Cholangiolocellular Component Predicts a Biologically Distinct Subgroup of Mass‐Forming Intrahepatic Cholangiocarcinoma

Cholangiolocellular carcinoma (CLC) is a histopathological variant of primary liver tumor with unique morphologies, and intrahepatic cholangiocarcinomas (iCCAs) frequently contain a CLC component; however, the biological characteristics of iCCA with CLC remain undescribed. In this study, 36 mass-forming iCCAs (MF-iCCAs), histologically small-duct type iCCA, were classified into CLC(+) iCCAs and CLC(-) iCCAs by the presence/absence of the CLC component. Two genetic subgroups were generated using highly expressed genes in CLC(+) iCCA and CLC(-) iCCA. As the results of clinicopathological and genetic analyses, CLC(+) iCCA had better overall survival and upregulation of stromal- and oxidation-related genes, whereas CLC(-) iCCA showed upregulation of proliferation- and hypoxia-related genes. Two genetic subgroups of iCCA were identified: iCCA-G1, which was related to CLC, and iCCA-G2, which was unrelated to CLC. iCCA-G1 comprised all 14 CLC(+) iCCAs [CLC(+)G1] and 7 of 19 CLC(-) iCCAs [CLC(-)G1], whereas iCCA-G2 was composed only of CLC(-) iCCAs [CLC(-)G2]. CLC(+)G1 and CLC(-)G1 exhibited similar patterns of somatic gene alterations compared with CLC(-)G2. Angiogenesis-related genes were upregulated in CLC(+)G1, and the number of tumor vessels was larger in CLC(+)G1, followed by CLC(-)G1, compared with CLC(-)G2. Further, SPP1 (encoding osteopontin) was identified as a highly expressed angiogenesis-related gene in CLC(+) iCCA. Immunohistochemical expression of osteopontin was high in CLC(+) iCCA, showing apical and/or cytoplasmic expression patterns, which should facilitate the histopathological classification of iCCA-G1 and iCCA-G2. CLC component is useful for predicting a distinct genetic subgroup of MF-iCCA with better prognosis, high angiogenesis, and different gene alteration patterns, indicating different carcinogenic pathways of MF-iCCA.