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I read with interest the report by Matsumoto and colleagues1 of a patient with ulcerative colitis and multiple microcarcinoid tumours, and would like to describe a similar recent case encountered in our department. A 44 year old man with an 18 year history of ulcerative colitis underwent total colectomy after a diagnosis of high grade dysplasia in a rectal biopsy. The resection specimen revealed a mucinous adenocarcinoma of the rectum invading the submucosa, but not involving the muscularis propria, perirectal fat, or lymph nodes. There was also active ulcerative colitis of mild to moderate severity involving the distal 200 mm of the colon and rectum. The inflamed segment was extensively sampled and all sections showed multifocal endocrine cell proliferation within the muscularis mucosae and the superficial submucosa (fig 1). Most foci comprised clusters of between five and 50 cells, which were typically arranged in small nests and cords, but there were four larger endocrine cell aggregates from 1 to 2.5 mm maximum diameter. Some of the submucosal nests were closely apposed to nerves and ganglion cells. Immunohistochemistry on representative sections showed expression of cytokeratin, chromogranin, synaptophysin, and CD56 within the endocrine cells and close apposition to S100 protein positive nerves and dendritic cells. There was no evidence of endocrine cell hyperplasia within the overlying mucosa or in the normal proximal bowel.
Although there are several reports of neuroendocrine tumours arising in patients with inflammatory bowel disease, the finding of microscopic and multifocal endocrine cell proliferations is much more rare. Indeed, the most appropriate terminology for these lesions is not clear. Matsumoto and colleagues1 used the term “microcarcinoids” to describe the endocrine proliferations in their patient. The lesions were described as “multiple small islands of cells” but the sizes of the lesions were not documented. Maruyama and colleagues2 described a non-colitic patient with multiple, variably sized endocrine cell proliferations and five typical grossly evident carcinoid tumours in the colon. They suggested that the microscopic lesions should be subdivided into microcarcinoids, endocrine cell microproliferations (ECMPs), and transitional forms. The smaller ECMPs and transitional lesions did not exhibit expansile growth or intervening fibrous stroma. Abe et al,3 in describing a case of multiple duodenal endocrine cell proliferations, defined carcinoid tumours as greater than 3 mm diameter, microcarcinoids as between 0.5 and 2.9 mm, and lesions smaller than 0.5 mm (which they interpreted as hyperplastic) as “endocrine cell micronests”. According to these criteria, most of the lesions in our case would be classified as ECMPs or micronests. Regardless of the terminology, it would appear that these cases show a spectrum of endocrine cell proliferation, but whether these are truly hyperplastic or neoplastic is not clear.
As discussed by Matsumoto et al,1 it has been suggested previously that colonic endocrine cell hyperplasia in association with inflammatory bowel disease may represent a response to injury or inflammation. However, although this hypothesis may reasonably explain mucosal endocrine cell proliferation, the distribution of the lesions within the submucosa and muscularis mucosae in our patient and in some previous reports1,2,4 is less readily understood, particularly because the crypt endocrine population was not hyperplastic in these cases. Maruyama and colleagues2 noted in their case that the submucosal endocrine cells were often associated with ganglion cells and S100 positive dendritic cells, and postulated that the proliferation involved a subpopulation of endocrine cells associated with submucosal nerve fibres. This suggestion is supported by the findings in our case. As noted by Matsumoto et al,1 deeply located endocrine cell proliferations are unlikely to be identified on endoscopic biopsies. Indeed, our patient underwent four colonoscopic examinations in the 12 months before surgery and no endocrine lesions were identified in a total of 24 biopsy samples examined during that period. Therefore, the incidence of such lesions may be underestimated, although whether this is a clinically relevant finding is not clear.
We appreciate the valuable comments regarding our case report published in the December 2003 issue of the journal.1 We are impressed by a similar case of ulcerative colitis complicating microcarcinoids described above.
As has been stated above, there are no established criteria that distinguish microcarcinoids from endocrine cell micronests (ECMs) occurring in the intestine. Thus, the terminology seems to be confused. However, the diagnosis of microcarcinoids in our case was based on the criteria for gastric carcinoids reported by Itsuno et al.2 For an analysis of autoimmune gastritis, Itsuno and colleagues2 defined microcarcinoids as lesions composed of endocrine cells over 0.5 mm, and ECMs as lesions between 0.1 and 0.5 mm in size. Because all the lesions in our case measured over 0.5 mm, and they consisted of crowding micronests, we judged them to be “microcarcinoids”. We apologise for the insufficient descriptions provided in our report.
Although such a distinction has not been shown to be appropriate for endocrine cell tumours in the large intestine, the application of the criteria seems to be reasonable, because ECMs and microcarcinoids in both autoimmune gastritis and ulcerative colitis are probably a consequence of chronic inflammation. The clinical relevance of the distinction of microcarcinoids from ECMs for the management of ulcerative colitis needs to be evaluated further.
As has been recommended, we performed immunostaining for S-100 protein in the microcarcinoids of our case. However, the procedure failed to identify positive cells within the lesions. Thus, the association of nerve fibres is unlikely to explain the submucosal nature of the microcarcinoids in our case.
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