DLL3 Expression in Neuroendocrine Carcinomas and Neuroendocrine Tumours: Insights From a Multicentric Cohort of 1294 Pulmonary and Extrapulmonary Neuroendocrine Neoplasms
Year: 2025
Type: article
Study design: Observational Study
Abstract: Delta-like ligand 3 (DLL3) is frequently expressed in pulmonary small cell neuroendocrine carcinoma (SCNEC) and has emerged as a promising therapeutic target. However, limited data on DLL3 expression in other neuroendocrine neoplasms (NEN), such as extrapulmonary SCNEC, large cell neuroendocrine carcinomas (LCNEC), mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN), gastroenteropancreatic neuroendocrine tumours (GEP-NET), and pulmonary carcinoids, impedes an estimation if other types of NEN might be suitable candidates for anti-DLL3 therapies. We evaluated DLL3 expression in 1294 NEN and 479 non-neuroendocrine carcinomas, correlating the findings with histological subtypes, tumour localisation, and overall survival (OS). Furthermore, we explored the concordance of DLL3 expression during metastatic progression in 67 paired primary NEN and metastases. DLL3 expression was significantly higher in NEC (64.0%) compared to GEP-NET and pulmonary carcinoids (10.1%, p < 0.001), particularly in SCNEC (80.4%), followed by LCNEC (62.6%) and MiNEN (28.6%). DLL3 was common in pulmonary carcinoids (41.5%), but rare in GEP-NET (5.1%) and non-neuroendocrine carcinomas (1.3%). Overall DLL3 expression was highly concordant between metastases and corresponding primary NEN (92.5%, p < 0.001). In univariable analyses, DLL3-expressing pulmonary carcinoids (p = 0.005) and GEP-NET (p = 0.018) were associated with decreased OS, but this was not retained in multivariable analyses adjusting for stage and grade (p = n. s.). No prognostic impact was observed in pulmonary (p = 0.708) or GEP-NEC (p = 0.87). Our study highlights significant differences in DLL3 expression across NEN subtypes and localisations, with largely concordant expression in metastases. DLL3-based therapies may be effective in many NEC and pulmonary carcinoids, while DLL3 appears to be a minor therapeutic target for GEP-NET and non-neuroendocrine carcinomas.
Source: Endocrine Pathology
Authors: Maxime Schmitt, Hanibal Bohnenberger, Detlef Klaus Bartsch, Daniel-Christoph Wagner, Anne-Sophie Litmeyer, Albert Grass, Anja Rinke, Christine Koch, Marcus Kremer, Matthias Evert, Bruno Märkl, Alexander Quaas, Markus Eckstein, Konrad Steinestel, Carsten Denkert, Katja Steiger, Günter Klöppel, Atsuko Kasajima, Markus Tschurtschenthaler, Sebastian Foersch, Moritz Jesinghaus
Institutions: Philipps University of Marburg, Universitätsklinikum Gießen und Marburg, Universitätsmedizin Göttingen, University of Göttingen, Johannes Gutenberg University Mainz, University Medical Center of the Johannes Gutenberg University Mainz, University Hospital Frankfurt, München Klinik, Pathologisches Institut, University of Regensburg, University Hospital Augsburg, University Hospital Cologne, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Bundeswehrkrankenhaus Ulm, Technical University of Munich, German Cancer Research Center, Deutsches Konsortium für Translationale Krebsforschung
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,190
OpenAlex ID: W4408972884