Small bowel carcinomas in celiac or Crohn's disease: distinctive histophenotypic, molecular and histogenetic patterns

Abstract

Non-familial small bowel carcinomas are relatively rare and have a poor prognosis. Two small bowel carcinoma subsets may arise in distinct immune-inflammatory diseases (celiac disease and Crohn's disease) and have been recently suggested to differ in prognosis, celiac disease-associated carcinoma cases showing a better outcome, possibly due to their higher DNA microsatellite instability and tumor-infiltrating T lymphocytes. In this study, we investigated the histological structure (glandular vs diffuse/poorly cohesive, mixed or solid), cell phenotype (intestinal vs gastric/pancreatobiliary duct type) and Wnt signaling activation (β-catenin and/or SOX-9 nuclear expression) in a series of 26 celiac disease-associated small bowel carcinoma, 25 Crohn's disease-associated small bowel carcinoma and 25 sporadic small bowel carcinoma cases, searching for new prognostic parameters. In addition, non-tumor mucosa of celiac and Crohn's disease patients was investigated for epithelial precursor changes (hyperplastic, metaplastic or dysplastic) to help clarify carcinoma histogenesis. When compared with non-glandular structure and non-intestinal phenotype, both glandular structure and intestinal phenotype were associated with a more favorable outcome at univariable or stage- and microsatellite instability/tumor-infiltrating lymphocyte-inclusive multivariable analysis. The prognostic power of histological structure was independent of the clinical groups while the non-intestinal phenotype, associated with poor outcome, was dominant among Crohn's disease-associated carcinoma. Both nuclear β-catenin and SOX-9 were preferably expressed among celiac disease-associated carcinomas; however, they were devoid, per se, of prognostic value. We obtained findings supporting an origin of celiac disease-associated carcinoma in SOX-9-positive immature hyperplastic crypts, partly through flat β-catenin-positive dysplasia, and of Crohn's disease-associated carcinoma in a metaplastic (gastric and/or pancreatobiliary-type) mucosa, often through dysplastic polypoid growths of metaplastic phenotype. In conclusion, despite their common origin in a chronically inflamed mucosa, celiac disease-associated and Crohn's disease-associated small bowel carcinomas differ substantially in histological structure, phenotype, microsatellite instability/tumor-infiltrating lymphocyte status, Wnt pathway activation, mucosal precursor lesions and prognosis.

Separation of Low- Versus High-grade Crohn’s Disease-associated Small Bowel Carcinomas is Improved by Invasive Front Prognostic Marker Analysis

“…glandular histotype] in comparison with its loss to form diffuse or mixed cancerous growths, as already suggested in a previous investigation of a smaller series. 1 In addition to this architectural evaluation on the whole cancer tissue, we found that selective investigation of the tumour invasive front for foci of Tb and/or PDCs substantially improved separation of more from less aggressive cases. Moreover, a significant association of Tb and PDC with lymph node metastases was found.…”

“…This retrospective study included 47 patients with primary non-ampullary CrD-SBCs, mostly from the ileum [n = 44], two from the jejunum, and one from the duodenum. The patients, some of whom have been partly studied in previous series, 1,2,14 had surgical resection and complete survival data from 15 tertiary referral Italian inflammatory bowel disease centres participating in the Small Bowel Cancer Italian Consortium. Neuroendocrine neoplasms were excluded.…”

“…15 Tumour histotype was classified as: a] glandular, b] diffuse, c] mixed [glandular plus diffuse], d] medullary, and e] non-medullary solid types, as previously described. 1,18 Two cases resembling in part medullary cancers, one of which was Epstein Barr virus-positive and reinterpreted as lymphoepithelioma-like cancer, 19 were omitted from this study, as recommended by Lugli et al, 9 owing to technical difficulties in assessing Tb and PDC status. WHO tumour grade was based on the proportion of gland formation and categorised as grade 1 [well differentiated, >95%], grade 2 [moderately differentiated, 50% to 95%], or grade 3 [poorly differentiated, 0% to 49%].…”

“…A previous study of small bowel carcinomas [SBCs] by our group found that glandular versus non-glandular histology and density of tumour-infiltrating T lymphocytes [TILs] were significant predictors of patient survival. 1 The underlying immune-mediated predisposing disorder was also of prognostic value in SBCs; indeed, coeliac disease-associated cancers show a more favourable outcome than those associated with Crohn's disease [CrD]. 2,3 CrD-associated SBC [CrD-SBC] as a whole showed poor prognosis [5-year overall survival rate: 26-38%], 3 and this is partly due to the advanced stage at diagnosis and to their often incidental finding at surgical resection for bowel stricture.…”

“…4,5 However, we recently identified a smaller histological subset of CrD-SBCs, especially among those showing glandular differentiation, which was associated with less aggressive disease. 1 The identification of factors which may improve the histopathological prediction of CrD-SBC prognosis is lacking, up till now.…”