Gross Intrahepatic Mass Formation Predicts the Primary Site of Perihilar Cholangiocarcinoma Based on Molecular Pathologic Studies

Background/Purpose Intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA) are clinically and genetically distinct. However, the classification of perihilar cholangiocarcinoma (phCCA) with an intrahepatic tumor mass remains unclear. This study aimed to position phCCA near the hilar plate (hCCA) within an extrahepatic–intrahepatic framework using pathological and molecular analyses. Methods Among 357 resected invasive CCAs, 100 hCCAs were histologically classified as either hCCA with (hCCA‐M) or hCCA without (hCCA‐NM) a grossly evident intrahepatic mass. Transcriptomic comparison of 9 typical eCCAs and 39 mass‐forming iCCAs identified three contextual markers, which were examined by immunohistochemistry in 309 additional cases. Results Among 100 hCCAs, 85 were hCCA‐NM and 15 hCCA‐M. Claudin 18 (CLDN18) and mesothelin (MSLN) were identified as extrahepatic contextual markers, and serpin family A member 1 (SERPINA1) as an intrahepatic contextual marker. SERPINA1 was more highly expressed in hCCA‐M than in hCCA‐NM, regardless of microscopic liver parenchymal invasion, whereas CLDN18 and MSLN were similarly expressed in both. Cluster analysis revealed that hCCA‐NM clustered with eCCA, whereas hCCA‐M clustered with iCCA. Conclusions Gross intrahepatic mass formation indicates an intrahepatic contextual profile and provides a useful criterion for subclassifying hCCA. This contextual framework shows that hCCA‐M and hCCA‐NM represent biologically distinct tumor groups.