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Aims: Patients with Crohn's disease (CrD) have an elevated risk for the development of small bowel adenocarcinomas (SBAs). Actionable isocitrate dehydrogenase 1 (IDH1) mutations have been reported to be more frequent in CrD-SBAs than in sporadic SBAs. The present study aimed to investigate the clinicopathological and immunophenotypical features, as well as methylation profiles, of IDH1-mutated CrD-SBAs., Methods and Results: An international multicentre series of surgically resected CrD-SBAs was tested for IDH1 mutation. Clinicopathological features, immunophenotypical marker expression and O6-methylguanine-DNA methyltransferase (MGMT) and long interspersed nuclear element-1 (LINE-1) methylation were compared between IDH1-mutated and IDH1 wild-type CrD-SBAs. Ten (20%) of the 49 CrD-SBAs examined harboured an IDH1 mutation and all the mutated cancers harboured the R132C variant. Compared to IDH1 wild-type cases, IDH1-mutated CrD-SBAs showed significantly lower rates of cytokeratin 7 expression (P = 0.005) and higher rates of p53 overexpression (P = 0.012) and MGMT methylation (P = 0.012). All three dysplastic growths associated with IDH1-mutated SBAs harboured the same IDH1 variant (R132C) of the corresponding invasive cancer, and all were of non-conventional subtype (two serrated dysplastic lesions and one goblet cell-deficient dysplasia). In particular, non-conventional serrated dysplasia was significantly associated with IDH1-mutated CrD-SBAs (P = 0.029). No significant cancer-specific survival difference between IDH1-mutated CrD-SBA patients and IDH1 wild-type CrD-SBA patients was found (hazard ratio = 0.55, 95% confidence interval = 0.16-1.89; P = 0.313)., Conclusions: IDH1-mutated CrD-SBAs, which represent approximately one-fifth of total cases, are characterised by distinctive immunophenotypical features and methylation profiles, with potential therapeutic implications. Moreover, IDH1-mutated non-conventional, serrated dysplasia is likely to represent a precursor lesion to such CrD-SBAs., (© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Non-ampullary small bowel adenocarcinoma is a rare neoplasm with an ominous prognosis, whose incidence is higher in some chronic immuno-inflammatory conditions, such as coeliac and Crohn's disease. Recently, claudin 18.2, a transmembrane protein normally expressed in gastric mucosa, has been recognized as a novel pan-cancer therapeutic target, and several clinical trials with claudin-18-directed drugs have shown promising results on various gastrointestinal malignancies. This is the first study focusing on claudin-18 expression in small bowel adenocarcinomas. The immunohistochemical expression of claudin-18 (clone 43-14A) was assessed in 81 small bowel adenocarcinomas of diverse aetiologies and correlated with several clinico-pathologic features and patient survival. We found that 28% of adenocarcinomas were immunoreactive for claudin-18, with cutoff values of ≥1% at any intensity, while 6% of cancers showed immunoexpression of ≥75% with 2+/3+ score. Moreover, claudin-18 (≥1%) was positively associated with cytokeratin 7 (CK7) and MUC5AC expression, showing CK7+/MUC5AC+ carcinomas the highest rate of positive cases, whereas a negative correlation was found between claudin-18 and CDX2 expression. In addition, some cancer-adjacent dysplastic growths and foci of gastric-type metaplasia in Crohn's disease-associated cases showed claudin-18 immunoreactivity. Survival analysis showed a non-significant trend towards a worse cancer-specific survival for claudin-18-positive cases. A fraction of small bowel adenocarcinomas, mainly sporadic or Crohn's disease-associated, and often exhibiting a non-intestinal immunoprofile, expressed claudin-18, suggesting that claudin-18-directed targeted therapy is worth investigating in such cancers., (© 2022. The Author(s).)

In this paper, we will continue the description of histological findings of infantile and paediatric small bowel alterations with the main clinical pictures and differential diagnosis. We emphasise once again the need to evaluate the biopsies in an adequate clinical contest and with a systematic approach, including epithelial alterations, lamina propria changes, mucosal architecture, and the distribution of inflammation, together with other morphological signs more specific of certain diseases. We describe the histological findings of coeliac and Crohn's disease, gastrointestinal food allergic diseases, Langerhans cell histiocytosis, nutritional deficiencies and infections. Finally, we suggest the principal issues in the drafting the pathological report for appropriate interpretation and usefulness in clinical practice., (Copyright © 2022 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Most Crohn's disease-associated small bowel carcinomas (CrD-SBCs) are diagnosed in advanced stage and have poor prognosis. To improve diagnosis and therapy, a better knowledge of tumour precancerous lesions, histotypes and prognostic factors is needed. We investigated histologically and immunohistochemically 52 CrD-SBCs and 51 small bowel carcinomas unrelated to inflammatory disease, together with their tumour-associated mucosa, looking for Crohn-selective changes. Histologic patterns and phenotypic markers potentially predictive of CrD-SBC histogenesis and prognosis were analysed. Cytokeratin 7 or MUC5AC-positive metaplastic changes were found in about half of investigated CrD-SBCs, significantly more frequently than in CrD-unrelated SBCs. They correlated with metaplastic changes of their associated mucosa, while being absent in normal ileal mucosa. Histologic patterns suggestive for progression of some cytokeratin 7 and/or MUC5AC-positive metaplastic lesions into cancer of the same phenotype were also observed. Patient survival analyses showed that tumour cytokeratin 7 or MUC5AC expression and non-cohesive histotype were adverse prognostic factors at univariable analysis, while cytokeratin 7 and non-cohesive histotype were also found to predict worse survival in stage- and age-inclusive multivariable analyses. Besides conventional dysplasia, hyperplasia-like non-conventional lesions were observed in CrD-SBC-associated mucosa, with patterns suggestive for a histogenetic link with adjacent cancer. In conclusion the cytokeratin 7 and/or MUC5AC-positive metaplastic foci and the non-conventional growths may have a role in cancer histogenesis, while tumour cytokeratin 7 and non-cohesive histotype may also predict poor patient survival. Present findings are worth being considered in future prospective histogenetic and clinical studies., (© 2021. The Author(s).)

Background and Aims: Crohn's disease-associated small bowel carcinoma is a rare event, usually reported to have a severe prognosis. However, in previous investigations we have found a minority of cases displaying a relatively favourable behaviour, thus outlining the need to improve the histopathological prediction of Crohn's disease-associated small bowel carcinoma prognosis., Methods: As in recent studies on colorectal cancer, a substantial improvement in prognostic evaluations has been provided by the histological analysis of the tumour invasive front; we therefore systematically analysed the tumour budding and poorly differentiated clusters in the invasive front of 47 Crohn's disease-associated small bowel carcinomas collected through the Small Bowel Cancer Italian Consortium., Results: Both tumour budding and poorly differentiated cluster analyses proved highly effective in prognostic evaluation of Crohn's disease-associated small bowel carcinomas. In addition, they retained prognostic value when combined with two other parameters, i.e. glandular histology and stage I/II, both known to predict a relatively favourable small bowel carcinoma behaviour. In particular, association of tumour budding and poorly differentiated clusters in a combined invasive front score allowed identification of a minor subset of cancers [12/47, 25%] characterised by combined invasive front low grade coupled with a glandular histology and a low stage [I or II] and showing no cancer-related death during a median follow-up of 73.5 months., Conclusions: The improved distinction of lower- from higher-grade Crohn's disease-associated small bowel carcinomas provided by invasive front analysis should be of potential help in choosing appropriate therapy for these rare and frequently ominous neoplasms., (Copyright © 2019 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)