{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T16:39:22Z","timestamp":1788021562495,"version":"build-2784847793"},"reference-count":17,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T00:00:00Z","timestamp":1708905600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005687","name":"Goethe-Universit\u00e4t Frankfurt am Main","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005687","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Histopathology"],"published-print":{"date-parts":[[2024,5]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>The histological subtype of intrahepatic cholangiocarcinoma (iCCA) is associated with different mutational characteristics that impact clinical management. So far, data are lacking on the presence of small duct iCCA (SD\u2010iCCA) and large duct iCCA (LD\u2010iCCA) in a single patient. The aim of the current study was to determine the presence and degree of intratumoural heterogeneity of SD\u2010 and LD\u2010iCCA features in different tumour regions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>All patients treated with surgically resected iCCA at Frankfurt University Hospital between December 2005 and March 2023 were retrospectively analysed. Histomorphological features of SD\u2010 and LD\u2010iCCA were evaluated by an expert hepatobiliary pathologist. Tissue samples suspicious for subtype heterogeneity were further investigated. Immunohistochemistry for N\u2010cadherin, S100P, MUC5AC, MUC6, TFF1 and AGR2 and mutational profiling with the Illumina TruSight Oncology 500 (TSO500) assay were performed separately for the SD\u2010 and LD\u2010iCCA regions. Of 129 patients with surgically resected iCCA, features of either SD\u2010 or LD\u2010iCCA were present in 67.4% (<jats:italic>n<\/jats:italic>\u2009=\u200987) and 24.8% of the patients (<jats:italic>n<\/jats:italic>\u2009=\u200932), respectively; 7.8% (<jats:italic>n<\/jats:italic>\u2009=\u200910) had histomorphological features of both SD\u2010 and LD\u2010iCCA, seven patients (5.4%) of which had sufficient formalin\u2010fixed, paraffin\u2010embedded tissue for further analysis. Heterogeneity of both subtypes could be confirmed with immunohistochemistry. In five of seven (71.4%) patients, molecular profiling revealed intratumoural differences in genetic alterations between the SD\u2010 and LD\u2010iCCA region. In one patient, a BRAF mutation (p.V600E) was found in the SD\u2010iCCA but not in the LD\u2010iCCA region of the tumour.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>A marked portion of patients with iCCA exhibits both SD\u2010 and LD\u2010iCCA in different tumour regions. In case of the presence of histopathological heterogeneity, mutational profiling should be considered to avoid missing therapeutically relevant genetic alterations.<\/jats:p><\/jats:sec>","DOI":"10.1111\/his.15162","type":"journal-article","created":{"date-parts":[[2024,2,27]],"date-time":"2024-02-27T06:09:49Z","timestamp":1709014189000},"page":"1061-1067","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Heterogeneity of small duct\u2010 and large duct\u2010type intrahepatic cholangiocarcinoma"],"prefix":"10.1111","volume":"84","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2378-1455","authenticated-orcid":false,"given":"Maximilian N","family":"Kinzler","sequence":"first","affiliation":[{"name":"Goethe University Frankfurt University Hospital, Medical Clinic 1  Frankfurt am Main 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Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"Gretser","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt University Hospital, Dr Senckenberg Institute of Pathology  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Bein","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt University Hospital, Dr Senckenberg Institute of Pathology  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"Finkelmeier","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt University Hospital, Medical Clinic 1  Frankfurt am Main Germany"},{"name":"Frankfurt Cancer Institute (FCI) Goethe University Frankfurt  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg","family":"Trojan","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt University Hospital, Medical Clinic 1  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Zeuzem","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt University Hospital, Medical Clinic 1  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas A","family":"Schnitzbauer","sequence":"additional","affiliation":[{"name":"Department of General, Visceral, Transplant and Thoracic Surgery Goethe University Frankfurt, University Hospital  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie C","family":"Demes","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt University Hospital, Dr Senckenberg Institute of Pathology  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henning","family":"Reis","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt University Hospital, Dr Senckenberg Institute of Pathology  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J","family":"Wild","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt University Hospital, Dr Senckenberg Institute of Pathology  Frankfurt am Main Germany"},{"name":"Frankfurt Cancer Institute (FCI) Goethe University Frankfurt  Frankfurt am Main Germany"},{"name":"Frankfurt Institute for Advanced Studies (FIAS)  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2309-9624","authenticated-orcid":false,"given":"Dirk","family":"Walter","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt University Hospital, Medical Clinic 1  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