Prostate cancer (CaP) is the second most common malignancy in men, with an incidence of more than 3.6 million in the United States [1]. CaP is heterogeneous, comprising of various subtypes, each possessing unique histological and molecular characteristics and exhibiting diverse clinical behaviors. Incidence and mortality rates associated with CaP are notably higher in black men compared to white men. The underlying factors contributing to this racial diversity are multifaceted and include both socioeconomic factors and genetic susceptibility [2]. Histologically, the two most prevalent subtypes of CaP are acinar adenocarcinoma (Fig. 1A), which constitutes approximately 95% of all prostate cancers, and ductal adenocarcinoma (Fig. 1B), which makes up 0.4% to 0.8% of cases [2]. Rarely high-grade neuroendocrine carcinomas (NEPC) may arise in the prostate, usually in the setting of treatment with androgen-deprivation therapy (ADT). This treatment-related neuroendocrine CaP (t-NEPC) (Fig. 2) is highly aggressive and histologically may show variable components of admixed adenocarcinoma. Sarcomas involving the prostate are exceedingly rare and can be of various histologic types including tumors arising from the specialized prostatic stroma [2].

The clinical behavior of acinar adenocarcinoma varies widely, from indolent to aggressive tumors. Ductal adenocarcinoma on the other hand has an aggressive clinical course and the presence of any proportion of this subtype in needle core biopsy carries a greater risk of biochemical failure after subsequent radical prostatectomy [3]. Matched for grade, stage, and nodal status, patients with ductal adenocarcinoma have worse metastasis-free survival after radical prostatectomy, compared to acinar adenocarcinoma [4]. Moreover, ductal adenocarcinoma has been reported to be less responsive to ADT, compared to acinar adenocarcinoma [4]. Gleason score (GS) and grade groups (GG) are independent predictors of biochemical recurrence, metastasis, and prostate cancer–specific mortality [5]. Other histologic parameters including the presence of intraductal carcinoma, cribriform Gleason pattern 4 and percentage of Gleason pattern 4 in GG 2 and GG 3 cancers can further help stratify patients for therapeutic triaging [6].

The development and biological behavior of CaP are influenced by an interplay of genetic and epigenetic factors. These include chromosomal aberrations with resultant functional gains/losses in target genes, gene fusions, and epigenetic alterations including histone modification and DNA methylation. The interrogation of the molecular landscape of large cohorts of both primary and metastatic CaP has provided significant insight into these tumors, which in turn has helped delineate individual risk profiles for surveillance strategies and to guide personalized treatment options. Moreover, genetic testing has implications beyond the affected individual. Confirming a hereditary predisposition to CaP can prompt testing and enhanced surveillance for at risk family members [7]. The use of molecular/genetic testing is becoming more relevant in the era of personalized medicine and has now been incorporated into various clinical guidelines. Although this field has expanded rapidly, there are still opportunities to develop robust predictive biomarkers to further streamline therapeutic guidelines for the treatment of CaP. This short narrative review provides an overview of the molecular underpinnings of CaP and briefly reviews the current status of the therapeutic options for the management of these tumors.