the differential diagnosis of colitis in endoscopic biopsy specimens: a review article

The Differential Diagnosis of Colitisin Endoscopic Biopsy Specimens

A Review Article

Lisa A. Cerilli, MD; Joel K. Greenson, MD

� Context.—A variety of inflammatory disorders mayaffect the colon, with widely differing clinical outcomesand management. These conditions encompass a spectrumof acute and chronic conditions.

Objective.—Review the pathology of the major colitidesand highlight the most diagnostically useful features.

Data Sources.—Review of recent literature supplement-ed with personal experience in the field of gastrointestinalpathology.

Conclusions.—The etiologies associated with the varioustypes of colitis are diverse and the range of histologicchanges is somewhat limited. Nevertheless, the combina-tion of clinical and endoscopic data coupled withhistopathology allows for accurate classification in themajority of cases.

(Arch Pathol Lab Med. 2012;136:854–864; doi: 10.5858/arpa.2012-0205-RA)

Interpretation of inflammatory colorectal biopsies hasbecome more challenging as newer and more subtle

forms of colitis have been described. This review focuses onkey diagnostic features that will hopefully allow the surgicalpathologist to differentiate normal from abnormal and acutefrom chronic colitis as well as to identify new forms of colitisand unusual presentations of classic diseases such asulcerative colitis (UC) and Crohn disease (CD).

HISTOLOGY OF NORMAL COLONIC MUCOSA

The colonic mucosa is made up of tubular crypts alignedperpendicular to the muscularis mucosae. The distancebetween the crypts and the internal diameter of the crypts isconstant. A slight variation in crypt architecture, intercryptalspacing, and occasional crypt branching may occur innormal biopsies and is no cause for concern. The epitheliumlining the crypts resembles that of the small intestine exceptfor a higher proportion of goblet cells interspersed amongthe absorptive cells.

The lamina propria that surrounds the crypts normallycontains eosinophils, lymphocytes, plasma cells, and a fewhistiocytes. It is important to know where the biopsy camefrom in the colon to determine if the cellularity is within

normal range. Relative to the left colon and rectum, theright colon contains greater numbers of inflammatory cellsin the lamina propria. Normally there are many moreplasma cells and eosinophils in the lamina propria of theright colon. The closer one gets to the ileocecal valve, themore inflamed the lamina propria looks. The left side of thecolon contains significantly fewer cells within the laminapropria, and the surface epithelium contains more gobletcells and fewer absorptive cells relative to the right colon(Figure 1, A and B).

Eosinophils are a normal constituent in the laminapropria, and their quantity and distribution have been thesource of several investigations. One study quantified thenumber of mucosal eosinophils regarded as a normalfinding in the right and left colon in 198 colon mucosalbiopsies from those with normal endoscopic exams.1 Fifty-five percent of biopsies from the ascending colon containedeosinophils in the crypt epithelium, compared with only 5%of biopsy specimens from the descending colon. Laminapropria eosinophils were, on average, 3 times morenumerous in the ascending relative to the descending colon.Interestingly, mucosal eosinophils were slightly morenumerous in samples obtained in April and May, corre-sponding to periods of highest pollen counts, but thisrelationship did not attain statistically significance. One canconclude that intramucosal eosinophils are more numerousnormally in the proximal colon, but show only mildfluctuations with ambient allergen exposure. Another studyexamined the variability in colonic eosinophils dependingupon where in the United States patients lived.2 This reviewof 256 mucosal biopsies from patients without symptomsfound that the mean number of eosinophils per intercryptalspace was highest in the southern United States, a 35-folddifference between the mean eosinophil concentrations ofpatients in New Orleans compared with Boston. It remainselusive why individuals residing in the southern parts of the

Accepted for publication April 3, 2012.From the Department of Pathology, University of Michigan

Medical School, Ann Arbor.The authors have no relevant financial interest in the products or

companies described in this article.Presented at the New Frontiers in Pathology: An Update for

Practicing Pathologists meeting; October 14, 2011; Ann Arbor,Michigan.

Reprints: Joel K. Greenson, MD, Department of Pathology,University of Michigan Hospitals, Room 5218, Box 5602, MedicalScience Bldg 1, 1301 Catherine St, Ann Arbor, MI 48109-5602(e-mail: [email protected]).

854 Arch Pathol Lab Med—Vol 136, August 2012 Differential Diagnosis of Colitis––Cerilli & Greenson

United States harbor greater numbers of eosinophils in theirlamina propria.

In the right colon, Paneth cells are a normal constituent,and in children they may be even be present in the normaltransverse colon. When Paneth cells are encountered in theleft colon and rectum, their presence provides a usefulmarker of previous mucosal injury. Most of the time, left-sided Paneth cells are associated with UC, but they are notspecific to this condition. It is simply that UC is thecondition that most commonly results in chronic damage inthis segment of the colon.

Occasional intraepithelial lymphocytes, typically T cells,are a normal finding. There should be approximately 1lymphocyte for every 20 epithelial cells. There tend to be afew extras on the right side as compared with the left side,and one should not count intraepithelial lymphocytesoverlying a lymphoid aggregate (where they are normallypresent in large numbers).

PREPARATION ARTIFACT

Histology of the enema effect is typified by an edematouslamina propria with extravasated red blood cells, some ofwhich may be lysed. In addition, there is often mucinextravasation and flattening of the surface epithelium(Figure 2). In some cases the surface epithelium may becompleted stripped away. This can be particularly frustratingwhen trying to evaluate the surface epithelium for thechanges of lymphocytic colitis (LC) or collagenous colitis(CC). The longer the time interval between the enema andthe endoscopy, the more pronounced these changes canbecome. If the patient has an enema the night before aprocedure, neutrophils may reside in the epithelium,mimicking acute colitis. Occasionally some of these changeswill be seen in patients who have not had an enema butinstead have had some endoscope trauma. This can occur inpatients undergoing colonoscopy when the entire colon isvisually inspected first and rectal biopsies are performedlast.

Oral sodium phosphate bowel preparations have alsobeen associated with histologic changes in the colon.3

Endoscopically, aphthous lesions similar to those of CDmay be seen, but the lesions are not friable and biopsy

results do not show features of chronicity. Oral sodiumphosphate bowel preparations should be avoided in patientswith suspected graft-versus-host disease, as the apoptosiscaused by the preparation can mimic mild GVHD.

INFECTIOUS COLITIS

Acute infectious-type colitis or acute self-limited colitis(ASLC) may be caused by a variety of infectious agents.Although some cases of ASLC may be caused by knownbacterial pathogens such as Campylobacter, Shigella, orSalmonella, in the majority of cases, the exact pathogen isnot identified. Acute self-limited colitis is defined as atransient, presumably infectious colonic inflammation thatpresents with the acute onset of bloody diarrhea. Patientsgenerally recover in 10 to 14 days without residualinflammation or recurrent symptoms. Acute self-limitedcolitis usually has a constellation of generic histologic

Figure 1. A, This image of the normal cecum illustrates that the right colon has more inflammatory cells in the lamina propria and more absorptivecells on the surface of the mucosa as compared with the normal rectum (shown in B). Also note the presence of a few Paneth cells at the base of themucosa in A. B, The normal rectum, with much fewer inflammatory cells in the lamina propria and more goblet cells on the surface of the mucosa(hematoxylin-eosin, original magnification 3200).

Figure 2. This medium-power view of the rectal mucosa showsflattening of the surface epithelium with mucin depletion secondary todamage from a sodium phosphate enema. Also note the presence ofextravasated red blood cells at the base of the mucosa, many of whichhave been lysed. These red cells cause the mucosa to lookerythematous and hence ‘‘inflamed’’ to the endoscopist (hematoxylin-eosin, original magnification 3200).

Arch Pathol Lab Med—Vol 136, August 2012 Differential Diagnosis of Colitis—Cerilli & Greenson 855

findings such that, with the exception of some viral andparasitic infections, specific findings that allow for adiagnosis of a particular pathogen are lacking.

The majority of infectious colitides are never biopsied, asthe patient’s symptoms often resolve before the patient hastime to see a gastroenterologist. If the patient’s symptomspersist, then (from a clinical perspective) it may be difficultto determine if the patient’s acute-onset bloody diarrhea isdue to acute onset UC or acute infectious colitis. Colorectal

biopsies are then used to help make this distinction. Hence,the diagnosis of ASLC on such biopsies can have a profoundeffect on patient management.

Pathology

Within the first 4 days of onset of bloody diarrhea, thereare mucosal edema, acute cryptitis, crypt ulcers, andabscesses.4 About a week to 9 days later following theonset of bloody diarrhea, clinical resolution begins, heraldedby histologic regenerative changes in the epithelium withmucus depletion and increased mitotic figures in cryptepithelial cells. There may also be a few persistent foci ofcryptitis. This later finding, which we term focal activecolitis, can be confused with smoldering CD and/orischemia. The most reliable histologic criteria for distin-guishing ASLC from acute-onset UC are the preservation ofcrypt architecture and the lack of plasmacytosis in thelamina propria in ASLC4,5 (Figure 3, A and B). The presenceof either or both of these features should make one think ofa chronic colitis and not ASLC. Small granulomas, usuallysecondary to crypt rupture, may be encountered in ASLCand should not lead one to an automatic diagnosis of CD.

The presence of focal active colitis in a patient who doesnot have a history of chronic inflammatory bowel diseaseshould be interpreted conservatively, as the vast majority ofcases turn out to be self-limited.6–8 Focal active colitis ismore likely to be secondary to CD in pediatric patients,especially those who are teenagers.9 Focal active colitis canbe seen not only in CD, but also in association withnonsteroidal anti-inflammatory drug (NSAID) use, ische-mia, infections, partially treated UC, and as an isolated(incidental) finding in patients undergoing endoscopy toexclude neoplasia. Unfortunately, there are no particularhistologic parameters of focal active colitis, such as amount,location, or distribution of the inflammation, that correlatewith outcome or allow for selection of those at higher riskfor inflammatory bowel disease.7

Resolving ASLC can have a hypercellular lamina propriawith increased lymphocytes, neutrophils, eosinophils, and afew plasma cells. This finding may fool the pathologist into

Figure 3. A, This medium-power view of acute infectious colitis shows intact crypt architecture with diffuse cryptitis. This contrasts nicely with B,

which shows acute onset ulcerative colitis. B, There is marked lamina propria inflammation with basal plasma cells and crypt distortion despite the

fact that the patient has only had symptoms for a short time. One should not see these chronic changes in acute infectious colitis (hematoxylin-eosin,

original magnification 3100).

Figure 4. This image shows the classic mushroom- or volcano-shapedpseudomembrane on the surface of the mucosa in a case of Clostridiumdifficile–associated pseudomembranous colitis (hematoxylin-eosin,original magnification 340).


making the diagnosis of chronic colitis; however, on closeinspection, basal plasma cells and crypt distortion will notbe present. In some instances of resolving ASLC, a modestincrease in intraepithelial lymphocytes may be seen. Thepresence of some residual surface epithelial damage andincreased intraepithelial lymphocytes can sometimes beconfused with lymphocytic colitis; however, the clinicalcontext is different enough to usually prevent confusion.

Specific Pathogens in Infectious Colitis

Bacterial infections may affect the colon in a number ofways. Although some pathogens damage the bowel throughdirect mucosal invasion, others produce toxins, which inturn cause tissue injury and symptoms. Clostridium difficileinfection is a good example of the latter mechanism, as thetoxins produced by the bacteria cause direct tissue damage.The diagnosis should be suspected in anyone who developsdiarrhea during a course of antibiotics or within 6–8 weeksof completing treatment. The diagnosis can be confirmed bythe detection of C difficile toxin in stool, and a subset ofpatients undergo sigmoidoscopy or colonoscopy withbiopsy. Clostridium difficile infection can often be identifiedendoscopically and histologically by its characteristic pseu-domembrane formation (Figure 4). It should be pointed outthat C difficile infection does not always have pseudomem-branes, as some cases have biopsy findings identical to thoseof any other generic ASLC. If severe mucosal damageoccurs, with coagulative necrosis and pseudomembranes,the histologic features may overlap with those of ischemiccolitis or enterohemorrhagic Escherichia coli infections.

Many bacteria have specific surface epithelial adherencefactors that help the organisms invade and damage themucosa. Shigella, Salmonella, Campylobacter, Yersinia, andsome strains of E coli all adhere to the epithelium andinduce an acute colitis. Infection may spread to mesentericlymph nodes with either Yersinia or Salmonella, andsystemic involvement may occur. Some of these bacterialinfections cause histologic changes that are characteristic ofa given organism. Yersinia may show stellate foci of necrosiswithin lymphoid aggregates and aphthous lesions in thearea of the appendix and ileocecal valve. The reactivelymphoid tissue in this region may lead to intussusception.Salmonella (typhoid fever) may have a characteristic grossappearance with raised longitudinal folds with ulceratedmucosa overlying hyperplastic Peyer patches. The biopsyfindings in such cases can show aggregates of macrophagesfilled with cellular debris.

The enterohemorrhagic strain of E coli, O157:H7, isassociated with a spectrum of clinical presentations, themost unusual of which is that of an afebrile illness. Oftendespite a high volume of diarrhea, only a few leukocytes arepresent in the stool, and the bacteria cannot be grown onroutine culture. Therefore, a high index of suspicion isnecessary clinically. Patients may develop nonbloodydiarrhea, hemolytic uremic syndrome, an acute abdomen,and thrombotic thrombocytopenic purpura, and may evendie from the infection. This strain is highly virulent, and onlya very small number of viable bacteria are required toproduce symptomatic infection. The histologic features ofenterohemorrhagic E coli are typically similar to the patternof injury associated with acute ischemic colitis. The presenceof fibrin thrombi within lamina propria capillaries may be aclue to the diagnosis. Imaging may also suggest ischemiccolitis, with thumbprinting on plain films, and edematousthickening of the colonic wall. Although any segment or the

entire colon may be involved, the presence of right-sidedinjury should raise the question of E coli rather thanischemic colitis or inflammatory bowel disease.10 Inflam-mation and injury are usually contiguous rather thansegmental with E coli.

Mycobacterial infection often manifests specific histologicchanges, as Mycobacterium tuberculosis infection inducescaseating granulomas whereas Mycobacterium avium-intra-cellulare generates aggregates of foamy macrophages.Patients with inflammatory bowel disease who are treatedwith strong immunomodulatory therapy are at increasedrisk of these infections, so one must have a low threshold forordering acid-fast stains if one encounters lots of granulo-mas in such a patient.

MICROSCOPIC COLITIS

Collagenous Colitis

Patients with CC present with a history of chronic waterydiarrhea, and a significant minority of patients also haveabdominal pain and weight loss. Middle-aged to elderlywomen are most often affected, although even childrenhave been reported with CC.11 As many as 40% of patientshave a concomitant autoimmune disease such as celiacsprue, thyroiditis, rheumatoid arthritis, or Sjogren syn-drome.12,13 There also appears to be a strong associationwith NSAID use.14

Colonoscopy yields normal or near normal mucosa,although there are a few reports of linear mucosal tearsthat were thought to occur upon insufflation duringendoscopy.15 In addition, there are rare reports of CC withpseudomembranes.16

It appears as though some luminal antigen or antigens areimportant in the pathogenesis. Diversion of the fecal streamwill cause the histologic changes of CC to regress, whereasreestablishing the fecal stream will induce a relapse of boththe abnormal collage layer and clinical symptoms.17

Pathologic Features

At low power, biopsies of CC will often show a pinksubepithelial stripe with an intact crypt architecture and anincrease in superficial lamina propria mononuclear cells.Importantly, the lamina propria contains increased plasmacells and eosinophils and the surface epithelium oftencontains patchy numbers of intraepithelial lymphocyteswith surface damage and entrapped cellular elements(Figure 5, A). The surface epithelium is not infrequentlystripped off of the thickened collagen table. The subepithe-lial collagen generally blends imperceptibly with thebasement membrane to form a hypocellular pink band thatoften entraps small capillaries. The entrapment of capillar-ies, along with chronic inflammatory cells, is a useful clue tothe diagnosis.

The thickness of the collagen often varies from site to sitein individual patients and should be evaluated only in well-oriented sections. The normal basement membrane of thecolon measures 2 to 5 lm, whereas in CC the thickness ofthe collagen usually ranges from 10 to 30 lm. Moreimportant than the thickness of the subepithelial collagenis its irregularity. One should not be dissuaded from thediagnosis just because the collagen is less than 10 lm thick.Although it may seem intuitive that the intensity ofsymptoms correlates with the thickness of the collagenlayer, this is in fact not the case.18,19 Biopsies obtained fromthe rectum and sigmoid colon may show less thickening and


may be in the normal range. When in doubt, particularly inthose cases with only minimal or very patchy subepithelialcollagen, a trichrome stain can be helpful to highlight thecollagenous band and the irregular strands of collagen alongits lower border (Figure 5, B and C).

Care should be taken not to overinterpret a thickenedbasement membrane as CC. Surface epithelial damage andincreased lamina propria inflammation should always bepresent in cases of CC. Intraepithelial neutrophils may beseen, but they are usually less prominent than theintraepithelial lymphocytes. Large numbers of crypt ab-scesses are probably indicative of either superimposedinfection or a separate diagnosis such as UC. Paneth cellmetaplasia may be a marker of CC that is more refractory totherapy.18

Differential Diagnosis

A number of lesions may mimic some of the histologicchanges of CC, including LC, chronic inflammatory bowel

disease, solitary rectal ulcer/mucosal prolapse, enema effect,ischemia, and radiation colitis. Lymphocytic colitis looksidentical to CC except for the absence of subepithelialcollagen. Chronic inflammatory bowel disease typicallyshows more architectural distortion and the fibrosis involvesdeeper aspects of the lamina propria than is seen in CC.Mucosal prolapse also shows fibrosis in deeper portions ofthe lamina propria as well as muscular proliferation andcrypt distortion. Enema effect may mimic some of thesurface epithelial damage seen in CC as well as making itdifficult to evaluate the surface epithelium. Ischemia oftenhas fibrosis and hyalinization of the lamina propria that maybe misdiagnosed as CC; however, the increased plasma cellsin the lamina propria and the increased intraepitheliallymphocytes seen in CC will be absent. Radiation colitis alsoshows hyalinization of the lamina propria, usually withtelangiectatic blood vessels and atypical endothelial cellsand fibroblasts. The hyaline material does not stain asintensely on the trichrome stain as does the collagen in CC.

Figure 5. A, This high-power view shows surface damage with increased intraepithelial lymphocytes and irregular subsurface collagen deposition.Note that there is a superficial plasmacytosis and eosinophils seem to cluster around the collagen bundles. B, This trichrome-stained section showsthe irregular subsurface collagen entrapping a small capillary and inflammatory cells. C, This trichrome-stained section of lymphocytic colitiscontrasts what a normal basement membrane looks like compared with collagenous colitis. Note the intense surface lymphocytosis and epithelialdamage (hematoxylin-eosin, original magnification 3200 [A]; Masson trichrome, original magnifications 3200 [B and C]).

Figure 6. This high-power view shows intense surface damage with increased intraepithelial lymphocytes and a normal basement membrane (noincreased subepithelial collagen). Note the superficial plasmacytosis in the lamina propria (hematoxylin-eosin, original magnification 3200).


Prognosis and Therapy

Some patients with CC will have a spontaneousremission, and others will respond to simple over-the-counter antidiarrheal agents. Most patients, however, willrequire some form of therapy, and several trials haveconfirmed the effectiveness of budesonide over placebo inCC.19–21 The histologic response to therapy is variable, but adecrease in the subepithelial collagen layer as well as thelymphoplasmacytic infiltrate in the lamina propria is foundin about half of the patients.22 The usual response requiresapproximately 2 weeks, but relapse is frequent whenbudesonide is discontinued.22 In one study, patients whowere taking NSAIDs were more likely to require cortico-steroid therapy, presumably reflecting more severe disease,but this association requires additional data to substanti-ate.23 Rarely, patients with refractory disease may require adiverting ileostomy. The overall course of the disease tendsto wax and wane, but it is generally not as severe as UC orCD.

LYMPHOCYTIC COLITIS

Clinical Features

There is considerable overlap of both the clinical andpathologic features of LC and CC. Patients typically havechronic watery diarrhea with normal or near normalendoscopic findings. There tends to be less of a femalepredominance in LC as compared with CC, but the agerange is quite similar.

The medications ranitidine, Cyclo 3 Fort (Pierre FabreMedicament, Castres, France), and ticlopidine have beenreported to cause lymphocytic colitis.24–26 For each of thesedrugs, the colitis resolved upon drug withdrawal andrecurred with a rechallenge. To date, there is compellingevidence to suggest a high or intermediate probability ofcausality for 17 drugs with the development of LC.27

The association between LC and celiac disease is evenstronger than the association between CC and celiacdisease.28 In a study of 29 celiac sprue patients, nearlyone-third had colonic lymphocytosis that was histological-ly, quantitatively, and immunohistochemically indistin-guishable from LC, and a smaller subset also manifestedfeatures of lymphocytic gastritis.29 Possible clues to makeone suspicious that the lymphocytosis is possibly celiacsprue related include the lack of surface epithelialabnormalities, the lack of increased cellularity of the laminapropria, and the lack of ongoing watery diarrhea aftertreatment with a gluten-free diet.30 In addition, studieshave shown an increased incidence of HLA A1, DQ2 andDQ1, 3; a decrease in HLA-A3; and increased rates ofcarriage of the tumor necrosis factor a gene polymorphism(308) in LC patients relative to control patients.31–33 Thesefindings suggest that gastrointestinal epithelial T-cellinfiltration may be an immunologic response common ingenetically susceptible individuals sensitized to absorbedluminal antigens, and that colonic lymphocytosis mayoccur as a response to a number of antigens, includinggluten.

Pathologic Features

In general, LC resembles CC, but lacks the abnormalincrease in the subepithelial collagen table (Figure 5, C).Because of the shared histopathologic features apart fromthis, and the highly similar clinical features between CC and

LC, it has been suggested that these are the same disease indifferent stages of evolution, but in fact these are moreaccurately regarded as 2 separate but related entities.

Additional requisite histologic abnormalities includesurface epithelial damage with increased intraepitheliallymphocytes, which is often more prominent in LC (Figure6). Just as in CC, there is generally a superficialplasmacytosis without crypt distortion in LC. There maybe fewer lamina propria eosinophils in LC than areencountered in CC. The surface damage and lymphocytosismay be patchy and the lamina propria plasmacytosis tendsto be diffuse. The pathologist must avoid evaluating thenumber of intraepithelial lymphocytes overlying a lymphoidfollicle, as one should see numerous intraepithelial lym-phocytes in these areas normally. It is important toremember that there are more intraepithelial lymphocytesin the right colon as compared with the left colon, to avoidmisinterpretation of the right colon as hypercellular. A fewfoci of cryptitis or a rare crypt abscess may be seen in LC,but more neutrophilic inflammation than this suggestsanother diagnosis.

Recently it has been recognized that some cases oflymphocytic colitis have less surface damage and moreintraepithelial lymphocytes in the deeper crypt epithelium.Another variation of LC has been described with collectionsof histiocytes and poorly formed granulomas underneaththe surface epithelium.34


The differential diagnosis of lymphocytic colitis issomewhat narrower than that of CC. The resolving phaseof infectious colitis can mimic LC, as there can be surfacedamage and a modest increase in intraepithelial lympho-cytes. Lymphocytic colitis–like changes have also beendescribed in an outbreak of chronic diarrhea linked to thewater supply of a cruise ship.35 This so-called colonicepithelial lymphocytosis seemed to have less surfacedamage as compared with lymphocytic colitis. There arealso reports of lymphocytic colitis–like histology in patientswith constipation as well as in patients with endoscopicabnormalities.36,37 Hence, it is important for the pathologistto make sure the clinical history is consistent with LC beforemaking this diagnosis.

Be aware that some histologic features normally associ-ated with inflammatory bowel disease, including cryptirregularity and neutrophilic cryptitis and even cryptabscesses, may be encountered in a minority of those withLC, and that the presence of one or more of these featuresshould not necessarily be interpreted as evidence incom-patible with LC.38 And lastly, CC may be confused withlymphocytic colitis in cases for which only rectal biopsies areobtained or when the subepithelial collagen table in CC ispatchy and fairly thin. In the latter, a Masson trichrome stainis particularly helpful to help identify small patches ofsubepithelial collagen that are not apparent on routinehematoxylin-eosin staining.


Therapy for LC is quite variable and is largely identical tothat for CC. Some patients’ symptoms will resolvespontaneously, whereas others may require over-the-counter antidiarrheal medications such as bismuth subsa-licylate, or in other cases, 5-aminosalicylic acid compoundsor immunosuppressants. Overall, LC is associated with abenign course, with resolution of diarrhea and abnormal


histopathology in more than 80% of patients within 38months in one study, which is commensurate with mostother studies with follow-up data.39 There is a small subsetof patients who have LC and spruelike changes in theirsmall-bowel biopsies that remain refractory to therapy. Onerecent study showed a benefit with the tumor necrosis factora antagonists infliximab or adalimumab for those withsevere refractory LC, but the data are too limited todetermine its utility among these patients overall.40

DRUG-INDUCED COLITIS

Mycophenolate mofetil, an immunosuppressive agent,was Food and Drug Administration–approved in early 1995for organ rejection prophylaxis in renal or cardiac transplantpatients, and in 2000 to manage liver transplant rejection.Colonic biopsies from patients with mycophenolate mofetil–related diarrhea are altered by prominent crypt cellapoptosis and marked regenerative epithelial changes, oftenwith increased eosinophils, crypt dilatation, and cryptdistortion (Figure 7). The changes are similar and sometimesindistinguishable from intestinal graft-versus-host diseasein bone marrow transplant patients.41 Diagnostic distinctionis clinically relevant, because the treatment for mycophe-nolate mofetil toxicity is dosage reduction of mycophenolatemofetil and subsequent clinical evaluation of the diarrhea,whereas treatment for graft-versus-host disease is oftenmycophenolate mofetil. Crypt abscesses and Paneth meta-plasia may be present as well, which may cause confusionwith inflammatory bowel disease. Rare cases may mimicischemia.42

Nonsteroidal anti-inflammatory medications are nearlyubiquitous in our society and have the potential to damageany segment of the gastrointestinal tract. In the lower tract,nonspecific ulcers and erosions are often seen, and changesresembling ischemia have also been described.43 Nonste-roidal anti-inflammatory medications may cause perforationor bleeding of colonic diverticula, have been implicated inrelapse to inflammatory bowel disease and the developmentof CC, and may exacerbate bleeding of colonic angiodys-plasia.43,44

ISCHEMIC COLITIS

Clinical Features

The etiology of ischemic colitis is multifactorial, giving riseto a wide range of clinical presentations depending on theduration and severity of the underlying pathology. Whereasapproximately 90% of cases of ischemic colitis occur inpatients older than age 60, often with comorbidities such ascardiovascular disease, ischemic colitis can also affectyounger, seemingly healthy people secondary to medica-tions or previous abdominal surgery.45 Symptoms mayrange from transient bloody diarrhea or abdominal pain to afull-blown surgical emergency due to an infarcted bowel.The incidence of ischemic colitis is thought to have beenunderestimated because it often has a mild and transientnature.

Although lack of blood flow to the mucosa is the ultimatecause of ischemic colitis, there is a long list of conditionsthat can lead to this. Ischemic necrosis may be due toatherosclerosis, low-flow states secondary to hypovolemia,vasculitis,46 adhesions, various drugs such as pseudoephed-rine,47 and even long-distance running. In some instances,drugs may induce nonocclusive vasospasm (catecholamines,cocaine),48 whereas in other cases, medication such asestrogen replacement therapy causes occlusive thrombo-sis.49 Enterohemorrhagic strains of E coli (such as E coliO157:H7) can also cause an ischemic-type colitis, presum-ably because of fibrin thrombi that develop during thistoxin-mediated infection.50

Pathologic Features

Gross examination in mild cases may show only patchesof pale edematous mucosa with admixed areas of petechialhemorrhage or superficial ulceration. More involved cases ofischemia show geographic areas of ulceration, sometimesaccompanied by pseudomembranes and marked submuco-sal edema. Endoscopically this submucosal edema can beprominent enough to mimic a tumor or mass lesion.51

The watershed areas around the splenic flexure are themost common sites for ischemia, but nearly any site can beinvolved, including the proximal rectum. In chronic stages,stricture, mucosal atrophy and granularity, or a segmentalmucosal pattern of distribution may ensue that resemblesCD. Apart from the overall clinical impression, rectalsparing and rapid resolution on serial examinations helpsdistinguish ischemia from inflammatory bowel disease.

Acute ischemic lesions of the colon show superficialmucosal necrosis that may spare the deeper portions of thecolonic crypts. The remaining crypts typically have awithered or an atrophic appearance. There may be strikingcytologic atypia, to the point where care should be taken toavoid overcalling these reactive changes dysplastic (Figure 8,A and B). Ischemic colitis may often have pseudomem-branes as well as hemorrhage into the lamina propria, andhyalinization of the lamina propria. A trichrome stain can beevaluated in some cases if necessary to highlight thehyalinization of the lamina propria. Although cryptitis andcrypt abscesses may be encountered, these are usually notprominent. Some vessels may be affected by plateletthrombi and necrosis. Depending on the severity of thedecreased blood flow, these ischemic lesions may regress ontheir own or lead to perforation or strictures. The chronicphase of ischemia is often more difficult to diagnose, as theonly histologic findings may be strictures and areas ofsubmucosal fibrosis.

Figure 7. This medium-power view of mycophenolate colitis showsdilated and distorted crypts lined by regenerative epithelium. Note therather empty lamina propria and the eosinophil-rich debris within thecrypts (hematoxylin-eosin, original magnification 3100).



The differential diagnosis of ischemic colitis includesinfectious lesions such as C difficile colitis and enterohemor-rhagic E coli as well as drug-induced lesions such as NSAIDsand even some chronic colitides such as CC, radiation colitis,and CD. Because pseudomembranes may be seen in bothischemia and C difficile colitis, it may be particularly difficult todifferentiate these two. The presence of atrophic or withered-appearing microcrypts, lamina propria hemorrhage, full-thickness mucosal necrosis, and the endoscopic impressionof a localized process, polyp, or mass are markers of ischemia,whereas the endoscopic identification of diffuse pseudo-membranes favors the diagnosis of C difficile.51 The presenceof a hyalinized lamina propria is a rather specific and sensitivemarker for ischemia in colon biopsies with pseudomem-branes.51 The presence of an ischemic-appearing lesion in theright colon should also make one think of enterohemorrhagicE coli, especially if fibrin thrombi are present.

Differentiating chronic ischemic ulcers from NSAID-induced damage or CD may be impossible, especially onbiopsy material. Radiation exposure often causes arterialdamage that can manifest itself as ischemia in the gut. Insome instances the hyalinized appearance of the laminapropria in radiation colitis and the subepithelial collagen inCC can mimic the hyalinized lamina propria one sees inischemia. The presence of telangiectatic vessels and atypicalendothelial cells and fibroblasts should help identifyradiation colitis, whereas the inflammatory component ofCC should help with its identification.

Lastly, the regenerative epithelial changes in ischemiamay mimic dysplasia. Recognition of the surroundingischemic changes is the key to avoiding this pitfall. Insummary, because the differential diagnosis includes avariety of other entities, an accurate diagnosis of ischemiccolitis requires a combination of clinical suspicion andradiographic, endoscopic and histologic findings.


The prognosis for ischemic colitis depends entirely on theunderlying etiology of the ischemia as well as the severity of

the process. Overall, about a third of cases are mild andtransient, and will resolve with simple supportive care,whereas 15–20% may require surgery. In more severe cases,decompression of a distended colon may be required, andempiric broad-spectrum antibiotics are important to mini-mize bacterial translocation and sepsis that may occur withthe loss of mucosal integrity.52 Ischemia in a long-distancerunner is likely to be transient and self-limited, whereassevere thromboembolic disease may lead to a life-threat-ening bowel infarct with perforation and peritonitis.

Treatment is entirely dependent on the acuteness andseverity of the condition.

For the unfortunate 15% to 20% of patients who requiresurgery, there is an associated mortality rate of up to 60% insome series.53 As would be expected, those with totalcolonic ischemia have a worse prognosis than those withsegmental involvement.54

DIVERSION COLITIS

Clinical Features

Defunctioning of the large bowel by ileostomy orcolostomy is performed for a number of conditions,including CD, fecal incontinence, idiopathic constipation,and sphincter-saving operations for large-bowel neoplasia.Diversion colitis is the colitis that develops in the bypassedor excluded segments of the colon. Although diversioncolitis is often an incidental finding in asymptomaticpatients, some patients may present with mucoid or bloodydischarge or abdominal pain. The colitis occurs 3 to 36months following bypass and completely regresses within 3months of reestablishment of the fecal stream.55,56

A deficiency of short-chain fatty acids is thought to be thecause of diversion colitis. Short-chain fatty acids are themain source of energy for colonocytes, and they are usuallyderived from fermentation of dietary starches by normalcolonic bacterial flora. Once the fecal stream is diverted,dietary starches are no longer present. This lack ofcolonocyte nutrition leads to an inflammatory reaction.The inflammation can be reversed by giving short-chain

Figure 8. A, This medium-power view of ischemic colitis shows a hyalinized, smudgy-appearing lamina propria with markedly regenerative cryptepithelium. Note that there is very little inflammation yet the surface is sloughing. B, This high-power view shows atrophic or withering crypts withnuclear atypia. Although this atypia is regenerative, it can easily be misinterpreted as dysplasia if viewed out of context. The hyalinized lamina propriais a key to the correct diagnosis (hematoxylin-eosin, original magnifications 3100 [A] and 3200 [B]).


fatty acids via enemas several times a week, or byreestablishing the fecal stream.57

Pathologic Features

The gross and endoscopic features of diversion colitisinclude erythema, friability, edema, and nodularity withaphthous ulcers. Histologically, diversion colitis has thepotential to take on a wide spectrum of changes rangingfrom mild colitis to those reminiscent of severe activechronic UC. The hallmark of the condition relates to thegrossly apparent nodularity, which corresponds to largelymphoid aggregates with prominent germinal centers(Figure 9). The remaining features of diversion colitis aremore variable. In some instances, the inflammation maymimic severe UC with crypt distortion and marked chronicinflammation of the lamina propria. In other cases, patchycryptitis and aphthous lesions may mimic CD.58 Because ofthe nonspecific nature of these histologic changes, it isimperative that the pathologist knows that he or she islooking at material from a diverted segment of colon (mostoften a Hartmann pouch).


As many people with diverted segments of colon haveinflammatory bowel disease, the main differential diagnosisis generally that of recurrent CD or UC. The aphthouslesions may also mimic infectious colitis. Definitive diagno-sis requires the knowledge that the pathologic changes areoccurring in a diverted segment.


Prognosis is excellent because diversion colitis willcompletely regress once the fecal stream is reestablished.If this is not possible, then the inflammation can bereversed by giving short-chain fatty acids via enemas.57 Asdiversion colitis is often asymptomatic, therapy is often notnecessary.

DIVERTICULAR DISEASE–ASSOCIATED COLITIS

Clinical Features

Diverticular disease–associated segmental colitis is avariant of chronic colitis limited to segments of the leftcolon in the distribution of the diverticula. The diseasemimics inflammatory bowel disease and can be indistin-guishable from UC on histologic grounds alone. This colitisis restricted to the mucosa and is not a manifestation ofdiverticulitis. Patients often present with hematochezia andcramping abdominal pain.

There is also a form of diverticulitis that mimics CD.Studies suggest that Crohn-like changes within the sigmoidthat harbors diverticular disease are an idiosyncraticinflammatory response to the diverticulosis rather thancoexistent CD in the overwhelming majority of patients whodo not have a prior diagnosis of inflammatory boweldisease.59 Pathologists should be cautious about making thediagnosis of sigmoid Crohn colitis in the context ofdiverticulitis unless there is CD in other parts of the bowel.

Pathologic Features

Colonoscopic evaluation reveals patchy or confluenthyperemia, often accentuated on the crests of mucosalfolds. The mucosa may appear granular, and an exudate isvariably present. The distribution is predominantly de-scending colon and sigmoid, in the region of diverticulardisease. Histologically, the mucosa undergoes changes thatmimic full-blown inflammatory bowel disease, with in-creased lymphoplasmacytic lamina propria cellularity, basallymphoid aggregates, acute cryptitis, and even cryptabscesses. Distorted crypt architecture is frequent, as issurface epithelial sloughing and Paneth cell metaplasia.60

Rectal sparing provides a helpful diagnostic clue to thediagnosis.


The main differential diagnosis is between diverticulardisease–associated colitis and UC. The key to the correctdiagnosis is to recognize that the distribution of disease isidentical to the distribution of the diverticula. Crohn diseaseis also in the differential diagnosis, because of the presenceof rectal sparing. Clinical and endoscopic information, suchas inflammation limitation to a segment of diverticulardisease, is critical, so the pathologist can provide an accurateinterpretation of the biopsy.


The majority of those affected, if followed during severalyears, remain well, usually resolving completely within afew weeks or months without recurrence.61 The treatment ofdiverticular disease–associated colitis varies from therapiesaimed at diverticulitis (fiber and antibiotics) to anti-inflammatory therapies similar to those used for UC. Somepatients are refractory to medical management and requiresurgical resection.62 Extension of colonic inflammation indiverticula-free areas is not a feature of this condition.

UC VERSUS CD

Traditionally, UC and CD have been distinguishedclinically and histologically by anatomic distribution as wellas by patterns of inflammation associated with them. Crohndisease is classically regarded as a discontinuous diseasewith skip areas, whereas UC is characterized as a diffusemucosal disease of the colon with continuous and symmet-

Figure 9. This diverted segment of colon contains strikingly enlargedlymphoid aggregates with germinal centers as well as occasional cryptabscesses and surface erosions. One could easily misdiagnosis this aschronic inflammatory bowel disease without the appropriate historythat these biopsies came from a diverted segment (hematoxylin-eosin,original magnification 3200).


ric involvement, virtually always involving the rectum.Other than backwash ileitis, UC has traditionally beenregarded as sparing the small bowel completely.

Several recent publications have challenged these tradi-tional views regarding the anatomic distribution of UC.63–66

Several studies based on colorectal biopsies from chronicUC patients have demonstrated rectal sparing, patchy ratherthan diffuse colitis, and even complete rectal healing duringthe course of chronic disease.66,67 Rare case reports ofpatients with histologically documented UC associated withsmall intestinal involvement also appear in the literature,further challenging the classic dogma relating to theanatomic distribution of UC. It is important to correctlyseparate inflammatory bowel disease patients definitively asCD or UC (or other), because an ileal pouch–analanastomosis ‘‘pouch’’ procedure is generally contradictedin CD because of a high risk of morbidity related topouchitis, fistulas, incontinence, or anastomosis leaks.

Diffuse duodenitis has now been well described inpatients with confirmed diagnoses of UC.68,69 Duodenalinvolvement is often diagnosed when there is persistentnausea, vomiting, and/or bloody diarrhea in patients whohave already had their colons resected for UC.

Pathologic Features

Endoscopically, findings are similar to those of colonicUC, with diffusely erythematous, friable mucosa. Histolog-ically, the features are similar to UC within the large bowel,showing diffuse mucosal inflammation with basal plasma-cytosis of the lamina propria, neutrophilic cryptitis, cryptabscesses, and mucosal crypt distortion.


The major item in the differential diagnosis, of course, isCD. No other clinical, radiographic, or endoscopic featuresof CD should be present, nor should gross or microscopicfindings of CD exist in either the duodenal biopsy inquestion or in previous specimens. The recognition ofduodenal involvement by UC suggests that rather thanautomatically diagnosing CD in all patients presenting withpancolitis and diffuse duodenitis, one should consider thepossibility of UC with an aberrant anatomic distribution, asthese patients may be candidates for successful reanasto-mosis or ERPT procedures.

It remains to be determined whether duodenal involve-ment by UC is a previously unrecognized complication ofchronic UC, a component of a variant type of UC, orpossibly a completely different concurrent disease entity.Although this type of small intestinal involvement is nottypical of the natural history of UC, it is possible that it is arare complication of UC. As traditional views regarding thedistribution of UC are already changing, further studies areneeded to better understand and characterize the issue ofupper small intestinal inflammation in UC.

Prognosis and Treatment

Patients with duodenal involvement by UC in theliterature have done well when treated with medical therapyfor UC.

CROHN COLITIS

It is very difficult to make a definitive diagnosis of Crohncolitis in endoscopic biopsy material. Without the presenceof terminal ileal disease, all one can really hang one’s hat on

is the presence of epithelioid granulomas. Care must betaken not to misinterpret crypt rupture or mucin granulo-mas, which can be found in any active colitis. Crypt rupturegranulomas often have large multinucleated giant cells and/or eosinophils within the granuloma. It is helpful to examinemultiple levels to make sure a granuloma is not associatedwith a ruptured crypt. In our experience it is common to findgranulomas in biopsies of children with CD, but they aremuch less common in older adult patients.

Although patchy or focal inflammation is the hallmark ofCD, UC is often patchy once therapy has been instituted.Skip lesions are another feature felt to be a hallmark of CD;however, one may have skip lesions in fulminant UC as wellas in patients with left-sided UC who have a cecal patch.64,70

One may also have rectal sparing in UC because of therapyor longstanding burnt-out disease and even in acute-onsetdisease in children.70 Ultimately, when dealing withendoscopic biopsies, there is no substitute for clinical andendoscopic correlation. The more information one has, themore likely one can make a firm diagnosis. Even when onehas all the appropriate information, there are still cases thatdefy classification. In such cases there is no shame in callingsomething active chronic colitis, unclassified type.

SUMMARY

Recognition of specific histologic features or a combina-tion of features coupled with clinical and endoscopic dataallows for accurate classification in the majority of cases. Insome cases, the necessary clinical and/or endoscopicinformation may not be available and pathologists will haveto do the best they can to describe the abnormalities seen.

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the differential diagnosis of colitis in endoscopic biopsy specimens: a review article

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