Assessment of Circulating Neuroendocrine Tumor Markers at Prostate Cancer Diagnosis: An Investigation of Prostate Cancer With Neuroendocrine Features

BACKGROUND: Neuroendocrine prostate cancer (NEPC) is characterized by its aggressive biological behavior and poor prognosis, distinguishing it from prostate adenocarcinoma. Although several studies have investigated tumor markers associated with neuroendocrine differentiation and treatment outcomes, there is a lack of research focusing specifically on treatment-naive prostate cancer. This study aims to evaluate neuroendocrine differentiation and the relationship between neuroendocrine markers (neuron-specific enolase (NSE) and pro-gastrin releasing peptide (pro-GRP)) and the aggressiveness of prostate cancer at the time of diagnosis. METHODS: A total of 310 prostate cancer cases diagnosed through biopsy between October 2019 and January 2024 were analyzed. This study focused on neuroendocrine tumor markers, NSE and pro-GRP, to evaluate the incidence of neuroendocrine differentiation. Furthermore, the relationship between these markers and tumor aggressiveness was examined, as determined by clinical T-stage (cT), lymph node (LN) metastasis, and distant metastasis at the time of diagnosis. RESULTS: The incidence of positive neuroendocrine markers, defined as the presence of at least one marker exceeding the normal threshold, was 25.8%. A significant correlation was identified only between prostate-specific antigen (PSA) and pro-GRP (p < 0.001). No significant relationships were observed between PSA and NSE, or between NSE and pro-GRP (p = 0.434 and p = 0.918, respectively). In multivariate analyses for cT ≥ 3, PSA, Ki-67, and pro-GRP were significant factors (p < 0.01, p < 0.001, and p = 0.0153, respectively). For positive LN metastasis, PSA and Ki-67 were significant (p = 0.0178 and p < 0.0001, respectively). For positive distant metastasis, PSA, Ki-67, and pro-GRP were significant (p < 0.001, p = 0.0130, and p = 0.0128, respectively). CONCLUSIONS: Neuroendocrine tumor markers, specifically NSE and pro-GRP, were positive in approximately 25% of treatment-naive prostate cancer cases. While NSE did not correlate with tumor aggressiveness, pro-GRP was associated with it and emerged as an independent factor related to tumor aggressiveness. These findings suggest that, despite both markers being linked to the same tumor type, they may exhibit distinct biological characteristics, warranting further investigation.