Section 1 -

Pitfalls in the Diagnosis of Inflammatory Bowel Diseases Laura W. Lamps Professor of Pathology, Director of Anatomic Pathology University of Arkansas for Medical Sciences

One of the most common tasks facing the practicing surgical pathologist is making the distinction between chronic idiopathic inflammatory bowel disease (i.e., Crohn's disease and ulcerative colitis) and other forms of colitis. Many infections and drug reactions mimic CIIBD, and distinguishing between them on histologic grounds alone, without additional clinical, laboratory, or radiographic information, may be impossible. In this lecture, some of the more common entities that mimic CIIBD will be discussed, and helpful information that may aid the pathologist in working through the differential diagnosis will be given. Since the implications (prognostic, therapeutic, and insurance) for the patient are considerable, carefully thinking through the other entities that can produce a CIIBD-like pattern before making a diagnosis of Crohn's or ulcerative colitis may save the patient years of misguided therapy and follow-up. Infectious Mimics of CIIBD. Many infectious agents, including viruses, bacteria, fungi, and parasites, mimic CIIBD. Some of the more common infectious mimics of CIIBD are summarized in the table at the end of this section. CMV. Ulceration is the most common CMV-related lesion in the gastrointestinal tract, and segmental ulcerative lesions and linear ulcers mimicking Crohn's disease are well-described. CMV inclusions are often found deep within ulcer bases rather than at the edges of ulcers or in the superficial mucosa, and the typical "owl's eye" inclusions are usually present within endothelial and stromal cells. Examination of multiple levels and use of immunohistochemistry may be invaluable in finding the rare cell containing an inclusion. CMV also commonly superinfects both ulcerative colitis and Crohn's disease patients, and some authorities recommend routine use of CMV immunohistochemistry in patients with CIIBD exacerbations. Salmonellosis. The characteristic pathology is most prominent in the ileum, appendix, and colon, and is associated with Peyer's patches. Grossly, the bowel wall is thickened, and raised nodules may be seen corresponding to hyperplastic Peyer's patches. Apthoid ulcers overlying Peyer's patches, linear ulcers, discoid ulcers, or full thickness ulceration and necrosis are common as disease progresses. Characteristically, the histiocyte is the predominant inflammatory cell in typhoid fever. Occasional lymphocytes and plasma cells are seen, but neutrophils are not prominent. Non-typhoid Salmonella species (e.g. S. enterica and S. muenchen) typically produce pathologic features of acute infectious-type colitis, although occasionally, significant crypt distortion may be seen. The gross and histologic features of Salmonella infection may mimic either Crohn's or ulcerative colitis. Clinical presentation (rapid onset vs. chronic) and stool cultures may be invaluable. Shigella Species. The large bowel (particularly the left colon) is typically affected in shigellosis, but the ileum may be involved. Histologically, early disease usually features cryptitis, crypt abscesses (often superficial), and ulceration; pseudomembranes may be seen as well. Apthoid ulcers similar to Crohn's disease may also be seen. As disease continues, there is increased mucosal destruction with many neutrophils in the lamina propria. Marked architectural distortion mimicking idiopathic inflammatory bowel disease is commonly seen; therefore shigellosis, particularly later in the course of the disease, may be extremely difficult to distinguish from Crohn's or ulcerative colitis both endoscopically and histologically. Stool cultures and clinical presentation may be very helpful in this instance. Yersinia. Yersinia is one of the most common causes of bacterial enteritis in Western and Northern Europe. Grossly, involved bowel has a thickened, edematous wall with nodular inflammatory masses and apthoid ulcers centered around Peyer's patches. Both suppurative and granulomatous patterns of inflammation may be seen, and a mixture of the two is common. Both species cause lymphoid hyperplasia, epithelioid granulomas with prominent lymphoid cuffing, transmural lymphoid aggregates, giant cells, mucosal ulceration, cryptitis, and concomitant lymph node involvement. Crohn's disease and yersiniosis may be very difficult to distinguish from one another. In fact, isolated granulomatous appendicitis has in the past frequently been interpreted as primary Crohn's disease of the appendix. However, patients with granulomatous inflammation confined to the appendix rarely develop generalized inflammatory bowel disease. Features that may favor Crohn's include cobblestoning of mucosa and creeping fat grossly, and changes of chronicity microscopically including crypt distortion, thickening of the muscularis mucosa, and prominent neural hyperplasia. However, some cases are indistinguishable on histologic grounds. Cultures, serologic studies, and PCR assays may be helpful in confirming the diagnosis. Aeromonas Species. Aeromonas species are increasingly recognized as causes of gastroenteritis. Endoscopially, signs of colitis may be seen including edema, friability, erosions, exudates, and loss of vascular pattern; the features are often segmental and may mimic Crohn's. The histologic features are often those of acute self limited or focal active colitis, although focal architectural distortion can be seen. Stool cultures should be relied upon to recover the organism. Mycobacteria. Multiple, segmental lesions with skip areas are common in MTb infection of the bowel; strictures and ulcers are common endoscopic findings as well, along with thickened mucosal folds and inflammatory nodules. The ulcers are often circumferential and transverse. The characteristic histologic lesion is the caseating granuloma, which may be present at any level of the wall of the gut. They are often confluent, with a rim of lymphocytes at the periphery of the granulomas. Apthoid ulcers and ulceration, as well as inflammation of submucosal vessels, may be seen as well. Crohn's disease may be very difficult to distinguish from tuberculosis; features favoring Crohn's are linear rather than circumferential ulcers, transmural lymphoid aggregates, deep fistulas and fissures, and lack of caseation in the granulomas. Tuberculosis also commonly lacks mucosal cobblestoning. M. kansasii and M. bovis may cause a similar histologic picture. Acid-fast stains may demonstrate organisms, but culture may be required; in addition, excellent PCR assays are available. In immunocompetent patients, the granulomatous response to MAI, either necrotizing or non-necrotizing, can mimic Crohn's disease. Bacilli stain with acid-fast stains, and culture and PCR assays may also be helpful. Organisms are generally harder to detect in healthy patients. Actinomycosis (Actinomyces israelii). Actinomyces causes significant mural inflammation and fibrosis that may extend into surrounding structures. Perianal fistulas and chronic (often granulomatous) appendicitis due to actinomycosis have also been described. The inflammatory reaction is predominantly neutrophilic, with abscess formation. Palisading histiocytes and giant cells, as well as frank granulomas, often surround the neutrophilic inflammation. Both the gross and microscopic findings can mimic Crohn's disease. Gram stains will highlight the filamentous, gram positive organisms. Entamoeba Histolytica. The cecum is most commonly involved, but any level of the large bowel or appendix may be affected. Small ulcers are the early lesion, which may coalesce to form large, irregular ulcers that are often geographic or serpiginous. Intervening mucosa is often normal. The ulcers often have associated inflammatory exudate or inflammatory polyps. Ulcers may undermine adjacent mucosa to produce the classic "flask-shaped" lesion. Histologically, the earliest lesion is a mild neutrophilic infiltrate. In more advanced disease, ulcers are often deep, extending at least into the submucosa, with undermining of adjacent normal mucosa. There is associated necroinflammatory debris; the organisms are generally found within this purulent material. Invasive amoebae are occasionally seen within the bowel wall. The adjacent mucosa is usually normal, but may show gland distortion and inflammation. The organisms, which may be very few in number, resemble macrophages with foamy cytoplasm and a round, eccentric nucleus; the presence of ingested red blood cells is pathognomonic of E. histolytica. Both the gross and microscopic features of amoebiasis may be confused with Crohn's disease or ulcerative colitis, and amoebae may resemble macrophages. Amoebae are trichrome positive; in addition, macrophages stain with immunostains for alpha-1-antitrypsin and chymotrypsin, whereas amoebae do not. Morphololgic feature mimicking CIIBD Organism Architectural distortion Salmonella species, Shigella, Amoeba, Aeromonas species Granulomatous inflammation Yersinia, MTb, MAI, Actinomyces, rarely syphilis Lymphohistiocytic inflammation LGV, Salmonella, Yersinia, Histoplasma Gross skip lesions Yersinia, amoebiasis, CMV Transmural lymphoid aggregates Yersinia Diversion Colitis. This occurs in segments of the large bowel that are excluded from the fecal stream, for instance in patients with an ileostomy or colostomy. It is found in 50-100% of patients following colonic bypass, and is cured by surgical reversal of this condition. Symptoms (including bloody or mucoid discharge, abdominal pain, and tenesmus) occur increasingly with increased duration of diversion. Endoscopically, the diverted segment may appear either normal or inflamed. Ulcers, erosions, nodularity, and strictures may develop after long periods of diversion. Histologic features include apthous ulcers, lymphoid hyperplasia or scattered lymphoid aggregates, lamina propria plasmcytosis, cryptitis, and crypt abscesses. Architectural distortion is usually not prominent. Differentiation from inflammatory bowel disease in a patient with that history may be very problematic. Lack of significant architectural distortion and milder inflammatory changes help to differentiate from ulcerative colitis. Crohn's disease may be difficult if not impossible to distinguish from diversion colitis. Resolution of histologic changes with treatment for diversion colitis supports that diagnosis. Diverticular-Disease Associated Colitis. This occurs primarily in older persons presenting with painless hematochezia. Colonoscopic evaluation generally reveals patchy or confluent hyperemia, often accentuated on the crests of mucosal folds. The mucosa may appear granular. The distribution is predominantly descending colon and sigmoid, in the region of diverticular disease; the rectum is almost always spared. Histologic features include cryptitis, crypt abscesses, basal lymphoplasmacytosis, crypt distortion, and granulomas in 25-30 percent of cases. Prominent lymphoid aggregates may also be present. It can be very challenging to differentiate diverticular-associated colitis from Crohn's, ulcerative proctitis, or ulcerative colitis with rectal sparing. Patients with ulcerative colitis and rectal sparing tend to be younger and lack diverticula. In addition, even in ulcerative colitis with rectal sparing, the rectal mucosa is usually not absolutely normal (shows some features of quiescent colitis). Patients with Crohn's and ulcerative colitis tend to have involvement of other segments of the bowel as well, and Crohn's has other gross features not seen in diverticular disease-associated colitis. Some studies have also suggested that a subset of patients with this disease are at increased risk for developing conventional ulcerative proctitis. NSAID-associated Colitis. Colitis and ileitis due to NSAID usage may occur after only weeks of use. Patients generally present with abdominal pain, cramping, and intermittent bloody stool (may be normal or diarrheal). Colonoscopy reveals mucosal erythema and friability, generally with apthous or geographic-type ulcers. Any region of the colon may be involved, and ileal involvement is common. Risk of colonic injury increases with advancing patient age, duration of use, quantity, and use of other medications along with NSAIDS. Most patients' symptoms resolve with cessation of NSAID administration. Histologic features include patchy cryptitis, increased intra-epithelial lymphocytes, superficial erosions, and regenerative mucosal changes. There may be focal architectural disarray (variation in distribution and size), but not significant distortion (budding, branching, or "animal shapes"), granulomas, or pyloric-type metaplasia. Ileal or right colon involvement by NSAID-related injury often mimics Crohn's, both grossly and microscopically. In the absence of pyloric-type metaplasia or granulomas, NSAID should be strongly considered in the differential diagnosis of ileal ulcers. The clinician should be advised to take a careful medication history (including over the counter medications), and small bowel follow-through may also be helpful. 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