Diversity in cell differentiation, histology, phenotype and vasculature of mass-forming intrahepatic cholangiocarcinomas.

AIMS Mass-forming intrahepatic cholangiocarcinomas (MF-iCCAs), involving small bile ducts, bile ductules, or canals of Hering, remain treated as a single entity. We aimed to examine the diversity in histology, phenotype, and tumor vasculature of MF-iCCAs. METHODS AND RESULTS Based on morphology and immunophenotype, we classified MF-iCCAs into small bile duct (SBD), cholangiolocarcinoma (CLC), ductal plate malformation (DPM), and hepatocellular carcinoma (HCC)-like subtypes. Genetic correlations among the histological subtypes were examined by multi-region tumor sequencing. Vasculatures and other clinicopathological features were compared among tumor groups with various proportions of the histological subtypes in 62 MF-iCCAs. Cases of pure SBD, CLC, DPM, and HCC-like subtypes numbered 18 (29%), 7 (11.3 %), 0 (0%) and 2 (3%), respectively; the remaining 35 (56.4%) cases comprised several components. Genetic alterations, IDH1/2, KRAS, TP53, PBRM1 and BAP1, were shared among SBD, CLC, DPM and hepatoid components within a tumor. We uncovered distinct vascularization mechanisms among SBD, CLC and DPM subtypes with a prominent vessel co-option in CLC tumors. iCCA with DPM pattern had the highest vascular densities (mean microvascular density,140/mm2; arterial vessel density, 18.3/mm2). Increased CLC component was correlated with longer overall survival time (r =0.44, P =0.006). Pure SBD tumors had a lower 5-year overall survival rate, compared with MF-iCCA with CLC pattern (30.5% vs. 72.4%, P = 0.011). CONCLUSIONS MF-iCCAs comprise four histological subtypes. Given their sharing some driver gene alterations, indicating they can have a common cell origin, SBD, CLC and DPM subtypes, however, differ in cell differentiation, histology, phenotype or tumor vasculature.