Transition Zone PSA Density Does Not Improve Detection of Clinically Significant Prostate Cancer over Whole-Gland PSA Density: A Volume-Stratified Analysis in 3,958 Patients

Introduction: Transition zone PSA density (TZ-PSAD) was proposed to improve prostate cancer detection by normalizing PSA to the compartment most affected by benign prostatic hyperplasia (BPH). If valid, TZ-PSAD should provide the greatest benefit in large prostates where BPH predominates. We tested this assumption across prostate volume categories in the largest MRI-based cohort reported to date. Materials and Methods: We analyzed 3,958 consecutive patients who underwent multiparametric MRI with manual zonal segmentation and combined MRI-guided targeted plus systematic transperineal biopsy (March 2010–June 2025). Diagnostic accuracy of TZ-PSAD versus whole-gland PSAD was compared using receiver operating characteristic analysis with DeLong testing. Volume-stratified subgroup analysis (<30 mL, 30–50 mL, and >50 mL) assessed performance consistency. Clinical utility was evaluated by decision curve analysis (DCA). Results: Of 3,958 patients, 1,629 (41.2%) had clinically significant prostate cancer (International Society of Urological Pathology grade group: ≥2). TZ-PSAD achieved marginally superior area under the curve (AUC) (0.768 vs. 0.758, p < 0.001; ΔAUC 0.010). Volume-stratified analysis revealed inconsistent performance: TZ-PSAD was inferior in small prostates (<30 mL: ΔAUC −0.017, p = 0.015), modestly beneficial at intermediate volumes (30–50 mL: ΔAUC +0.013, p = 0.026), and nonsignificant in large glands (>50 mL: ΔAUC +0.006, p = 0.462). DCA confirmed fewer than 1 additional cancer detected per 1,000 patients at clinically relevant thresholds. Limitations include the retrospective single-center design, absence of PI-RADS-stratified analysis, and incomplete capture of 5-alpha reductase inhibitor exposure. Conclusion: TZ-PSAD fails to outperform whole-gland PSAD in prostates >50 mL, where its theoretical rationale is strongest. The additional complexity of zonal segmentation is not justified for routine clinical use.