Abstract 1170P
Background
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a rare and heterogeneous subgroup of tumors with an extremely variable clinical behaviour and challenging management. A critical need is to identify molecular diagnostic criteria to discriminates grade 3 neuroendocrine tumors (NETs) from neuroendocrine carcinomas (NECs). These two entities have a completely different natural history, but their recognition is based only on the assessment of cell differentiation. The negative Notch regulator DLL3 is a new therapeutic target that was found to be highly expressed in certain tumors with neuroendocrine features.
Methods
We retrospectively analyzed a case series of 43 patients with large- or small-cell GEP-origin NENs histologically confirmed by an expert pathologist. DLL3, PD-L1 and RB1 were evaluated by immunohistochemistry. The expression of DLL3 was correlated with disease stage, RB1 loss, 68Ga-PET/CT scan response and clinical outcomes.
Results
DLL3 was found to be expressed only in high-grade (G3) GEP-NEN. Moreover, it was significantly associated with the presence of poorly differentiated NEC classification: the 77.8% of NEC patients (7 out of 9) had a DLL3 positive neoplasia, while none of the 4 patients with G3 NET showed expression of this marker (p= 0.021). Expression of DLL3 correlated with loss of RB1 (p< 0.001), negative 68Ga-PET/CT scan (p= 0.001) and unfavourable clinical outcome with implication for patient treatment and follow-up. Median progression-free survival (PFS) and overall survival (OS) were, respectively, 41.9 and 72.9 months in patients with a DLL3-negative neoplasia versus 7.9 and 11.7 months in DLL3-positive patients (p= 0.0054 for PFS and p= 0.0036 for OS). No correlation was found between the presence of DLL3 and PD-L1 expression.
Conclusions
DLL3 might represent an objective histological marker to be combined with cell morphological analysis for the diagnosis of poorly differentiated NEC. The high percentage of DLL3 expression in NEC patients also indicates a potential opportunity for a DLL3 targeted therapy in this subset.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.