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Although c-MYC alterations have been implicated in NEC pathogenesis, c-MYC expression across NEC subtypes and anatomical sites, as well as in NET, remains incompletely defined. We analysed c-MYC immunohistochemically in 1380 resected NEN using the Immunoreactive Score (IRS: negative 0\u20131, weak 2\u20133, moderate 4\u20138, strong 9\u201312). Overall, c-MYC positivity (IRS\u2009\u2265\u20092) was observed in 13.3% of NEN. Expression was detected in 43% of NEC (164\/381), including strong staining in 19.4%, whereas it was rare in NET and pulmonary carcinoids (20\/999; 2%; p\u2009\u2264\u20090.001). Within NEC, c-MYC expression was enriched in LCNEC and MiNEN compared with SCNEC and Merkel cell carcinoma (p\u2009\u2264\u20090.001) and occurred more often in gastroenteropancreatic than in pulmonary NEC (57.6% vs. 37.3%; p\u2009\u2264\u20090.001). Among NET, G3 tumours showed the highest positivity rate (6\/35; 17.1%), although this was significantly lower than in NEC (p\u2009\u2264\u20090.001), with strong expression observed in only one NET G3 (2.9%). No association between c-MYC expression and survival was identified in either NEC or NET. Our study confirms c-MYC expression as a common event in NEC and highlights differences across histological subtypes and anatomical sites, while demonstrating its absence in most low-proliferative NET. A subset of NET G3 tumours exhibits weak to moderate c-MYC expression at levels far below those seen in NEC, suggesting that strong c-MYC positivity may support a NEC classification in borderline cases but does not represent a definitive discriminatory marker.<\/jats:p>","DOI":"10.1007\/s12022-026-09935-x","type":"journal-article","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T04:56:04Z","timestamp":1789188964000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Divergent c-MYC Expression Patterns in NET and NEC: Insights from a Multicentre Cohort of 1380 Neuroendocrine Neoplasms"],"prefix":"10.1007","volume":"37","author":[{"given":"Maxime","family":"Schmitt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Ofner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Detlef Klaus","family":"Bartsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel-Christoph","family":"Wagner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Rinke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Gress","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Kremer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Evert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nic G","family":"Reitsam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktorie","family":"Koberova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"M\u00e4rkl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Quaas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Eckstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konrad","family":"Steinestel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Pagenstecher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ursula","family":"Keber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"Denkert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Steiger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Foersch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00fcnter","family":"Kl\u00f6ppel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsuko","family":"Kasajima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanibal","family":"Bohnenberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moritz","family":"Jesinghaus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,12]]},"reference":[{"key":"9935_CR1","volume-title":"WHO Classification of Tumours: Digestive system tumours","author":"WHO Classification of Tumours Editorial Board","year":"2019","unstructured":"WHO Classification of Tumours Editorial Board (2019) WHO Classification of Tumours: Digestive system tumours. 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For full transparency, all relevant financial and non-financial relationships disclosed by the authors are reported below. Atsuko Kasajima and Moritz Jesinghaus are members of the Editorial Board of Endocrine Pathology. They were not involved in the editorial handling or peer-review process of this manuscript. Maxime Schmitt provides unpaid scientific advice to Leica Microsystems and ATTO-TEC. He has received no honoraria, consulting fees, salary, research funding, or other financial compensation from these companies. Detlef Klaus Bartsch is a member of the Executive Committee of the European Neuroendocrine Tumour Society (ENETS). The APSIN study led by Detlef Klaus Bartsch has received funding from German Cancer Aid. Daniel-Christoph Wagner has received honoraria from Agilent, Amgen, AstraZeneca, Janssen, Roche, Bristol Myers Squibb (BMS), MSD, Sanofi, and Merck KGaA, and research funding from BMS and Amgen. Anja Rinke has received honoraria from Advanz Pharma, AstraZeneca, Boehringer Ingelheim, Esteve Pharmaceuticals, Falk Foundation e.V., Fortbildung in der GHE e.V., Ipsen Pharma, Novartis Pharma, and SERB Pharmaceuticals GmbH; support for attending meetings and\/or travel from Ipsen Pharma GmbH; and has served on advisory boards for Novartis, Ipsen, Esteve, and the European Neuroendocrine Tumour Society (ENETS). Thomas Gress has received honoraria from Advanz Pharma, AstraZeneca, Boehringer Ingelheim, Esteve Pharmaceuticals, Falk Foundation e.V., Fortbildung in der GHE e.V., Ipsen Pharma, Novartis Pharma, and SERB Pharmaceuticals GmbH; support for attending meetings and\/or travel from Ipsen Pharma GmbH; and has served on advisory boards for Novartis, Ipsen, Esteve, and the European Neuroendocrine Tumour Society (ENETS). Nic G. Reitsam has received travel support from Bruker Spatial Biology and serves as an Editorial Board member of PLOS Medicine. Markus Eckstein has received consulting fees from Ferring, AstraZeneca, Janssen (Johnson & Johnson), Genomic Health, Diaceutics, Gilead, MSD, Merck, and Bicycle Therapeutics; honoraria for lectures, presentations, and educational activities from AstraZeneca, Roche, Janssen (Johnson & Johnson), Owkin, Diaceutics, Ferring, Eisai, Merck, Bicycle Therapeutics, and Zytomed Systems; payments for expert testimony from AstraZeneca, Janssen (Johnson & Johnson), Astellas, Genomic Health, Diaceutics, Gilead, MSD, Merck, and Bicycle Therapeutics; and travel support from AstraZeneca, Roche, MSD, Janssen (Johnson & Johnson), Diaceutics, Astellas, Ferring, Eisai, Merck, and Bicycle Therapeutics. He serves on the Clinical Advisory Board of Bicycle Therapeutics and on the boards of the BRIDGE Consortium, the European Society of Uropathology (ESUP), and the International Society of Urological Pathology (ISUP). He has received equipment, materials, services, and\/or research funding from STRATIFYER, Janssen (Johnson & Johnson), AstraZeneca\/MedImmune, Owkin, Gilead, Bicycle Therapeutics, BMS, and QUiP GmbH, and reports stock ownership in Bicycle Therapeutics and MSD. Konrad Steinestel has received consulting fees and honoraria from AstraZeneca, Merck Sharp & Dohme, Bristol Myers Squibb, Sanofi, and Boehringer Ingelheim, and has served on Data Safety Monitoring Boards or Advisory Boards for Merck Sharp & Dohme, Bristol Myers Squibb, and AstraZeneca. Carsten Denkert has served on advisory boards for MSD Oncology, Daiichi Sankyo, AstraZeneca, and BioNTech RNA Pharmaceuticals GmbH; has received speaker honoraria from AstraZeneca and licensing fees from VMscope digital pathology software; and has received institutional research funding from Myriad and the German Breast Group. He is an inventor on patents WO2020109570A1, WO2015114146A1, and WO2010076322A1. Atsuko Kasajima has received consulting and advisory fees from Boehringer Ingelheim GmbH and speaking and lecture fees from Ipsen Pharma GmbH. Hanibal Bohnenberger is a member of the Boehringer Ingelheim Pathology Advisory Board for a study of obrixtamig in neuroendocrine neoplasms. This activity is unrelated to the present study. Moritz Jesinghaus has received honoraria from Novartis Pharma. Katharina Ofner, Marcus Kremer, Matthias Evert, Viktorie Koberova, Bruno M\u00e4rkl, Alexander Quaas, Axel Pagenstecher, Ursula Keber, Katja Steiger, Sebastian Foersch, and G\u00fcnter Kl\u00f6ppel declare no competing interests.","order":2,"name":"Ethics","label":"Competing Interests","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"During manuscript preparation, the authors used ChatGPT (OpenAI Ireland Ltd., Dublin, Ireland) and Perplexity AI (Perplexity AI Inc., San Francisco, CA, USA) exclusively for linguistic support and spelling correction. All generated suggestions were carefully reviewed, revised where necessary, and fully verified by the authors, who retain complete responsibility for the final content of the manuscript.","order":3,"name":"Ethics","label":"Regarding the use of AI-assisted technologies","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"39"}}