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Here we analyzed six cases, including pure and mixed forms with adenocarcinoma, using histopathology, immunohistochemistry, next-generation sequencing, and genome-wide DNA methylation profiling. Morphologically, prominent intraductal extension of NECa was a frequent and striking feature. In mixed tumors, NECa and adenocarcinoma components shared pathogenic genetic alterations and highly concordant DNA methylation profiles. Frequent aberrations in tumor suppressor proteins p53, RB, and PTEN\/AKT were observed, mirroring molecular features described in therapy-related NECa and correlating with tumor behavior. Notably, a null pattern of p53 immunoreactivity represented the predominant aberrant expression pattern. In addition, a previously unreported\n                    <jats:italic>NRAS<\/jats:italic>\n                    mutation was detected in one case. Collectively, we describe the morphological, genetic and epigenetic features of six cases of de novo NECa of the prostate. These findings, if verified in larger cohorts of patients, will provide new insights into the biology and histogenesis of de novo prostatic NECa and may inform future diagnostic and therapeutic strategies.\n                  <\/jats:p>","DOI":"10.1007\/s00428-026-04549-4","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:57:10Z","timestamp":1787025430000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pathologic and multi-omic characterization of de novo neuroendocrine carcinoma of the prostate: A single center experience"],"prefix":"10.1007","author":[{"given":"Ioanna-Maria","family":"Grypari","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Souzana","family":"Logotheti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Panopoulou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Lazaros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Mesiakaris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Efthalia","family":"Kontogianni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aristidis G","family":"Vrahatis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angeliki","family":"Saetta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9613-4681","authenticated-orcid":false,"given":"Vasiliki","family":"Tzelepi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"4549_CR1","doi-asserted-by":"publisher","first-page":"e793","DOI":"10.1016\/j.clgc.2017.04.006","volume":"15","author":"E Zaffuto","year":"2017","unstructured":"Zaffuto E, Pompe R, Zanaty M et al (2017) Contemporary Incidence and Cancer Control Outcomes of Primary Neuroendocrine Prostate Cancer: A SEER Database Analysis. 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Ethical approval was obtained from the Research, Ethics and Deontology Committee of the University Hospital of Patras (approval no. 426\/26.10.2023). The requirement for informed consent was waived because the study was based on the retrospective analysis of pseudo-anonymized archival pathology material.","order":1,"name":"Ethics","label":"Compliance with ethical standards","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All authors read and approved the final manuscript. Part of this work has been presented at the 36th European Congress of Pathology (7-11 Sept 2024) and the 19th Panhellenic Congress of Pathology (18-21, June 2025)","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}}]}}