Loss of ARID1A Expression Presents a Novel Pathway of Carcinogenesis in Biliary Carcinomas

Objectives: Given frequent inactivating mutations in a chromatin-remodeling gene (ARID1A) in intrahepatic cholangiocarcinoma in recent exome sequencing analysis, this study investigates the clinicopathologic significance of the loss of ARID1A expression in biliary carcinomas. Methods: We examined the inactivating mutations in ARID1A by immunohistochemistry and the relationship with clinicopathologic features in 13 patients with combined hepatocellular-cholangiocarcinoma (cHC-CC), 49 with intrahepatic cholangiocarcinoma (ICC), 17 with intraductal papillary neoplasm of the bile duct (IPNB), 72 with extrahepatic cholangiocarcinoma (EHCC), and 43 with gallbladder carcinoma (GBC). Results: The loss of ARID1A expression was detected in one (7.7%) cHC-CC, nine (18.4%) ICCs, zero IPNBs, 11 (15.3%) EHCCs, and four (9.1%) GBCs. Biliary carcinomas with loss of ARID1A expression showed distinct features; all were macroscopically mass forming or a flat-infiltrating type and histologically tubular adenocarcinoma with abundant fibrous stroma. IPNB, papillary adenocarcinoma, and biliary intraepithelial neoplasia (BilIN) did not harbor loss of ARID1A expression. There was no significant correlation between loss of ARID1A expression and TNM factors or International Union Against Cancer stage. There was no biliary carcinoma harboring both loss of ARID1A expression and KRAS mutations. Conclusions: Inactivating mutations in ARID1A may be involved in a novel pathway of carcinogenesis in biliary carcinomas, which is different from the pathway via IPNB and BilIN associated with KRAS mutations.