Comparison of Whole‐Gland and Transition Zone PSA Density in Predicting Clinically Significant Prostate Cancer in PI‐RADS 3 Lesions

Abstract

ABSTRACT Background PI‐RADS 3 lesions represent a clinical gray zone in prostate cancer diagnostics, often leading to unnecessary biopsies. Additional biomarkers are needed to improve risk stratification and safely exclude clinically significant prostate cancer (csPCa). This study aimed to compare the performance of whole‐gland prostate‐specific antigen density (PSAD) and transition zone PSA density (TZ‐PSAD) in predicting csPCa and to evaluate their clinical utility in biopsy decision‐making. Methods We conducted a single‐center retrospective cohort study between 2022 and 2024, including 395 biopsy‐naïve patients with PI‐RADS 3 lesions on mpMRI. All patients underwent systematic and cognitive targeted prostate biopsy. PSAD and TZ‐PSAD were calculated using MRI‐derived prostate and transition zone volumes. Clinically significant prostate cancer (csPCa) was defined as ISUP Grade Group ≥ 2. Diagnostic performance was assessed using receiver operating characteristic (ROC) analysis, and area under the curve (AUC) values were compared using the DeLong test. Optimal cut‐off values were determined using the Youden index. Multivariable logistic regression was performed to evaluate predictors, and clinical utility was assessed using 10‐fold cross‐validated decision curve analysis. Results Among 395 patients, clinically significant prostate cancer (csPCa) was detected in 22 cases (5.6%). In ROC analysis, AUC values were 0.737 for PSA, 0.902 for PSAD, and 0.927 for TZ‐PSAD. Both PSAD and TZ‐PSAD demonstrated significantly higher discriminative performance than PSA ( p < 0.001), while no statistically significant difference was observed between PSAD and TZ‐PSAD ( p = 0.163). In multivariable analysis, only TZ‐PSAD remained statistically significant (OR = 1.06; 95% CI: 1.02–1.10; p = 0.009). Using a TZ‐PSAD threshold of ≥ 0.331 ng/mL 2 , 74.9% of biopsies could be avoided, while the csPCa detection rate among biopsied patients increased to 35.7%. In comparison, a PSAD threshold of ≥ 0.15 ng/mL 2 resulted in a 65.8% reduction in biopsies with a csPCa detection rate of 19.3%. The number of missed csPCa cases was identical in both strategies ( n = 2). Decision curve analysis indicated a potential net clinical benefit of TZ‐PSAD over PSAD within low‐to‐intermediate probability thresholds despite comparable ROC performance. Conclusion TZ‐PSAD demonstrated discriminative performance comparable to PSAD, remained an independent predictor in multivariable analysis, and reduced unnecessary biopsies without compromising the detection of clinically significant prostate cancer in patients with PI‐RADS 3 lesions. The zone‐specific normalization of PSA may account for PSA elevation related to benign prostatic hyperplasia (BPH) and may facilitate more individualized biopsy decision‐making in patients with PI‐RADS 3 lesions. These findings suggest that TZ‐PSAD may serve as a clinically useful parameter for reducing unnecessary biopsies in patients with PI‐RADS 3 lesions; however, further prospective and multicenter studies are warranted to validate its role in clinical practice.