New Perspectives in Inflammatory Bowel Disease
Moderators: Dr. Stanley Hamilton and Dr. Carolyn C. Compton
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.
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.
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
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 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 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.
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
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
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|
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
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.
- Chetty R, Roskell DE. Cytomegalovirus infection in the gastrointestinal tract. J Clin Pathol 47:968-72, 1994.
- Kraus MD, Feran-Doza M, Garcia-Moliner ML, et al. Cytomegalovirus infection in the colon of bone marrow transplant patients. Mod Pathol 11;29-36, 1998.
- Kambham N. Vij R. Cartwright CA. Longacre T. Cytomegalovirus infection in steroid-refractory ulcerative colitis: a case-control study. American Journal of Surgical Pathology 28:365-73, 2004.
- Kraus MD, Amatya B, Kimula Y. Histopathology of typhoid enteritis: morphologic and immunophenotypic findings. Mod Pathol 12:949-55, 1999.
- Boyd JF. Pathology of the alimentary tract in Salmonella typhimurium food poisoning. Gut 26;935-44, 1985.
- McGovern VJ, Slavutin LJ. Pathology of salmonella colitis. Am J Surg Pathol 3:483-490, 1979.
- Mallory FB. A histological study of typhoid fever. J Exp Med 3:611-38, 1898.
- Speelman P, kabir I, Islam M. Distribution and spread of colonic lesions in shigellosis: a colonoscopic study. J Infect Dis 150:899-903, 1984.
- Mathan MM, Mathan VI. Morphology of rectal mucosa of patients with shigellosis. Rev Inf Dis 13 Suppl 4:S314-8, 1991.
- Surawicz CM. The role of rectal biopsy in infectious colitis. Am J Surg Path 12 Supp.1:82-8, 1988.
- Lamps LW, Madhusudhan KT, Greenson JK, et al. The role of Y. enterocolitica and Y. pseudotuberculosis in granulomatous appendicitis: a histologic and molecular study. Am J Surg Path 25:508-15, 2001.
- Dudley TH, Dean PJ. Idiopathic granulomatous appendicitis, or Crohn's disease of the appendix revisited. Hum Pathol 24:595-601, 1993.
- Deutsch SF, Wedzina W. Aeromonas sobria associated left sided segmental colitis. Am J Gastro 92;2104-6, 1997.
- Travis LB, Washington JA. The clinical significance of stool isolates of Aeromonas. Am J Clin Path 85;330-6, 1986.
- Horvath KD, Whelan RL. Intestinal tuberculosis: return of an old disease. Am J Gastroenterol 93;692-6, 1998.
- Marshall JB. Tuberculosis of the gastrointestinal tract and peritoneum. Am J Gastroenterol 88;989-99, 1993.
- Roth RI, Owen RL, Keren DF, et al. intestinal infection with MAI in acquired immune deficiency syndrome (AIDS): histological and clinical comparison with Whipple's disease. Dig Dis Sci 5:497-504, 1985.
- Ferrari TC, Couto CA, Murta-Oliveira C, et al. Actinocycosis of the colon: a rare form of presentation. Scand J Gastroenterol 35; 108-9, 2000.
- Variyam EP, Gogate P, Hassan M, et al. Nondysenteric intestinal amebiasis: colonic morphology and search for Entamoeba Histolytica adherence and invasion. Dig Dis Sci 34;732-40, 1989.
- Brandt H, Tamayo P. Pathology of human amebiasis. Hum Pathol 1:351-85, 1970.
- Ma CK, Gottlieb C, Haas PA. Diversion colitis: a clinicopathologic study of 21 cases. Hum Pathol 1990;21:429-36.
- Makapugay LM, Dean PJ. Diverticular disease-associated chronic colitis. Am J Surg Path 1996;20:94-102.
- Goldstein NS, Cinenza AN. The histopathology of nonsteroidal anti-inflammatory drug-associated colitis. Am J Clin Path 1998;110:622-28.
- Makapugay LM, Dean PJ. Colitis due to nonsteroidal anti-inflammatory drugs. Lab Invest 1996;74:61A.