Hematological Inflammation Markers in the Prediction of Clinically Significant Prostate Cancer and the Individualization of Biopsy Decisions for PI‐RADS 3 Lesions: A Two‐Center Retrospective Study

ABSTRACT Background PI‐RADS 3 lesions represent a diagnostic “gray zone” in which biopsy decision‐making is particularly challenging, with reported clinically significant prostate cancer (csPCa) detection rates ranging from 13% to 50%. This study evaluated the predictive value of the systemic immune‐inflammation index (SII), neutrophil‐to‐lymphocyte ratio (NLR), and platelet‐to‐lymphocyte ratio (PLR)—alone and in combination with PSA density (PSAD) and PI‐RADS score—for the detection of prostate cancer (PCa) and csPCa, with a specific focus on the PI‐RADS 3 subgroup. Methods In this two‐center retrospective observational study, 982 patients who underwent prostate biopsy between 2020 and 2025 were included. csPCa was defined as ISUP Grade Group ≥ 2. Univariable and multivariable logistic regression analyzes were performed to identify independent predictors of PCa and csPCa. In the PI‐RADS 3 subgroup ( n = 251), two predictive models were compared using receiver operating characteristic analysis and the DeLong test: Model 1 (age, free/total PSA ratio, PSAD) and Model 2 (Model 1 + SII + NLR). Results Of the 982 patients, 188 (19.1%) were diagnosed with PCa and 150 (15.3%) with csPCa. In the overall cohort, NLR ≥ 2.11 was independently associated with csPCa (OR, 15.924; 95% CI, 2.472‐102.567; p = 0.004), whereas SII did not retain independent significance. PLR showed an inverse association with PCa, possibly reflecting tumor‐related platelet dynamics. In the PI‐RADS 3 subgroup, SII ≥ 661.37 (OR, 2.317; p = 0.039) remained an independent predictor of PCa alongside age, free/total PSA ratio, and PSAD ≥ 0.20 (OR, 6.111; p = 0.013), while NLR showed borderline significance. The addition of SII and NLR to the clinical model increased the AUC from 0.795 to 0.816 in the PI‐RADS 3 subgroup, although this improvement did not reach statistical significance ( p = 0.134). Conclusions Systemic inflammatory markers—particularly SII and NLR—provide complementary predictive information in the pre‐biopsy risk stratification of prostate cancer. SII emerged as an independent predictor of PCa specifically within the PI‐RADS 3 gray zone, while NLR independently predicted csPCa in the overall cohort. These routinely available, low‐cost parameters may serve as practical adjuncts to PSA derivatives and mpMRI in the individualization of biopsy decisions, particularly for PI‐RADS 3 patients.