To biopsy or not biopsy, that is the question - PI-RADS 3 prostate lesions - validation of clinical and radiological parameters for biopsy decision-making.

[OBJECTIVES] Multiparametric MRI (mpMRI) enhances prostate cancer (PCa) detection, especially when combined with targeted or MRI–ultrasound fusion biopsy. However, PI-RADS 3 lesions remain diagnostically indeterminate, with variable malignancy risk and heterogeneous clinical management. This study aims to identify clinical and radiological predictors of PCa and clinically significant PCa (csPCa) in patients with PI-RADS 3 lesions in order to enhance risk stratification. By disentangling patient- and disease-specific characteristics from imaging findings, the study evaluates their independent prognostic value. The primary objective is to validate non-imaging parameters as reliable tools for risk stratification in indeterminate cases, thereby supporting clinical decision-making when radiological assessment alone is inconclusive.

[PATIENTS AND METHODS] In this retrospective cohort study, 671 patients with 981 PI-RADS 3 lesions underwent mpMRI and MRI–ultrasound fusion-guided transrectal biopsy, including both targeted and systematic cores. Histopathological evaluation was based on ISUP grading. Logistic regression models were used to assess associations between clinical/radiological factors and biopsy outcomes.

[RESULTS] Overall cancer detection per lesion was 36.9%, with csPCa detected in 15.8% of lesions and 42.8% of positive biopsies. PSA density emerged as the strongest predictor of both PCa and csPCa, while prostate volume was inversely associated. csPCa was more commonly found in patients undergoing primary biopsy and those with posterior lesion localization. In selected low-risk groups, csPCa detection was rare, suggesting potential to avoid unnecessary biopsies, with specificity reaching up to 90%.

[CONCLUSIONS] Overlapping benign conditions and interobserver variability contribute to uncertainty in the interpretation of PI-RADS 3 lesions with regard to the indication for biopsy. PSA density and clinical context support risk-adapted decision-making, aligning with current guideline recommendations. A personalized approach is recommended to balance the risks of under- and overdiagnosis in managing PI-RADS 3 lesions.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s12894-025-01986-2.