Divergent c-MYC Expression Patterns in NET and NEC: Insights from a Multicentre Cohort of 1380 Neuroendocrine Neoplasms

Schmitt M, Ofner K, Bartsch DK, Wagner DC, Rinke A, Gress T, Kremer M, Evert M, Reitsam NG, Koberova V, Märkl B, Quaas A, Eckstein M, Steinestel K, Pagenstecher A, Keber U, Denkert C, Steiger K, Foersch S, Klöppel G, Kasajima A, Bohnenberger H, Jesinghaus M (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Endocrine Pathology Humana Press

Book Volume: 37

Article Number: 39

Journal Issue: 1

DOI: 10.1007/s12022-026-09935-x

Abstract

Neuroendocrine neoplasms (NEN) comprise well-differentiated neuroendocrine tumours (NET) and neuroendocrine carcinomas (NEC), whose distinction is clinically critical. 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 0–1, weak 2–3, moderate 4–8, strong 9–12). Overall, c-MYC positivity (IRS ≥ 2) 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 ≤ 0.001). Within NEC, c-MYC expression was enriched in LCNEC and MiNEN compared with SCNEC and Merkel cell carcinoma (p ≤ 0.001) and occurred more often in gastroenteropancreatic than in pulmonary NEC (57.6% vs. 37.3%; p ≤ 0.001). Among NET, G3 tumours showed the highest positivity rate (6/35; 17.1%), although this was significantly lower than in NEC (p ≤ 0.001), 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.

Authors with CRIS profile

Markus Eckstein Institute of Pathology

Involved external institutions

Universitätsklinikum Gießen und Marburg (UKGM) DE Germany (DE) Städtisches Klinikum München DE Germany (DE) Universitätsklinikum Regensburg DE Germany (DE) Universität Augsburg DE Germany (DE) Universitätsklinikum Köln DE Germany (DE) Bundeswehrkrankenhaus Ulm DE Germany (DE) Technische Universität München (TUM) DE Germany (DE) Universitätsmedizin der Johannes Gutenberg-Universität Mainz DE Germany (DE) Universitätsklinikum Göttingen DE Germany (DE)

How to cite

APA:

Schmitt, M., Ofner, K., Bartsch, D.K., Wagner, D.C., Rinke, A., Gress, T.,... Jesinghaus, M. (2026). Divergent c-MYC Expression Patterns in NET and NEC: Insights from a Multicentre Cohort of 1380 Neuroendocrine Neoplasms. Endocrine Pathology, 37(1). https://doi.org/10.1007/s12022-026-09935-x

MLA:

Schmitt, Maxime, et al. "Divergent c-MYC Expression Patterns in NET and NEC: Insights from a Multicentre Cohort of 1380 Neuroendocrine Neoplasms." Endocrine Pathology 37.1 (2026).

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