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
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
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.
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 . 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
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.
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 .
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
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 .
Features most consistent with Behçet's disease
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 . 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 .
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. . 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 .
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
. 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
. 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 .
Gastrointestinal involvement has been reported in 3 to 26% of patients with Behçet's disease,
depending on the geographic location of the population studied . In patients from Turkey and the
Mediterranean G.I manifestations are rarely reported
, while in the Far East patients may
initially present with GI symptoms . 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
. Endoscopic examination
usually reveals rounded, punched out ulcers without evidence of surrounding colitis
. Ulcers are
commonly deep and perforation may be the presenting symptom, particularly in children . 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
. This has led to an
emphasis in recent years on medical management wherever possible 
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 .
Interestingly, histologic features of mucosal ischemia are usually not mentioned in pathologic
descriptions of Behçet's syndrome . 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 . 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 .
The vessels involved are scattered through the submucosa and subserosal fat . The vasculitis is
histologically similar to that evident in cutaneous lesions . Although a few case reports mention
the presence of granulomas, this is distinctly uncommon and is not reported in other involved organs
. 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 .
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
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
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 . 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
. Interestingly, only 4% of Turkish Behçet's disease patients were ASCA positive, but only 8 of
the 85 patients had clinically evident gastrointestinal involvement .
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 . 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 .
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