Stesura Seveso 139Archivio Italiano di Urologia e Andrologia 2021; 93, 2 ORIGINAL PAPER No conflict of interest declared. the evalution of mpMRI combined with clinical parame- ters (i.e., PSA density, digital rectal examination) instead scheduled prostate biopsies in the reevaluation of men enrolled in Active Surveillance protocols (4-7); there- fore, mpMRI quality and radiologist expertice represent a central topic in the decision making for prostate biop- sy. The detection rate of csPCa is directly related with the PI-RADS score (8, 9) and the results depend on clinical parameters, the number of previous negative biopsies and the quality of targeted mpMRI/TRUS fusion biopsy procedures; the gray zone of mpMRI evaluation is still today represented by the diagnosis of a PI-RADS 3 lesion that could harbour the presence of a clinically significant prostate cancer (csPCa) in about 20-25% of the cases (10- 12). At the same time, the number of PI-RADS score 3 diagnosed by radiologists should be limited to a low per- centage among all the mpMRI procedures similarly as reported by pathologists for the diagnosis of Atypical Small Cell Acinar Proliferation. In this study, we report the detection rate for csPCa in men with PIRADS score 3 diagnosed by reference vs affil- iated radiological centers. PATIENTS AND METHODS From January 2017 to December 2020, 950 men (medi- an age 64 years; range: 47-75 years) with negative digi- tal rectal examination underwent mpMRI for abnormal PSA values (median 6.3 ng/ml; range 2.9-102 ng/ml); 680 and 270 underwent initial and repeated prostate biopsy. In 500 men mpMRI was performed at our Hospistal Imaging Department considered aa a reference center; on the contrary, 450 patients were submitted to mpMRI by outpatient radiological affiliated centers. All mpMRI examinations were previously performed using a 1.5 Tesla scanner equipped with surface 16 channels phased-array coil placed around the pelvic area with the patient in the supine position; multi-planar turbo spin-echo T2-weighted, and axial diffusion weighted imaging, and axial dynamic contrast (ADC) enhanced MRI were performed for each patient (4). All the mpMRI index lesions characterized by a PI-RADS (version 2) > 3 underwent targeted cores (TPBx: four cores) combined with extended systematic prostate Introduction: The detection rate for clinical- ly significant prostate cancer (csPCa) in men with mpMRI PI-RADS score 3 diagnosed by affiliated radi- ology centers vs radiological reference center was evaluated. Materials and methods: From January 2017 to December 2020, 950 men (median age 64 years) underwent mpMRI for abnormal PSA values (median 6.3 ng/ml). Among the 950 patients who underwent mpMRI 500 were evaluated by a refer- ence center and 450 by outpatient radiological affiliated cen- ters. All the mpMRI index lesions characterized by a PI-RADS 3 underwent targeted cores combined with extended prostate biopsy. Two radiologists of the radiological reference center revised all the mpMRI lesions 3. Results: Overall, 361/950 (38%) patients had a mpMRI lesion PI-RADS score 3: 120/500 cases (24%) vs 241/450 cases (53.5%) were diagnosed by reference vs affiliated radiological centers. The detection rate for cT1c csPCa was equal to 26.7% (35/120 cases) vs 16.6% (40/241 cases) in men with PI-RADS 3 lesions diagnosed in the reference vs the affiliated radiological centers (p < 0.05). Among the 241 PI-RADS score 3 lesions diagnosed by affiliated radiological centers 86/241 (35.7%) and 36/241 (15%) were downgraded (PI-RADS scores < 3) and upgraded (PI-RADS score 4) by the dedicated radiologists of the reference center. Conclusions: In our series, about 35% and 15% of PI-RADS score 3 lesions diagnosed by affiliated radiological centers were downgraded and upgraded when revised by experencied radiol- ogists, therefore a second opinion is mandatory especially in men enrolled in active surveillance protocols in whom mpMRI is recommended to reduce the number of scheduled repeated prostate biopsies. KEY WORDS: Prostate cancer; MRI and prostate cancer; PI-RADS score 3; Transperineal targeted biopsy. Submitted 21 February 2021; Accepted 14 March 2021 INTRODUCTION Multiparametric magnetic resonance imaging (mpMRI) is strongly recommended before biopsy for the diagnosis of clinically significant prostate cancer (csPCa) (1) in order to reduce the risk of overdiagnosis and to improve the cost- effectiveness of prostate biopsy (2). Recently, the European Association of Urology guidelines (3) suggested mpMRI PI-RADS score 3 lesions diagnosed by reference vs affiliated radiological centers: Our experience in 950 cases Pietro Pepe 1, Giuseppe Candiano 1, Ludovica Pepe 1, Michele Pennisi 1, Filippo Fraggetta 2 1 Urology Unit, Cannizzaro Hospital, Catania, Italy; 2 Pathology Unit, Cannizzaro Hospital, Catania, Italy. DOI: 10.4081/aiua.2021.2.139 Summary Archivio Italiano di Urologia e Andrologia 2021; 93, 2 P. Pepe, G. Candiano, L. Pepe, M. Pennisi, F. Fraggetta 140 biopsy (at least 12 cores); the procedure was performed transperineally using a tru-cut 18 gauge needle (Bard; Covington, GA, USA) under sedation and antibiotic pro- phylaxis (5). The TPBx was done using an Hitachi 70 Arietta ecograph, Chiba, Japan) supplied by a bi-planar trans-rectal probe (13). The data have been collected fol- lowing the START criteria (14). Two radiologists of the radiological reference center with 11 years of experience blinded to pre-imaging clinical parameters evaluated the mpMRI data separately and independently. The detection rate for csPCa in men with PIRADS score 3 diagnosed by affiliated vs radiological reference center was evaluated; in addition, all PI-RADS 3 lesions diagnosed in the affiliated radiological centers were revised by the dedicated radiologists and compared with biopsy histology results. For statistical analysis a p value < 0.05 was considered statistically significant. RESULTS Overall, 361/950 (38%) patients had a mpMRI lesion PI- RADS score 3: 120/500 cases (24%) vs 241/450 cases (53.5%) were diagnosed by reference vs affiliated radiol- ogy centers, respectively. The PI-RADS 3 lesions were located in the peripheric and anterior zone of the gland in 190 and 171 cases; moreover, 151 (41.8%) vs 210 (58.2%) men underwent cognitive vs fusion targeted biopsy procedure, respec- tively. The detection rate for T1c csPCa was equal to 26.7% (35/120 cases) vs 16.6% (40/241 cases) in men with PI-RADS 3 lesions diagnosed in the reference vs the affiliated radiological centers (p < 0.05) (Table 1): in detail, 24 and 11 vs 25 and 15 of the csPCa were located in the peripheric and anterior zone of the prostate, respectively. None had significant complications (Clavien-Dindo grade I) (15) from prostate biopsy that needed hospital admission. The clinical parameters (i.e., PSA, weight, PSA density) and the biopsy quantitative histology (i.e., number of positive cores, greatest percentage of cancer and Grade Group) is reported in Table 1; a normal parenchyma was diagnosed in the remaining 286/361 (79.2%) men. The median diameter of PI-RADS 3 index lesions was 10 mm. vs 9 mm. in men with csPCa vs normal parenchy- ma, respectively. Among the 241 PI-RADS score 3 lesions diagnosed by affiliated radiological centers 86/241 (35.7%) and 36/241 (15%) were respectively downgrad- ed (PI-RADS scores < 3) and upgraded (PI-RADS score 4) by dedicated radiologist of the reference center. The presence of csPCa was significantly correlated with the ADC value (Table 1). DISCUSSION The improvement of diagnostic imaging by mpMRI has allowed targeted biopsies of the suspicious area, increas- ing the diagnosis of csPCa and reducing the number of unnecessary systematic biopsy. Although mpMRI is strongly recommended in men can- didate for prostate biopsy (3) or in men enrolled in active surveillance protocols (7), still today, systematic biopsy should be always combined with mpMRI/TRUS fusion biopsy because the increased false negative rate (5, 14) of mpMRI (about 20% of the cases) (6) and the variable diagnostic accuracy of the different mpMRI/TRUS fusion biopsy platforms (17). While the risk of clinically signif- icant in case of PIRADS 4-5 is well established, PIRADS 3 lesions are presented as equivocal and at low risk of aggressive disease with the identification of csPCa is not neglegible (6, 8-11-12). The PI-RADS 3 lesions identified on mpMRI are consid- ered to be “a gray area” in the diagnosis protocol of PCa (18, 19). The main objectives regarding PIRADS 3 score are to accurately diagnose csPCa and avoiding unneces- sary biopsies that could have undesirable side effects on patients and thus, avoiding overdiagnosis and overtreat- ment. In a recent review, Maggi et al. (20) demonstrated the superiority of combined target and systematic biopsy in detecting csPCa in patients with PIRADS 3 lesions; more- over, they also found that combining PIRADS 3 score with a PSAD > 0.15 ng/ml/ml could improve the detec- tion rate of csPCa on prostate biopsy (21). In addition, to identify the PI-RADS score at high risk for csPCa irrespective of clinical findings many parameters have been reported: index lesion diameter, shape and location of the lesion and the ADC values (6, 9, 11). Wu et al. (22) showed that higher ADC values (0.830×10-3 mm2/sec) were significantly associated with low-risk prostate cancer; on the contrary, Kim et al. (23) reported a mean ADC value for csPCa equal to (0.741 ± 0.164) ×10-3 mm2/sec. In our series, the detection rate for T1c csPCa was equal to 26.7% (35/120 cases) vs 16.6% (40/241 cases) in men with PI-RADS 3 lesions diagnosed in the reference vs the affiliated radiological centers; in detail, among the 241 PI-RADS score 3 lesions diagnosed by affiliated radiolog- ical centers 35.7% (86/241) and 15% (36/241) were downgraded (PI-RADS scores < 3) and upgraded (PI- Table 1. Quantitative biopsy histology, clinical parameters and ADC values in men with PI-RADS (prostate imaging-reporting and data system) score 3 lesions and clinically significant prostate cancer (csPCa). Radiological Radiological P value reference center affiliated centers Overall number of patients with csPCa: 75/361 35/120 40/241 < 0.05 (26.7%) (16.6%) csPCa csPCa Median PSA values (ng/ml) 8.7 9.1 > 0.05 Grade group (ADC value) 35 pts 40 pts 1 (0.750 ± 0.162) - 2 < 0.05 2 (0.635 ± 0.117) 28 19 < 0.05 3 (0.489 ± 0.093) 17 19 > 0.05 Median number of positive TPBx cores 1.5 1.0 > 0.05 Median number of systematic positive cores 4 (1-9) 5 (1-12) > 0.05 Median GPC (range) 50% 50% > 0.05 Median prostate weight (grams) 50 46 > 0.05 Median mpMRI lesion index diameter (mm) 10 9 > 0.05 PSA: Prostate specific antigen; TPBx: Targeted transperineal fusion biopsy; GPC: Greatest percentage of cancer for single core; ADC: Apparent diffusion coefficient; mpMRI: Multiparametric magnetic resonance imaging; pts: Patients. RADS score 4) by dedicated radiologist of the reference center. In addition, PSA density and ADC value of 0.747×10-3 mm2/sec, threshold obtained from ROC curve analysis improved the diagnosis for csPCa in the presence of PI-RADS 3 lesions. Regarding our results some considerations should be made. Firstly, the results were evaluated on biopsy spec- imens and not on the entire prostate gland or by per- forming a template mapping biopsy; secondly, although our study represent the real life clinical practice a quali- ty control of the affiliated radiological centers was unknown. Finally, a greater number of patients and a centralized evaluation of mpMRI results should be performed; more- over, among the 361 men with PI-RADS score 3 only 210 (58.2%) underwent fusion targeted prostate biopsy. 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