Adenomyoma/adenomyomatosis-associated mural intracholecystic neoplasms: analysis of clinico-pathologic, imaging, and molecular features of a consecutive case series.

Adenomyoma/adenomyomatosis (AM) of the gallbladder is generally considered an incidental and innocuous finding; however, neoplastic lesions, including intracholecystic neoplasms (ICNs), flat-type dysplasia, and carcinomas, may arise within AM. AM-associated ICNs, composed of mural cystically dilated glands containing florid papillary proliferations lined by mucinous and/or overtly dysplastic epithelium, are very rare and poorly characterized. This study aimed at investigating the clinico-radiologic, phenotypic/immunophenotypic, and molecular features of a mono-institutional case series of four AM-ICNs (0.2% of cholecystectomies). Immunohistochemistry for CDX2, MUC2, MUC5AC, MUC6, MUC1, HER2, ß-catenin, and p53, as well as next-generation sequencing of 110 tumor-related genes (AmoyDx® Comprehensive Panel), were performed. Our study confirms the AM-ICN-associated clinico-demographic characteristics previously described, including the relatively low frequency of associated invasive carcinoma (one case, 25%), although high-grade dysplasia (HGD) was observed in three out of four cases. In two cases, imaging findings suspicious for neoplasm were seen. Segmental-type AM was seen in two cases. Predominantly cell phenotype was gastric foveolar in two AM-ICNs and pancreatobiliary in the other two cases (both with HGD), while the immunophenotype was hybrid/mixed in all cases. No case had nuclear ß-catenin expression nor Wnt pathway or KRAS gene alterations. One case showed both HER2 point mutation and HER2 amplification, while the AM-ICN associated with an invasive adenocarcinoma harbored TP53 mutation and p53 overexpression. In conclusion, our findings suggest the separation of AM-ICNs from other gallbladder dysplastic lesions.