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.

Aims: To evaluate the biological significance of dense vascular networks associated with low-grade NENs, we assessed the impact of PDGFRα tissue expression in 77 GEP/NEN patients, associating PDGFRα expression with the morphological characterization in low-grade tumors. Methods and results: Paraffin-embedded specimens of 77 GEP- NEN tissues, collected from January 2006 to March 2018, were evaluated for PDGFRα tissue expression and correlations with clinicopathological characteristics. PDGFRα tissue expression was significantly correlated with grade and the NEN growth pattern (p < 0.001) but not with gender, primary site or lymph nodes metastatic status. PDGFRα staining was mainly localized in the vascular pole of the neuroendocrine cells and in Enterochromaffin (EC) cells. In particular PDGFRα tissue expression was significantly more expressed in G2 (p < 0.001) than G1 and G3 cases (p 0.004; p < 0.0002;) and correlated with an insular growth pattern. PDGFRα tissue expression was associated with the Ki67 index and we found a significant negative trend of association with the Ki67 proliferation index (P < 0.001): thus PDGFRα expression is referred to morphological and not to proliferative data. Conclusions: PDGFRα represents an effective target for new anti-angiogenic treatment in WD- GEP-NENs, in particular in G2 cases, and in G3 cases only when there is a mixed insular-acinar pattern. In this context, it is important to carefully delineate those tumors that might better respond to this type of treatment alone or in combination. Further investigation of the relationship between PD-L1 and PDGFRa is warranted, and may contribute to optimize the therapeutic approach in patients with GEP-NENs.

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