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In this study, 36 mass\u2010forming iCCAs (MF\u2010iCCAs), histologically small\u2010duct type iCCA, were classified into CLC(+) iCCAs and CLC(\u2212) iCCAs by the presence\/absence of the CLC component. Two genetic subgroups were generated using highly expressed genes in CLC(+) iCCA and CLC(\u2212) iCCA. As the results of clinicopathological and genetic analyses, CLC(+) iCCA had better overall survival and upregulation of stromal\u2010 and oxidation\u2010related genes, whereas CLC(\u2212) iCCA showed upregulation of proliferation\u2010 and hypoxia\u2010related genes. Two genetic subgroups of iCCA were identified: iCCA\u2010G1, which was related to CLC, and iCCA\u2010G2, which was unrelated to CLC. iCCA\u2010G1 comprised all 14 CLC(+) iCCAs [CLC(+)G1] and 7 of 19 CLC(\u2212) iCCAs [CLC(\u2212)G1], whereas iCCA\u2010G2 was composed only of CLC(\u2212) iCCAs [CLC(\u2212)G2]. CLC(+)G1 and CLC(\u2212)G1 exhibited similar patterns of somatic gene alterations compared with CLC(\u2212)G2. Angiogenesis\u2010related genes were upregulated in CLC(+)G1, and the number of tumor vessels was larger in CLC(+)G1, followed by CLC(\u2212)G1, compared with CLC(\u2212)G2. Further,\n                    <jats:italic>SPP1<\/jats:italic>\n                    (encoding osteopontin) was identified as a highly expressed angiogenesis\u2010related 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\u2010G1 and iCCA\u2010G2. CLC component is useful for predicting a distinct genetic subgroup of MF\u2010iCCA with better prognosis, high angiogenesis, and different gene alteration patterns, indicating different carcinogenic pathways of MF\u2010iCCA.\n                  <\/jats:p>","DOI":"10.1111\/cas.70348","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T16:02:03Z","timestamp":1772985723000},"page":"1510-1523","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cholangiolocellular Component Predicts a Biologically Distinct Subgroup of Mass\u2010Forming Intrahepatic Cholangiocarcinoma"],"prefix":"10.1111","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1849-5078","authenticated-orcid":false,"given":"Naoto","family":"Kubota","sequence":"first","affiliation":[{"name":"Department of Molecular Pathology, Research Institute Tochigi Cancer Center  Tochigi Japan"},{"name":"Department of Pathology 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Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4215-4385","authenticated-orcid":false,"given":"Nobuyoshi","family":"Hiraoka","sequence":"additional","affiliation":[{"name":"Division of Molecular Pathology National Cancer Centre Research Institute  Tokyo Japan"},{"name":"Department of Diagnostic Pathology National Cancer Center Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirofumi","family":"Shirakawa","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Research Institute Tochigi Cancer Center  Tochigi Japan"},{"name":"Department of Hepato\u2010Biliary\u2010Pancreatic Surgery Tochigi Cancer Center  Tochigi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moriaki","family":"Tomikawa","sequence":"additional","affiliation":[{"name":"Department of Hepato\u2010Biliary\u2010Pancreatic Surgery Tochigi Cancer Center  Tochigi 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