Int J Colorectal Dis DOI 10.1007/s00384-015-2157-2
LETTER TO THE EDITOR
Gastrointestinal Crohn-like disease following BCG therapy Marco Pizzi & Laura Albertoni & Lavinia Stefanizzi & Claudia Mescoli & Massimo Rugge
Accepted: 8 February 2015 # Springer-Verlag Berlin Heidelberg 2015
Sir, Crohn’s disease (CD) is a chronic inflammatory gastrointestinal disease characterized by segmentary, transmural, and fistulizing inflammation; in about 30 % of the case, CD is associated with epitheliod non-necrotizing granulomas. Since its original description, the histological similarities between CD and intestinal tuberculosis led to the hypothesis of a copathogenetic role of mycobacterial infection, and further studies on CD patients demonstrated an immunological response closely resembling that observed in TBC patients [1]. We report the first case of Crohn-like inflammatory gastrointestinal disease, developed shortly after intra-vescical administration of an attenuated strain of Mycobacterium bovis (Bacillus of Calmette Guerin [BCG]), for the treatment of superficial bladder carcinoma. We feel that this unusual case may trigger some original speculation on the pathogenesis of CD and documents a possible (previously unknown) complication of BCG immunotherapy. A 62-year-old male underwent both esophago-gastroduodenoscopy (EGDS) and colonoscopy for dyspepsia and colorectal cancer screening. EGDS was unremarkable but for a diffuse hyperaemia of the gastric antrum, colonoscopy revealed multiple aphthous lesions and sigmoid colon diverticula. Multiple representative biopsy samples were obtained from both the gastric and the ileo-colic mucosa. On histology, the gastric antral and angular mucosa displayed a low-grade inflammation, mainly consisting of lymphocytes and plasma cells. Occasional epithelioid/mature granulomas surrounding gastric foveolae were also faced. The gastric oxyntic mucosa showed minimal to mild inflammation, with occasional monoM. Pizzi (*) : L. Albertoni : L. Stefanizzi : C. Mescoli : M. Rugge Department of Medicine-DIMED, General Pathology and Cytopathology Unit, University of Padova, Padova, Italy e-mail:
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nuclear nodular infiltrates. Modified Giemsa and ZiehlNielsen stains failed to demonstrate the presence of microorganisms consistent with Helicobacter pylori or Mycobacteria spp., respectively. The gastric histological findings were assessed as consistent with focally enhanced gastritis, with micro-granulomatous features. As for the intestinal biopsy sampling, the ileal mucosa was characterized by thin, regular villi, without other histological changes. The right (caecal) and left (sigmoid) colon mucosa featured regenerative changes of the surface epithelium, coexisting with mild distortion of the crypts’ architecture. A moderate to severe mixed inflammatory infiltrate within the lamina propria was associated with small mature granulomas and low-grade cryptitis. The Bcombined^ histological findings of both the upper and the lower GI tract were initially assumed as consistent with CD. Subsequent clinical information, however, excluded any clinical symptom consistent with inflammatory bowel diseases. A thorough clinical history revealed that the patient was under treatment with intra-vescical BCG for a superficial bladder carcinoma. Such clinical information suggested the hypothesis of Crohn-like granoulomatous gastro-enteritis and only clinical follow-up was recommended. Subsequent molecular tests (DNA obtained from both gastric and intestinal tissues samples) excluded any mycobaterial infection. Local BCG immunotherapy was stopped 12 months after initial GI procedures. At endoscopic/histological follow-up, urinary bladder mucosa did not feature any residue of cancer lesion. At present (36 months after first GI endoscopy), no gastrointestinal symptoms have ever appeared, further supporting the histological diagnosis of Crohn-like granulomatous gastrocolic disease. Since its first application by Morales in 1972, direct intravescical instillation of BCG has become the treatment of choice for non-muscle invasive bladder carcinoma [2]. BCG local-immunotherapy is generally well tolerated, being
Int J Colorectal Dis
sometime associated with local and systemic side effects. The latter can result from either BCG absorption/dissemination (e.g., pneumonitis, osteomyelitis, hepatitis, sepsis) or from a hyperimmune reaction to mycobacterial administration (e.g., flu-like symptoms) [2]. Of note, gastrointestinal side effects are extremely rare, with only one case of non-granulomatous ulcerative ileitis being reported in the literature so far [3]. To the best of our knowledge, this is the first case of BCGrelated gastric and intestinal inflammatory disorder featuring histological lesions suggestive of CD. The exclusion of CD is reliably based on the patient’s clinical history (i.e., no gastrointestinal symptoms of ileo-colic disease, as consistently ascertained at both the time of endoscopic procedure, and in the following long-term follow-up). The widespread involvement of both the gastric and the colonic mucosa together with the diffuse granulomatous reaction prompt the differential diagnosis with disseminated BCG infection (i.e., BCG-itis). According to internationally validated criteria, several histological and endoscopic features support a diagnosis of hyperimmune Crohn-like reaction, rather than BCG-itis: (i) the granulomatous lesions were sparse (200 μm) coalescent granulomas, most frequently associated with central necrosis. Focally enhanced gastritis and/or colitis are rarely found and aphthous ulcers are usually associated with more penetrating ones [4]. From a pathogenetic perspective, the association between BCG immunotherapy and a Crohn-like inflammatory disorder is intriguing, since, in both, immune responses are character-
ized by one and the same adaptive immunological profile (i.e., TH1 reactions). Furthermore, CD has been specifically associated with polymorphisms of genes like NOD2, ATG16L1, and IRGM, involved in innate immune responses against mycobacterial infections [1]. In the present case, it is conceivable that BCG administration elicited a hyperimmune TH1 response, which was in turn responsible for the development of a multisite inflammatory disease with Crohn-like features. This hypothesis is further supported by the epidemiological evidence that children vaccinated with BCG experience a threefold increase of the life-long risk of developing CD. In conclusion, this extremely unusual case documents a possible (previously unknown) complication of BCG immunotherapy that should be taken into account whenever facing a granulomatous inflammatory disorder of the gastrointestinal tract. Acknowledgments We are deeply grateful to the patient ([C.F.] a colleague, and a friend of us), who has allowed us to report his clinical history. Consent statement The patient provided his written informed consent.
References 1. Xavier RJ, Podolsky DK (2007) Unravelling the pathogenesis of inflammatory bowel disease. Nature 448(7152):427–434, PMID: 17653185 2. Gandhi NM, Morales A, Lamm DL (2013) Bacillus Calmette-Guérin immunotherapy for genitourinary cancer. BJU Int 112(3):288–297. doi:10.1111/j.1464-410X.2012.11754.x, PMID: 23517232 3. Satgé D, Pommepuy I, Hassan T, Goburdhun J, Flejou JF (2002) Ulcerative terminal ileitis after BCG therapy for bladder carcinoma. Histopathology 41(3):266–268, PMID: 12207790 4. Makharia GK, Srivastava S, Das P, Goswami P, Singh U, Tripathi M, Deo V, Aggarwal A, Tiwari RP, Sreenivas V, Gupta SD (2010) Clinical, endoscopic, and histological differentiations between Crohn's disease and intestinal tuberculosis. Am J Gastroenterol 105(3):642–651. doi:10.1038/ajg.2009.585, PMID: 20087333
