{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T14:05:03Z","timestamp":1789567503644,"version":"build-2803163510"},"reference-count":19,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003042","name":"Else Kr\u00f6ner-Fresenius-Stiftung","doi-asserted-by":"publisher","award":["2020_EKEA.129"],"award-info":[{"award-number":["2020_EKEA.129"]}],"id":[{"id":"10.13039\/501100003042","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003042","name":"Else Kr\u00f6ner-Fresenius-Stiftung","doi-asserted-by":"publisher","award":["2023_EKES.07"],"award-info":[{"award-number":["2023_EKES.07"]}],"id":[{"id":"10.13039\/501100003042","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003042","name":"Else Kr\u00f6ner-Fresenius-Stiftung","doi-asserted-by":"publisher","award":["2024_EKCS.08"],"award-info":[{"award-number":["2024_EKCS.08"]}],"id":[{"id":"10.13039\/501100003042","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","award":["70116777"],"award-info":[{"award-number":["70116777"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","award":["70116778"],"award-info":[{"award-number":["70116778"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","award":["70116726"],"award-info":[{"award-number":["70116726"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["CA230411"],"award-info":[{"award-number":["CA230411"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008672","name":"Wilhelm Sander-Stiftung","doi-asserted-by":"publisher","award":["Nr. 2024.022.1"],"award-info":[{"award-number":["Nr. 2024.022.1"]}],"id":[{"id":"10.13039\/100008672","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001652","name":"Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg","doi-asserted-by":"publisher","award":["IZKF\u2010FAU D41"],"award-info":[{"award-number":["IZKF\u2010FAU D41"]}],"id":[{"id":"10.13039\/501100001652","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001652","name":"Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg","doi-asserted-by":"publisher","award":["IZKF\u2010FAU D45"],"award-info":[{"award-number":["IZKF\u2010FAU D45"]}],"id":[{"id":"10.13039\/501100001652","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Histopathology"],"abstract":"<jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Small cell carcinoma of the bladder (SmCCB) is a rare and aggressive malignancy that remains poorly defined. Using the transcriptional taxonomy established for small cell lung carcinoma (SCLC), we aimed to stratify SmCCB by dominant transcription factors and assess associations between IHC\u2010defined phenotype, neuroendocrine differentiation and therapeutic biomarker expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>\n                      A retrospective multi\u2010institutional cohort of 88 SmCCBs was assembled. Of these, 79 cases underwent immunohistochemical characterization for ASCL1, NEUROD1, POU2F3, YAP1 and HNF4\u03b1, along with classical neuroendocrine markers, therapeutic biomarkers and antibody\u2013drug conjugate targets. NECTIN4 amplification was also assessed by fluorescence in situ hybridization (FISH). Six IHC\u2010defined subgroups were identified: ASCL1\u2010driven (41.8%), NEUROD1\u2010driven (25.3%), POU2F3\u2010driven (20.3%), YAP1\u2010driven (6.3%), mixed (5.1%) and full\u2010negative (1.3%). ASCL1\u2010driven, NEUROD1\u2010driven and mixed tumours were classified as\n                      <jats:italic>High\u2010NE<\/jats:italic>\n                      , with diffuse NE marker expression, whereas POU2F3\u2010driven, YAP1\u2010driven and full\u2010negative tumours were classified as\n                      <jats:italic>Low\u2010NE<\/jats:italic>\n                      , with weak or absent expression. Overall membranous Nectin\u20104 expression was low or absent but significantly higher in\n                      <jats:italic>Low\u2010NE<\/jats:italic>\n                      tumours (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.001).\n                      <jats:italic>NECTIN4<\/jats:italic>\n                      amplification occurred in 21.9% (16\/73), comparable to that reported in non\u2010neuroendocrine urothelial carcinoma. Conversely, DLL3 and SLFN11 were significantly overexpressed in\n                      <jats:italic>High\u2010NE<\/jats:italic>\n                      tumours, while expression of the remaining targets was almost entirely absent.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      SmCCB may be stratified into two IHC\u2010defined phenotypic groups with distinctive neuroendocrine differentiation and therapeutic biomarker profiles. Taken together, low membranous Nectin\u20104 expression and preferential DLL3 and SLFN11 expression in\n                      <jats:italic>High\u2010NE<\/jats:italic>\n                      tumours support further investigation of alternative therapeutic strategies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/his.70284","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T13:16:22Z","timestamp":1789564582000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immunohistochemical stratification of bladder small cell carcinoma reveals two major phenotypes with distinct therapeutic biomarker profiles"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8143-7292","authenticated-orcid":false,"given":"Nazario P","family":"Tenace","sequence":"first","affiliation":[{"name":"Pathology Unit IRCCS San Raffaele Scientific Institute  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1914-0743","authenticated-orcid":false,"given":"Maurizio","family":"Colecchia","sequence":"additional","affiliation":[{"name":"Pathology Unit IRCCS San Raffaele Scientific Institute  Milan Italy"},{"name":"Vita\u2010Salute San Raffaele University  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4860-4626","authenticated-orcid":false,"given":"Arndt","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Institute of Pathology University Hospital Erlangen, Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg (FAU)  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0055-325X","authenticated-orcid":false,"given":"Maurilio","family":"Ponzoni","sequence":"additional","affiliation":[{"name":"Pathology Unit IRCCS San Raffaele Scientific Institute  Milan Italy"},{"name":"Vita\u2010Salute San Raffaele University  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4969-5216","authenticated-orcid":false,"given":"Claudio","family":"Doglioni","sequence":"additional","affiliation":[{"name":"Pathology Unit IRCCS San Raffaele Scientific Institute  Milan Italy"},{"name":"Vita\u2010Salute San Raffaele University  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0808-1232","authenticated-orcid":false,"given":"Sebastian","family":"Rauch","sequence":"additional","affiliation":[{"name":"Institute of Pathology University Hospital Erlangen, Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg (FAU)  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3084-2458","authenticated-orcid":false,"given":"Marco","family":"Moschini","sequence":"additional","affiliation":[{"name":"Department of Urology and Division of Experimental Oncology, URI, Urological Research Institute IRCCS San Raffaele Scientific Institute  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3007-2756","authenticated-orcid":false,"given":"Andrea","family":"Necchi","sequence":"additional","affiliation":[{"name":"Vita\u2010Salute San Raffaele University  Milan Italy"},{"name":"Department of Medical Oncology IRCCS San Raffaele Hospital, Vita\u2010Salute San Raffaele University  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2178-0494","authenticated-orcid":false,"given":"Alberto","family":"Briganti","sequence":"additional","affiliation":[{"name":"Vita\u2010Salute San Raffaele University  Milan Italy"},{"name":"Department of Urology and Division of Experimental Oncology, URI, Urological Research Institute IRCCS San Raffaele Scientific Institute  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7267-4181","authenticated-orcid":false,"given":"Francesco","family":"Montorsi","sequence":"additional","affiliation":[{"name":"Vita\u2010Salute San Raffaele University  Milan Italy"},{"name":"Department of Urology and Division of Experimental Oncology, URI, Urological Research Institute IRCCS San Raffaele Scientific Institute  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5418-3349","authenticated-orcid":false,"given":"Markus","family":"Eckstein","sequence":"additional","affiliation":[{"name":"Institute of Pathology University Hospital Erlangen, Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg (FAU)  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"crossref","DOI":"10.1177\/23523735251370956","article-title":"Small cell carcinoma of the bladder: review of pathogenesis, presentation, and management","volume":"11","author":"Simon NI","year":"2025","journal-title":"Bladder Cancer"},{"key":"e_1_2_9_3_1","volume-title":"Urinary and male genital tumours","author":"WHO Classification of Tumours Editorial 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Oncol."},{"key":"e_1_2_9_20_1","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1016\/j.ccell.2024.06.006","article-title":"Targeting the mSWI\/SNF complex in POU2F\u2010POU2AF transcription factor\u2010driven malignancies","volume":"42","author":"He T","year":"2024","journal-title":"Cancer Cell"}],"container-title":["Histopathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/his.70284","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/his.70284","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/his.70284","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T13:16:26Z","timestamp":1789564586000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/his.70284"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,16]]},"references-count":19,"alternative-id":["10.1111\/his.70284"],"URL":"https:\/\/doi.org\/10.1111\/his.70284","archive":["Portico"],"relation":{},"ISSN":["0309-0167","1365-2559"],"issn-type":[{"value":"0309-0167","type":"print"},{"value":"1365-2559","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,16]]},"assertion":[{"value":"2026-08-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"his.70284"}}