Pathologic and multi-omic characterization of de novo neuroendocrine carcinoma of the prostate: A single center experience.

De novo neuroendocrine carcinoma (NECa) of the prostate is a rare, aggressive malignancy distinct from therapy-related forms, that remains poorly characterized at the molecular level. Here we analyzed six cases, including pure and mixed forms with adenocarcinoma, using histopathology, immunohistochemistry, next-generation sequencing, and genome-wide DNA methylation profiling. Morphologically, prominent intraductal extension of NECa was a frequent and striking feature. In mixed tumors, NECa and adenocarcinoma components shared pathogenic genetic alterations and highly concordant DNA methylation profiles. Frequent aberrations in tumor suppressor proteins p53, RB, and PTEN/AKT were observed, mirroring molecular features described in therapy-related NECa and correlating with tumor behavior. Notably, a null pattern of p53 immunoreactivity represented the predominant aberrant expression pattern. In addition, a previously unreported NRAS mutation was detected in one case. Collectively, we describe the morphological, genetic and epigenetic features of six cases of de novo NECa of the prostate. These findings, if verified in larger cohorts of patients, will provide new insights into the biology and histogenesis of de novo prostatic NECa and may inform future diagnostic and therapeutic strategies.