Molecular pathology of rare histologic variants and treatment-resistant lineages of prostate cancer

Rare histological variants of prostate cancer-including ductal adenocarcinoma, intraductal carcinoma of the prostate (IDC-P), neuroendocrine carcinoma, basal cell/adenoid cystic carcinoma, squamous cell carcinoma, sarcomatoid carcinoma, and stromal tumors-exhibit highly diverse biological behaviors and distinct molecular features. Accurate pathological recognition is essential, as these entities frequently diverge from conventional acinar adenocarcinoma in morphology, genomic alterations, therapeutic responsiveness, and clinical outcomes. Intraductal carcinoma of the prostate (IDC-P) and ductal adenocarcinoma often display genomic instability and aggressive clinical behavior, including enrichment for homologous recombination repair (HRR) defects and hypoxia-related pathways. Neuroendocrine subtypes, including de novo and treatment-related NEPC as well as double-negative prostate cancer (DNPC), are characterized by androgen receptor (AR) independence, RB1/TP53 loss, low prostate-specific antigen (PSA) production, and poor prognosis, reflecting lineage plasticity under therapeutic pressure. Other rare tumors-such as basal cell carcinoma/adenoid cystic carcinoma, squamous cell carcinoma, and stromal tumors (STUMP and prostatic stromal sarcoma)-demonstrate unique pathological patterns and limited responsiveness to standard systemic therapies, underscoring the importance of tailored diagnostic and management strategies. This review integrates the histopathological, molecular, and emerging spatial transcriptomic insights across this spectrum of rare and treatment-resistant prostate cancer subtypes. By highlighting shared mechanisms such as genomic instability, androgen receptor (AR) pathway bypass, and microenvironmental remodeling, we outline key diagnostic considerations and evolving therapeutic implications relevant to precision oncology.