Vanoli, Alessandro

AimsPatients 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 resultsAn 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).ConclusionsIDH1‐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.

Context.— Comprehensive genomic profiling has demonstrated that approximately 20% of pancreatic carcinomas with acinar differentiation harbor potentially targetable BRAF fusions that activate the MAPK pathway. Objectives.— To validate the above finding by BRAF break-apart fluorescence in situ hybridization (FISH) in a large series of pure acinar cell carcinomas (ACCs), evaluate tumors for the presence of BRAF V600E mutations, and compare clinicopathologic features of tumors with BRAF rearrangements with those without. Design.— Thirty cases of pure ACC and 6 cases of mixed acinar-neuroendocrine carcinoma (ACC-NEC) were retrieved. A break-apart FISH probe was used to detect BRAF rearrangements. Immunohistochemistry for BRAF V600E was performed. Results.— BRAF rearrangements by FISH were found in 6 of 36 cases (17%), 5 of which were pure ACC and 1 was a mixed ACC-NEC. Follow-up was available in 29 of 36 cases (81%). The median survival was 22 months for BRAF-rearranged cases and 16 months for BRAF-intact cases; the 2-year overall survival was 50% for BRAF-rearranged cases and 35% for BRAF-intact cases. No significant clinicopathologic differences were identified in cases with BRAF rearrangement compared with those without BRAF rearrangement. BRAF V600E mutation was identified in 2 of 34 cases (6%), both of which were pure ACC and were BRAF-intact by FISH. Conclusions.— This study supports the finding that BRAF rearrangements are present in approximately 20% of cases and identified BRAF V600E mutations in approximately 5% of cases. These cases may benefit from targeted therapy.