Exploring the expression of DLL3 in gastroenteropancreatic neuroendocrine neoplasms and its potential diagnostic
1State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Pathology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China.
Abstract:
Delta-like protein (DLL3) is a novel therapeutic target. DLL3 expression in gastroenteropancreatic neuroendocrine tumors (GEP-NECs) is poorly understood, complicating the distinction between well-differentiated neuroendocrine tumors G3 (NET G3) and poorly differentiated NEC. DLL3 immunohistochemistry (IHC) was performed on 248 primary GEP-NECs, correlating with clinicopathological parameters, NE markers, PD-L1, Ki67 index, and prognosis. Achaete-scute complex-like 1 (ASCL1) IHC was performed on some GEP-NECs. DLL3 IHC was conducted on 36 GEP-NETs, 29 gastric adenocarcinomas (GACs), and metastatic tumors (9 lymph node metastases and 19 distant metastases). DLL3 expression rates were 54.8% in GEP-NECs at the primary site, associated with small cell neuroendocrine carcinoma (SCNEC) (p < 0.001), chemotherapy before baseline (p = 0.015), and at least two NE markers (p = 0.048). DLL3 expression in metastatic GEP-NECs was similar to that of primary tumors. Expression rates in NET G1, NET G2, NET G3, and GACs were 0%, 0%, 15.8%, and 0%, respectively, highlighting DLL3 as a powerful tool for identifying poorly differentiated NEC. DLL3 expression was related to ASCL1 in GEP-NECs, especially in SCNEC. It was not correlated with progression-free survival (PFS) or overall survival(OS), regardless of cutoff value (1%, 50%, 75%). In conclusion, DLL3 targeted therapy may offer potential for the treatment of poorly differentiated NEC of the digestive system, although further studies are needed to validate its efficacy.
Insights
Delta-like protein 3 (DLL3) is a potential therapeutic target in gastroenteropancreatic neuroendocrine tumors (GEP-NECs). DLL3 expression helps distinguish poorly differentiated NEC from well-differentiated neuroendocrine tumors, indicating its value in targeted therapy.
Area of Science:
- Oncology
- Gastroenterology
- Molecular Pathology
Background:
- Delta-like protein 3 (DLL3) is an emerging therapeutic target in neuroendocrine neoplasms.
- Understanding DLL3 expression is crucial for differentiating gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) from well-differentiated neuroendocrine tumors (NETs).
Purpose of the Study:
- To investigate DLL3 expression in primary and metastatic GEP-NECs.
- To correlate DLL3 expression with clinicopathological features, neuroendocrine markers, and patient prognosis.
- To assess DLL3's utility in distinguishing poorly differentiated NEC from other GEP neoplasms.
Main Methods:
- DLL3 immunohistochemistry (IHC) on 248 primary GEP-NECs, 36 GEP-NETs (G1-G3), and 29 gastric adenocarcinomas (GACs).
- Correlation analysis with clinicopathological parameters, neuroendocrine markers, PD-L1, Ki67 index, and survival outcomes (PFS, OS).
- ASCL1 IHC performed on a subset of GEP-NECs.
Main Results:
- DLL3 was expressed in 54.8% of primary GEP-NECs, significantly associated with small cell NEC (SCNEC), prior chemotherapy, and multiple neuroendocrine markers.
- DLL3 expression in metastatic GEP-NECs mirrored primary tumor expression.
- DLL3 expression was absent in NET G1/G2, low in NET G3 (15.8%), and absent in GACs, confirming its role in identifying poorly differentiated NEC.
- DLL3 expression correlated with ASCL1, particularly in SCNEC.
- No significant correlation was found between DLL3 expression and progression-free survival (PFS) or overall survival (OS).
Conclusions:
- DLL3 is a valuable biomarker for identifying poorly differentiated GEP-NECs, especially SCNEC.
- DLL3 expression is linked to ASCL1, suggesting a potential pathway in GEP-NEC pathogenesis.
- Targeted therapy using DLL3 inhibitors may hold promise for treating poorly differentiated digestive system NEC, warranting further clinical investigation.
