Comprehensive molecular-clinical profiling of cholangiocarcinoma according to pathologic subtypes

Background: Pathologically, cholangiocarcinoma (CCA) can be classified into small duct type and large duct type. This study evaluated clinical and molecular features of CCA according to its pathological subtype. Methods: We analyzed 107 patients with CCA from three independent cohorts who underwent curative surgical resection. Clinical data, gene expression profiles, and mutation status were compared between pathological subtypes. Results: Sixty four (59.8 %) and 43 (30.2 %) patients were categorized as small duct type and large duct type, respectively. The large duct type was significantly associated with N1 stage and higher preoperative serum CEA and CA 19-9 levels. Survival outcomes were significantly poorer in patients with large duct type CCA. Transcriptomic analysis identified 146 differentially expressed genes between the two subtypes, which were validated in an independent cohort. Pathway analysis demonstrated enrichment of inflammation-related and AKT/KRAS-associated signaling pathways in the large duct type. Mutation analysis showed that KRAS and PIK3CA mutations were more frequent in the large duct type, while IDH1/2 mutations and FGFR2 fusions were more common in the small duct type. Conclusions: Pathological subtypes of CCA exhibit distinct clinical outcomes and molecular characteristics. Classification based on pathological subtype provides a useful framework for understanding the clinical and molecular heterogeneity of CCA.