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Published on: August 14, 2012
DLL3 Expression in Neuroendocrine Carcinomas and Neuroendocrine Tumours: Insights From a Multicentric Cohort of 1294
Maxime Schmitt1, Hanibal Bohnenberger2, Detlef Klaus Bartsch3
1Institute of Pathology, Philipps University Marburg and University Hospital Marburg, Baldingerstrasse, Marburg, Germany.
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.
Insights
Delta-like ligand 3 (DLL3) is highly expressed in neuroendocrine carcinomas (NEC) and pulmonary carcinoids, suggesting potential for anti-DLL3 therapies. DLL3 expression is largely consistent between primary tumors and metastases, but less common in GEP-NET and non-neuroendocrine carcinomas.
Area of Science:
- Oncology
- Molecular Pathology
- Therapeutic Development
Background:
- Delta-like ligand 3 (DLL3) is a validated therapeutic target in small cell neuroendocrine carcinoma (SCNEC).
- Limited data exists on DLL3 expression across diverse neuroendocrine neoplasm (NEN) subtypes and localizations.
- Understanding DLL3 expression patterns is crucial for expanding anti-DLL3 therapy eligibility.
Purpose of the Study:
- To comprehensively evaluate DLL3 expression across various NEN subtypes, including extrapulmonary SCNEC, large cell neuroendocrine carcinomas (LCNEC), mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN), gastroenteropancreatic neuroendocrine tumours (GEP-NET), and pulmonary carcinoids.
- To assess the concordance of DLL3 expression between primary NEN and their metastases.
- To correlate DLL3 expression with histological subtypes, tumor localization, and overall survival (OS).
Main Methods:
- Immunohistochemical analysis of DLL3 expression in 1294 NEN and 479 non-neuroendocrine carcinomas.
- Correlation of DLL3 expression with histological subtypes, tumor site, and patient survival data.
- Analysis of paired primary NEN and metastatic samples (n=67) to determine expression concordance.
Main Results:
- DLL3 expression was significantly higher in neuroendocrine carcinomas (NEC) (64.0%) compared to GEP-NET (5.1%) and non-neuroendocrine carcinomas (1.3%).
- SCNEC (80.4%) and LCNEC (62.6%) showed high DLL3 expression, while pulmonary carcinoids had moderate expression (41.5%).
- DLL3 expression was highly concordant between primary tumors and metastases (92.5%).
Conclusions:
- DLL3 is differentially expressed across NEN subtypes, with high prevalence in NEC and pulmonary carcinoids, indicating their suitability for anti-DLL3 therapies.
- DLL3 expression is consistent during metastatic progression, supporting its role as a reliable therapeutic target.
- DLL3 is a less relevant target for GEP-NET and non-neuroendocrine carcinomas due to low expression rates.
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