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Among the EP-SCNC cohort, <jats:italic>HER2<\/jats:italic> mutations were found in 5.5% of samples (7\/128); urinary bladder (4 cases), and one case each in samples from the colon, anal canal, and uterine cervix. In SCLCs, <jats:italic>HER2<\/jats:italic> mutations were rare, detected in only 0.8% (1\/119) of cases. We also identified eight EP-SCNCs and five SCLC cases with <jats:italic>HER2<\/jats:italic> gene variants of uncertain significance (VUS). <jats:italic>HER2<\/jats:italic> gene amplification was detected in 2.3% (3\/128) of EP-SCNCs, but no amplification was found in SCLCs. The differences in <jats:italic>HER2<\/jats:italic> mRNA expression were not statistically significant among tumor groups in the EP-SCNCs and SCLCs cohorts. RNA-seq analysis revealed high <jats:italic>HER2<\/jats:italic> mRNA expression in seven EP-SCNCs and four SCLCs. An immunohistochemistry (IHC) analysis of 10 available tumors with high mRNA expression revealed HER2 protein positivity in 8 cases. The prognostic value of HER2 overexpression in EP-SCNC patients was not established in our study. Furthermore, EP-SCNC patients with high <jats:italic>HER2<\/jats:italic> mRNA expression were generally younger, with a mean age of 60\u00a0years. These findings highlight the potential of HER2 as a therapeutic target in EP-SCNC, warranting further investigation into its clinical implications.<\/jats:p>","DOI":"10.1007\/s00428-025-04285-1","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T16:04:48Z","timestamp":1760457888000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["HER2 aberration is a potential predictive biomarker for extrapulmonary small cell neuroendocrine carcinoma contrary to small cell lung cancer"],"prefix":"10.1007","author":[{"given":"Nikola","family":"H\u00e1jkov\u00e1","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kl\u00e1ra","family":"Pavl\u00ed\u010dkov\u00e1","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji\u0159\u00ed","family":"Dvo\u0159\u00e1k","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Hojn\u00fd","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Krkavcov\u00e1","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petr","family":"Waldauf","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pavel","family":"Dundr","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie","family":"Dr\u00f6sslerov\u00e1","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mari\u00e1n","family":"\u0160vajdler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pavel","family":"Fabian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miroslava","family":"Fl\u00eddrov\u00e1","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Hrudka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6152-6343","authenticated-orcid":false,"given":"Radoslav","family":"Mat\u011bj","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,10,14]]},"reference":[{"issue":"4","key":"4285_CR1","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1002\/cncr.31124","volume":"124","author":"A Dasari","year":"2018","unstructured":"Dasari A, Mehta K, Byers LA, Sorbye H, Yao JC (2018) Comparative study of lung and extrapulmonary poorly differentiated neuroendocrine carcinomas: a SEER database analysis of 162,983 cases. 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