Comparison of Albumin In-Situ Hybridization in Genetically Characterized Cholangiocarcinoma and Tumors of Other Origins.

Abstract

Intrahepatic cholangiocarcinoma is a rare liver cancer that is difficult to diagnose due to its morphologic and immunophenotypic overlap with metastatic tumors from other primary sites, a challenge further complicated by the liver's role as one of the most common destinations for metastatic spread. FGFR fusions and IDH1/2 mutations are characteristic of intrahepatic cholangiocarcinoma, and recent studies have shown that inhibitors targeting these alterations significantly improve survival. However, diagnosis remains challenging and often relies on molecular techniques that are not universally available, limiting the potential impact of these therapies. Albumin mRNA in situ hybridization (albumin ISH) is a well-established test that aids in the diagnosis of cholangiocarcinoma, yet its expression level has not been systematically evaluated in relation to tumor genetic background. Using a cohort of 63 cholangiocarcinomas and 157 tumors of other origins, we demonstrate that nearly all (93%) cholangiocarcinomas with FGFR fusions and IDH1/2 mutations (8 and 20 cases, respectively) showed strong albumin ISH positivity, whereas tumors with other characteristic cholangiocarcinoma alterations in BAP1, ARID1A, or PBRM1 were less likely to be positive and showed comparatively weaker expression. These findings suggest that albumin ISH may serve as a valuable screening tool for identifying tumors with actionable targets, while also posing an intriguing link between albumin expression and specific carcinogenesis pathways.