Neuroendocrine cells in prostate cancer correlate with poor outcomes: A systematic review and meta-analysis.

OBJECTIVES To determine the prognostic utility of reporting neuroendocrine staining at prostate cancer diagnosis, we performed a systematic review and meta-analysis. Specifically, we aimed to understand the variability in reporting of neuroendocrine staining, and determine whether different reporting approaches impact the correlation between staining and patient outcome. METHODS Medical databases were searched to identify studies where adenocarcinoma specimens were stained with any of four neuroendocrine markers: Chromogranin A (CgA), Neuron Specific Enolase (NSE), synaptophysin and CD56. Prevalence of neuroendocrine staining and correlation to patient outcomes were analysed using a random-effects model. All statistical tests were two-sided. RESULTS Sixty-two studies spanning 7,616 patients were analysed. The pooled prevalence for the most common marker, CgA (41%), was similar to NSE (39%) and higher than synaptophysin (31%). Prevalence of CgA staining was significantly influenced by reporting criteria, where objective thresholds reduced the variation in prevalence to 26%. No correlation was found between CgA prevalence and tumour grade. Patients positive for CgA staining using objective criteria had more rapid biochemical progression (hazard ratio 1.98 (95% CI = 1.49 to 2.65)) and poorer prostate cancer-specific survival (hazard ratio: 7.03 (95% CI = 2.55 to 19.39)) compared to negative patients, even among those with low risk cancers. CONCLUSION Discrepancies in the reported prevalence of neuroendocrine cells in adenocarcinoma are driven by the inconsistent scoring criteria. This study unequivocally demonstrates that when neuroendocrine cell staining is assessed with objective criteria it identifies patients with poor clinical outcomes. Future studies need to determine the exact quantifiable thresholds to report neuroendocrine cell staining, to identify patients at higher risk of progression.