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We examined a prevalence of FGFR2 genetic alterations and their clinicopathological significance in combined hepatocellular\u2013cholangiocarcinoma (cHCC-CCA). FGFR2 expression, which is a surrogate marker for FGFR2 genetic alterations, was immunohistochemically assessed in the liver sections from 75 patients with cHCC-CCA, 35 with small duct-type iCCA, 30 with large duct-type iCCA, and 35 with hepatocellular carcinoma (HCC). FGFR2 genetic alterations were detected by reverse transcription-PCR and direct sequence. An association of FGFR2 expression with clinicopathological features was investigated in cHCC-CCAs. FGFR2 expression was detected in significantly more patients with cHCC-CCA (21.3%) and small duct-type iCCA (25.7%), compared to those with large duct-type iCCA (3.3%) and HCC (0%) (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). FGFR2-positive cHCC-CCAs were significantly smaller size (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05), with more predominant cholangiolocarcinoma component (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01) and less nestin expression (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Genetic alterations of ARID1A and BAP1 and multiple genes were significantly more frequent in FGFR2-positive cHCC-CCAs (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). 5\u2032\/3\u2032 imbalance in FGFR2 genes indicating exon18-truncated FGFR2 was significantly more frequently detected in FGFR2-positive cHCC-CCAs and small duct iCCAs, compared to FGFR2-negative ones (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). <jats:italic>FGFR2::BICC<\/jats:italic> fusion was detected in a case of cHCC-CCAs. FGFR2 genetic alterations may be prevalent in cHCC-CCAs as well as small duct-type iCCAs, which suggest cHCC-CCAs may also be a possible therapeutic target of FGFR2 inhibitors.<\/jats:p>\n                <jats:p><jats:bold>Graphical Abstract<\/jats:bold><\/jats:p>","DOI":"10.1007\/s00428-024-03792-x","type":"journal-article","created":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T02:01:30Z","timestamp":1711504890000},"page":"915-923","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Expression of fibroblast growth factor receptor 2 (FGFR2) in combined hepatocellular-cholangiocarcinoma and intrahepatic cholangiocarcinoma: clinicopathological study"],"prefix":"10.1007","volume":"484","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2514-760X","authenticated-orcid":false,"given":"Motoko","family":"Sasaki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasunori","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuni","family":"Nakanuma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,27]]},"reference":[{"key":"3792_CR1","unstructured":"Sempoux C, Kakar S, Kondo F, Schirmacher P (2019) Combined hepatocellular-cholangiocarcinoma and undifferentiated primary liver carcinoma. 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The work described herein was conducted in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Informed consent was obtained for experimentation with human subjects.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Informed consent was obtained for experimentation with human subjects.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}