Serum (‐2)proPSA/freePSAratio, (‐2)proPSA/freePSA density, prostate health index, and prostate health index density as clues to reveal postoperative clinically significant prostate cancer in men with prostate‐specific antigen 2–10 ng/mL
Authors: Ferro Matteo , Crocetto Felice , La Civita Evelina , Fiorenza Mariano , Jannuzzi Giuseppe , Carbone Gianluigi , Sirica Rosa , Sicignano Enrico , Pagano Giovanni , Imbimbo Ciro , Terracciano Daniela 
Published: May 2024

AbstractBackgroundThere is a strong clinical need to fill the gap of identifying clinically significant prostate cancer (csPCa) in men with prostate‐specific antigen (PSA) gray zone values. Promising, but not definitive results have been obtained using PSA derivatives such as prostate health index (PHI) and PHI density (PHID) and the percentage (‐2)proPSA/free PSA (%p2PSA/fPSA). Thus, this study aimed to compare the diagnostic value of PHI, PHID, %proPSA/fPSA, and (‐2)proPSA/freePSA density (‐2pPSA/fPSAD) for csPCa in the patients with PSA within 2–10 ng/mL.MethodsSerum samples and clinicopathological features were prospectively collected from 142 patients who underwent robot‐assisted radical prostatectomy between September 2021 and December 2023. According to the inclusion criteria, the patients with total PSA within 2 and 10 ng/mL and negative or suspicious digital rectal examination were enrolled. We used two different classifications for csPCa: 1) patients with Gleason score (GS) ≥ 7(4 + 3) and 2) patients with GS ≥ 7(3 + 4). The receiver operating characteristic curves and the area under the curve (AUC) values were used to assess the diagnostic performance.ResultsOf the 142 men included, 116 (82%) patients were diagnosed with csPCa as GS ≥ 3 + 4 and 107 (75%) defined as csPCa as GS ≥ 7(4 + 3), respectively. We found that p2PSA/fPSA, p2PSA/fPSAD, PHI, and PHID were significantly higher in csPCa classified as GS ≥ 7(3 + 4) as well as GS ≥ 7(4 + 3), with p‐values 0.027, 0.054, 0.0016, and 0.0027, respectively. AUCs of the analyzed variables were higher when used to predict csPCa as GS ≥ 6 compared to csPCa as GS ≥7(4 + 3), with an AUC equal, respectively, to 0.679 (95% CI: 0.571–0.786), 0.685 (95% CI: 0.571–0.799), 0.737 (95% CI: 0.639–0.836), and 0.736 (95% CI: 0.630–0.841) in the first subgroup and with an AUC equal, respectively, to 0.653 (95% CI: 0.552–0.754), 0.665 (95% CI: 0.560–0.770), 0.668 (95% CI: 0.568–0.769), and 0.670 (95% CI: 0.567–0.773) in the second, respectively. Both PHID and p2PSA/fPSAD allowed improvement in the diagnostic accuracy with respect to PHI and p2PSA/fPSA ratio, however the differences were not statistically significant (p = 0.409, 0.180 for csPCa as G ≥ Gleason grade (GG) 2 and 0.558 and 0.087 for csPCa as G ≥ GG3, respectively). We found that PHI, PHID, p2PSA/fPSA ratio, and p2PSA/fPSAD showed higher sensitivity, specificity, and positive predictive value when used to predict csPCa as GG ≥ 2, whereas negative predictive value of all four parameters was higher when used to predict GG ≥ 3.ConclusionsIn men with a PSA level between 2 and 10 ng/mL, PHI and PHID, p2PSA/fPSA, and p2PSA/fPSAD showed good diagnostic performance for postoperative csPCa. However, PHID and p2PSA/fPSAD had a small advantage over PHI which needs to be further investigated for the reduction of unnecessary surgical interventions. This finding suggests that it could be a promising biomarker for making the treatment‐decision strategy.