Abstract
Neuroendocrine neoplasms (NENs) are rare, heterogeneous and ubiquitous tumors commonly localized in the gastrointestinal tract, lung, and pancreas. The clinical behavior of NEN is highly unpredictable; in fact, low-grade cases can unexpectedly be associated with metastases. Currently, the 2010 WHO NEN classification employs histological differentiation and the proliferation index for grading tumors but fails to provide reliable prognostic and therapeutic indications. Therefore, there is an urgent need for a better characterization of G2/G3 NENs. Similar to several other tumors, NENs possess immune-escape mechanisms, but very little has yet been done to characterize this crucial aspect. There are no available data describing PD-L1 expression in these tumors. Here we provide, for the first time, evidence of PD-L1 tissue expression in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). PD-L1 expression was significantly associated with a high-grade WHO classification (G3) (P<0.001) but not with gender, primary site, or lymph node status. The PD-L1 positivity rate and signal intensity are directly correlated (P<0.001) with a grade increase from G1 to G3. In particular in G3 cases, we observed a dichotomy between the morphology (WD- and PD-NENs) and Ki67. Moreover, our study demonstrated a significant association with the grade and PD-L1 expression levels in immune-infiltrating cells (P<0.001). In particular, G3 tumors are characterized by strong PD-L1 expression in both the tumor and infiltrating immune cells (P<0.001), reflecting an unfavorable environment for T-cell-mediated tumor aggression. These findings suggest that NENs might acquire resistance to immune surveillance by upregulating PD-L1 and inhibiting peritumoral and intratumoral infiltrating lymphocytes. Here we demonstrate that PD-L1 is currently the best-known biomarker for G3 NENs, becoming the new gold standard for G3 NEN discrimination. Furthermore, pharmacological approaches using anti-PD-1 antibodies may become the logical choice for the treatment of G3 cases with a poor prognosis.
Highlights
Neuroendocrine neoplasms (NENs) are commonly localized in the gastrointestinal tract, lung, and pancreas.[1]
G3 tumors are characterized by strong Programmed death ligand 1 (PD-L1) expression in both the tumor and infiltrating immune cells (Po0.001), reflecting an unfavorable environment for T-cell-mediated tumor aggression. These findings suggest that NENs might acquire resistance to immune surveillance by upregulating PD-L1 and inhibiting peritumoral and intratumoral infiltrating lymphocytes
PD-1 has been detected in tumor-infiltrating lymphocytes (TILs) present in the tumor microenvironment, where PD-L1 aberrant expression is associated with a poor prognosis in several human tumors.[28,29]
Summary
Neuroendocrine neoplasms (NENs) are commonly localized in the gastrointestinal tract, lung, and pancreas.[1]. The defined range (G1: o2 mitoses/10 HPF; G2: 2–20 mitoses/10 HPF; G3: 420 mitoses/10 HPF) appears very broad, including many heterogeneous clinical, morphological and prognostic conditions.[13] A few recent papers[14] indicated that despite the assessment of the proliferation fraction, some tumors, identified as NECs, do not show the expected poorly differentiated morphology These reports indicate that these patients do not respond to cisplatin-based chemotherapy, the gold standard therapeutic approach to high-grade PD-NECs,[14] and have a better prognosis. Nivolumab administration may become the pharmacological choice for Ki67460% PD-NENs, identified in this study as the tumors with the highest PD-L1 expression
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
