Clinical meaning
Prostate cancer pathogenesis involves a multistep process from prostatic intraepithelial neoplasia (PIN) to invasive adenocarcinoma. Key molecular alterations include TMPRSS2-ERG gene fusion (found in ~50% of prostate cancers), loss of PTEN tumor suppressor, TP53 mutations (associated with castration resistance), and androgen receptor amplification/mutation. The androgen receptor (AR) signaling axis is the central therapeutic target: testosterone is converted to dihydrotestosterone (DHT) by 5-alpha reductase, and DHT binds AR to activate transcription of proliferative genes. Castration-resistant prostate cancer (CRPC) develops through AR amplification, AR splice variants (AR-V7), intratumoral androgen synthesis, and bypass signaling pathways. The clinician must apply risk stratification (NCCN guidelines), prescribe stage-appropriate therapy across the spectrum from active surveillance to combination systemic therapy, manage treatment toxicities, and integrate genomic testing into clinical decision-making.
Diagnosis & workup
Diagnostics & workup: - Apply shared decision-making for PSA screening: begin discussion at age 50 (general population) or 40-45 (Black men, BRCA2 carriers, family history) - Interpret PSA in clinical context: PSA >4 ng/mL warrants further evaluation; free PSA% <10% increases cancer suspicion - Order multiparametric MRI (mpMRI) prostate before biopsy (PI-RADS scoring: 4-5 suspicious for clinically significant cancer) - Order MRI-targeted + systematic transrectal or transperineal prostate biopsy - Apply ISUP Grade Group system (replaces Gleason): Grade Group 1 (Gleason 3+3=6) through Grade Group 5 (Gleason 9-10) - Order genomic testing: Decipher, Oncotype DX Prostate, or Prolaris for risk stratification in intermediate-risk disease - Stage advanced disease: technetium-99m bone scan, CT abdomen/pelvis, PSMA-PET/CT (more sensitive for recurrence and metastasis)