Prognostic significance of neuroendocrine differentiation and PD-L1 expression in treatment-naïve prostate cancer

PURPOSE: Prostatic adenocarcinoma with neuroendocrine differentiation (PaNED) is distinct from treatment-related and de-novo neuroendocrine prostate carcinomas, yet remains under-investigated in treatment-naïve patients. This study aimed to evaluate the associations of NED extent, synaptophysin intensity score (SIS), and PD-L1 expression with other histomorphological features and prognosis in treatment-naïve PaNED. MATERIALS AND METHODS: Seventeen patients with PaNED diagnosed between 2014 and 2024 were retrospectively analyzed. NED was classified as diffuse (≥ 30%) or focal (< 30%), and SIS was scored as weak (+ 1), moderate (+ 2), or strong (+ 3). PD-L1 expression was assessed using tumor proportion score (TPS, cut-off ≥ 1%) and combined positive score (CPS, cut-off ≥ 10). Clinicopathological data and survival outcomes were evaluated. RESULTS: The mean age was 65.2 ± 6.6 years, and 47.1% (n = 8) of the cases were Grade Group 5. Diffuse NED was observed in 70.6% of cases, and strong synaptophysin expression in 35.3%. PD-L1 TPS and CPS positivity were detected in 17.6% and 35.3% of patients, respectively. Neither NED extent nor percentage was significantly associated with PD-L1 expression or prognosis. A moderate negative correlation was found between SIS and PD-L1 CPS (rho = -0.48, p = 0.051). Strong synaptophysin expression was significantly associated with shorter overall survival (p = 0.031). CONCLUSIONS: In treatment-naïve PaNED, higher SIS was correlated with lower PD-L1 CPS values, and strong synaptophysin expression was associated with poorer survival. Assessment of SIS in morphologically suspected neuroendocrine areas may provide additional prognostic information and help predict the PD-L1 response. Larger studies are required to validate these findings.