Neuroendocrine differentiation in prostate neoplasms

Neuroendocrine (NE) cells in the prostate are part of the diffuse NE system and are found in both the normal prostate and acinar adenocarcinomas, occasionally exhibiting Paneth cell-like morphology.NE cells produce peptide hormones and biogenic amines that influence the differentiation and growth of the prostate glands through paracrine signaling; however, they do not show proliferative activity and lack androgen receptors (AR).Prostate tumors with NE differentiation are classified into five groups: (1) acinar adenocarcinomas with partial NE differentiation, detectable only by immunohistochemistry, (2) adenocarcinomas with Paneth cell-like differentiation, (3) NE tumors/carcinoids (NET), (4) small cell NE carcinomas (SCNEC), and (5) large cell NE carcinomas (LCNEC).The significance of partial and Paneth cell-like differentiation in adenocarcinomas remains under discussion and plays a minor role in routine diagnostics. NETs are extremely rare and appear to behave similarly to NETs of the gastrointestinal tract. In contrast, SCNECs and LCNECs are aggressive tumors with important clinical relevance, as they have a poor prognosis and require aggressive treatment.Therapy-associated neuroendocrine prostate carcinomas (t-NEPC) are recognized as a distinct entity for the first time in the WHO classification (5th edition, 2022). It arises through transdifferentiation via epigenetic changes following androgen deprivation and is characterized by AR loss and high proliferation, among other features. As with primary NE carcinomas, aggressive therapy is indicated. Therefore, a follow-up biopsy is recommended for castration-resistant progressive prostate cancer to confirm this aggressive phenotype.