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Cholangiolocellular Component Predicts a Biologically Distinct Subgroup of Mass‐Forming Intrahepatic Cholangiocarcinoma
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Cholangiolocellular Component Predicts a Biologically Distinct Subgroup of Mass‐Forming Intrahepatic Cholangiocarcinoma
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Cholangiolocellular Component Predicts a Biologically Distinct Subgroup of Mass‐Forming Intrahepatic Cholangiocarcinoma
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Journal Article
Cholangiolocellular Component Predicts a Biologically Distinct Subgroup of Mass‐Forming Intrahepatic Cholangiocarcinoma
2026
Overview
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.
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