—  SPECIALTY CONFERENCE  —

Gastrointestinal Pathology

Case 3 - Behçet's Disease

John Hart
University of Chicago
Chicago, Illinois


Click on each slide thumbnail image for an enlarged view
Case History
This 52 year-old male initially presented in 2003 with complaints of episodic crampy abdominal pain and fatigue but no diarrhea. In September 2004 he developed rectal bleeding. Stool cultures at that time were negative, but he was started on antibiotics for possible infectious colitis. Colonoscopy revealed ulcers in the right colon and biopsies documented acute colitis without crypt architectural distortion. Biopsies of the ileum were normal. A small bowel follow-through and upper endoscopy with biopsies of the stomach and duodenum revealed no abnormalities. The patient denied NSAID use. Serologic testing revealed negative ASCA and ANCA titers, but a positive anti-OMPC antibody titer. He was treated with I.V. prednisolone for possible Crohn's colitis and improved. Over the next year he had a couple more episodes of abdominal pain. A repeat colonoscopy with biopsies in September 2004 revealed no abnormalities.

The patient was seen at the University of Chicago in December 2004 with continued complaints of crampy abdominal pain without diarrhea. He reported a 10-pound weight loss over the last six months. A Doppler ultrasound of the mesenteric vessels revealed no abnormalities. He then developed rectal bleeding. The patient admitted to taking small doses of a NSAID to alleviate pain from a traumatic rib fracture. A colonoscopy documented a single large ulcerated lesion in the cecum. The terminal ileum and the rest of the colon appeared normal. Biopsies from the lesion revealed acute colitis, while biopsies of the remainder of the colon were normal. The bleeding continued and a right hemicolectomy was performed. Gross examination revealed a single 10.4 x 5.8 cm cecal ulcer. The surrounding colonic mucosa was unremarkable, as was the terminal ileum. A section of the ulcer is submitted for your review.

The patient was instructed to discontinue all NSAID use. Subsequently it was learned that the patient suffered from numerous bouts of aphthous ulceration of the mouth and throat over the past 5 years, which had not responded to anti-viral therapy, but did seem to improve with steroids. Over the next 10 months the patient reported several episodes of crampy abdominal pain without diarrhea, identical to those he suffered prior to the hemicolectomy. He then developed recurrent rectal bleeding and underwent colonoscopy on 10/11/05. It revealed a single large colonic ulcer just distal to the anastomosis. The ileum and the rest of the colonic mucosa appeared unremarkable. Biopsies revealed ulceration with surrounding normal colonic mucosa. The patient denied any NSAID use and a urine screen for NSAIDs was negative.


Case 3 - Figure 1 - Low power view from the edge of the ulcer
Case 3 - Figure 2 - Medium power view of the opposite edge of the ulcer
Case 3 - Figure 3 - Low power of serosal vessels


Case 3 - Figure 4 - High power view of phlebitis (note the normal appearing artery)
Case 3 - Figure 5 - High power of second vein from figure 3 showing phlebitis
Case 3 - Figure 6 - Another low power view of serosal vessels


Case 3 - Figure 7 - High power to exhibit phlebitis (note the normal appearing artery)
Case 3 - Figure 8 - Higher power to demonstrate mixed inflammatory cell infiltrate invading vein wall
Case 3 - Figure 9 - Luminal narrowing of serosal vein


Case 3 - Figure 10 - Higher power vein of venous luminal sclerosis
Case 3 - Figure 11 - Normal colon directly adjacent to the ulcer (the ileum was also normal


Histologic Findings
Sections from the cecal ulcer reveal non-specific mucosal and submucosal inflammatory changes. The most striking feature is the presence of a phlebitis involving scattered small and medium sized serosal veins. The vessels involved are located within normal adipose tissue some distance beneath the ulcer. The vasculitic infiltrate is composed primarily of lymphocytes, but neutrophils can be seen in some of the vessel walls. Mural and intimal fibrosis is evident in some of the affected vessels, with partial or total occlusion of a few of the veins. Interestingly, the mucosal changes do not suggest ischemia. Sections obtained immediately surrounding the ulcer reveal completely normal mucosa. Likewise, sections of the ileum are entirely unremarkable.

Differential Diagnosis
Purely on a histologic basis this case falls into the differential diagnosis of a solitary cecal ulcer. Reported etiologies include uremia, CMV infection, NSAID (and other drug) toxicity, thromboembolism, vasculitis, bacterial infection (e.g., Campylobacter jejuni), parasitic infection (e.g., Entamoeba histolytica), cecal diverticulitis, and foreign body impaction [1]. However, in view of the chronic relapsing clinical course, and the recurrence after resection, the differential in this case can be limited to the following possibilities:

NSAID induced injury: NSAID induced ulceration can develop anywhere in the gastrointestinal tract, and cecal ulcers are not uncommon. Sections generally do not reveal specific histologic features, although in some cases mild colitis of the surrounding mucosa may be evident, sometimes with patchy thickening of the subepithelial collagen layer. In this patient NSAID induced ulceration was a leading diagnostic consideration at the time of colectomy. However, the recurrence of ulceration while the patient was completely off NSAIDs, and the presence of recurrent oral aphthous ulcers, argues against this etiology. Phlebitis is also not reported as a histologic feature of NSAID induced ulcers.

Crohn's colitis: Although ulcers are a characteristic feature of Crohn's disease, there is a complete lack of other clinical and histologic features to support this diagnosis in this patient. The presence of a single G.I. ulcer should never be interpreted as consistent with Crohn's disease, a trap that some pathologists fall into because of the presence of chronic mucosal and mural changes at the ulcer edges. A chronic ulcer of any etiology will exhibit crypt architectural distortion and submucosal fibrosis, and even foci of pyloric metaplasia may be evident [2].

Enterocolic Lymphocytic Phlebitis: This ill-defined vasculitis occurs almost exclusively in the gastrointestinal tract and most often involves the right colon. It is defined histologically by a lymphocytic infiltration of small and medium sized veins, and causes mucosal ulceration at the affected site. The degree of lymphocytic infiltration of the vein walls is generally greater than is evident in this case. Also, recurrent ulceration after surgical resection is distinctly uncommon in enterocolic lymphocytic phlebitis. Finally, oral aphthae have not been described in this condition [3, 4, 5, 6] .

Behçet's disease: Gastrointestinal involvement in Behçet's disease most often involves the ileocecal region, producing ulceration as seen in this case. Lymphocytic phlebitis is the most characteristic histologic feature. Recurrent disease after surgical resection is common. Oral aphthae are the most frequent clinical manifestation of Behçet's disease [7].

Diagnosis
Features most consistent with Behçet's disease

Discussion
Behçet's disease was first described in a paper published by Behçet in a German dermatology journal in 1937 (8). This primary systemic vasculitis can involve small veins (and arteries) in any organ, but oral, genital, skin, and ocular involvement are most characteristic. Presentation generally occurs in the second to fourth decade of life, but children and older adults can also be affected. There is a notable male predominance among patients from Silk Route countries, while a female predominance is reported in North America and Europe [7]. Mortality rates are low throughout the world, but legal blindness, a dreaded complication, develops in 50-90% of Turkish and Japanese patients with ocular involvement. The incidence of blindness may be lower in the future with newer treatment modalities [7].

The etiology of Behçet's disease is unknown, but a genetic component is highlighted by the narrowly restricted geographic distribution of cases (along the silk route between the Mediterranean and East Asia) and the association with the HLA-B51 locus. In other parts of the world the incidence is significantly lower (Behçet's disease is particularly uncommon in the United States). Immunologic studies suggest an altered host immune response with aberrant T-cell responses and formation of immune complexes, but a self-antigen has not been identified to date. Proposed candidates have included heat shock proteins, tropomyosin, retinal-S- antigen, con-stimulatory molecules, and endothelial cell antigens, including alpha-enolase. [9]. An ongoing search to identify an infectious agent that might be a trigger for the development of Behçet's disease has been fruitless thus far [7].

Since there is no single pathognomonic clinical feature, histologic finding, or laboratory test to diagnose Behçet's disease a variety of diagnostic algorithms have been proposed [7, 10] . A consensus classification proposed by an International Study Group has been validated and has gained wide utilization for research studies, and also as a diagnostic tool [11, 12] . In this system recurrent oral ulceration (at least three episodes in a year) must be present, along with at least two of the following: recurrent genital ulcers, ocular involvement, skin lesions and a positive pathergy test. Recurrent oral aphthous ulceration, the sine qua non of Behçet's disease, may precede other systemic manifestations by decades. Cigarette smoking may suppress mouth ulcers, and relapse after cessation of smoking has been documented (similar to ulcerative colitis). Chronic relapsing ocular involvement, which occurs in 30-70% of patients, may manifest as uveitis, retinitis, scleritis, keratitis, or posterior uveitis. Pathergy, defined as hypersensitivity of the skin following minor trauma, is common in Middle Eastern patients but rare in other patient groups. It can be demonstrating by pricking the skin with a sterile needle, and is considered present if a sterile erythematous papule develops within 48 hours. Recently a Japanese group has developed revised criteria in order to correct a perceived tendency for over diagnosis of Behçet's disease by use of the international consensus system. Diagnosis of the complete form of Behçet's disease requires manifestation of all four of the major diagnostic features (oral and genital ulcers, ocular and skin lesions). The "incomplete" for requires three of the four major criteria, or two main symptoms along with two other symptoms (e.g., arthritis, vasculitis, epididymitis, CNS or G.I. involvement). Behçet's disease is "suspected" when a single main symptom is present along with one or more of the additional symptoms in a recurring form [10].

Gastrointestinal involvement has been reported in 3 to 26% of patients with Behçet's disease, depending on the geographic location of the population studied [13]. In patients from Turkey and the Mediterranean G.I manifestations are rarely reported [14, 15, 16, 17] , while in the Far East patients may initially present with GI symptoms [18]. The common clinical manifestations of gastrointestinal involvement include G.I. bleeding, abdominal pain, anorexia, weight loss, and diarrhea. In about 75% of patients GI involvement is localized to the ileocecal region [16, 19, 20] . Endoscopic examination usually reveals rounded, punched out ulcers without evidence of surrounding colitis [19, 21] . Ulcers are commonly deep and perforation may be the presenting symptom, particularly in children [22]. Surgical resection of an ulcerated or perforated segment of bowel is often followed by recurrent ulceration near the anastomosis, as was seen in the patient under discussion [19, 20, 23, 24, 25] . This has led to an emphasis in recent years on medical management wherever possible [20] (see below).

The histologic features of gastrointestinal Behçet's disease in biopsy specimens are entirely non-specific. Ulceration in a background of normal mucosa is the most common appearance [26]. Interestingly, histologic features of mucosal ischemia are usually not mentioned in pathologic descriptions of Behçet's syndrome [27]. In the Japanese literature the term "simple ulcer" is used to describe cases in which Behçet's syndrome is suspected but involvement of other organs is not present, so that criteria for a definite diagnosis are not met [28]. In resection specimens the characteristic vasculitis can be appreciated. It usually involves small vessels, particularly venules, and is characterized by intramural mononuclear cell and neutrophilic infiltrates, which can result in fibrosis and luminal occlusion. In early lesions the mural infiltrate appears to be primarily neutrophilic [28]. The vessels involved are scattered through the submucosa and subserosal fat [27]. The vasculitis is histologically similar to that evident in cutaneous lesions [29]. Although a few case reports mention the presence of granulomas, this is distinctly uncommon and is not reported in other involved organs [27]. It is possible that some case reports of Behçet's disease with granulomas actually represent examples of Crohn's disease from areas where Crohn's disease is uncommonly diagnosed [30].

The distinction between Behçet's disease and Crohn's disease can be difficult in an individual patient. Involvement of the ileocecal region is most common in both disorders, as is a chronic relapsing course. However, fistulas are distinctly uncommon in Behçet's disease and perianal disease is not reported. Intestinal perforation is a rare event in Crohn's patients but is common in Behç et's patients with gastrointestinal involvement. In contrast, stricture formation is common in Crohn's disease and is rarely reported in Behçet's disease. These differences are reflected in the gross and microscopic appearance of resected intestinal segments. In Behç et's disease deep rounded punch out ulcers develop that are not accompanied by surrounding chronic transmural inflammation and fibrosis,. In contrast, Crohn's disease is characterized by fissuring longitudinal ulcer surrounded by transmural inflammation and fibrosis.

Recently several cohorts of patients with Behçet's disease were tested for the NOD2/CARD15 mutations most commonly identified in patients with Crohn's disease. No mutations were identified in Turkish, Korean, or Arab Behçet's patients, or in a small number of Caucasian patients from England [31, 32, 33] . Of course it must be noted that with the exception of the English patients, NOD2/CARD15 mutations are also not reported in patients with Crohn's disease from these regions.

Serologic tests for pANCA and ASCA have also been performed in groups of Behçet's disease patients. The rate of pANCA positivity in Behçet's patients does not differ from healthy controls [34]. However, in studies of Korean and Israeli patients with colonic involvement by Behçet's disease the ASCA titer was elevated in 42% and 48.1% respectively (comparable to the 49.4% rate in Korean Crohn's disease patients [34, 35] . Interestingly, only 4% of Turkish Behçet's disease patients were ASCA positive, but only 8 of the 85 patients had clinically evident gastrointestinal involvement [36].

Inflixamab, a monoclonal antibody that inhibits TNF-alpha and is now a mainstay of therapy for Crohn's disease, is also efficacious in the treatment of Behçet's disease [37]. This agent is useful not only for gastrointestinal disease, but also oral, genital, and ocular lesions (38, 39, 40). The success of this agent, particularly in severe cases, has supplanted the use of numerous previously utilized medications , including steroids, calcineurin inhibitors, cyclophosphamide, azathioprine, interferon-alpha, thalidomide, pentoxifylline, dapsone, colchicine, and methotrexate [41].

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