Non-Conventional Histologies of Prostate Cancer: From Morphology to Biology-Driven Precision Oncology

Non-conventional prostate cancer histologies represent a small but clinically significant subset characterised by aggressive behaviour, atypical biomarker profiles, and reduced dependence on androgen receptor signalling. Evidence indicates these histologies reflect dynamic biological states driven by genomic instability, lineage plasticity, and therapeutic selection rather than static morphologic entities, with several morphologies acting as accessible, if imperfect, surrogates for actionable alterations. We performed a translational narrative review integrating anatomic pathology, genomic and epigenomic biology, and biomarker-selected therapy, searching PubMed/MEDLINE, Embase, Cochrane CENTRAL, the ASCO Meeting Library, ESMO publications, and APCCC through May 2026, spanning neuroendocrine, ductal, intraductal, cribriform, adenosquamous, sarcomatoid, adenoid cystic, signet ring cell, and mucinous subtypes. These histologies are individually uncommon but are consistently associated with advanced stage and inferior survival. Neuroendocrine prostate cancer is the most aggressive phenotype and a major mechanism of resistance to AR-directed therapy, driven by combined RB1 and TP53 loss, epigenetic reprogramming, and lineage plasticity, and marked by DLL3 expression. Cribriform and intraductal carcinoma are often enriched for BRCA2 and DNA-repair deficiency, whereas ductal differentiation is associated with mismatch-repair deficiency in a subset, with implications for PARP inhibition and checkpoint blockade. Emerging strategies include platinum-based chemoimmunotherapy and investigational lineage-directed agents targeting DLL3, STEAP1, KLK2, and TROP-2, alongside radioligands. These histologies are best viewed as biologically distinct, evolving disease states. By integrating pathology, molecular biology, and biomarker-selected therapy into one translational pathway, this review reframes non-conventional histology as a prompt for early molecular characterisation and adaptive, biology-driven treatment.