Rare prostate cancer histologies: detection, characteristics and treatment

Relatively rare histologies of prostate cancer collectively account for <5% of all prostate cancers and comprise mucinous adenocarcinoma, intraductal carcinoma, ductal adenocarcinoma, neuroendocrine prostate cancer (including treatment-emergent small-cell neuroendocrine carcinoma), sarcomatoid carcinoma and basal cell carcinoma. These histologies have distinct morphological, molecular and clinical features from each other and the most common histological type, acinar adenocarcinoma. The perceived rarity of these histologies often reflects sampling limitations rather than biological prevalence, as many treatment-emergent phenotypes are seldom encountered in routine practice owing to the infrequent use of metastatic biopsies. These histologies demonstrate aggressive behaviour, atypical metastatic patterns and reduced responsiveness to conventional therapies. Despite their clinical importance, these entities remain under-represented in standard guidelines and clinical trials. Histological types and subtypes, such as ductal, mucinous, intraductal, neuroendocrine and sarcomatoid carcinomas, pose diagnostic and therapeutic challenges, and conventional screening with PSA exhibits limitations, so they are often diagnosed at advanced stages. Multiparametric MRI, immunohistochemistry and genomic profiling are crucial tools for accurate recognition and risk stratification. Histological type-specific genomic alterations, including DNA repair deficiencies, RB1 and TP53 loss, and mismatch repair mutations, provide potential therapeutic opportunities, but treatment recommendations are still largely extrapolated from acinar adenocarcinoma. Limited retrospective data suggest worse outcomes for patients with a rare histology than those with typical acinar adenocarcinoma, highlighting the urgent need for prospective registries and dedicated clinical trials. Rare histologies of prostate cancer are an under-recognized source of morbidity and mortality. Improved diagnostic precision, incorporation of molecular profiling and collaborative data collection efforts are essential to develop evidence-based strategies.