Exploring the expression of DLL3 in gastroenteropancreatic neuroendocrine neoplasms and its potential diagnostic value

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.

Keywords: ASCL1; Delta-like protein; Gastroenteropancreatic neuroendocrine tumors; Immunohistochemistry; Therapeutic target.

Fig. 1

(a) DLL3 staining was positive in the cytomembrane, cytoplasm, and nucleus, in which cytoplasmic and membranous staining was diffuse, whereas intermittent perinuclear staining was punctate. The second picture also showed the heterogeneity of DLL3 staining. (b) In MiNENs, the neuroendocrine component exhibited positive DLL3 expression, whereas the adenocarcinoma component showed negative. (c) The staining of DLL3 was positive in NET G3, while negative in NET G1, NET G2, and GACs. NEC Neuroendocrine carcinoma. NET Neuroendocrine tumor. GAC Gastric adenocarcinoma.

Fig. 2

(a) The expression rate of DLL3 in primary tumors and metastatic tumors. The expression rate of DLL3 between ASCL1 negative proup and ASCL1 positive group in GEP-NECs (b), GEP-SCNEC (c), and GEP-LCNEC (d). GEP-NECs Gastroenteropancreatic neuroendocrine carcinomas. GEP-SCNEC Gastroenteropancreatic small cell neuroendocrine carcinoma, GEP-LCNEC Gastroenteropancreatic large cell neuroendocrine carcinoma.

Fig. 3

(a) The positive reactions for ASCL1 were located in the nucleus, with only one case showing an unusual dot-like positivity around the nucleus. (b) The expression of ASCL1 and DLL3 in 111 cases. (c) In the samples with co-expression of DLL3 and ASCL1, the spatial distribution of tumor cells expressed by DLL3 and ASCL1 was consistent.

Fig. 4

Kaplan-Meier survival curves for progression-free survival (PFS) and overall survival (OS) of GEP-NECs patients (n = 199) according to DLL3 status with the cut-off value 1%(a), 50%(b), and 75%(c).