 1 6 1 M a l a bsorpti on pattern, N SA I D i nj u ry i n the prox i m a l s m a l l i ntest i n e . D u o d en a l c h a n g es a re typica l ly m i l d a n d d e m o n ­ strate a m a l a bsorption pattern o f i nj u ry. This exa m p l e sh ows m i l d vi l l ous b l u nting (crypt t o vi l l o u s ratio o f 1 : 1 t o 1 :2).

Fig u re 3 . 1 62 M a l a bsorpti on pattern, N SAI D i nj u ry i n the proxi m a l s m a l l intesti n e . V i l l o u s ti ps m a y conta i n m i l d or pro m i nent i ntraepi­ th e l i a l lymph ocytosis. Altho u g h N SAI D injury i n the proxi m a l sm a l l i ntestine featu res a m a l a bsorption patte rn, severe atrophic lesions have not been re porte d .

238

AT LAS

0 F

GAST R0 I N TEST I N A L

PAT H O LOGY

R EACTIVE D U O D E N O PATHY Reactive duodenopathy has been ascribed to chronic exposure to acid, such a s i n cases of gastric antral Helicobacter infection, gastric heterotopia , and Zollinger-Ellison syndrome . Histologic changes are predominantly limited to the bulb , but are sometimes seen as far as the second portion of the duodenum. Historically, reactive duodenopathy has been char­ acterized by three main pathologic features , all of which may vary in severity, and include (Figs . 3 . 1 63-3 1 69) : 1 . Increased plasma cell infiltration 2: Neutrophils in the lamina propria or epithelium (or in both) 3. Reactive epithelial changes including villous blunting Although surface gastric foveolar metaplasia and Brunner gland hyperplasia are often prominent findings , and are sometimes used as diagnostic criteria, these are not absolute cri­ teria because they may be missed due to sampling error, and can be found in cases without

Figure 3 . 1 63 M a l a bsorption pattern, rea ctive duoden opathy. This low power view shows v i l l o u s b l u nt i n g (crypt to v i l l o u s rati o 1 : 1 ) cha racte ristic of m a l a bsorpti o n patte rn of i nj u ry; h owever fu rther exa m i n ation reve a l s i ntra m u cosa l B ru n n e r g l a nds, i n creased c h ro n i c infl a m m ation i n a n expanded l a m i n a propria, surfa ce epith e l i a l dam­ age (arrow), and g a stric fove o l a r m eta plasia (arrowhead). The con­ ste l l ation of fi n d i n g s is consistent with rea ctive duodenopathy.

Figure 3 . 1 65 M a l a bsorption pattern, rea ctive d u o d e n opathy. At fi rst g l a nce, this low power view sh ows a pro m i nent pattern of v i l ­ l o u s b l u n t i n g ; h owever fu rther exa m i n ation revea l s s u bt l e g a stric fove o l a r m etaplasia (arrowheads) arising i n a backg ro u n d of exu ber­ ant intra m ucosal B ru n n e r g l a n d s a n d a n expa nded l a m i n a propri a .

F i g u re 3 . 1 64 M a l a bsorption patte rn, rea ctive d u o d e n o pathy. H i g h power view of a v i l l o u s tip sh ows gastric fove o l a r m eta p l a s i a (arrow) a n d I E Ls.

Figure 3 . 1 66 M a l a bsorption pattern , rea ctive duodenopathy. On h i g h e r power, it i s easier to a p p reciate the foca l g a stric foveo l a r meta p l a s i a (arrow) a n d m i l d i ntraepith e l i a l lymphocytosis (arrow­ heads) .

Ch a pter 3

Figu re 3 . 1 67 M a l a bsorption patte rn, rea ctive duodenopathy. The vi l l i i n t h i s exa m p l e a re b l u nted. Abundant I E Ls (arrowheads) a re read i ly identifi a b l e , as is foca l gastric foveo l a r meta p l a s i a (arrow).

5 MALL

BOWE L

239

F i g u re 3 . 1 68 M a l a bs o rpt i o n patte r n , rea ctive d u oden opathy (PAS/AB). A PAS/AB sta i n h i g h l i g hts the acidic mucin of the goblet ce l l s (rig ht) b l u e-purple. The g a stric fove o l a r meta p l a s i a (left) con­ ta i n s n e utra l m uc i n s which sta i n eosinoph i l ic.

Fig u re 3 . 1 69 M a l a bsorption patte rn, gastric h ete roto p i a . Reac­ tive d u o d e n o pathy i s often a n isol ated fi n d i n g , but d o not fo rget to system atica l l y check fo r u nderlyi n g gastric oxyntic g l a n d h etero­ top i a . The p i n k and b l u e m ixtu re of pa rieta l and chief ce l l s may be foca l , but these acid-secret i n g g l a n d s can be the u n d e rlying cause of pe ptic-type i nj u ry i n adjacent m u cosa a n d resu l t i n m isi nterpreta­ tion u n l ess specifica l ly i d entified. inflammation. Both the surface gastric foveolar metaplasia and villous blunting are features indicating chronic mucosal injury. When severe , acid inj ury can cause duodenal ulcers , resulting in a clinical condition termed "peptiC ulcer disease . " See also Peptic Ulcer Dis­ ease , Acute Duodenitis, this chapter; however while 9 5 % of peptic ulcer disease has been ascribed to Helicobacter infection, the milder changes of reactive duodenopathy do not carry this bacterial association. In fact, some authors argue that there is insufficient evidence to ascribe gastric foveolar metaplasia to a "peptic" disorder, since only 1 6 . 4 % of patients with metaplasia have detectable Helicobacter infection 92 As a result, there exists some degree of uncertainty regarding diagnostic criteria and terminology. Alternative nomenclature include gastric foveolar metaplasia with chronic inflammation, chronic peptic duodenopathy, active chronic peptic duodenitis (in the presence of acute inflammation) , and peptic-type duo­ denopathy. Although the later terms containing "peptic" are discouraged by some due to the inaccurate implication of a peptic or Helicobacter etiology, these terms are retained by institutional conventions and often used interchangeably. Regardless of terminology, the his­ tologiC findings overlap with many of the differential diagnoses found in the malabsorption

240

AT LAS

0 F

GASTR0 I NT ESTI N A L

PAT H O LOGY

pattern , and can result in some diagnostic difficulty In mild cases, nearly normal mucosa may be seen with only a borderline increase in plasma cells, intraepithelial lymphocytosis , and mild villous blunting. When faced with these mild changes , examination of gastric biopsies can help distinguish upstream Helicobacter infection from NSAlD-induced injury to the proximal duodenum . In the absence of a definitive etiology for a mild malabsorption pattern of inj ury, a descriptive report listing the differential diagnoses should suffice (see the preceding Sample Note) . KEY F EAT U R ES of Reactive D u o d e n o pathy: •

•

•

•

Reactive duodenopathy is often attributed to increased acid in the duodenum. Causes include increased gastric acid, Helicobacter gastritis , gastric heterotopia, N SAl D , and Zollinger-Ellison syndrome . Pathologic features include : increased lamina propria plasma cells , neutrophilic infiltra­ tion , and reactive epithelial changes. Surface gastric foveolar metaplasia and intramucosal Brunner glands may or may not be

present. •

•

Mild changes may cause a nonspecific malabsorption pattern. Severe changes, such as ulceration, may be termed peptic ulcer disease, which has been associated with Helicobacter infection far more frequently than the milder peptic duodenitis (9 5 % vs . 1 6 % ) . PEARLS & PITFALLS

When ava i l a b l e , proxima l d u ode n a l or b u l b biopsies s h o u l d be exa m i ned for peptic­ type c h a n ges, particu l a rly when patchy i ntraepith e l i a l l y m p ho cytosis is fou n d i n the d i sta l d u od e n u m . The h e l pfu l presence of g a stric foveo l a r m eta p l a s i a a n d peptic­ type c h a n ges a re fou n d more frequently i n the proxi m a l duoden a l b i o psies, wh i l e downstre a m c h a nges a re often n o n specific.

S MALL I NTESTI NAL BACT E R IAL OVE RG ROWTH Small intestinal bacterial overgrowth (SlBO) i s defined a s excessive anaerobic enteric bacte­ ria in the small bowel , specifically > 1 0 0 , 000 colony forming units per milliliter (CFU/mL) on culture of a duodenal aspirate . The most common causes for bacterial overgrowth are diminished gastric acid secretion and small intestine dysmotility; these lead to disruption of the normal homeostatic mechanisms that control enteric bacterial populations . Distur­ bances in gut immune function and anatomic abnormalities of the GI tract increase the likelihood of developing SlBO (Table 3 . 4) and are found in two-thirds of patients 93

TABLE 3 .4: C o n d i t i o n s P re d i s p o s i n g to B a cte r i a l Overg rowt h Anatomic Abno rma l ities

Abnormal Motil ity

S u rg i c a l a n a sto mosi s

D i a beti c n e u ropathy

Other

H y p oc h l o rh yd r i a - p roton p u m p i n h i b itors - H2 b l ockers, - a u to i m m u n e g a stritis

S u rg i c a l b l i n d l oo p s

C o n n ective tissue d i s o rd e rs (scleroderma)

I m m u n od efi c i e n cy states

Str i ct u res (Cro h n d i sease, r a d i a t i o n -

R a d i a t i o n enteritis

Alcoholism

i n d u ced) -- --- --- ------

S m a l l bowe l d iverti c u l a S m a l l bowel d u p l ication

C ro h n d isease

C irrho s is

Pse u d o - o b str u ct i o n

C h ro n i c p a n c reatitis

A m y l o i d osis

E n d stage re n a l d i sease Adva n ce d age

C h a pter 3

S M A LL

BOWEL

241

Deconjugation of bile salts and metabolic breakdown of carbohydrates by the bacteria cause clinical symptoms of bloating, abdominal distention, abdominal pain or discomfort, diarrhea , steatorrhea , fatigue, and weakness . Patients may also present with anemia, defi­ ciency of fat soluble vitamins (A, D, E , K) , and vitamin B or protein deficiency Local dam­ l2 age and inflammatory changes in the small bowel result in nonspeCific histologic features that vary from normal to a profound malabsorption pattern . One study found that more than half of biopsies from SIBO patients were histologically unremarkable, and that villous blunting (crypt to villous ratio of >3 : 1 ) was the only feature more common as compared to controls (Figs . 3 . 1 70-3 . 1 76) 93 In the absence of a definitive etiology for a mild mal­ absorption pattern of injury, a descriptive report listing the differential diagnoses should suffice . Culture of a small bowel aspirate obtained during endoscopy is the gold standard for diagnosis . Antibiotic therapy remains the mainstay of treatment, the goal of which is to reduce or eliminate bacterial overload and reverse the mucosal inflammation associated with malabsorption . 94

Fi g u re 3 . 1 70 M a l a bsorpti on patte rn, 5 I B O . This d i sta l d u o d e n a l bio psy sh ows m a rked vi l l ous b l u nting (reve rsed crypt to v i l l o u s ratio 3 : 1) which ra ises the m a l a bsorpti on pattern d ifferenti a l d i a g n osis. A d u o d e n a l a s p i rate performed at the time of biopsy g rew > 1 00,000 CFU/mL, confi r m i n g the p resence of 5 I BO .

Fig u re 3 . 1 7 1 M a l a bsorption patte rn , 5 I BO. A h i g h powe r view of the vi l l ous tips fro m the previous fig u re reve a l s abundant I E Ls (som e o f which a re h i g h l i g hted b y arrowheads) .

Fig u re 3 . 1 72 M a l a bsorption patte rn, 5 I BO. This exa m p l e of con­ fi rmed 5 1 BO sh ows m i l d v i l l o u s b l u nting and m a rked expansion of the l a m i n a p ropria with c h ro n i c i n fl a m m atory ce l l s .

F i g u re 3. 1 7 3 M a l a bso rption patte rn, 5 I BO . A h i g h power view of the v i l lous tips from the p revious fi g u re reve a l s abu ndant I E Ls (som e o f w h i ch a re h i g h l i g hted b y arrowheads) .

242

AT LAS

0 F

GASTR0 I N T EST I N A L

PAT H O LOGY

F i g u re 3 . 1 74 M a l a bsorption patte r n , 5 I B O . D u o d e n a l biopsies freq uently a rrive at the l a bo ratory stating " ru l e out ce l i a c d isease . " A q u ick g l a nce a t this biopsy sh ows featu res com pati b l e with ce l i a c d i sease, s u c h as vi l l ous b l u nting (crypt t o vi l l ous ratio 1 : 1 ), a l a m i n a propria expanded with c h ro n i c infl a m m atory ce l ls, a n d intraepithe­ l i a l lymph ocytosis; h owever c u l t u re of a d u o d e n a l a s p i rate g rew > 1 00,000 CFU/m L of a n a e ro b i c ba cte ria , confi r m i n g 5 I B O . Add i ­ t i o n a l c l i n ica l information revealed negative ce l i a c d i sease specific antibodies.

Figure 3 . 1 7 5 M a l a bso rption pattern , 5 I BO . Higher power exa m i ­ n ation o f t h e p revious fig u re sh ows I E Ls (so m e o f w h i c h a re h i g h ­ l i g hted b y arrowheads) .

F i g u re 3 . 1 7 6 M a l a bsorpt i o n patte rn , 5 I B O . These vi l l i s h ow i ntra e p i th e l i a l l y m p h o cytes (so m e of w h i c h a re h i g h l i g hted by arrows) that a re eve n l y d i stri buted a l on g the fu l l l e n gth of the vi l l i . B y compa riso n , ce l i a c d isease m a y demonstrate a crescendo of I E Ls towa rd the tips of the vi l l i . KEY F EATU R E S o f S m a l l I ntest i n a l Bact e r i a l Overg rowt h : •

•

•

•

•

•

SBIO i s defined a s the growth of anaerobic enteric bacteria > 1 00,000 CFU/mL from a duodenal aspirate . Causes include: decreased acid secretion or motility, anatomic abnormalities, and altered gut immunity Patients experience bloating, diarrhea , steatorrhea, and fat soluble vitamin deficiency Histology shows a nonspecific malabsorption pattern than can range from very mild intra epithelial lymphocytosis to total villous atrophy Although radiolabeled carbon and hydrogen breath tests are available , the gold standard of diagnosis is culture of duodenal aspirates. Antibiotics are the mainstay of treatment .

Ch a pte r 3

S M A LL

B OWE L

243

FAQ: What if a sma l l bowel aspirate was n ot sent for culture at the time of endos­ copy, and a m a l a bsorption pattern is p resent on biopsy? Answer: C u l tu re of sm a l l bowe l fl u i d is the p referred m eth o d , but oth e r l a borato ry tests s u c h a s h y d rog e n b reath test, 1 4C-xyl ose b reath test, a n d b i l e a c i d breath test a re ava i l a b l e if an aspi rate was n ot perfo rmed 9 5 I t i s wo rthwh i l e to eva l u ate fo r 5 1 BO beca u se it is treata b l e , and beca u se exc l u s i o n of 5 1 BO ca n n a rrow the h i sto l o g i c d i ffe renti a l d i a g n o s i s .

G LUTE N S E N S ITIVE ENTEROPATHY (CELIAC D I S EAS E) Celiac disease is an immune-mediated systemic disorder caused when exposure to gluten (found in wheat, barley, and rye) triggers inflammation in the small intestine in genetically susceptible individuals . Also known as sprue, nontropical sprue, celiac sprue, gluten sensi­ tive enteropathy, and gluten-induced enteropathy, the estimated prevalence of celiac disease approaches 1 % in Europe and North America 96 . 97 Diagnosis requires careful correlation of four main characteristics , including ( 1 ) a variable combination of gluten-dependent clini­ cal manifestations , (2) celiac disease specific antibodies , (3) genetic predisposition includ­ ing HLA-DQ2 or HLA-DQ8 haplotypes, and (4) histologiC features of enteropathy 98-10 1 A pathologist who understands the clinical, serologic , and genetic factors of celiac disease provides the benefit of a more useful and integrated pathology report . Clinical manifestations are myriad, and most biopsies received in the laboratory state only "rule out celiac disease . " Table 3 . 5 provides some examples of the clinical manifesta­ tions , particularly those in which screening for celiac disease is advantageous . Serologic testing should be performed while a patient is on a gluten-inclusive diet and calls for

TABLE 3.5 : C o n d i t i o n s in w h i c h C e l i a c Disease Occurs M o re Freq u e n t l y t h a n in t h e G e n e r a l Pop u l at i o n a n d/or for Whom a G l ut e n - Free D i et M a y Be Be n efic i a l Celiac Disease C o m m o n (>2 times Preva l ence of General Population)

Ce liac Disease Less Common But Treata b l e

Sym pto matic m a l a bsorption

P u l m o n a ry h e m o s i d e rosis

D i a rrhea with weight l oss

U n exp l a i n ed m a l e o r fe m a l e i nfert i l ity

C h ro n i c d i a rrhea with or without a b d o m i n a l p a i n

Dys p e p s i a

C h ro n i c i ro n d efi c i e n cy a n d a n e m i a

A m e n o rrhea

M eta b o l i c b o n e d i sease and p re m a t u re oste o p o rosis

C h ro n i c fat i g u e

Post p ra n d i a l b l o a t i n g a n d g a s e o u s n ess

A p p a rent m a l a bsorpt i o n of thyro i d re p l a cement m e d i cati o n ------- --- ---

U n ex p l a i n e d weight l oss

E p i l epsy or ataxia

A b n o rm a l e l evated l iver e n zymes

C o n stipation

I n c i d e nta l d i scovery of v i l l o u s atro p h y e n d osco p i ca l l y o r

Recu rrent a b d o m i n a l p a i n

h i sto l o g i c a l ly D e r m atitis h e rpetifo rm i s Peri p h e ra l n e u ropathy O ra l a p h t h o u s u l cers G rowth fa i l u re D i s c o l o red teeth or d eve l o p m e nta l ly syn c h ro n o u s e n a m e l l oss Thyro i d d i sease I rrita b l e bowel syn d ro m e D o w n a n d Tu r n e r syn d ro m e s

244

ATLAS

0 F

GAST R0 I N T EST I N A L

PAT H O LOG Y

celiac disease specific antibodies, namely, deamidated antigliadin antibodies (DGP) , tissue transglutaminase antibody (TTG-IgA) , and antiendomysial antibody (EMA-IgA) , each of which are >90% sensitive and specific for CD I 0 2-107 Note that antigliadin antibody (AGA­ IgA and AGA-IgG) is no longer recommended due to its comparatively low sensitivity and specificity (as low as 7 5 % to SO % , each) 1 08 ; however testing for IgA deficiency remains essential since this condition can show false negative serologic results and is found in 2 % to 3 % of patients with celiac disease. 1 09. 1 10 As an adj unct to serologic testing, genetic testing has evolved over the past decade , and may be useful in cases with equivocal serologic and histologic findings . Haplotypes HLA-DQ2 (encoded by alleles Al * 0 5 and Bl * 02) or HLA­ DQS (encoded by alleles Al * 03 and B l * 0302) are found in 3 0 % to 40% of the population and are inherited in families and geographically. 1 1 l-1 l 3 This genetic information can be exploited since celiac disease develops in a minority of the population, and nearly all celiac patients have the isoform DQ2 (9 5 % ) or DQS ( 5 % ) 1 14 , 1 15 Thus, the presence of either one of these haplotypes is permissive for celiac disease , and conversely the absence of both these haplotypes essentially excludes celiac disease (negative predictive value 9 9 % ) 1 16 Despite advances in serologic and genetic testing , adequate small bowel biopsies for histopathology remain critical for diagnosis and should similarly be obtained before insti­ tuting a GFD . In one study, when �4 duodenal biopsy specimens were submitted from 1 3 2 , 3 5 2 patients without known celiac disease , the probability of a new diagnosis of celiac disease was significantly increased O . S % vs . 0 . 7 % , P 40 i ntraepith e l i a l lymphocytes per 1 00 enterocytes fo r mod ifi ed M a rs h (Oberh uber); > 2 5 i ntraepith e l i a l lymphocytes per 1 00 enterocytes fo r Co razza .

•

•

•

•

•

•

•

Testing guidelines (Table 3 . 6) are provided by the American College of Gastroenterology. Biopsy recommendations : four single-pass biopsies from the distal duodenum and two from the bulb , preferably submitted separately Histologic features include : intraepithelial lymphocytosis (>2 5 IELs per 1 0 0 entero­ cytes) , crypt hyperplasia, and villous atrophy, but are not diagnostic in isolation . A crescendo in the number of IELs from the base of the crypts to the tips of the villi is characteristic. Grading mechanisms exist, including the modified Marsh and Corazza systems (Table 3 . n. The presence o f neutrophils does not exclude a diagnosis o f CD . Immunohistochemistry for IELs is not useful if biopsies are otherwise unremarkable on routine H&E stain.

•

Treatment is lifelong adherence to a strict GFD .

•

RCD has a n increased risk for EATCL

FAQ: H ow m a n y I E Ls a re considered " i n creased " in celiac disease?

Answer: O ri g i n a l M a rsh descri pti o n s of ce l i a c d i sease did not specify a cut-off

n u m be r fo r I E Ls, w h e re a s O b e rh u be r et a l . 89 s u g g ested that >40 I E Ls per 1 00 e n t e rocytes i n d i cates a n o n g o i n g i m m u n o l o g i c process. S i n ce t h a t t i m e , the th res h o l d h a s d ropped, with Corazza et a l . 1 27 s u p port i n g a th resh o l d of 2 5 I E Ls per 1 00 entero cytes. For c o m p a r i so n , the n u m be r of I E Ls i n the n o rm a l sm a l l i ntest i n e h a s b e e n re ported a s 1 1 t o 23 I E Ls per 1 00 enterocytes . 86,87 , 1 28

FAQ: Are I E Ls more prominent at the vi l l o u s tips vs. the crypts i n celiac d isease?

Answe r : Yes ,

I n n o rm a l vi l l i , the I E Ls ten d to be m o re n u m e ro u s a l on g t h e l ate ra l a s pects of the v i l l i co m p a red with the t i pS . 1 29 , 1 30 I n contrast, the v i l l i fro m patients with ce l i ac d i sease s h ow a n esca l at i o n i n the n u m be r of I E Ls as o n e proceeds fro m the crypts towa rd the vi l l o u s t i p s , 87,1 28 , 1 3 1 Th i s c resce n d o of I E Ls towa rd the t i p s in ce l i ac d i sease refl ects i m m u n o l o g i c c ross-ta l k between l u m i n a l g l i a d i n a nt i g e n s and the m i g ratory i n fl a m m atory cel l s of the l a m i n a pro p r i a ( F i g . 3 . 1 96) .

250

AT LAS

0 F

GAST R0 I N TESTI N A L

PAT H O LOGY

Figure 3 . 1 96 M a l a bsorption pattern, crescendo pattern of I E Ls . This v i l l o u s tip conta i n s n u m e rous I E Ls (som e o f which a re m a rked by the arrowh eads) . N ote how the n u m be r of I E Ls d rops preci pi­ tously as one approaches the base of the vi l l us.

FAQ: How does o n e count t h e n u m ber of I E Ls i n 1 00 enterocytes? Answer: A re l i a b l e o bj ective m e a s u re i s needed i n t h e eva l u ation of ce l i a c d i s­

e a s e , a n d a ra p i d m et h o d of co u nt i n g I E Ls ca n be p e rfo r m e d by co u nt i n g 20 epithe l i a l ce l l s at the d i sta l a pex of each of 5 vi l l i (Fi g . 3 . 1 9 7 ) . 85.87.88 The n u m be r if I E Ls with i n th i s a rea ca n be expressed a s I E Ls per 1 00 enterocytes .

Fig u re 3 . 1 97 Cou nti n g I E Ls i n vi l l ou s tips. Sta rting at t h e center­ m ost enterocyte, cou n t 1 0 epith e l i a l ce l l s towa rd either s i d e. With i n t h i s s p a n o f 2 0 epith e l i a l cel l s (bra cketed b y arrows), count t h e I E Ls (on e exa m ple is i n d i cated by an a rrowhead); this exa m p l e conta i n s at least 4 . When this process i s performed a cross 5 vi l l ous t i p s , the resu lts can be q u antified as I E Ls per 1 00 enterocytes . FAQ: W h at is t h e sig n ificance o f neutro p h i l s i n b i opsies f o r CD?

A n swer: Wh i l e the p res e n ce of n e utro ph i l s i n d u od e n a l b i o psies ca n p ro m pt con­

s i d e ra t i o n for C ro h n d i sease and peptic inju ry, s i g n ifi c a n t d u o d e n a l n e u trop h i l i a i s rep o rted i n ce l i a c patie nts ( 5 6 % o f ped iatric a n d 2 8 % of a d u lt) a n d i s associ ated with m o re a ctive d i sease. 1 3 2 T h u s , the fi n d i n g s of d u od e n a l n e utro ph i l s in b i o ps i e s oth e rw i se c o n s i stent w i t h ce l i a c d i sease s h o u l d n ot precl ud e a d i a g n o s i s of ce l i a c d i sease (Fi g . 3 . 1 98).

C h a pte r 3

Figure 3 . 1 98 N eutro p h i l s in ce l i a c d isease (arrowheads) . Althoug h n e utro p h i l s a re not a c l assic featu re o f ce l i a c d isease, s i g n ificant d u o d en a l n eutrop h i l ia i s re ported i n ce l i a c patients and has been associ ated with m o re active disease. The fi n d i n g of n e utro p h i l s does not p rec l u d e a d i a g n osis of ce l i a c d isease.

FAQ: Is i m m u n o h istochemist ry for T-cel l m a rkers usefu l i n t h e d i a g nosis of celiac disease?

Answer: N o .

T h e I E Ls fo u n d i n ce l ia c d i sease a re p red o m i n a ntly C D 8+IC D3+ T-ce l l s . Acco rd­ i n g l y, some a ut h o rs and pra ctices a dvocate the use of C D 8 and C D 3 i m m u n o h is­ toch e m i c a l sta i n s to i m p rove detect i o n of I E Ls; h oweve r i m m u n osta i n s fo r T-ce l l m a rke rs d o n ot i m p rove detect i o n o f g l ute n -sens itive enteropathy w h e n H & E sta i n e d sect i o n s a re u n re m a rka b l e ( F i g . 3 . 1 9 9) . 1 33

Figure 3 . 1 99 C o m b i n e d CD3 a n d CDX2 i m m u n o h i stoch e m i ­ cal sta i n . T h i s CD3 i m m u n osta i n (h i g h l i g hts C D 3 + T-ce l l s o f c e l i a c disease red) has b e e n overl a i d on a CDX2 i m m u n osta i n (h i g h l i g hts enterocytes n u c l e i brown). T h i s practice is e m p l oyed by some l a bo­ ratories, but is u n n ecessa ry a s studies have shown that i m m u n os­ ta i n s do n ot i m p rove the detection of c e l i a c d isease.

S M A LL

B OWE L

251

252

AT LAS

0 F

GAST R0 I N T EST I N A L

PAT H O LOG Y

FAQ: H ow q u ickly do c l i n ica l a n d h i st o l o g i c feat u res i m p rove aft e r a G F D is i n stituted?

Answer: In m ost patients, d i a rrhea res p o n d s with i n days of i n stituti n g a G F D , a n d

m e a n t i m e t o reso l ut i o n i s 4 weeks. 99 With i n d a y s o f sta rt i n g a G F D , t h e re i s evi­ d e n c e of d i m i n ished s u rfa ce e p i th e l i a l d a m a g e and a red u ction i n the n u m be r of I E Ls; h owever it m a y be >3 m o n t h s befo re n o rm a l h i sto l ogy is a p p reciated , even with a d h e re n ce to a stri ct G F D .

FAQ: What is a g l uten ch a l l en g e , a n d h o w q u ickly do h i stologic lesions e m e rg e fo l lowi n g i n stitution?

Answe r : A g l uten c h a l l en g e i s t h e p rocess w h e reby a patient with suspected b u t

u n p roven c e l i a c d i sease o n a G F D reve rts to a n o r m a l g l ute n - i n c l u sive d i et u n d e r m e d i ca l s u p e rv i s i o n t o e n a b l e d i a g n osti c testi n g . Th i s w a s ro uti n e fo r d i a g n os i s i n t h e p a st , b u t i s n ow l ess freq u e n t l y u sed beca u s e o f t h e h i g h positive p re­ d i ct i v e va l u e of spec ific ce l i a c s e ro l o g y testi n g . I t re m a i n s a u sefu l d i a g n osti c test i n patients with perm i ssive h a p l otypes ( H LA-D02 o r D08), b u t with n o r m a l s e ro l o g i c a n d h i sto l o g i c resu lts w h i l e o n a G F D . A d i et conta i n i n g at l e a st 1 0 9 of g l uten p e r d a y fo r 6 to 8 weeks i s t h e n o rm a l g l uten c h a l l e n g e p r i o r to re peat b i o psy1 34, 1 35 ; h owever l ower doses of g l uten (3 g/d a y) c a n p rod u ce d i a g n osti c c h a n g e s i n a s l ittl e a s 2 weeks of g l u t e n i n g esti o n . 1 36 T h i s i n fo r m a t i o n ca n be l ev e ra g ed fo r patie nts w h o deve l o p severe sym pto m s fo l l ow i n g g l uten i n g esti o n (ce l i a c c r i s i s) a n d ca n n ot to l e rate a fu l l g l uten c h a l l e n g e . I t m a y a l so p rove u se­ fu l fo r fo l l owi n g refra cto ry p a t i e nts who e i t h e r su rreptiti o u s l y o r u n i nte n t i o n a l l y i n g est g l ute n .

N O N G LUTE N PROTE I N S E N S ITIVITY Sensitivity to nongluten proteins occurs most commonly with cow's milk, but soy, egg, and wheat proteins are also culprits . O ther types o f food sensitivities , especially among adults , are not well understood. Infants with cow's milk or soy sensitivity may present at 1 week to 3 months of age with protracted vomiting, diarrhea , protein-losing enteropathy, dehydration, anemia from chronic blood loss in the stool , and failure to thrive . 1 37 Rapid onset reactions can develop within 1 hour o f food ingestion, are IgE mediated, and do not result in histologic changes. 138 Slow onset reactions may be either IgE- or T cell-mediated immune reactions which can result in macrophage influx and cytokine-mediated muco­ sal damage . l 38 Biopsy specimens show a malabsorption pattern similar to celiac diseas e , with patchy areas of villous atrophy, intraepithelial lymphocytosis , edema , a n d increased mononuclear cell infiltrate in the lamina propria (Figs . 3 . 2 00 and 3 . 2 0 1 ) . Mild to severe mucosal e osinophilia and intraepithelial eosinophils can be seen in nongluten protein sensitivity, 1 39 and can help distinguish these two entities . In addition, IELs have been reported as fewer than seen in celiac diseas e . 139 When offending antigens are removed from the diet , the clinical and histologic abnormalities resolve , and characteristically recur when challenged . K E Y F EATU R E S o f N o n g l uten Pr ot e i n S e n s it ivity: •

•

•

•

•

C ow's milk, soy, egg, and wheat proteins can cause hypersensitivity reactions in the small bowel . Infants commonly present with vomiting, diarrhea , dehydration, and failure to thrive . Histologic features show a patchy malabsorption pattern, similar to celiac disease . Mucosal eosinophilia is more common in nongluten protein sensitivity than in celiac disease . Treatment is avoidance of offending antigens .

C h a pte r 3

Figure 3 . 200 M a l a bsorption patte rn , n o n g l uten protei n sensitiv­ ity. H i sto l o g i c featu res of n o n g l uten prote i n sensitivity a re s i m i l a r t o those seen i n ce l i a c d i sease. These i n c l u d e v i l l o u s atrophy, crypt hyperp l a s i a , and i ntraepith e l i a l lymphocytosis.

5 M A L L

BOWE L

253

Figure 3.201 M a l a bsorption patte rn , n o n g l uten prote in sensitiv­ ity. H i g h m a g n ification of an inta ct v i l lous t i p from a patient with soy prote i n a l l ergy sh owed ma rked i ntraepith e l i a l lymph ocytosis.

TROPICAL S P R U E Tropical sprue is an acquired intestinal malabsorption syndrome of unknown etiology that affects residents , tourists , and expatriates of tropical regions specific to West Africa, Central America , South America , the Caribbean, Puerto Rico , South East Asia, and the Indian sub­ continent . The etiology remains elusive , but most evidence suggests an infectious cause, and the term "postinfective tropical malabsorption" is sometimes used 140 . 141 Symptoms include chronic nonbloody diarrhea , weight loss , bloating, and abdominal cramping. In severe cases , folate and vitamin B deficiency can lead to anemia and neurologic symptoms . 12 In the United States , the typical scenario is a patient with chronic diarrhea who has lived in or recently visited a tropical region. Travelers returning to nontropical regions generally recover completely after treatment , which includes antibiotics and restoration of fluids , electrolytes, and vitamins . 142 The entire small bowel including the ileum is usually affected in tropical sprue. Thus, biopsies from both the duodenum and the ileum should show simi­ lar features of villous blunting, intra epithelial lymphocytosiS, and increased lamina propria chronic inflammation (Figs . 3 . 202-3 . 2 0 7) . By contrast, celiac disease primarily affects the proximal small bowel .

Figure 3.202 M a l a bsorption patte rn , duoden u m i n tropical spru e . T h i s duoden a l biopsy sh ows a com b i n ation o f crypt hyperplasia a n d v i l l o u s b l u nting (crypt t o vi l lous ratio 1 : 1 ) w i t h i n creased l a m i n a pro­ pria chro n i c infl a m m atio n . The d iffe renti a l d i a g nosis based on this ph oto alone is exten sive.

Figure 3 . 203 M a l a bsorption patte rn , duoden u m i n tropical sprue. H ig h e r m a g n ification of the previous fig u re sh ows i n creased mono­ n u c l e a r ce l l s i n the l a m i n a p ropria and m a rked l y i n c reased I E Ls (arrowheads) a l o n g the vi l l i .

254

ATLAS

0 F

GAST R0 I N T E S TI N A L

PAT H O LOG Y

Figure 3 . 204 M a l a bsorpti on pattern , d u o d e n u m in tropical sprue. H i g h e r m a g n ification of the p revious fi g u re h i g h l i g hts the i ntraepi­ the l i a l lymph ocytosis (arrowheads) .

F i g u re 3 . 2 0 5 M a l a bsorptio n patte rn , term i n a l i l e u m i n t ro p i c a l s p r u e . Te rm i n a l i l e a l b i o ps i e s of t h e s a m e p a t i e n t s h o w s i m i l a r fi n d i n g s a s seen i n t h e d u o d e n u m . There i s m i l d v i l l o u s b l u nt i n g a n d expa n s i o n of t h e l a m i n a p ropr ia w i t h c h ro n i c i n fl a m m a t o ry ce l l s .

F i g u re 3 . 206 M a l a bsorpt i o n patte r n , term i n a l i l e u m in tro p i ca l s p ru e . H i g h e r m a g n ification o f the p rev i o u s fi g u re sh ows h i stol­ ogy a n a l o g o u s to that seen i n the d u o d e n u m . There a re i n creased l a m i n a p ro p r i a m o n o n u c l e a r ce l l s a n d I E Ls (arrowh eads) . In the a bsence of any c l i n i c a l i nfo rm ati o n , the p a ra l l e l fi n d i n g s in the duoden u m and TI s h o u l d p ro m pt s u s p i c i o n fo r tro p i ca l s p ru e . F u r­ ther i nvesti gation reve a l e d that symptoms c o i n c i d e d with return from a visit to India 3 months prior; i nfect i o u s eti o l o g ies h a d been exte nsively excl uded .

Figure 3.207 M a l a bsorpti o n pattern, term i n a l i l e u m i n tro p i c a l sprue. The vi l lous t i p s o f the term i n a l i l e u m s h o w m a rked i ntraepithe­ l i a l lym phocytosis (arrowheads) s i m i l a r to that seen in the duoden u m .

K E Y F EATU R E S o f Tropical S p r u e : •

Tropical sprue is an acquired malabsorptive syndrome .

•

Patients usually report a n abrupt onset, associated with travel t o the tropics .

•

•

•

Histology includes a malabsorptive pattern throughout the small bowel . The terminal ileum shows villous blunting and IELs similar to that seen in the duodenum. Exclusion of infectious etiologies and response to treatment are required for diagnosis .

C h a pter

3

5 M ALL

BOWE L

255

FAQ: H ow is a diag nosis of tropical sprue est a b l ished?

Answer: The d ia g n osti c poss i b i l it i e s in p a t i e nts w i th d i a rrhea a cq u i red in t h e

tro p i c s a re q u ite exte n sive a n d i n c l u d e a l a rg e n u m be r of i nfect i o u s eti o l o g i es, i n c l u d i n g Enta m oeba h istolytica, Giardia la mblia, Strongylo ides stercora lis, Cryp­ tosporidium parvum, Isospora belli, a n d Cyclospora cayetanensis, a m o n g oth e rs. Exc l u s i o n of these ca uses by sto o l a n d sero l o g i c testi n g i s n ecessa ry. U pper endos­ copy with b i o psy sh ows a n o n specific m a l a bsorpt i o n pattern of i nj u ry ; ta n d e m i l e a l b i o psies s h owi n g s i m i l a r c h a n ges a re stro n g l y s u g g estive o f tro p i c a l sprue; h owever the d i a g n o s i s i s u lt i m ately confi rmed by a response to treatment.

COM M O N VARIABLE I M M U N O D E F I C I E N CY Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder char­ acterized by impaired B-cell differentiation with defective immunoglobulin production . It is the most prevalent severe antibody deficiency affecting both children and adults . "Variable" refers to the heterogeneous clinical manifestations of this disorder, which include recurrent infections , chronic lung disease , autoimmune disorders , gastrointestinal disease , and sus­ ceptibility to lymphoma . CVID is not a Single disease, but rather a collection of hypogam­ maglobulinemia syndromes resulting from many genetic defects . The diagnosis of CVID relies on the presence of all four of the following features : 1 . Significantly reduced total serum concentration of IgG 2. Low IgA and/or IgM 3 . Poor or absent response to immunization 4. The absence of any other defined immunodeficiency state (i. e . , CVID is a diagnosis of exclusion) Small bowel biopsies from patients with CVID can display a host of nonspecific features including villous atrophy, prominent intra epithelial lymphocytosis , apoptotic activity, acute inflammation and mucosal granulomata . Because of the immunocompromised status of these patients , the histologic changes are likely secondary to opportunistic infections (particularly Giardia) , but can raise the differential diagnoses of celiac disease , Crohn disease , and even autoimmune enteritis . 143 The absence of plasma cells is a helpful specific feature of CVID and distinguishes it from the aforementioned differential diagnoses (Figs . 3 . 208-3 . 2 1 0) 144 In particular, always consider CVID in patients who appear to have refractory sprue .

F i g u re 3 . 208 M a l a bsorption patte rn , CVI D . T h i s l ow power view of the duoden u m sh ows a m a rked m a l a bsorption pattern of i nj u ry with crypt hyperp l a s i a , tota l atrophy of vi l l i , expa nsion of the l a m i n a propria with infl a m m atory ce l ls, a n d i ntra e pith e l i a l lymphocytosis. At this m a g n ificatio n , the diffe renti a l d i a g n osis is broad, but if o n e is i n t h e h a bit o f exa m i n i n g fo r t h e presen ce o f n o rm a l cel l u l a r constitu­ ents, the d i a g n osis w i l l becom e a p p a rent.

Figure 3 . 209 M a l a bsorptio n patte rn , CVI D . H i g h e r m a g n ification of the previous p h oto h i g h l i g hts the m a rked intra epith e l i a l lympho­ cytosis (arrowheads) . The l a m i n a propria conta i n s m ixed acute and chro n i c infl a m m atory i nfi ltrate, but a p a ucity of p l asma cel ls.

256

AT LAS

0 F

GAST R0 I NT EST I N A L

PAT H O LOGY

Fig u re 3 . 2 1 0 M a l a bsorption patte rn, CVI D . T h i s h i g h e r power view of the l a m i n a propri a i n p revious fig u re shows a com p l ete lack of p l a s m a ce l l s, consistent with CVI D . Routi n e exa m i n ation of the l a m i n a propria fo r plasma ce l l s s h o u l d be performed i n a l l biopsies. KEY F EATU R E S of Common Va ria b l e I m m u n o d eficiency: •

CYID is the result of ineffective immunoglobulin production .

•

Patients often present with recurrent infections , such as Giardia.

•

•

•

Histologic changes are likely secondary to opportunistic infections and can mimic other disease entities . Patients may show an absence of plasma cells in the lamina propria. The presence of plasma cells does not exclude CYI D , and can be seen in up to one third of patients . P EARLS & P ITFALLS

Path o l o g i sts h ave g reat d i ffi c u l ty n oti n g featu res that h ave been subtra cted from n o rm a l tissue, s u c h a s l a c k of p l a s m a cel l s . To a l l evi ate th i s b l i n d spot a n d p revent m i ssed d i a g n oses, ro u t i n e ide ntification of plasma ce l l s , g o b l et ce l l s , P a n eth ce l l s, a n d e n te roe n d ocri n e ce l l s s h o u l d be p e rfo rm e d fo r every s m a l l bowe l b i o p sy. W h e n b i opsies a re exa m i ned i n a system a t i c a n d c o n s i stent m a n n e r, the a bs e n ce of a n o rm a l c o n stitu e n t w i l l n ot be over l o o ked .

FAQ: Do a l l patients with CVI D lack p l a s m a c e l l s ? Answe r : N o . About o n e th i rd o f patients with CVI D h ave p l a s m a ce l l s p resent, a lt h o u g h hypo­ fu n cti o n a l . The a bsence of plasma ce l l s i n t h e s m a l l bowel b i o psy i s a specific b u t n ot sen sitive m a rker fo r CVI D . 1 44

AUTO I M M U N E E NTEROPATHY Autoimmune enteropathy (AlE) is a rare condition characterized by intractable diarrhea , is associated with a predisposition to other autoimmunity and may present with extraint­ estinal manifestations . Suggested diagnostic criteria for AlE require all of the following l 45 although we have encountered adult cases with preserved villous architecture : 1 . Severe villous atrophy not responding to dietary restriction 2. Circulating gut autoantibodies

or

associated autoimmune conditions

3 . Lack of severe immunodeficiencies

C h a pte r 3

S M A LL

BOWE L

257

This condition is more common in infants , but AlE is increasingly recognized in adults 146 Patients with AlE may have more systemic forms of autoimmune disease that can be char­ acterized into syndromes , such as immunodysregulation , polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) ; or autoimmune phenomena , polyendocrinopathy, candidiasis, and extodermal dystrophy (APECED) . 147 The maj ority of patients with AlE have an altera­ tion in regulatory T-cell function . A number of gene mutations have been linked to AlE , the most common of which is found on the FOXP3 gene (responsible for T-regulatory cell activity) and is seen in up to two-thirds of patients 148 Biopsies from these patients may demonstrate a malabsorption pattern of injury, but are particularly striking for the marked reduction in numbers of goblet or Paneth cells and display of prominent crypt apoptoses (Figs . 3 . 2 1 1 -3 . 2 1 5) . If one is in the routine habit of searching for these components in all biopsies , this diagnosis will not be missed.

F i g u r e 3 . 2 1 1 M a l a bsorpti o n patte rn , Al E . Low m a g n ification sh ows a seve re m a l a bsorption patte rn of i nj u ry with crypt hyper­ p l a s i a , tota l v i l l o u s atrophy, a n d re lative ly inta ct crypt a rch itecture .

Figure 3 . 2 1 2 M a l a bso rption pattern, AlE. H i gher m a g n ificatio n of the previous fi g u re shows intraepith e l i a l lym phocytosis (arrowheads) i n the fl atte ned s u rfa ce epithe l i u m . I n the a bsence of c l i n ica l a n d sero l o g i c i nfo rmati o n , t h e fi n d i n g s a re n o n specific, b u t i f o n e is i n t h e h a bit o f exa m i n i n g for t h e presence o f n o rm a l ce l l u l a r constitu­ ents, the d i a g n osis wi l l becom e a p p a rent.

Figure 3 . 2 1 3 M a l a bso rptio n pattern, A l E . H ig h e r m a g n ification o f the sa m e c a s e shows I E Ls a n d apoptotic a ctivity at the crypt bases (arrowheads) . N ote the com p l ete a bsence of Paneth ce l l s.

Fig u re 3 . 2 1 4 M a l a bsorption patte rn, a n other exa m p l e of A l E . This l ow power view shows ma rked c rypt hyperp l a s i a a n d vil lous atro­ p h y. There i s l a m i n a p ropria expa n s i o n , but the crypt a rch itectu re is re latively i ntact. These features a re a n o n specific m a l a bsorption pattern of i n j u ry.

258

AT LAS

0 F

GAST R0 I NT EST I N A L

PAT H O LOGY

Fig u re 3 . 2 1 5 M a l a bsorption pattern, lack of Paneth ce l l s i n A l E . H i g h e r power m a g n ification o f t h e previous fig u re sh ows a com p l ete a bsence of P a n eth ce l l s in a patient with A l E . KEY F EATU R E S o f Autoi m m u n e Entero pat hy: •

AlE is characterized by intractable diarrhea , not responsive to dietary restriction .

•

Although primarily a disease of infants , adult onset cases have been documented .

•

AlE i s associated with systemic forms of autoimmune disease such a s lPEX and APECED .

•

•

•

Up to two-thirds of patients have a mutation on the FOXP3 gene , which is responsible for regulatory T-cell function. Absence or reduction in numbers of goblet and/or Paneth cells and the presence of crypt apoptoses are diagnostic features . The presence of antigoblet cell or antienterocyte antibodies is found in the maj ority of cases. PEARLS & PITFALLS

P a t i e n t s c a r ry i n g a d i a g n o s i s of ce l i a c d i se a s e w h o a re n o n respo n s i ve to a G F D s h o u l d be eva l u ated fo r A l E a s a n a l te r n ative d i a g n o s i s . R e m e m ber: T h e m a l a b­ so rpti o n patte rn of i nj u ry i s n o n specifi c , a n d wh i l e ce l i a c d i sease i s m o re c o m ­ m o n th a n A l E , n e i t h e r of these d i a g n oses ca n be esta b l i s h e d on h i sto l o g y a l o n e . A n e c d ota l l y, we h a v e s e e n seve ra l c a s e s of " n o n re s po n s ive ce l i a c d i se a s e " ( N R C D) s u bseq u e n t l y d i a g n osed a s A l E a n d re s p o n d to A l E b a s e d t h e ra p i e s (i m m u n os u p p ress i o n ) .

FAQ: How a re a nt i g o b l et cel l and antienterocyte a nti bodies used i n t h e d i a g no­ sis of Al E?

Answer: The presence of a nt i g o b l et ce l l o r a n t i e n te rocyte a ntibodies i s su pportive

of the d i a g n o s i s . Antienterocyte anti bod i e s (AEA) h ave been detected in 85% to 87% of patients with A I E 1 46, 1 47 but a re n ot specific fo r A l E a s they may be fou n d i n othe r d i se a ses s u c h a s l B O , H IV i n fect i o n , a n d a l l e rg i c enteropathy. These a n t i bod­ ies h ave a l so been detected i n fi rst-de g ree asym pto m at i c re l atives . 1 45 T h u s , the p resence of these a ntibodies m a y be h e l pfu l in c h a l l e n g i n g cases, but s h o u l d be i nterpreted in the p roper c l i n i ca l sett i n g .

CO LLAG E N O U S E NTERITIS Collagenous enteritis , also known a s collagenous sprue, i s poorly defined i n the literature due to its infrequency. Best characterized as an easily overlooked subpattern of malabsorp­ tion pattern , collagenous enteritis exhibits a prominent subepithelial collagen layer in a

C h a pte r

3

S M ALL

BOWE L

259

background of variable villous blunting and increased lamina propria inflammatory cells (Figs . 3 . 2 1 6 and 3 . 2 1 7) . The use of a histochemical stain such as Masson trichrome may be helpful in highlighting the collagen deposition (Figs . 3 . 2 1 8 and 3 2 1 9) , but careful observa­ tion remains the best tool to prevent overlooking this feature (Figs . 3 . 22 0 and 3 . 2 2 1 ) . Addi­ tional helpful histologic characteristics include surface epithelial detachment and superficial ulceration , similar to that seen in collagenous colitis (Figs . 3 . 222 and 3 . 223) 149 IELs are variable and may indicate celiac disease as the underlying etiology 1 49 Other reported asso­ ciations include collagenous gastritis , collagenous colitis , lymphocytic colitis , lymphocytic gastritis , ulcerative j ej unitis, and medication inj ury (i . e . , olmesartan , an angiotensin 2 receptor blocker) 9 1 , 1 50 Treatment of known underlying disease , such as adherence to a GFD in celiac disease and discontinuation of offending medications in medication injury, is the mainstay of treatment . Some patients show clinical and histologiC response to immu­ nosuppressive therapy 1 50

Figure 3 . 2 1 6 M a l a bsorption patte rn, co l l agenous enteritis in the j ej u n u m . Low m a g n ification s h ows a m a l a bso rpti on patte r n , with crypt hyperp l a s i a , vi l lous atrophy, and m i l d expansion of the l a m i n a p ro p ri a . An a b n o rm a l ly t h i ckened co l l a g e n b a n d (arrowh eads) i s p rese nt at t h e basement mem bra n e . T h i s patient w a s ta king o l m es­ a rta n , a m e d i cation that has been i m p l i cated in co l l agenous sprue.

F i g u re 3 . 2 1 7 M a l a bso rpti on patte r n , co l l a g e n o u s enteritis i n t h e j ej u n u m . H i g h e r m a g n ifi cation o f t h e p revious fi g u re sh ows entra pped infl a m m atory ce l l s and sma l l vesse ls (arrows) i n a n i rreg u­ l a r col l a g e n band.

Figu re 3 . 2 1 8 M a l a bsorption pattern, c o l l a g e n o u s enteritis i n the j ej u n u m ( M asso n 's tri chrome). A trich ro m e sta i n of the p revious fig­ u re h i g h l i g hts the i rreg u l a r conto u r of the c o l l a g e n band. N ote how the c o l l a g e n percolates downwa rd between the ce l l s of the l a m i n a p ropri a . Entra pped sma l l vessels (arrows) a re a l so present. Com p a re with the n ext fi g u re .

F i g u re 3 . 2 1 9 N o r m a l basement m e m bra n e . A tri chrome sta i n of a n o r m a l basement membra n e featu res a d e l i cate band of co l l agen with a re l atively crisp contour.

260

ATLAS

0 F

GAST R0 I N T EST I N A L

PAT H O LOGY

Fig u re 3 . 220 M a l a bso rptio n pattern , co l l a g e n o u s e nteritis in the duode n u m . Low m a g n ification shows a severe m a l a bsorption pat­ tern with crypt hyperp l a s i a a n d v i l l o u s atrophy. The fi n d i n g s a re n o nspecifi c so far, but if o n e is in the h a bit of reviewi n g a l l l ayers of the biopsy, im porta nt clues (e . g . , a patchy c o l l a g e n a b n o r m a l ity) w i l l n ot be m i ssed .

Figure 3 . 2 2 1 M a l a bsorpti o n pattern, co l l agenous enteritis in the duoden u m . H i g h e r m a g n ification of the previous fig u re shows focal a b n o rm a l ities of the co l l a g e n l ayer. Entra pped i n fl a m m atory c e l l s a n d vascu l a r stru ctu res ( arrows) a re present.

Figure 3.222 M a l a bsorption pattern , co l l a g e n o u s e nteritis i n the duoden u m . Detachment and stri p p i n g of epith e l i a l ce l l s a bove the a b n o rm a l co l l agen layer ( a rrow) is com m o n i n co l l agenous e nteritis, s i m i l a r to its counterp a rt in the co l o n . N ote the tota l lack of v i l l o u s projections i n t h i s biopsy.

Figure 3.223 M a l a bsorpti o n pattern , co l l agenous enteritis i n the duoden u m . The surface epith e l i a l ce l l s h ave stri pped off this biopsy. N ote the pro m i n e nt a n d i rreg u l a r co l l agen layer with e ntra pped ves­ sels ( arrow) .

KEY F EATU R E S of C o l l a g e n o u s E nterit i s : •

•

•

•

•

Collagenous enteritis is also known as collagenous sprue. Histologic findings of subepithelial collagen deposition may be overshadowed by the malabsorption pattern of injury. A Masson trichrome stain can help highlight the collagen layer. Other histologic findings can include variable villous atrophy, increased lamina propria inflammatory cells , intraepithelial lymphocytosis , detachment of strips of epithelial cells , and superficial ulceration. Associated diseases include celiac disease, collagenous gastritis, collagenous coli­ tis , lymphocytic colitis, lymphocytic gastritis , ulcerative j ejunitis and olmesartan­ induced injury.

C h a pte r 3

5 MALL

BOW

EL

261

Fi g u re 3 . 224 M a l a bsorption patte rn, subepith e l i a l col lagen depo­ sition at a n i l eostomy site. Cycles of a cute o r chro n i c m ucosa l injury can i n crease the co l l a g e n d e position at the basement mem bra n e ; a n expanded subepith e l i a l co l l a g e n ta b l e a l o n e d o e s n o t meet t h e criteria fo r co l l agenous enteritis.

PEARLS & PITFAllS

An a ltered or t h i ckened c o l l a g e n ta b l e can a l so occu r a s a h ea l i n g m e ch a n i s m fo l l ow i n g e ros i o n o r u l ce rati o n ; fo r exa m p l e , a th i ckened b a s e m e n t m e m b ra n e i s freq u e n t l y observed at i l eostom y sites. Remem ber t o con s i d e r the c l i n ica l context ( F i g . 3 . 2 24) .

FOAMY MACRO P HAG E PATTE R N

Fi g u re 3.225 Foa my m a crophage pattern, Wh i p p l e d i sease. When foa m y m a cro p h a g e s a re p a rti c u l a rl y p ro m i n e nt, Mycobacterium avium-intracellulare infection a n d Whipple disease a re the front- l i n e d iffe re n t i a l consideratio n s . This c a s e was u lt i m ately d i a g n osed a s Wh i p p l e d isease b a s e d on the a b u n d a nt, coarsely g l o b u l a r, PAS rea ctive cyto p l a s m i c i n c l usi ons, a rea ctive Wh i p p l e i m m u n oh isto­ c h e m i c a l sta i n (not shown), and a n e g ative AFB speci a l sta i n (not shown).

Fi g u re 3 . 2 26 Foamy m a crop h a g e patte r n , Wh i p p l e d i sease. O n h i g h e r powe r, t h e foa m y m a c ro p h a g e s a re bette r a p preci­ ate d . N ote the d i l ated l a cte a l (arrowhead), a d i sti n ctive feature of Wh i p p l e d i sease.

262

AT LAS

0 F

GAST R0 I N T EST I N A L

PAT H O LOGY

F i g u re 3 . 2 27 F o a m y m a c ro p h a g e patte r n , Wh i p p l e d i se a s e ( PAS/D) . The PAS/D speci a l sta i n h i g h l i g hts the contents of t h e foamy m acrophages: a b u n d a nt, coa rsely g l obu l a r, PAS rea ctive cyto­

p l a s m i c i n c l usions a re seen . This patient presented with a rth ra l g i a s a n d d i a rrh ea, a n d a l l sym ptoms responded t o antibiotic thera py.

The foamy macrophage pattern in the small bowel primarily invokes the differential diag­ nosis of Mycobacterium avium intracellulare, Whipple disease, and nonspecific histiocytosis (Figs . 3 . 2 2 5-3 . 2 2 7 ) . This pattern generally refers to sheets of foamy macro phages in the lamina propria, exclusive of organized epitheliOid histiocytes seen in granulomatous inflam­ mation. If the clinical impression is of a mass lesion , other neoplastic considerations on H&E include langerhans cell histiocytosis , mast cell neoplasms , melanoma, and infiltrating carcinomas . Sorting through these histologically similar processes usually requires ancillary special stains and chart review. In this section , the most common and clinically relevant diagnoses will be discussed. C H E C K L I ST: Et i o l o g i c C o n s i d e rati o n s for t h e Foamy M a cro p h a g e Pattern o

M ycoba cte ri u m avi u m i ntra ce l l u l a re

o

Wh i p p l e D isease

o

N o n specific Histi o cytos i s

o

Oth e r co n s i d e ra t i o n s , La n g e rh a n s Ce l l H i st i o cytos i s , M a st Ce l l N eo p l a s m s , M e l a n o m a , a n d Ca rc i n o m a s

MYCOBACTERIUM AVIUM-INTRACELL ULARE Mycobacterium avium and intracellulare are two species o f atypical mycobacterium that are collectively referred to as mycobacterium avium-intracellulare (MA l) , previously termed myco­ bacterium avium complex (MAC) . MAr is ubiquitous in the environment and the most com­ mon human pathogen of the atypical mycobacteria. It is transmitted by inhalation into the respiratory tract and by ingestion into the gastrointestinal tract. MAr is considered an AIDS-defining opportunistic infection primarily affecting those with CD4 counts less than 50 cellS/ill, but it can also be seen in the non-HIV setting, such as in individuals otherwise immunocompromised (i. e . , patients on chemotherapy or heavy immunosuppressive agents) . Mycobacterium avium accounts for more than 9 5 % of infections in AIDS patients , whereas Mycobacterium intracellulare is responsible for 40% of infections in the immunocompetent. IDfection of the bowel most commonly is associated with weight loss, abdominal pain, and diarrhea . Histologically, MAr is characterized by variably blunted villi engorged with foamy macrophages (Figs . 3 . 2 28-3 . 2 3 0) . In contrast to Whipple disease , MAr organisms are deli­ cate , uniform rods on both PAS and AFB special stains (Figs . 3 . 2 3 1 and 3 . 2 32) . In addition, dilated lacteals and fat droplets are absent , providing further helpful points of distinction from Whipple disease. Treatment includes two or three antimicrobials for at least 12 months .

C h a pter 3

5 MALL

BOWE L

263

Figure 3 . 228 Foa my m acrophage pattern, Mycobacterium avium­

Figure 3 . 229 Foamy m a cro p h a g e pattern, Mycobacterium avium­

intracellulare (MAO. This biopsy featu res b l u nted vi l l i and a n expa n­ sion of the l a m i n a propria by a b u n d a n t foamy m a crophages. D i l ated l a ctea ls and fat d ro p l ets a re a bsent, featu res favori n g a low power d i a g nosis of MAl over W h i p p l e d isease. M o reover, c h a rt review reve a l ed a h i story of H IV/A I D S , a c l i n ic a l feature m o re com mon to MAl than Whipple d i sease.

intracellulare (MA O . H i g h e r power better i l l ustrates the expa nsion of the l a m i n a propria by n u m ero u s foa m y macrophages.

Figure 3 . 230 Foa m y m a crop h a g e pattern, Mycobacterium a vium­

Figure 3.231 Foamy m a crop h a g e pattern, Mycobacterium a vium­ intra cellu/are ( MA l) (PAS/D) . A PAS/D speci a l sta i n h i g h l i g hts the red , u n ifo rm baci l l i c h a ra cteristic of MAl. They a re a l m ost difficult to a p p reciate, even on o i l m a g n ification, due to th e i r d e l i cate size. Compare to the more g l o b u l a r and coa rse PAS rea ctive i n c l usions chara cteristic of Wh i p p l e d isease (Fig . 3 . 236).

intracellu/are ( MAl) . H i g h est power reve a l s a s p ri n k l i n g of l a m i n a p ropria n e utroph i l s a m o n g t h e foa m y m a crophages.

F i g u re 3 . 23 2 Foa m y m a c ro p h a g e patte r n , Mycoba cteriu m a vium-intracellulare (MAl) (AFB). An AFB specia l sta i n confi rms the myco bacte ri u m i nfection by h i g h l i g h t i n g the a b u n d a n t red bac i l l i (Wh i p p l e disease is A F B n o n reactive) .

264

AT LAS

0 F

GAST R0 I N T EST I NA L

PAT H O LOGY

K EY F EATU R E S of Mycobacterium a vium-intracellulare: •

Mycobacterium avium-intracellulare (MAl) is the most common human pathogen of the atypical mycobacteria.

•

•

•

•

•

It is transmitted by inhalation into the respiratory tract and by ingestion into the gastro­ intestinal tract.

MAl is considered an AIDS-defining opportunistic infection but also affects individuals otherwi.se immunocompromised . Histologically, MAl is characterized by variably blunted villi engorged with foamy mac­ rophages on H&E . In contrast to Whipple disease , MAl organisms are delicate , uniform rods on both PAS and AFB special stains . Dilated lacteals and fat droplets are absent . PEARLS & PITFALLS

S i n ce MA l is c o n si ste n t l y i d entified in i m m u n oc o m p ro m i sed patie nts, it serves as an i m p o rta nt red fl a g that the patient i s at risk fo r oth e r s n e a ky i nfect i o u s a g e nts a n d m a l i g n a n c i e s . Look twi c e fo r th ese e a s i l y m i ss-a b l e a d d iti o n a l i n fe cti o u s a g e nts i n b i o ps i e s o f t h e tu b u l a r g a stro i ntest i n a l tract: • • •

• • • • •

Cyto m eg a l ov i r u s Ade n ovi rus H e rpes s i m p l ex v i ru s Cryptospo ridium Isospora Ca n dida S p i rochetosi s Syp h i l it i c or Lym p h o g ra n u l o m a ve n e re u m proctoco l it i s

WH I P PLE D I S EAS E Whipple disease is very rare and caused by the gram-positive actinobacterium Tropheryma whipplei. Although the mode of transmission is not entirely understood, fecal-oral transmis­ sion has been postulated based on an increased incidence among sewage treatment workers and identification of the organisms in human waste and oral samples . 1 5 1-153 Despite over a hundred years of experience with Whipple disease , the core clinical features endure : Whipple disease remains a disease of adult white men who often report years of arthralgias followed by abdominal pain , malabsorption , weight loss , and diarrhea . 1 54 More recently, an association wi.th non-HIV immune-mediated conditions has been reported, which may reflect overlapping and complicated disease presentations or perhaps a predisposition to Whipple disease by particular immunosuppressed hosts , such as those patients on high­ dose steroids for sarcoidosis , ankylosing spondylitis , IBD , or rheumatoid arthritis . Prior to antibiotics , Whipple disease was universally fatal . Although antibiotics can lead to rapid resolution of disease symptoms , unfortunately up to 3 0 % of patients relapse , particularly those with CNS involvement. Consequently, antibiotic therapy for Whipple disease is often long term (at least 1 2 months) , and can sometimes be lifelong. Histologically, classic Whipple disease is characterized by villous blunting, lamina propria expansion by numer­ ous foamy macrophages, and scattered dilated lacteals and fat droplets (Figs . 3 . 2 3 3 and 3 . 2 34) . The foamy macro phages contain abundant PAS reactive , variably-sized cytoplas­ mic inclusions (Figs . 3 . 23 5 and 3 . 23 6 ) . The organisms can be confirmed by a T whipplei immunohistochemical stain (Fig. 3 . 2 3 7) or PCR assay targeting I whipplei's 1 6 S ribosomal genes. Importantly, direct (inadvertent) antibiotic treatment of Whipple disease can result in dramatic treatment effects that can resemble normal or near normal histology, requiring a low-threshold for a careful chart review, discussion with a clinician , and ordering confirma­ tory ancillary studies (Figs . 3 . 2 3 8-3 . 2 44) . A summary of the distinguishing features of MAl versus Whipple disease can be found in Figure 3 . 245 and Table 3 . 8 .

C h a pter 3

S M AL L

B OWE L

265

F i g u re 3 . 2 3 3 Foa m y m a cro p h a g e patte rn, classic Wh i p p l e d is­ ease. This biopsy orig i n ated from a 62-ye a r-o ld m a n with a h i story of a rthra l g ias, d i a rrhea, a n d s i g n ificant weight loss. The sma l l bowel biopsy sh ows b l u nted vi l l i with p ro m i nent foa m y macrophages a n d scattered d i l ated l a ctea l s a n d fat d ropl ets (arrowh eads) . These c l i n i­ copath o l o g i c features a re h i g h l y suggestive of Wh i p p l e d isease .

F i g u re 3 . 234 Foa m y m a c ro p h a g e patte rn , c l a s s i c Wh i p p l e d i sease. T h i s case o f W h i p p l e d i sease a lso featu res b l u nted vi l l i , prorT,1 i nent foamy macro p h a g es, a n d scattered d i l ated lactea ls a n d fat d ropl ets (arrowheads) , h isto logic features o f c l a s s i c Wh ipple d i s­ ease. A PAS/D speci a l sta i n h i g h l ig hted a b u n d a nt, variably sized cyto p l a s m i c i n c l usions, a W h i p p l e i m m u n o h istoch e m i c a l sta in was rea ctive, a n d a n AFB speci a l sta i n was n o n reactive (n ot shown) .

Figure 3 . 235 Foa my m a crophage patte rn, classic Wh ipple d isease (PAS/D) . A PAS/D speci a l sta i n h i g h l i g hts a b u ndant vari a b l y-sized cyto p l a s m i c i n c l u s i o n s .

Figure 3 . 236 Foamy m acrophage pattern , classic Wh i p p l e disease (PAS/D) . On h i g h est power, the va riably sized cyto p l a s m i c i n clusions cha racteristic of Wh i p p l e d i sease a re best a ppreciate d . The coa rse and g l o b u l a r nature of these i n c l usions contrast with the more d e l i ­ cate a n d u n ifo rm baci l l i s e e n w i t h MAl (compare w i t h the cha ra cte r­ istic i n c l usions of MA l in F i g u re 3 . 23 1 ) .

Figure 3 . 237 Foa my m acrophage pattern, cl assic Wh i p p l e d i sease (Wh i p p l e i m m u n o h istoch e m i c a l sta i n ) . The Wh i p p l e i m m u nosta i n is diffusely reactive is this classic case of Wh i p p l e d isease. D i l ated l a c­ tea l s a n d fat d roplets a re a l so seen (arrowheads) . This i m m u n osta i n i s n ot widely ava i l a b l e , b u t c a n be a ccessed v i a refe re n ce centers a n d l a rge consu ltati o n-based centers.

Figure 3.238 Foamy macrophage pattern, Wh i p p l e disease with partia l h istologic treatment effect. Fol lowi ng 6 months of Whipple­ based thera py, the biopsy sh ows less prominent featu res of Wh i p­ ple d isease. Although foamy m acrophages (brackets) and scattered d i l ated lactea ls and fat d roplets a re sti l l seen on H & E , these featu res a re much less prominent than th ose seen in classic Whipple d isease histology. Such dam pened features have been described with patients ea rly in their antibiotic course for Whipple d isease and a re referred to as Whipple disease with partial histologic treatment effect. Compare this image with classic Whipple disease seen in Figures 3 . 233-3.234.

266

AT LAS

0 F

GAST R0 I N T EST I N A L

PAT H O L O GY

Figure 3 . 239 Foamy macro p h a g e pattern, Wh i p p l e d isease with partia l h isto l o g i c treatment effect. H ig h e r power of p revious i m a g e . Wh i p p l e d isease w i t h pa rti a l h i sto l o g i c treatment effect refe rs t o cases with atten u ated features o f Wh i p p l e disease on H & E , PAS/D, and a W h i p p l e i m m u n osta i n . As seen h e re , v i l l o u s b l u nt i n g , foa m y m a cro p h a ges, d i l ated l a ctea ls, a n d fat d ro p l ets (arrowheads) a re detecta b l e but n ot p ro m i nent. Co m p a re this i m a g e with c l a ss i c Wh i p p l e d i sease s e e n i n F i g u res 3 . 233-3 .234.

Figure 3.240 Foamy macro p h a g e patte rn , Whipple d isease with p a rtia l h isto l o g i c treatment effect ( PAS/D). Cha racteristic of Whipple d isease with parti a l h isto l o g i c treatment effect, cyto p l a s m i c i n c l u ­ sions (arrowh ead) a re p resent o n a PAS/D speci a l sta i n ; h oweve r they a re very subtle com pared to those of classic Wh ippl e d isease. Compare this image with classic W h i p p l e disease i n F i g u re 3 . 2 3 6 .

F ig u re 3 . 2 4 1 Foa m y m a c ro p h a g e patte r n , Wh i p p l e d i sease with p a rt i a l h isto l o g i c treatm ent effect (Wh i p p l e i m m u n osta i n) . A Wh i p p l e i m m u nosta i n is rea ctive but sh ows atte n u ated rea ctivity com pared to that seen with classic Wh i p p l e disease. Co m p a re this i m a g e with classic Wh i p p l e d isease (Fi g . 3 . 237).

F i g u r e 3 . 242 Foa my macrophage pattern, W h i p p l e d isease with com plete h isto logic treatment effect. Of n ote, Whipple disease can h i stologica l ly a ppear as a n essenti a l ly norm a l biopsy, as depicted i n t h i s case. W h e n there a re no h istologic features o f Wh ipple disease on both the H&E and a PAS/D, and a Wh ipple i m m unoh istochemical sta in is positive, the preferred designation is Whipple disease with complete histologic treatment effect. Patients with this morphology h ave often been on Wh ipple d isease antibiotic thera py for an extended period of time or had a remote history of Whipple disease therapy. Based on l i m ited long-term clinica l fol l ow-up data, the clin ical sign ifica nce of Wh ipple disease with h istologic treatment effect is u n known.

Figure 3 . 243 Foamy macro p h a g e pattern, Wh i p p l e disease with com p l ete h i stologic treatment effect (PAS/AB). By defi n it ion, a PAS/ AB fa i l s to d e m o n strate a n y c h a racte ristic Wh i p p l e cyto p l a s m i c incl usions with com p l ete h isto l o g i c treatment effect.

Figure 3 . 244 Foamy macro p h a g e pattern, W h i p p l e d isease with com p l ete h isto l o g i c treatm ent effect (Wh i p p l e i m m u n osta i n ) . The Whipple i m m u n osta i n is foca l ly positive in ra re m a cro phages deep i n the m u cosa . This s u btle pattern of rea ctivity is typica l for Wh i p p l e disease w i t h com p l ete h isto l o g i c treatment effect. If this biopsy had been m o re superficia l , the ra re d i a g n osti c m a c rophages wou l d h ave been entire l y m issed .

C h a pter 3

Figure 3. 245 MA l versus classic Wh i p p l e d i sease. A: MAl, H&E, b l u nted vi l l i and a n expa n s i o n of the l a m i n a p ropria by a b u n d a n t foamy m a crophages a re seen and d i l ated l a ctea ls a n d fat d ro p l ets a re l a ck i n g , featu res favo ri n g a low power d i a g n osis of MA l over W h i p p l e d i sease; B, MA l, a PAS/D speci a l sta i n h i g h l i g hts t h e red , u n iform, a l m ost d ifficult t o a p p reci ate baci l l i . C: MAl, a n A F B speci a l sta i n con­ fi rms the mycobacte ri u m infection by h i g h l ighting the a b u n d a n t red baci l l i ( " red sna ppers") with i n the m a crophage cytoplasm . D: Wh i p p l e d i sease, H&E, b l u nted v i l l i with prom i n ent foamy macrophages a n d scattered d i l ated l a ctea ls a n d fat d roplets favor a low power d i a g n osis of W h i p p l e disease over MAl. E : Wh i p p l e d isease, a PAS/D h i g h l i g hts a b u n d a nt, coa rse ly g l o b u l a r, variably sized cyto p l a s m i c i n cl u sions. F : Wh i p p l e d isease, the Wh i p p l e i m m u n o h istochemical sta i n is diffusely rea ctive is t h i s clas­ sic case of W h i p p l e d isease.

5 M ALL

B OWE L

267

268

ATLAS

0 F

GAST R0 I N TEST I N A L

PAT H O LOGY

TABLE 3 . 8 : A Comparison of Mycobacterium intracellulare (MAl) versus

Wh ipple Disease MAl

Whipple Disease

D i a rrhea

+

+

H IV+

+

B l u nted vi l l i

±

Foa m y m a c ro p h a ges

++

+ - ---

++ --- ---

D i l ated l a ctea l s

++

F a t d ro p l ets

++

D e l i cate, u n ifo r m

Cyto p l a s m i c i n c l u s i o n s

Coa rse, v a ri a b ly sized g l o b u les

bac i l l i PAS AFB Wh i p p l e I H C

+

++

--- ----

+ ++

KEY F EATU R E S o f W h i p p l e Disease: •

Whipple disease is caused by the gram-positive actinobacterium Trop heryma whipp lei.

•

It is much less common than MAl .

•

Fecal-oral transmission is presumed .

•

•

•

•

Adult white men constitute the most common demographic , b u t i t i s also seen enriched in non-HIV immune-mediated conditions . Up to 30% of patients relapse, especially those with CNS involvement. Histologically, classic Whipple disease is characterized by villous blunting, lamina pro­ pria expansion by numerous foamy macrophages , and scattered dilated lacteals and fat droplets . The foamy macrophages contain abundant PAS reactive , variably-sized cytoplasmic inclusions .

•

Confirmatory tests include the T whipplei immunohistochemical stain or PCR assay.

•

Histologic treatment effects resemble normal or near normal histology.

•

The T whipplei immunohistochemical stain cannot distinguish viable from nonvi­ able organisms .

P EA R LS & P ITFALLS

Wh i p p l e d i sease with h istologic treatment effect can be seen in patie nts who a re n ot specifi ca l l y treated for Wh i pp l e d i sease! For exa m p l e , we h ave seen Wh i p p l e d i sease with h i sto l o g i c treatment effect i n patients o n b ro a d s pectru m a n t i b i ot­ ics fo r myoca rd it i s , u ri n a ry tract i nfect i o n s , a n d p n e u m o n i a . These p at i en ts h a d u n reco g n ized Wh i p p l e d i sease a n d were i n d i rect l y (a n d u n kn o w i n g l y) treated for Wh i p p l e d i sease a s a con seq u e n ce of b ro a d spectru m a nt i b i ot i c s for u n re l ated m e d i ca l cond iti o n s . Alth o u g h t h e a nt i b i otics res u l ted i n n e a r n o rm a l s m a l l bowe l h i st o l o g y on H & E , a d d i ti o n a l stu d i es confi rmed t h e spa rse l y d i stri b u ted PAS/D, T. wh ipplei rea ctive cyto p l a s m i c g l o b u l es , confirm i n g t h e d i a g n o s i s of Wh i p p l e d i sease with h i sto l o g i c treatm e n t effect. I n s u m m a ry, a low t h resh o l d for rou t i n e l y co n s i d e r i n g Wh i pp l e d i sease i s worthwh i l e , p a rtic u l a rl y i n p a t i ents with co m p l i­ cated c l i n ica l presentati o n s .

C h a pter 3

FAQ : C a n t h e T. whipple i i m m u n osta i n d i st i n g u i s h v i a b l e fro m n o n v i a b l e organisms? Answe r : N o .

U n fo rtu n a te l y, t h i s i m m u n osta i n ca n n ot d i sti n g u i s h v i a b l e from nonvi a b l e org a n ­ i s m s , a n d b a cteri a l rem n a nts c a n pers i st i n m a cro p h a g e s fo r yea rs . 1 55-1 57 Von H e rbay et a l . fo u n d convers i o n from positive to n e g ative Wh i p p l e P C R res u lts occu rred befo re c l e a ra n ce of PAS positive foa m y m a c ro p h a g e s . 1 57 Th i s s u g g e sts that D N A deg ra d a t i o n of the o rg a n ism occ u rs e a r l y in treatment a n d that ba cte­ ria l prote i n re m n a nts ca n pers i st fo r some t i m e th e reafter. As s u c h , the b i o l o g i c s i g n ifica nce o f Wh i p p l e d i sease with h i sto l o g i c treatment effect i s u n c l e a r. I n t h e se cases, it i s wo rthwh i l e to corre l ate with the patie nt's c l i n ica l sym pto m s a n d peR stu d ies to h e l p g u i d e c l i n i ca l m a n a gement d e c i s i o n s . For exa m p l e , i n the sym p­ to matic patient with Wh i p p l e d i sease a n d h i sto l o g i c treatment effect, resu m i n g o r conti n u i n g treatment i s req u i re d ; howeve r i n those asym ptomatic patients w i th h i sto l o g i c treat m e n t effect, c l ose c l i n i ca l fo l l ow-u p with a low thres h o l d to res u m e Wh i p p l e d i sease t h e ra py m a y be a reaso n a b l e a p p roa ch .

N O N S PECI F I C S CATT E R E D MACRO PHAG ES The lamina propria o f the normal small bowel i s populated b y mononuclear inflamma­ tory cells , such as lymphocytes, plasma cells , and macrophages. Occasionally macrophages can be mildly increased (particularly after reading about Whipple disease with treatment effect ! ) , raising concerns for Whipple disease and or MAl. In general , a chart review coupled with PAS and AFB special stains can sort through the maj ority of these problematic cases . For example , MAl is easy to dismiss in an immunocompetent individual lacking a his­ tory of diarrhea and where no PAS or AFB positive cytoplasmic inclusions are seen. More often than not, a slight prominence of macrophages signifies nothing more than a slight prominence of macrophages. Perhaps their presence represents a reparative response to a nonspecific, incidental , or incipient mechanical, medication , or infectious related inj ury. Regardless , when this finding is rare or seen in isolation , it carries no specific meaning.

D I LAT E D LACTEAL PATTE R N

Figure 3 . 246 D i l ated l a ctea l patte rn , c l i n i ca l ly sm a l l bowe l obstruc­ ti o n . D i l ated l a ctea l s (arrowheads) a re m ost com m o n l y c a u sed by o bstru ctive c h a n ges (neoplasms, adhesions, strictures, a n d fistu l a s) a n d rad iation i nj u ry.

5 M ALL

BOWE L

269

270

AT LAS

0 F

GAST R0 I N T EST I N A L

PAT H O LOG Y

Lacteals are blind-ended lymphatic channels and normal constituents of the small bowel lamina propria (Fig. 3 . 246) . Normally these delicate structures are difficult to discern at low power; on high power they appear as slightly expanded "slits" containing pale, eosino­ philic serum . When dilated , the engorged structures are more readily apparent and invoke a variety of etiologic possibilities, as discussed below. CH ECKLIST: Etio l o g i c C o n s i d e rati o n s fo r t h e D i l ated Lacteal Patt e r n o

Pri m ary Lym p h a n g i e cta s i a

o

Seco n d a ry Lym p h a n g i ecta s i a

o

Obstr u ction

o

Adj a cent N e o p l a s m

o

Ad h e s i o n s

o

Stri ctu res

o

Fistu l a s

o

I nfl a m m atory B o w e l D i sease

o

Prev i o u s Surgeries

o

I nfection

o

Wh i p p l e D i sease

o

R a d i ation I nj u ry

P R I MARY LYM PHAN G I ECTAS IA Primary lymphangiectasia (Waldmann disease) was first described i n 1 9 6 1 . 158 It remains a rare and poorly understood disease clinically characterized by lymph and albumin leakage into the bowel lumen , resulting in diarrhea , hypogammaglobulinemia; hypoalbuminemia, and lower limb edema . Histologically, dilated lymphatics can be seen in the mucosa or submucosa of the intestines in either a focal or diffuse distribution. 159 Only a few familial cases have been reported , the maj ority are presumed sporadic. 1 58 The diagnosis requires clinicopathologic correlation and , importantly, exclusion of the infinitely more common secondary forms of lymphectasia . The cornerstone of management is a life-long, low­ fat diet-enriched with medium-chain triglycerides , which theoretically minimizes fatty engorgement of the "leaky" lymphatic system. 1 60 Surgical resection is reserved for those with both localized disease and symptoms unresponsive to diet management . Additional clinical associations include malabsorption , osteomalacia (related to vitamin D defiCiency) , pleural effusions , iron defiCiency anemia, and "yellow nail syndrome , " or dystrophic ridg­ ing of the nail with loss of the nail lunula . 1 61 Decades of disease have been associated with B-cell lymphomas in rare cases , although the cases are too few to establish a meaningful relationship .

S ECO N DARY LYM P H AN G I ECTAS IA Identical histologic findings are seen w.ith secondary lymphangiectasia, or lymphangiectasia secondary to some other etiology; therefore , identification of the dilated lymphatic inj ury pattern is only part of the diagnosis I Meticulous scrutiny of the background mucosa and thorough chart review may yield clues to the underlying etiology, the most common of which are obstructive changes (as can be seen w.ith nearby neoplasms , adhesions , strictures, and fistulas) , infections (Whipple disease) , and radiation inj ury Obstructive changes in the small bowel are often seen in association with dilated lymphatics, increased IELs , and a sprinkling of neutrophils in the lamina propria or epithelium . Confirmation of a history of small bowel obstruction , such as conclusive radiographic studies, intraoperative findings , or an extensive history of adhesions , strictures, or fistulas can be most satisfying when these histologic features are seen (Figs . 3 . 247-3 . 2 5 1 ) . Unfortunately, these same findings can be seen in nonobstructed patients , who may have partial , subclinical , transient , or evolving

C h a pter 3

5 MA L L

BOW E L

271

F i g u r e 3 . 247 D i l ated l a ctea l patte r n , c l i n i ca l l y sm a l l bowel obstructio n . I n this exa m p l e , d i l ated l a ctea ls (arrowheads) were seen seco n d a ry to a sma l l bowel obstru ction i n a patient with a h i story of n u m erous abdo m i n a l operations a n d extensive serosa l a d h esions.

Figure 3 . 24 8 D i l ated l a ctea l patte r n , c l i n i ca l ly s m a l l bowe l obstru ction. At h i g h e r power, a spri n kl i n g of i ntrae pith e l i a l neutro­ p h i l s is seen (arrowh eads) , a fi n d i n g not u n co m m o n seen in sm a l l bowel obstructio n .

Figure 3. 249 D i l ated l a ctea l patte rn, Cro h n d isease. This bio psy orig i n ated from a patient with an exten sive h i story of sm a l l bowe l Cro h n d isease, strictu res, a n d a d h esive d isease. D i l ated l a ctea l s (a rrowh eads) a re seen i n a d d i t i o n t o g a stric foveo l a r m eta p l a s i a (bracket), pyloric g l a n d m eta p l a s i a , m i l d a rch itectu ra l distortio n , a n d reactive epith e l i u m (mucin atte n u ation) .

Figure 3.250 D i l ated l a ctea l pattern, ra d i ation thera py. Radiation i nj u ry i n the s m a l l bowe l , s i m i l a r to that i n oth e r sites, m a n ifests a s ectatic Iymphovascu l a r spaces, pro m i nent b l ood vesse ls, l a m i n a propria hya l i n izatio n , a n d stro m a l atyp i a . At t h i s power, o n l y scat­ tered d i l ated l a ctea ls (arrowheads) a re appreciated .

Figure 3 . 2 5 1 D i l ated l a ctea l patte rn, rad i ation thera py. On h i g h e r powe r, the d i l ated l a ctea ls (a rrowheads) a n d h a p h aza rd b l ood ves­ sels (asterisks) c h a ra cteristi c of rad iation i nj u ry a re see n . T h i s patient h a d a h i story of ra d i ation thera py for c h o l a n g iocarci n o m a . Recog n i ­ t i o n o f the rad iati o n i nj u ry pattern is a rem i n d e r t h a t the patient h a s a reaso n a b l e r i s k o f h a rbori n g a sneaky m a l i g n a n cy, req u i ri n g care­ fu l exa m i n ation of the backgro u n d m u cosa and a low t h res h o l d fo r orderi n g deeper secti ons.

272

ATLAS

0 F

GAST R0 I N T EST I N A L

P AT H O LOG Y

obstruction. Difficult cases such as these require a less dogmatic approach and a careful note discussing the differential diagnostic considerations . Dilated lacteals can also be red flags to a diagnosis of radiation enteritis or Whipple disease , in the appropriate clinical setting. KEY F EATU R E S of Lym p h a n g iecta s i a : •

Primary: •

•

•

Clinically, it is characterized by lymph and albumin leakage into the bowel lumen, resulting in diarrhea , hypogammaglobulinemia, and lower limb edema . Histologically, dilated lymphatics are seen in the mucosa or submucosa of the intestines in either a focal or diffuse distribution .

•

Predominantly sporadic in nature .

•

Treatment is a life-long low-fat diet-enriched with medium-chain triglycerides .

•

•

Primary lymphangiectasia is a diagnosis of exclusion.

Surgical management is reserved for those unresponsive to diet management with localized disease .

Secondary: •

•

•

Histologically identical to primary lymphangiectasia . Common causes include obstructive changes (neoplasms , adhesions , strictures, and fistulas) , radiation injury, and Whipple disease. Lymphangiectasia is most often an incidental or subclinical finding.

P E A R LS & P ITFALLS

O cc u l t m a l i g n a n ci e s o c c a s i o n a l l y l u rk in d i l ated l a ctea l s . As a resu l t , d i l ated l a c­ tea l s c a n s e rve a s p re c i o u s c l u es to m a l i g n a n cy i n a n oth e rw i se b u sy-a p pe a r i n g s m a l l bowe l b i o p sy. M a ke s u re to ro u t i n e l y c h e c k a l l l a cte a l s , a n d m a ke s u re to c h e c k t h e m tw ice i n t h o s e c a s e s with a h i story of m a ss l e s i o n o r m a l i g n a n cy ( F i g s . 3 . 2 5 2-3 . 2 5 4 ) .

Figure 3 . 25 2 D i l ated l a ctea l patte rn, m etastatic a lveo l a r rha bdo­ myosarco m a . In this exa m p l e , the d i l ated l a ctea l s h a rbor metastatic a lveo l a r rh a bdomyosa rco m a (arrowheads) in a patient with a h i s­ to ry of widely m etastatic d isease and a s m a l l bowe l obstru cti o n . T h e m a l i g n a n t ce l l s a l m ost b l e n d i nto t h e n o rm a l ly busy-a ppearing duoden a l m u cosa (arrowhead); routi n e inspection of the l a ctea ls was critical to a rriving at the correct d i a g nosis.

Figure 3 . 2 5 3 D i l ated l a ctea l pattern , m etastatic a lveo l a r rh abdo­ myosa rco m a . A co nfi rm atory M yo D 1 was stro n g l y positive i n the i n d i cated ce l l s, supporting the above d i a g n osis.

C h a pter 3

Figure 3 . 254 D i l ated l a cteal patte rn, metastatic m e l a n o m a . M e l a ­ n o m a , m a m m a ry carci n o m a , a n d p a n creatic aden oca rci n o m a a re n otori ous fo r occu pying d i l ated l a ctea ls of the s m a l l bowe l . T h i s exa m p l e features a focus o f m etastatic m e l a n o m a l u rk i n g i n the e n g o rg ed l a cte a l (arrowhead), u n d e rscori n g the point that all l a c­ tea ls s h o u l d be ca refu l l y i n s pected fo r metastasis.

FAQ : Is t h e fi n d i n g of i s o l at e d I y m p h e ct a s i a a l ways c l i n i ca l l y i m p o rt a nt ( F i g . 3 . 25 5 ) ? Answer: N o .

I n a recent study o f 1 , 866 con secutive e n d osco p i c exa m i n a t i o n s , l y m p h a n g i ec­ ta s i a was c l i n i ca l ly su spected in 3 . 2 % a n d h i stolog i ca l l y confi rmed in 1 . 9%. No c l i n i c a l evidence of m a l a bsorpt i o n was i d e ntifi e d , even in those with su bseq uent b i o psies sh owi n g pers i stent l ym p h a n g i e cta s i a , s u g g esti n g l y m p h a n g i e cta s i a i s often a n i n c i de nta l o r s u b c l i n ica l fi n d i n g . 1 62

Figure 3 . 255 D i l ated l a ctea l pattern , n ot fu rth er specifi e d . D i l ated l a ctea l s a re ro uti n e l y seen and th e ir p resence is not a l ways c l i n i ca l ly sign ificant.

FAQ: What is the d ifference betwee n " ly m p h a n g i ecta s i a " and " ly m p h a n g i om a " ?

Lym p h a n g i e cta s i a refe rs t o t h e d i l at i o n o f i n d i g e n o u s l a ctea l s i n a typ i ca l l y fl at ( n o n p o l y p o i d ) b i o p sy. In c o ntrast, l y m p h a n g i o m a refe rs to a m a l fo r m a t i o n of l y m p h a t i c vesse l s a n d is m o re l i ke l y to p re s e n t e n d o s co p i ca l l y as a p o l y p , n od­ u l e or m a s s .

S M A LL

B OWE L

273

274

ATLAS

0 F

GAST R0 I N T EST I N A L

PAT H O LOGY

M ETAPLAS IA AN D H ETE ROTOPIA

F i g u re 3 . 25 6 The s m a l l bowel m u cosa c a n featu re n o n n ative epith e l i u m , such a s i n rea ctive duodenopathy, g astric h eteroto p i a , p y l o r i c g l a n d m eta p l a s i a , a n d p a n creatic h eteroto p i a . The c l i n ical s i g n ifi c a n ce of recog n iz i n g these c h a n g e s varies. For exa m p l e , a patch of gastric m eta p l a s i a , gastric h eteroto p i a , or p a n creatic h et­ e rotopia can exp l a i n the c l i n ica l i m p ression of a n o d u l e , b u m p , or polyp. G a stric fove o l a r m eta plasia can serve as a d i a g n ostic c l u e to ca refu l l y look for Helicobacter, a n d g a stric fove o l a r m eta p l asia a n d pyl o ri c g l a n d m eta p l asia can serve a s evi dence of c h ro n i c m u co­ sal inju ry. In the i l l u strated exa m p l e , pyloric g l a n d m eta p l as i a is shown (asterisks). Pyloric g l a n d m eta p lasia is h i sto l o g i ca l ly identica l to pyl oric g l a n d s of the gastric card i a a n d a ntru m a n d to B ru n n e r g l a n ds o f the duo den u m . These g l a n d s a re com posed o f n e utra l m u c u s-secret i n g ce l l s with a b u n d a nt c l e a r foa m y cyto p l asm a n d basa l ly l ocated n u c l e i . C H E C KLIST: Et i o l o g i c C o n s i d e rati o n s f o r M et a p l a s i a , H eterot o p i a , a n d Ect o p i a s

( F i g . 3.256): 0

Reactive D u o d e n o pathy

0

Gastric Hete roto p i a

0

P a n c reatic Hete roto p i a

0

Pyl o ri c Gla n d M eta p l a s i a

0

M ecke l D iverti cu l u m

R EACTIVE D U O D E N O PATHY As discussed i n the malabsorption pattern , reactive duodenopathy refers t o gastric foveolar epithelium in the small bowel mucosa as a result of chronic acid exposure (Figs . 3 . 2 5 73 . 259) . The surface gastric foveolar metaplasia can be seen on H&E , but subtle cases may be highlighted by a PAS special stain , staining the neutral mucin eosinophilic . Similarly, if a combination PAS/Alcian blue stain is employed, the gastric metaplastic zones still remain eosinophilic, but the acidic mucin of goblet cells stains basophilic (Figs . 3 . 2 60 and 3 2 6 1 ) . Histologic changes also include variable increased plasma cell infiltration , neutrophils , villous blunting, and Brunner gland hyperplasia . In contrast to peptic ulcer disease, the histologic findings of reactive duodenopathy are milder and they lack a strong associa­ tion with Helicobacter infections . As such, some experts suggest abandoning the previously interchangeable terms "chronic peptic duodenopathy," "active chronic peptic duodenitis , and "peptic-type duodenopathy" due to their misguided inference of a Helicobacter etiology. See also Malabsorption Pattern , this Chapter.

Ch a pter

3

5 MA L L

BOWE L

275

F i g u re 3 . 2 5 7 Rea ctive d u o d e n o pathy refers to m etapl astic gas­ tric fove o l a r e p ithe l i u m (brackets) in the sma l l bowel m u cosa . It is most com m o n l y associ ated with excessive acid ity, Helicobacter, or N SAI D-re l ated damage. Zones of su rface gastric fove o l a r meta plasia a re com posed of back-to-back m eta p l a stic ce l l s that create reg ions that l a c k g o b l et ce l l s o r enterocytes . By com p a riso n , the n o rm a l s m a l l bowel m u cosa i s p u n ctuated b y g o b l et ce l l s (arrowh eads) that a re scattered s i n g l y between enterocytes. Fu rth er com p a rison sh ows that i n d ividua l g o b l et ce l l s conta i n a vo l u m i n o u s mucin vacu­ ole, i n contra st to the m o re d e l i cate apical mucin ca p seen i n the gastric meta p l astic ce l l s (brackets) .

F i g u re 3 . 25 8 Reactive d u o d e n o pathy, s m a l l bowe l obstructi o n . T h i s case features scattered d i l ated l a cte a l s (a rrowh eads) i n addi­ tion to gastric fove o l a r meta p l a s i a .

F i g u re 3 . 2 5 9 Reactive d u o d e n o pathy, sm a l l bowel o bstructi o n . H i g h e r power o f a n a ltern ate fie l d from t h e s a m e patient. N ote the tiny apical mucin caps i n a zone lacking goblet ce l l s .

F i g u re 3 . 260 M eta p l a stic g a stric fove o l a r epith e l i u m (PAS/AB). For j u n i o r tra i n ees, the d isti n ction between m eta p l a st i c gastric fove o l a r epith e l i u m and goblet ce l l s can be c h a l l e n g i n g on H & E . I n s u btle cases, a PAS/AB can be especi a l ly usefu l . O n a PAS/AB , the n e utra l m u c i n o f the m eta p l astic g a stric fove o l a r epith e l i u m a p p e a rs eosinoph i l i c (bracket) ; i n contrast, t h e a c i d i c m u c i n o f the g o b l et ce l l s appears deeply basoph i l i c (arrowhead). Ag a i n , n ote that m eta plastic gastric foveola r epith e l i a l ce l l s a re l i ned u p back to back a n d create long ru n s o r zones of meta p l a s i a , as opposed to goblet ce l l s, which a re m o re sparsely d istri buted a m o n g the enterocytes. Alth o u g h the d i stinction between m eta pl astic g a stric foveolar epi­ th e l i u m a n d g o b l et ce l l s is not criti ca l to d i scern i n the sma l l bowe l , these d i st i n ctions become c l i n ica l ly i m porta nt when eva l u ating fo r Ba rrett m u cosa in the esoph agus, for exa m p l e .

276

AT LAS

0 F

GAST R0 I N T E ST I N A L

PAT H O LOGY

Figure 3 . 2 6 1 Reactive duodenopathy (PAS/AB). The eosi n o p h i l i c meta p l a stic g a stric fove o l a r epith e l i u m (h i g h l i g hted by brackets) a n d the basoph i l i c goblet ce l l (h i g h l i g hted by a n arrowhead). This case was com p l i cated by He/icobacter d u o d e n itis, em phasizing the i m porta nce of routi n e l y l ooki n g fo r He/icoba cter in g a stric m eta­ p l a stic zones. KEY F EATU R E S of React ive D u o d e n o pathy: •

•

•

•

Reactive duodenopathy is seen in up to 7% of small bowel mucosal biopsies . Alternative terms include gastric foveolar mucin cell metaplasia, active chronic peptic duodenitis , chronic peptic duodenopathy, and peptic-type duodenopathy. Common causes include excessive acidity, Helicobacter, or NSAID-related damage . Severe cases with ulcerations are termed peptic ulcer disease, which has a stronger association with Helicobacter.

GASTRIC H ETE ROTO PIA Heterotopic tissue refers t o histologically normal tissue found i n abnormal anatomic sites. More specifically, gastric heterotopia describes the presence of both gastric foveolar epithelium and oxyntic glands in the small bowel mucosa (Figs . 3 . 2 62-3 . 266) . Although some experts

Fig u re 3 . 262 G a stri c heteroto p i a . On l ow power, the polypoid nature of this biopsy i s a p p reciated . Both .g a stric fove o l a r ep ithe­ l i u m (arrowheads) and oxyntic g l a nds (brackets) a re seen i n the sma l l bowel polypectomy speci m e n , m eeti n g t h e d i a g n ostic criteria for gastric h eterotopia .

Fig u re 3 . 263 G a stric h eterotop i a . On h i g h e r power, gastric foveo­ lar epith e l i u m (brackets) and oxyntic g l a n d s a re better seen . An a rea of n o rm a l s m a l l bowel epith e l i u m is l i ned by ba ck-to-back entero­ cytes p u n ctuated by g o b l et cel l s (arrowheads) .

C h a pter

F i g u re 3 . 264 G a stric h eterotop i a (PAS/AB). A PAS/AB easily d is­ t i n g u ishes between the d iffuse zones of eosi noph i l i c gastric foveo­ l a r epith e l i u m (bracket) and the scattered basoph i l i c g o b l et ce l l s (arrowheads) .

BOWE L

277

denal polyp is easily a p p reci ated at low power. The d i a g nosis of gastric h eterotopia was rendered based on the identification of both gastric fove o l a r epith e l i a l ce l l s (bracket) a n d oxyntic g l ands (arrow­ heads) .

advocate this finding is an embryologic remnant, others suggest it is a metaplastic response to small bowel inj ury 92, 1 63-166 In the largest study, gastric heterotopia was identified in 1 . 9 % of over 28 ,000 duodenal biopsies and was found i n the duodenal bulb i n 66% of cases . 92 Patients with gastric heterotopia were 1 /5 as likely to have Helicobacter pylori gastritis , compared to those patients with a normal duodenum , suggesting this phenomenon is not a metaplastic response to mucosal injury Further, this finding was associated with three times the number of fundic gland polyps, leading the authors to suggest these presumed congenital patches may be influenced by proton pump inhibitors . Similar findings were recently replicated by others , l 66 KEY F EATU R E S of G a st ric H eteroto p i a :

Gastric heterotopia is seen in 1 . 9% of duodenal biopsies .

•

It is most common in the duodenal bulb and is associated with fundic gland polyps.

•

Histologically, it consists of gastric foveolar epithelium and oxyntic glands .

•

5 MA L L

F i g u re 3 . 265 G a stric heteroto p i a . The n od u l a r n atu re of th is duo­

F i g u re 3 . 266 G a stric h eteroto p i a is g e n e ra l l y a low power dia g ­ n osis, but s o m e case s req u i re high power t o a p p reci ate the focal oxyntic glands (arrowh ead), as i n this case.

•

3

The histogenesis is controversial ; embryologic remnant versus metaplastic response to injury, possibly responsive to proton-pump inhibitors .

278

AT LAS

0 F

G ASTR 0 I N T E S T I N A L

PAT H O LOGY

FAQ: What if o n l y superfici a l g a stric fove o l a r epithe l i u m is p resent a n d u n derly­ i n g gastric g l a n d s a re n ot see n ? A n swer: " Re a ctive d u od e n o path y " i s t h e p refe rred t e r m w h e n o n l y s u p e rfi c i a l

g a stric fove o l a r epithe l i u m i s see n .

PAN C REAT I C H ETE ROTO P I A Pancreatic tissue identified a t sites not anatomically o r vascularly connected t o the pancreas is termed pancreatic heterotopia , also known as pancreatic rest, or ectopic or aberrant pan­ creas (Fig. 3 . 2 6 7) . The putative etiologic origin is aberrant embryonic rotation of the dorsal and ventral buds , such that "pancreas bits" are positioned in nonphysiologic sites . Although the incidence of pancreatic heterotopia is not well established, it is seen in 1 3 . 7 % of autop­ sies in one small series . 1 67 Pancreatic heterotopia has been reported in a variety o f sites, including the gastrointestinal tract, lung, mediastinum , and fallopian tube. 168 It is most commonly seen in the gastrointestinal tract, particularly in the stomach and small b owel . Most cases are asymptomatic, especially small lesions . Symptomatic patients can present with abdominal pain , gastrointestinal bleeding, pancreatitis , or obstruction . 169 Although not required , nor routinely practiced, pancreatic heterotopia can be stratified into four types based on the modified Heinrich classification scheme l 70 : Type 1 : Acini , ducts , and islets Type 2: Ducts only Type 3: Acini only Type 4: Islets only KEY F EATU R E S of Pancreat i c H eterot o p i a : •

Pancreatic heterotopia i s pancreatic tissue at ectopic sites.

•

Seen in up to 1 3 . 7% of autopsies.

•

•

•

•

Sites of involvement include the gastrointestinal tract (most common in the stomach and small bowel) , lung, mediastinum, and fallopian tube. Most cases are asymptomatic. Among symptomatic patients , abdominal pain, gastrointestinal bleeding, pancreatitis, or obstructive symptoms are common . Lesions can include clinically significant diagnosis : chronic pancreatitis, pseudocysts , and neoplasia.

F i g u re 3 . 267 P a n creatic h eteroto p i a refe rs to p a n creatic tissue i d entified at sites not a n atomica l l y or vasc u l a rl y conn ected to the pan creas. This high power image reve a l s the cha racteristi c two-ton e natu re o f p a n creatic a c i n a r ce l l cytoplasm w i t h peri p h era l baso p h i l i a a n d centro l u m i n a l eosi n o p h i l i a .

C h a pter 3

5 M ALL

BOWE L

279

FAQ : Are t h e re a n y c l i n i ca l l y s i g n ifi c a n t d i a g n o s e s l i n ke d to p a n c r e a t i c h eterot o p i a ? Answer: Yes .

Any d i a g n os i s that occu rs i n the n ative p a n c re a s can theoretica l ly occ u r i n h etero­ to p i c p a n c rea s. Be s u re to look ca refu l l y for c h ro n i c p a n c reatitis, pseu docysts, a n d n e o p l a s i a . 1 68. 1 7 1 . 1 72

PYLO R I C M ETAPLAS IA Pyloric metaplasia (pseudo-pyloric metaplasia) arises secondary to chronic mucosal dam­ age and is characterized by the replacement of the normal mucosal crypts with glands that resemble pyloriC glands of the stomach or Brunner glands of the duodenum. Morphologi­ cally, pyloric metaplasia can be identified by its acinar structure lined by epithelial cells with abundant clear-to-foamy cytoplasm and small ovoid or round nuclei which may be flattened against the basement membrane (Figs . 3 . 2 68-3 . 2 73) . These cells which appear

Figure 3 . 268 Pyloric meta p l a s i a . This biopsy i s from the term i n a l i l e u m o f a patient with Cro h n disease. Pyloric m eta plasia (arrow) i s visi ble from l o w m a g n ification beca use t h e p a l e cytoplasm contrasts n icely with the d a rker infl a m m atory backg ro u n d . N ote a l so the back­ g ro u n d crypt d ropout, crypt shortfa l l , a n d basa l lymphoplasmacyto­ sis, in kee p i n g with the esta b l ished h i story of Cro h n d i sease.

Fig ure 3 .269 Pyloric m eta p l a s i a . The pyloric g l a n d (arrowhead) is h i stolog i ca l ly i n d isti n g u ishable from true pyloric g l a nds found in the gastric a ntru m . The a c i n a r stru ctu re i s com posed of ce l l s with abun­ d a n ce clea r to foa m y cytoplasm a n d sma l l rou n d o r ovoid, basa l l y l ocated n u c l e i . T h e base of a sma l l bowel crypt i s pictu red a t right fo r com p a ri so n .

Figure 3 . 27 0 Pyloric m eta p l as i a . The g l a nds of pyloric m eta pla­ s i a (arrowheads) a re i d entica l to those of the g a stric a ntru m . I n this exa m p l e , some of the n uclei a re pressed fl at a g a i nst the basement m e m bra n e . This exa m p l e is from a case of i l e a l Cro h n d i sease.

F i g u re 3 . 2 7 1 Pyl oric meta p l as i a . Alth o u g h pyloric m etaplasia is associated with Cro h n d i sease, the fi n d i n g i s nonspecific and indi­ cates only the p resence of c h ro n i c inju ry. T h i s b i opsy with pyloric m eta p l a s i a (a rrows) is ta ken from near a n i l eostomy site. As with most n o n n e o p l asti c biopsies, c l i n ica l h i sto ry is i m perative.

280

ATLAS

0 F

GAST R0 I N T E ST I N A L

PAT H O LOGY

Figure 3 . 2 7 2 Pyl oric meta p l a s i a . These pyl o ri c g l a n d s (arrow) h ave replaced the crypts in the sma l l bowel as a resu l t of c h ro n i c i nj u ry.

F i g u re 3 . 2 7 3 Pyloric meta p l a s i a . T h i s b i o psy comes fro m a n 83-year-old m a n with c h ro n i c N SA I D use. N ote the s l i g h t a rch itec­ tural d i stort i o n , and the p rese nce of pyl oric meta p l asia (a rrow) . T h i s fi n d i n g may be s u btle i n some cases, a n d the g l a nds a re most often fou n d i n the deep m u cosa, as seen here .

adjacent to ulcers and have been termed ulcer-associated cell lineage (UACL) . The UACLs produce endothelial growth factors and trefoil pep tides that promote mucosal proliferation and healing. 173.1 74 Although pyloriC metaplasia has been cited as highly predictive of Crohn disease, 1 75 it can also be a nonspecific reparative reaction found in intestinal ulcers , NSAID­ induced injury, or chronic pouchitis . FAQ: I s pyloric g l a n d meta p l a s i a i n i l e a l pouch biopsies a d efi n itive marker for C ro h n disease? A n swer: N o .

Pyl o ri c g l a n d m eta p l a s i a i s m o re com m o n i n patie nts w h o expe ri e n ce com p l i ca ­ t i o n fo l l ow i n g a n I PAA ( 5 5 %) a s c o m p a red to th ose w h o fo l l ow a n o r m a l postop­ e rative cou rse ( 1 2%) . The p reva l e n ce i s h i g h e r i n patie nts with Cro h n d i sease of t h e pouch (7 7 %) a s c o m p a red to u l ce rative c o l itis pati e n ts with c h ro n i c po u c h itis (22%) , but ca n n ot be u sed a s a defi n itive m a rker fo r Cro h n d i sease . 77

PEARLS & PITFALLS

C o n s i d e r Meckel Divert i c u l u m When G a st r i c o r P a n c reatic Tissue Is Seen i n t h e S m a l l Bowel

M eckel d iverti cu l u m i s the m o st com m o n c o n g e n ita l a n o m a l y of the sma l l bowe l . I t a ri ses a s a resu lt o f fa i l u re of i nvol u t i o n o f t h e o m p h a l o m esenteric d u ct (a l so termed " v i te l l i n e d u ct " ) . The o m p h a l o m esenteri c d u ct co n n ects t h e e m b ryo n i c m i d g ut t o t h e yo l k s a c ventra l ly, a n d n o rm a l ly n a rrows p rog ressive ly u nti l its o b l it­ e rat i o n by the tenth week of gestatio n . F a i l u re to i nvol ute resu lts in th i s con g e n ita l o u t p o u c h on t h e a nti m esenteric b o rd e r of t h e i l e u m (Fi g . 3 . 2 7 4 ) . M eckel d iv e r­ t i c u l u m i s a n exa m p l e of a true d ivert i c u l u m beca u se it conta i n s a l l l ayers of t h e s m a l l bowe l wa l l : m u cosa , s u b m u cosa, a n d m uscu l a ri s p ro p ri a . I t i s a l so described a s " t h e ru l e of 2's " beca u se it occ u rs i n a p p roximately 2% of the p o p u l a ti o n , is l ocated with i n 2 feet of t h e i l eoceca l v a l v e , i s 2 i n ch e s i n l e n g t h , p resents m ost com m o n l y at 2 yea rs of age, and has a m a l e :fem a l e ratio of 2:1 . 1 76-1 78 Alth o u g h m ost cases a re a sy m ptomatic, a p p roxi m a te l y 2% c o m e t o m e d i c a l attenti o n a n d req u i re s u rg ica l resect i o n based o n o bstru ct i o n , b l e ed i n g , intu ssuscepti o n , v o l v u ­ l u s , perfo rati o n , o r i nfl a m matio n . U p to 1 12 of c a s e s conta i n h eteroto p i c g a stric (52%) o r pa n c reatic tissue (5%) a n d n e o p l a s i a i s ra re (but ca n i n c l u d e g a stro i ntesti­ n a l tract stro m a l t u m o rs, n e u ro e n d ocri n e t u m o rs , and aden oca rc i n o m a ) .

C h a pte r 3

F i g u re 3 . 2 7 4 Meckel d iverticu l u m . T h i s g ross i m a g e depicts a congen ita l outpouch i n g on the a nti m esenteric border of the i l e u m . Alth o u g h t h e majority o f patients a re asym ptomatic, com mon i n d i ­ cations for resection i n c l u d e persistent gastro i ntesti n a l bleeding (as in this case), obstructi o n , i ntussu scepti o n , volvu l u s, perfo rati o n , or i n fl a m m at i o n . H isto log i ca l ly u n re m a rk a b l e s m a l l bowe l m u cosa i s com m o n w i t h h eterotopic tissues s e e n i n u p t o 5 0 % o f cases (gastri c > pan creas). Neoplasia is ra re .

P I G M E NTS AN D EXTRAS

Fig u re 3 . 2 7 5 P i g m ent exa m ple, pse u d o m e l a n osis d u oden i . Com­ mon eti o l og ies of p i g m ent and p i g m e nt- l i ke materi a l i n the sm a l l bowel i n c l u d e tita n i u m , I n d i a i n k tattoo, pseudom e l a n osis d u o d e n i , fo rm a l i n , m e l a n o m a , a n d 90 yttri u m - l a be l ed m i c rospheres. I n t h i s exa m p l e , pse u d o m e l a nosis d u o d e n i was d i a g n osed based on t h e brown -black p i g m e n t seen i n m a c ro p h a g es l o cated at the vi l l ous tips. The patient h a d a h i story of ren a l fa i l u re , a s is com m o n fo r patients with this fi n d i n g . CH ECKLIST: Eti o l o g i c C o n s i d e rati o n s f o r P i g m e nts a n d Ext ras ( F i g . 3.275) o

Tita n i u m

o

Tattoo P i g m e n t

o

Pse u d o m e l a nosis D u od e n i

o

Form ali n P i g m ent

o

Melanoma

o

90Yttri u m -Labe led M i cro s p h e res

5 M ALL

BOWE L

281

282

AT LAS

0 F

GAST R0 I NT EST I N AL

PAT H O LOGY

TITAN I U M (" P EY E R PATCH P I G M E NT") Along the tubular gastrointestinal tract, titanium deposition is unique to the terminal ileum, and can be used to declare the origin of the biopsy site without looking at the accompany­ ing requisition . This pigment is fine in texture , dark-brown to black in color, and confined to the macrophage cytoplasm (Figs . 3 . 2 76-3 . 2 8 1 ) . Historical studies using scanning elec­ tron microscopy, backscattered electron imaging, and X-ray energy spectroscopy of routine histologic sections determined the pigment represents titanium, aluminum, and silicon 1 79although for simplicity's sake , this pigment is usually referred to as titanium alone . The ingestants originate from food additives in thickening and whitening agents (e.g. , tooth­ paste) and arrive in the lymphoid aggregates o f the terminal ileum (Peyer patches) via routine i.mmunosurveillance-related trafficking.

Fi g u re 3.276 Tita n i u m p i g m ent. Without refe re n c i n g any paper­ work, the ori g i n of this tissue is i l e u m ba sed on the p ro m i n e n t l y m p h o i d a g g regates, re latively s h o rt vi l l i , a n d tita n i u m p i g m e n t (bracket).

Fi g u re 3.277 Tita n i u m p i g m ent. T h e p i g m e n t (arrowheads) i s e a s i e r t o discern o n h i g h e r power. The cha ra cteristic p i g m e n t is fi n e i n texture , d a rk-brown to b l a c k i n color, a n d confi n e d with i n t h e m acrophage cyto p l a s m .

Figure 3 . 2 7 8 Tita n i u m p i g m ent. I n a d d ition to tita n i u m p i g m e nt, this i m a g e a lso featu res a i r a rtifact that was i ntro d u ced at time of endoscopy (arrowheads) . Air a rtifact is a lso known as " pseudo l i po­ m atous c h a n g e " based on its rese m b l a nce to matu re fat. Alth o u g h mature fat has cel l u l a r deta i l s u c h as a n u cleus, a i r a rtifact l acks cel­ l u l a r deta i l a n d a n uc l e u s , a n d it a ppears a s va ri a b l y-sized e m pty spaces that gently push the l a m i n a p ropria constituents aside. Air a rtifact is frequently fou n d i n term i n a l i l e u m a n d colonic m u cosa l biopsies.

Figure 3.279 Tita n i u m p i g m ent. H i storic studies determ i n e d this pigment conta i n s va ri a b l e a m o u nts of tita n i u m , a l u m i n u m , a n d sili­ con, a lthough today th is p i g m e nt is s i m p l y referred to as "tita n i u m . "

C h a pte r

Figure 3.280 Tita n i u m pigment. Tita n i u m pigment o ri g i nates from i n g ested thicke n i n g a n d wh ite n i n g agents fou n d in toothpaste a n d oth e r con s u m a b l es. U n d e r o i l i m m ersi o n , note the fi n e q u a l ity o f t h e tita n i u m p i g ment. Com p a re this i m a g e t o the coa rse pigment seen i n tattoo and m e l a n i n pigment (Figs. 3 . 282-3 .287 and 3 . 300-3 .305).

3

5 M ALL

BOWE L

283

Figure 3.281 Tita n i u m pigment. N ote the bland cytologic featu res of the m a crophages: the chrom ati n is u n iform, the n u c l e a r conto u rs a re sm ooth a n d reg u l a r, a n d neither p l eo m o rph i s m , necrosis, n o r atypica l m i toses a re see n . T h i s case is u n l i kely t o cause concern for m e l a n o m a , based on the b l a n d cyto l o g i c featu res and fi n e texture of the p i g m e nt; however cautious observers may e m ploy an 5 1 00 prote i n i m m u nosta i n (remember to use a red chromogen for easier visi b i l ity), which should be negative i n tita n i u m pigment a n d positive in m e l a n omas.

TATTOO PIG M E NT Preoperative tattooing of luminal lesions was introduced in 1 9 5 8 . 1 8 0 It is useful for targeted surveillance of endoscopically monitored lesions , localizing the lesion at time of surgery, and improved local lymph node dissections . Although a variety of dyes have been used over the years (e.g. , methylene blu e , indigo carmine , toluidine blue, lymphazurine , hematoxy­ 181 lin , eosin , and indocyanine green) , India ink remains the most widely employed agent. This tattoo pigment can be easily mistaken for Titanium since both are dark brown-black and distributed within the cytoplasm of macro phages (Figs . 3 . 282-3 287) . Helpful clues include that tattoo pigment is usually very prominently distributed (since its sole purpose is

Figure 3 . 2 8 2 Tattoo pig ment. Like tita n i u m , I n d i a i n k tattoo pig­ m e n t is a l so d a rk brown- b l a ck a n d confi n ed with i n the cyto p l asm of m a crop h a ges; however tattoo p i g m e nt i s typ i ca l ly m o re coa rse, c l u m py, and c o n s p i c u o u s . Co m p a re with the m o re fi n e p i g m e n t s e e n i n tita n i u m pigment ( F i g s . 3 . 276-3 .28 1 ) .

Fig u re 3 . 283 Tattoo pigment. Tattoo p i g m ent is a p p l ied for ta r­ g eted surve i l l a nce of en doscopica l l y m o n itored lesions, loca l iz i n g the l esion at time o f s u rgery, a n d i m p roved l oca l lym ph n o d e dissec­ tions. S i n ce tattoo pig m ent is intended to h e l p l oca l ize lesions at the g ross l evel (without any visu a l a ids), tattoo pigment is a l m ost a lways e a s i e r to identify t h a n the fi n e r a n d sparsely d i stributed tita n i u m p i g m ent (co m p a re with Fig u res 3 . 2 7 6-3 . 28 1 ) . I n d i a i n k is t h e most com m o n l y used tattoo agent to date.

284

ATLAS

0 F

GAST R0 I N TE S T I N A L

PAT H O LOGY

F i g u re 3 . 284 Tattoo p i g m ent. Th is case featu res m o re sparsely d i strib uted tattoo p i g m ent. S u c h fi n d i n g s a re co m m o n at t h e peri p h e ry o f the tattoo site o r i n rem otely a p p l ied tattoos (g reater than a few months).

F i g u re 3.285 Tattoo p i g m e nt. U n d e r o i l i m m e rsi o n , the d e n s e , c l u m ped tattoo p i g m e nt is a p p a rent.

Figu re 3 . 2 86 Tattoo p i g m e nt. In this fi e l d , the tattoo p i g m ent density varies from intense ( left) to m o re sparsely distri buted (right). N ote that the p i g m ent is confi ned to the m a c ro p h a g e cytop l a s m , a n d the m a c ro p h a g e n u c l e i a re b l a n d a n d u n ifo r m . This c a s e is u n l i kely to cause concern for melanoma based on the b l a n d cyto­ l o g i c featu res of the m acrophages a n d the i ntensely b l a ck cha racte r of the tattoo pigm ent; h owever cautious observers may e m p l oy a n S 1 00 protei n i m m u n osta i n (re m e m be r t o u s e a red c h romogen fo r easier visi b i l ity), which s h o u l d be neg ative in tita n i u m p i g m e nt a n d positive i n m e l a n o m a s .

Figure 3.287 Tattoo p i g m ent.

for gross visibility with the naked eye) and it is not restricted to the terminal ileum, unlike titanium.

PS E U DO M E LAN O S I S D U O D E N I The first report of pseudomelanosis duodeni emerged in 1 9 76 182 Like the counterpart in the colon (pseudomelanosis coli) , the name is an unfortunate misnomer. The pigment is not melanin but instead represents iron with variable amounts o f calcium, lipofuscin , magne­ sium , aluminum, potassium, silica , and sulfur. 183- 1 85 The coarse and variably brown-black pigment is identified within the cytoplasm of macro phages , and can usually be highlighted with special stains for iron (83 %) and or calcium (24%) 186 The indicated macrophages are most commonly seen in the villous tips (Figs . 3 . 288-3 . 2 9 3 ) . Pseudomelanosis duodeni is

C h a pte r

3

5 MA

II BOWEl

285

Figure 3 . 2 8 8 Pseudomela nosis d u o d e n i . S m a l l bowe l biopsies a re a m o n g the m ost time consu m i n g beca use of the varied d i a g n oses that ca n h i d e i n the busy backgro u n d . As this case i l l u strates, the patchy l a m i n a propria pigment d e position (arrowheads) ca n be dif­ ficult to d iscern at low power in the n o r m a l l y busy-a ppeari n g s m a l l bowel m u cosa .

F i g u re 3.289 Pseud o m e l a nosis d u oden i . O n h i g h e r power, the cha racteristic brown-black p i g m e n t of pseudo m e l a n osis duodeni is better a p p reciated . Despite the m i s n o m e r, the pigment is not m e l a ­ n i n b u t , i n stead, is i ro n w i t h vari a b l e a m o u nts o f ca l c i u m , l i pofusci n , m a g n esi u m , a l u m i n u m , potass i u m , s i l ica, a n d o r su lfu r. Alth o u g h a cute i nfl a m m ation is seen , it is u n re l ated t o t h e pigment.

Figure 3.290 Pseudomel a n osis duoden i . Pseudomelanosis duodeni is associated with p a rticu l a r c l i n ica l featu res, such a s hypertension, gastrointesti n a l b l eed i n g , ren a l fa i l u re, d i a betes, a n d with pa rticu l a r medications, such as i ron a n d antihypertensive medications.

F i g u re 3.291 Pse u d o m e l a nosis d u o d e n i . At higher power, n ote the coarse n atu re of this brown-black pigment confi ned with i n the m a c ro p h a g e cytoplasm .

Figure 3 . 292 Pseud o m e l a nosis d u o d e n i . U n d e r o i l i m me rs i o n , the pigment is com posed of u n iformly sized and u n iformly sha ped pack­ ets of brown pig ment.

Figure 3 . 2 9 3 Pse u d o m e l a n os i s d u o d e n i . N ote the u n iform a n d

b l a n d cyto log ic featu res o f the m acrophages; n o atypica l featu res a re see n .

286

AT LAS

0 F

GAST R0 I N TEST I N A L

PAT H O LOGY

associated with hypertension, gastrointestinal bleeding, renal failure , diabetes , and with particular medications , such as iron and antihypertensive medications (hydrocholorthia­ 186,187 zide , atenolol, lisinopril/quinapril, and irbesartan) P EA R LS & P ITFALLS

Pse u d o m e l a n os i s d u od e n i is reco g n ized e n d oscop i c a l ly i n o n l y 36% of cases . 1 86 Do n ot be a l a rmed if you r h i sto l o g i c d i a g n o s i s h a s n o e n d osco p i c co u n te rpa rt.

FORMALI N P I G M E NT (AC I D FORMALD E HY D E H E MATI N ) Formalin pigment (acid formaldehyde hematin) i s a bothersome tissue artifact seen in any tissue that is fixed in a formalin tissue preservative . It carries neither clinical nor pathologic importance . It is a sparsely distributed , finely granular, dark brown-black, birefringent crystal most commonly seen in bloody backgrounds (Figs . 3 . 294-3 . 2 99) . Unlike titanium ,

Figure 3 .294 Form a l i n p i g m ent. Alth o u g h t h i s exa m p l e of fo r­ m a l i n p i g m e n t orig i n ates from the eso p h a g u s , it exe m p l ifies the cha racteristic features of form a l i n pigment. O n low power, fo rm a l i n pigment c a n l o o k i n sect- l i ke d u e t o t h e stra n g e sha pes created by the condensed p i g me ntati o n .

Figure 3 . 295 Form a l i n p i g m e nt. O n higher power, n ote that a por­ tion of the form a l i n p i g m e n t is out of focus (arc). Form a l i n pigment is typica l ly not entire l y o n the s a m e p l a n e as the associated tissue and, conseq u ently, is cha racte ristica l ly partly out of focus, p rovid i n g a h e l pfu l c l u e t o t h e identification o f fo rm a l i n p i g m ent.

Figu re 3 .296 Form a l i n p i g m e n t (arc). U n d e r o i l i m m e rs i o n , n ote that the p i g m e n t is fi n e l y g ra n u l a r a n d d a rk b row n . Featu res that disti n g u ish form a l i n pigment from any oth e r pigment d iscussed in this sectio n include a n extracellular l o cation and its p ropensity to be o n l y partly i n focus. An a rc h i g h l ig hts a portion that i s n ot i n the sa m e plane, a re l i a b l e feature of form a l i n p i g m ent.

F i g u re 3 .2 9 7 Form a l i n p i g m e n t (arc). I n this a ltern ate fi e l d , the fi n e l y g ra n u l a r n atu re of the pigment a n d its extracellular l ocation is better a p p reciated . An a rc h i g h l i g hts a portion of the pigment that is out of focus.

C h a pter 3

·

5 MALL

BOWE L

287

.

Fig u re 3 . 298 Form a l i n p i g m e n t (arc). There is n e ither c l i n i ca l n o r path o l o g i c i m porta n ce t o identification o f fo rm a l i n p i g m e nt. T h e i m po rta n ce o f reco g n iz i n g t h i s p i g m e n t is s i m p l y n ot t o confuse i t with a n y o f t h e oth e r p i g m e nts d i scu ssed i n this secti o n . An a rc h i g h l i g hts a portion of the p i g m e n t that is out of focus.

F i g u re 3 .299 Form a l i n p i g m e n t (arc). Form a l i n p i g m e n t is seen entra pped with l u m i n a l d e b ri s . An a rc h i g h l i g hts a portion of the pigment that is out of focus.

tattoo , and pseudomelanosis , formalin pigment is not seen in the confines of a macrophage and is often not even on the same plane as the examined tissue, features that can serve as helpful clues to the pigment's identification . Various experts have noted that formalin pig­ ment collects in tissues especially rich in fats , such as liver and kidney, 188, 1 89 and theorize that this fatty microenvironment may promote formalin pigment precipitation through donation of triglycerides .

M E LANOMA Of all the pigments i n this section , melanoma pigment i s the one pigment that i s N O T T O BE MISSED . Whereas the prior mentioned pigments are found i n macrophages with bland nuclear features, melanoma pigment is seen in unequivocally malignant cells with prominent nucleoli , pleomorphism, and hyperchromasia. Atypical mitoses are often eaSily identified. The pigment itself is coarse , variably sized, and highlighted by the Fontana-Masson special stain (Figs . 3 . 300-3 . 3 0 5 ) . Additional speCial stains and immunostains are often reassuring

Figu re 3 . 300 M e l a n o m a . F ro m l o w powe r, coa rse b rown p i g ­ m e n t is s e e n with i n the cytop l a sm of overtly m a l i g n ant ce l ls; b e n i g n m a crophages wo u l d not h ave such l a rge, p l e o m o r p h i c n u clei with p ro m i n ent n u cleol i . M o reove r, I y m p h ovascu l a r i nvasion is d e m o n ­ strated i n a d i l ated l a cte a l (arrowheads) . The patient h a d a h i sto ry of cuta neous m a l i g n a nt m e l a n o m a a n d was fou n d to h ave widely m etastatic disease involving the s m a l l bowe l , l iver, a n d bra i n .

Figure 3 . 30 1 M e l a n o m a . Alth o u g h n o m e l a n i n p i g m ent is seen i n this fig u re , oth er cha racteristic featu res of m e l a n o m a a re see n , i n c l u d i n g a packeted o r nested a rch itectu re (arcs), p ro m i n ent n ucle­ o l i , a n d a h i g h n uclear to cyto p l a s m i c ratio. H a lf of m e l anomas a re a m e l a n otic.

288

AT LAS

0 F

GAST R0 I N TEST I NA L

PAT H O LOGY

Figure 3 . 302 M e l a n o m a . At h i g h e r power, pleom orphism is evi­ dent with n u c l e a r size vary i n g 3 to 4 times a m o n g the m a l ig n a nt ce l l s . N ecrosis is a l so seen a l o n g with eccentrica l l y p l a ced n u c l e i , p ro m i n e n t n u cleo l i , a n d brown p i g m e nt.

F i g u re 3 . 303 M e l a n o m a . U n d e r o i l i m m e rsi o n , the coa rse l y d i s­ tributed brown p i g m e n t is seen i n ce l l s bea ri n g l a rg e n u cl e i with p ro m i n ent n u c l eo l i . O n H & E , this p i g m e n t ca n be n oth i n g oth e r t h a n m e l a n i n based on the m a l i g n a n t cyto logic features. M e l a n o m a i m m u n osta i n s c a n confirm this i m p ress i o n .

Figure 3 . 304 M e l a n o m a . U n d e r o i l i m m e rs i o n , a g a i n n ote the cyto l o g i ca l l y m a l ig n a nt featu res of the lesio n a l cells, i n c l u d i n g l a rg e n u cl e i , p ro m i n e nt n u c l e o l i , a n d I y m p h ovascu l a r s p a c e i n v a s i o n (arrowheads h i g h l ight the endoth e l i u m ) . N ote t h a t the cha racteristic m e l a n i n p i g m ent i s coarse, brow n , and vari a b l y sized .

F i g u re 3 . 305 M e l a n o m a , Fonta na-Masso n . The m e l a n o m a p i g ­ ment ca n be confi rmed w i t h a Fonta n a-M asson specia l sta i n , which h i g h l i g hts the m e l a n i n pigment b l a ck.

(melanoma is S l OO protein reactive , variably reactive for Melan-A and Mart- I , and the pig­ ment is highlighted by the Fontana-Masson special stain) .

90YTT R I U M- LAB E L E D M I CROS P H E RES A s mentioned i n the Stomach Chapter, Pigments and Extras subsection, 90yttriumclabeled microspheres are used in the targeted treatment of unresectable primary and metastatic hepatic malignancies . Inadvertent delivery to nontarget organs can result in unintentional radiation inj ury Affected organs include the esophagus , stomach , small bowel , pancreas , and gallbladder. The background mucosa shows a radiation pattern of inj ury with lamina propria hyalinization , atypical stromal , endothelial , and epithelial cells , and prominence of ectatic , damaged vessels . The characteristic microspheres are 30 to 40 11m in diameter, uniformly opaque, deep purple and perfectly round, and radioactive emissions occur as far out as 1 4 days postdelivery (Figs . 3 . 306-3 . 3 1 1 ) . CMV immunostains are recommended in all cases since such patients are typically immunocompromised. Moreover, radiation atypia can obscure or overlap with CMV viral cytopathic effect . A comparison summary of the pigments can be found in Figure 3 . 3 1 2 .

C h a pte r

3

5 M ALL

BOWE L

289

Figure 3 . 306 9Dyttri u m - l a beled m i crosph e res a n d ra diation i nj u ry. T h i s patient h a d a h i story of u n resecta b l e hepatoce l l u l a r carci n o m a treated with sel ective i ntern a l ra d i atio n thera py w i t h 90 yttri u m _ l a beled m icrospheres. He p resented with n a usea a n d vomiti n g , a n d biopsies o f u l ce rated sma l l bowel m u cosa a re shown . N ote t h e foca l u l ceration with n u merous em bedded 90yttri u m - l a beled m icrosph e res (arrowh eads) . A CMV i m m u n o h istoche m i c a l sta i n was negative.

Fi g u re 3 . 307 9Dyttri u m - l a beled m i crospheres and rad iation i nj u ry. Alth o u g h 90 yttri u m-labeled m i crospheres a re n ot seen i n this fi e l d , this i m a g e sh ows the classic features o f a ra diation pattern o f i nj u ry with n u m erous ectatic, d a m a ged vessels (brackets). G a stric foveo l a r m eta p l a s i a is a l so see n , a featu re o f chro n i c m u cosa l i n j u ry. A C M V i m m u noh i stoch emical sta i n w a s negative.

Figure 3 . 308 90Yttri u m - l a be l ed m i c rospheres and rad iation i nj u ry. H i g h e r power s h ows the c h a ra cteristi c 90 yttri u m - l a be l e d m i cro­ spheres that a re 30 to 40 11m i n d i a m ete r, u n ifo rm ly opaque, deep purple, and perfectly rou n d . The associated m u cosa sh ows a rad i a ­ tion patte rn o f i nj u ry with l a m i n a propria hya l i n ization a n d atypica l stro m a l a n d epith e l i a l ce l ls.

Fig u re 3 . 309 9Dyttri u m - l a beled m icrospheres and ra d i ation i nj u ry. H i g h e r power sh ows the 90yttri u m - l a beled m i crospheres em bedded i n infl a m mati o n , stro m a l hya l i n izatio n , and m a rkedly atypica l stro m a l a n d epith e l i a l ce l l s, features cha racteristic o f rad iation i nj u ry.

Fig u re 3 . 3 1 0 9Dyttri u m - l a beled m icrosp h e res a n d rad i ation i nj u ry. N ote the associated ectatic vessels (arrowheads) with atypi ca l endo­ th e l i a l ce l l s res u l t i n g from rad iation d a m a g e .

Figure 3 . 3 1 1 9Dyttri um-labeled m icrospheres a n d radiation i nj u ry. U nder o i l i m m ers i o n , the u n iform ly opaque, deep purple, and per­ fectly round stru ctu res cha racteristic of 9°yttri um-labeled m icrospheres a re see n . Also n ote the backg round stro m a l hya l i n izati on and asso­ ciated epith e l i a l atypia (arrowhead); both featu res a re secondary to radiation i nj u ry. A CMV i m m u n o h istoch emical sta i n was negative.

290

ATLAS

O F

GASTRO I N T E ST I N A L

PAT H O LO G Y

Fig u re 3 . 3 1 2 Pigment Com posite. This composite i m a g e conta ins the a bove m entioned p i g m e nts at 1 00x to best differentiate the morphologic subtleties. A: Tita n i u m pigment is fi n e in texture , d a rk­ brown to black in color, a n d confi n e d with i n macro p h a g e cyto p l a s m . B: Tattoo p i g m e n t is a lso d a rk brown-black a n d confined with i n the cytoplasm of m a crophages but, u n l ike tita n i u m , it is m o re coa rse, c l u m py, a n d conspicuous since its sole pu rpose is to be g rossly identifiable. C: Pseu d o m e l a n osis pig­ ment consists of coa rse brown-black pigment confined with i n the macrophage cyto p l a s m . As shown here, pseudomelanosis pigment is com posed of u n iformly sized and u n iformly sha ped packets of brown pigment that a re m ost typica l l y seen in m acrophages in the vi l lous tips i n patients with hypertension, gastrointesti n a l bleed i n g , ren a l fa i l u re, d i a betes, a n d i n those with i ron a n d antihypertensive medication thera py. D : Form a l i n pigment is a bothersome pigment with neither c l i n ical n o r path o l o g i c i m po rta n ce (except to n ot m i stake it for a n y of the other pigments discussed here with i n !) . On low it often looks i nsect- l i ke a n d on h i g h power it is fi n e l y g ra n u l a r, d a rk brow n , exc l usively extracel l u l a r, a n d partia l ly out of focus since it is on m u lti p l e p l a nes. E: M e l a n i n pigment is va riably coa rse, brown , a n d with i n the cytoplasm of overtly m a l i g n a nt ce l l s . F: 90yttri u m - l abeled microspheres a re 30 to 40 �m i n d i a m eter, u n iformly opaque, deep purple, perfectly rou n d , a n d associated with a rad i ation pattern of i nj u ry.

KEY F EATU R E S : P i g m e nts a n d Extras •

•

Titanium deposition is unique to the terminal ileum and is likely introduced through ingested toothpaste . Tattoo pigment (usually India ink) is preoperatively applied for lesion localization in future procedures: targeted surveillance of endoscopically monitored lesions , localizing the lesion at time of surgery, and improved local lymph node dissections .

C h a pte r 3

•

•

•

•

Pseudomelanosis duodeni consists of iron with variable amounts of calcium, lipofuscin, magnesium, aluminum, potassium, silica , and or sulfur and is associated with hype rten­ sion, gastrointestinal bleeding, renal failure , diabetes , and with particular medications . Formalin pigment is a tissue artifact with neither clinical nor pathologic importance; it is not seen in the confines of a macrophage and is often not even on the same plane as the examined tissue. Melanoma pigment is seen in unequivocally malignant cells and confirmed with the fol­ lOWing diagnostic panel (S l O O reactive , variably reactive for Melan-A and Mart- I , and the pigment is highlighted by the Fontana-Masson speCial stain) . 9 Dyttrium-labeled microspheres are used in the targeted treatment of unresectable pri­ mary and metastatic hepatiC malignancies ; inadvertent delivery to nontarget organs can result in inadvertent radiation inj ury; CMV immunostains are recommended in all cases .

N EAR M ISSES S N EAKY A D E N OCARCI N O MA

Figure 3 . 3 1 3 Acute d u o d e n itis with g a stric foveo l a r m eta p l a s i a a n d rea ctive epith e l i a l cha n g e . The c l i n i ca l i m p ress i o n o f a m a ss l e s i o n i n s p i red d e e p e r secti o n s on t h i s b u sy- a p p e a ri n g biopsy, a lthough n o h i sto l o g i c featu res of m a l i g n a n cy a re rea d i l y a p p a rent on this fi rst leve l .

This case was received a s "prominent ampulla , concerning for malignancy" (Fig. 3 . 3 1 3 ) . The initial sections show duodenal mucosa with acute and chronic inflammation, gastric foveolar metaplasia, and marked reactive epithelial change (Fig. 3 . 3 1 3 ) . Although these his­ tologiC features can account for a nodular clinical impression, deeper sections were pursued based on the clinical suspicion for malignancy. The first set of deeper sections were Similarly concerning, but definitive malignancy was not seen. Deeper sections were repeated. And repeated. And repeated. In this case , the tissue block was exhausted and on the 38th level ( ! ! I ) , clear lymphovascular invasion and infiltrating adenocarcinoma were seen (Figs . 3 . 3 1 4 and 3 . 3 1 5) . When the histology does not fi t the clinical scenario, consider deeper sections . When the deeper sections are not conclusive , consider repeat deeper sections or recommend rebiopsy (in this case , the patient was too unstable for a subsequent biopsy) .

5 M ALL

BOWE L

291

292

ATLAS

0 F

GASTR0 I N T EST I N AL

PAT H O LOGY

F i g u re 3 . 3 1 4 I nfi ltrat i n g poorly-d iffe re ntiated a d e n oca rci n o m a a n d Iym p h ovascu l a r space i nvasi o n . Deeper secti o n s w e re p e r­ fo rmed u n t i l t h e b l ock was exh a u ste d . T h i s photo m i c ro g ra p h rep resents t h e 38t h (a n d fi n a l) sectio n , w h i ch shows desm o p l a s i a , infi ltratin g aden ocarci noma (arrowheads), a n d Iymphovasc u l a r space i nvasion (asterisk) . These deeper sectio n s show a n entirely d ifferent biopsy com p a red to the i n it i a l sections a n d we re sufficient fo r che­ moth e rapy i n itiati o n .

F i g u r e 3 . 3 1 5 S n e a ky a d e n ocarci n o m a i n vo l v i n g the d u o d en a l m u cosa . U nder o i l immersion, note the n uclear i rregu l a rities, abundant p i n k cytoplasm, and cytoplasmic m uc in d roplet (arrowhead) charac­ teristic of pancreatobiliary adenocarcin o m a . U nfortu nately, som etimes 38 leve ls a re requ i red for the u ltimate diagnosis a n d someti mes only a few m a l ignant cel l s a re present! When the clin ica l scenario a n d the histology a re n ot a l igned, deeper sections (a nd deeper sections a n d deeper sections a n d deeper sections) a re often requ i red.

I SOS PORA

F i g u re 3 . 3 1 6 Isospori a s i s . This i nterm ediate power view s h ows how easy it is to m iss Isospora. At l ow power, o n l y gastric fove o l a r m eta plasia a n d perhaps a s l i g h t i n crease i n l a m i n a propria eosino­ phils is see n . Oth er fields of this sa m e case were essent i a l l y n o rm a l , e m p h a s i z i n g that every b i opsy n eeds a few h i g h power fi e l d s of attention fo r such extre me l y s u bt l e d i a g n oses.

F i g u re 3 . 3 1 7 Isosporiasis. On higher power, a slight prom inence of l a m i n a propria eosinoph ils serves as a red flag to the diagnosis. Arrow­ heads h i g h l ight the Isospora organ isms, which a re obl igate intrace l l u l a r parasites and a re found in t h e para n u clear o r subnuclear cytoplasm .

F i g u re 3 . 3 1 8 Isosporiasis. On h i g h e r power, the Isospora o rg a n ­ i s m s (arrowheads) a re s e e n em bedded with i n the epith e l i u m . U n less the epith e l i a l com p a rtment is d i l ig e ntly i n spected i n every biopsy, these o rg a n isms wou l d a l m ost certa i n l y be m issed .

C h a pter

3

5 MALL

BOWE L

293

Isosporiasis is among the more common protozoan causes of severe diarrhea in AIDS patients (Figs . 3 . 3 1 6-3 . 3 1 8) 190 The Isospora belli organisms are spread via contaminated water or fecal-oral contamination. They localize to the small bowel surface and are exceedingly easy to miss owing to sometimes unremarkable background mucosa and sparsely distributed organ­ isms (Figs . 3 . 3 1 6-3 .32 1 ) . Diagnostic confirmation is facilitated through identification of the oocysts in stool samples or duodenal aspirates . 191 Standard therapy consists of trimethoprim­ sulfamethoxazole , which is often long term in severely immunocompromised patients. Cryptosporidia and microsporidia infections can manifest with similar clinical symptoms and are frequent differential considerations , especially on board examinations ' Cryptospo­ ridia are small (2 to 5 11m) , rounded basophilic structures that attach to the small bowel and pancreatobiliary epithelium (Figs . 3 . 322-3 . 32 6) . The organisms can be all too easy to miss on H&:E and are best highlighted by Giemsa , silver, or PAS special stains . Microsporidium was recently reclassified from a parasite to a fungus . It is an obligate intracellular organism that is best seen with electron microscopy.

Figure 3 . 3 1 9 Isosporiasis (arrowhead) . O i l m a g n ificatio n .

Figure 3 . 320 I sospori a s i s . The Isospora o rg a n isms a re nested with i n the d u o d e n a l epith e l i u m a n d h ave a peri p h e ra l c l e a ri n g (arrowheads) o r h a l o that rep resents a parasitophorous vacuole o n l y s e e n d u ri n g s o m e sta ges o f deve l o pment.

F i g u re 3 . 3 2 1 I sospori a s i s . T h e l a rg e size o f Isospora ca n h e l p d i sti n g u i s h i t from oth er i n tra ce l l u l a r protozoa , such as Cydospora . This Isospora o rg a n i s m is l a rg e r th a n the n u c l e u s o f the n e i g h bo ri n g enterocyte . N ote t h a t the peri p h e ra l c l e a r i n g o r h a l o i s sti l l p res­ ent. C h a rt review revealed the patient was from C a m eroon and p re­ sented with d i a rrhea . He was u lt i m ately dete rm i n ed to h ave AI D S .

Figure 3 . 322 Cryptosporid iosis. Cryptosporidiosis is n ot a n infre­ quent cause of d i a rrh ea in the i m m u n ocomprom ised patient. At low power, the biopsy shows mild v i l l o u s b l u nting a n d crypt hyperplasi a . There is neither a rch itectura l d i stortion n o r infl a m m atory injury.

294

ATLAS

0 F

GAST R0 I N TEST I NA L

PAT H O LOGY

Fi g u re 3 . 323 Cryptosporid iosis. The h i sto l o g i c "ch atte r" a rtifact m a kes this biopsy difficu lt, rep l icati n g the " re a l l ife " issues p ra ctic­ ing path o l og ists routi n e l y face.

Figure 3 . 325 Cryptosporidiosis. The org a n isms a re best a ppreci­ ated at high power, u n d e rscori n g the d ifficu lty i n d i a g nosis u n l ess "the l ayers " a re d i l i g ently inspected in a l l cases. Alth o u g h Cryp­ tosporidia a re o b l i g ate i ntrace l l u l a r org a n isms, they a re extra cyto­ p l a s m i c a n d l ive with i n the m icrovi l l i of the enterocyte, h e n ce their cha racteristic surface locati o n.

Figure 3 . 324 Cryptospori d i osis. A t h i g h power, the cha ra cteristic

2 to 5 11m, rounded baso p h i l i c structu res a re seen attached to the

sma l l bowel epith e l i u m .

Figure 3 . 326 Cryptospori d i osis. The o rg a n isms a re seen " d a nc­ i n g " on the superfic ia l epith e l i u m . In d ifficu lt cases, the o rg a n isms can be h i g h l ig hted by G iemsa, silver, o r PAS spec i a l sta ins.

GIARDIA DUODENALIS ( GIARDIA LAMBLIA O R GIARDIA INTESTINALlS)

Figure 3.327 G i a rdiasis. At low power, the duodenal m u cosa looks fa i rly u n re m a rka b l e , except for the h a p h aza rd l y a rra n g e d l u m i n a l debri s cha racteristic o f g i a rdiasis. This patient was c l i n i ca l ly t h o u g ht to h ave a n occu lt m a l ig n a n cy based on the p rofo u n d weight loss, but a l l sympto m s resolved with Giardia e ra d i catio n .

Ch a pter

3

5 M A L L

BOWE L

295

Giardia is the most common intestinal protozoan causing diarrhea in humans (Fig. 3 . 3 2 7 ) . 1 92 Part of the protozoan's success stems from its ability to infect both the immunocompromised and immunocompetent and its ability to be perpetuated in silent carriers (or asymptomatic patients) . This awareness of asymptomatic Giardia infections is important such that one is not misled by a lack of diarrhea-it happens ! Nevertheless , treatment of these asymptomatic cases is critical for prevention of onward spread. The cyst is transmitted via contaminated water or via fecal-oral route , and the flagellated trophozoite adheres to the intestinal epithe­ lium . On duodenal mucosa biopsies, the organisms haphazardly swirl close to the mucosal surface . They can bear such a haphazard arrangement that they can be mistaken for luminal debris to the untrained eye . On closer examination, the trophozoites have been described as clown-faced or pear-shaped based on their peculiar binucleate structure (Figs . 3 . 328-3 . 332) . Diagnosis can be confirmed with stool smears for the trophozoites or cysts , stool antigen assays , or serologic studies. The only FDA approved treatment is furazolidone (Furoxone) , 190

F i g u re 3 . 3 2 8 G i a rd i a s i s . On h i g h e r power, the Giardia o rg a n ­ i s m s a re better visu a l ized (arro wheads) . N ote that t h e ba ckg ro u n d m u cosa is essenti a l l y n o r m a l a n d p rovides n o clues t o the infection, m a k i n g routine i nspecti on fo r g i a rd i asis critica l i n every sma l l bowel b i o psy. This patient was a n avid h i ke r and l i ke l y contracted the o rg a n isms by d r i n k i n g conta m i n ated water o r t h ro u g h i n a d e q u ate hyg i e n e practices.

Figure 3 . 329 G i a rdiasis. On h i g h est power, the trophozoites a re best see n . Note how the cu p-sha ped o rg a n isms swirl near the duo­ dena l epith e l i u m .

Figure 3.330 G i a rdiasis. O n a busy day, this low power view m i g h t s e e m l e s s t h a n i nte rest i n g but it u n d e rscores t h a t exa m i nation o f the l u m i n a l contents i s essenti a l fo r every b i o psy! A bra cket h i g h ­ l i g hts the foca l co l l ecti on of Giardia org a n isms, w h i c h a re often best a ppreciated at i nterm e d iate power.

Figure 3 . 3 3 1 G i a rd i a sis. T h i s patient h a d recu rrent g i a rdiasis that fa i l e d medica l m a n a gement a n d consequently i m m u n odeficiencies were considere d . Alth ough p l a s m a ce l l s were identified, he was u ltim ate l y d i a g n osed with CVI D based on a b n o r m a l seru m i m m u ­ noglobu l i n levels. W h e n consideri n g i m m u n odeficiencies re lated to recu rre nt g i a rd i a s i s , it is i m po rta nt to a ssess fo r goblet cel l s a n d Paneth ce l l s (either c a n b e l ost with Al E) , p l a s m a cel l s ( u p t o 6 7 % of those with CVI D show a loss of plasma ce l l s) , a n d i n creased a pop­ totic bodies (wh i ch a re a n o nspecific feature of various i m m u ne­ m ediated p rocesses) .

296

AT LAS

0 F

GAST R0 I N TE S TI N A L

PAT H O LOGY

F i g u re 3 . 3 3 2 G i a rd i a s i s . H i g h e r power sh ows the cu p-sh a ped forms characteristic of g i a rd i a sis. although metronidazole is the most common first-line therapy In the unusual case of recur­ rent or medically nonresponsive giardiasis , consider the following immunodeficiencies : C H ECKLI ST: I m m u n odeficiencies Associated wit h G i a rd iasis D

I gA Defi c i e n c i e s

D

Com m on Var i ab l e I m m u nodefi c i e n cy (CV I D)

D

Auto i m m u n e Enteropathy

D

I PEX S y n d ro m e ( I m m u n od ysreg u l at i o n , P o l ye n d o cr i n o p a t h y, Entero p a t h y, X-Linked I n h er ita n ce)

D

APECED Syndrome (Auto i m m u n e p h e n o m e n a , Polyendocr i n opathy, Ca ndid iasis, and Ectoder m a l Dystrophy)

D

X-Linked Aga m m a g l obu l i n e m i a

CO M M O N VARIABLE I M M U N O D E F I C I E N CY

F i g u re 3 . 333 C o m m o n va ria b l e i m m u n od efici e n cy (CV I D ) . T h i s b i o psy o ri g i n ated fro m a 7 -ye a r-old b o y w i t h a h istory o f c h ro n i c d i a rrhea . It w o u l d be easy t o enterta i n C e l i a c d isease i n t h i s case based o n the v i l l ou s b l u nti n g, crypt hyperp l a s i a , and intraepith e l i a l lymphocytosis (not a p p reciated at t h i s power) .

Figu re 3 . 334 Com m o n vari a b l e i m m u n odeficiency (CVID). H ig h e r power o f p revious i m a g e . A t this power, a com p l ete l a c k o f p l a s m a ce l l s is see n . I n oth e r fi elds, p ro m i n ent a p o ptotic bodies were a lso see n , fu rther s u p p o rt i n g a path o l o g i c suspicion of CVI D . Titration of seru m i m m u n og l o b u l i n s was d i a g nostic of CVI D a n d the pati ent c l i n i ca l ly responded to i n travenous i m m u no g l o b u l i n a d m i n istratio n . I m po rtantly, goblet ce l l s a n d Paneth cel l s a re see n , m a k i n g concomi­ tant A l E l ess l i kely.

C h a pte r 3

S M A LL

B OWE L

297

CVID is characterized by hyp ogammaglobulinemia , a lack of functional plasma cells , impaired response to vaccinations , and chronic infections (including Giardia and bacte­ rial infections) (Figs . 3 . 3 3 3 and 3 3 34) . A lack of plasma cells is helpful, but only seen in two-thirds of cases; identification of plasma cells cannot exclude CVID l 44 Therefore , clinicopathologic correlation is essential with titration of serum immunoglobulins serving as an essential component to the diagnosis .

CO LLAG E N O U S E NTERITIS

Figure 3 . 335 Co l lagenous enteritis i n a patient with ce l i a c disease. At low power, m i l d v i l l o u s b l u nting and prom i n e n t subepith e l i a l col­ l a g e n a re see n . The m ost com m o n d i a g n oses l i n ked to co l l agenous enteritis include co l l agenous col itis, lym ph ocytic col itis, a n d ce l iac d i sease. In this case, co l l a g e n o us enteritis was a m a n ifestation of c l i n i ca l ly confi rmed ce l i a c d isease. The c l i n i c a l sympto m s a n d h i sto­ l o g i c changes a bated with a d h erence to a G F D . Collagenous enteritis can be easily missed at l o w magnification, particularly since the archi­ tectural pattern often remains intact (Fig. 3 . 3 3 5 ) . Remember to spend a moment at higher magnification to routinely inspect all the layers of the small bowel . Doing so may reveal an altered collagen table or otherwise eaSily missed diagnoses (Figs . 3 . 3 3 6-3 . 340) .

Fig u re 3 . 336 Co l l a g e n o u s enteritis i n a patient with ce l i a c disease. At h i g h e r power, the p ro m i n e n t su bepith e l i a l co l l a g e n sh ows an i rreg u l a r border a n d conta i n s entra pped ca p i l l a ries. In additi o n , moderate v i l l o u s b l u nting a n d a m i l d p ro m i n e n ce o f I E Ls a re see n .

Figure 3.337 Co l la genous e nteritis i n a patient with celiac disease.

298

ATLAS

0 F

GAST R 0 I N T EST I NA L

PAT H O LOGY

Figure 3 . 338 Co l l agenous enteritis i n a patient with co l l agenous co l itis. This case o f co l l agenous e nteritis o ri g i n ated from a pati ent with a h i story of co l lagenous col itis a n d sh ows a p rom i n ent, i rreg u l a r su bepith e l i a l co l lagen table with e ntra pped ca p i l l a ries.

Figure 3 .339 C o l l a g e n o u s e nteritis i n a patient with col l a g e n o u s co l itis.

Figure 3 .340 Co l l a genous enteritis i n a patient with co l l a g e n o u s colitis. Pro m i nent entra pped ca p i l l a ries a re seen with i n t h e expanded subepith e l i a l co l l agen ta b l e . N ote that i ntraepith e l i a l lymph ocytosi s can be patchy i n co l lagenous enteritis a n d is n o t s e e n i n this fie l d .

S N EAKY N EU RO E N DOCRI N E TU M O R

Figure 3 . 3 4 1 S n e a ky n e u roen docri n e t u m o r. T h i s b i o psy was s u b m itted a s a d u o d e n a l polyp. At low power, g a stric fove o l a r m eta p l as i a a n d B ru n n e r g l a n d hyperp l a s i a a re see n , fi n d i n g s that cou l d acco u n t fo r the i m p ression of a polyp; h owever every biopsy deserves closer i n spection .

Ch a pte r 3

5 M ALL

BOWE L

299

Small b owel biopsies can be treacherous because o f all the potential hiding places for sneaky diagnoses (Fig. 3 . 34 1 ) . Microscopic neuroendocrine tumors , for example , can be easily obscured by a busy and "abused" small bowel biopsy (Figs . 3 34 1-3 345) and yet diligent inspection is critical as even microscopic neuroendocrine tumors can behave aggressively. When dealing with a challenging case of crushed and cauterized tissue , consider a chromogranin and synaptophysin immunostain , deeper sections , or ask for a repeat biopsy.

Figure 3 . 342 S n e a ky n e u roendocri n e tu m o r. At h ig h e r power, the gastric fove o l a r m eta p l asia and crushed lymphoid a g g regates a re bette r a p p reciate d .

Figure 3 . 343 S n e a ky n e u roendocri n e tumor. At this power, n ote the Bru n n er g l a n d s a re p ushed a p a rt by an expa n s i l e p rocess, a n a l a rm i n g fi n d i n g that deserves cl ose inspecti o n . B rackets h i g h l i g h t pockets o f neopl astic ce l l s a rra nged i n n ests, suggestive o f a n e u ro­ endocri n e neoplasm. The diag nosis of this sneaky n e u roendocri n e t u m o r is particu l a rl y ch a l l e n g i n g i n such a busy ba ckg ro u n d .

Figure 3 . 344 S n e a ky n e u ro e n docri n e t u m o r. H ig h e r power. The neopl astic ce l ls (brackets) a re poorly preserved , crushed, a n d cou l d easily be m ista ken for crushed lymph ocytes i f n ot ca refu l ly i n spected at h i g h e r power.

Fig u re 3 . 345 Sneaky n e u roendocri n e t u m o r (arc). Altern ative fie l d .

300

ATLAS

0 F

GAST R0 I N T EST I N A L

PAT H O LOGY

Refere n ces 1. Holmes R, Hourihane D O , Booth C c . The mucosa o f the small intestine . Postgrad Med J. 1 9 6 1 ; 3 7 7 1 7-724. 2. Dobbins WO 3rd. The intestinal mucosal lymphatic in man. A light and electron microscopic study. Gastroenterology. 1 9 6 6 ; 5 1 (6) :994- 1 0 0 3 . 3 . Rubin W The epithelial "membrane" of the small intestine . Am ] Clin Nutr. 1 9 7 1 ;24( 1 ) :45-64 . 4. Robertson HE. The pathology of Brunner's glands . Arch Pathol Lab Med. 1 9 4 1 ;3 1 : 1 1 2- 1 3 0 . 5 . Ugwu BT, Legbo IN, Dakum N K , et a l . Childhood intussusception: A 9-year review. Ann Trap Paediatr. 2000;20(2) 1 3 1 - 1 3 5 6 . Ekenze S O , Mgbor S O , Okwesili O R . Routine surgical intervention for childhood intussuscep­ tion in a developing country. Ann Afr Med. 2 0 1 0 ;9 ( 1 ) : 2 7-30 . 7 . Batts K P, Ketover S , Kakar S , et al. Appropriate use of special stains for identifying Helicobacter pylori: Recommendations from the Rodger C. Haggitt Gastrointestinal Pathology Society. Am ] Surg Pathol. 2 0 1 3 ;3 7( 1 1 ) : e 1 2-e2 2 . 8 . Graham DY, Opekun AR, Willingham F F, et al. Visible small-intestinal mucosal inj ury i n chronic N SAID users . Clin Gastroenterol Hepatol. 2005 ; 3 ( 1 ) : 55-5 9 . 9 . Dilauro S , Crum-CianOone N F Ileitis: When i t i s not Crohn's disease . Curr Gas troenterol Rep. 2 0 1 0 ; 1 2 (4) : 249-25 8 1 0 . Klein M , Linnemann D , Rosenberg ] . Non-steroidal anti-inflammatory drug-induced colopathy. BM] Case Rep. 20 1 1 ;20 1 1 . 1 1 . Aftab AR, Donnellan F, Zeb F, et al. N SAID-induced colopathy. A case series . ] Gastrointestin Liver Dis. 2 0 1 0 ; 1 9 ( 1 ) 89-9 1 . 1 2 . Haskell H , Andrews CW Jr, Reddy S I , et al. Pathologic features and clinical significance o f "backwash" ileitis i n ulcerative colitis . Am ] Surg Pathol. 2 0 0 5 ; 2 9 ( 1 1 ) : 1 472-148 1 . 1 3 . Zuhlsdorf M , von Eiff M , Thomas M , et al. Decrease in arterial oxygen partial pressure within the first 24 h of rhGM-CSF administration in AML patients . Eur ] Haematol. 1 9 9 7 ; 5 9 ( 5 ) : 293-2 9 8 . 1 4 . Wright C L , Riddell RH . Histology o f the stomach and duodenum i n Crohn's disease. Am ] Surg Pathol. 1 99 8 ; 2 2 (4) : 3 83-39 0 I S . Lin J , McKenna BJ , Appelman H D . Morphologic findings i n upper gastrointestinal biopsies o f

patients with ulcerative colitis : A controlled study. Am ] Surg Pathol. 2 0 1 0 ;34( 1 1 ) : 1 67 2- 1 67 7 . 1 6 . Michaelsson G , Kraaz W, Gerden B , et al . Increased lymphocyte infiltration i n duodenal mucosa from patients with psoriasis and serum IgA antibodies to gliadin. Br ] Dermatol. 1 9 9 5 ; 1 33 (6) : 896-904 1 7 . Michaelsson G , Kraaz W, Hagforsen E, et al . Psoriasis patients have highly increased numbers of tryptase-positive mast cells in the duodenal stroma . Br] Dermatol. 1 99 7 ; 1 3 6(6) : 866-8 7 0 . 1 8 . Michaelsson G, Kraaz W, Hagforsen E , et a l . The skin and the gut i n psoriasis : The number of mast cells and CD3+ lymphocytes is increased in non-involved skin and correlated to the number of intraepithelial lymphocytes and mast cells in the duodenum. Acta Derm Venereal. 1 9 9 7 ; 7 7 ( 5 ) : 343-346 1 9 . Higgens CS , Allan RN . Crohn's disease of the distal ileum. Gut. 1 98 0 ; 2 1 ( 1 1 ) : 9 3 3-94 0 . 2 0 . Okada M , Yao T , Fuchigami T , et a l . Anatomical involvement and clinical features i n 9 1 Japanese patients with Crohn's disease . ] Clin Gastroenterol. 1 9 8 7 ;9(2) : 1 65-1 7 1 . 2 1 . Pescatori M , Interisano A , Basso L , e t al. Management o f perianal Crohn's disease. Results o f a multicenter study in Italy. Dis Colon Rectum. 1 9 9 5 ;38(2) : 1 2 1 - 1 2 4 . 2 2 . McKee RF, Keenan RA . Perianal Crohn's disease-is it a l l bad news' D i s Colon Rectum. 1 9 9 6 ;39(2) 1 3 6- 1 4 2 . 2 3 . Jones G WJ r , Dooley M R , Schoenfield L] . Regional enteritis with involvement of the duodenum. Gastroenterology. 1 9 6 6 ; 5 1 (6): 1 0 1 8- 1 02 2 . 24. Yamamoto T . Factors affecting recurrence after surgery for Crohn's disease. World] Gastroenterol. 2005 ; 1 1 (26) :397 1-3979 . 2 5 . Penner RM , Madsen KL, Fedorak RN . Postoperative Crohn's disease. Injlamm Bowel Dis. 2005 ; 1 1 (8) 765-777 26. De Petris G, Lopez J 1 . Histopathology of diaphragm disease of the small intestine : A study o f 1 0 cases from a single institution. Am ] Clin Pathol. 2008 ; 1 3 0(4) : 5 1 8-5 2 5 . 2 7 . McKinsey J F, Gewertz B L . Acute mesenteric ischemia. Surg Clin North Am. 1 9 9 7 ; 7 7 (2) : 3 0 7-3 1 8 .

Ch a pter 3

28. Reinus JF, Brandt LJ , Boley Sj . Ischemic diseases of the bowel . Gastroenterol Clin North Am. 1 9 90 ; 1 9 (2) 3 1 9-343 2 9 . Cappell MS. Intestinal (mesenteric) vasculopathy. I. Acute superior mesenteric arteriopathy and venopathy. Gastroenterol Clin North Am. 1 99 8 ; 2 7(4) : 783-8 2 5 , vi . 3 0 . Thomas DP, Roberts HR. Hypercoagulability in venous and arterial thrombosis . Ann Intern Med. 1 9 9 7 ; 1 26(8) 638-644 3 1 . Martinelli I, Mannucci PM, De Stefano V, et al. Different risks of thrombosis in four coagula­ tion defects associated with inherited thrombophilia : A study of 1 5 0 families. Blood. 1 9 9 8 ; 92(7) 2 3 5 3-2 3 5 8 3 2 . Acosta S , Alhadad A, Svensson P, et a l . Epidemiology, risk and prognostic factors i n mesenteric venous thrombosis . Br] Surg. 2008 ; 9 5 ( 1 0) : 1 245- 1 2 5 1 . 3 3 . Wilcox MG, Howard TJ , Plaskon LA , et al . Current theories of pathogenesis and treatment of nonocclusive mesenteric ischemia . Dig Dis Sci. 1 9 9 5 ;40(4) : 7 09-7 1 6 . 3 4 . Sudhakar C B , Al-Hakeem M , MacArthur J D , e t al. Mesenteric ischemia secondary t o cocaine abuse: Case reports and literature review. Am ] Gastroentero!' 1 9 9 7 ;92(6) : 1 053-1054. 3 5 . Endress C , Gray DG, Wollschlaeger G . Bowel ischemia and perforation after cocaine use . A]R A m ] Roentgeno!. 1 9 92 ; 1 59 ( 1 ) 73-7 5 . 3 6 . Granger D N , Hollwarth M E , Parks D A . Ischemia-reperfusion injury: Role of oxygen-derived free radicals . Acta Physiol Scand Supp!. 1 986 ;548 :47-63 . 3 7 . Hahn T, McCarthy PL Jr, Zhang MJ , et al . Risk factors for acute graft-versus-host disease after human leukocyte antigen-identical sibling transplants for adults with leukemia. ] Clin Onea!. 2008;26(35) 5 728-5 734 3 8 . Gale RP, Bonin MM, van Bekkum DW, et al. Risk factors for acute graft-versus-host disease. Br ] Haemato!' 1 9 8 7 ; 67(4) : 3 9 7-406 . 3 9 . Flowers ME , Inamoto Y , Carpenter PA, e t al. Comparative analysis of risk factors for acute graft­ versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. Blood. 2 0 1 1 ; 1 1 7( 1 1 ) : 3 2 1 4-32 1 9 . 4 0 . Lerner K G , Kao G F, Storb R, e t a l . Histopathology o f graft-vs . -host reaction (GvHR) in human recipients of marrow from HL-A-matched Sibling donors . Transplant Pmc. 1 9 7 4 ; 6 ( 4) : 3 6 7-3 7 1 . 4 1 . Epstein RJ , McDonald GB, Sale GE, e t al. The diagnostic accuracy o f the rectal biopsy in acute graft-versus-host disease: A prospective study of thirteen patients Gastroenterology. 1 9 8 0 ; 78(4) : 764-7 7 1 . 42. Snover D C . Mucosal damage simulating acute graft-versus-host reaction in cytomegalovirus colitis . Transplantation. 1 985 ;39(6) : 669-670. 4 3 . Lumadue JA, Manabe YC, Moore RD , et al . A clinicopathologic analysis of AIDS-related cryp­ tosporidiosis Aids . 1 9 98 ; 1 2 ( 1 8) 2459-2466. 44. Papadimitriou ] C , Drachenberg CB, Beskow C O , et al. Graft-versus-host disease-like features in mycophenolate mofetil-related colitis . Transplant Pmc. 200 1 ;33(3) : 2 2 3 7-22 3 8 . 4 5 . Shulman HM, Kleiner D , Lee SJ, et a l . Histopathologic diagnosis of chronic graft-versus-host disease: National Institutes of Health Consensus Development Proj ect on criteria for clinical tri­ als in chronic graft-versus-host disease: II. Pathology Working Group Report. Bioi Blood Mari·ow Transplant. 2006 ; 1 2 ( 1 ) : 3 1-47 46. Washington K, Jagasia M . Pathology of graft-versus-host disease in the gastrointestinal tract . Hum Patho!. 2009 ;40(7) : 909-9 1 7 . 4 7 . Sale GE, Shulman HM, McDonald GB, e t al. Gastrointestinal graft-versus-host disease i n man . A clinicopathologic study of the rectal biopsy. Am ] Surg Patho!. 1 979 ;3 (4) : 2 9 1-299 48. Selbst MK, Ahrens WA, Robert ME, et al. Spectrum of histologic changes in colonic biopsies in patients treated with mycophenolate mofetil. Mod Patho!. 2009;22(6) : 73 7-743 . 49 . Al-Absi AI , Cooke CR, Wall BM, et al . Patterns of inj ury in mycophenolate mofetil-related coli­ tis . Transplant Pmc. 2 0 1 0 ;42(9) : 3 5 9 1-3 5 9 3 5 0 . Lee S , de B o e r WB, Subramaniam K, et al. Pointers a n d pitfalls of mycophenolate-associated colitis . ] Clin Patho!' 2 0 1 3 ;66( 1 ) : 8- 1 1 . 5 1 . Papadimitriou J C , Cangro C B , Lustberg A , e t al. Histologi c features o f mycophenolate mofetil-related colitis : A graft-versus-host disease-like pattern. Int ] SLlrg Patho!. 2 0 0 3 ; 1 1 (4) : 2 9 5-302 .

5 MALL

BOWE L

301

302

AT LAS

0 F

GAST R0 I NT EST I N A L

PAT H O LOGY

5 2 . Wu T, Abu-Elmagd K, Bond G, et al. A schema for histologic grading of small intestine allograft acute rej ection. Transplantation. 2003 ; 7 5 (8) : 1 24 1 - 1 248. 5 3 . Wu T, Bond G, Martin D , et al. Histopathologic characteristics of human intestine allograft acute rej ection in patients pretreated with thymoglobulin or alemtuzumab . Am ] Gastroentero!' 2006; 1 0 1 (7) 1 6 1 7- 1 624. 54. White FY, Reyes J , Jaffe R, et al . Pathology of intestinal transplantation in children . Am ] Surg Patho!. 1 995 ; 1 9(6) 687-698 5 5 . Lee RG, Nakamura K, Tsamandas AC, et al. Pathology of human intestinal transplantation . Gastroenterology. 1 9 9 6 ; 1 1 0(6) : 1 820- 1 834. 5 6 . Berthrong M , Faj ardo LF Radiation inj ury in surgical pathology Part II. Alimentary tract. Am ] Surg Patho!. 1 9 8 1 ;5(2) : 1 5 3- 1 78 . 5 7 . Panis Y, Poupard B , Nemeth J , e t al. Ileal pouch/anal anastomosis for Crohn's disease . Lancet. 1 99 6 ; 347(9005) 854-8 5 7 . 5 8 . Colombel J F, Ricart E , Loftus E V Jr, e t a l . Management of Crohn's disease of the ileoanal pouch with infliximab . Am ] Gastroentero!' 2003;98( 1 0) : 2239-2244 . 5 9 . Hartley JE, Fazio vw, Remzi FH, et al. Analysis of the outcome ;o f ileal pouch-anal anastomosis in patients with Crohn's disease. Dis Colon Rectum. 2004;47( 1 1 ) : 1 808- 1 8 1 5 . 6 0 . Fonkalsrud EW Endorectal ileoanal anastomosis with isoperistaltic ileal reservoir after colec­ tomy and mucosal proctectomy Ann Surg. 1 9 84 ; 1 99(2) : 1 5 1- 1 5 7 . 6 1 . Lohmuller J L , Pemberton JH, Dozois RR, e t a l . Pouchitis and extra intestinal manifestations o f inflammatory bowel disease after ileal pouch-anal anastomosis . Ann Surg. 1 99 0 ; 2 1 1 (5 ) : 622627; discussion 7-9 . 6 2 . Mignon M , Stettler C , Phillips SF Pouchitis-a poorly understood entity Dis Colon Rectum. 1 995 ; 3 8 ( 1) 1 00- 1 03 6 3 . Romanos J , Samarasekera D N , Stebbing JF, et al. Outcome of 200 restorative proctocolectomy operations : The John Radcliffe Hospital experience . Br] Surg. 1 9 9 7 ;84(6) : 8 1 4-8 1 8 . 6 4 . Stahlberg D , Gullberg K, Liljeqvist L , e t al. Pouchitis following pelvic pouch operation for ulcerative colitis. Incidence, cumulative risk, and risk factors. Dis Colon Rectum. 1 996;39(9) : 1 0 1 2-1 0 1 8 . 6 5 . Becker JM, Stucchi AF Treatment of choice for acute severe steroid-refractory ulcerative colitis is colectomy Inflamm Bowel Dis. 2009 ; 1 5 ( 1 ) 146-149 66. Hahnloser D , Pemberton JH, Wolff BG, et al. Results at up to 20 years after ileal pouch-anal anastomosis for chronic ulcerative colitis . Br] Surg. 2007 ;94(3) : 333-340. 6 7 . Merrett MN , Mortensen N, Kettlewell M , et al. Smoking may prevent pouchitis in patients with restorative proctocolectomy for ulcerative colitis . Gut. 1 99 6 ; 3 8 (3) : 3 62-364. 68. Penna C , Dozois R, Tremaine W, et al. Pouchitis after ileal pouch-anal anastomosis for ulcerative colitis occurs with increased frequency in patients with associated primary scleroSing cholangi­ tis . Gut. 1 996;38(2) : 234-2 3 9 . 6 9 . Yantiss RK, Sapp HL, Farraye FA, et a l . Histologic predictors o f pouchitis i n patients with chronic ulcerative colitis . Am ] Surg Patho!. 2004;2 8(8) : 9 9 9- 1 006. 7 0 . de Silva HJ , Millard PR, Soper N , et al. Effects of the faecal stream and stasis on the ileal pouch mucosa. Gut. 1 9 9 1 ; 32 ( 1 0) : 1 1 66- 1 1 69 . 7 1 . Nasmyth D G , Johnston D , Godwin P G , e t al. Factors influencing bowel function after ileal pouch-anal anastomosis . Br] Surg. 1 9 8 6 ; 73 (6) :469-4 7 3 . 7 2 . Coukos J A , Howard LA, Weinberg J M , et al. ASCA I g G a n d C B i r antibodies a r e associated with the development o f Crohn's disease and fistulae following ileal pouch-anal anastomosis . Dig Dis Sci. 2 0 1 2 ; 5 7 (6) 1 544- 1 5 5 3 . 73 . d e Silva HJ , Millard P R , Kettlewell M , et a l . Mucosal characteristics o f pelviC ileal pouches. Gut. 1 9 9 1 ; 32 ( 1 ) : 6 1-65 74. Shepherd NA, Healey Cj , Warren BF, et al. Distribution of mucosal pathology and an assessment of colonic phenotypic change in the pelvic ileal reservoir. Gut. 1 9 9 3 ;34( 1 ) : 1 0 1- 1 0 5 . 7 5 . McLaughlin S D , Clark S K , Bell AJ , et a l . Incidence and short-term implications o f prepouch ileitis following restorative proctocolectomy with ileal pouch-anal anastomosis for ulcerative colitis. Dis Colon Rectum. 2009 ; 5 2 (5) : 8 79-883. 7 6 . McLaughlin SD, Clark SK, Bell AJ , et al. An open study of antibiotics for the treatment of pre­ pouch ileitis following restorative proctocolectomy with ileal pouch-anal anastomosis. Aliment Pharmacal Ther. 2 0 0 9 ; 29 ( 1 ) : 69-74 .

C h a pte r 3

77. Agarwal S, Stucchi AF, Dendrinos K, et al. Is pyloric gland metaplasia in ileal pouch biopsies a marker for Crohn's disease Wig Dis Sci. 2 0 1 3 ; 5 8 ( 0) : 2 9 1 8-292 5 . 7 8 . Kalach N , Huvenne H , Gosset P, et al. Eosinophil counts i n upper digestive mucosa of Western European children: Variations with age , organs, symptoms , Helicobacter pylon status, and patho­ logical findings . ] Pediatr Gastroenterol Nutr. 2 0 1 1 ; 5 2 (2) 1 75- 1 8 2 7 9 . Lowichik A, Weinberg A G . A quantitative evaluation of mucosal eosinophils i n the pediatric gastrointestinal tract. Mod Pathol. 1 99 6 ; 9(2) : 1 1 0- 1 1 4 . 8 0 . Challacombe D N , Wheeler EE, Campbell PE. Morphometric studies and eosinophil cell counts in the duodenal mucosa of children with chronic nonspecific diarrhoea and cow's milk allergy. ] Pediatr Gastroenterol Nutr. 1 9 8 6 ; 5 (6) : 887-89 1 . 8 1 . Gonsalves N . Food allergies and eosinophilic gastrointestinal illness . Gastroenterol Clin North Am. 2 0 0 7 ;36( 1 ) 75-9 1 , vi. 8 2 . Maluenda C, Phillips AD , Briddon A, et al. Quantitative analysis of small intestinal mucosa in cow's milk-sensitive enteropathy. ] Pediatr Gastroenterol Nutr. 1 984;3(3) : 349-3 5 6 . 8 3 . Pratt CA, Demain J G , Rathkopf M M . Food allergy and eosinophilic gastrointestinal disorders : Guiding our diagnosis and treatment . CUlT Probl Pediatr Adolesc Health Care. 2 0 0 8 ; 3 8(6) : 1 70- 1 8 8 . 8 4 . Walker M M , Salehian S S , Murray C E , e t a l . Implications of eosinophilia i n the normal duo­ denal biopsy - an association with allergy and functional dyspepsia . Aliment Pharmacol Ther. 2 0 1 0 ;3 1 ( 1 ) 1 2 29- 1 2 3 6 8 5 . Goldstein N S . N on-gluten sensitivity-related small bowel vi.llous flattening with increased intraepithelial lymphocytes : Not all that flattens is celiac sprue. Am ] Clin Pathol. 2004 ; 1 2 1 (4) 546-5 5 0 8 6 . Biagi F, Luinetti 0 , Campanella J , et a l . Intraepithelial lymphocytes i n the villous tip : Do they indicate potential coeliac disease? ] Clin Pathol. 2004;5 7(8) : 83 5-839 . 8 7 . Jarvinen TT, Collin P, Rasmussen M , e t al. Villous tip intraepithelial lymphocytes a s markers o f early-stage coeliac disease . Scand] Gastroenterol. 2004;39(5) :428-433 88. Veress B , Franzen L, Bodin L, et al. Duodenal intraepithelial lymphocyte-count revisited. Scand ] Gastroenterol. 2004;39(2) : 1 38- 1 44 . 8 9 . Oberhuber G, Granditsch G , Vogelsang H . The histopathology o f coeliac disease : Time for a standardized report scheme for pathologists . Eur ] Gastroenterol Hepato!. 1 9 9 9 ; 1 1 ( 0) : 1 1 8 5- 1 1 94. 9 0 . Goldstein JL, Eisen GM, Lewis B , et al. Video capsule endoscopy to prospectively assess small bowel inj ury with celecoxib , naproxen plus omeprazole , and pl.acebo. Clin Gastroenterol Hepatol. 2005 ;3(2) 1 3 3- 1 4 1 . 9 1 . Rubio-Tapia A , Herman ML, Ludvigsson JF, e t al . Severe sprue like enteropathy associated with olmesartan. Mayo Clin Proc. 2 0 1 2 ; 8 7 (8) : 732-738 92. Genta RM , Kinsey RS , Singhal A , et al . Gastric foveolar metaplasia and gastric heteroto­ pia in the duodenum: No evidence of an etiologic role for Helicobacter pylon. Hum Patho!. 2 0 1 0 ;4 1 ( 1 1 ) 1 5 93- 1 60 0 . 9 3 . Lappinga PJ , Abraham S C , Murray J A , et al. Small intestinal bacterial overgrowth : Histo­ pathologic features and clinical correlates in an underrecognized entity. Arch Pathol Lab Med. 2 0 1 0 ; 1 34(2) 2 64-2 70 94. Haboubi NY, Lee GS, Montgomery RD . Duodenal mucosal morphometry of elderly patients with small intestinal bacterial overgrowth: Response to antibiotic treatment. Age Ageing. 1 9 9 1 ; 2 0 0 ) 29-32 9 5 . Dukowicz AC, Lacy BE, Levine GM . Small intestinal bacterial overgrowth: A comprehensive review. Gastroenterol Hepatol (N Y) 2007 ;3(2) : 1 1 2- 1 2 2 . 9 6 . Fasano A , Berti I , Gerarduzzi T , et a l . Prevalence of celiac disease i n at-risk and not-at-risk groups in the United States: A large multicenter study. Arch Intern Med. 2 0 03 ; 1 63(3) : 2 86-292 97. Dube C , Rostom A, Sy R, et al. The prevalence of celiac disease in average-risk and at-risk West­ ern European populations : A systematic review. Gastroenterology. 2005 ; 1 2 8(4 suppl 1 ) : S5 7-S6 7 . 9 8 . Freeman HJ . PEARLS &: PITFALLS i n the diagnosis of adult celiac disease. Can ] Gastroentero!' 2008;22(3) 2 73-280 9 9 . Murray JA, Watson T, Clearman B , et al. Effect of a gluten-free diet on gastrointestinal symptoms in celiac disease. Am ] Clin Nutr. 2004;79(4) : 669-673 .

5 M ALL

BOWE L

303

304

ATLAS

0 F

GAST R0 I N T ESTI N A L

PAT H O LOGY

1 00 . Rostom A, Murray JA, Kagnoff MF American Gastroenterological Association (AGA) Insti­ tute technical review on the diagnosis and management of celiac disease . Gastroenterology. 2006 ; 1 3 1 (6) 1 9 8 1-2 0 0 2 . 1 0 1 . Rubio-Tapia A , Hill lD, Kelly CP, et a1. A C G clinical guidelines : Diagnosis and management of celiac disease. Am ] Gastroenterol. 2 0 1 3 ; 1 08(5 ) : 6 5 6-6 76. 1 02 . Burgin-Wolff A, Gaze H , Hadziselimovic F, et a1. Antigliadin and antiendomysium antibody determination for coeliac disease. Arch Dis Child. 1 99 1 ; 66(8) : 9 4 1 -947. 1 03 . Chorzelski TP, Beumer EH, Sulej J , et a1. IgA anti-endomysium antibody. A new immunological marker of dermatitis herpetiformis and coeliac disease. Br] Dermatol. 1 984 ; 1 1 1 (4) : 3 9 5-402 . 1 04 . Ferreira M , Davies SL, Butler M , e t a1. Endomysial antibody: I s i t the best screening test for coeliac disease? Gut. 1 9 9 2 ; 33 ( 1 2) : 1 63 3- 1 6 3 7 1 0 5 . Grodzinsky E , H e d J , Skogh T . IgA antiendomysium antibodies have a high pOSitive predictive value for celiac disease in asymptomatic patients . Allergy. 1 9 94;49 (8) : 5 93-5 9 7 1 0 6 . Kumar V, Lerner A, Valeski JE, et a 1 . Endomysial antibodies i n the diagnosis of celiac disease and the effect of gluten on antibody titers . Immunol Invest. 1 9 89 ; 1 8 ( 1 -4) : 5 3 3-544. 1 0 7 . Sulkanen S, Halttunen T, Laurila K, et a1. Tissue transglutaminase autoantibody enzyme-linked immunosorbent assay in detecting celiac disease. Gastroenterology. 1 9 9 8 ; 1 1 5 (6) : 1 322- 1 3 2 8 . 1 0 8 . Husby S , Koletzko S , Korponay-Szabo I R , e t a 1 . European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease . ] Pediatr Gastroenterol Nutr 2 0 1 2 ; 54( 1 ) 1 3 6- 1 60 1 09 . Conrad K, Roggenbuck D , lttenson A, et a1 . A new dot immunoassay for simultaneous detection o f celiac specific antibodies and IgA-deficiency. Clin Chem Lab Med. 2 0 1 2 ; 50(2) : 3 3 7-343 1 1 0 . McGowan KE , Lyon ME, Loken SD, et a1. Celiac disease: Are endomysial antibody test results being used appropriately? Clin Chem. 200 7 ; 5 3 ( 1 0 ) : 1 775-1 78 1 . 1 1 1 . Kim CY, Quarsten H , Bergseng E , et al. Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease . Proc Natl Acad Sci U S A. 2004 ; 1 0 1 ( 1 2) 4 1 75-4 1 79 . 1 1 2 . Lundin KE , GJ ensen HA, Scott H , e t a1. Function of D Q 2 and D Q 8 a s HLA susceptibility mol­ ecules in celiac disease . Hum Immunol. 1 994;4 1 ( 1 ) : 24-2 7 . 1 1 3 . Paulsen G, Lundin KE , Gj ensen HA, e t al. HLA-DQ2-restricted T-cell recognition of gluten­ derived pep tides in celiac disease . Influence of amino acid substitutions in the membrane distal domain of DQ beta 1 * 0 20 1 . Hum Immunol. 1 9 9 5 ;42(2) 145- 1 5 3 1 1 4. Sollid LM , Markussen G, Ek J , et a 1 . Evidence for a primary association of celiac disease t o a particular HLA-DQ alphalbeta heterodimer. ] Exp Med. 1 9 89 ; 1 69 ( 1 ) : 345-3 5 0 . 1 1 5 . SoUid LM , Thorsby E . The primary association of celiac disease t o a given HLA-D Q alphalbeta heterodimer explains the divergent HLA-DR associations observed in various Caucasian popula­ tions . Tissue Antigens. 1 99 0 ; 36(3) 1 3 6- 1 3 7 . 1 1 6 . Hadithi M , von Blomberg B M , Crusiu s J B , e t a 1 . Accuracy of serologic tests and HLA-DQ typing for diagnOSing celiac disease. Ann Intern Med. 200 7 ; 1 47(5): 294-302 1 1 7 . Lebwohl B , Kapel RC, Neugut AI , et a1. Adherence to biopsy guidelines increases celiac disease diagnosis . Gastrointest Endosc. 2 0 1 1 ; 74( 1 ) : 1 03- 1 09 . 1 1 8 . Bonamico M , Thanasi E , Mariani P, e t a1. Duodenal bulb biopsies in celiac disease : A multicenter study. ] Pediatr Gastroenterol Nutr 2008 ;47(5) : 6 1 8-62 2 . 1 1 9 . Evans KE , Aziz I , Cross S S , et a 1 . A prospective study of duodenal bulb biopsy i n newly diag­ nosed and established adult celiac disease . Am ] Gastroenterol. 20 1 1 ; 1 06( 1 0) : 1 83 7- 1 742 . 1 2 0 . Gonzalez S , Gupta A, Cheng J , et a1. Prospective study of the role of duodenal bulb biopsies in the diagnosis of celiac disease . Gastrointest Endosc. 2 0 1 0 ; 72 (4) : 75 8-765 . 1 2 1 . Harris LA, Park JY, Voltaggio L, et a1. Celiac disease : Clinical, endoscopiC , and histopathologic review. Gastrointest Endosc. 2 0 1 2 ; 76(3) : 62 5-640. 122. Shah VH, Rotterdam H , Kotler DP, et a1. All that scallops is not celiac disease . Gastrointest Endosc. 2 0 00 ; 5 1 (6) : 7 1 7-72 0 . 1 2 3 . Cellier C , Delabesse E , Helmer C , et a l . Refractory spru e , coeliac disease, a n d enteropathy­ associated T-cell lymphoma . French Coeliac Disease Study Grou p . Lancet. 2 0 0 0 ; 3 5 6(92 2 5 ) : 2 03-2 0 8 . 1 2 4 . Malamut G, Afchain P, Verkarre V, e t a 1 . Presentation and long-term follow-up of refractory celiac disease: Comparison of type I with type I I . Gastroenterology. 2009 ; 1 3 6( 1 ) : 8 1 -9 0 .

Ch a pte r 3

1 2 5 . Sieniawski M, Angamuthu N, Boyd K, et al. Evaluation of enteropathy-associated T-cell lym­ phoma comparing standard therapies with a novel regimen including autologous stem cell transplantation. Blood. 2 0 1 0 ; 1 1 5 ( 1 8) : 3664-3 670 . 1 2 6 . Chandesris M O , Malamut G, Verkarre V, et al. Enteropathy-associated T-cell lymphoma: A review on clinical presentation, diagnosis, therapeutic strategies and perspectives. Gastroenterol Clin BioI. 2 0 1 0 ; 34( 1 ) 5 9 0-605 127. Corazza GR, Villanacci V, Zambelli C, et al. Comparison of the interobserver reproducibility with different histologiC criteria used in celiac disease. Clin Gastroenterol Hepatol. 2 0 0 7 ; 5 (7) : 838-843 . 1 2 8 . Goldstein N S , Underhill ] . Morphologic features suggestive of gluten sensitivity in architectur­ ally normal duodenal biopsy specimens . Am ] Clin Patho/. 200 1 ; 1 1 60 ) 63-7 1 . 1 2 9 . Green PH, Rostami K , Marsh MN. Diagnosis o f coeliac disease. Best Pract Res Clin Gastroentero/. 2005 ; 1 9(3) 389-400 1 3 0 . Pellegrino S, Villanacci V, Sansotta N, et al. Redefining the intraepithelial lymphocytes threshold to diagnose gluten sensitivity in patients with architecturally normal duodenal histology Aliment Pharmacal Ther 20 1 1 ; 3 3 (6) : 69 7-706 1 3 1 . Mino M , Lauwers GY. Role of lymphocytic immunophenotyping in the diagnosis of gluten-sen­ sitive enteropathy with preserved villous architecture . Am] Surg Pathol. 2003;27(9) : 1 23 7- 1 242 . 1 3 2 . Moran C] , Kolman OK, Russell GJ , et al. Neutrophilic infiltration in gluten-sensitive enteropa­ thy is neither uncommon nor insignificant: Assessment of duodenal biopsies from 267 pediatric and adult patients . Am] Surg Fathol. 20 1 2 ;36(9) : 1 339-1 345 1 3 3 . Hudacko R, Kathy Zhou X, Yantiss RK. Immunohistochemical stains for CD3 and CD8 do not improve detection of gluten-sensitive enteropathy in duodenal biopsies. Mod Pathol. 2 0 1 3 ;2 6(9) 1 2 4 1 - 1 245. 1 3 4 . Rujner J , Socha J , Romanczuk W, et al. [ Individual sensitivity of j ej unal mucosa to small doses of gluten in coeliac disease] Wiad Len. 2002 ; 5 5 (9- 1 0 ) 5 54-5 60 1 3 5 . Ansaldi N, Tavassoli K, Faussone D, et al. [ Clinico-histological behavior of celiac patients after gluten load following the definitive diagnosis] Pediatr Med Chir 1 9 88 ; 1 00 ) : 3-6 . 1 3 6 . Leffler D , Schuppan D, Pallav K, et al. Kinetics of the histological , serological and symptomatic responses to gluten challenge in adults with coeliac disease . Gut. 2 0 1 3 ; 62(7) : 9 9 6- 1 004. 1 3 7 . Parker SL, Leznoff A, Sussman GL, et al. Characteristics of patients with food-related com­ plaints . ] Allergy Clin Immunol. 1 9 9 0 ; 86(4 pt 1 ) 5 03-5 1 1 1 3 8 . Walker-Smith ] . Cow's milk allergy: A new understanding from immunology. Ann Allergy Asthma Immunol. 2003 ;90(6 suppl 3) 8 1-83 1 3 9 . Phillips AD , Rice SJ , France NE, et al. Small intestinal intra epithelial lymphocyte levels in cow's milk protein intolerance . Gut. 1 9 79 ;20(6) : 5 09-5 1 2 . 1 4 0 . Cook Gc. Aetiology and pathogeneSiS o f postinfective tropical malabsorption (tropical sprue) . Lancet. 1 984; 1 (8379) : 72 1-723 1 4 1 . Tomkins AM , Drasar BS, James WP Bacterial colonisation of j ejunal mucosa in acute tropical sprue Lancet. 1 9 75 ; 1 (7898) : 5 9-62 . 1 4 2 . Walker MM. What is tropical sprue! ] Gastroenterol Hepatol. 2003 ; 1 8(8) : 88 7-8 9 0 . 1 4 3 . Washington K, Stenzel TT, Buckley RH , et al. Gastrointestinal pathology i n patients with common variable immunodefiCiency and X-linked agammaglobulinemia. Am ] Surg Patho/. 1 9 9 6 ; 2 0 ( 0) 1 240- 1 2 5 2 . 1 44. Daniels J A , Lederman HM, Maitra A, et a l . Gastrointestinal tract pathology i n patients with common variable immunodeficiency (CVID) : A clinicopathologic study and review. Am ] Surg Patho/. 2 0 0 7 ; 3 1 ( 1 2) 1 800- 1 8 1 2 1 45 . Gentile N M , Murray JA, Pardi D S . Autoimmune enteropathy: A review and update o f clinical management . CUff Gastroenterol Rep. 20 1 2 ; 1 4( 5 ) : 380-385 . 1 4 6 . Akram S , Murray JA, Pardi D S , et al. Adult autoimmune enteropathy: Mayo clinic rochester experience. Clin Gastroenterol Hepatol. 2 0 0 7 ; 5 ( 1 1 ) : 1 282- 1 2 9 0 ; quiz 45 . 1 4 7 . Montalto M , D'Onofrio F, Santoro L, et al. Autoimmune enteropathy in children and adults . Scand ] Gastroenterol. 2009 ;44(9) : 1 029- 1 0 3 6 . 1 4 8 . Moes N , Rieux-Laucat F, Begue B , et al. Reduced expression of FOXP3 a n d regulatory T-cell function in severe forms of early-onset autoimmune enteropathy Gastroenterology. 20 1 0 ; 1 39(3) : 770-778

S M A LL

B OWE L

305

306

AT LAS

0 F

GAST R0 I N T E S T I N A L

PAT H O LOGY

1 49 . Gopal P, McKenna BJ . The collagenous gastroenteritides: Similarities and differences. Arch Pathol Lab Med. 20 1 0 ; 1 34( 1 0) 1485- 1 489 1 5 0 . Maguire AA, Greenson JK, Lauwers GY, et a!. Collagenous sprue: A clinicopathologic study of 1 2 cases. Am ] Surg Pathol 2009 ; 3 3 ( 1 0) : 1 440- 1 449 . 1 5 1 . Maiwald M, Schuhmacher F, Ditton HJ , et a!. Environmental occurrence of the Whipple's disease bacterium (Tropheryma whippelii) . Appl Environ Microbiol 1 9 9 8 ; 64(2) : 760-762 1 5 2 . Gross M, Jung C , Zoller WG. Detection of Tropheryma whippelii DNA (Whipple's disease) in faeces. ftal ] Gastroenterol Hepatol 1 9 9 9 ; 3 1 0 ) : 70-72 . 1 5 3 . Schbniger-Hekele M, Petermann D , Weber B, et al. Tropheryma whipplei in the environ­ ment : Survey of sewage plant influxes and sewage plant workers . Appl Environ Microbiol 2 0 0 7 ; 73( 6) : 2033-2035 . 1 54 . Arnold CA, Moreira RK, Lam-Himlin D , et al. Whipple disease a century after the initial descrip­ tion: Increased recognition of unusual presentations , autoimmune comorbidities , and therapy effects . Am ] Surg Pathol 20 1 2 ; 3 6(7) 1 066- 1 073 1 5 5 . Maizel H , Ruffin J M , Dobbins WO 3 rd . Whipple's diseas e : A review o f 19 patients from one hospital and a review of the literature since 1 9 5 0 . Medicine (Baltimore) . 1 9 7 0 ;4 9 ( 3 ) : 1 7 5-2 0 5 . 1 5 6 . von Herbay A, Ditton HJ , Maiwald M. Diagnostic application of a polymerase chain reaction assay for the Whipple's disease bacterium to intestinal biopsies. Gastroenterology. 1 99 6 ; 1 1 0(6) : 1 7351 74 3 . 1 5 7 . v o n Herbay A, Maiwald M , Ditton HJ , et a l . Histology of intestinal Whipple's disease revisited. A study of 48 patients . Virchows A rch. 1 9 9 6 ;429(6) : 3 3 5-343 . 1 5 8 . Waldmann TA, Steinfeld JL, Dutcher TF, et al. The role of the gastrointestinal system in "idio­ pathiC hypoproteinemia . " Gastroenterology. 1 96 1 ;4 1 : 1 9 7-2 0 7 . 1 5 9 . Vignes S , Bellanger J . Primary intestinal lymphangiectasia (Waldmann's disease) . Orphanet] Rare Dis. 2008 ; 3 : 5 . 1 60 . Jeffries GH , Chapman A, Sleisenger M H . Low-fat diet i n intestinal lymphangiectasia. Its effect on albumin metabolism. N Engl ] Med. 1 964 ; 2 7 0 : 7 6 1-766. 1 6 1 . Freeman HJ , Nimmo M . Intestinal lymphangiectasia in adults . World ] Gastrointest Oncol 20 1 1 ;3(2) : 1 9-23 1 6 2 . Kim JH, Bak YT, Kim JS, et al. Clinical significance of duodenal lymphangiectasia incidentally found during routine upper gastrointestinal endoscopy. Endoscopy. 2009 ;4 1 (6) : 5 1 0-5 1 5 . 1 6 3 . Wolff M . HeterotopiC gastriC epithelium i n the rectum: A report o f three new cases with a review of 87 cases of gastric heterotopia in the alimentary canal. Am] Clin Pathol 1 9 7 1 ; 5 5 ( 5 ) : 604-6 1 6 . 1 64 . Hoedemaeker PJ . HeterotopiC gastriC mucosa in the duodenum. Digestion. 1 9 70 ;3(3): 1 65- 1 73 . 1 6 5 . Lessells AM , Martin D F Heterotopic gastric mucosa i n the duodenum. ] Clin Pathol 1 9 8 2 ; 3 5 (6) 59 1-595 166. Conlon N , Logan E , Veerappan S , et al. Duodenal gastriC heterotopia : Further evidence o f an association with fundic gland polyps. Hum Patho!. 2 0 1 3 ;44(4) :636-642. 167. De Castro Barbosa JJ , Dockerty MB, Waugh JM. Pancreatic heterotopia ; review of the literature and report of 4 1 authenticated surgical cases , of which 25 were clinically significant. Surg Gyne­ col Obstet. 1 946;82 : 5 2 7-542 . 1 68 . Trifan A, n,rcoveanu E , Danciu M , et al. Gastric heterotopiC pancreas : An unusual case and review of the literature . ] Gastrointestin Liver Dis. 2 0 1 2 ; 2 1 (2 ) : 209-2 1 2 . 1 6 9 . Jiang LX, Xu J , Wang Xw, e t al. Gastric outlet obstruction caused by heterotopic pancreas : A case report and a quick review. World ] Gastroenterol 2008 ; 1 4(43) : 6 7 5 7-67 5 9 . 1 70 . Gaspar Fuentes A, Campos Tarrech JM, Fernandez Burgui J L , e t a l . [Pancreatic ectopiasl . Rev Esp Enferm Apar Dig. 1 9 7 3 ; 39 (3) : 2 5 5-2 6 8 . 1 7 1 . Emerson L, Layfield LJ , Rohr L R , et al. Adenocarcinoma arising i n association with gastric het­ erotopic pancreas: A case report and review o f the literature . ] Surg Oncol 2004 ; 8 70 ) : 5 3-5 7 . 1 72 . Yan M L , Wang YD , Tian Y F, et a l . Adenocarcinoma arising from intrahepatic heterotopic pan­ creas : A case report and literature review. World ] Gastroenterol 20 1 2 ; 1 8(22) : 288 1-2884. 1 73 . Plaut AG. Trefoil peptides in the defense of the gastrointestinal tract . N Engl ] Med. 1 9 9 7 ; 336(7) 5 06-5 0 7

C h a pte r 3

1 74 . Wright NA, Pike CM, Elia G. Ulceration induces a novel epidermal growth factor-secreting cell lineage in human gastrointestinal mucosa. Digestion. 1 990;46(suppI 2) : 1 2 5- 1 3 3 . 1 7 5 . Koukoulis GK, K e Y, Henley J D , e t al. Detection of pyloric metaplasia may improve the biopsy diagnosis of Crohn's ileitis. ] Clin Gastroenterol. 2002 ;34(2) 1 4 1-143 . 1 7 6 . Rashid OM, Ku JK, Nagahashi M, et al. Inverted Meckel's diverticulum as a cause of occult lower gastrointestinal hemorrhage . World ] Gastroenterol. 20 1 2 ; 1 8(42) : 6 1 5 5-6 1 5 9 . 1 77 . Soderlund S . Meckel's diverticulum i n children; a report of 1 1 5 cases . Acta Chir Scand. 1 9 5 6 ; 1 1 0(4) 26 1-274 1 78 . Park JJ, Wolff BG, Tollefson MK, et al. Meckel diverticulum: The Mayo clinic experience with 1 476 patients ( 1 95 0-2 002) . Ann Surg. 2005 ; 2 4 1 (3) 529-5 3 3 . 1 79 . Shepherd N A , Crocker P R , Smith A p, et a l . Exogenous pigment i n Peyer's patches . Hum Pathol. 1 9 8 7 ; 1 8 ( 1 ) 5 0-54 1 80 . Sauntry JP, Knudtson KP A technique for marking the mucosa of the gastrointestinal tract after polypectomy Cancer 1 9 5 8 ; 1 1 (3) : 607-6 1 0 1 8 1 . Trakarnsanga A, Akaraviputh T EndoscopiC tattooing o f colorectal lesions : I s i t a risk-free procedure? World ] Gastrointest Endosc. 2 0 1 1 ;3 ( 1 2) 2 5 6-2 60. 182. Bisordi WM , Kleinman MS. Melanosis duodeni. Gastrointest Endosc. 1 9 7 6 ; 2 3 ( 1 ) : 3 7-38 . 1 8 3 . Cantu JA, Adler D G . Pseudomelanosis duodeni . Endoscopy. 2005 ;3 7(8) 789 1 84 . Rex DK, Jersild RA. Further characterization of the pigment in pseudomelanosis duodeni in three patients . Gastroenterology. 1 98 8 ; 9 5 ( 1 ) : 1 7 7- 1 8 2 . 1 8 5 . Fernando S S . Pseudomelanosis duodeni : A case report with electron-probe X-ray analysis . Pathology. 1 99 0 ; 2 2 (3) 1 69- 1 72 1 8 6 . Giusto D, Jakate S . Pseudomelanosis duodeni: Associated with multiple clinical conditions and unpredictable iron stainability - a case series. Endoscopy. 2008 ;40(2) : 1 65- 1 6 7 . 1 8 7 . d e Magalhaes Costa M H , Fernandes Pegado Mda G, Vargas C , e t al. Pseudomelanosis duodeni associated with chronic renal failure . World ] Gastroenterol. 20 1 2 ; 1 8( 1 2) : 1 4 1 4- 1 4 1 6 . 1 88 . Holmes EJ Remarks o n further properties of formalin pigment. Arch Dermatol. 1 9 7 1 ; 1 03(5): 565-566. 189. Zhou C , Gilbert JD, Yool A , et al. Basal epithelial formalin pigment deposition in the kidneys-a useful marker for ketoacidosis at autopsy ] Forensic Leg Med. 2 0 1 3 ;20(4) : 305-3 0 7 . 1 9 0 . Nissapatorn V, Sawangj aroen N . Parasitic infections i n HIV infected individuals : Diagnostic & therapeutic challenges Indian ] Med Res. 2 0 1 1 ; 1 34(6) : 878-897 1 9 1 . Bhaijee F, Subramony C , Tang SJ , et al . Human immunodefiCiency virus-associated gastrointes­ tinal disease: Common endoscopic biopsy diagnoses. Patholog Res Int. 2 0 1 1 ; 20 1 1 : 24792 3 . 1 9 2 . Prasertbun R, Sukthana Y , Popruk S . Real-time PCR: Benefits for detection of mild and asymp­ tomatic giardia infections . Trop Med Health. 2 0 1 2 ;40(2) : 3 1-3 5 .

S M A LL

B OWE L

307

CHAPTER OUTLINE The U n re m a r k a b l e C o l o n Foca l Active C o l itis Pattern •

• • • • • •

Acute Self- l i m ited Col itis • I nfection • M ed i cation • C h e m i c a l s or I rrita nts I nfla m m atory Bowe l D i se a se I sch e m i c C o l itis I rrita b l e Bowe l Syn d ro m e Antibiotic- a ssoci ated Colitis N o n stero i d a l Anti - i n fl a m m atory Dr u g s Bowel Preparatory Artifa ct

Acute C o l itis Patte r n • • •

I nfect i o n M ed i cation I nf l a m m atory Bowe l D i sease

I sc h e m i c Co l it i s Pattern • • •

I sch e m i a I nfect i o n M e d i cation

Pse u d o m e m b r a n o u s Pattern • •

I sch e m i a Clostridium difficile Co l itis and Oth e r I nfect i o n s

C h ro n i c C o l it i s Pattern • • • •

• • •

I nf l a m matory Bowel D i sease Diverticula r D i sease D ivers i o n -a ssoci ated Colitis Syp h ilitic and Lym p h o g ra n u l o m a Ve nere u m Proctoco l itis Cord Col itis Syndro m e I p i l i m u m ab Colitis Res i n s

Eosi n o p h i l i a Pattern • • • • • • •

I d i opath i c Eos i n o p h ilic Col itis I nf l a m m atory Bowe l D i sease All e rgy M ed i cations I nfect i o n Pa rasite Col l a g e n Va scu l ar D i so rd e r a n d Va sc u l itis

G r a n u l o m atous Pattern • • • • • • • • • • •

I nf l a m m atory Bowe l D isease N o n specific M u cosa l I nj ury D i v e rti cu l a r D i sease I nfect i o n s M ed i cation Sarcoidosis Va scu l a r I nj u ry P n e u m atosis Cysto ides I ntesti n a l i s Auto i m m u n e D i seases Cord Col itis Syndro m e Lym p h o p ro l ife rative D i s o rders

P i g m e nts a n d Extras • • • • • •

M e l a n o s i s Coli Tattoo P i g m ent Air Artifa ct P n e u m atosis Cysto ides I n testi n alis M u c i p h a g es Res i n s

Near M isses • • • • •

En d o m etriosis B e n i g n S i g n et R i n g Cell C h a n g e P u l se Gra n ulom ata Apo ptotic Colo pathy S p iroch etosis

Lym p h ocyt i c Pattern • • • •

Lym p h ocytic Colitis Colla g e n o u s C o l itis M ed i cati o n s Viral I nfecti o n

309

310

ATLAS

O F

GASTRO I NT E S T I N A L

PAT H O LOGY

TH E U N RE MARKABLE CO LO N Endoscopically, the unremarkable colon appears as homogeneous pink mucosa, but regional landmarks allow for reasonably accurate anatomic localization; for example , proximally, the ileocecal valve and appendiceal orifice identify the cecum, whereas the appearance of a tri­ angular lumen signifies entrance into the transverse colon. Moving distally, the acute bend of the splenic flexure indicates the approach of the descending colon. Further anatomic localization at the sigmoid and rectum become more difficult but is aided by luminal nar­ rowing, thickened mucosal folds , presence of diverticula , and ultimately calibration marks on the colonoscope. Histologically, the colon divides into the mucosa , submucosa , muscularis propria, and serosa (Fig. 4 . 1 ) . The mucosa is composed o f a single cell layer o f columnar cells lin­ ing colonic crypts , the investing lamina propria, and a thin underlying layer of smooth muscle-the muscularis mucosae . These mucosal crypts are oriented parallel to one another and perpendicular to the muscularis mucosae , such that crypts appear orderly and uniform, like a row of test tubes when seen on a well-oriented cross section (Figs . 4 . 2-4 . 5 ) . When

Figure 4 . 1 N o r m a l co l o n . Th is resection speci m e n i l l u strates t h e fou r m a i n layers of the co l o n : m ucosa , s u b m u cosa , m uscu l a ris p ro­ pria, and seros a . The m u cosa consists of epith e l i u m (E), l a m i n a p ro­ pria (L), and m u scu l a ris m u cosae ( M M ) . The s u b m u cosa sits between the m uscu l a ris m u cosae and the m uscu l a ris propria, and it consists of loose fi b rocon nective tissue a n d I y m p h ovascu l a r c h a n n e l s . The m uscu l a ri s p ro p ri a consists of i n n er circu l a r a n d outer l o n g itu d i n a l l y orientated m uscle fibers . T h i s is covered b y su bserosal fi b ro a d i pose tissue and the outermost serosa .

Figure 4 . 2 Test tubes in a rack, p rofi l e v iew. N o r m a l col o n i c a rch i­ tectu re is a n a logous to a p rofi l e view of test tubes i n a rack, with each test tube (or crypt) superi m posa b l e u po n its n e i g h bo r based o n u n iform size and d i stri buti o n .

Figure 4 . 3 N o rm a l col o n . A wel l-oriented co lonic sectio n i l l u strates the o rderly natu re of the co l o n i c crypts. Th ey a re eve n l y spaced a n d a rra n g e d i n p a ra l l e l , l i ke a row o f test tu bes i n a rack. T h e crypt bases extend down to a l m ost touch the m u scu l a ris m u cosa e .

C h a pter

4

COLON

31 1

cut en face, these crypt openings remain orderly and evenly spaced, providing a top-down view of test tubes in a rack or a "bed of flowers" architecture (Figs . 4 . 6 and 4 . 7) . Lining the surface epithelium is a combination of absorptive columnar cells and mucous-secreting goblet cells that may be punctuated by very rare intra epithelial eosinophils and mast cells ; neutrophils in the epithelium are never normal . By comparison, the deep crypt epithelium additionally contains Paneth cells and endocrine cells (Figs . 4 . 8 and 4 . 9 ) . These Paneth cells are normally limited to the cecum and ascending colon, and their presence distal to the transverse colon signifies metaplasia, typically due to chronic injury. Similarly, the contents of the colonic lamina propria vary depending on location . This supportive stroma contains a wide variety of cells arranged among loosely organized strands of collagen , occasional slips of smooth muscle , nerve twiglets , and small lympho­ vascular spaces that lack the potential for lymphovascular spread of tumor. 1 The cellular

F i g u re 4 . 4 N o r m a l co l o n . An i n n o m i n ate g roove i n the co l o n sh ows crypts bra n c h i n g from a centra l l u m e n ( a rrows) . T h i s is a n o r­ m a l stru ctu re in the co l o n a n d s h o u l d not be m i staken fo r the crypt d i stortion seen in chro n i c colitis.

F i g u re 4.5 N o r m a l co l o n . An i n n o m i n ate g roove i n the co l o n sh ows crypts exte n d i n g a w a y from a centra l l u m e n i n a n orderly and sym m etric fas h i o n . N ote that the backg ro u n d crypts a re evenly spaced, i n d icat i n g a l a ck of c h ro n i c i nj u ry (ch ro n icity) . This norm a l stru cture, s e e n period i ca l ly a l o n g the l e n gth o f the co l o n i c m u cosa , shou l d n ot be m ista ken for the crypt bra n c h i n g of ch ro n i c col itis.

F i g u re 4.6 Test tubes i n a rack, ta ngenti a l vi ew. When viewed from a bove, the test tubes a re s u p e r i m posa b l e u po n t h e i r n e i g h bors based on u n iform size a n d d i stri buti o n , a n a l o g o u s to a ta ngenti a l view o f n o rm a l co l o n i c a rch itecture .

Figu re 4 . 7 N o r m a l co l o n . W h e n c u t i n cross secti o n , t h e colonic crypts a p pear l i ke a n even ly spaced bed of flowers. Eve n when m a l o ri ented, or ta ngenti a l ly sectioned, the n o rm a l co l o n i c mucosa shows an o rderly d istri bution of co l o n i c crypts .

31 2

ATLAS

O F

GASTRO I N T E S T I N A L

PAT H O LOGY

Figure 4 . 8 Normal co l o n , Paneth cel l versus endocri n e ce l l . Paneth cel l s (arrowhead) a re fou n d in the crypt bases of the right and tra ns­ ve rse co lon . Their n u clei abut the basement m e m bra n e , wh i l e their coa rse, p i n k cytoplasmic g ra n u l es p o l a rize towa rd the crypt l u m e n . By com p a rison, endocri n e cel l s (arrow) a re fou n d scattered throug h­ out the crypt bases a l o n g the l e ngth of the co l o n . Th e i r n u c l e i face the l u m e n , wh i l e their fi n e , reddish cyto p l a s m i c g ra n u les abut the basement mem bra n e .

Figure 4. 1 0 N o r m a l right co l o n . The rig h t c o l o n is rich i n Paneth cel l s at the crypt bases. In additi o n , m ixed c h ro n i c infl a m m atory cells a re abundant i n the l a m i n a p ropria, i n c l u d i n g scattered eosi n o p h i ls.

Figure 4 . 9 Normal co l o n , P a n eth ce l l versus endocri n e ce l l . The P a n eth ce l l (arrowhead) conta i n s l a rg e r, coa rse, pink g ra n u l e s re l eased towa rd the crypt l u m e n , whereas t h e endocri n e ce l l (arrow) conta i n s s m a l l , fi n e , red d i s h g ra n u les re l e a sed towa rd the crypt basement m e m b ra n e . P a n eth cel l s i n the l eft co l o n s i g n ify evi d e n ce of c h ro n i c i nj u ry.

Figure 4. 1 1 N o r m a l right co l o n . The l a m i n a p ropria of the right co l o n conta i n s su bsta n ti a l n u m bers of lymphocytes, plasma ce l l s , a n d eosi n o p h i l s .

composition is predominantly lymphocytic a n d plasmacytic, with varying numbers o f eosinophils a n d mast cells . This normal complement of inflammatory cells decreases in concentration approaching the rectum; knowledge of this prevents overdiagnosis of "chronic colitis" (Figs . 4 . 1 0-4 . 1 3 ) . See also Chronic Colitis , this chapter. A rare neutrophil in the lamina propria or capillary vessel is likely insignificant. The right colon contains more absorptive cells and fewer goblet cells than the left colon, a reflection of the differing func­ tions of the right colon (to absorb excess fluid) versus the left colon (to lubricate the lumen and facilitate elimination of the luminal contents) . Muciphages, while not native inhabit­ ants , are so commonly found in the rectum that they are considered by many as normal variants . These colonic macrophages contain abundant cytoplasmic mucin from "clean up" o f nonspecific mucosal inj ury (Figs . 4 . 1 4 and 4 . 1 5) 2 ; when excessive , one might consider pathologic entities such as metabolic storage disorders or infection with Mycobacterium avium-intracellulare. See also Muciphages , Near Misses , this chapter.

C h a pte r

4

COL0 N

31 3

F i g u re 4 . 1 2 N o r m a l l eft co l o n . C o m p a red to the right c o l o n (Figs. 4. 1 0 a n d 4. 1 1 ) , the n o rm a l l eft co l o n conta i n s fewer l a m i n a propria infl a m m atory ce l ls. Alth o u g h eosi n o p h i l s m a y b e present i n t h e left co l o n , they a re fa r l ess com m o n as com p a red t o t h e right co l o n . N ote, a l so, the lack of Paneth ce l l s at the crypt bases.

F i g u re 4. 1 3 N o rm a l rectu m . The recta l l a m i n a p ropria is pauci­ ce l l u l a r a n d m o re goblet ce l l s a re seen com p a red to their density in p roxi m a l sites. Red-co l o red endocri n e ce l l s a re n o rm a l ly present throughout the co l o n , but n ote the a bsence of Paneth ce l ls i n the crypt bases.

Figure 4. 1 4 N e a r-no rm a l rect u m , m u ciphages i n the rectu m . M u ci­ phages ( a rrow) may cl uster or can be fou n d d ispersed singly i n the

F i g u re 4 . 1 5 N e a r- n o r m a l rectu m . H i g h e r m a g n ification of previ­ ous fi g u re sh ows the a m p h o ph i l i c and b u b b l y cyto p l a s m of the m u ci p h a g es .

l a m i n a p ro p ri a , p a rti c u l a rly in the rect u m . They a re a n o n specific sign of m u cosa l i nj u ry.

The cellular composition of the submucosa is similar to that of the lamina propria, but includes larger lymphovascular structures that, in contrast to those of the lamina propria, can facilitate lymphovascular spread of tumor cells . Other submucosal cells include adi­ pocytes , ganglion cells , and nerve axons , the latter two of which compose the superficial Meissner plexus and the deeper Henle's plexus. These ganglion cells are not normally pres­ ent in the mucosa , and when found there indicate prior mucosal injury. The muscularis propria surrounds the submucosa with its inner circular and outer lon­ gitudinal layers of smooth muscle, which sandwich the myenteric plexus of Auerbach . Externally, the subserosal connective tissue and the mesothelial-derived serosa encase the bowel . Sites not entirely covered by serosa include the posterior surface of the ascending and descending colon and portions of the rectum (posterior aspect of the upper third , pos­ terior and lateral aspects of the middle third , and the entire lower third) , features important for assessing radial margins in resection specimens of colonic neoplasms . Grossly visible through the serosa are the external longitudinal layers of the muscularis propria , which appear as three distinct bands , or taenia coli , on the right colon and become confluent on the left.

314

AT LA5

0 F

GAST R0 I N TEST I N A L

PAT H O LOGY

PEARLS & PITFALLS

TABLE 4.1 : D i st i n ctive Diffe r e n ce s a m o n g Reg i o n s of the Large Bowel Cecu m , Asce n d i n g , Tra n sverse Colon

• • •

D i st a l C o l o n

• •

S i g m o i d C o l o n a n d Rect u m

• • • •

Conta i n s h i g hest d e n s i ty of i n fl a m m atory c e l l s , i n c l u d i n g eosi n o p h i l s (cecu m > tra n sve rse) Conta i n s h i g h est d e n s ity o f a bso rptive c e l l s (ce c u m > tra n sverse) P a n eth ce l l s a re norm a l constitue nts of crypt base Lowe r d e n s ity of i n fl a m m ato ry ce l l s Presence o f P a n et h ce l l s i n d i cates c h ro n i c i nj u ry Typ i ca l ly conta i n s l owest d e n sity of i n fl a m m ato ry ce l l s, h i g h est d e n sity of g o b l et cel l s Presen ce o f P a n eth ce l l s i n d i cates c h ro n i c i nj u ry S l i g h t c rypt a rch itectu ra l d i stort i o n m a y be n o r m a l I n creased n u m bers o f l a m i n a p ro p r i a m u c i p h ages

FOCAL ACTIVE CO LITIS PATT E R N

F i g u re 4 . 1 6 Foca l a ctive col itis patte r n . Except fo r a n isolated col l ection of n eutro p h i l s i nvad i n g the crypt epith e l i u m (arrow), this co l o n ic biopsy a ppears essentia l ly n o rm a l ; the backg ro u n d crypts a re eve n l y spaced a n d o rderly.

Focal active colitis (FAC) is a histologic pattern characterized by single foci of neutrophilic crypt injury without features of chronic inj ury (chronicity) (Figs . 4 1 6-4 2 3 ) The pat­ tern encompasses a spectrum of histologic changes, ranging from a single crypt abscess (neutrophils in the crypt lumen) and single focus o f cryptitis (nqmophils in the crypt epithelium) to multiple discrete foci of cryptitis , or even crypt abscesses within a series o f colorectal biopsie s . 3 Segmental distribution and features o f architectural distortion

C h a pter

4

COLON

31 5

Figure 4. 1 7 Foca l a ctive co l itis patte r n . H i g h e r m a g n ification of the p revious case sh ows eve n l y spa ced a n d o rderly crypt a rch itec­ ture and an isol ated focus of acute infl a m mation in the epith e l i u m (cryptitis) ( a rrow) .

Fig u re 4 . 1 8 Foca l active colitis pattern. H i g h e r m a g n ification of the p revious case shows the s i n g l e focus of cryptitis ( a rrow) . The s u rro u n d i n g crypts a re u n affected.

Fig u re 4 . 1 9 Foca l a ctive colitis patte r n . This l ow m a g n ification emphasizes the o rderly a rch itectu re of the co l o n i c crypts. Cut i n cross sectio n , they appear l i ke an eve n ly spaced bed of flowers. A s i n g l e isol ated focus o f acute infl a m m ation ( a rrow) is p resent at the s u rface.

Fig u re 4.20 Foca l active colitis pattern . H i g h e r m a g n ifi cation of the p rev i o u s case shows a n isol ated focus of a cute i nfl a m mation ( a rrow) i n a backg ro u n d of u n re m a rka ble col o n i c m u cosa .

Fig u re 4 . 2 1 Foca l a ctive colitis patte r n . H i g h e r m a g n ification of the p revious case sh ows a sma l l neutroph i l ic a bscess at the co l o n i c s u rfa ce.

Fig u re 4 . 2 2 Foca l a ctive col itis patte r n . The low- m a g n ificatio n p h oto e m p h asizes the foca l ity o f t h e c h a n g es i n this bio psy. T h e backgro u n d co l o n i c crypts a re eve n l y spaced, a n d o n l y a s i n g l e , isol ated focus o f a cute infl a m m ation ( arrow) is present.

31 6

ATLAS

O F

GAST R O I N T E ST I N A L

PAT H O LOGY

Fig u re 4.23 Foca l a ctive col itis patte rn . H i g h e r m a g n ification of the previous case reve a l s an isol ated crypt a bscess with neutroph i l s a n d eosi n o p h i l s i n t h e crypt l u m e n (arrow) .

and chronicity are absent, by definition. Similar to most patterns , the FAC pattern does not represent a discrete disease entity, but instead represents multiple clinical prodromes that have similar histologic features. These include acute self-limited colitis, inflamma ­ tory bowel disease , ischemic colitis, irritable bowel syndrome , bowel preparation artifact, antibiotic-associated colitis (i e . , Clostridium difficile colitis) , and medication injury (i . e . , nonsteroidal anti-inflammatory drugs , NSAIDs) . Among these patients , clinically signifi­ cant diarrhea is the most common indication for colonoscopy; however, FAC is also an incidental finding in asymptomatic patients undergoing routine cancer surveillance colo­ noscopy. As a result, determining the significance of FAC requires correlation with clinical and microbiologic information.

PEARLS & PITFALLS

A d i a g n os i s of i nfl a m m atory bowe l d i se a se ( I B O) m a y be re n d e red if a d d i ti o n a l h i sto l o g i c featu res, s u c h a s m u cosa l d i stort i o n , c h ro n i c i n fl a m m a t i o n o f t h e l a m i n a p ro p ri a , o r epith e l i o i d g ra n u l o m a s a re p resent.4 Ofte n , h owever, these a d d i ti o n a l featu res a re i n suffi c i e n t l y deve l o ped to esta b l i s h a c l e a r- c u t d i a g n o s i s of I B O . A l th o u g h FAC m a y be a h a rb i n g e r t o l B O , espec i a l l y i n ch i l d re n , t h e re i s a prepon­ d e ra n ce of a cute self- l i m ited c o l itis, a n t i b i ot i c-associ ated col i t i s , and m e d i ca t i o n i nj u ry a m o n g these patients.

C H E C KLIST: Eti o l o g i c C o n s i d e rat i o n s for t h e FAC Pattern o

Acute S e l f- l i m ited C o l itis o

I nfection

o

M ed i cation

o

C h e m i ca l s or I rrita nts

o

I nfl a m m atory Bowel D isease

o

I sch e m i c Col itis

o

Irritable Bowe l Syndro m e

o

Antibioti c-Associ ated C o l itis ( Clostridium difficile Co l itis)

o

N o n stero i d a l Anti-infl a m m atory Dr u g s ( N SAI Os)

o

B owe l Pre paratory Artifa ct

C h a pter

ACUTE S ELF-LI M ITED COLITIS B y definition, acute self-limited colitis i s one that resolves i n less than 4 weeks . A n identifi­ able infectious agent is found in approximately half of cases, the most common pathogens of which are Campylabaeter jejunales, Salmonella, Shigella, and Yersinia. Clinical clues favor­ ing infectious colitis include acute onset , fever within the first week of disease onset, and at least 10 bowel movements in a 24-hour period. By contrast, the maj ority of patients eventually diagnosed with lED have a more insidious onset , lack a fever within the first week of onset , and have no more than six bowel movements in a 24-hour period . The remaining cases o f acute self-limited colitis for which stool cultures are negative are the result of viral infection, parasitic infection , medication reaction, or other chemical irritants . Histologically, biopsies show a predominantly acute inflammation restricted to the mucosa in either a patchy or diffuse fashion . Erosions , ulcerations , and neutrophilic involvement of crypt epithelium (cryptitis) and crypt lumens (crypt abscesses) may be seen, but features of chronicity (e . g . , crypt distortion , crypt dropout, crypt shortfall , increased lamina propria chronic inflammation) are absent . KEY F EATU R ES of t h e Focal Active Co l it i s Pattern : •

FAC refers to individual foci of neutrophilic inflammation in the absence of chronicity

•

The most common etiology is acute self-limited colitis .

•

•

•

Acute self-limited colitis is defined as a diarrheal illness less than 4 weeks in dura­ tion, and is most commonly attributed to infection even though half of these patients have negative stool cultures. Other associations with FAC include inflammatory bowel disease, ischemic colitis , irritable bowel syndrome , antibiotic-associated colitis , and NSAIDs. FAC in asymptomatic patients undergoing surveillance endoscopy is likely of no clinical significance and may be related to bowel preparation artifact.

ACUTE COLITIS PATT E R N

Fig u re 4 . 24 Acute col itis patte r n . Low m a g n ification revea l s a b u n ­ d a n t crypt a bscesses (arrowheads) i n a backgro u n d o f p reserved crypt a rch itect u re . By defi n it i o n , a c u te col itis l a cks fea t u res of c h ro n i c i nj u ry (ch ro n icity) .

Acute colitis describes an injury pattern similar to FAC , but more severe or diffuse, the features of which include cryptitis (acute inflammation in the crypt epithelium) (Figs . 4 . 2 4 and 4 . 2 5 ) , crypt abscesses (acute inflammation i n the crypt lumina) (Fig. 4 . 2 6 ) , erosions, and ulcerations in the absence of chroniCity This pattern of inj ury is entirely nonspeCific, but is most commonly caused by acute viral and bacterial infections , medications (NSAIDs,

4

COLON

317

31 8

AT LAS

0F

GAST R0 I NT ESTI N A L

PAT H O LOGY

Figure 4.25 Acute colitis pattern, cryptitis. N e utro p h i l s cross the basement m e m bra n e and i nfi ltrate the crypt epith e l i u m (arrows) .

Figure 4 . 26 Acute col itis patte rn, crypt a bscess. An a g g reg ate of neutro p h i l s fi l l s a crypt l u m e n , fo rm i n g a crypt a bscess.

Kayexalate , sevelamer, ipilimumab , etc . ) and emerging or partially treated inflammatory bowel disease . Although ancillary findings of lamina propria hemorrhage or fibrin deposi­ tion may be seen in acute colitis pattern , the distinctive findings of microcrypts or pseu­ domembranes raise a unique set of differential diagnoses, and are therefore discussed as separate patterns within this chapter. See also Ischemic Colitis Pattern and Pseudomem­ branous Pattern, this chapter. CH ECKLIST: Eti o l o g i c Consid erat i o n s for the Acute C o l itis Pattern o

I nfect i o n (Cyto m e g a l ovirus, Sa lmon ella, Shigella, Cam pylobacter)

o

M e d i ca t i o n ( N SA I Ds, Kayexa late, seve l a m er, i p i l i m u m ab)

o

I nfl a m m a tory B owe l Disease, e m erg i n g or parti a l ly treated

CYTO M EGALOVI R U S KEY F EATU R E S o f Cyt o m e g a l o v i r u s (CMV) Colitis: •

•

•

•

•

•

CMV colitis is most frequently seen among immunocompromised patients , transplant patients , and the elderly. Endothelial cells , macrophages , and stromal cells are preferentially affected by CMY, although epithelial involvement is common (Figs . 4 . 2 7-4 . 3 0) The viral cytopathic effect is characterized by cytomegaly (cell enlargement) contain­ ing both nuclear ( "owl's eye" ) and cytoplasmic inclusion bodies that have a distinc­ tive magenta tinctorial quality (Figs . 4 . 3 1 -4 . 34) An inflammatory backdrop of mononuclear cells often accompanies the acute colitis (Figs . 4 . 3 5 and 4 . 3 6) Biopsies of the ulcer base are most likely to yield diagnostic CMV viral cytopathic effect. CMV immunostains are not necessary if classic viral cytopathic effect is seen on H&E .

C h a pter

4

COLON

319

Figure 4.27 Acute colitis patte rn, Cyto m e g a l ovirus. This infected endoth e l i a l cel l (arrowhead) b u l ges i n to the l u m e n of a sma l l vascu­ lar space. This m a rked l y e n l a rged ce l l is easy to spot, even at low m a g n ifi catio n .

Fig u re 4 . 2 8 Acute co l itis patte r n , Cyto m e g a l ovirus. This s m a l l vessel sh ows a b n o rm a l h o b n a i l - l i ke en doth e l i a l ce l ls . O n e ce l l sh ows cha ra cte ristic e n l a rgement with both n u c l e a r a n d cytoplas­ mic expa nsion (arrowh ead) . N ote the tinctori a l change i n this CMV infected ce I I .

Fig u re 4 . 2 9 Acute co l itis pattern, Cyto m e g a l ovirus. C M V prefer­ enti a l ly infects endoth e l i a l ce l l s. This s m a l l ca p i l l a ry sh ows a m a rk­ edly e n l a rged e n d oth e l i a l ce l l with n u c l e a r i n c l u s i o n s (arrowh ead) cha racte ristic of C M V. N ote the m o n o n u c l e a r ce l l i nfi ltrate i n the backg ro u n d .

Figu re 4 . 30 Acute col itis pattern, Cyto m e g a l ovirus. T h e e n l a rged n u c l e u s i n this infected endoth e l i a l ce l l (arrowhead) shows the ch a r­ acteristic tinctori a l change of CMV.

Figure 4 . 3 1 Acute co l itis patte rn , Cyto m e g a l ovirus. V i ra l cyto­ path i c effect of CMV i n c l udes n u c l e a r a n d cyto p l a s m i c expa n s i o n resu lti n g i n ce l l u l a r e n l a rgem ent ( " cyto m e g a l y " ) , a s we l l as both n u c l e a r and cyto p l a s m i c i n c l usion bodies (arrowh eads) .

F i g u re 4 . 3 2 Acute co l it i s p a tte r n , Cyto m e g a l ov i r u s . These e n l a rged ce l l s (arrowheads) show cha racte ristic i n c l usions of cyto­ m e g a l ov i ru s i nfecti o n . Note the t i n ctori a l q u a l ity of these infected cells.

320

AT LAS

0 F

GAST R0 I N T EST I N A L

PAT H O LOGY

F i g u re 4.33 Acute col itis patter n , Cyto m e g a l ovirus. Both cyto­ p l a s m i c a n d n u c l e a r i n cl usions a re evi d e n t in these i n fected ce l l s (arrowheads). T h e t o p right ce l l shows the cha racteristic "owl's eye " n u clear i n cl usion of CMV.

Figure 4.34 G a n g l io n ce l l . G a n g l io n ce l l s (arrow) can be m ista ken fo r CMV i n fected ce l l s due to t h e i r a m ph o p h i l i c and vo l u m i n o u s cyto p l a s m . When i n d o u bt, corre l ation with a C M V i m m u nosta i n m a y be necessa ry.

F i g u re 4 . 3 5 Acute co l itis patte r n , Cyto m e g a l ov i r u s . Alth o u g h C M V i n fectio n s (arrowhead) c a u s e a cute i n fl a m m ation a n d u l cer­ ation of the m u cosa, it can be accom p a n ied by a p ro m i n e n t m o n o­ n u cl e a r backd rop, as seen h e re .

Figure 4.36 Acute col itis pattern, Cytomegalovirus. Higher m a g n i ­ ficatio n o f the p revious c a s e shows a CMV infected cel l (arrowhead) with a p ro m i n ent m o n o n u c l e a r backdro p com posed p ri m a ri l y of plasma cel l s and lym phocytes . Scattered n eutrophils a re a lso present.

SALM O N E LLA KEY F EATU R E S of Salmonella I nfecti o n : •

Salmonella i s a gram-negative bacteria transmitted through contaminated food (meat,

•

Infection is divided into two groups :

dairy, eggs , produce) and water that can survive partial cooking, freezing, and drying. 5 ( 1 ) Typhoid serotypes include S. typhi and S. paratyphi. (2) Nontyphoid serotypes include S. enteritidis, S. typhimurium, S. muenchen, S. Newport, and S. paratyphi, among others 5 •

Clinical presentation of typhoid species includes fever, abdominal rash, hepatospleno­ megaly, leukopenia, abdominal pain, headache , watery diarrhea that progresses to hematochezia, and perforation.

•

N ontyphoid species cause less severe illness .

•

Treatment is supportive care and antibiotics .

Ch a pte r

•

Acute inflammation and a mononuclear backdrop are present 6 .7

•

Architectural distortion of crypts may raise the question of inflammatory bowel disease .

•

C O L0 N

321

Histologic features of typhoid fever include involvement of the ileum, right colon, and appendix with hyperplastic Peyer patche s , deep ulceration , and necrosis (Figs . 4 . 3 7-4 . 4 1 ) .

•

•

4

Nontyphoid infection shows an acute colitis , but features can overlap with typhoid fever.s Culture is reqUired for definitive diagnosis .

Figure 4.37 Acute colitis patte r n , Salmonella infectio n . Sca n n i n g m a g n ifi cation sh ows a n acute co l itis with prom inent crypt a bscesses, but re l ative ly preserved crypt a rch itecture . Alth o u g h s l i g htly d is­ torted due to the crypt a bscesses, these cross-sectioned crypts look l i ke a n eve n l y spaced bed of flowers.

Fig u re 4 . 3 8 Acute co l itis patte rn , Sa lmonella i n fectio n . Ag a i n , n ote t h e re l ative ly preserved crypt a rch itectu re as t h e backdrop to th is acute colitis with a b u n d a n t crypt a bscesses.

Figure 4.39 Acute co l itis pattern, Salmonella infection . This biopsy sh ows m u ltiple crypt a bscesses a n d a b u ndant acute infl a m mati o n , b u t n o s i g n ificant crypt a rch itectu ra l c h a n ges.

F i g u re 4 . 40 Acute col itis patte r n , crypt a bscess in Sa lmonella infecti o n . Abu ndant neutro p h i l s fi l l the crypt l u m e n .

322

ATLAS

0 F

GAST R0 I N T EST I N AL

PAT H O LOGY

F i g u re 4 . 4 1 Acute co l itis patte r n , Sa lmonella i n fecti o n . La m i n a p ropria h e m o rrh a g e a n d a b u n d a nt cryptitis a n d crypt a bscesses a re p resent.

S H I G E LLA KEY F EATU R E S of Shigella I nfect i o n : •

•

•

•

•

•

•

•

•

•

•

Shigella i s a n invasive gram-negative bacillus and a maj or cause of diarrhea across the world.

S. dysenteriae is the most virulent and most common , but S. sonnei and S. jlexnen are increasingly reported in the United States. Shigella has the highest infectivity rate among all enteric gram-negative bacteria, with food- and water-borne transmission , as well as the fecal-oral route ; rare instances of sexual transmission are also reported . Outbreaks are associated with crowded living conditions and poor sanitation, with chil­ dren less than 6 years most commonly affected . Patients present with fever, abdominal pain, and watery diarrhea, followed by bloody diarrhea with mucus and pus . Onset of symptoms begins within 1 2 to 50 hours after ingestion of contaminated food or water. Medical complications are most commonly seen with S. dysenteriae, and include severe dehydration, sepsis , toxic megacolon and perforation. Autoimmune phe­ nomena such as reactive arthritis , reactive arthropathy, and hemolytic-anemic syn­ drome also occur. 9 Treatment is supportive care and antibiotics . Histologic findings include a left colon predominant acute colitis , sometimes with terminal ileum involvement . Early changes appear as a diffuse acute colitis , with or without pseudomembranes (Figs . 4.42-4 . 4 5 ) . 1 0 Later changes may show patchy or segmental involvement , and concomitant architec­ tural distortion may raise the question of inflammatory bowel disease . l l

Ch a pte r

4

C O L0 N

323

Figure 4.42 Acute colitis pattern , Shigella infecti on . At low m a g n i ­ ficat i o n , the crypt a rch itectu re is rel ative ly preserved. There i s a b u n ­ dant acute infl a m m ation i nvo lving both the crypts - a n d t h e surfa ce epith e l i u m (arrowheads) .

Figure 4.43 Acute colitis patte rn, Shigella infectio n . H i g h e r m a g ­ n ification o f the p revio u s case sh ows surface n e utro p h i l ic a bscess.

Figure 4.44 Acute co l itis pattern, Shigella i nfecti o n . La m i n a pro­ pria h e m orrh a g e (a rrow) a n d a b u n d a nt cryptitis (arrowh ead) a re p resent.

Figure 4 . 4 5 Acute colitis pattern, Shigella infecti o n . N e utro p h i l s a re present with i n t h e co l o n i c epith e l i u m (arrow) a n d with i n t h e crypt l u m e n (arrowheads) .

CAMPYLOBACTER KEY F EATU R E S of Campylobacter I nfect i o n :

Campylobacter is a gram-negative food and water-borne bacterium found in under­ 1 cooked poultry, raw milk, and untreated water. 2

C. jejuni is most commonly associated with fo od-b orne gastroenteritis , followed by C. coli and C. laridis. 12-14 •

Watery diarrhea is the most common presentation, accompanied by fever and cramp­ ing abdominal pain . 1 2 Infants , children, and young adults are most commonly affected, and there i s a higher incidence in HIV-positive patients , particularly with C. fetus. 1 2

•

Autoimmune complications such as Guillain-Barre syndrome , Henoch-Schbnlein pur­ pura , and reactive arthropathy are associated . 12 Treatment is supportive care , with resolution within 1 to 2 weeks . Antibiotics may be needed in immunocompromised patients , or those with severe , recurrent, or dissemi­ nated infection . I S Histologic features include a n acute colitis (Figs . 4 . 46-4 . 49) and stool culture i s neces­ IS sary for definitive diagnosis .

324

ATLAS

0 F

GASTR0 I N TE STI N A L

PAT H O LOGY

Figu re 4.46 Acute col itis pattern, Campylobacter infectio n . Abun­ dant crypt a bscesses (arrowheads) i n d i cate the p resence of a n acute co l itis. N ote the eve n ly spaced " bed of flowers" a ppearance of the co l o n i c crypts (cut i n cross section); there is n o evidence of chro n icity in this i m a g e from the right col o n .

Figu re 4.47 Acute colitis pattern, Campylobacter i n fectio n . N e u ­ tro p h i l s (arrow) h ave crossed t h e crypt basement m e m bra n e a n d a re p resent betwee n the co l o n i c epith e l i a l cel l s.

Figure 4.48 Acute col itis pattern, Campylobacter infectio n . H i g h e r m a g n ification o f cryptitis sh ows neutro p h i l s (arrowheads) with i n t h e col o n i c crypt epith e l i u m .

Figure 4.49 Acute colitis pattern, crypt a bscess i n Campylobacter infectio n . A l a rge co l l ectio n of neutro p h i l s is present with i n this crypt l u m en (crypt a bscess) . N ote the neutro ph i l cross i n g t h ro u g h the crypt epith e l i u m (cryptitis) (arrowhead).

ISCH E M I C CO LITIS PATTE R N

Fig u re 4 . 5 0 Isch e m i c co l itis patte rn . T h i s exa m p l e shows s m a l l a n d with e red crypts n e a r t h e s u rface. T h e s u rface epith e l i u m h a s s l o u g h e d off i n some a reas, a n d l a m i n a p ropria h e m o rrh a g e a n d hya l i n izatio n a re p resent.

Ch a pte r

F i g u re 4 . 5 1 Isch e m i c co l itis patte rn . The stri k i n g fi n d i n g at l ow m a g n ification is the presen ce of " m i crocrypts " (arrow) . N ote the co l l a pse of the hya l i n ized l a m i n a p ropria i n this a re a , ca using a con­ densation of these crypts . Loo k at the l eft portion of this image fo r contra st to re latively n o rm a l crypts a n d l a m i n a propri a .

Mucosal ischemia causes a highly characteristic pattern of inj ury, including features o f sur­ face inj ury, loss of mucin , lamina propria hemorrhage and hyalinization , withered crypts , atrophic microcrypts , and lamina propria collapse (Fig. 4 . 5 0) . The architectural pattern of withered crypts and microcrypts is distinctive at low magnification, and one might even refer to this pattern of inj ury as the "microcrypt pattern" (Fig. 4 . 5 1 ) . Although ischemic inj ury is top among the differential diagnoses, other considerations include vascular injury (such as that seen in radiation colitis , amyloidosis , or vasculitis) , infection (particularly Escherichia coli 0 1 5 7 : H 7 and Clostridium difficile) , and medications (NSAlDs , Kayexalate , and sevelamer) . CH ECKLIST: Et i o l o g i c Considerat i o n s fo r t h e I s c h e m i c Co l itis Pattern o

Isch e m i a

o

I nfection ( E . coli, C difficile)

o

M ed i cation ( N SA I Ds, Kayexa l ate , seve l a m e r, i pili m u m a b , oth e rs)

ISCH E M IA Decreased blood flow and lack of oxygen to the GI tract result in necrosis or tissue dam­ age , causing ischemia . There are several weak points in the colonic blood supply, known as watershed areas, which result from incomplete anastomosis of the marginal arteries and lack of sufficient collateral circulation. These watershed areas are more vulnerable to ischemic inj ury than other parts of the colon and include the splenic flexure (or Griffith's point) , the rectosigmOid region at Sudeck's point, and the ileocecal region. Among the older population, ischemic disease is typically attributable to atherosclerotic mesenteric vascular disease , but the causes of colonic ischemia are many (Table 4 . 2 ) . The histologiC findings are dependent on the timing of the ischemic event (Figs . 4 . 5 2-4 . 63 ) . Early and minimal injury, for example, occurs first as degeneration and sloughing of superfiCial epithelial cells, edema , and vascular congestion. Later, the epithelial cells become markedly attenuated and the crypts appear compressed and atrophic ("microcrypts") as the lamina propria swells and hemorrhages. Within 5 hours of total acute vascular occlusion , almost the entire intestinal wall appears necrotic. These changes are devoid of acute inflammation until reperfusion occurs . Paradoxi­ cally, reperfusion further inj ures the tissues by introdUCing oxygen free radical formation , 1 6 the severity of which is dependent on the duration of the preceding hypoxia .

4

C O L0 N

325

326

AT LAS

0 F

GAST R0 I N T EST I N AL

PAT H O LOGY

TABLE 4.2: C a u s e s of C o l o n i c I s c h e m i a Va scu l a r Occ l u s i o n •

A rte ri a l o r ve n o u s t h ro m bo s i s

•

Va scu l itis

•

Ath e rosc lerosis

• • •

Embolus R a d iation Amyloidosis

Low- F l ow States •

Low card i a c o u t p u t

•

Dehydrat i o n

•

•

•

Hypote n s i on/shock Vasospasm S p l a n c h n i c s h u nt i n g , such as i n extre m e ath l eticism ( m a rath o n ru n n e rs)

M e c h a n i c a l O b st r u ct i o n

•

I leus

•

Mass l e s i o n s

•

Vo lvu l u s

•

• •

I ntussuscept i o n Hernia Feca l i m p a ct i o n

F i g u re 4.52 Isch e m i c col itis pattern , ea rly. Early isch e m i c c h a n g es m a y show o n l y l a m i n a p ropria h e m o rrhage a n d edema with e a rly slou g h i n g of the superfi c i a l epith e l i u m .

F i g u re 4.53 Isch e m i c colitis pattern, ea rly. La m i n a propria h e m o r­ rh age (arrowh eads) is present.

F i g u re 4 . 5 4 Isch e m i c col itis pattern , withered crypts. Crypt epithe­

F i g u re 4.55 Ischemic col itis pattern . This low m a g n ification i m a g e emphasizes t h e microcrypt pattern. Sma l l , withered crypts a re present (arrow) a l on g with l a m i n a propria hya l i n ization. N ote the homogenous pink a ppeara n ce of the lamina propria i n the a rea of the a rrow. By com­ pariso n , the lamina propria at the base of the field is sti l l preserved.

lium becomes d a m a g ed and s l o u g h s , giving a " with e red " a p pe a r­ a n ce to the crypts (arrowheads) . Com p a re these with ered crypts to the right side of the p h oto, which a re better preserve d .

Ch a pte r

4

C O L0 N

327

Fi g u r e 4 . 5 6 Isch e m i c co l itis patte rn . N ote the m i crocrypt pat­ tern of i nj u ry at sca n n i n g m a g n ificatio n . There is a g radient of crypt with e r i n g a n d d isso l ution that worsen s as the s u rface epith e l i u m is a p p roa c h e d . Also, n ote the re latively h o m o g e n e o u s p i n k appear­ a n ce of the hya l i n ized l a m i n a propri a .

Figure 4.57 Isch e m i c colitis patte rn, m icrocrypts. M i crocrypts with resid u a l withered epithe l i u m can be seen at the left (arrows), w h i l e crypts t h a t h ave com p l ete l y l o st t h e i r epith e l i u m a re s e e n on t h e ri g h t (a rrowh eads) . Ag a i n , n ote the q u a l ity o f the l a m i n a propria, w h i ch a p p e a rs densely p i n k , rath e r t h a n the typ i c a l co l o rless (or wh ite) a ppea ra n ce .

Figure 4 . 5 8 Isch e m i c col itis patte r n , early with eri n g crypts . The surface epith e l i u m i n this exa m p l e shows early s l o u g h i n g . The crypt epith e l i u m sh ows loss of cytoplasmic m u c i n .

Fig u re 4 . 5 9 Isch e m i c co l itis patte r n , early witheri n g crypts. The s u rfa ce epith e l i u m sh ows atte n u ated epith e l i a l ce l l s with l oss of cyto p l a s m i c m u c i n . The crypt epith e l i u m shows a n early "withered' a ppeara n ce with u n d u l ation of the crypt l u m i n a l surface (a rrow) .

Figu re 4 . 6 0 Isch e m i c colitis patte rn, e a r l y l a m i n a p ropria hya l i n ­ izatio n . T h i s e a rly isch e m i c i n j u ry sh ows ba ckg ro u n d l a m i n a p ropria h e m o rrh a g e and m i n i m a l crypt d a m a g e ; howeve r, n ote the p res­ ence of l a m i n a p ropria hya l i n izati on s u rro u n d i n g the top ri ght crypt (arrowh eads) . T h i s h o m o g e n o u s p i n k m ateri a l eventu a l ly re p l aces the l a m i n a p ropria.

Figure 4.61 Isch e m i c colitis patter n , ea rly l a m i n a propria hya l i n iza­ tio n . S i m i l a r to the p revious exa m p l e , these crypts show only ea rly s i g n s of cyto p l a s m i c m u cin l oss; h oweve r, n ote the foc a l hya l i n e deposits (arrowheads) i n the l a m i n a propri a .

328

ATLAS

0 F

GAST R0 I N TEST I N A L

PAT H O LOGY

F i g u re 4 . 6 2 Isch e m i c col itis patte r n , e a rl y re p e rfu s i o n i nj u ry. N ota b l e in the F i g u res 4 . 5 2-4 . 6 1 is the n e a r-co m p l ete a bsence of a cute infl a m m atio n . N eutro p h i l s a re d rawn to the site of i nj u ry o n l y after re perfusion occu rs, a n d therefore a re n ot s e e n i n ea rly o r a cute isch e m i a . This exa m p l e sh ows early reperfusion i nj u ry with a n early n eutro p h i l i c i nfi ltrate (arrowhead) .

F i g u re 4 . 6 3 Isch e m i c c o l i t i s patte r n , e a r l y re p e rfu s i o n i nj u ry. H i g h e r m a g n ification of the p revious fi g u re sh ows crypt destruction d u e to a neutroph i l ic i nfi ltrate .

KEY F EATU R E S of I sc h e m i a : •

•

•

Ischemia can b e caused b y vascular occlusion, low flow states, o r mechanical obstruction. The most common cause of ischemia among the elderly is atherosclerosis of the mesenteric arteries . Watershed areas prone t o ischemia due t o lack of s� fficient collateral circulation: •

•

•

•

•

The splenic flexure (or Griffith's point)

•

The rectosigmoid region (Sudeck's point)

•

The ileocecal region

Early histologic findings include sloughing of superficial epithelial cells , edema , and vascular congestion. Later stages include lamina propria hemorrhage , hyalinization, and microcrypt for­ mation, followed by coagulative necrosis Acute inflammation is absent unless reperfusion occurs . Underlying vasculitis and radiation inj ury can cause ischemic mucosal changes (Figs . 4 64-4 . 66) .

•

Beware not to overcall crush artifact from biopsy forceps as ischemic change .

•

Pseudomembranes may be seen.

Figure 4.64 Ischemic col itis pattern, radiation i nj u ry. Withered m icro­ crypts (arrowheads) ca n be seen in radiation i nj u ry. This patient had rad iation proctitis secondary to radiation treatment for bladder cancer.

Fig u re 4.65 Isch e m i c colitis patte rn, rad i ation i nj u ry. H i g h e r m a g ­ n ificati o n o f the previous i m a g e reve a l s the p resence o f a b u n d a n t a po ptoses (arrowheads), a red fla g t o rad iation - i n d u ced injury.

C h a pte r

4

COL0 N

329

Figure 4.66 Cel l u l a r atypia of ra d i ation i nj u ry. La rge, atypica l ce l l s ( a rro w) a re seen fo l l ow i n g ra d i ation i n j u ry. Th e i r presen ce c a n ra ise concern for recu rrent m a l ig n a n cy, but n ote the a b u n d a n t cyto p l a s m , which conserves the n u c l e a r-to-cyto p l a s m i c (N : C) ratio . Another c l u e is the p rom i n e n t vesicu l a r appeara n ce o f these atypical ce l l s .

PEARLS & P ITFALLS

C r u s h Art ifact fro m B i o psy Forceps Can M i m ic I sc h e m i c I nj u ry

C a u te ry effect a n d c ru s h i nj u ry d u e to b i o psy fo rce p s ( " sq u eeze a rtifa c t " ) m a y stri p epith e l i a l cel l s from the s u rfa ce a n d crush g l a n d s that c a n be m i staken fo r atro p h i c m i crocrypts ( F i g . 4 . 67-4 . 6 8 ) . To contra st, true isch e m i c i nj u ry wi l l show l a m i n a propria h e m o rrh a g e and d e g e n e rative cel l u l a r c h a n ges, such a s l oss of the a p i ca l brush bord e r and g h ost l i ke n u c l e i . T h e re i s n o tissue response to b i o psy forceps squ eeze a rtifa ct .

. . .

• I

�-;:-

"�,:

.. ,

"

Figure 4.67 Crush ("sq u eeze " ) a rtifa ct m i m icki n g isch e m i c col itis pattern . Crush a rtifact from biopsy fo rceps ca n d islodge crypt epi­ th e l i u m , leaving beh ind a n em pty space that m i m i cs the m i crocrypts of isch e m i a . Avoid this p itfa l l by n oti n g the a bsence of oth e r isch­ emic features, such a s l a m i n a propria h e m o rrhage, loss of cytop l as­ mic m u ci n , a n d l a m i n a propria h ya l i n izati o n .

Fig u re 4 . 6 8 Caute ry a rtifact m i m icki n g isch e m i c colitis pattern . Cautery causes therm a l inj u ry a n d d i storts the co l o n i c crypts . I n this exa m p l e , o n e m ight consider the poss i b i l ity of ischemic injury, d u e to the l oss of s u rfa ce epith e l i u m a n d p resence of s m a l l e r crypts ( a rrows) . N ote, h owever, the a bsence of l a m i n a p ropria hem orrhage o r hya l i n izati o n .

330

ATLAS

0 F

GAST R0 I N T E S TI N A L

PAT H O LOGY

PEARLS & PITFALLS

Eva l u a t i o n for U n d e r l y i n g Vascu l it i s Can be Tricky in B i o psy M at e r i al

Which c a m e fi rst, the c h i cken o r the e g g ? A l th o u g h u nd e r l y i n g vasc u l itis ca n cer­ ta i n ly ca u se m u co s a l i s c h e m i a , vascu l a r t h ro m b i a n d i n fl a m m atory c h a n ges c a n be seco n d a ry to i s ch e m i c- re p e rfu s i o n i nj u ry. As a resu lt, p ri m a ry vascu l a r i nj u ry s h o u l d be eva l u ated i n a reas n ot d i rectly s u bj a ce n t to isch e m i a o r u l cerati o n , a n d c l ose c l i n i c a l , rad i o l og i c , a n d sero l o g i c corre l a t i o n s h o u l d b e performed i n cases s uspected of p ri m a ry vascu l itis (Fig . 4 . 69-4 . 7 2 ) .

Figure 4.69 Isch e m i c co l itis patte r n , ve n u l itis i n Beh c;:et d isease. One should a l ways consider vascu l itis as a cause of isch e m i a o r u l cer­ ation , but take care to look in a reas away from u l ce rs . Th i s exa m p l e shows a stri king lym phocytic ven u l itis (arrow) t h a t has obl iterated the sma l l vei n . It is easier to sea rch for sma l l m uscu l a r a rteries (pictu red top rig ht) a n d then look in the p roxi m ity fo r the p a i red ve i n .

Figure 4 . 7 0 Isch e m i c col itis pattern, ven u l itis i n Behc;:et disease. N ote how the m a rked ly d a m a g ed a n d i nfl amed vein (arrow) blends i nto the backg ro u n d . By contrast, the pristi n e a n d u n affected a rtery is easily identified.

Figure 4 . 7 1 Isch e m i c colitis patte r n , system i c l u p u s e rythem ato­ sus (SLE). T h i s seg ment of co l o n was resected fo r isch e m i a . N ote the exten sive su rface u l ce rati o n . An u n d e rlying vessel sh ows a l a rge fi brin thrombus (arrow). H oweve r, d u e to the p roxi m ity to the u l cer, it is u n c l e a r wh eth e r the vascu l a r c h a n g e is causative or the result of the u l ce r. O n e m ust search for vascu l a r changes away from the u l cer bed .

Figure 4 . 7 2 Isch e m i c col itis pattern, l e u kocytoclastic vascu l itis in system i c l u pu s e ryth em atosus (SLE). S u re enough, fu rth e r exa m i n a ­ t i o n i n t h e p revious c a s e revea led ka ryorrhectic debris (arrowheads) of sm a l l vessel necrotizi n g vascu l itis, consistent with the patient's h i story of S L E .

C h a pter

4

C O L O N

331

I N F ECTI O N (Escherichia coli 01 5 7 : H 7 a n d Clostridium diHicile) Certain infectious agents also produce an ischemic pattern of injury, namely enterohemor­ rhagic E. coli (E. coli 0 1 5 7 : H7) and C. difficile (Fig. 4 73-4 . 75) The histologic distinction between ischemia and infection can be nearly impossible , but observers cite the presence of lamina propria hyalinization as a feature of ischemia that is absent in infectious colitis (Fig. 4 . 76) 1 7 Another clue is the distribution of disease , as infection diffusely involves the colon , whereas ischemia preferentially involves the watershed areas. Undoubtedly, stool studies remain the gold standard for diagnosis . KEY F EATU R E S of I nfect i o n : •

Infection b y E. coli 0 1 5 7:H7 o r C. difficile can be histologically identical t o ischemia.

•

Hyalinized lamina propria and withered crypts are not typical of C. difficile colitis .

C. difficile colitis is more diffusely distributed in the colon compared to ischemic colitis . Fibrin thrombi are seen in association with E. coli 0 1 5 7:H7 infection, but are not specific. Pseudomembranes are a feature of infectious colitis , but can also be seen in ischemic colitis .

Fig u re 4 . 7 3 Isch e m i c col itis patte r n , Esch erich ia coli i n fecti o n . I nfection c a n cause isch em ic- l i ke featu res. T h i s exa m p l e o f E . coli i nfection sh ows with e red a n d atro p h i c crypts with p a rti a l s u rface d e n u dation and l oss of cyto p l a s m i c m u ci n . The fi n d i n g s a re n e a rly i n d isti n g u is h a b l e from th ose of true isch e m i c i nj u ry.

Figure 4 . 7 4 Isch e m i c col itis patte rn, entero h e m o rrh a g i c Esch ­ erich ia coli i n fectio n . A clue to enterohemorrh a g i c E. coli infection (stra i n 0 1 5 7 : H 7 ) is the presence of fibrin thrombi (arrowheads) with i n sma l l capi l la ry vesse ls. Foca l resi d u a l crypt bases rem a i n (arrows) .

Fig u re 4 . 7 5 Isch e m i c col itis patte r n , Clostridium diffici/e i n fec­ ti o n . The a rch etypal feature of C diffici/e colitis i s the p resence of pseudomem bra n es; h owever, ea rly C diffici/e col itis sh ows isch e m i c pattern featu res, s u c h as the m i crocrypt pattern s e e n h e re . An ea rly pseudomem bra n e is pictured, but these a re not a lways present.

F i g u re 4 . 7 6 I s ch e m i c co l itis patte r n , l a m i n a propria hya l i n e . Alth o u g h s i g n ifi cant h isto l o g i c overl a p exists between i n fectious a n d isc h e m i c eti olog ies, the p resence of lamina propria hya l i n ization is cited as a d isti nctive featu re of isch e m i a . A homogenous pink hya­ line m ateri a l rep l a ces the l a m i n a propria and its cel l u l a r constituents.

332

AT LAS

0 F

GAST R0 I NT E ST I N A L

PAT H O LOGY

TABLE 4.3: Mechanism of Medications Causing I schemic Colitis

Vasospasm •

Va sopressors

•

Coca i n e

•

•

D i g ita l i s O v e r the c o u nter n a s a l d e c o n g e sta nts

Thrombosis •

O ra l co ntra ceptives

Direct M u cosa l Damage •

•

•

•

N SA I D s Potass i u m c h l o r i d e Kayexa l ate (sod i u m p o l ystyre n e s u lfo n ate) Seve l a m e r

M E D I CATI O N I NJ URY A number of medications cause ischemic inj ury by a variety of mechanisms (Table 4 . 3 ) . Also known as polystyrene sulfonate , Kayexalate is a cation exchange resin used to treat hyperkalemia and is commonly found among the medication regimens of renal failure patients . The resin can be found anywhere along the GI tract, as it is administered via naso­ gastric tube, orally, or via rectal enema . Kayexalate was introduced in 1 95 8 with the notable absence of any randomized clinical trial regarding its efficacy and safety In the early use of Kayexalate , complications included bowel concretions and medication bezoars within the bowel . As a result, the original water-based suspension was replaced by a sorbitol suspen­ sion that caused an intentional osmotic diarrhea , thereby reducing bowel impactions . How­ ever, not long after, reports of colonic necrosis and resulting death surfaced, with evidence that sorbitol was the responsible agent . 1 S In a more recent systematic review of 58 cases , Kayexalate (with and without sorbitol) was linked to ischemic colitis , colonic necrosis, perforation and bleeding, with a notable mortality rate of 3 3 % among patients manifesting GI inj ury 19 See also Resins , Pigments , Esophagus Chapter. KEY C H A RACT E R I ST I C M o r p h o l og i c Featu res of Kayexa l at e : •

Purple on H&E .

•

H o t pink o n PAS/AB .

•

Narrow, rectangular "fish-scales" or a "mosaic" appearance due to cracking lines at regular intervals . These "fish-scales" are seen in both small and large crystal fragments (Figs . 4 . 7 7 and 4 78) .

Fig u re 4 . 7 7 I s ch e m i c c o l itis patte r n , Kayexa l ate (sod i u m po ly­ styre n e s u l fo n ate) . T h i s seg m e n t of co l o n was a l m ost e n t i re l y n ecrotic. E m bedded i n the l u m i n a l d e b ri s were n u m e ro u s p u r p l e res i n crysta l s .

Figu re 4 . 7 8 Ischemic co l itis pattern , Kayexa late. H i g h e r m a g n ifica­ tion of the p revious case sh ows a "fish-sca l e " o r mosaic pattern of cracki n g l i nes with i n the i rreg u l a r resin crysta l s . The isch e m i c colitis pattern and s i g n ificant m o rbid ity a re associated with this fi n d i n g .

Ch a pte r

•

Can be differentiated from sevelamer crystals (a phosphate lowering agent with pos­ sible injurious potential) , which show broad, curved, irregularly spaced "fish-scales" with a variably eosinophilic to rusty brown color on H&E stain, and a violet color on PASID 20 P EA R LS & P ITFALLS

A lways Check the Lu m i n a l Co ntents

In the setti n g of co l o n i c i s c h e m i a , u l ce rat i o n , a n d n ec ro s i s , ta ke a m o m e n t to check the l u m i n a l conte nts for p a rti c u l ate m atte r or em bedded c rysta l l i n e mate ria l that m i g ht i n d i cate p i l l fra g m e nts. Corre l ation with the patient's m e d i cation h i sto ry (a n d h i sto ry of hyperka l e m i a o r re n a l fa i l u re) m a y a l so be h e l pfu l . G iven the h i g h m o rta l ity rate a ssociated with Kayexa l ate- i n d u ced G I i n j u ry, a path o l og i st s h o u l d a d v i se the c l i n ica l tea m t o d i sconti n u e the m e d i cation a n d keep the patient u n d e r c l ose observati o n .

PS E U DO M E M BRAN OUS PATTE R N

Fig u re 4.79 Pseudomem bra n o u s pattern . This fi brin cap a l o n g the s u rfa ce of the co l o n i c m u cosa is the h a l l m a rk of pseudomembra n o u s pattern . A pseudomembrane is yellow-white exudate on the colonic mucosa that histologically cor­ responds to a superficial fibroinflammatory exudate (Fig. 4 . 79) . The pseudomembrane is composed of fibrin, mucin , and neutrophils , and may have a laminated or layered appear­ ance . Some regard "pseudomembranous colitis" as synonymous with C. difficile colitis , but this is not accurate . In practice , pseudomembranes are also found in ischemia and with other enterotoxic infections (Shigella, Salmonella, and enterohemorrhagic E. coli) , and his­ tologic distinction between these entities is not possible . Some observers cite the presence of lamina propria hyalinization as a feature favoring ischemia . I ! Another indicator is the distribution of disease as infection diffusely involves the colon , whereas ischemia preferen­ tially involves the watershed areas (Fig. 4 . 80) . Undoubtedly, stool studies remain the gold standard for diagnosis . CH ECKLI ST: Eti o l o g i c C o n s i derat i o n s for Pseu d o m e m b r a n o u s Pattern o

I s ch e m i a

o

Clostridium difficile Col itis

o

Sa lmonella

o

Sh igella

o

Entero h e m orr h a g i c Esch erichia coli

4

C O L0 N

333

334

ATLAS

0 F

G A ST R0 I N T EST I N AL

PAT H O LOGY

F i g u re 4.80 Pse u d o m e m bra n o u s patte r n , C. difficile. H i sto log i­ ca l l y, d i sti n g u is h i n g isch e m i c pse u d o m e m bra n e s fro m C . difficile pseudomem bra nes can be i m possi b l e . H owever, the g ross d i stribu­ tion of d isease i n C. difficile co l itis is d iffuse (pictu red h e re). whereas isch e m i c col itis is typica l ly segmenta l .

K E Y F EATU R E S o f Clostridium difficile C o l it i s : •

•

•

•

•

Some physicians use "pseudomembranous colitis" synonymously with C. difficile colitis , but pseudomembranes are not specific for this infection. Potent toxins are produced by the bacteria (Toxin A and toxin B) . Oral antibiotic use causes a shift in the normal protective gut flora, resulting in C. difficile infection .

Clostridium difficile is the most common nosocomial GI pathogen. Patients present with watery to bloody diarrhea, fever, leukocytosis , and abdominal pain.

•

Complications include toxic megacolon, perforation, and reactive polyarthritis .

•

Treatment i s supportive care and antibiotics , but fulminant cases may require surgery.

•

•

•

Histologic features are primarily an acute colitis with pseudomembrane formation. Bal­ looned and exploding crypts with volcanic exudate may be seen (Figs . 4 . 8 1 -4 . 8 7 ) Severe disease may feature full-thickness mucosal necrosis . The differential diagnosis includes ischemia, Salmonella, Shigella, and enterohem­ orrhagic E. coli.

F i g u re 4 . 8 1 Pse u d o m e m bra n o u s pattern, ea rly. At sca n n i n g m a g ­ n ifi cati o n , the ea rly pseudomem bra n es (arrows) a re visi b l e as erup­ tive fi broinfl a m m atory debris along the col o n i c s u rfa ce.

Figure 4.82 Pseudomem bra nous pattern, ea rly. H ig h e r m a g n ifi ca­ tion of the p revious case sh ows the fibrin (arrowhead) e ru pti n g from the co l o n i c s u rface a m idst n u m e rous neutro p h i l s .

Ch a pte r

4

C O L0 N

335

F i g u re 4 . 8 3 Pse u d o m e m bra n o u s patte r n , e a r l y. T h e e ru ptive pseudom em bra n e i s h a rd to m iss, even at l ow m a g n ification . I nter­ est i n g l y, t h e ba ckg ro u n d m u cosa someti mes s h ows l ittl e to n o c h a n g e , as s e e n h e re .

Figure 4 . 8 4 Pseudom e m bra n o u s pattern, m a rked . Severe cases of pse u d o m e m bra n o u s colitis may req u i re colectomy, a s in t h i s c a s e . There i s extensive t i s s u e necrosis a n d only ra re res i d u a l crypts (arrowh eads) rem a i n .

F i g u re 4 . 8 5 Pseu d o m e m bra n o u s patte r n . The crypt epith e l i u m beg i n s t o s l o u g h a n d t h e l a m i n a propria is edematous. T h e su rface sh ows a b u n d a n t fi bri n a n d a cute infl a m matory ce l l s .

Figure 4.86 Pse u d o m e m bra n o u s pattern . T h e pseudomembra n e is com posed o f fi bri n , a cute infl a m m atory ce l l s, a n d oth er cel l u l a r debris.

F i g u re 4 . 8 7 Pse u d o m e m b ra n o u s p a tte r n . A d ra m a t i c (a n d bea utifu l ) exa m p l e o f a n eru ptive pse u d o m e m b ra n e . T h e exten­ sive fi bro i n fl a m m ato ry debris a p p e a rs to eru pt fro m a s i n g l e crypt (arrowhead} .

336

AT LAS

0 F

GAST R0 I N T EST I N A L

PAT H O LOGY

C H RO N I C CO LITIS PATTE RN

Fig u re 4.88 C h ro n i c col itis patte r n . This rectal biopsy rep resents m a rked active c h ro n i c colitis. The a ctive i nj u ry is i m p a rted by crypti­ tis and crypt a bscesses (best seen at h i g h e r power) and the c h ro n i c com ponent refers t o i ncreased l a m i n a propria chro n i c infl a m mati o n , P a n eth ce l l meta p l a s i a , a n d a rch itect u ra l d istortion [a vi l l o n od u l a r s u rface, abnorm a l crypt config u rati o n , crypt d ropout, crypt shortfa l l , a n d basa l lym p h o p l a s m a cytosis (brackets)]. This n o n specifi c pattern s i m p l y i n d icates a ctive chro n i c m u cosal i nj u ry. This identical patte rn can be ca used by I B D , infect i o n , medication i nj u ry, among oth e rs . Ascri b i n g th i s i nj u ry patte rn t o a specific etio l ogy req u i res ca refu l c l i n icopatho l o g i c corre l ati o n .

The term "chronic colitis" encompasses a wide spectrum o f morphology and invokes a wide range of etiologic considerations (Fig. 4 . 88) . IBD is only one of many potential causes of the chronic colitis pattern . Nearly identical histology can be seen in the setting of diverticular disease , ipilimumab colitis , syphilitic proctocolitis , chronic infections , medication inj ury, or radiation inj ury, among others ; therefore , the chronic colitis pattern is pathognomic for neither IBD nor any other specific etiologic agent . Accordingly, ascrib­ ing this nonspecific inj ury pattern to a speCific etiology can be challenging and always requires clinicopathologic correlation. Accurate diagnosis is absolutely essential to ensure appropriate clinical management : IBD is managed with immunosuppression and life-long surveillance , ipilimumab colitis is cured with drug cessation, and syphilitic proctocolitis is cured with antibiotics . This section will cover the maj or etiologic considerations of the chronic colitis pattern with emphasis on clinicopathologic "red flags" and clues to the underlying etiology

CH ECKLI ST: Eti o l o g i c C o n s i derat i o n s fo r t h e C h r o n i c C o l it i s Pattern o

I nf l a m m atory Bowel D i sease

o

Diverti c u l a r D i sease

o

D i vers i o n -Associated Col itis

o

Syph i l itic and Lym p h o g ra n u l o m a Ve n ere u m Proctocol itis

o

Cord Co l itis Syndro m e

o

I p i l i m u m ab Col itis

o

Resi n s

C h a pte r

A Pattern-Based Approach to Colitis

Step

1

Classify

C;�

/--""'''� '---

ACU�

C hro�

�

Active

Step

2

Inactive

I

Grade

Mild

Moderate

Marked

Ste p 3 C l i n icopathologic correl ation

See Note Fig ure 4 . 89 A pattern-based a p p roach to col itis. N avigati n g the chro n i c col itis pattern can be treacherous s i n ce there a re so m a n y v a r i e d eti o l o g i c poss i b i l ities. W e reco m m e n d a systematic, three­ step patte rn-based a p p roach to colitis. This s i m p l e a p p roach can p rovide a h e l pfu l fra m ework fo r a l l col itis cases, reg a rd l ess of the i n h e rent com p l exities: Step 1 : C l assify the i nj u ry pattern a s acute colitis vs. a ctive c h ro n i c col itis vs i n a ctive c h ro n i c col itis; ste p 2: G rade the col itis as m i l d , moderate, or m a rked; step 3 : c l i n icopatho­ logic corre l at i o n , " See note . "

A T H R E E-STE P APP ROACH T O TH E C H RO N I C CO LITIS PATTE R N Undoubtedly, navigating the chronic colitis pattern can be treacherous because there are so many varied etiologic possibilities . Adoption of a simplified, three-step pattern-based approach to colitis can provide a helpful framework for all colitis cases , despite their inher­ ent complexities (Fig. 4 . 89) .

STE P 1 : CLASSI FY TH E I NJ U RY PATTE R N AS ACUTE CO LITIS VS . ACTIVE C H RO N I C CO LITI S VS I NACTIVE CH RO N I C CO LITIS Acute colitis As discussed earlier, the acute colitis pattern lacks any features of chronic mucosal injury, by definition . Features of the acute colitis pattern can include cryptitis (acute inflammation in the crypt epithelium) , crypt abscesses (acute inflammation in the lumen of the crypt) , erosions , and ulcerations . Not all features are required simultaneously for the diagnosis of "acute colitis pattern"; one feature alone satisfies the diagnostic criteria . See also Acute Colitis , this chapter.

4

C O L0 N

337

338

ATLAS

0 F

GAST R0 I NT EST I N A L

PAT H O LOGY

Chronic colitis The "chronic colitis pattern" is a broad term that encompasses a laundry list of descriptors , provided later. Similar to the diagnosis of "acute colitis pattern , " not all features need be present at once to satisfy the diagnostic criteria of the "chronic colitis pattern . " •

Pyloric gland metaplasia •

•

Pyloric glands are always abnormal in the colon. PyloriC gland metaplasia is indistinguishable from pyloriC glands at any other site (Figs . 4 . 9 0 and 4 . 9 1 ) .

Fig u re 4.90 C h ro n i c co l itis patte r n , pyloric g l a n d meta p l a s i a . Pyl o ric-type g l a n d s a re n o rm a l ly fo u n d i n the sto m a ch a n d p roxi m a l duode n u m . Their p resen ce i n t h e co l o n i n d icates c h ro n i c m u cosal i nj u ry.

Fig u re 4.92 Chro n i c co l itis pattern , Paneth ce l l m eta p l a s i a . Pa n eth ce l l s a re n o rm a l ly fo u n d i n the sma l l bowe l , right co l o n , and tra ns­ verse col o n . Paneth ce l l s i n the desce n d i n g co l o n , s i g m o i d , and rec­ tum a re a b n o rm a l a n d i n d i cate c h ro n i c m u cosa l i nj u ry. To the j u n ior tra i nee, Pa n eth ce l ls ca n someti m es be confused with e n docri n e ce l l s a n d eosi n o p h i l s . I m portant poi nts of d i sti n ction i n c l u de t h a t the g ra n u les o f P a n eth ce l ls (arrows) a re m o re l i ghtly eosi n o ph i l ic, l a rg e and coarse, and a g g regate near the co l o n i c l u m e n . In con­ trast, the g ra n u les of endocri n e cel l s (arrowheads) a re m o re deeply eosi n o ph i l ic, fi n e l y g ra n u l a r, a n d a g g regate towa rd the basement m e m bra n e . Eosi n o p h i l s (circle) have brightly o ra n g e , coa rse g ra n ­ u l es, which a re usu a l ly easy t o identify, especi a l l y a cco m p a n ied by cha racteristic b i l obed n u c l e i .

Figure 4 . 9 1 C h ro n i c co l itis patte r n , p y l o r i c g l a n d m eta p l a s i a . These pyloric g l a n d s h a ve a b u n dant foa my-to-cl e a r cyto p l asm a n d sma l l , rou n d or ovoid n u clei t h a t m a y be fl attened a g a i n st t h e base­ ment m e m bra n e .

Figure 4 . 9 3 C h ro n i c col itis pattern, Paneth cel l meta plasia (arrows) versus en docri n e ce l l s (arrowheads) . Endocri n e ce l l s a re n o r m a l l y s e e n throug hout the bowe l ; t h e i r p resen ce d o e s not sign ify chro n i c m u cosal i nj u ry.

Ch a pte r

•

•

COL0 N

339

Paneth cell metaplasia •

•

4

Although Paneth cells are normal constituents of the small bowel, right colon , and transverse colon, their presence in the descending colon, sigmoid , and rectum is always abnormal (Figs . 4 . 9 2-4 94) .

Increased lamina propria chronic inflammation Architectural distortion (Figs . 4 . 95-4 . 9 8 ) , compare to normal colon architecture (Figs . 4 . 2 , 4 . 3 , 4 . 6 , and 4 . 7) •

Villonodular surface

•

Abnormal crypt configuration (Figs . 4 . 99-4 1 02)

Figure 4.94 C h ro n i c co l itis patte rn , Paneth ce l l m eta p l a s i a (arrow) versus endocri n e ce l l s (arrowheads) versus degra n u lating eosi n o p h i l (circle) .

Fig u re 4.95 C h ro n i c col itis pattern, m a rked a ctive c h ro n i c col itis, u l cerative col itis. This b i o psy orig i n ates fro m a pati ent with l o n g ­ sta n d i n g u l cerative colitis. Wh i l e the acute component is best seen at h i g h e r power, featu res of chro n icity a re easily seen at this m a g ­ n ificatio n : vi l l o n od u l a r s u rface, a b n o r m a l crypt confi g u rati o n , crypt shortfa l l , and basa l I y m p h o p l a s m a cytosis (brackets) . N ote the va ry­ i n g sizes of the crypts ra n g i n g from s l i g htly e n l a rged (asterisk) to l a rg e , com p l ex, bra n c h i n g structu res (arrowheads) . Arch itect u ra l d i stortion can b e assessed o n eith e r l o n g itud i n a l ly orientated speci­ mens, a s i n this exa m p l e , o r ta n g enti a l l y e m bedded sections, a s seen i n F i g u re 4 . 9 6 . C o m p a re to a l o n g itu d i n a l p rofi l e o f n o rm a l colon a rch itectu re (Figs. 4 . 2 a n d 4.3 ) .

Fig u re 4.96 C h ro n i c col itis patte r n , m a rked a ctive c h ro n i c colitis, d iversion co l itis. T h i s b i o psy ori g i n ates fro m a patient with active ch ro n i c m u cosa l i nj u ry seco n d a ry to d ivers i o n co l itis. N ote that the a rch itectural c h a n g es can be e a s i l y a ssessed o n ta ngenti a l ly em bedded tissue secti ons, as in this case. The n o n u n iform size a n d d istri bution o f the crypts a re featu res of a rch itectural d i stortio n . Aste risks h i g h l i g h t m i c rocrypts a n d a rrowh e a d s h i g h l i g h t l a rg e , co m p l ex, bra n c h i n g crypts. N o rm a l l y, crypts a re u n iformly d istrib­ uted with u n iform a m o u nts of interve n i n g l a m i n a propri a . This case fea t u res crypt d ro p o u t with l a rg e zones of i n creased a cute a n d c h ro n i c infl a m m atory ce l l s i n t h e l a m i n a propria a n d n o i nterve n ­ i n g crypts (circles) . Compare to ta ngentia l p rofi les o f n o r m a l co l o n a rchitectu re ( F i g s . 4 . 6 a n d 4 . 7 ) .

340

ATLAS

0 F

GAST R0 I N T E S T I NA L

PAT H O LOGY

Figure 4.97 C h ro n i c col itis patte r n , m a rked a ctive c h ro n i c coli­ tis, sigmoid co lon . Crypt a bscesses a re easily see n , as a re featu res of c h ro n i c m u cosa l inju ry, such as a m i l d ly vi l l o n od u l a r s u rfa ce, i ncreased c h ro n i c infl a m m ation i n the l a m i n a propri a , a n d a b n o r m a l crypt confi g u rations a n d d i stri butions.

F i g u re 4 . 9 8 C h ro n i c co l itis patter n , m a rked a ctive chro n i c c o l i ­ t i s , l eft co l o n . Featu res o f c h ro n icity i n c l u d e a v i l l o n od u l a r s u rfa ce, i n creased l a m i n a p ropria c h ro n i c infl a m mation, abnormal crypt con­ fig u rations and d i stributions, and crypt d ropout (asterisks) .

Figure 4.99 Chro n i c col itis patte rn , abnormal crypt confi g u rati o n .

Fig u re 4. 1 00 C h ro n i c col itis patte r n , a b n o r m a l crypt confi g u ra ­ tion, s i g m o i d , d iverticu l a r d isease. T h e a p p e a ra n ce o f th is s i g m o i d biopsy exe m p l ifies c h ro n i c m u cosa l i nj u ry i n the setting o f d iverticu­ lar disease. This image features bifid a n d bra n c h i n g crypts (asterisks) that a re no l o n g e r s u pe ri m posa b l e beca use of varying sizes a n d d is­ tributions. Oth er features of chro n icity i n c l u d e a vil lonodu l a r s u rface, i n creased c h ro n i c i n fl a m m ation in the l a m i n a p ropria, and Pa n eth cel l m eta plasia (circles) .

N o r m a l ly, crypts a re u n iform U - o r tube-s h a ped stru ct u res when viewed i n p rofi l e a n d u n iform c i rcu l a r structu res when viewed tan­ genti a l ly, s i m i l a r to test tubes i n a ra ck o r a bed of flowers (Figs. 4.2, 4 . 3 , 4 . 6 a n d 4.7). When the crypts d e p a rt from this n o rm a l expected confi g u rati o n , a rch itectu ra l d i stortion i s p resent. This centra l crypt rese m b les a bstract a rt, perh a ps a Picasso m use, a m a p of a w i n d i n g river, o r a n u n g racefu l backb e n d . If s i m i l a r wild i m a g e ry a cc u rate ly describes the crypt confi g u rati o n , t h e n a rch itectura l d i stort i o n i s p resent.

•

•

Crypt dropout Crypt shortfall The basal crypts do not sit directly on the muscularis mucosae (Figs . 4 . 1 03 and 4 . 1 04) . Crypt shortfall can occur in the presence or absence of basal lymphoplasmacytosis . Basal lymphoplasmacytosis •

•

•

•

A basal layer of lymphoplasmacytic inflammation prevents the basal crypts from sitting directly on the muscularis mucosae (Figs . 4 . 1 05-4 . 1 09) .

Ch a pter

4

C O L0 N

341

F i g u re 4 . 1 0 1 C h ro n i c col itis patte r n , a b n o rm a l crypt confi g u ra­ tion . B ifid crypts refer to two fused crypts and a re a sign of chro n i c m u cosa l i n j u ry.

Figure 4 . 1 02 Chronic col itis pattern, abnormal crypt configuratio n . This stri king exa m p l e o f a bnorm a l crypt confi g u ration resem bles two people d a n ci n g . If crypts can invoke vivid i m a g e ry, then abnorm a l crypt confi g u ration is present and chronic m u cosal injury h a s occu rred .

F i g u re 4 . 1 03 C h ro n i c colitis patte r n , crypt d ropout a n d crypt s h o rtfa l l . Crypt dropout: at low power, the expected u n ifo rm d istri­ bution of crypts is a bsent; some crypts appear " m issi n g " (asterisks) . Crypt s h o rtfa l l : in additi o n , some crypts a re fl oati n g i n the l a m i n a propri a ; these crypts a re n o t a n ch o red t o t h e m u scu l a ri s m u co­ sae but, i n stead, "fa l l short" of the m u scu l a ri s m u cosae (brackets) . Alth o u g h both the crypt d ropout a n d shortfa l l a re foca l a n d m i l d , they s i g n ify chro n i c m u cosa l i nj u ry.

F i g u re 4 . 1 04 C h ro n i c co l itis patte r n , crypt s h o rtfa l l . At h i g h e r power, we see the crypts "fa l l short" o f the m uscu l a ri s m u cosae based o n a spri n k l i n g of l a m i n a propria con stituents. This exa m p l e i l l ustrates t h a t not a l l cases o f crypt shortfa l l a re d u e to b a s a l Iym­ phoplasmacytosis. Sometimes, crypt sho rtfa l l is due to crypts simply floati n g a bove the m uscu l a ris m u cosae.

F i g u re 4. 1 05 Chro n i c col itis patte rn , basa l I y m p h o p l a s m a cytosis and crypt s h o rtfa l l . T h i s case featu res a c o n s p i c u o u s exa m p l e of basa l lymphoplasmacytosis. N ote the basa l band of intense Iym pho­ p l a s m a cyti c infl a m m ation (brackets) that p revents the basa l crypts fro m d i recti n g sitti n g on the m u scu l a ri s m u cosae (asterisks) . T h i s fi n d i n g is a l ways a bn o rm a l a n d i s a feature of chro n i c m u cosa l i nj u ry.

Fi g u re 4 . 1 06 C h ro n i c co l itis patte rn, basa l Iymphoplasmacytosis. O n h i g h e r power, the band of infl a m matory ce l l s consists predomi­ n a ntly of p l a s m a cel ls , lymph ocytes, eosi n o p h i ls, a n d scattered h is­ tiocytes .

342

ATLAS

0 F

GAST R0 I NT E ST I N A L

PATHO LOGY

Figure 4. 1 07 C h ro n i c co l itis patte rn, basa l Iymphoplasm a cytosis and crypt s h o rtfa l l , Cro h n disease. This bio psy is from a patient with Cro h n disease. I n addition to basa l Iymphoplasmacytosis and crypt shortfa l l (brackets) a l so n ote the bifid crypts (arrowheads) .

Figure 4 . 1 08 C h ro n i c col itis pattern, basa l I ym p h o p l a s m a cytosis. Basa l I y m p h o p l a s m a cytosis is often best appreciated o n low power. An a sterisk h i g h l i g hts the m u scu l a ris m u cosae a n d brackets h i g h ­ l i g h t the basa l Iymphoplasmacytosis a n d crypt shortfa l l .

Fig u re 4 . 1 09 C h ro n i c co l itis patte r n , basa l I y m p h o p l a s m a cyto­ sis a n d crypt shortfa l l (brackets) . Asterisks h i g h l i g h t the m u scu l a ris m u cosae. Of all the histologic features of chronicity, the assessment of architectural distortion is perhaps the most subj ective . Recall , the normal colon has a flat surface with uniform-sized crypts separated by uniform amounts o f lamina propria , which rest directly on the mus­ cularis mucosae (Figs . 4 . 2 , 4 . 3 , 4 . 6 and 4 . 7) . Normal colon architecture is analogous to "test tubes in a rack" with each crypt (or test tube) nearly identical to and superimposable on its neighbor because of similar size, shape, and distribution. In contrast , architectural distortion may feature a villonodular surface with crypts of various widths , heights , and distribution . These haphazard crypt configurations are no longer superimposable because of dissimilar size , shape, and distribution (Figs . 4 . 99-4 . 1 02 ) . The variable lamina pro ­ pria can result in "crypt dropout," or dissolution of the expected uniform crypt distribu­ tion . Although normal basal crypts have an orderly and neat arrangement directly above the muscularis mucosae , architectural distortion often features crypts that fall short of the muscularis mucosae ("crypt shortfall') (Figs . 4 . 1 03 and 4 . 1 04) . Crypt shortfall can occur in the presence or absence of basal lymphoplasmacytosis (a variably thickened band of lymphoplasmacytic inflammation that prohibits the basal crypts from having an orderly arrangement with the muscularis mucosae) (Figs . 4 . 1 05-4 . 1 09) .

C h a pte r

Figure 4. 1 1 0 C h ro n ic col itis patte r n , m i l d active c h ro n i c col itis. M i l d a ctive chro n i c changes a re subtle a n d often n ot u n e q u ivoca l ly a p p a rent at low power, as i n this case. This rectal biopsy has a cute i n j u ry in the fo rm of foc a l cryptitis (not shown) and c h ro n ic i nj u ry (m i l d l y i n creased l a m i n a propria chro n i c infl a m mation a n d foca l Pan­ eth ce l l meta p l a s i a , n ot shown).

4

C O L0 N

343

Fig u re 4 . 1 1 1 C h ro n i c c o l itis pattern, m a rked active chro n i c colitis. M a rked changes wou ld be u n ive rsa l l y recogn ized by m ost path olo­ g i sts beca u se the fi n d i n g s a re p ro m i n e ntly d i sp l ayed . This rect a l biopsy sh ows m a rked c h a n ges w i t h a vi l lonod u l a r surfa ce, ch ro n i c infl a m m ation i n the l a m i n a p ropri a , w i l d l y abnormal crypt confi g u ra­ tions, crypt d ropout, crypt shortfa l l , a n d basal lymphoplasm acytosis.

Chronic colitis can be further classified as either active or inactive depending on the presence or absence of a concomitant acute component . Active chronic colitis includes histologic features of chronicity AND a concomitant acute component (ulceration, erosion, cryptitis , and or crypt abscess) , whereas inactive chronic colitis refers to any of the histo­ logic features of chronicity in the absence of an acute colitis component .

STE P 2 : G RA D E TH E CO LITIS AS M I LD, M O D E RATE, O R MARKE D "Colitis" is a broad term that describes a spectrum of mucosal injury. It describes histologic features of inj ury whether seen in isolation or combination, and regardless of the promi­ nence or extent of disease ; for example , the term "chronic colitis" appropriately describes a sigmoid biopsy with five isolated Paneth cells as well as a sigmoid biopsy showing marked architectural distortion, crypt shortfall , basal lymphoplasmacytosis , and 55 Paneth cells . * * A s a result, additional descriptors allow for a more precise description of the pathology and can be helpful in monitoring the evolution of disease course and therapy response . Colitis can be qualified as mild, moderate , or marked depending on the overall intensity of the mucosal injury. Mild changes are quite subtle to the extent that not all pathologists would agree on offiCially recognizing, or findings that are not readily apparent at low p ower (Fig. 4 . 1 1 0) . Marked changes encompass all features described above and in prominent proportions ; these changes would be universally agreed on by most, if not all pathologists (Fig. 4 . 1 1 1 ) . Moderate changes , literally, fall in between those of the mild and marked categories (Fig . 4 1 1 2 ) .

STE P 3 : CLI N I CO PATHOLOG I C CO R R E LATI O N , "SEE N OTE" Steps 1 and 2 can b e performed i n a vacuum because pure morphology dictates colitis classification and grading. The far more interesting aspect of this three-step pattern-based approach is the final step . In step 3, the histologic findings are situated in the specific clinical setting. The entire clinicopathologic context is integrated to share the pathologist'S particu­ lar perspective on this particular mucosal injury pattern . This note cannot be "quick-texted" or "macro-ed" for mass reproduction because it is based on the unique clinicopathologic

* * Thankfully, it is not necessary to count pyloric and Paneth cells for the diagnOSiS of pyloriC gland metaplasia or Paneth cell metaplasia , respectively.

344

AT LAS

0 F

GAST R0 I N T EST I N A L

PAT H O LOGY

Figure 4. 1 1 2 Ch ro n i c colitis patte rn , moderate active c h ro n i c coli­ tis. Moderate changes a re m o re conspicuous th a n those of the m i l d category a n d a re identifi a b l e at l o w power, as i n t h i s case. Th is recta l biopsy sh ows a vi l l o n od u l a r s u rface, i n creased chro n i c infl a m mation i n the l a m i n a propria, a b n o r m a l crypt confi g u rations with bifid and q u a d rafid g l a nds, a n d crypt d ropout.

features of the unique case in question . The succeeding section will introduce and empha­ size clinicopathologic "red flags" to quickly home in on the underlying etiology and to guide direct etiologic specific therapy. Sample notes are included to illustrate the utility of the three-step pattern-based approach to colitis.

FAQ: What time fra m e is req u i red fo r the deve l o p m e nt of featu re s of chronic m u cosal i nj u ry? Answer: S u rp r i s i n g l y, h i sto l o g i c featu res of c h ron i c m u cosa l i nj u ry can be seen with as few a s 7 2 h o u rs of i nj u ry, any sort. Th i s i n c l u d e s at l e a st 3 d a ys of d i a rrh ea due to self- l i m ited i nfect i o n s , m e d i cations, e m e rg i n g l B O, a m o n g m a n y oth ers. As a resu lt, featu res of c h ro n i c ity m e re l y confi rm at l e a st 7 2 h o u rs of m u cosa l i nj u ry ; they a re pathog n o m i c fo r n o specific eti o l ogy. Adopt i o n o f the th ree-step patte rn­ based a pp roach to c o l i t i s s e rves a s s i m p l e , com p re h e n s ive g u i d e to n a v i g a t i n g th i s n o n specific i nj u ry p a ttern .

I N FLAM MATO RY BOWEL D I S EAS E IBD is a chronic systemic inflammatory disease whose maj or disease manifestations impact the gastrointestinal tract (GlT) . IBD can be further subclassified as Crohn disease , ulcerative colitis , and type-indeterminate . The type-indeterminate category is a provisional category reserved for those 5 % to 1 0 % of cases that cannot be definitively delineated into the Crohn or ulcerative colitis category because of conflicting or insufficient clinicopathologic evi­ dence . Eighty percent of the type-indeterminates are eventually classified as either ulcer­ ative colitis or Crohn disease within the subsequent 8 years based on evolving clinical , radiographic, and histologic evidence 2 1 Ulcerative colitis and Crohn disease constitute the maj ority of IBD and are seen in 4 to 20 per 1 00 ,000 persons in the United States . All subtypes are enriched in Caucasians and Ashkenazi Jews , with males more commonly affected in ulcerative colitis and a female bias seen in Crohn disease 22 In general, IBD displays a bimodal distribution of age at time of first presentation. The first wave of patients present between 1 5 and 30 years of age and the second peak occurs between 60 and 70 years . Most patients present with a history of bloody diarrhea and weight loss and the disease course is characterized by alternating periods of disease flares and remissions . Endoscopically, both ulcerative colitis and Crohn disease

Ch a pte r

4

C O L0 N

34S

display variable loss of vascular pattern , erythema , friability, erosions , and ulcerations . Histologically, both are characterized by active chronic inflammatory injury Although IBD primarily affects the intestinal tract, 1 0 % to 1 5 % of patients have extraintestinal manifesta­ tions , including ankylosing spondylitis, seronegative arthritis , primary sclerosing cholangitis, conjunctivitis, iritis , episcleritis , uveitis , anemia , pyoderma gangrenosum , and erythema nodosum . Patients with ulcerative colitis and HLA-B27 carry a particularly strong risk of ankylosing spondylitis and uveitis . Stomatitis and oral aphthous lesions/ulcerations are more common in Crohn disease . All IBD patients will eventually enter a surveillance program based on an increased risk of neoplasia . Surgical candidates include patients who develop neoplasia and those whose symptoms fail medical treatment .

FAQ: If the c l i n icopath ologic d ia g n osis is l B O , why s h o u l d we bother with fu rt h e r s u b c l assificati o n as u l cerative co l itis o r Crohn d isease? W h y d o e s s u bclassifica­ tion matter? Answer: Co rrect I B D s u b c l a ss i fi cati o n is critica l to e n s u re a p p ro p ri a te s u rg i ­

ca l m a n a g e m e n t . U l ce rative col itis m a y b e m a n a g ed with re m ova l o f t h e enti re co l o rectu m beca u se the enti re c o l o re ctu m i s at risk fo r the i n fl a m m atory d i sea se­ dysp l a s i a-ca rc i n o m a seq u e n c e . In contrast, the sta n d a rd of ca re in Cro h n d i se a se is conservative seg m e nta l resect i o n to preserve as m u c h of the bowe l l e n gth (a n d q u a l ity o f l ife) a s poss i b l e beca use o f t h e i n c rea sed risk o f su bseq u e n t G I T i nj u ries and bowe l - s h o rte n i n g s u rgeries. Anoth e r i m porta nt s u rg i ca l m a n a g e m e n t con s i d ­ e rati o n centers on the o pti on o f the i l ea l - pouch a n a l a n a sto m o s i s ( I PAA) . I PAA i s the p refe rred s u rg i ca l o pti on fo l l ow i n g a tota l p roctocol ectom y beca u se it a l l ows fo r G I T conti n u ity a n d p reservation of the a n a l sph i n cter ( F i g s . 4 . 1 1 3 and 4 . 1 1 4) .

"-... Anus Figure 4. 1 1 3 N o r m a l bowel a n atomy featu res the co l o n d ra ped over a n d fra m i n g the sma l l bowe l .

Figu re 4 . 1 1 4 I lea l-pouch a n a l anastomosis ( I PAA) . Closure of a tota l proctoco l ectomy req u i res either an ostomy/stom a site or an I PAA (in this i l l ustration the co l o n is " g rayed out" to represent rem ova l). I PAA is the p referred surgica l a pproach because it m a i ntains G IT conti n u ity a n d avoids the need for a permanent ostomy bag (see F i g . 4 . 1 1 5) . I PAA involves anastomosis o f t h e i l e u m t o t h e a n u s . A rese rvoi r is cre­ ated by stitch i n g two l oops of i l e u m together and rem ovi ng the i nter­ n a l wa l l s . The resu lti n g reservoi r is i n the shape of a " J " a n d often termed a "J-pouch . " I PAA is the sta ndard of ca re foru lcerative co l itis pati ents but is genera l ly contra i n d icated i n Crohn cases beca use of i n creased risks of disease fl a res. I n stead, Crohn disease patients a re offered a perm a nent ostomy (either an i l eostomy or col ostomy) .

346

ATLAS

O F

GASTRO I N T E ST I N A L

PAT H O LO G Y

Patients with u l cerative c o l itis a re e l i g i b l e fo r a n I PAA b u t those with Cro h n d i s­ ease a re n ot, i n g e n e ra l , based on t h e i n creased risk of d i sease fl a res a n d pouch co m p l i cati o n s . I n stead , C ro h n d i sease patie nts a re offe red a perm a n e nt osto m y : the b o w e l i s atta ched to t h e a nte ri o r a bd o m i n a l wa l l a n d o p e n s i nto a n ostomy bag t h ro u g h w h i c h the feca l stre a m exits, n ecessitati n g a d d iti o n a l hyg i e n e a n d m a i nten a n ce issues ( F i g s . 4 . 1 1 5-4 . 1 1 6) . Co rrect I B O s u b c l a ssifi ca t i o n i s critica l to e n s u re o pti m a l s u rg i ca l m a n a ge m e n t a n d req u i res awa re n ess of the I B O " ru l e s " ( c l a s s i c I B O presentati o n s) , the I B O " re a l ities" ( n o n c i a ss i ca l l B O p resentations), a n d I B O m i m ics, d i scu ssed su bseq u e n t l y.

Colon

""

I le u m

Hartmann pouch

F i g u re 4 . 1 1 5 I l eostom y. In this i l l ustrati o n , the backg ro u n d col­ o rectum is shaded g ray to re prese nt a prior tota l p roctoco l ectom y. An i l eostomy i n vo lves bri n g i n g the sm a l l bowel thro u g h the anterior abdom i n a l wa l l to form a stom a site. The bowel is then attached to a n ostomy bag thro u g h which the fecal stream exits.

Fig u re 4 . 1 1 6 Col ostom y (with H a rtm a n n p o u c h ) . A col ostomy i nvolves bri n g i n g the colon thro u g h the a n terior abdom i n a l wa l l to fo rm the stom a site. The ostomy bag is then atta ched to the sto m a , thro u g h w h i c h the fecal stre a m exits. An additi o n a l H a rtm a n n pouch p roce d u re is someti m es performed under em e rgent conditions o r when there is i n s ufficient hea lthy bowe l fo r p ri m a ry a n a sto m osis. The H a rtm a n n p roce d u re i nvolves sewi n g over the p roxi m a l rec­ tum so that the rectum rem a i n s in situ a s a b l i n d pouch ( H a rtm a n n pouch). Th is pouch is excl uded from t h e feca l stre a m a n d su scep­ tible to d iversion col itis.

Inflammatory Bowel Disease " Rules" : Classic Presentations The IBD "rules" are among the first concepts introduced in medical school, emphasizing their fundamental clinical importance . The rules enumerate the discriminating features of ulcerative colitis and Crohn disease , allowing their reliable distinction. The rules sum­ marize ulcerative colitis as a mucosa restricted process that starts at the rectum and pro­ gresses in a diffuse manner toward the proximal colon (Figs . 4 . 1 1 7-4 . 1 1 9 ) . According to the rules, these changes are limited to the colorectum and pseudopolyps are restricted to ulcerative coliti s . In contrast , the rules dictate that Crohn disease is a transmural disease with p ossible upper GIT involvement, rectal sparing , and a patchy progression pattern, resulting in "skip lesions . " As a result o f transmural involvement, predictable transmural pathology is to be expecte d , including a stiff or "pipe"-like b owel wall , creep­ ing fat , fissure s , fistulas , strictures, sinus tracts , and transmural lymphoid aggregates and fibrosis (Figs . 4 . 1 2 0-4 . 1 24) . In addition , according to the rules , mucosal "cobbles toning"

Ch a pte r

4

C O L0 N

347

Fig u re 4 . 1 1 7 I B D " ru l es, " u l cerative col itis, g ross exa m i nation . G ross exa m i nation can revea l h e l pfu l d i a g nostic c l u es to the d i a g ­ n o s i s o f u l ce rative col itis versus Cro h n d i sease. F i rst, note that this speci m e n is a tota l p roctoco lectomy, the sta ndard of care fo r u l cer­ ative co l itis patients. Additi o n a l clues to the d i a g n osis of u l cerative co l itis incl ude recta l-based d i sease that p rogresses in a d iffuse m a n ­ n e r. Lastly, the wa l l is o f avera g e thickn ess a n d wo u l d fee l fl o p py upon exa m i n ation; both features sugg est m u cosa-restricted d i sease.

Figure 4 . 1 1 8 I B D " ru l es, " u l ce rative col itis, g ross exa m i n ati o n . T h i s speci m e n sh ows s i m i l a r featu res ascribed t o classic u l cerative co l itis, i n c l u d i n g d iffuse d i sease progression and a thin bowel wa l l secondary t o m u cosa-restricted d i sease.

Fig u re 4 . 1 1 9 Chro n i c colitis patte rn, IBD " ru l es, " u l ce rative col itis. This image rep resents h isto l o g i c features ascribed to classic u l cer­ ative co l itis. The m u cosa is a l m ost entirely u l cerated, a n d i n creased m u cosa l a cute and c h ro n i c infl a m m ation a re see n . Also n ote that the bowel wa l l is of average th i ckness seco n d a ry to m u cosa-restricted d i sease.

Figure 4 . 1 20 I B D " ru l e s , " C ro h n d i sease, g ross exa m i n a ti o n . T h e fi rst g ross c l u e t o t h e d i a g n os i s o f Cro h n d isease is the seg­ m e nta l n a t u re of t h e speci m e n . S e g m e n ta l resect i o n s a re the sta n d a rd of c a re fo r C ro h n d i sease patients based on the patchy d i sease d i stri b u t i o n and p ro p e n s ity for futu re bowel s h o rte n i n g operati o n s . Tra n s m u ra l disease m a n ifests with tra n s m u ra l path o l ­ o g y : 1 . An o bstru ct i n g strictu re was t h e i n d i cation for t h i s resec­ t i o n (a rrow) ; 2. The bowel wa l l i s t h i ck, fi b rotic, and wo u l d fe e l " p i pe - l i k e " o r h eavy a n d i n fl exi b l e on g ross exa m i n ation (a rrow­ heads); 3 . The e d g e of the spec i m e n d e m o n strates " cree p i n g fat " o r i rreg u l a r a n d sca rred serosa l f a t fro m re peated bouts o f tra ns­ m u ra l d i sease (bracket) .

i s unique t o Crohn disease and describes alternating linear ulcerations with edematous mucosa (Figs . 4 . 1 2 5 -4 . 1 2 6) . O f all of the rules , those that most consistently p oint to Crohn disease inclu de epithelioid granulomata and transmural inflammation and lym­ phOid aggregates away from inj ured mucosa. Classic IBD presentations abide by the aforementioned rules and allow reliable subclassification as ulcerative colitis or Crohn disease (Fig. 4 . 1 2 7 , Table 4 4) .

348

ATLAS

0 F

GAST R0

,\I T E S T I N A L

PAT H O LOGY

Figure 4. 1 2 1 I B D " ru l es, " Cro h n d isease, g ross exa m i n ation . This case a l so featu res classic sti g m ata associated with typica l C ro h n d isease, i n c l u d i n g patchy tra n s m u ra l disease: n ote t h e seg m e n ta l n atu re of the resection), thick bowel wa l l , a n d fistu l a (fo rceps) . A n a rc h i g h l i g hts pseudopolyps, a feature traditi on a l ly descri bed in u l cer­ ative col itis, accord i n g to the I B D " ru l es. "

Figure 4. 1 22 I B D " ru les, " Cro h n d isease, g ross exa m inati o n . This segmenta l resection d i s p l ays n u me rous stri ctu res (hi g h l i g hted by tooth picks) i n a patient with a lon g-sta n d i n g history of Crohn disease. Each bowel resection leaves the patient with prog ressively l ess bowe l a n d may result in i ncreased d i a rrhea a n d fu rther com p l i cations. As a resu lt, segmenta l resections a re the sta nda rd of care for patients with Cro h n disease i n an effort to p reserve bowel length and q u a l ity of l ife .

Figure 4. 1 23 C h ro n i c co l itis pattern, I B D " ru l es, " Cro h n d isease. This resect i o n speci m e n d e m o n strates c l a ss i c fea t u res typica l l y ascribed t o Cro h n d isease, i n c l u d i n g tra n s m u ra l lym p h o i d a g g re­ gates, g ra n u l omata , and fi brosis. The overly in g m u cosa shows a ctive chro n i c i nj u ry as we l l , features best seen at h i g h e r power.

Figure 4 . 1 24 C h ro n i c colitis pattern, I B D " ru l es, " Cro h n d i sease.

Figure 4. 1 25 I B D " ru l es, d i sease, g ross exa m i nati o n . This ton i n g , a featu re m ost com m o n ly i m a g e i l l u strates m u cosa l ( associated with Cro h n d i se, e . ls pattern is a resu l t of l i n e a r u l ce r­ ations and interve n i n g m u cos� . tOdema a n d rese m bles cobbl estoned streets.

F i g u r e 4. 1 26 I B D " ru l es, " C ro h n d isease, g ross exa m i n atio n , m ucosa l cobblesto n i n g .

H i g h e r power i l l ustrates a n u m be r of l a rge g ra n u l o m ata .

Ch a pte r

....,. .

Figure 4. 1 27 C h ro n i c co l itis pattern , I B D " ru l es," " m a croscopic" exa m i n ati o n . H e l pfu l d i a g n ostic c l u e s to the d i a g n o s is of u l ce r­ ative col itis versus Cro h n d i sease can a l so be gathered by looki n g at t h e g l ass s l i d es from a c ross t h e roo m , with out even u s i n g the m i crosco p e ! I l l u strated a bove a re two u n i q u e tota l p roctocol ec­ tomy resection speci m e n s a rra n ged i n six para l l e l s l ides (from top to bott o m : a p pe n d ix, cecu m , asce n d i n g co l o n , tra n sverse co l o n , l eft co l o n , a n d , fi n a l l y, rect u m ) . T h e case o n the l eft shows m u co­ sal restricted disease that diffuse ly i n volve a l l s l i des, perh a ps most severe i n the rectum where the m u cosa is entire l y she a red off. The case o n the right d i s p l ays tra n s m u ra l d i sease, n ote the thick bowel wa l l . Also n ote the patchy d i sease d i stri bution with d i seased sec­ tions i n te rru pted by u n i nvo lved seg m ents. Recta l sparri n g is pres­ ent. Without u s i n g the m icroscope, we have gathered h e l pfu l clues that favor classic u l cerative col itis i n the case o n the l eft a n d classic Cro h n d i sease i n the case o n the ri ght.

SAM P L E N OTE: C LI N ICAL H ISTORY OF A LONG· ESTABL I S H E D U LC E RAT I V E COLITIS H I STORY

Rectum, Biopsy: •

Marked active chronic proctitis .

Note: The history of ulcerative colitis is noted. The biopsy shows marked active chronic proctitis with cryptitis , crypt abscesses , architectural distortion , and increased chronic inflammation. These findings support the established history of ulcerative colitis . Negative for dysplasia, granulomata , and viral cytopathic effect.

4

C O L0 N

349

350

AT LAS

0 F

GAST R0 I NT E ST I N A L

PAT H O LOGY

TABLE 4.4: I n f l a m m ato ry Bowel Disease " Rules" U l ce rative Colitis

Cro h n Disease

Active c h ro n i c co l itis

Yes

Yes

Depth of i n volve m e n t

M u cosa l restricted

Tra n s m u ra l

R e cta l i n volvement

Yes

No

P rog ress i o n patte rn

D iffuse, m ost severe d i sta l l y

Patchy ( " s k i p l e si o n s " )

U p per tract a n d s m a l l bowel i n v o l v e m e n t

No

Yes

Pse u d o polyps

Yes

No

" P ipe_ l i k e " bowel wa l l

No

Yes

" C ree p i n g fat "

No

Yes

Fissu res, fi st u l a s, stri ctu re s, s i n u s tra cts

No

Yes

M u cosa l " co b b l esto n i n g "

No

Yes

Tra n s m u r a l l y m p h o i d a g g regates

No

Yes

Tra n s m u r a l fi b rosis

No

Yes

G ra n u l o m ata

No

Yes

SAM PL E N OTE : N O C L I N ICA L H I STORY P ROVI D E D; T H I S SAM PL E N OT E IS R E F E R R E D TO AS "G E N E RA L C H RO N I C CO LITIS" I N S U BS E QU E NT S U BS E CT I O N S Note: The earlier findings are etiologically nonspecific and can be seen i n the following settings : diverticular disease , diversion-associated colitis , syphilitic and lymphogranuloma venereum proctocolitis , * * chronic nonspeCific infection, chronic medication inj ury, and inflammatory bowel disease , among others . Clinical correlation is required .

Reference: Arnold CA, Limketkai EN , llIei PE, et al. Syphilitic and lymphogranuloma venereum (LGV) procto­ colitis : Clues to a frequently missed diagnosis . Am ] Surg Pathol. 2 0 1 3 ;3 7 ( 1 ) : 38-46. * * I f sexually transmitted infectious proctocolitis is a clinical consideration, clinical studies provide the best means to establish this diagnosis (syphilis: serum RPR, RPR titer, and a treponemal specific serology such as fluorescent treponemal antibody; lymphogranuloma venereum (LGV) : rectal swab collected in the absence of lubricant for Chlamydia trachomatis nucleic acid probe test or culture and LGV PCR) .

FAQ: I s it reaso n a b l e to top- l i n e a d i a g nosis as u lcerative co l itis or Crohn disease a n d e l i m in ate t h e note?

Answer: Top- l i n i n g a d i a g n o s i s of I B O wo u l d be d i scou ra g e d based on the i n h e r­ e n t co m p l exities of the c h ro n i c co l it i s patte rn . Reca l l , the c h ro n i c col itis patte rn i s eti o l o g i ca l ly n o n specifi c . T h e re a re no pathog n o m i c featu res of I B O ; there a re n o h i sto l o g i c featu res that ca n re l i a b l y d i st i n g u i sh I B O fro m d ive rtic u l a r d i se a s e , d ivers i o n -a ssociated co l itis, syp h i l it i c o r L G V proctoco l itis, cord c o l itis syn d ro m e , i p i l i m u m a b co l it i s , vascu l itis, rad i at i o n i nj u ry, a u to i m m u n e d i seases, a m o n g oth e rs ; t h e refo re, the th ree-step a p p ro a c h to c o l itis i s s u g g ested i n a l l c a s e s : c l a ssifica­ tion (step 1 ) , g ra d e (ste p 2 ) , a n d c l i n i co p a th o l o g i c corre l ation/ " see n ote " (ste p 3) (Fig. 4 . 89) . Th i s syste m a t i c a p p ro a c h ca n be u n iversa l l y a p p l i e d to a l l cases of ch ro n i c col itis, reg a rd l ess of the com p l exity. In th is m a n n e r, the th ree-step a p p roach a l l ows fo r a deta i led m o rp h o l o g i c d e scri pti o n and con s i d e ration of the re levant d iffe rentia l eti o l og i es i n the specific c l i n icopath o l o g i c setti n g .

Ch a pter

Inflammatory Bowel Disease " Reality " : Nonclassic I B D Presentations Table 4 . 4 captures the "rules" of IBD , whereas this section briefly discusses the "reality" of IBD , otherwise known as the nonclassic IBD presentations . The essential message is that every "rule of IBD" has a known exception. Awareness of the spectrum of nonclassical pre­ sentations allows for an appreciation of both the breadth and depth of IBD and is critical for accurate diagnosis and appropriate clinical management. The discussion below pairs the select "IBD rule" with its corresponding "reality" to emphasize the challenges of navigating the chronic colitis pattern . These inherent complexities further emphasize the utility of the descriptive three-step pattern-based approach to colitis .

Depth of Involvement "Rule": Ulcerative colitis is mucosa restricted and Crohn disease is transmural. Depth of Involvement "Reality ": Ulcerative colitis can be transmural and Crohn disease can be mucosal restricted. In reality, Crohn disease is occasionally superficial or limited to the mucosa. These cases are referred to as "ulcerative colitis-like" Crohn disease or "superfiCial Crohn disease" in the literature 23 Likewise , severe ulcerative colitis disease flares can present with transmural disease , such as in the rare case of toxic megacolon (Fig. 4 . 1 2 8) . Toxic megacolon is a life­ threatening condition associated with a 16% mortality rate and seen in up to 10% of hospi­ tal admissions for ulcerative colitis 2 4.25 Criteria include colonic dilatation greater than 6 cm and systemic toxicity. Although 4 6 % are associated with ulcerative colitis, toxic megacolon can also be seen in Crohn disease (2 . 3 % ) , Behc;:et disease , infections (particularly C. diffi cile) , ischemia, collagenous colitis , lymphoma , and medication injury 2 4-26 The pathogenesis may relate to a combination of acute and extensive transmural inflammatory damage , ischemia , and local increased nitric oxide levels leading to smooth muscle relaxation and dilatation 26 Emergent proctocolectomy is common and often accompanied by high-dose intravenous steroids (assuming infections have been excluded) and correction of underlying and associ­ ated abnormalities such as dehydration , electrolyte disturbances , and anemia.

Disease Progression "Rule": Ulcerative colitis is rectal based and progresses in a diffuse manner, and Crohn disease spares the rectum and progresses in a patchy manner. Disease Progression "Reality ": Ulcerative colitis can spare the rectum and show patchy disease distribution, and Crohn disease can involve the rectum and progress in a diffuse manner.

Fig u re 4 . 1 28 I B D " re a l ity, " defy i n g the d e pth of involvement " ru l e . " The depth of involvement ru l e is that u l cerative co l itis i s m u cosa l restricted a n d Cro h n d i sease is tra n sm u ra l , but the reverse ca n be the rea l ity. This i m a g e re p resents an e m e rgent col ectomy for toxic m egacolon i n a patient with severe u l cerative colitis. N ote the d iffusely edematous a n d bl oody speci m e n . The co rrespond­ i n g h isto l o g i c sections sh owed tra n s m u ra l a ctive c h ro n i c col itis (not shown), e m p h asizi n g that u l ce rative col itis can d efy the " depth of i nvolvement ru l e " in seve re a n d a cute cases.

4

C O L0 N

351

352

ATLAS

0 F

GAST R0 I N TE S T I N A L

PAT H O LOGY

Figu re 4 . 1 29 I B D " rea l ity, " defying the d isease p rogression " ru l e . " T h e d i sease p rog ression ru l e is that u l cerative col itis is recta l based and p rog resses i n a d iffuse m a n n e r and Cro h n d isease spares the rectum a n d progresses i n a patchy m a n n er. The rea l ity is that u l cer­ ative colitis can show recta l spari n g a n d (th erefore) show patchy d i s­ ease d i stribution a n d Cro h n disease ca n be m u cosa l restricted a n d d iffusely involve t h e colorectu m . T h i s tota l p roctocol ectom y speci­ men o ri g i n ates from a patient with u l ce rative col itis who deve loped flat, m u ltifoca l dysp l a s i a , req u i ri n g defi n itive s u rg i c a l m a n agement. N ote the re l ative recta l-spari n g (bracket) . Recta l spari n g i n u lcerative col itis is m ost com m o n i n the setti n g of treatment effect, p a rti c u l a rly i n patients u s i n g recta l steroid enemas, a n d i n the pediatric setti n g . Recta l spari n g s h o u l d n o t detract from t h e esta bl ished d i a g n osis of u l cerative col itis.

Figure 4 . 1 30 IBD " real ity, " defying the d i sease progression " ru l e . " T h e ceca l red patch/peri a p p e n d i c i a l d i sease is a n other very i m por­ tant I B D exception seen i n up to 86% of u l cerative co l itis patients. This tota l proctocol ectomy speci m e n orig i n ates from a patient with u l ce rative col itis refracto ry to m e d i ca l m a n a g em ent. N ote the d if­ fuse d i sease p rocess from the rectum (asterisk) thro u g h the tra ns­ verse co l o n , a bit of right co l o n m u cosa l clearing (bracket), and a b l u s h of e rythema s u rro u n d i n g the a ppendic ea l o rifice (arc) . The bi opsy sh owed m a rked a ctive c h ro n i c col itis s i m i l a r to that seen in the rectum (not shown). Those not aware of this i m porta nt IBD " real­ ity" may m isi nterpret these fi n d i n g s a s representi n g patchy d i sease and (erroneousl y) ra ise concerns fo r Cro h n d isease. M i scl ass ifica­ tion as Cro h n d i sease wou l d res u l t i n s u rg i c a l m i s m a n a g ement with a perm a n ent osto my performed fo r Cro h n d isease i n stead of the p refe rred I PAA performed fo r u l cerative colitis. The ceca l red patch/ p e ri a p p e n d icea l d isease i s enti re l y consistent with this patient's esta bl ished h i story of u l cerative col itis.

The reality is treated or severe Crohn disease can exhibit rectal-based or confluent disease , manifesting as diffuse disease progression . Similarly, ulcerative colitis can defy the disease progression rule by showing patchy disease progression , findings most com­ monly seen in the setting o f treatment effect or in children 2 7 ,28 N otorious diagnostic pitfalls in ulcerative colitis include rectal sparing, which occurs in up to 64% of ulcerative colitis patients at some point , and can be enhanced by medical therapy (Fig 4 . 1 2 9) 2 7 , 29 The cecal red patch, also known as periappendicial disease , is another important, under­ recognized diagnostic pitfall in ulcerative colitis (Fig. 4 . 1 3 0) Briefly, this finding is typi­ cally seen with left-sided disease , a spared transverse colon , and a patch of active chronic disease around the appendiceal orifice . This finding is seen in up to 86% of ulcerative colitis cases and , consequently, is a notorious rule-breaker that can erroneously raise , concerns for Crohn disease to those unfamiliar with this IBD "reality. , 30-33 Awareness of this important exception is critical to avoid misclassifying a case o f rectal involved Crohn disease as ulcerative colitis, resulting in the inappropriate surgical management (segmen­ tal resection with permanent ostomy for Crohn disease versus total proctocolectomy with IPAA in ulcerative colitis) .

Upper-Tract Involvement "Rule": Ulcerative colitis is colorectum restricted and Crohn disease can involve the entire CIT Upper-Tract Involvement "Reality": Ulcerative colitis can involve the upper-tract and Crohn dis­ ease can be colorectum restricted. The reality is that ulcerative colitis can extend beyond the colorectum in a variety of settings . Up to 1 7 % of ulcerative colitis cases display "backwash ileitis . ,, 34 This process most commonly occurs in the setting of severe pancolitis whereby the inflammatory milieu refluxes into the contiguous small bowel, resulting in local inflammatory and reactive

Ch a pte r

4

C O L0 N

353

changes in the adj oining 1 to 3 cm of the terminal ileum . The inflammatory changes in the small bowel are usually of the same severity as, if not less than , that of the contiguous colon and there is no association with IPAA pouch complications 34 A study of upper tract biopsies in patients with ulcerative colitis found 1 0 % were associated with diffuse chronic duodenitis described as intense plasmacytosis , patchy cryptitis , variable villous blunting, and reactive changes 3 5 Forty per cent of these patients had pouch complications , raising the possibility that diffuse chronic duodenitis may serve as a surrogate marker for potential pouch complications . Crohn disease can also break the upper-tract involvement rule : the reality is that up to 2 0 % of Crohn disease cases are restricted to the colorectum 36 Aware­ ness of this upper tract involvement rulelreality is critical for proper IBD subclassification and surgical management.

Fissures and Transmural Lymphoid Aggregates and Infl ammation" Rule": These fi ndings are unique to Crohn disease. Fissures and Transmural LymphOid Aggregates and Infl ammation "Reality ": Thesefi ndings can be seen in either ulcerati ve colitis or C rohn disease. The reality is that up to 2 7 % of ulcerative colitis resection cases show fissuring ulcers 37 and these cases are more likely to have fulminant disease with transmural lymphoid aggre­ gates and inflammation. Beware ; fissures and transmural disease do not always signify Crohn disease, j ust as mucosa-restricted disease does not always Signify ulcerative colitis . See also Depth of Involvement "Rule"I"Reality, " this chapter.

Pseudopolyps and Granulomata "Rule": Pseudopolyps are unique to ulcerative colitis, and granu­ lomata are unique to Crohn disease. Pseudopolyps and Granulomata "Reality ": Pseudopolyps and granulomata can be seen in either ulcerative colitis or Crohn disease. The reality is that neither pseudopolyps nor granulomata are pathognomonic for ulcer­ ative colitis or Crohn disease . Granulomata and pseudopolyps can be seen in either set­ ting (Figs . 4 . 1 3 1 and 4 . 1 3 2 ) . Although, ulcerative colitis granulomata are most commonly associated with damaged crypts , Crohn disease granulomata are characteristically po orly­ formed and unassociated with damaged crypts (Figs . 4 . 1 3 3 and 4 . 1 34) .

F i g u re 4 . 1 3 1

IBO " re a l ity, " defying the pseudo polyps " ru l e . " The I B O ru les teach that pseudopo lyps a re u n i q u e to u l cerative col itis, but the rea l ity is that they can be seen i n either u l cerative col itis o r Cro h n d isease. This seg m e nta l resection speci m e n i s from a patient with l o n g-sta n d i n g Cro h n d i sease a n d sh ows n u m e rous pseudopol­ yps (arcs) .

F i g u re 4 . 1 32 I B O " re a l ity, " defying the pseudopolyps " r u l e . " The co rresp o n d i n g h i sto l o g i c section sh ows that the pse udopolyp is n ot a true polyp but, i n stea d , consists of an island of semi-i ntact bowel fl a n ked by severe u l ce rat i o n s (asterisks), resu lti n g in a polypoid a ppeara n ce .

354

AT LAS

0 F

GAST R0 I N T EST I N A L

PAT H O LOGY

Figu re 4 . 1 33 I B D " re a l ity, " defyi n g the g ra n u loma " ru l e . " Although the IBD ru les state that g ra n u lo m ata a re u n iq u e to Cro h n disease, the rea l ity i s they can be seen i n eithe r u l cerative col itis o r Cro h n disease. This exa m p l e i l l ustrates a crypt ru ptu re g ra n u loma, com m o n ly seen i n the setti n g of u lcerative col itis. N ote that the macrophage co l l ec­ tions a re intimately associated with the d a m aged crypt.

Figure 4 . 1 34 G ra n u l om a in Cro h n d isease. In contrast to the crypt ru ptu re g ra n u l o mata of u l ce rative col itis, the g ra n u l o m ata seen i n Cro h n d isease a re often easy t o m i ss, a s i n t h i s exa m p l e . An a rc h i g h l i g hts this m a crophage co l l ecti o n .

SAM P L E N OTE***: ESTABLI S H E D H I STO RY OF LE FT-S I D E D U LC E RATIVE COLITIS AN D N EW, FOCAL P E RIAPP E N D I C EA L D I S EAS E Rectum, Biopsy: •

Marked active chronic proctitis .

Transverse, Biop sy: •

Colonic mucosa with nondiagnostic findings .

Cecum, Biop sy: •

Marked active chronic colitis .

Note: The history of ulcerative colitis is noted . The rectal and cecal biopsies show marked active chronic colitis with cryptitis , crypt abscesses , architectural distortion , and increased chronic inflammation . The transverse colon is unremarkable . The "cecal red patch"/periappendiceal involvement is seen in up to 86% o f ulcerative colitis cases and is compatible with the established history. Negative for dysplasi a , granulomata , and viral cytopathic effect.

References: Mutinga ML, Odze RD , Wang H H , et al. The clinical Significance of right-sided colonic inflam­ mation in patients with left-sided chronic ulcerative colitis. Injlamm Bowel Dis. 2 0 04 ; 1 0(3) : 2 1 5-2 1 9 . D'Haens G, Geboes K, Peeters M , e t al. Patchy cecal inflammation associated with distal ulcerative colitis : A prospective endoscopic study Am ] Gastroenterol. 1 9 9 7 ; 9 2 (8) : 1 2 7 5- 1 2 7 9 . Yang S K , lung HY, Kang GH, et a l . Appendiceal orifice inflammation a s a skip lesion i n ulcer­ ative colitis : An analysis in relation to medical therapy and disease extent . Gastrointest Endosc. 1 999 ;49(6) 74 3-74 7 Groisman GM , George ] , Harpaz N . Ulcerative appendicitis in universal and nonuniversal ulcerative colitis . Mod Pathol. 1 994;7(3): 322-325 .

* * * U no history is provided, see general chronic colitis sample note (JBD subsection, this chapter) .

Ch a pte r

CU RABLE I N F LAM MATO RY BOWEL D I S EAS E M I M I CS As stated earlier, the chronic colitis pattern is challenging because nearly identical histology can be caused by diverse etiologies with differing management strategies . All IBD mimics discussed subsequently are 1 0 0 % curable , assuming the etiology can be identified . S orting through the differential diagnostic possibilities and arriving at the correct etiology requires thorough clinicopathologic correlation. This section will focus on common and emerging IBD mimics with emphasis on the clinicopathologic "red flags" to quickly uncover the causative etiology and the corresponding cure . Owing to the inherent challenges of the chronic colitis pattern , this subsection will illustrate the utility of the three-step pattern­ based approach to colitis . Although this approach requires a bit of chart review, it is essen­ tial to ensure appropriate clinical management and to avoid the diagnostic pitfall of IBD . Remember, not all chronic colitis is caused by IBD .

CH ECKLIST: C u r a b l e I nfl a m matory Bowel Disease M i m ics o

D iverti cu l a r D isease

o

D ivers i o n -Associated Col itis

o

Syp h i l itic and Lym p h o g ra n u l o m a Ve n e re u m Proctoco l itis

o

Cord Co l itis Syn d ro m e

o

I p i l i m u m a b Col itis

o

Res i n s

D IVERTI CU LAR D I S EAS E In the United States, diverticular disease is extraordinarily common, seen in at least 70% of Westernized patients over 80 years of age and accounting for 2 3 % of all patients who present with acute lower gastrointestinal bleeding 38 The formation of colon diverticula is predominantly blamed on the "Western diet" and its low-fiber content . Low-fiber diets result in low-bulk feces with increased transit time , increased muscle bulk due to expanded elastin and collagen deposition , 39-41 tenia shortening, luminal narrowing, and increased intraluminal pressures . As the tenia shorten , the mucosa becomes increasingly redundant and subj ect to prolapse, mechanical, and ischemic damage . Rising intraluminal pressures culminate in herniation of the delicate mucosa and submucosa through weaknesses in the bowel wall , resulting in diverticular formation (Figs . 4 . 1 3 5-4 . 1 40) . Histologically, the active chronic colitis of diverticular disease is indistinguishable from IBD and any other cause of chronic colitis , further emphasizing the utility of the three-step pattern-based approach to colitis (Figs . 4 . 1 4 1 -4 . 1 44) . While a variety of mechanistic theories exist , some propose an immune component because some patients respond to immunosuppression and a small portion eventually progress to IBD (most commonly ulcerative colitis) . 4 2 -44 It is unclear if the diverticular disease-IBD connection is merely coincidental or if diverticular disease can trigger IBD in genetically susceptible individuals . Important red flags to the diagnosis of diverticular disease include a history constipation, gross impression of diverticul a , or tissue origin designated as sigmoid colon in an adult or elderly patient . The nomenclature surrounding colon diverticular disease can be a point of confusion . "Diverticular disease" is the broadest term that encompasses "diverticulosis , " "diverticulitis ," and "segmental coli­ tis associated with diverticulosis" (SCAD syndrome) or "diverticular-associated segmental colitis" (DAC) o

"Diverticulosis" refers to diverticula lacking inflammation . o

o

Colon diverticula are most commonly false diverticula (acquired via increased intra­ luminal pressures and involve only the mucosa and submucosa) .

"Diverticulitis" refers to an epicenter of inflammatory damage within the diverticula with extension into the adj acent bowel wall . o

Diverticulitis is caused by impacted fecaliths .

4

C O L0 N

355

356

AT LAS

0 F

GAST R0 I N TE S TI N A L

PAT H O LOGY

Fig u re 4 . 1 35 Diverticu l a r d isease, e n doscopic i m a g e . Diverticu l a r o rifices a re read i l y a p p a rent d u ri n g en doscopic exa m i n at i o n . They appear a s variably sized m u cosa l outpo u c h i n g s , as seen h e re .

Fig u re 4 . 1 36 Diverti c u l a r disease, resectio n speci m e n . T h i s sig­ m o i d ecto m y resection sh ows n u m e ro u s m u cosa l outpo u c h i n g s (a rcs) o r d i ve rticu l a . The pati e n t p resented w i t h the c l a s s i c triad of d iverti c u l itis: fever, abd o m i n a l p a i n , and l e u kocytosis. I m a g i n g stu d i es reve a l ed a p e rfo ration (instru m e n t) , req u i ri n g e m e rg e n t resecti o n . Alth o u g h u n co m p l i cated cases c a n be treated with a nt i b i otics, bowe l rest, and pain contro l , com p l i cated cases may req u i re s u rg i ca l resecti o n . Co m m o n com p l i ca t i o n s i n c l u d e stric­ t u re , a bscess, fistu l a , obstru ction , c l i n i ca l ly s i g n ifica nt b l e ed i n g , or p e rfo ration .

Figure 4 . 1 37 Divertic u l a r d isease, resecti o n speci m e n . Lon g itu­ d i n a l secti ons show the profi les of n u m e rous d ivertic u l a (asterisks) . Divertic u l a a re m ost l i ke l y to occu r at the wea kest poi nts of the bowel wa l l , between the ta e n i a e a n d a l o n g the vasa recta pen etra­ tion poi nts. Ba sed o n t h i s i n t i m ate association of the d iverticu l a a n d vessels, d iverticu l a r re l ated infl a m m atory d a m a g e ca n resu l t i n d a m a g e t o t h e adj a cent vesse l s a n d , conseq uently, gastro i ntesti n a l bleed i n g .

F i g u re 4 . 1 3 8 D iverti cu l a r d i se a s e , resect i o n spec i m e n . T h i s exa m p l e sh ows a d iverti cu l u m i n association with a n (eva cu ated) h e m o rrh a g i c a bscess cavity (instrument) . This i m a g e e m p h a s izes that diverticu l a r re l ated infl a m m atory d a m a g e can e rode i n to a dj a ­ cent vessels, cu l m i n at i n g i n c l i n i c a l l y s i g n ifi c a n t b l e ed i n g . Als o, n ote the thick bowel wa l l (bracket) fro m repeated bouts of tra ns­ m u ra l d isease.

•

SCAD syndrome or DAC refers to luminal inflammatory damage . •

•

•

In this pattern , the inflammatory changes are generally restricted to the luminal seg­ ment of colon involved by diverticular disease . SCAD syndrome has no requirement for overt features of "diverticulitis" or diverticula centered inflammatory damage ; SCAD is not eqUivalent to "diverticulitis . " Some theorize SCAD syndrome stems from progressed diverticulitis 45

Ch a pte r

4

C O L0 N

357

Figure 4 . 1 39 C h ro n i c col itis patte r n , d iverti c u l a r d isease. Diver­ ticu l a a re classified as true or fa lse d e p e n d i n g on the i n vo lved wa l l l ayers . "True d i verticu l a " a re congen ita l a n d i nvolve a l l l a yers o f the wa l l , i n c l u d i n g the m u cosa, s u b m u cosa , m uscu l a ris propri a , serosa, a n d adventiti a . M eckel diverti cu l u m i s the most com m o n type of true diverticu l u m seen i n the tu b u l a r G IT. See a lso Meta p lasia and H eterotop i a , S m a l l Bowel Cha pter. " Fa lse d iverticu l a " a re a cq u i red outpo u c h i n g s a n d i n volve o n l y the m u cosa and s u b m u cosa, as seen in this exa m p l e . Co l o n d ivertic u l a a re by fa r the most com m o n exa m p les o f fa lse diverticu l a . N ote t h a t t h e d iverticu l u m exte nds deeply thro u g h the bowel wa l l .

Figure 4. 1 40 C h ro n i c col itis patte rn, diverti c u l a r d i sease. At low power, n ote the cl ose association between the diverticu l u m a n d the n e a rby vessel ( a rrow) . W h e n d ivertic u l a r disease-re l ated infl a m m a ­ tory d a m a g e spi l l s o v e r i nto adjacent vessels, c l i n i ca l ly sign ifi c ant bleed i n g can occur.

Figure 4. 1 4 1 C h ro n i c col itis patte r n , d iverticu l a r disease. At t h i s power, features o f c h ro n i city a re easily see n : there is fa r t o o m u c h l a m i n a propria c h ron i c infl a m m ation for the s i g m o i d co l o n ; vari a b l e amou nts o f l a m i n a propria a re s e e n s p l a y i n g the crypts (m i l d a rchi­ tectu ra l d i storti o n ) . Cryptitis a n d P a n eth ce l l m eta p l asia were a lso identified (not a p p a rent at this power) . It is criti ca l to avoid a top l i n e d i a g n osis of s i m i l a r h i stology as I B D based on this n o nspecifi c h i stology.

F i g u re 4 . 1 42 C h ro n i c co l itis patte r n , d i ve rticu l a r d i sease. O n lower power o f t h e p revious case, w e see that t h e a ctive c h ro n i c changes a re confi ned with in t h i s ta ngentia l section o f a d iverticu l u m . T h e u n involved c o l o n i c m u cosa was u n re m a rka b l e . Thus, t h e active chro n i c col itis is due to d i vertic u l a r disease. Rem ember chro n i c co l i ­ t i s i s n ot a lways I B D . A l s o note t h e cl ose p roxim ity o f the d iverticu­ lum to nea rby vesse ls (arcs) .

358

AT L A S

0 F

GAST R0 I N T EST I NA L

PAT H O LOGY

F i g u re 4 . 1 43 C h ro n i c col itis patte r n , d i ve rti cu l a r disease. T h i s i ntermedi ate powe r e m p h asizes a s i m i l a r l esso n . T h i s left co l o n sec­ tion sh ows a ctive c h ro n i c colitis with cryptitis, crypt a bscesses, a v i l l ifo rm m u cosa l s u rfa ce, i n creased l a m i n a p ropria chro n i c infl a m ­ mati o n , a n d Paneth c e l l meta p l a s i a .

F i g u re 4 . 1 44 C h ro n i c col itis patte r n , d iverti c u l a r d i sease. Low power sh ows that the a ctive chro n i c c h a n g es a re confined with i n a d iverticu l u m . The backgro u n d co l o n i c m u cosa was u n re m a rk a b l e ; therefore, the a ctive c h ro n i c i nj u ry w a s ascribed t o diverticu l a r d i s­ ease. Alth o u g h this d i a g n ostic p itfa l l is easy to avoid on resection speci m e n s when the d ivertic u l a a re i m poss i b l e to i g n o re, biopsies of d iverticu l a r o rifices a re n otoriously treacherous, p a rticu l a rly when u n l a be l l e d , beca use the fi n d i n g s can be i n d i sti n g u is h a b l e from th ose of I B D . H e l pfu l red fl ags to the d i a g n osis of d ivertic u l a r d is­ e a se i n cl u d e a h i sto ry of d iverti c u l osis o r tissue orig i n a s s i g m o i d colon i n a n a dult o r elderly patient.

KEY F EATU R E S of Divert i c u l a r Disease: •

Diverticular disease is an extremely common lED mimic.

•

Cause : primarily the "Western" diet.

•

Cure : sigmOidectomy and high-fiber diet.

•

•

Red flags : history or gross impression of diverticular disease , tissue designated as sigmoid colon, and adult or elderly patient. Diverticular disease is a clinicopathologic diagnosis requiring both correlation with the appropriate clinical impression of diverticula and the histologic impres­ sion of active chronic colitis. P EA R LS & PITFALLS

P a t i e nts with d iv e rti c u l i t i s c a n h ave stri k i n g c l i n i ca l ove rl a p with t h o s e with I B D . Extra i ntesti n a l m a n i fe sta t i o n s s u c h a s a rth ro p a t h i e s , a n ky l o s i n g s p o n d y l i t i s , pyod e r m a g a n g re n o s u m , a n d e ryt h e m a n o d o s u m h a ve b e e n d e sc r i bed i n both sett i n g s . 46 P EARLS & P ITFALLS

The h i sto ry o r g ross i m p re s s i o n of d ivertic u l a r d i sease and the d e s i g n at i o n of the tissue site a s " s i g m o i d co l o n " a re ve ry i m porta nt red fl a g s . R e m e m b e r, d ivertic­ u l a r- a ssoci ated co l it i s i s fa r m o re c o m m o n t h a n I B D a n d its m a n a g e m ent i s com­ p l ete l y d i st i n ct. Always consider d iverti c u l a r d i sease before I B D i n b i o psies of the l eft c o l o n showi n g active c h ro n i c c o l itis. PEARLS & P ITFALLS

" D ivert i c u l u m " refe rs to a s i n g l e m u cosa l outpo u c h i n g a n d " d i v e rti cu l a " refe rs to m o re t h a n o n e . W h e n in d o u bt or p ressed fo r t i m e , u se " d iverti cu l a r d isease " beca use th i s term covers both the s i n g u l a r a n d p l u ra l for m s .

Ch a pter

FAQ: What are the H i n chey criteria?

Answe r : The H i nchey c riteria we re ada pted by s u rg e o n s to describe the c l i n i c a l

exte nt of d iverti c u l itis. T h ey p red i ct r i s k of adverse outcomes fo l l owi n g a s u rg i ca l p roced u re . 47 Alth o u g h path o l o g i sts do n ot i n c l u d e the H i n c h ey sta ge i nto fo rma l re ports, it i s h e l pfu l to be awa re of this term i n o l ogy to a p p reci ate the s u rg e o n 's c l i n i ca l i m p ress i o n s .

Sta g e I : Perico l i c abscess o r ph l eg m o n ; r i s k o f d e a t h l ess th a n 5% Sta g e I I : Pelvic abscess; ri sk of death l ess t h a n 1 0% Sta g e I I I : Ge n e ra l ized p u ru l ent perito n itis: risk of d eath 5 % Sta g e IV: Ge n e ra l ized feca l pe riton itis; risk o f d e a t h 5 7 %

FAQ: Where a re c o l o n d iverticu l a most l i k e l y identified?

A n s w e r : D i v e rti cu l a a re m o st l i kely to occu r at t h e wea kest p o i n t of the bowe l

wa l l , between t h e coa l esced , l i n ea r m u s c l e b u n d l e s (ta e n i a e) a n d the vasa recti pen etrat i o n po i nts .

SAM PLE N OTE***: H ISTO RY O F D I VE RTI CU LAR D I S EAS E P ROVI D E D

Diverticular Orifice, Biopsy: •

Marked active chronic colitis .

Note: The history of diverticular disease is noted. The aforementioned findings would sup­ port the clinicopathologic diagnosis of diverticular disease-associated colitis .

DIVERS I O N -ASSOCIAT E D CO LITIS Diversion-associated colitis is an important, curable IBD mimic a n d it is seen i n patients with complicated surgical histories . It is an iatrogenic consequence of surgical detour of the fecal stream away from a segment of colorectum and deprivation of essential luminal elements in the exclu ded bowel segment . Surgical diversion of the bowel is performed when a diseased b owel segment is removed and the remaining b owel is not suffiCiently long to reestablish continuity, the anal sphincter is removed , or the remaining bowel seg­ ment has excessive inflammation that precludes immediate anastomosis . Red flags in the chart may inclu de a history of colonic resection fo r, as an example , diverticular disease, neoplasms , necrotizing entero colitis , intra-abdominal trauma , IBD , and Hirschsprung disease (Fig. 4 . 1 4 5 ) . At least 7 0 % of diverted patients report classic stigmata of diver­ sion-associated colitis , such as abdominal pain , tenesmus, rectal bleeding, and promi­ nent rectal discharge . 4 s. 49 Endoscopic and intraoperative findings include mild to marked mucosal friability, erosions , ulcerations , aphthous lesions or ulcerations , and a nodular mucosa secondary to prominent lymphoid aggregates , restricted to the exclu ded bowel segment (Fig. 4 . 1 4 6) . 49 Corresponding histologic features include a mild to marked patchy or diffuse active chronic colitis with florid lymphoid aggregates , conspicuous ger­ minal centers , and aphthOid lesions or ulcerations (Figs . 4 . 1 4 7-4 . 1 5 2 ) . Diversion -asso­ ciated colitis can occur as few as 3 months following ostomy formation , and its features can persist through the duration o f the diversion (Figs . 4 . 1 5 3 and 4 . 1 5 4) 50 Ostomy reversal is curative with resolution of symp toms seen as early as 2 months following reestablishment of continuity 5 1

* * * I f no history is provided, see general chronic colitis sample note (lBD subsection, this chapter) .

4

C O L0 N

3S9

360

AT LAS

0 F

GAST R0 I N T EST I N A L

PAT H O LOG Y

Figure 4 . 1 45 G u nshot wound to the abdomen , radiog ra p h . This ra d i o g ra p h is of a tra u m a patient who p rese nted with a g u nshot wo u n d to the abdomen (an a rrow h i g h l ig hts the m a i n b u l l et fra g­ m ent) . H is colon was perforated and req u i red emergent resectio n . T h e patient w a s too u n sta b l e fo r i m m ed i ate a n a stomosis a n d , con­ sequently, the p rox i m a l colon was d iverted th ro u g h the a nterior bowel wa l l to fo rm a temporary col ostomy site a n d the rectum was left as a b l i n d pouch ( H a rtm a n n pouch). Any h i story of bowel resec­ tion is a red fl ag for consideration of diversion-associated co l itis. See a l so F i g u re 4 . 1 1 6 .

F i g u re 4 . 1 46 Divers i o n - a ssociated col itis, resect i o n speci m e n . O n ce t h e patient recovered 3 m o nths later, h e retu rned t o t h e oper­ ati n g roo m to reesta blish G I T conti n u ity throug h col ostom y revers a l a n d a n astomosis o f the d iverted colon t o the rect u m . The s u rgeons n oted the recta l m u cosa appeared n od u l a r ( arrows) a n d subm itted a segment fo r h isto logic eva l u atio n .

Figure 4. 1 47 Chro n i c col itis pattern, d iversion col itis. Correspond­ i n g whole mount sectio n s of the rectum show florid lymphoid a g g re­ gates, conspicuous germ i n a l centers, and a phthoid lesions (not seen at this power) .

Fig u re 4 . 1 48 C h ro n i c col itis patte r n , d ivers i o n col itis. H i g h e r power o f p revious case.

KEY F EATU R E S of Divers i o n -Associated C o l it i s : •

•

Diversion-associated colitis is an important lBD mimic. Cause : surgical detour of the fecal stream leads to a short chain fatty acid deficiency in the excluded bowel segment.

•

Cure : reestablishment of bowel continuity

•

Red flags : prior bowel resection.

•

Diversion-associated colitis is a clinicopathologic diagnosis requiring both correla­ tion with the appropriate clinical history of diversion and the histologic impression of active chronic colitis with florid lymphoid aggregates and prominent germinal centers and aphthoid lesions/ulcerations .

Ch a pte r

4

C O L0 N

361

Fig u re 4 . 1 49 Chro n i c col itis pattern, d iversion colitis. This i m a g e sh ows m a rked a ctive chro n i c col itis with cryptitis, crypt a bscesses, i n creased chro n i c infl a m m ation in the l a m i n a propri a , and a rch itec­ tura l d i storti o n . It wou l d be cruci a l to avoid the d i a g n ostic pitfa l l of I B D based on these n o n specific h isto l o g i c fi n d i n gs. This exa m p l e of active chro n i c col itis was d u e to d iversion-associ ated colitis based o n the deta i l e d c l i n i c a l h istory. The patient had a n u n eventfu l recov­ ery fo l l owi ng col ostomy reversa l . S u bsequent recta l biopsies 1 year later were u n re m a rka b l e .

Fig u re 4. 1 50 C h ro n i c col itis patte rn, d iversion colitis. This case of d iversi on -associ ated co l i tis features crypt ruptu re g ra n u l o m ata i n a backgro u n d of active c h ro n i c colitis. These fi n d i n g s supported the c l i n i copath o l o g i c d i a g n osis of d iversion-associ ated col itis based o n the h i story o f d iversion a n d the h isto l o g i c fi n d i n g s of a ctive chro n i c colitis.

F i g u r e 4 . 1 5 1 Chro n i c col itis pattern , d iversion colitis. This case of diversion-associated colitis sh ows l ess stri k i n g features. Wh i l e there a re no p ro m i n e n t l y m p h o i d a g g regates i n this p h oto m ic rog ra p h , t h e patient w a s 4 months status post d iversion re l ated t o a l a rg e obstructi n g s i g m o i d t u m o r. This recta l biopsy sh ows the n o nspecific pattern of m o d e rate a ctive c h ro n i c col itis: cryptitis, crypt a bscess, a s l i g htly vi l l o n o d u l a r s u rfa ce, i n creased l a m i n a propria chro n i c infl a m ­ m a t i o n , a n d Paneth ce l l meta p l a s i a ( n o t shown).

Fig u re 4. 1 5 2 C h ro n i c colitis pattern , d ivers i o n c o l itis. H i g h e r power sh ows cryptitis a n d crypt a bscess with m a crop h a g e co l l ec­ tions a g g regati n g a ro u n d the da m a ged crypts (arc) . Diversion-asso­ ci ated col itis i s due to a deficiency of short-ch a i n fatty acids i n the exc l u ded bowel seg m e nt.

362

ATLAS

0 F

GASTR0 I N TEST I N A L

PAT H O LOGY

Figure 4. 1 53 C h ro n i c col itis patte r n , d iversion col itis. This resec­ tion speci men orig i n ated fro m a patient with a 20-yea r h i story of d ivers i o n . No resi d u a l co l o n i c epith e l i u m is p resent in t h i s fi e l d . N ote t h e tra n s m u ra l l y m p h o i d a g g regates a n d d isorg a n ized mes­ enchym a l tissue.

Fig u re 4 . 1 5 4 C h ro n i c co l itis patte rn , d ivers i o n col itis. H i g h e r power o f p revious i m a g e .

FAQ: H o w does a n a b s e n ce of t h e feca l strea m resu lt i n d iversion-associated col itis? A n sw e r : S h o rt- c h a i n fatty a c i d s a re t h e p ri m a ry e n e rg y re s o u rce of co l o n i c

e n t e rocytes a n d o r i g i nate fro m b a ct e ri a l fe rme ntati o n . D i v e rs i o n d e p rives t h e exc l u d e d bowel seg m e n t fro m t h e feca l stre a m , b a cte ri a , b a cte ria fe r m e ntati o n p ro d u cts, a n d i m p o rta nt e n e rg y resou rces, res u l t i n g i n th i s pecu l i a r p a tte r n of c h ro n i c c o l i t i s . In s u p p o rt of t h i s t h e o ry, e n e m a s rich in s h o rt-c h a i n fatty a c i d s ( p a r­ t i c u l a rl y b u ty rate a n d g l uta m i n e) c a n a m e l i o rate or reve rse d iv e rs i o n-a ssoci ated c o l i t i s S2-57

SAM P L E N OTE***: H I STO RY O F D I V E RS I O N PROV I D E D

Nodularity, Diverted Bowel Segment, Biopsy: •

Colonic mucosa with mild chronic active colitis , prominent lymphoid aggregates with conspicuous germinal centers , and aphthoid lesions/ulcerations .

Note: The aforementioned findings would support the clinicopathologic diagnosis of diver­ sion-associated colitis .

SYP H I LITIC AN D LYM P H O G RAN U LOMA VE N E R E U M PROCTOCO LITIS Syphilitic a n d lymphogranuloma venereum (LGV) proctocolitis are both important emerg­ ing IBD mimics . A recent report details clinical red flags such as HIV-positive men who have sex with men (MSM) who usually present with rectal bleeding, anal pain , and tenesmus 58 Ulcerations are the most common endoscopic abnormality, but nodules, polyps , and mass lesions up to 4 cm have also been reported (Fig. 4 . 1 5 5) . Overlapping histologic features with IBD included active chronic colitis , skip lesions , aphthoid lesions , granulomata , for­ eign body giant cells , fibrosis , Paneth cell metaplasia, and lymphOid aggregates. Based on the presentation of mass lesions and the striking histologic overlap with IBD , malignancy

* * * I f no history is provided, see general chronic colitis sample note (lBD subsection, this chapter) .

Ch a pte r

4

C O L0 N

363

and IBD are common diagnostic pitfalls . Our experience shows features favoring infection include the presence of an intense infiltrate of submucosal plasma cells and a lack of the following features: architectural distortion , acute crypt centric damage , and eosinophilia (Figs . 4 1 5 6-4 1 68) . Before diagnosing IBD , always consider the possibility of a curable infection, especially in the HIV setting. To underscore this crucial point , the previously referenced study showed all cases were clinically confirmed to have syphilitic and or LGV infections and all patients completely responded to antibiotics , even those with mass lesions and those scheduled for "IBD" segmental resections . 5 8

Figure 4 . 1 55 Syp h i l it i c p roctoco l itis, e n d osco p i c i m a g e . This endoscopic i m a g e sh ows bleed i n g recta l u l cerations, the m ost com­ mon presentation of syph i l itic and LGV proctoco l itis. Oth er com mon endoscop i c fi n d i n g s i n cl u d e n o d u l es, polyps, a n d m a ss lesions. Red fl ags to this d i a g n osis i n c l u d e a h isto ry of H IV+ M S M behaviors, but such a h i story is ra rely p rovided, u n derscoring the uti l ity of the three­ step pattern-based a p p roach to c h ron i c colitis.

Figure 4 . 1 56 C h ro n i c col itis pattern, syph i l itic p roctoco l itis. The a ctive c h ro n i c col itis of syph i l is (a n d or LGV) can be stri k i n g l y sim i l a r t o t h a t seen with I B D : overl a p p i n g h i sto l o g i c featu res i n cl ude skip lesions, a phthoid lesions, g ra n u l omata, fo re i g n body g i a nt c e l l s , fi b rosis, P a n eth ce l l m eta p l as i a , a n d lym p h o i d a g g reg ates. N ote the i nten sity a n d va g u e n od u l a rity of the deep m o n o n u clear infl a m ­ mation of t h i s recta l biopsy. The a rch itectu ra l d i stortion a n d ra re cryptitis is s u btle.

Figure 4. 1 57 C h ro n i c col itis pattern, syp h i l itic p roctocol itis. H igher power sh ows copious p l a s m a ce l l s i n the deeper aspects of this biopsy. Eosi noph i l s a re not p ro m i nent. I ntense p l a s m a ce l l s a n d a lack of eosi n o ph i l i a a re fi n d i n g s more suggestive of infecti o n a n d less com m o n ly s e e n i n I B D . T h i s patient w a s cl i n i ca l ly d i a g n osed with syp h i l i s and LGV studies were negative. The recta l bleed i n g and u lcer­ ation were cured by a ntibiotics. A CMV i m m u n osta i n was n egative.

Figure 4 . 1 58 C h ro n i c co l itis pattern, LGV p roctoco l itis. The active chro n i c col itis of LGV is indisti n g u is h a b l e from syph i l is . This endo­ sco p i c m u cosa l resection of a recta l m a ss sh ows u l ceration ( l eft) with intense, deep mononuclear infl a m m ation . The adj o i n i n g recta l m u cosa is re latively we l l -preserved (right).

364

AT LA5

0 F

GAST R0 I N T EST I N A L

PAT H O LOGY

Figure 4 . 1 59 C h ro n i c col itis patte r n , LGV p roctocolitis. H i g h e r power shows copious p l a s m a ce l l s deep i n the s u b m u cosa . T h i s patient w a s c l i n ica l ly d i a g n osed with LGV based o n positive n u c l e i c acid a m p l ification stu d i e s fro m a recta l swa b , fever, a n d i n g u i n a l lymphadenopathy. T h e recta l p a i n a n d m a ss lesion were c u red with antibiotics. Remember, the m orph o l ogy of syp h i l itic and LGV p roc­ toco l itis is identica l and patients can be co-infected . It is, therefore, i m perative that c l i n icians consider the possi b i l ity of both infections when this m o rphol ogy is seen i n patients with a h i story of H IV+ MSM behaviors. A CMV i m m u nosta i n was n eg ative .

Figure 4. 1 60 C h ro n i c col itis patte rn , syp h i l itic a n d LGV p rocto­ colitis. T h i s recta l b i o psy was from a you n g man c l i n ica l ly t h o u g h t t o h ave recta l ca ncer b a s e d o n h i s ove ra l l i l l-appea ra n ce a n d the presen ce of a recta l mass. B i o psy of the recta l m a ss sh ows i n tense m o n o c u l a r i n fl a m m ation a n d g ra n u lomata . N o i ntact epith e l i u m is see n . AFB a n d G M S special sta i n s for m i croo rg a n isms were nega­ tive. A C M V i m m u nosta i n was n egative.

Fig u re 4. 1 6 1 Chro n i c col itis patte r n , syph i l itic a n d LGV p rocto­ colitis. H i g h e r power sh ows copious p l a s m a ce l l s deep in the sub­ m u cosa . After suggesti n g the poss i b i l ity of syph i l is a n d or LGV, the patient was a sked deta i l ed q u esti o n s a bout his sexu a l behavior. He reve a l e d h i g h-risk behaviors a n d s u bseq u e ntly tested positive for syph i l is, LGV, and H IV. H is c l i n i c a l sym ptom s and m a ss lesions resolved with antibiotics and HAART t h e ra py. Alth o u g h the m o r­ p h o l ogy a n d G I T fi n d i n g s can be c u red by a p p ro priate reco g n ition of this I B D m i m ic, many of these patients have u n recogn ized H IV.

F i g u re 4 . 1 62 C h ro n i c col itis patte r n , syp h i l itic p ro ctiti s . S i m i l a r fi n d i n g s c a n be seen i n syp h i l itic a n d or LGV i nvolv i n g a n a l m u cosa . N ote t h e i ntense m o n o n u c l e a r infl a m mation with a ba n d l i ke d i s­ tri bution at the i n te rfa ce betwee n the sq u a m ou s e p i th e l i u m a n d l a m i n a pro p ri a . T h i s patient w a s c l i n i ca l ly confirmed t o h ave syph i l is (LGV studies were negative) a n d the rectal m a ss was cu red with a nti­ biotics. A CMV i m m u nosta i n was negative .

KEY F EATU R E S of Syp h i l itic or LGV Proct o co l itis Patt e r n : •

Both are curable IBD mimics .

•

Cause : Syphilitic and or LGV infections .

•

Cure : Antibiotics .

•

Red flags : HIV+ MSM.

•

Syphilitic and LGV proctocolitis are a clinicopathologic diagnosis requiring both correlation with the appropriate clinical history and histologic findings .

Ch a pte r

F i g u re 4 . 1 63 C h ro n i c col itis patte rn, syp h i l itic p roctitis. H i g h e r p o w e r o f the p rev i o u s i m a g e sh ows c o p i o u s p l a s m a ce l ls . T h i s patient w a s u lt i m ate ly dete rm i n ed t o have H IV.

4

C O L0 N

365

F i g u re 4 . 1 64 C h ro n i c col itis patte r n , syp h i l it i c p roctitis. T h i s patient w a s sched u l ed for a proctectomy fo r p res u m ed Crohn d i s­ ease ba sed on a h i story of bl oody d i a rrhea a n d weight l oss. The bio psy shows a n intense ba n d l i ke pattern of c h ro n i c i nfl a m mation .

L Figure 4. 1 65 C h ro n i c col itis pattern, syph i l itic proctitis. An a ltern a­ tive fi e l d sh ows a n u l cer o n the l eft. The intense ba n d l i ke pattern of chro n i c infl a m mation is easy to a p p reci ate at low power.

F i g u re 4 . 1 67 C h ro n i c col itis patte r n , syp h i l itic p roctitis. U n d e r h i g h est power, syph i l itic a n d LGV p roctoco l itis show p o o l s o f plasma ce l l s , particu l a rly i n the deeper aspects of the biopsy.

Figu re 4 . 1 66 Chron i c co l itis pattern , syph i l itic p roctitis (Trepone­ mal i m m u n osta i n ) . The red chromogen disti n g u ishes the trepon ema I org a n isms from the background m e l a n ocytes (arc) . U n fo rtu n ately, this i m m u noh istoch emica l sta i n is fa r too insensitive to be c l i n ica l l y usefu l . Corre l ation with perti nent c l i n ical stud i es rem a i n s the m ost effective way to esta b l ish the diagnosis of syp h i l itic a n d or LGV proctoco l itis.

F i g u re 4 . 1 68 C h ro n i c colitis patte r n , I B D . In contrast to syp h i ­ l itic a n d L G V p roctocol itis, I B D m o re com m o n l y shows a predomi­ n a n ce of eosi n o p h i ls, lymphocytes, a n d macrophages i n the deeper aspects of the biopsy, as seen here .

366

ATLAS

0 F

GAST R0 I N T EST I NA L

PAT H O LOGY

FAQ: Are t h e re a n y anci l l a ry studies to co nfi rm syph i litic a n d LGV i nfect i o n s ? An swe r : W i t h p re a p p rova l , t h e C e n te rs fo r D i sease C o n t ro l a n d P reve n ti o n

p rovi d e s free syp h i l i s a n d LGV i m m u n osta i n s a n d PC R -b ased testi n g o n p a r­ affi n e m bedded t i s s u e s . ( F o r m o re i nfo r m a t i o n , see t h e Spec i m e n S u b m i ss i o n G u id e l i n es of t h e CDC's I nfect i o u s D i seases Path o l ogy B ra n c h .) S i lver sta i n s a n d Treponemal i m m u n osta i n s a re fa r t o o i n sen sitive t o confi rm o r exc l u d e syp h i l it i c i n fect i o n s , a n d t h e re a re n o ro uti n e co m m e rci a l ly ava i l a b l e L G V stud ies ava i l a b l e fo r t h e path o l og i st . 58 U n t i l sensitive d i a g n ostic too l s a re ro uti n e l y ava i l a b l e to t h e path o l o g i st, c l i n i ca l sero l og i es p rov i d e t h e best m e a n s to esta b l i s h th i s d i a g n o s i s (deta i l ed e a rl i e r) . A CMV i m m u nosta i n i s reco m m ended i n a l l cases d u e to ove rl a p­ p i n g m o r p h o l ogy.

FAQ: Wou l d you consider syph i l it i c a n d LGV proctoco l itis if t h e patient were presumed H IV negative? O r fem a l e ? Answer: Yes.

P re s u m ed H I V n e g a t i v i ty i s s o m et i m e s e q u iva l e n t to u n recog n i zed H I V. I n d e e d , seve ra l o f t h e stu d y p a t i e n ts i n t h e a bove refe re n ced s e r i e s w e re p re s u m e d H I V n e g a t i v e . 58 Aft e r t h e d i a g n os i s of s y p h i l i t i c a n d L G V p roctoco l it i s w a s s u g g este d , a t h o ro u g h sexu a l b e h a v i o r h i sto ry was e l i c ited , h i g h - r i s k s e x u a l b e h a v i o rs w e re reve a l e d , a n d a n H I V test w a s p e rfo r m e d a n d dete r m i n e d to be p o s i t i v e . Recog n it i o n of th i s pattern of i nj u ry is c r i t i ca l to e n s u re p ro p e r c l i n i ca l m a n a g e m e n t , dete rm i n e H I V sta t u s , reso l v e sym pto m s , a n d to p re v e n t o n w a rd tra n s m i s s i o n of H I V, syph i l i s , a n d LGV. A l th o u g h a s u s p i c i o n fo r s y p h i ­ l i t i c a n d LGV p roctoco l it i s i s stre n g t h e n e d by a h i st o ry of H I V p o s i t i v i ty i n m a n w i t h a n a l receptive sex u a l c o n t a ct , d o n o t l et a l a c k o f stated h i st o ry d i s s u a d e yo u .

SAM PLE N OTE***: SYP H I LITIC O R LGV PROCTOCO LITIS (H IV+ MSM H ISTO RY PROVI D E D)

Rectum, Biopsy: •

Rectal mucosa with marked active chronic proctitis with intense lymphohistiocytic infiltrate and copious submucosal plasma cells .

Note: The history of HIV and rectal ulceration is noted. The corresponding histologiC sec­ tions show an intense lymphohistiocytic infiltrate and copious submucosa plasma cells. No Significant architectural distortion, acute crypt centric damage , and eosinophilia are seen . These findings were recently reported in association with syphilitic and or LGV infections . Clinical serologies provide the best means to establish this diagnosis (syphilis : serum RPR, RPR titer, and a treponemal speCific serology such as fluorescent treponemal antibody; Lymphogranuloma venereum: rectal swab collected in the absence of lubricant for Chla­ mydia trachomatis nucleic acid probe test or culture and LGV PCR) . A CMV immunostain is nonreactive .

Reference: Arnold CA, Limketkai BN , Illei FB , et al . Syphilitic and lymphogranuloma venereum (LGV) procto­ colitis : Clues to a frequently missed diagnosis Am ] Surg Fathal. 2 0 1 3 ;3 7( 1 ) : 38-46.

* * * I f no history is provided , see general chronic colitis sample note (lBD subsection, this chapter) .

C h a pter

CORD CO LITIS SYN D RO M E Cord Colitis Syndrome (CCS) is an emerging IBD mimic . Red flags include culture-negative , antibiotic-responsive watery diarrhea in patients with a history of umbilical cord transplanta­ tion . CCS is a diagnosis of exclusion , and should be considered after GVHD, viral or bacte­ rial infection, and medication injury have been excluded . In the largest series, its incidence was 1 0 . 6 % and the median time of diarrhea onset was 1 3 1 days from transplantation 59 Most patients were febrile, required hospitalization, and all responded to a 10 to 1 4 days of antibiotics, even those with recurrent diarrhea . Endoscopic and histologic features can be indistinguishable from IBD . Endoscopic images show edema , erythema , or ulcerations . His­ tologically, active chronic colitis is seen , which can be accompanied by granulomata, archi­ tectural distortion, and Paneth cell and pyloriC metaplasia (Fig. 4 . 1 69) . Apoptotic bodies are not prominent, a feature which helps distinguish CCS from GVHD . See also GVHD , Lym­ phocytic Pattern, Esophagus Chapter. More recently, Bradyrhizobium enterica was identified in biopsies from patients with CCS and organism levels declined with antibiotic therapy 60 CCS was not identified in 1 ,2 6 1 patients who underwent non-cord-blood transplantations , suggesting that the cord colitis syndrome represents a distinct clinicopathologic entity 59 KEY F EATU R E S of t h e Cord C o l itis Syn d ro m e : •

C C S represents another curable l B D mimic.

•

Cause : Bradyrhizobium enterica.

•

Cure : Antibiotics.

•

Red flags : Umbilical cord transplantation.

•

The cord colitis syndrome is a clinicopathologic diagnosis requiring both correla­ tion with the appropriate clinical history (history of umbilical cord transplanta­ tion) and histologic findings (active chronic colitis) .

PEARLS & PITFALLS

A l th o u g h C C S fi n d i n g s a re m o st c o m m o n l y re p o rted i n t h e co l o n , bewa re a d d i t i o n a l pote n ti a l s ites of i nv o l v e m e n t i n c l u d e t h e sto m a c h , d u o d e n u m , a n d l ive r. 6 1

Fig u re 4 . 1 69 C h ro n i c col itis patte rn, cord col itis syn d ro m e . This image sh ows a ctive c h ro n i c colitis with a poorly fo rmed g ra n u lo­ m ata (center, base). This h isto l o g i c patte rn i s entire l y eti o l o g i ca l l y n o n specific a n d c a n b e i n d isti n g u ishable from Cro h n d i sease, or a n y oth e r c a u s e o f a ctive c h ro n i c col itis, em phasizi n g the i m porta nce of c l i n i copath o l o g i c corre l atio n . Source: Photo m icrog ra p h courtesy of D r. Andrew M . B e l l izz i , U n iversity of I owa Hospita l & C l i n ics, I owa City, I owa .

4

COLON

367

368

ATLAS

0 F

GAST R0 I N TE S T I N A L

PAT H O LOGY

SAM P L E N OTE***: H ISTO RY O F U M BI LICAL CORD TRA N S PLANTAT I O N AN D D IA R R H EA

Colon (biopsy): •

Mild active chronic colitis with scattered granulomata and Paneth cell metaplasia.

Note: The history o f umbilical cord transplantation, antibiotic responsive watery diar­ rhea , and negative infectious work-up is note d . The biopsy shows mild active chronic colitis with scattered granulomata and Paneth cell metaplasia . Such findings can be seen in the setting o f CCS and these p atients o ften respond to a 10 to 14 day course o f metronidazole ± fluoroquinolone . Apoptotic b o dies are not prominent . There are no histologic features o f GVHD . A CMV immunostain and AFB/GMS special stains are negative .

References: Gupta NK, Masia R. Cord colitis syndrome : A cause of granulomatous inflammation in the upper and lower gastrointestinal tract. Am ] Surg Pathal. 20 1 3 ; 3 7 (7) 1 1 09- 1 1 1 3 . Herrera A F, Soriano G , Bellizzi AM , e t al . Cord colitis syndrome i n cord-bloodstem-cell transplanta­ tion. N Engl ] Med. 2 0 1 1 ; 3 6 5 (9) 8 1 5-824

I P I LI M U MAB CO LITIS Ipilimumab i s one of a n emerging field of chemotherapeutic agents whose mechanism is based on enhancing immune-mediated destruction of tumors 62 Specifically, ipilimumab tar­ gets the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) found on cytotoxic T-lym­ phocytes and regulatory T cells 63 CTLA4 normally functions to suppress T-cell activation. Consequently, ipilimumab binding of CTLA4 removes CTLA4's suppressive effects and , instead, promotes cytoxic T-cell activation and cytotoxic T-cell mediated destruction of the neoplastic cells . As an unintended consequence of stimulating the immune system, up to 60% of patients report immune related adverse effects within 1 1 to 1 4 days from the first dose 62-64 The most common site of involvement is the GIT (stomach , small bowel , and colon) , followed by the skin 65 The diarrhea is described as watery and culture-negative. Com­ mon endoscopic findings range from normal to marked ulcerations (Fig. 4 . 1 70) . Histologic * * *If no history is provided, see general chronic colitis sample note (IBD subsection, this chapter) .

Figure 4 . 1 7 0 I p i l i m u m a b colitis, endoscopic i m a g e . The red fl a g t o i p i l i m u m a b colitis is a h i story o f m e l a n o m a . This n ovel drug works by sti m u lating the i m m u n e m e d i ated destruction of the n e o p l a s m , a n d G IT com p l a i nts a re com m o n . This endosco pic i m a g e shows a p ro m i nent rectal u l ceration .

Fig u re 4 . 1 7 1 C h ro n i c co l itis patte r n , i p i l i m u m a b co l itis. Co rre­ spon d i n g h isto l o g i c sectio n s show moderate a ctive c h ro n i c col itis with cryptitis, crypt a bscesses, i n c reased chro n i c i nfl a m m ation i n the l a m i n a p ropri a , crypt d ropout, crypt shortfa l l , a n d basal lym p h o p l as­ macytosis. In the a bsence of a c l i n i ca l h i story, i p i l i m u m a b colitis can be endosco p i ca l ly and h i sto l o g i ca l ly i n d isti n g u is h a b l e from I B D , or any oth er cause of a ctive chro n i c col itis.

Ch a pte r

4

COL0 N

369

sections show active chronic injury with increased apoptotic bodies , granulomata , and eosin­ ophilia (Figs . 4 1 7 1-4. 1 76) Small bowel biopsies can also show villous blunting and promi­ nent intra epithelial lymphocytosis , mimicking celiac disease . This IBD mimic is cured with drug cessation. Death and perforation attributed to immune-related adverse events are rare ( 1 %) but are associated with delayed recognition, underscoring the importance of recognizing ipilimumab-associated inJury 62 , 65 We have never encountered a case submitted with "ipili­ mumab" listed on the requisition. The most frequent red flag to this diagnosis is a history of melanoma .

Fig u re 4. 1 7 2 C h ro n i c col itis patte rn, i p i l i m u m a b co l itis. An a lter­ n ative fi e l d sh ows s i m i l a r fea t u res. Alth o u g h t h i s case was s u b m it­ ted in co n s u ltati o n to u s as Cro h n d i sease, t h i s c u ra b l e I B D m i m i c e m p h asizes that n ot a l l exa m p les o f a ctive c h ro n i c col itis a re d u e to IBD.

F i g u re 4. 1 7 3 C h ro n i c col itis patte r n , i p i l i m u m a b col itis. H i g h e r power o f previous case. W e n oted " ru l e-out m e l a n o m a " on t h e req u i sition a n d confi rmed i p i l i m u m a b thera py after exa m i n i n g the m edication l i st.

Figu re 4 . 1 7 4 C h ro n i c co l itis patte r n , i p i l i m u m a b col itis, U l cer debris, crypt a bscesses, cryptitis, a n d i n creased c h ro n i c infl a m ma­ tion a re shown .

F i g u r e 4 . 1 7 5 C h ro n i c co l itis patte rn , i p i l i m u m a b co l itis, H i g h e r p o w e r s h ows b a s a l I ym p h o p l a s m a cyto s i s a n d c rypt s h o rtfa l l (bra cket) : the basa l l ayer o f l y m p h ocytes a n d p l a s m a ce l l s p re­ vents the crypts fro m d i rectly contact i n g the m u scu l a ris m u cosae (asterisks) .

370

AT LAS

0 F

GAST R0 I N T E S T I NA L

PAT H O LOGY

Fig u re 4 . 1 76 C h ro n i c col itis pattern, i p i l i m u m a b col itis. This case sh ows a m i l d ly v i l l o n od u l a r s u rface, i n creased l a m i n a propria c h ro n i c i n fl a m m at i o n , a n d scattered P a n eth ce l l meta p l a s i a . The patient's sympto m s a n d recta l path ology reversed with d ru g cessatio n .

K E Y F EATU R E S o f I pi l i m u m a b-Associated C o l it i s : •

•

•

Ipilimumab colitis i s a n emerging l B D mimic . Cause : ipilimumab targets and inhibits CTLA4's suppressive effects , resulting in enhanced cytotoxic T mediated destruction of the neoplasm. Cure : Drug cessation and or concomitant high-dose immunosuppressive therapy.

•

Red flag: history of melanoma.

•

Mortality is low but linked to delayed recognition .

•

Ipilimumab-associated colitis is a clinicopathologic diagnosis requiring both cor­ relation with the appropriate clinical history (ipilimumab administration) and his­ tologic findings (active chronic colitis) .

PEARLS & P ITFALLS

I p i l i m u m a b i s u n d o u bted ly a pro m i s i n g new c h e m ot h e ra pe u t i c a g e n t for m e l a ­ n o m a . I t i s a l so u n d e r a ctive study fo r i t s pote n ti a l ro l e i n treati n g oth e r m a l i g n a n ­ c i e s , s u c h a s p rostate c a n c e r, l u n g ca ncer, m etasta t i c ren a l ca ncer, l y m p h o m a , a n d p a n c reatic ca n c e r. A s a resu lt, con s i d e r a c h a rt review for i p i l i m u m a b t h e ra py when a h i story of t h e a bove m a l ig n a ncies i s e n c o u ntere d .

SAM P L E N OTE***: C LI N I CA L H ISTO RY O F A M ETASTAT I C M E LA N O M A AN D I P I LI M U MA B T H E RAPY

Rectum, Biopsy: •

Marked active chronic proctitis .

Note: The history of metastatic melanoma and ipilimumab therapy is noted. Active chronic proctitis is a known side-effect of ipilimumab therapy. In such cases, symptomatology and histology normalize with ipilimumab cessation or high-dose immunosuppression. Correla­ tion with microbiologic and infectious studies recommended. Negative for malignancy. A CMV immunostain is negative .

* * * I f no history is provided , see general chronic colitis sample note (lBD subsection, this chapter) .

Ch a pte r

R ES I N S Any chronic medication inj ury can result in histologically identical findings to those seen in IBD . Pay particular attention for medication resins , identification of which can provide etiologic specific clues to the background injury pattern . Medication resins can be easy to overlook in the histologically "busy" morphology of active chronic colitis but their recogni­ tion can save a patient's life , as in the case of Kayexalate mediated inj ury (Fig. 4 . 1 7 7) .

F i g u re 4. 1 7 7 C h ro n i c col itis patte rn, Kayexa late. Kayexa l ate resin displ ays n a rrow, reg u l a r "fish-sca l e s " a n d appears p u rp l e on H & E . Kayexa l ate i s n otori ous fo r ca u s i n g u l cerati o n s a n d isch e m i a , fea­ tures h istori c a l l y attri buted to the hyperosmotic effects of its sorbitol d i l u e nt. GIT i nj u ry can be fatal a n d , therefo re, it is i m porta nt to a l e rt the c l i n i c i a n s to this fi n d i n g so that the me dication l i st can be safely a djusted.

LYM PH OCYTIC PATTE RN

F i g u re 4. 1 7 8 Lym p h ocyt i c patte r n , l y m p h ocyt i c col itis. N u m e r­ ous i ntraepith e l i a l lymphocytes (arrowh eads) a re identifi a b l e at h i g h m a g n ification .

The lymphocytic colitis pattern is characterized as the presence of normal crypt architecture with increased surface intraepithelial lymphocytes (IEls) , which is further defined as > 1 5 t o 20 IEls per 1 00 surface epithelial cells (normal range i s < 5 t o 1 0 IEls/ l OO epithelial cells) (Fig. 4 . 1 78) . As with all numerically defined inflammatory disorders of the GI tract, the threshold for disease is widely ranging (in this case , 10 to 60 IEls , with a median of

4

C O L0 N

371

372

AT LAS

0 F

GAST R0 I N T E S TI N A L

PAT H O LOGY

20 to 39) 66-69 The main differential diagnosis includes microscopic colitis , an entity that encompasses both lymphocytic colitis and collagenous colitis . Injury from medications and viral infection are also considerations in the differential diagnosis . CH ECKLIST: Et i o l o g i c C o n s i d erati o n s fo r t h e Lym p h o cyti c Pattern D

Lym p h o cytic Col itis

D

Co l l a g e n o u s Col itis

D

M e d i ca t i o n s

D

Vi ra l I nfect i o n

LYM P H OCYT I C CO LITIS K E Y F EATU R E S o f Lym p h ocyti c C o l it i s : •

This is a form of microscopic colitis having the following triad : 1 . Chronic nonbloody diarrhea 2. Normal endoscopy findings 3. Colonic epithelial lymphocytosis without a thickened subepithelial collagen table.

•

•

•

•

•

•

•

•

•

Increased IELs is generally defined as: > 15 to 2 0 IELs per 1 00 surface epithelial cells . 70 This is a disease of middle-aged to elderly women (mean age 59 to 67 years) , but can occur at any age 70 and in men . Patients present with nonbloody watery diarrhea. Although numerous studies have described lymphocytiC colitis causing a chronic diarrhea , 66 more recent studies suggest that patients may have a single attack in 6 0 % o f cases. Most cases are idiopathic, but infectious triggers have been implicated, including C. jejunl and E. coli. 66.6 7 Ten percent of patients have a positive family history of inflammatory intestinal dis­ 66,6 ease, including ulcerative colitis , Crohn disease , collagenous colitis , and celiac disease . 7 Treatment includes removal of any known offending agents (see medications below) and medical therapy Cloperamide, bismuth subsalicylate , mesalamine , budesonide) . In addition to IELs , there is increased lamina propria cellularity, mostly lymphocytes and plasma cells , and also eosinophils (Figs . 4 . 1 7 9-4 1 83) Changes are greater in the right colon than the left.

Fig ure 4 . 1 79 Lym p h o cyti c patter n , l y m p h ocytic co l itis. At sca n ­ n i n g m a g n ificatio n , the biopsy appears " busy. " There is i n creased m o n o n u c l e a r d e n sity of the l a m i n a p ro p ri a , but p reserved crypt a rch itectu re .

F i g u re 4 . 1 80 Lym p h o cyti c patte r n , l y m p h o cytic col itis. H i g h e r m a g n ification o f the p revious case sh ows i n creased ce l l u l a rity of the i ntraepith e l i a l lymph ocyti c component in addition to the l a m i n a p ropria lymphocytosis.

C h a pte r

Figure 4. 1 8 1 Lym ph ocytic pattern, lymphocytic co l itis. The crypts rem a i n eve n l y spa ced a n d oriented p e rpe n d i c u l a r to the c o l o n i c surfa ce. The l a m i n a propria sh ows a n i n creased density o f m o n o n u ­ clear ce l ls, w h i l e the crypt a n d s u rfa ce epith e l i u m conta i n s i n creased i ntra epith e l i a l lymph ocytes.

4

COL0 N

373

Figure 4. 1 8 2 Lym p h ocyt i c patte r n , l y m p h o cyti c col itis. H i g h e r m a g n ification o f the previ ous case s h ows t h e presence o f i ntraepi­ th e l i a l lymphocytes a l o n g the co l o n i c s u rfa ce epith e l i u m . Also, n ote the atten u ated appeara nce of the epith e l i a l ce l ls .

F i g u re 4. 1 8 3 Lym p h ocyt i c patte r n , l y m p h o cyti c c o l i t i s . M a n y observers specifica l ly cite t h e presence o f i n creased i ntraepith e l i a l lym phocytes ( I E Ls) a l o n g t h e s u rface epith e l i u m . Alth o u g h I E Ls a re a lso p rese nt i n the crypt epith e l i u m (a rrows), contrast the density of I E Ls that a re p resent a l o n g the s u rfa ce epith e l i u m (arrowheads) . PEARLS & P ITFALLS

When ava i l a b l e , check t h e u p pe r GI b i o psies fo r I E Ls .

T h e p rese nce o f coex i st i n g u p p e r a n d lower G IT i ntra e p i th e l i a l l y m p h ocytosis (such a s t h e fi n d i n g of sprue- l i ke changes i n t h e s m a l l bowe l A N D l y m p h ocyt i c c o l itis) cou l d i n d i cate a syste m i c p rocess. F e w data a re ava i l a b l e reg a rd i n g th i s entity, a lt h o u g h associati o n s w i t h a utoi m m u n e e n te ropathy a n d m e d i cation i nj u ry ( i . e . , o l m esarta n/Ben i c a r) exist. Th i s is best reported a s " ly m p h ocyt i c enteroco l it i s " a n d d i scu ssed i n a n ote o r d i rectly with the c l i n i c i a n . 7 1

FAQ: Do I E Ls ove r ly i n g a l y m p h o i d a g g regate i n d i cate l y m p h o cytic colitis?

A n swer: N o . Reca l l : I n t h e epith e l i u m ove r l y i n g l y m p h o i d a g g regates, I E Ls a re freq u e n t a n d

they re p resent m esse n g e rs of t h e i m m u n o l o g i c c ross-ta l k between t h e l u m i n a l a nt i g e n s a n d t h e l y m p h o i d fo l l i c l es . D i sco u n t a reas o f i n c reased I E Ls that d i rectly overl i e lymphoid a g g regates (Figs. 4 . 1 84 a n d 4 . 1 85) .

374

ATLAS

0 F

GAST R0 I N T ESTI N A L

PAT H O LOGY

Figure 4 . 1 84 Lym p hocytic pattern m i mic, i ntraepithe l i a l lym pho­ cytes overlyi n g a lymphoid a g g regate. U n d e r n o rm a l conditi o n s , the epith e l i u m overlyi n g a lym p h o i d a g g regate conta i n s n u m e rous I E Ls (arrowheads). This a rea should be discou nted when eva l uati n g for I E Ls.

Figure 4 . 1 85 Lym p hocytic pattern m i m ic, i ntraepith e l i a l lympho­ cytes overlyi n g a lym phoid a g g regate. The epith e l i u m overlyi n g a lym phoid a g g regate a lways shows I E Ls (arrowheads) as part of the n o rm a l i m m u no l o g i c crossta l k between the lym phoid o rg a n a n d the l u m i n a l antigens.

COLLAG E N O U S CO LITIS KEY F EATU R E S of C o l l a g e n o u s Colitis: •

•

This is a form o f microscopic colitis having preserved crypt architecture , abnormal subepithelial collagen deposition, increased IELs, and a normal colonoscopic appearance . 7 2 , 7 3 This is a disease of middle-aged to elderly women (mean age 5 7 to 66 years) , but can occur at any age . The female preponderance is striking compared to that for lymphocytic colitis .

•

Patients present with nonbloody watery diarrhea, which may be nocturnal.

•

Most cases are idiopathic , but infection has b een implicated , including C. difficile and

Yersinia. •

Proposed mechanisms of disease include abnormal immunologic response to environ­ mental exposures and abnormal collagen metabolism. 74

•

Treatment includes removal of any known offending agents (see medications below) and medical therapy is generally effective (loperamide, bismuth subsalicylate , mesalamine , budesonide) l5

•

Histologic features include increased intra epithelial lymphocytosis with an abnormal subepithelial collagen table (Figs . 4 . 1 86-4 . 1 9 6) . This is defined as thickening and irregularity of the basement membrane profile; from the lower border of the collagen table, strands of collagen extend into the lamina propria entrapping fibroblasts and small capillaries . 7 6 ,77 FAQ: Do t reatment p rotoco l s for lymphocytic and col la g e nous colitis d iffer? Answer: N o .

Lym p hocyt i c a n d co l l a g e n o u s col itis res p o n d t o s i m i l a r treatment p rotocol s/B a n d m o st centers treat both entities u n d e r a " m i croscop i c c o l iti s " u m b re l l a pro­ toco l . Therefore , w h e n stru g g l i n g to determ i n e whether a case i s better c l a ssified a s l y m p h ocyt i c co l it i s versus co l l ag e n o u s c o l itis, rest reassu red that the pati e n t receives a p p ro p ri ate m a n a ge m e n t reg a rd l ess of t h i s d i st i n cti o n . W e h a n d l e e q u iv­ oca l cases by fi rst rep o rti n g the presence of l y m p h ocyt i c c o l itis, a n d then s u g g est that an e a r l y or evo l v i n g col l ag e n o u s col itis ca n n ot be e n t i re l y exc l u d e d based on the h i sto l o g i c fi n d i n g s .

Ch a pte r

4

COL0 N

375

Figure 4. 1 86 Lym p h ocytic pattern , co l l a genous col itis. Sca n n i n g m a g n ification sh ows c o l o n i c m u cosa with norm a l crypt a rch itecture, but a n a b n o r m a l l y thick base m e n t m e m bra n e (arrow) a n d a subepi­ the l i a l s p l it (arrowhead).

Figure 4. 1 87 Lym p hocytic pattern, collagenous col itis (trichro m e sta in). A trichrome stai n h i g h l i g hts the abnormal col lagen table i n blue (arrowheads). N ot only is the collagen table thickened, but it displays an i rre g u l a r conto u r and conta i n s entrapped sma l l vessels (arrow) .

F i g u re 4 . 1 88 N o r m a l s u b e p i th e l i a l co l l a g e n ta b l e (tri c h ro m e sta i n ) . By compariso n , the c o l l a g e n ta b l e (arrowhead) o f the n o r m a l c o l o n is th i n . M o re i m portantly, h owever, the conto u r o f the co l lagen table is sm ooth a n d n ot rag g e d .

F i g u r e 4 . 1 89 N o r m a l subepith e l i a l c o l l a g e n ta b l e . O n routi n e

Figure 4 . 1 90 Lymph ocytic pattern , col l agenous col itis. S u rface e p i ­ the l i u m deta c h i n g from the i rreg u l a r col la g e n table is a com mon fea­ tu re of col l agenous col itis. Alth o u g h i ntraepith e l i a l lymphocytes a re sta n d a rd , collagenous col itis may a lso show occasio n a l n e utro p h i l s (arrowheads), a fin d i n g t h a t d o e s n ot n e cessa ri ly s i g n i fy i n fectio n .

Figure 4. 1 9 1 Lym p hocytic pattern, collagenous colitis (trichro m e sta i n ) . A tri c h ro m e sta i n h i g h l i g hts the abnorm a l ly i rreg u l a r subepi­ the l i a l col l a g e n ta b l e blue. N ote the entra pped sma l l vessels (arrow­ heads) a n d othe r n u c l e i .

H & E , t h e n o r m a l co l lagen ta b l e (arrowheads) m a y b e pro m i n ent, but it reta i n s a smooth , l i n e a r profi l e and does n ot conta i n entra pped ce l l s or vessels.

376

AT LAS

0 F

GAST R0 I N T ESTI NA L

PAT H O LOGY

Figure 4 . 1 92 Lym phocytic pattern , co l l agenous colitis. On routine H & E sta i n , this subepith e l i a l collagen is exte n d i n g downwa rd i nto the l a m i n a p ropri a . Th is trickl i n g down between the infl a m m atory ce l l s (arrowhead) h a s been l i ke n ed to " c a n d l e wax d r i p p i n g s " by some observers.

Fig u re 4. 1 94 Lym p hocytic pattern, co l la g e n o u s col itis. By defi n i ­ t i o n , col l a genous col itis conta i n s n u m erous intraepith e l i a l lympho­ cytes (arrowheads) .

F i g u r e 4 . 1 96 Lym p h ocytic patte r n , co l l a g e n o u s c o l i t i s . H i g h e r m a g n ification o f t h e p revious case sh ows a n i rreg u l a r lower border of the co l l a g e n ta b l e (arrowheads). a n d collagen exte n d i n g down i n to the lamina propria l i ke " c a n d l e wax d r i p p i n g s " (arrow) .

Figure 4. 1 93 Lym phocyti c pattern, co l l agenous colitis (tric h ro m e sta i n ) . The th i ckened co l l a ge n ta b l e (arrowheads) i s evident b y tri­ c h ro m e sta i n , which a l so h i g h l i g hts the i rreg u l a r l ower bord e r of the co l l a g e n layer. N ote how the c o l l a g e n e ntraps ce l l s and a lso trickles downwa rd between the i n fl a m m atory ce l l s of the l a m i n a propri a .

Figure 4 . 1 95 Lym p h ocytic patte r n , co l l a g e n o u s co l itis. At sca n ­ n i n g m a g n ification, this exa m p l e shows a prom i n e n t subepith e l i a l co l l ag e n ta ble (arrowheads) .

Ch a pte r

Figure 4. 1 97 Lym p h ocyt i c patte r n , c o l l a g e n o u s colitis. I ntra epi­ th e l i a l lymph ocytes (arrowheads) a re a n o rm a l com p o n e n t of col­ l a g e n o u s col itis.

FAQ: Does co l l a g e n o u s colitis exist in the absence of I E Ls? An swe r: N o . T h e p resence o f a n a bn o rm a l co l l a g e n ta b l e is someti mes fo u n d i n i s o l a ti o n , a n d o n e m i g h t won d e r i f th i s re p resents co l l a g e n o u s co l it i s . A s a tec h n i c a l defi n it i o n , co l l a g e n o u s co l itis i s both " c o l l a g e n o u s " a n d a " c o l itis, " m ea n i n g t h a t a n i nfl a m ­ m atory component m u st be p resent ( F i g . 4 . 1 9 7 ) . Cases t h a t s h ow a b n o rm a l co l l a­ g e n i n the a bsen ce of a c o l itis a re best h a n d l ed descri ptively, a s oth e r d iffe re n t i a l d i a g n oses (hea l e d e ro s i o n , so l i ta ry recta l u l ce r syn d ro m e , m e d i cation rea cti o n , etc . ) a re poss i b l e .

M E D I CATI O N An expanding list of medications i s implicated i n lymphocytic pattern , a s noted below. By far, N SAIDs are the most common culprit and may result in FAC in addition to increased IELs . Ischemic-like changes and lamina propria hyalinization may also be seen, particularly in areas containing erosions . While the pathologist may suggest the possibility of medica­ tion inj ury, this is confirmed only when the offending agent is discontinued and this action results in resolution of clinical symptoms .

Medications Implicated in the Lymphocytic Pattern •

NSAIDs

•

Ticlopidine

•

Flutamine

•

Carbamazepine

•

Cimetidine

•

Ranitidine

•

Iansoprazole

•

Gold Salts

•

Paroxetine

•

Sertraline

•

Olmesartan

4

C O L0 N

377

378

ATLAS

0 F

GASTR0 I N TEST I N AL

PAT H O LOGY

EOS I N O P H I LIA PATT E R N

F i g u re 4 . 1 98 I ntra e p i th e l i a l eosi n o p h i l s . Scattered eosi n o p h i l s may be present with i n t h e n o r m a l co l o n i c epith e l i u m , b u t th ey a re typ i ca l l y sol ita ry. Ag g regates of i ntraepith e l i a l eos i n o p h i l s (arrow­ heads), such as seen h e re , a re a b n o rm a l .

I n the colon, eosinophils and other constituent inflammatory cells follow a decreaSing gra­ dient along the length of the colon, from proximal to distal (Fig. 4. 1 98) ?9. s 0 As a result of this gradient, the interpretation of eosinophilic density must be performed in the context of anatomic site. Normal eosinophil counts range from 10 to 70 eosinophils per high-power field (HPF) in the cecum to 1 to 30 in the rectum, but no universally accepted normal range has been established 81-s3 Moreover, geographic and seasonal differences , and par­ ticipation of eosinophils in various nonspecific inflammatory responses further contribute to eosinophil count variability. s4-s 6 Although mild increases in lamina propria eosinophil counts are difficult to delineate , definitive abnormal features include increased intraepithe­ lial eosinophils with eosinophil crypt abscesses , extensive degranulation, epithelial regen­ erative changes, and minimal active and chronic inflammation 8 7 The differential diagnOSiS is broad , and includes idiopathic eosinophilic colitis , inflammatory bowel disease, allergy, medication reaction , parasitic infections , collagen vascular disorders such as scleroderma, and vasculitides such as Churg-Strauss syndrome .

CH ECKLI ST: Et i o l o g i c C o n s i d erat i o n s fo r t h e Co l o n i c Eos i n o p h i l i a Pattern o

I d i o path i c Eosi n o p h i l i c Col itis

o

I n fl a m m atory Bowel D isease

o

A l l e rgy

o

M ed ications

o

I nfection

o

Pa ra site

o

Co l l a g e n Vascu l a r D i s o rd e r a n d Vascu l itis

I D I OPATH I C EOS I N O P H I LI C CO LITIS Primary eosinophilic gastrointestinal disorders represent a spectrum o f inflammatory gastrointestinal disorders in which eosinophils infiltrate the gut in the absence of known causes , and can only be diagnosed following exclusion of all other known causes of eosino­ philia (Figs . 4 . 1 9 9-4 . 2 0 1 ) 8s

Ch a pte r

Figure 4 . 1 99 Co l o n i c eosi n o p h i l i a patte rn, id iopath i c eosi noph i l i c co l itis. At sca n n i n g m a g n ificatio n , t h e crypt a rch itectu re is essentia l ly p reserved; h owever, the i n crease i n eosi noph i l s with i n the m u cosa and s u b m u cosa is stri ki n g .

4

COL0 N

379

Figu re 4. 200 Co l o n i c eosi n o ph i l i a pattern , id iopath i c eosinop h i l i c col itis. H i g h e r m a g n ification o f t h e p revious case sh ows a condensa­ tion of eosi noph i l s a ro u n d a s i n g l e crypt. The etio l ogy of this eos i n o­ p h i l i c i nfi ltrate is n ot a p p a rent in the biopsy.

F i g u re 4 . 2 0 1 Co l o n i c eosi n o p h i l i a patte r n , i d i opath i c eosi n o ­ p h i l i c col itis. Anot h e r h i g h m a g n ifi cation a re a fro m the p revious case sh ows a b u n d a n t eos i n o p h i l s traversing the m uscu l a ris propria (arrowheads) .

I N F LA M M ATO RY BOWEL D I S EAS E Eosinophils comprise a conspicuous component in the inflammatory infiltrate of b oth active and inactive lBD , including both ulcerative colitis and Crohn disease 89 , 9o Sheets of eosinophils and significant intra epithelial infiltration , however, are absent in IBD , and when found in cases of established lBD , should prompt further investigation. In comparison, among patients without an established diagnosis of IBD , the finding of an eOSinophil-rich infiltrate in the lamina propria is nonspecific, particularly in the absence of features of chronicity. As such , one might suggest the possibility of an emerging or early IBD among a list of differential diagnoses .

ALLE RGY AllergiC colitis results in an extensive eosinophilic infiltration of the mucosa (Figs . 4 . 2024 . 2 04) . The most common antigens are found in cow milk and soy formulas , and allergiC eosinophilic gastrointestinal disorders are among the most common causes of diarrhea and rectal bleeding in infants less than 1 year o f age . Other causative agents include wheat , eggs , corn, fish, seafood, and nuts , which may cause failure to thrive or food refusal in infants

380

AT LAS

0 F

GASTR0 I N TEST I N AL

PAT H O LOGY

F i g u r e 4 . 202 Co l o n i c eosi n o ph i l i a patte r n , a l l e rg i c col itis. T h i s i nte nse focus of l a m i n a p ropria eosi n o p h i l i a is acco m p a n ied b y i ntra e p i th e l i a l eosi n o p h i l s (arrowheads) . T h e i n creased c o l o n i c eosi n o p h i l i a i n t h i s case w a s attri buted t o t h a t patient's kn own c l i n i ­ cal h i story o f food a l lergies.

F i g u re 4 . 203 Colonic eosi n o p h i l i a patte rn , a l l e rg i c c o l itis. This biopsy comes from a n other patient with eosinoph i l i a d u e to known a l l e rg i c col itis. N ote the p ro m i n ence of i n tra epith e l i a l eosi n o p h i l s (arrowheads) .

F i g u re 4.204 Colonic eosi n o ph i l i a pattern, a l l erg i c col itis. An oth er fie l d from the previous fig u re with pro m i n ent i ntra e p ith e l i a l eosi n o­ p h i l s (arrowheads) .

and toddlers . Adults may demonstrate a hypersensitivity reaction to medications such as 5-amino-salicilates , NSAIDs, and antiepileptic drugs (see medications later) . Eosinophilia involves any of the gastric layers , including the muscularis propria and serosa. Mucosal involvement is the most common , reported to occur in 2 5 % to 1 0 0 % of cases, and patients typically present with nausea, vomiting, diarrhea, and abdominal pain B4 Some patients show occult blood loss , anemia, and protein-losing enterocolopathy Peripheral eosinophilia occurs in 50% to 60% of cases and the sedimentation rate is elevated in approximately 2 5 % of cases, both of which return t o normal following effective diet modification 84 Other medi­ cal treatments include montelukast (a leukotriene receptor antagonist) , cromolyn sodium (a mast cell stabilizer) , and oral steroids such as budesonide 9 1

M E D I CATI O N S A laundry list o f medications i s associated with medication-induced mucosal eosinophilia (Figs . 4 . 205-4 . 2 08) , including aspirin , clozapine , carbamazepine , diclofenac , enalapril , gemfibrozil, ibuprofen, nimesulide , rifampicin, tacrolimus, ticlopidine, therapeutic gold compounds 9 2 - 100 N ote that a number o f these are NSAIDs, a commonly implicated class o f drugs in various mucosal inj uries of the GIT. Practically speaking, an effort to review

Ch a pte r

4

C O L0 N

381

Figure 4. 205 Co l o n i c eosi n o p h i l i a pattern, chemothera py m e d i ­ c a t i o n rea ctio n . This co l o n i c biopsy sh ows a n i n c reased den sity o f l a m i n a p ropria infl a m m atory ce l l s , but is oth erwise n ot rem a rka b l e . It w a s taken from a patient with c h ro n i c d i a rrh ea fo l l owi n g chemo­ thera py fo r a gyneco l o g i c m a l i g n a n cy.

Figure 4 . 206 Co l o n i c eosinoph i l i a patte rn, chemothera py medica­ tion reaction. H ig h e r m a g n ifi cation of the previous case. Eosi noph i l s com prise a s i g n ificant proportion o f t h e l a m i n a p ropria i n fl a m m a ­ tory ce l l s. A concu rrent skin biopsy sh owed fi n d i n g s compatible with medication rea ctio n .

Figure 4 . 207 Col o n i c eosi n o p h i l i a pattern, myco p h e n o l ate m ed­ i cation rea ction . This c o l o n bio psy shows a s i n g l e focus of crypt d estru ction ( a rro w) s u rro u nded by an i n fl a m m atory i nfi ltrate . T h i s b i opsy is fro m a k i d n ey tra n sp l a n t patient t a k i n g myco p h e n o l ate m ofetil (an i m m u nosu ppressant).

Figure 4. 208 Co l o n i c eosinoph i l i a patte rn, myco p h e n o l ate medi­ cation reacti o n . H i g h e r m a g n ification of the p revious case shows p ro m i n ent eosi n o p h i l i a with a n eosi noph i l i c crypt a bscess ( arrow) .

the patient's drug list for known o ffenders and other pertinent clinical findings (such as concurrent dermatitis that might suggest drug reaction) may be helpful to include in the note .

I N F ECTI O N Tissue invading helminths elicit Significant eosinophilic responses in the colonic mucosa . Thus , the detection of a focal but dense eosinophilic infiltrate should prompt a search for helminthic larvae (Strongyloides stercoralis, Schistosoma spp . ova , or fragments of Trichuris trichiura) (Fig. 4 . 209-4 . 2 1 1 ) . Some lumen dwelling helminthes do not elicit an eosino­ philic response, including: tapeworms , Enterobius vermicularis, Angiostrongylus costaricen­ sis, Gnathostoma spp , Ascaris lumbricoides, hookworms , and nonhuman parasites such as Ancylostoma caninum or A. sum 87 Although initial tissue sections do not always contain the organism, obtaining deeper levels and suggesting serologic and stool evaluation may be appropriate in these cases .

382

ATLAS

0 F

GAST R0 I N TE STI N A L

PAT H O LOGY

'

F i g u r e 4 . 209 Co l o n i c e o s i n o p h i l i a p atte r n , Sch istosoma ova . An eosinoph i l ic i nfi ltrate s h o u l d pro m pt exa m i n ation fo r parasitic i nfections i n the co l o n . Sch istosoma ova can be m i staken fo r s m a l l ca l cified concreti ons or psa m m om a bodies. H i g h e r m a g n ifi catio n reveals the ca l cified sh e l l . The presence a n d location of a spine (not pictu red) can h e l p speciate the org a n i s m .

Figure 4 . 2 1 0 Col o n i c eosi noph i l i a pattern, Strongyloides l a rvae. This colon biopsy shows Strongyloides l a rvae associated with back­ g ro u n d acute and chro n i c infl a m m at i o n .

Figure 4 . 2 1 1 Co l o n i c eosinoph i l i a pattern, a d u l t fem a l e Strongy­ loides. Cut in cross sectio n , the a d u l t fem a l e Strongyloides is l a rg e r than the l a rvae s e e n i n the previous fig u re . The cross sectio n a l so revea l s the reproductive org a n s of the a d u lt org a n i s m .

COLLAG E N VASC U LAR D I S O R D E R AN D VASCU LITIS The presence of increased eosinophils i n the colon should raise the differential diagnosis of connective tissue disorders such as systemic lupus erythematosus, scleroderma , dermato­ myositis , and polymyositis . The gastrointestinal findings in connective tissue disorders are nonspecific but may prompt a note suggesting ancillary studies for serum autoantibodies . By comparison , speCific histologic features of vasculitis may be found in the submucosa , which contains abundant blood vessels and lymphatics ; for example , Churg-Strauss syn­ drome shows systemic necrotizing vasculitis, and the GI tract is affected in 30% of patients (Fig. 4 . 2 1 2 ) 101 Eosinophil-rich granulomas with necrosis involving medium- to small­ sized vessels are characteristic findings 1 0 2 Another systemic necrotizing inflammatory disease of small- and medium-sized arteries is polyarteritis nodosa , and it affects the GIT in up to 2 5 % of cases . 103 These lesions often involve bifurcations of arteries that lead to aneurysm, thrombosis or rupture of vessels-vessels that are often unavailable for review

Ch a pte r

4

C O L0 N

383

Fig u re 4 . 2 1 2 Co l o n i c eosi n o p h i l i a patte r n , C h u rg-Stra uss syn­ d ro m e . A s m a l l s u b m u cosa vessel i n a patient with known C h u rg ­ Stra uss syn d ro m e is ri nged b y eosi n o p h i l s (arrowheads) .

due to the superficial nature of endoscopic biopsies . The presence of an eosinophil-rich mucosal infiltrate and correlation with serologic or radiographic findings , however, can prompt steroid treatment.

PEARLS & PITFALLS

Eosi n o p h i l s may be t h e fi rst clue to a n e o p l astic process.

Syste m i c m a stocytos i s and La n g e r h a n s ce l l h i sti ocyto s i s a re ofte n acco m pa n i ed by a backg ro u n d i nfi ltrate of ben i g n eosi n o p h i l s , l i ke l y d rawn i n by c h e m o k i n es. In the sett i n g of i n c reased m u cosa l eos i n o p h i l i a , take a m o m ent to exa m i n e t h e su rro u n d i n g a rea for s u bt l e n e o p l a stic processes ( F i g s . 4 . 2 1 3-4 . 2 1 8) .

Fig u re 4. 2 1 3 Co l o n i c eosi n o p h i l i a pattern , syste m i c m a stocytosis. At low m a g n ificatio n , this co l o n i c biopsy s hows inta ct crypt a rch itec­ tu re . The l a m i n a pro p ri a appears a b n o r m a l with a m ixtu re of p a l l o r a n d eosi n o p h i l i a .

Figure 4 . 2 1 4 C o l o n i c eosin o p h i l i a pattern , system i c mastocytosis. H ig h e r m a g n ification of the p revious case shows an i ntense eosino­ p h i l i a i n the l a m i n a propri a . Reca l l that eosi n o p h i l s can be bysta n d ­ e rs of neoplastic p rocesses.

384

ATLAS

0 F

GAST R0 I N T EST I N A L

PAT H O LOGY

Figure 4 . 2 1 5 Co l o n i c eosinoph i l i a pattern, system i c mastocytosis. H ig h e r m a g n ifi cati o n of the p revious F i g u re sh ows a n a b u n d a n ce of mast ce l l s in the backgro u n d l a m i n a p ropria. These ce l l s h ave a "fried e g g " appeara n ce, with basop h i l i c g ra n u l a r cytop l asm a n d a periphera l h a l o .

Figure 4. 2 1 6 Colonic eosi n o ph i l i a patter n , system i c mastocytosis (CD 1 1 7 i m m u n osta i n ) . C D 1 1 7 is a normal m a rker for m a st ce l l s . The m a st cells a re densely packed i n sh eets.

,

Figure 4 . 2 1 7 C o l o n i c eosi n o p h i l i a patte rn, system i c m a stocytosis (tryptase i m m u nosta i n ) . Tryptase i s a l so a n o r m a l m a rker fo r m a st ce l l s . Aga i n , n ote the a b n o r m a l den sity of m a st c e l l s .

Figure 4. 2 1 8 Co l o n i c eosi noph i l i a patte rn , system i c m a stocytosis (CD25 i m m u n osta i n ) . CD25 is a cyto p l a s m i c sta i n that h i g h l i g hts an a b e rra nt m a rker i n system i c mastocytosis.

G RAN U LO MATO US PATTE RN

Fig u re 4. 2 1 9 G ra n u l o m atous patter n , Histoplasmosis. G ra n u l o ­ mata can be associated w i t h a v a r i e d l i st of d iffe renti a l d i a g n os­ tic considerations, i n c l u d i n g i n fe ctio n , m e d i cation i nj u ry, l S D , a n d d ivertic u l a r d i sease, a m o n g m a n y othe rs. T h i s case origi nated from a patient with an u n re m a rka ble h i story who p resented fo r screen i n g co l o n osco py. A sma l l n o d u l e w a s n oted , which h isto log i ca l l y con­ sisted of a g ra n u l o m a with fore i g n body g i a nt ce l ls .

F i g u re 4 . 2 2 0 G ra n u l o m atous patte r n , H istoplasmosis. H i g h e r power o f t h e p revious i m a g e . T h e pati e n t o ri g i n ated f rom O h i o where t h e therm a l ly d i m o rp h i c fu n g u s i s seen with reg u l a rity. The c h a ra cteristic yeast fo rms d i s p l ayed a u n ifo r m 2 to 3 Jlm size o n G M S o r PAS/D (n ot shown). An AFS speci a l study w a s neg ative .

Ch a pte r

Common etiologic considerations of the granulomatous pattern are listed subsequently (Figs . 4 . 2 1 9 and 4 . 220) .

C H E CK L I ST: Et i o l o g i c C o n s i d e rations fo r t h e G r a n u l o m ato u s Pattern D

I nfl a m m atory Bowel D i sease

D

N o n specific M u cosa l I nj u ry

D

D iverti c u l a r D isease

D

I nfect i o n s

D

M e d i cations

D

S a rco idosis

D

Va scu l a r I nj u ry

D

P n e u m atosis Cysto ides I ntesti n a l i s

D

Auto i m m u n e D i seases (i n c l u d i n g co m m o n va ri a b l e i m m u nodefi c i e n ci e s a n d c h ro n i c g ra n u l om a to u s d i sea se)

D

Cord Col itis Syn d ro m e

D

Lym p h o p ro l ife rative Disord e rs

Granulomata in the colon usually inspire a fair amount of clinical interest , particularly regarding potential underlying diseases . Cases without careful notes will invariably result in at least one of the following clinical inquiries : "Could this finding represent Crohn disease?" "Sarcoidosis?" "Mycobacterium or fungal infection?" Unfortunately, granulomata are entirely nonspeCific . The key to navigating the laundry list of considerations is to carefully scruti­ nize the background mucosa in search of other diagnostic clues, in addition to a thorough clinical chart review; for example, if the background shows active chronic colitis , the dif­ ferential diagnostic considerations narrow to those agents associated with both granulomata and active chronic mucosal injury, such as lED , diverticular disease, diversion , infections , medication (such as ipilimumab) , or cord colitis syndrome , as detailed in the chronic colitis pattern discussion, this chapter. While granulomata can be seen in either ulcerative colitis or Crohn cases , their morphology and distribution can serve as useful diagnostic clues . Granu­ lomata in ulcerative colitis are more commonly well-delineated structures seen in association with damaged crypts and extruded mucin, whereas granulomata in Crohn disease are more commonly poorly formed collections of epithelioid macrophages . Those cases accompanied by the additional red flags of upper-tract injury, transmural disease, and a patchy progres­ sion would favor a diagnosis of classic Crohn disease , and those with red flags of rectal­ based, mucosa-restricted , diffuse disease progression would favor classic ulcerative colitis (Figs . 4 . 2 2 1-4 . 2 2 5 ) . Granulomata are seen in up to 2 6 % of diverticular disease-associated colitis cases, the leading etiology in patients with changes restricted to the segment of colon 104 SyphilitiC and or LGV infections would be favored if chart involved by diverticular disease . review uncovered the red flags of HIV seropositivity in MSM and the histology showed an intense mononuclear infiltrate with copious plasma cells (Fig. 4 . 226). More common infec­ tious considerations include mycobacterial and fungal infections . Both are assessed with AFB and GMS special stains , or separate submission of tissue for cultures. MicrobiologiC cultures are preferred , when possible , because of improved sensitivities and the advantages of speciation and determination of drug susceptibility and resistance patterns . Diversion­ associated colitis would be a consideration if the granulomata were seen along with florid lymphoid aggregates in the excluded bowel segment of a patient with a history of diversion (Fig. 4 . 2 2 7) . Sarcoidosis involving the GIT is seen in less than 1 % of sarcoidosis patients and most commonly involves the stomach, followed by the colon. lOS The sarcoid granulomata are not uncommonly multifocal and striking, and their polyp or mass like appearance can raise clinical concerns for malignancy 1 0 6 Correlation with the clinical history of sarcoidosis or per­ tinent clinical red flags such as a history of bilateral hilar lymphadenopathy, elevated serum angiotensin converting enzyme levels, and j oint, skin, eye , or lung dysfunction can help build a case for sarcoidosis (Figs . 4 . 228 and 4 . 229) . If the background mucosa shows an ischemic

4

C O L0 N

385

386

ATLAS

0 F

GASTR0 I N TEST I N A L

PAT H O LOGY

Figure 4 . 2 2 1 G ra n u l o matous patte rn , Cro h n d isease. This h i g h ­ power view o f florid g ra n u l o m ata g ives few clues to a n eti o l o g i ca l ly specific diag nosis.

Figure 4.223 G ra n u lom atous pattern, Cro h n d i sease. M o re com­ m o n ly, g ra n u l om ata i n C ro h n d isease a re poorly formed or d ifficu lt to spot at l ow power, a s i n this case.

F i g u re 4 . 2 2 2 G ra n u l o m atous pattern , C ro h n d isease; h owever, on low power we see the g ra n u l om ata a re tra n s m u ra l a n d accom­ p a n ied by tra n s m u ra l chro n i c i nfla m m ation and fi brosis. M o reover, a ctive chro n i c i n fl a m m atory injury was seen in the sto m a c h , term i n a l i l e u m , a n d i n a patchy d istri bution thro u g h o u t t h e co l o n , support­ i n g a c l i n icopath o l o g i c d i a g n osis of Cro h n d i sease. G M S a n d AFB speci a l sta i n s were negative a n d infection a n d medication i nj u ry h a d b e e n c l i n i c a l l y excluded.

F i g u re 4 . 224 G ra n u l o m a t o u s patte rn , C ro h n d i sease. H i g h e r power o f p revious i m a g e . T h i s co l l ectio n o f m a crop h a g es b l e n d s a l m ost i m perceptibly w i t h the n e i g h boring l y m p h o cytes. AFB a n d G M S sta i n s were n o n contributory (the g ra n u lo m a was exha u sted o n deeper sections).

pattern of inj ury and the granulomata are centered on damaged vessels , a granulomatous vas­ culitis enters the differential diagnosis; similar findings can be seen in Crohn disease. Granulo­ mata may also serve as clues to an underlying autoimmune disease . If the background mucosa is devoid of plasma cells , consider common variable immunodeficiency (CVID) , which is accompanied by granulomata in up to 1 9 % of colonic specimens 107 In the pediatric setting, the granulomatous pattern of inj ury must invoke the possibility of chronic granulomatous disease (CGD) . In a recent study of 87 patients and 1 5 autopsy cases with established CGD , lOB 6 5 % of colon specimens had pigmented macrophages and 46% had granulomata . Granu­ lomata can also be a clue to a hematopoietic malignancy If atypical lymphOid cells are seen, maintain a low threshold for seeking a formal hematopathology consultation. 109 In summary scrutiny of the background histology and careful chart review can prove exceptionally helpful in ascribing clinical significance to the nonspecific finding of granulomata .

Ch a pte r

4

C O L0 N

387

Figure 4 . 225 G ra n u lomatous patte rn, u lcerative col itis. G ra n u lo­ m ata i n u l ce rative col itis a re u s u a l ly i n association with d a m aged crypts a n d extruded mucin, as seen in this case.

Figure 4.226 G ra n u l o m atous pattern, syp h i l itic and o r LGV infec­ tions. G ra n u lomata can a lso be seen in the setting of pecu l i a r infec­ tions. This recta l biopsy was from a patient c l i n i ca l ly confi rmed to be co-infected with syph i l is and LGV. The background m u cosa showed copious plasma cells and a lack of a rch itectu ra l distortion, a cute crypt centric damage, and eosi n o p h i l i a (not shown). S i n ce g ra n u l omata a re nonspecific fi n d i n gs, carefu l scruti ny of the backgro u n d m u cosa is essential to u n coveri ng the h idden etiologic agent to ensure proper treatment. AFB a n d GMS speci a l sta ins were negative.

Figure 4.227 G ra n u l o m ato us pattern, d iversion-associated col itis. These loose fore i g n body g i a n t ce l l s a n d macro p h a g e co l l ections a re seen i n association with d a m a ged crypts. The patient h a d a n esta bl ished h i story o f d iversion .

Fig u re 4 . 2 2 8 G ra n u l omatous patte rn, s a rco i d . This we l l -fo rmed g ra n u l o m a with fore i g n body g i a nt ce l l s o ri g i n ated from a patient with a long-sta n d i n g h i sto ry of sarcoidosis. The backgro u n d m u cosa was u n re m a rka b l e and AFB and G M S specia l sta i n s were n egative fo r m icroorg a n isms. This case was signed out as " co l o n i c m u cosa with scattered g ra n u lomata, otherwise nondiag nostic fin d i n gs, com­ pati b l e with the h i story of sarcoidosis . "

PEARLS & PITFALLS

P n e u m atosis Cystoides I ntest i n a l i s

P n e u m atosis cystoides i n testi n a l i s ( P C I ) i s a n other d i a g n osti c c o n s i d e ration when m a c ro p h a g e co l l ectio n s a re seen . Alth o u g h PCI does n ot featu re g ra n u l o m a s per se, b i opsy or crush a rtifa ct can c l o se l y rese m b l e g ra n u l o m a ta . Deeper secti ons a n d corre l ation with the e n dosco p i c i m p ress i o n ca n often c l a rify s u c h su bopti m a l spec i m e n s . Ca ution m u st be exerc i sed t o avoid m i s i nterpreti n g the fo re i g n body g i a nt ce l l co l l ecti o n s of PCI a s an evidence of C ro h n d isease. 1 1 o See a l so P n e u m a ­ t o s i s Cystoides I ntesti n a l i s , P i g m e nts a n d Extras, th i s c h a pte r.

388

AT LAS

0 F

G A STR0 I N TEST I N A L

PAT H O LOGY

F i g u re 4.229 G ra n u l o matous patte rn , s a rco i d . H ig h e r power of p revious case.

FAQ: What s h o u l d I do wit h a n i s o l ated g r a n u l o m a i n a n otherwise u n re m a r k a b l e b i o p s y i n a n otherwise u n re m a r k a b l e patient? Answe r : Despite the afo re m e n t i o n ed exh a u stive d iscuss i o n , n ot u n co m m o n l y, a

rog u e g ra n u l o m a i n the co l o n s i m p l y s i g n ifi e s a rog u e g ra n u l om a i n t h e co l o n . S u bseq u e n t A F B a n d G M S spec i a l sta i n s a l o n g with a ca refu l c h a rt review a re o b l i g ato ry i n a n effo rt to u n cover a d d i ti o n a l d i a g n ostic c l u e s . I f these sea rc h e s p rove u n revea l i n g , a ca refu l n ote ofte n h e l ps the c l i n i c i a n u nd e rsta n d t h e l i m ita­ tions of u n d e rsta n d i n g a n i s o l ated g ra n u l o m a .

SAM P L E NOTE: AN I S O LAT E D G RAN U LOMA I N T H E CO LON O F AN OTH E RWIS E H EALTHY I N D IVI D U A L

Colon, Random (biopsy) : •

Colonic mucosa with an isolated granuloma , otherwise nondiagnostic findings .

Note: The biopsy shows a single granuloma in otherwise unremarkable colonic mucosa . This inj ury pattern is etiologically nonspecific and most likely represents an incidental finding given the unremarkable clinical history (favor nonspecific, remote mucosal injury) . Negative for histologic features of active or chronic inflammatory disease . AFB and GMS special stains are negative .

SAM P L E N OTE: AN I S O LATE D G RAN U LOMA, BACKG ROU N D M O D E RATE ACTIVE C H RO N I C M U COSAL I NJ U RY, AN D N O H ISTORY P ROVI D E D Note: The biopsy shows a Single granuloma in a background o f moderate active chronic colitis . This inj ury pattern is etiologically nonspecific and can be seen in the setting of infection (including STI proctocolitis) , medication injury, IBD , diverticular disease , sar­ coidosis , vasculitides , autoimmune diseases, among others . Clinical correlation required. AFB and GMS special stains are negative .

Ch a pte r

P I G M E NTS AN D EXTRAS

Figure 4.230 M e l a n osis co l i . A va riety of co l o rfu l entities can be seen in the col o n . This is a stri king exa m p l e of m e l a n osis co l i , a fi nd­ i n g l i n ked to c h ro n i c laxative usage.

CH ECKLIST: Eti o l o g i c Considerat i o n s fo r P i g m e nts and Extras ( F i g . 4 . 230) D

M e l a nosis Co l i

D

Tattoo P i g m e nt

D

Ai r Artifa ct

D

P n e u m atos is Cysto ides I ntesti n a l i s

D

M u ci p h a g e s

D

Res i n s

M E LANOS I S CO LI (ALSO R E F E R R E D TO AS PS E U DO M E LANOS I S CO LI) Melanosis coli refers to coarse , brown-black pigment i n the cytoplasm o f the colon's resi­ dent macrophages. Despite the name , ultrastructural studies demonstrated the pigment is lipo fuscin , not melanin (this particular factoid is a favorite among those who write test questions ! ) 1 l 1 The pigment is derived from stimulant laxatives containing senna , aloe-emodin , chrysophanol, cascara , frangula , and rhein . 1 1 2 The purgative effects of such preparations stem from their ability to increase colonic motility and decrease colonic absorption, resulting in decreased transit time and softer stools . The endoscopic images in patients with melanosis coli can be impressive (Fig. 4 . 2 3 1 ) . Any region of the colon can be affected with no consistent regional pattern of involvement: some claim the distal colon is most affected, while others found the changes most pronounced proximally. l l 3, 1 14 Melanosis coli is seen in up to 7 3 % of patients with chronic laxative usage and in up to 6% of biopsy and autopsy cases . 1 l5 , 1 1 6 Such findings have been documented within 4 months of regular laxative usage and the findings reverse 6 to 1 1 months following cessa­ tion (Figs . 4 . 2 32-4 . 238) . 1 1 7 , 1 18 Early literature suggested anthracoid laxatives were a risk factor for colonic neoplasia based on provocative animal and human studies showing an increased association of melanosis coli in patients with adenomas and carcinomas. 1 l9 , 1 20 Today, this theory has been abandoned . 1 2 1 , 1 22

4

C O L0 N

389

390

ATLAS

0 F

GASTR0 I N T ESTI NA L

PAT H O LOG Y

Figu re 4 . 2 3 1 M e l a n osis co l i , e ndoscopic i m a g e . This en doscopic image shows stri king m ucos a l p i g m e nt depositi o n . This patient had a 1 0-ye a r h i story of sen n a i nta ke for c h ro n i c constipati o n .

Figure 4. 232 M e l a nosis col i . The cha racteristic brown-black pig­ ment i s with i n the cytoplasm of m acrophages. The p i g m e n t is l i po­ fusci n , n ot m e l a n i n .

Figure 4.233 M e l a n osis co l i . U n d e r o i l i m m e rsion, note t h e bland cytologic featu res of the m acrophages with perfectly rou n d n uclei, d e l i cate nucleoli, a n d a b u n d a n t cytoplasm. The backg ro u n d shows scattered n eutrop h i l s secondary to an u n related self- l i m ited i nfection .

F i g u re 4 . 234 M e l a n osis col i . An a lternate fi e l d s h ows c o a rse c l u m ps of cyto p l a s m i c p i g m e nt.

Figure 4.235 M e l a nosis co l i . This exa m p l e featu res a m o re typica l (less s u btle) case of m e l a n osis co l i .

Figure 4.236 M e l a nosis co l i . H i g h e r powe r of previous case.

C h a pte r

.

Figure 4.237 M e l a n osis col i . This is a n other s u btle case that wou l d be easy to m iss o n sca n n i n g m a g n ificati o n .

4

C O L0 N

391

F i g u r e 4 . 2 3 8 M e l a n osis col i . The l i pofu s c i n is h i g h l i g hted b y a Fonta n a M a ss o n speci a l sta i n (th is sta i n a l so h i g h l i g hts m e l a n i n p i g m e nt) .

TATTOO P I G M E NT Since tattoo pigment is applied to localize clinically suspicious lesions , its identification should prompt careful scrutiny for sneaky neoplasms (Figs . 4 . 2 39-4 . 243) . See also, Tattoo Pigment , Pigments and Extras , Small Bowel Chapter.

AI R ARTI FACT Endoscopy relies on air insufflation to expand the bowel for proper visualization . Through this process , increased intraluminal pressure can force air into the bowel wall . Cases with­ out a concomitant foreign body tissue response are classified as air artifacts . Air artifacts are so extraordinarily common that our eyes often glide right over this finding. When the foci are small and the tissue is of nonpolypoid or flat mucosa, it is easy to dismiss these peculiar foci as air artifacts . Difficulties arise in the case of subtle polyps for which the diagnostic dilemma is air artifact versus lipoma. Deeper sections and endoscopic correlation

Figure 4 .239 Tattoo . Preoperative a p p l i cation of tattoo pigment h e l ps to endoscopica l ly m o n itor suspicious lesions, locate the lesion at ti m e of s u rg e ry, a n d is associated with i m p roved local lymph node d i ssections. Tattoo p i g m ent, u n l i ke m e l a n osis co l i , i s d ra m atic s i n ce its s o l e pu rpose is for g ross visi b i l ity with the n a ked eye.

Figure 4. 240 Tattoo . I ndia ink rem a i n s the m ost widely employed tattoo a g e nt. N ote the b lack, coa rse cyto p l a s m i c g l obules with in the macro p h a g es. This exu berant case has e l i cited a fore i g n body giant ce l l rea cti o n (arrowheads) .

392

AT LAS

0 F

GAST R0 I N T EST I NA L

PAT H O LOGY

• ,

Figure 4 . 2 4 1 Tattoo. U n d e r o i l i m m e rs i o n , the coa rse, g l o b u l a r n a t u re o f the b l a c k tattoo p i g m e nt i s a p p a rent. N ote the b l a n d n u cl e a r featu res o f the h ost m a cro p h a g e s that d i s p l a y p e rfectly rou n d nuclei a n d d e l i cate n u c l eo l i .

Figure 4 . 242 Tattoo. T h i s case fea t u res tattoo p i g m e n t free­ floati n g i n the s u b m u cosa . The seg menta l resection occu rred a few h o u rs after the tattoo was a p p l ied (before a tissue response cou l d be mou nted) .

F i g u re 4 . 243 Tattoo. Th i s case is a m o re typica l (subtl e) exa m ­ p l e . Tattoo a p p l ication was a p p l ied 2 weeks before t h i s s e g m e n t a l resection . U n l i ke the skin counterpa rt, tatto o i n g o f the c o l o n i s not p e rfo r m e d fo r cosmetic o r a rtistic expressi o n . C o l o n tattoo s a re to loca l ize c l i n i ca l l y s u s p i c i o u s l es i o n s , a n d i d e ntificati o n of t h e p i g m e n t s h o u l d a l ways p ro m pt a thoro u g h eva l u ation fo r s n e a ky m a l igna ncies. can often clarify the issue. lipomas display a characteristic "pillow" sign when compressed (Figs . 4 . 244 and 4 . 24 5 ) . Histologic clues can be a bit subj ective and frustrating. In contrast to a lipoma , air artifact gently pushes apart the neighboring cellular constituents so that inflammatory and stromal cells as well as vascular and neural structures are seen coursing between the empty spaces . Additional helpful clues include a lack of nuclei within the empty spaces (in contrast to an adipocyte with a bona fide nucleus) and that the sizes and shapes of the empty spaces can be unnaturally large and bizarre (Figs . 4 . 246-4 . 2 5 2 ) . In contrast , lipomas have minimal intervening cellular components , clearly discernible nuclei , and the cytoplasm is more predictably uniform in size and shape (Figs . 4 . 2 5 3 and 4 . 2 54) . Note , well-differentiated liposarcomas violate these general tips, but they would present as large mass lesions for which air artifact would not enter in the differential diagnosis . In chal­ lenging cases , well-differentiated liposarcomas display MDM2 and CDK4 immunoreactivity (Fig. 4 . 2 5 5) . Some cases of entrapped air form cyst-like spaces and illicit a tissue response . These findings are classified as pneumatosis cystoides intestinalis , see next subsection.

Ch a pte r

4

COL0 N

393

F i g u r e 4 . 244 Li p o m a , e n d osco p i c i m a g e . T h i s e n d osco p i c a p p e a ra n ce o f a l i poma is fa i rly u n revea l i n g .

Fig u re 4.245 Li pom a , endoscopic i m a g e . H owever, u pon com­ press i o n , the " p i l low sig n " is see n . In this a n a l ogy, the i n strument is a head a n d the polyp i s its p i l l ow. N ote, how the "head" i n dents or displaces portions of the " p i l l ow. " This en doscopic fi n d i n g is h i g h ly suggestive of a l i po m a .

Fig u re 4 . 2 46 A i r a rtifa ct. T h i s resect i o n case o r i g i n ated from a patient with bowel p e rforatio n . N ote the l a rg e , b i l l owi n g , cloud l i ke a i r pockets co u rsi n g thro u g h the s u b m u cosa . Alth o u g h subtle cases of air a rtifact often raise the poss i b i l ity of a l i po m a , these particu l a r a i r pockets a re fa r t o o l a rge, biza rre, a n d convol uted t o be a n yth i n g oth e r t h a n entrapped a i r.

Figure 4.247 Air a rtifact. H i g h e r power sh ows t h e a i r pockets a re push i n g a p a rt the n o r m a l cel l u l a r constituents (n ote the lymphoid a g g reg ate i n the u pper left, vessels i n the middle, a n d g a n g l ion ce l l s i n the upper right) . I n additi o n , t h e a i r pockets have n o endoth e l i a l l i n i n g (to suggest a Iymphovascu l a r spa ce) or n u clei (to suggest a n a d i pocyte), both h e l pfu l c l u e s t o t h e d i a g n osis o f a i r a rtifact. Also, n ote there i s n o tissue response (th e re a re n o fo re i g n body g i a n t cel ls rea cti n g to t h e displ aced g a s ) . This e m e rgent bowe l resection occu rred a l m ost i m mediate ly after the perfo rati o n , befo re the tissue h a d sufficient time to rea ct to the i nfi ltrati n g gas.

Figure 4.248 Air a rtifact. An alternative fie l d sh ows l a rge, biza rre a i r pockets (asterisks), w h i c h dissect t h e resident tissue. Lipomas do n ot tend to perco l ate a ro u n d n ative structures such as g a n g l i o n ce l l cl us­ ters, nerves, fi b rous tissue, and blood vesse ls, as seen i n this exa m p l e o f a n a i r a rtifa ct. A l s o , there is no epith e l i a l l i n i n g a n d n o n uclei to suggest a Iym phovascu l a r space or a d i pocytic lesi o n , respectively.

Figure 4. 249 Ai r a rtifact. Ai r a rtifa cts ofte n i n s p i re the most con­ s i d e ration a ro u n d lymphoid a g g reg ates i n tissue subm itted as a polyp: co u l d the polyp represent a lymphoid a g g reg ate with nea rby a i r a rtifact or is the polyp a sma l l l i po m a ?

394

AT LA5

0 F

G A5TR0 I N TE 5T I N A L

PAT H O LOGY

.

"

$

.. , # ��� .,, -- , ,

.

"

•

... •

F i g u re 4 . 2 5 0 Air a rtifact. On h i g h e r power, l a rg e , i rreg u l a r a i r pockets seem t o d i ssect t h e tissue (asterisks) . A i r a rtifacts a re m ost p roblematic a ro u n d lym phoid a g g regates, w h e re the a i r spaces can compress n e i g h boring lymphoid cel l s a n d appear as if the a i r spaces h ave n u c l e i (arcs) . In these sce n a rios, look ca refu l l y for d efi n itive a i r pockets (asterisks). If defi n itive a i r pockets a n d adjoi n i n g lymphoid a g g regates a re seen, the i n d i cated focus i s most l i kely a n a i r a rtifact. Deeper sections can be reassuring in a m b i g u o u s cases.

� l.�• 4C

•

..

"\. ,

'"

'

Il1o

•

..

...

'

_

. ..

-;

r.

--...

-

' �'"

. .. It,.

..

.. _, I .

;

.. �s,. ..

:- --

,

,"

...:

.. (

..::.-

..

.

� -.

. .

., I �" " : • .".

_ .. ... .. • _ _ "'_ . • • - -

-:

..

•

..... ", � -

.

_

.:

"

"

• •

f•

•

�

. .:. .. " .:.\-. . : .. ., . . '

r 'I .. -.. - .. , " ... .., 6IfII' ",'

.. .

..

-

'" 'I.;

\

.

,�

"

.

.:'

.. ....:

�...

.. ..

' '

.... .

r

j

J

Figure 4 . 2 5 1 A i r a rtifact. The assigned resident i n terpreted t h i s p o l y p as a l i p o m a (brackets) .

. •

, \.

.

. .

J

-

.

-

, "

...

T ).

, . � . ' ., "

...

- " �.... .. Figure 4 . 2 5 2 A i r a rtifa ct. H i g h e r m a g n ifi cation s h ows that t h e em pty spaces l a ck the d i a g n ostic featu res of a l i p o m a : there a re n o n u cl e i l i n i n g these spaces. I n stea d , th is focus rep resents a i r a rtifact. N ote the i rreg u l a r, g a p i n g natu re of the em pty space. Deeper sec­ tions revealed a tubu l a r adenoma, accou nti n g for the c l i n ical i m p res­ sion of the polyp.

,

Figure 4.254 Lipo m a . H i g h power sh ows that each l i pocyte h a s i t s o w n sm a l l , peripheral n u cleus. A l s o the (be n ign) n e o p l a stic ce l l s h ave a u n iform a rch itectu re with few interve n i n g n o n l i pocyti c e l e­ m e nts. These key features of a l i poma contrast with fi n d i n g s in a i r a rtifacts .

Figure 4 . 2 5 3 Li p o m a . I n contrast to a i r a rtifacts, l i po m a s show cohesion of t h e lesi o n a l ce l l s . T h e re a re few i n te rve n i n g stro m a l ce l l s o r i n fl a m m atory ce l l s p resent, h e l pfu l d i sti n g u is h i n g fea t u res of a l i p o m a .

� Fig ure 4.255 We l l-d ifferentiated l i posa rcoma i nvolvi ng the co l o n i c serosa . I n contrast t o a b e n i g n l i po m a , t h i s a d i pocytic l e s i o n sh ows h i g h -g rade n uc l e a r features. N ote the hyperc h romatic, pleomorp h i c n u c l e i o f the a d i pocytes. T h i s patient h a d a 50 cm retroperiton e a l wel l-d iffe re ntiated l i p o s a rco m a t h a t foca l l y i nvolved t h e co l o n . M D M 2 a n d C D K4 were d iffusely positive i n the lesion a l cel l s .

Ch a pter

4

COL0 N

395

P N E U MATOS I S CYSTO I D ES I NTESTI NALIS Pneumatosis cystoides intestinalis (PCI) refers t o cyst-like structures impregnated with gas and lined by macrophages and foreign body giant cells . These structures are within the bowel wall and can be visualized endoscopically and radiographically (Figs . 4 . 2 5 6-4 . 2 62 ) . U p to 8 5 % of P C I cases are secondary to a n iatrogenic procedure , mechanical, bacterial , metabolic , or pulmonary dysfunction. 123 An association with collagen tissue disorders , AIDS, and glucorticoids has also been reported . While numerous theories of origin exist, the pre­ vailing view is that increased intraluminal pressures force gas through damaged mucosa , and a subsequent tissue response manifests as a foreign body giant cell reaction . PCI can be

Figure 4.256 P n e u m atosis cystoides i n testi n a l is (PCI). This pati ent had a l o n gsta n d i n g h i story of chro n i c obstructive p u l m o n a ry disease (CO P D) and p resented with abdom i n a l pa i n . The i m a g i n g study sh ows n u m erous air pockets with i n the bowe l wa l l . The bowe l wa l l h a s a spo n g e l i ke or swiss-cheese-l i ke foamy a p pe a ra n ce on i m a g i n g (bracket) . COPD causes P C I seco n d a ry t o i n creased i ntraabdo m i n a l pressu re , w h i c h fo rces g a s i nto t h e bowel wa l l .

Fig u re 4.257 P C I , endoscopic i m a g e . Co rrespo n d i n g endoscopic i m a g es of the bowel wa l l show n u m erous convol uted m u cosa l fo lds that appear a l m ost cerebriform .

Figure 4 . 2 5 8 P C I , en dosco p i c i m a g e . An a ltern ate view of the same case shows s i m i l a r features. The bowel wa l l is d istended with l a rge a i r pockets.

F i g u re 4 . 2 5 9 P C I . H i sto l o g i c sect i o n s show m u lt i p l e cyst- l i ke spa ces i n the m uscu l a ri s propri a .

396

ATLAS

0 F

GASTR0 I N TE S TI N A L

PAT H O LOGY

Figure 4. 260 PCI . Altern ate i m a g e , same patient.

Figure 4.261 PCI . H ig h e r power sh ows that the cyst-l i ke spaces a re l i n ed by h i stiocytes and fore i g n body g i a nt ce l l s .

Figure 4 . 2 6 2 PC I . H i g h est power sh ows the b l a n d featu res of t h e fo reign b o d y g ia n t cel ls l i n i n g the em pty spaces. seen anywhere along the tubular GIT, but most cases involve the bowel (colon 78 % , small bowel 5 7 % ) . 123 Patients are usually asymptomatic. When pneumatosis is identified, it is important to assure that there is not other pathology in the resection that may have initiated the rather eye-catching pneumatosis-a classic example is scleroderma (which results in sclerosis of the muscularis propria and obstruction) . CMV infection is also detected in some cases . Complications include obstruction, volvulus, intussception, ischemia, and perfora­ tion. Treatment is aimed at correcting the underlying disease or conservative medical therapy, where possible . See also, Pearls &. Pitfalls , Granulomatous Pattern, this chapter. =

=

M U C I P HAG ES Azzopardi described muciphages as mucoprotein-containing macrophages in the rectum in 1 96 6 . 1 2 4 The incidence was as high as 5 0 % of rectal biopsies and no correlation with sex, age , or underlying disease was found . Academic interest in muciphages was likely borne out of the 1 960s burgeoning understanding of Whipple disease, and a concern that muciphages represented Whipple disease involving the rectum. Today we know muciphages are extraor­ dinarily common with essentially no relation to Whipple disease . A more recent study describes the muciphages as superficially located in the lamina propria and found that up to 1 9 % present as nodules or polyps 2 These experts found a backdrop of increased chronic inflammation and mild fibrosis and suggest muciphages represent nonspecific, resolving

C h a pte r

4

C O L0 N

397

Figure 4. 263 M uciphages. M u ci p h a g es a re ben i g n oddities, m ost com m o n l y seen in the rectu m . They can be spotted at low power, as i n this case.

Figure 4 . 264 M u ci ph a g es a re m u co p rote i n-conta i n i n g m a c ro­ p h a ges that accu m u l ate seco n d a ry to prior recta l i nj u ry.

Fig u re 4.265 M u c i p h a ges. U n d e r o i l m a g n ificati o n , the b l a n d n uc l e a r featu res a re see n . D i s l odged m u c i p h a ges c a n occasi o n a l l y ra ise concerns for s i g n et ri n g ce l l carci n o m a . H e l pfu l c l u es t o t h e d i a g n os i s o f b e n i g n m u c i p h a g e s i n c l u d e the b l a n d cyto logy a n d l a c k of backg ro u n d dysp l a s i a a n d desm o p l a s i a . I n diffi c u l t cases, CD68 will confi rm their h i sti ocytic orig i n . M uciphages a re cytokera­ tin n o n reactive.

Figure 4. 266 M uci phages. Th is l ow-power image shows the c h a r­ a cteristi c d i stri b ution of muciphages as they decorate the superficial lamina p ro p ri a .

inj ury Their mucin presumably originates from "clean u p " of epithelial damage o r turnover (Figs . 4 . 2 63-4 . 2 6 9 ) . Detailed studies show the mucin contains neutral , weakly acidic , or strongly acidic mucin with predominantly sialomucin but also a smaller component of sul­ fated mucin . 2 The clinical importance of muciphages is simply to be aware of their benign and nonspecific nature . AFB and GMS speCial stains are not required upon identification because muciphages are not granulomata and have no association with infections . PEARLS & P ITFALLS

To those u nfa m i l i a r with m u ci p h a ges, they ca n appear a l a r m i n g at fi rst. An i nterest­ i n g consu ltatio n case fea t u red a p rostate b i opsy accom p a n i e d by bysta n d e r recta l tissue with p ro m i n e n t m uc i p h a g e s . The m u c i p h a ges h a d becom e d i s l odged and " sq u i s h ed " a n d ra ised concerns fo r s i g n et r i n g ce l l ca rci n o m a . H e l pfu l d i a g n osti c c l u es i n c l u d e that t h e m u ci ph a g e s d is p l a y b l a n d cyto l o g i c featu res, i m m u n o l a be l w i t h the h i sti ocytic m a rker C D 6 8 , a n d a re cytokera t i n n o n reactive.

398

AT LAS

0 F

GAST R0 I N TE STI N A L

PAT H O LOGY

Figure 4 .267 M uciphages. H i g h e r powe r of previous image. M uci­ phages a re h i sto l o g ica l ly identica l to foa m y m a crophages of a n y othe r site.

F i g u re 4.268 M u ciphages.

Figure 4.269 M u c i p h a g es. H i g h e r power of p revious case sh ows the m u ciphages strea m i n g th ro u g h the su perficia l l a m i n a p ropri a .

MEDICATION RES I NS Medication crystals c a n be seen anywhere along the tubular GIT, b u t are particularly com­ mon in the colon (Fig. 4 . 2 70) . See also Resins , Pigments , Esophagus Chapter.

figure 4.270 Medication res i n , seve l a m e r. Seve l a m e r resi n s show broad, i rreg u l a r "fish-sca les" with curvi l i n e a r poi nts of i ntersection a n d a two-tone co loration o n H&E, as i n this exa m p l e .

C h a pte r

4

C O L0 N

399

N EAR M ISSES E N DO M ETRIOS I S

F i g u re 4 . 2 7 1 E n d o m etriosis. This con s u ltation case o r i g i n ated from a 2 5-ye a r-old wom a n with a b l e ed i n g recta l m ass. I t was c l i n i­ ca l l y o m i n o u s appeari n g , l e a d i n g the s u rgeon to i nform the patient that the lesion was m ost l i ke l y m a l i g n a nt. Based o n the patient's you n g a g e , the fa m i l y asked for the case to be exte r n a l l y reviewed .

F i g u re 4 . 2 7 2 E n d o m etriosis. H i g h e r power shows convol uted g l a n d s s u rrou nded by a cuff of stro m a ce l l s and i nterm ixed l y m ­ phoid cel ls.

Fig u re 4.273 E n d o m etriosis. H i g h e r power of p revio u s i m a g e . C i l i a a re n ot d efi n itivel y i d e n tifi ed i n t h i s s u boptim a l speci m e n . B i o psies o f t h e lesion h a d ra ised concerns for a n i n fi ltratin g a d e n o­ carcin o m a beca use the g l a n d u l a r e l e m e nts were not reco g n ized a s e n d o m etri a l , the ove rlyi n g rea ctive c h a n g e s were i nterpreted a s dyspl a s i a , a n d n u m e ro u s m itotic fig u res were seen. Endometriosis is the presence of at least two of the three following features outside of the uterus : endometrial glands , stroma , and hemorrhage (Figs . 4 . 2 7 1 -4 . 2 73) . Up to 3 7 % of women with endometriosis have intestinal involvement, and any layer of the bowel can be involved . The clinicopathologic presentation is diverse and presentations can overlap with appendicitis, IBD , diverticular disease , infectious colitis, a surgical acute abdomen, malignancy. 1 25-1 2 8 Endometriosis involving the rectum commonly presents as bloody diar­ rhea. Associated pathologic findings can include strictures, ulceration, fissures , ischemia, and intussusception . 1 2 5 The lesions can appear as polyps or bleeding mass lesions , raising clinical concerns for malignancy. The overlying colonic epithelium can be markedly reactive

400

ATLAS

O F

GASTRO I N T E ST I N A L

PAT H O LOGY

and mimic dysplasia , leading to the misdiagnosis of colonic adenocarcinoma . Occasion­ ally, only the stromal component is seen and a diagnosis of sarcoma is entertained. In these cases , usually the endometrial glands can be identified on deeper sections . Confirmatory immunohistochemical stains include ER and PR to highlight the glandular components and CD 1 0 to highlight the endometrial stroma .

. .

'"

•

-, . . . . . , "

Figure 4.274 Endometriosis (ER i m m u n osta i n ) . An ER i m m u n osta i n shows d iffuse nuclear reactivity i n t h e indicated ce l l s and a C D l 0 high­ l i g hted the stro m a l component (not shown), supporti n g the revised diag nosis of endometriosis. We have seen s i m i l a r cases ra ise con­ cerns for spindle ce l l sarcomas when the g l a n d u l a r elements were n ot present. Deeper sections a n d a n ci l l a ry ER, PR, a n d CD 1 0 a re h e l pfu l diagnostic tools in c h a l l e n g i n g cases. Always consider endometriosis i n a rep rod u ctive aged woma n with a recta l mass. PEARLS & P ITFALLS

Always c o n s i d e r e n d o m etri o s i s (a ben i g n etio l og y) before m a l ig n a ncy in a rep ro­ d u ctive aged wo m a n with a recta l mass (Fi g . 4 . 2 7 4 ) .

B E N I G N S I G N ET R I N G CELL CHAN G E . .. I•

•#

•

•

�{;': ";.

.�

F i g u re 4 . 2 7 5 S i g n et ri n g ce l l c h a n g e . T h i s consu ltat i o n case was rece ived with a concern fo r i nfi ltra t i n g s i g n et ri n g ce l l c a rc i n o m a i n a b a c kg ro u n d o f C . difficile pse u d o m e m b ra n o u s c o l i t i s . T h i s focus sh ows u l ce r d e b ri s s u rro u n d i n g i s l a n d s of deta ched co l o n i c e p i th e l i u m .

F i g u re 4 . 2 7 6 S i g n et r i n g ce l l c h a n g e . H i g h e r power sh ows the detached co l o n i c epith e l i u m d i s p l ay a s i g n et ri n g l i ke m orph ology with a crescentic, peri pheral n u cl e u s compressed by a b u n d a n t cyto­ p l a s m i c m u c i n . G reat caution m u st be exe rcised when eva l u a t i n g u l cer d e b r i s beca use d e g e n e rati n g a n d d i s l odged n o r m a l epithe­ l i u m can appear m a rked l y atypica l .

Ch a pte r

F i g u r e 4.277 S i g n et ri n g ce l l c h a n g e . U n d e r oil i m m ersion the d e g e n e rati ng a n d dislodged g o b l et ce l l s show sig net ri n g l i ke mor­ p h o l ogy. These c h a n ges were i nterpreted as b e n i g n a n d rea ctive beca use the atypia was i n p roportion to the backgro u n d u l cerative a n d i n fl a m m atory c h a n g es , a n d the a dj o i n i n g i n ta ct m u cosa was negative fo r dysp lasia and m a l ig n a n cy.

4

COL0 N

401

Fig u re 4.278 S i g net rin g ce l l c h a n g e . Note the poor p reservation of the m ate rial and the backg ro u n d degenerative c h a n g es i n the neutro p h i l s . Based on the backg ro u n d , the centra l s i g n et ri n g l i ke ce l l was i nterpreted as a ben i g n , degenerating a n d d islodged gob­ l et cel l . Wh i l e n o additi o n a l speci a l sta i n s or i m m u n o h istoch e m i c a l sta i n s were performed i n this c a s e , i n d iffi cult cases additi o n a l stud­ ies c a n be of use. Ben i g n s i g n et ri n g ce l l change d isplays intact E-ca d h e r i n , a low Ki-67 p ro l ife ration index, and p53 is n o n reactive. If the c l i n ical concern fo r m a l i g n a n cy rem a i n s , repeat biopsy with gen e rous sa m p l i n g of the i nterfa ce of the u l cer and adjacent i ntact m u cosa may be worthwh i l e .

Signet ring cell change is a benign finding that c a n mimic signet ring cell carcinoma (Fig. 4 . 2 7 5-4 . 2 7 8) . The indicated cells have a crescentic, peripheral nucleus and contain abundant cytoplasmiC mucin . This peculiar pattern has been reported in the stomach , colon, gallbladder, a Peutz-Jeghers polyp , and is particularly common in the setting o f pseudomembranous colitis pattern . 1 29- 133 Although signet ring cell change c a n be seen anywhere along the CIT, the background mucosal is often markedly inj ured , suggesting this change is reparative in nature or due to mechanical or ischemic insult . Cytologic diagnostic clues include a lack of nuclear hyperchromasia , atypia , and prominent nucle­ oli. Architecturally, benign signet ring cell change lacks an infiltrative growth pattern and desmoplasia. In challenging cases, a reticulin or laminin special stain can be use­ ful by demonstrating the signet ring-like cells are completely confined within the base­ ment membranes . The indicated cells display intact E-cadherin , a low Ki- 6 7 proliferation index, and are p53 nonreactive . 1 33 O f note , the mitotic activity can be elevated in signet ring cell change , particularly if the background mucosa shows an increased mitotic rate . Atypical mitoses are not seen.

402

ATLAS

0 F

GAST R0 I N TESTI N AL

PAT H O LOGY

P U LS E G RAN U LOMATA

F i g u re 4.279 P u l se g ra n u l o m a . T h i s speci m e n was d e s i g n ated m esenteric m a ss and was c l i n i c a l l y concern i n g for m a l i g n a n cy. N ote the n o d u l a r a rchitect u re . Eosin o p h i l i c ribbons a n d fore i g n materi a l a re easily seen at t h i s power. Alth o u g h the case w a s s u b m itted i n consu ltati o n as scl e ros i n g mesente ritis, t h e eos i n o p h i l i c ri bbons a re c h a ra cteristic of p u lse g ra n u l o m ata . P u lse g ra n u l o m a a re b e n i g n lesions t h a t resu l t from e ntra pped " p u lse" o r food forced i nto p rivi­ leged sites (i . e . , bowel wa l l o r m esentery) via s i g n ificant tra u m a or m u cosa l i nj u ry.

F i g u r e 4 . 280 P u lse g ra n u l o m a . H ig h e r powe r of the p revio u s

i m a g e sh ows the ch a ra cteristic featu res of p u lse g ra n u l om a ta : eos i n o p h i l i c ri bbons o f hya l i n e m ateri a l i nterm ixed with a b u n d a nt h istiocytes, fore i g n body g i a n t ce l ls, a n d i nterspersed fore i g n m ate­ ria l . Alth o u g h the eosi n o p h i l i c m ateri a l l o o ks l i ke a m y l o i d , Congo red specia l sta i n s for amyloid a re a lways n egative. This patient h a d a h i story of perforated diverticu l a r d isease, which l i kely i ntroduced food and feca l materi a l into the a bdom i n a l cavity, p rov i d i n g a n id u s for the p u lse g ra n u l om ata .

Pulse granulomata are curious , benign lesions best characterized in the oral pathology lit­ erature in association with dental caries and dentures (Figs . 4 . 2 79 and 4 . 2 80) 134 These are also common findings in the tubular GIT, particularly in the background of bowel inj ury such as diverticular disease , IBD , neoplasia , perforation, fistula , or prior surgery 135- 1 38 The prevailing theory of origin is entrapped, impacted "pulse" or food introduced through mucosal trauma (Figs . 4 . 2 8 1 and 4 . 282) . An alternative theory suggests the eosinophilic ribbons (or "hyaline rings") represent vascular damage . 139 The nodules can range up to 10 cm, raising clinical concerns for malignancy; thorough sampling of the tissue and

Figure 4.2 8 1 Pu lse g ra n u l o m a , abdom i n a l com p u ted to m o g ra ­ phy. T h i s patient h a d a l o n g - h istory o f swa l l ow i n g fore i g n bod i es a n d self-infl i cted sta b wou n d s t h ro u g h the abdo m e n . The patient p resented with abdom i n a l pain; the a bdom i n a l study shows m eta l l i c objects (arcs) .

F i g u r e 4 . 2 8 2 P u lse g ra n u l o m a , e n dosco p i c i m a g e . T h i s e n d o­ sco p i c i m a g e sh ows n u m e ro u s swa l l owed m eta l h o o ks a n d pens i n the stomach.

Cha pter

Fi g u re 4 . 2 8 3 P u lse g ra n u l o m a . As a resu lt of n u m e ro u s self­ infl i cted a b d o m e n wou n d s , t h i s patient eventu a l l y deve l o ped a n enterocuta neous fistu l a . A rep resentative section shows classic fea­ tures of p u l se g ra n u lomata . At low power, a nodu l a r a rch itecture and c i rcu mferenti a l ste l l ate fi brosis a re see n .

4

COLON

403

Fi g u re 4 . 2 8 4 Pu lse g ra n u lo m a . H igher power s h ows t h e c h a ra c­ teristic featu res of p u l s e g ra n u l o m ata with eosi n o p h i l i c ri bbon s of hya l i n e m ateri a l i nterm ixed with a b u n d a n t h i stiocytes, foreign body g i a n t ce l ls, and interspersed fore i g n m ateri a l (arcs). Pu lse g ra n u lo­ m ata a re b e n i g n lesions that resu l t from entra pped " pul s e" or food i ntro d u ced thro u g h m u cosal tra u m a . Th ey can som etimes present a s m a ss lesions and, therefore, they can be c l i n i ca l ly concern i n g for m a l ig n a n cy.

Fi g u re 4.285 P u l se g ra n u l o m a . H i g h e r power of previo u s case. P u l s e g ra n u l o mata a re m o st com m o n l y seen i nvolvi n g the extern a l s u rfa ce o f t h e bowel wa l l i n patients with a h i story o f bowel re l ated tra u m a .

familiarity with the morphology can b e reassuring. The histologic features include nodular collections of eosinophilic ribbons of hyaline material intermixed with abundant histiocytes , circumferential stellate fibrosis in larger lesions , foreign material , and variable amounts of granulation tissue with microabscesses (Figs . 4 . 2 83-4 . 285) . Most cases are nodular and multifocal. The hyaline ribbons often raise concerns for amyloid, but the material is pre­ sumed food degradation material and is consistently Congo red negative . The most common mimic is sclerosing mesenteritis , particularly in mass lesions involving the mesentery Help­ ful clues to the diagnosis of pulse granulomata , however, include a history of bowel inj ury and the core histologiC features of eosinophilic ribbons of hyaline material intermixed with abundant histiocytes , circumferential stellate fibrosis in larger lesions , foreign material , and variable amounts of granulation tissue with microabscesses . Photomicrographs courtesy of Dr. Nicholas Nowacki , The Ohio State University Wexner Medical Center.

404

ATLAS

O F

GASTRO I N T E S T I N A L

PAT H O LO G Y

APOPTOT I C COLOPATHY

Figure 4.286 Apoptotic colopathy, mycophenolate m ofetil (M M F) . Th is recta l b i opsy orig i n ates from a patient with a h i story o f ren a l tra n s p l a n t w h o presented with watery d i a rrh e a . Low power sh ows i n creased l a m i n a p ropria c h ro n i c i nfl a m mati o n , i n c l u d i n g i n creased eosi n o p h i l s .

F i g u re 4 . 2 8 7 Apoptotic c o l o pathy, M M F. H i g h e r power sh ows i n creased l a m i n a propria eosi n o p h i l s and a crypt a bscess with foca l ly atte n u ated epith e l i u m a n d i n creased eosi n o p h i l s .

Figure 4 . 2 8 8 Apoptotic colopathy, M M F. Apoptotic bodies appear as fra g m ented , i rreg u l a r ce l l u l a r " bits " o r debris. The onset of d i a r­ rh ea coincided with a recent i n crease in M M F dose, a l l pertinent stool cultures were negative, a CMV i m m u n osta i n was n o n reactive, and n o oth e r m e d i cation c h a n g e s were n oted . All sym ptom s a n d h isto l o g i c abnormal ities reso lved with M M F cessat i o n . T h e d i a rrhea was attri buted to M M F. Apoptotic bodies are easy to overlook because they often require high power and a bit of time to identify (Figs . 4 . 2 8 6-4 . 2 88) . To the trainee , apoptotic bodies can be easily confused with IELs . Apoptotic bodies , however, appear as variably sized bits of cellular debris or degenerating dust, while lymphocytes show a uniform size and are more clearly recognized as intact cells . As a general rule, finding greater than one to two apoptotic bodies per tis­ sue fragment qualifies as abnormally increased . Increased apoptotic bodies can be helpful clues to the underlying diagnosis with differential considerations including the following : •

Infection (i. e . , CMV)

•

Medication (i e . , Mycophenolate Mofetil [MMF]!CellCept)

•

Graft versus Host Disease (GVHD)

•

Autoimmune diseases/immunodeficiencies (i. e . , CVID)

Ch a pte r

The featured case is an example of mycophenolate mofetil (MMF/CellCept)-associated colitis in a patient with a history of renal transplantation. MMF is an immunosuppressive medication whose mechanism of action is inhibition of an enzyme in the de novo pathway of purine synthesis . Since lymphocytes are exquisitely dependent on this pathway, they are inhibited . However, GIT epithelium is also dependent on the de novo pathway (albeit to a lesser extent than lymphocytes) and thus this medication damages GIT epithelium. 140 Myco­ phenolate is used most commonly to prevent acute cellular rej ection of transplanted solid organs but is also used in the treatment of autoimmune and inflammatory diseases, such as psoriasis , lupus nephritis, myasthenia gravis , among others . Common symptoms include watery diarrhea , nausea , vomiting, and abdominal pain . Its administration is associated with increased apoptotic bodies throughout the GIT and drug cessation reverses the pathology and symptoms . Clinicians are sufficiently familiar with the association of MMF and GIT side-effects that they often empirically lower or stop MMF without an endoscopiC biopsy. Importantly, MMF is also used in the setting of stem cell transplant to treat GVHD . Based on considerable clinicopathologic overlap , distinguishing MMF inj ury from GVHD can be challenging. Appropriate diagnOSiS is critical since MMF is treated with drug cessation and GVHD is treated with immunosuppression . Recent case control studies report that features favoring MMF include a triad of eosinophils > 15 per 1 0 HPF, an absence of endocrine cell aggregates , and an absence of apoptotic micro abscesses (degenerating crypts with lumi­ nal necrotic and apoptotic debris) 141 Features favoring GVHD including apoptotic micro­ abscesses , endocrine cell aggregates , hypereosinophilic degenerating crypts , architectural distortion, and a lack of eosinophilia. Others have reported similar findings . 142, 1 4 3 Clini­ cal correlation is essential with particular attention to history and date of transplantation : GVHD is not a diagnostic consideration in the absence of a transplant history, for example . Type of transplantation i s also important t o discern : GVHD i s infinitely more common with stem cell transplant than solid organ transplant. Correlation with the physical examination and laboratory studies is usually of use . Patients with apoptotic colopathy and concomitant cutaneous and or liver GVHD would be at considerable risk for GIT-GVHD and would benefit from increased immunosuppression. Lastly, reconciliation with the medication list is necessary since MMF is not a consideration if the patient lacks a history of MMF In sum­ mary, red flags for the pathologist to consider MMF colitis include a history of transplant or autoimmune diseases, culture negative watery diarrhea , and increased apoptotic bod­ ies . CMV immunostains are recommended in all cases of apoptotic prominence . See also, GVHD, LymphocytiC Pattern , Esophagus Chapter.

S P I ROCH ETOS I S

F i g u re 4.289 I n testi n a l s p i rochetosi s i n a t u b u l a r a d e n o m a . An a b ru pt transition (arrowhead) to n u c l e a r crowd i n g and stratification identified this co l o n i c polyp a s a tubu l a r a d e n o m a . At low m a g n ifi­ catio n , it wou l d be easy to m ove on to the n ext case a n d m iss the seco n d diag nosis i n this biopsy.

4

C O L0 N

405

406

ATLAS

O F

GAST RO I N T E ST I N A L

PAT H O LOGY

KEY F EATU R E S of I ntesti n a l S p i rochetosis: •

Intestinal spirochetosis is caused by an infection by spirochetes Brachyspira aalborgi and

B. pilosicoli •

•

•

•

•

•

The bacteria attach to the apical cell membrane of colonic epithelial cells . 1 44 The prevalence in Western nations is 2 % to 1 6 % , and there is a common associa­ tion with homosexual men and HIV/AIDS , although the clinical significance remains strongly debated . The infection i s also found i n otherwise healthy children , and o ther associations include diverticular disease, chronic idiopathic inflammatory bowel disease, hyper­ plastiC polyps, and adenomas (Figs . 4 . 29 0 and 4 . 2 9 1 ) 1 45 Fecal-oral route is the proposed mechanism of transmission. 14 6 Most cases are asymptomatic and found incidentally. 1 47 Other patients experience chronic watery diarrhea, abdominal pain, and anal discharge . Symptomatic patients may benefit from antimicrobial and antidiarrheal therapy.

\:1 Fi g u re 4. 290 H i g h e r m a g n ifi cation of the previous case. A fi n e "fuzzy " b l u e bord e r (arrowhead) is p resent o n t h e s u rfa ce of t h e epith e l i a l ce l ls, i n d i ca t i n g t h a t i n testi n a l s p i rochetosis is involving this tu b u l a r a d e n o m a .

Figure 4 . 2 9 2 I n testi n a l s p i rochetosis. E a s i l y m issed at low m a g n i ­ ficatio n , a mid- t o h i power review o f co l o n i c biopsies is req u i red to n ote the p resen ce of this " fuzzy" b l u e bord e r.

Figure 4.291 I n testi n a l spiroch etosis. W i t h a n o i l i m m e rsion objec­ tive, o n e can o n e a p p reciate the fi l a m ento u s a p p e a ra n ce of the spi­ rochetes (arrowheads) attached to col o n i c epith e l i a l ce l l s .

Figure 4.293 I n testi n a l spirochetosis. This d i a g nosis is cha l l e n g i n g d u e t o i t s s u btle fi n d i n gs a n d patchy nature . I n this exa m p l e , n ote h ow c h a l l e n g i n g it is to fi nd the s p i rochetosis on the surface epithe­ l i u m . C a refu l exa m i n ation along the crypt epith e l i u m reve a l s a m o re obvious fuzzy b l u e border.

Ch a pte r

Figure 4. 294 I n testin a l s p i roch etosis. The spirochetes (arrowhead) attach to the s u rfa ce epith e l i u m , ra re l y invading the m u cosa .

o

o

o

o

4

C O L0 N

407

Figure 4.295 I n testi n a l spiroch etosis.

Histologic findings may be patchy or involve multiple colonic segments . The spirochetes appear as a characteristic "fuzzy" basophilic border along the luminal surface of the colonic epithelium (Figs . 4 292-4 . 295) No inflammation or crypt architectural changes are present , making this an easily missed diagnosis unless one actively looks for it. The organisms stain with silver impregnation stains (Warthin-Starry, Dieterle , Steiner) (Figs . 4 . 296-4 . 298) . Tissue Gram stain will not stain the organisms .

FAQ: Does i ntesti n a l s p i rochetosis i n an ot h e rwise h e a lt h y ch i l d i m p l y sex u a l a b u se?

Answe r : N O !

Oth e rw i se h e a l th y c h i l d re n m a y have i n c i d e n ta l c o l o n ization with these o rg a n i sm s , a n d the fi n d i n g d o e s n o t i m p l y sexu a l a b u se . Sexu a l tra n s m i ss i o n was i n itia l ly p ro­ posed as a m ethod of tra n s m i s s i o n d u e to the h i g h e r p reva l e n ce in h o m osex u a l m e n , b u t th i s rem a i n s u n p rove n . Feca l o ra l tra n s m i s s i o n v i a conta m i n ated water so u rces and c o l o n ized feces i s fa r m o re l i ke l y.

�

. .

Figure 4.296 I n testi n a l s p i roch etosis (Wa rth i n-Sta rry si lver sta i n ) . A si lver sta i n , such a s the Wa rth i n-Sta rry p i ctu red h e re , h i g h l i g hts the fuzzy b l u e bord e r as a thick b l a ck l i n e .

Figure 4. 297 I n testi n a l spirochetosis (Wa rth i n-Sta rry si lver sta i n ) . H i g h e r m a g n ifi cation of the p revious c a s e sh ows the fi l a m entous s p i rochetes.

408

AT LAS

0 F

GASTR0 I N TEST I N A L

PAT H O LOG Y

Fig u re 4.298 Intesti n a l s p i rochetosi s (Wa rth i n-Sta rry si lver sta i n ) . T h e spiroch etes create a b l a ck border with si lver i m pre g n ation sta i n . I nd ivid u a l spiroch etes a re visi b l e u s i n g t h e o i l i m m ersion obj ective .

Refe re n ces 1. Eidelman S , Lagunoff D. The morphology of the normal human rectal biopsy. Hum Pathol. 1 9 72 ;3(3) 389-40 1 . 2 . Bej arano PA, Aranda-Michel J , Fenoglio-Preiser C . Histochemical and immunohistochemical characterization of foamy histiocytes (muciphages and xanthelasma) of the rectum. Am J Surg Pathol. 2000; 24(7) 1 009- 1 0 1 5 3 . Greenson JK, Stern RA , Carpenter SL, e t al. The clinical significance o f focal active colitis . Hum Pathol. 1 9 9 7 ;28(6) 729-733 4. Nostrant TT, Kumar NB, Appelman HD . Histopathology differentiates acute self-limited colitis from ulcerative colitis . Gastroenterology. 1 9 8 7 ;92(2) : 3 1 8-32 8 . 5 . Edwards BH. Salmonella and Shigella species. Clin Lab Med. 1 9 99 ; 1 9(3) : 469-487 , v. 6 . Kraus MD , Amatya B , Kimula Y Histopathology of typhoid enteritis: Morphologic and immu­ no phenotypic findings . Mod Pathol. 1 9 99 ; 1 2 ( 0) : 949-9 5 5 . 7 . McGovern VJ , Slavutin L] . Pathology of salmonella colitis. A m ] Surg Pathol. 1 9 79 ; 3 (6) :483-490 . 8 . Boyd JF Pathology o f the alimentary tract i n Salmonella typhimurium food poisoning. Geit. 1 98 5 ;2 6(9) 93 5-944 9. Islam MM, Azad AK, Bardhan PK, et al. Pathology of shigellosis and its complications. Histopa­ thology. 1 994;24( 1 ) 65-7 1 . 1 0 . Kelber M , Ament ME. Shigella dysenteriae 1 : A forgotten cause of pseudomembranous colitis . ] Pediatr. 1 9 7 6 ; 89 (4) 5 9 5-5 9 6 1 1 . Mathan MM, Mathan VI . Morphology of rectal mucosa of patients with shigellosis . Rev Inject Dis . 1 99 1 ; l 3 (suppI 4) S3 1 4-S3 1 8 1 2 . Blaser MJ , Berkowitz r D , LaForce F M , e t al. Campylobacter enteritis: Clinical and epidemiologic features. Ann Intern Med. 1 9 79 ; 9 1 (2) : 1 79-1 8 5 . 1 3 . Fields PI, Swerdlow D L . Campylobacter j ej uni. Clin Lab Med. 1 9 99 ; 1 9(3 ) : 489-504, v. 1 4 . Lambert ME, Schofield PF, Ironside AG, et al. Campylobacter colitis . Br Med j. 1 9 79 ; 1 (6 1 6 7) 8 5 7-85 9 . 1 5 . Price AB , Jewkes J , Sanderson PJ . Acute diarrhoea : Campylobacter colitis and the role of rectal biOpsy. ] Clin Pathol. 1 9 79 ; 3 2 ( 1 0) 990-9 9 7 1 6 . Granger DN , Hollwarth ME, Parks D A . Ischemia-reperfusion inj ury: Role of oxygen-derived free radicals . Acta Physiol Scand Suppl. 1 9 8 6 ;548:47-63 . 1 7 . Dignan CR, Greenson JK. Can ischemic colitis b e differentiated from C . difficile colitis i n biopsy specimens? Am ] Surg Pathol. 1 9 9 7 ; 2 1 (6) : 706-7 1 0 . 1 8 . Lillemoe KD , Romolo J L , Hamilton SR, e t al. Intestinal necrosis due t o sodium polystyrene (Kayexalate) in sorbitol enemas: Clinical and experimental support for the hypothesis . Surgery. 1 9 8 7 ; 1 0 1 (3) : 2 6 7-2 7 2 .

Ch a pte r

1 9 . Harel Z, Harel S , Shah PS, et al. Gastrointestinal adverse events with sodium polystyrene sulfo­ nate (Kayexalate) use : A systematic review. Am ] Med. 2 0 1 3 ; 1 2 6(3) : 2 64e9-e24. 20. Swanson B] , Limketkai BN , Liu TC, et al. Sevelamer crystals in the gastrointestinal tract ( GIT) : A new entity associated with mucosal injury Am ] Surg Pathol. 2 0 1 3 ;3 7( 1 1 ) : 1 686- 1 693 2 1 . Meucci G, Bortoli A, Riccioli FA, et al . Frequency and clinical evolution of indeterminate colitis : A retrospective multi-centre study in northern Italy GSMII (Gruppo di Studio per Ie Malattie 1nfiammatorie 1ntestinali) . Eur] Gastroenterol Hepatol. 1 9 99 ; 1 1 (8 ) : 9 09-9 1 3 . 2 2 . Ordas I , Eckmann L , Talamini M , e t al. Ulcerative colitis . Lancet. 2 0 1 2 ;380(9853) : 1 606- 1 6 1 9 . 2 3 . Soucy G , Wang HH, Farraye FA, e t al. Clinical and pathological analysis o f colonic Crohn's dis­ ease, including a subgroup with ulcerative colitis-like features. Mod Pathol. 20 1 2 ; 2 5 (2): 295-307. 24. Greenstein A] , Sa char DB, Gibas A, et al. Outcome of toxic dilatation in ulcerative and Crohn's colitis . ] Clin Gastroenterol. 1 9 8 5 ; 7(2) : 1 37-143 2 5 . Ausch C, Madoff RD , Gnant M, et a1. Aetiology and surgical management of toxic megacolon. Colorectal Dis. 2006;8(3) : 1 95-20 1 . 2 6 . Autenrieth DM, Baumgart D C Toxic megacolon. Injlamm Bowel Dis. 20 1 2 ; 1 8(3) : 5 84-59 1 . 2 7 . Odze R, Antonioli D , Peppercorn M , et al. Effect of topical 5 -aminosalicylic acid (5 -ASA) therapy on rectal mucosal biopsy morphology in chronic ulcerative colitis . Am ] Surg Pathol. 1 9 93 ; 1 7(9) 869-875 2 8 . Glickman ]N , Bousvaros A, Farraye FA, et al. Pediatric patients with untreated ulcerative coli­ tis may present initially with unusual morphologic findings . Am ] Surg Pathol. 2 0 0 4 ; 2 8 ( 2 ) : 1 9 0- 1 9 7 . 2 9 . Kleer C G , Appelman H D . Ulcerative colitis : Patterns of involvement i n colorectal biopsies and changes with time . Am ] Surg Pathol. 1998 ;22 (8) : 983-9 8 9 . 3 0 . Mutinga M L , O dze RD , Wang HH, e t al . The clinical Significance of right-Sided colonic inflamma­ tion in patients with left-sided chronic ulcerative colitis. Inflamm Bowel Dis. 2004; 1 0(3) : 2 1 5-2 1 9 . 3 1 . D'Haens G , Geboes K, Peeters M , e t al. Patchy cecal inflammation associated with distal ulcer­ ative colitis: A prospective endoscopic study. Am ] Gastroenterol. 1 9 9 7 ;92(8) : 1 2 75- 1 2 7 9 . 3 2 . Yang S K , lung HY, Kang G H , e t a l . Appendiceal orifice inflammation a s a skip lesion i n ulcer­ ative colitis : An analysis in relation to medical therapy and disease extent . Gastrointest Endosc. 1 999 ;49(6) 743-747 33. Groisman GM , George ] , Harpaz N. Ulcerative appendicitis in universal and nonuniversal ulcer­ ative colitis . Mod Pathal. 1 994;7(3 ) : 322-325 34. Haskell H , Andrews CW ]r, Reddy SI, et al. Pathologic features and clinical significance of "backwash" ileitis in ulcerative colitis . Am] Surg Pathal. 2 0 0 5 ; 29 ( 1 1 ) 1 472-148 1 . 3 5 . Lin J , McKenna B] , Appelman HD. Morphologic findings in upper gastrointestinal biopsies of patients with ulcerative colitis : A controlled study Am ] Surg Pathol. 2 0 1 0 ;34( 1 1 ) : 1 6 72- 1 6 7 7 . 3 6 . Yantiss RK, Odze RD . Diagnostic difficulties i n inflammatory bowel disease pathology Histopa­ thology. 2006 ;48(2) 1 1 6- 1 3 2 . 3 7 . Yantiss RK, Farraye FA, O'Brien M] , e t a l . PrognostiC Significance of superficial fissuring ulcer­ ation in patients with severe "indeterminate" colitis . Am] Surg Pathol. 2006;30(2) : 1 65- 1 70 . 3 8 . Machicado GA, Jensen DM. Acute and chronic management of lower gastrointestinal bleeding: Cost-effective approaches. Gastroenterologist. 1 9 9 7 ; 5 (3) 1 89-20 1 . 3 9 . Morson B C Pathology o f diverticular disease o f the colon. Clin Gastroenterol. 1 9 7 5 ;4( 1 ) : 3 7-5 2 . 4 0 . Whiteway ] , Morson B C Elastosis i n diverticular disease o f the sigmOid colon. Gut. 1 9 8 5 ; 26(3) 2 5 8-266 4 1 . Bode MK, Karttunen TJ , Makela ] , et al. Type I and III collagens in human colon cancer and diverticulosis . Scand ] Gastroenterol. 2000;35 (7) : 747-752 4 2 . Peppercorn MA. Drug-responsive chronic segmental colitis associated with diverticula: A clini­ cal syndrome in the elderly Am ] Gastroenterol. 1 9 9 2 ; 8 7 (5) : 609-6 1 2 . 43 . Makapugay LM , Dean PJ Diverticular disease-associated chronic colitis . Am ] Surg Pathol. 1 99 6 ; 2 0 0 ) 94- 1 0 2 . 44 . Ludeman L, Shepherd N A . What i s diverticular colitis7 Pathology. 2002 ;34(6) : 5 68-5 7 2 . 45 . Lamps LVI, Knapple WL. Diverticular disease-associated segmental colitis . Clin Gastroenterol Hepatol. 2 0 0 7 ; 5 ( 1 ) : 2 7-3 1 . 46. Klein S , Mayer L , Present DH, et al. Extraintestinal manifestations in patients with diverticulitis. Ann Intern Med. 1988 ; 1 08(5) : 700-70 2 .

4

C O L0 N

409

41 0

ATLAS

O F

GASTRO I N T E ST I N A L

PAT H O LO G Y

4 7 . Hinchey EJ , Schaal PG, Richards GK. Treatment of perforated diverticular disease o f the colon. Adv Surg. 1 9 78 ; 1 2 85- 1 0 9 . 4 8 . S o n DN , Choi DJ , Woo S U , et al . Relationship between diversion colitis and quality of life in rectal cancer. World ] Gastroenterol. 20 1 3 ; 1 9 (4) : 542-549 . 4 9 . Ferguson CM, Siegel RJ . A prospective evaluation of diversion colitis . Am Surg. 1 9 9 1 ; 5 7( 1 ) : 46-49 . 5 0 . Edwards CM , George B , Warren BF Diversion colitis: New light through old windows. Histopa­ thology. 1 99 9 ; 3 5 ( 1 ) : 86-87 5 1 . Glotzer DJ , Glick ME, Goldman H . Proctitis and colitis following diversion of the fecal stream. Gastroenterology. 1 9 8 1 ;80(3) : 438-44 1 5 2 . Scheppach W Treatment of distal ulcerative colitis with short-chain fatty acid enemas . A placebo-controlled trial . German-Austrian SCFA S tudy Group . Dig Dis Sci. 1 99 6 ;4 1 ( 1 1 ) : 2 2 5 4-2 2 5 9 . 5 3 . Kaya E , Gur ES, Ozgu