Neuroendocrine differentiation in usual-type prostatic adenocarcinoma: Molecular characterization and clinical significance.

Small 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.

We 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).

Benign 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).

NE 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.

The Prostate. 2020 Jul 10 [Epub ahead of print]

Harsimar Kaur, Iryna Samarska, Jiayun Lu, Farzana Faisal, Benjamin L Maughan, Sanjana Murali, Kaushal Asrani, Mohamed Alshalalfa, Emmanuel S Antonarakis, Jonathan I Epstein, Corinne E Joshu, Edward M Schaeffer, Juan Miguel Mosquera, Tamara L Lotan

Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland., Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland., Department of Urology, School of Medicine, Johns Hopkins University, Baltimore, Maryland., Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, Maryland., Division of Bioinformatics, GenomeDx Biosciences, Vancouver, Canada., Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois., Department of Pathology, Weill Cornell Medicine, New York, New York.