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 tumour 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 tumour sequencing. Vasculatures and other clinicopathological features were compared among tumour 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%), seven (11.3%), none (0%) and two (3%), respectively; the remaining 35 (56.4%) cases comprised several components. Genetic alterations, isocitrate dehydrogenase (IDH)1/2, KRAS, TP53, polybromo‐1 (PBRM1) and BRCA1‐associated protein 1 (BAP1), were shared among SBD, CLC, DPM and hepatoid components within a tumour. We uncovered distinct vascularisation mechanisms among SBD, CLC and DPM subtypes with a prominent vessel co‐option in CLC tumours. iCCA with a DPM pattern had the highest vascular densities (mean microvascular density,140/mm 2 ; arterial vessel density, 18.3/mm 2 ). Increased CLC component was correlated with longer overall survival time ( r = 0.44, P = 0.006). Pure SBD tumours had a lower 5‐year overall survival rate compared with MF‐iCCA with CLC pattern (30.5 versus 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 tumour vasculature.