BackgroundSmall cell neuroendocrine (NE) carcinomas of the prostate classically lose androgen receptor (AR) expression, may harbor loss of the RB1, TP53, and PTEN tumor suppressor genes, and are associated with a poor prognosis. However usual‐type adenocarcinomas may also contain areas of NE differentiation, and in this context the molecular features and biological significance are less certain.MethodsWe examined the molecular phenotype and oncologic outcomes of primary prostate adenocarcinomas with ≥5% NE differentiation (≥5% chromogranin A‐positive NE cells in any given tumor spot on tissue microarray) using three independent study sets: a set of tumors with paneth cell‐like NE differentiation (n = 26), a retrospective case‐cohort of intermediate‐ and high‐risk patients enriched for adverse outcomes (n = 267), and primary tumors from a retrospective series of men with eventual castration‐resistant metastatic prostate cancer (CRPC) treated with abiraterone or enzalutamide (n = 55).ResultsBenign NE cells expressed significantly lower quantified AR levels compared with paired benign luminal cells (P < .001). Similarly, paneth‐like NE carcinoma cells or carcinoma cells expressing chromogranin A expressed significantly lower quantified AR levels than paired non‐NE carcinoma cells (P < .001). Quantified ERG protein expression, was also lower in chromogranin A‐labeled adenocarcinoma cells compared with unlabeled cells (P < .001) and tumors with NE differentiation showed lower gene expression scores for AR activity compared with those without. Despite evidence of lower AR signaling, adenocarcinomas with NE differentiation did not differ by prevalence of TP53 missense mutations, or PTEN or RB1 loss, compared with those without NE differentiation. Finally, NE differentiation was not associated with time to metastasis in intermediate‐ and high‐risk patients (P = .6 on multivariate analysis), nor with progression‐free survival in patients with CRPC treated with abiraterone or enzalutamide (P = .9).ConclusionNE differentiation in usual‐type primary prostate adenocarcinoma is a molecularly and clinically distinct form of lineage plasticity from that occurring in small cell NE carcinoma.

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