Stesura Seveso Archivio Italiano di Urologia e Andrologia 2024; 96(2):12358 1 ORIGINAL PAPER MATERIALS AND METHODS From January 2011 to January 2023, 2,405 men (median age: 64 years; range: 41-86 years) underwent extended (median 20 cores; range: 16-22) or saturation (SPBx: median 26 cores; range: 22-30) transperineal prostate biopsy for the suspicion of cancer (9-11). Informed con- sents were obtained from all participants included in the study following institutional ethical committee approval. Before biopsy the patients underwent pelvic mpMRI using a 1.5 and 3.0 Tesla scanner (ACHIEVA 3T; Philips Healthcare Best, the Netherlands) equipped with surface 16-channel phased-array coil; multi-planar turbo spin- echo T2-weighted, axial diffusion weighted imaging (high b-value - 2000 s/mm2), and axial dynamic contrast enhanced MRI were performed for each patient (12). The systematic biopsy was performed transperineally and mpMRI lesions with PI-RADS score > 3 (1.380/2.405 equal to 57.4% of the cases) were submitted to targeted biopsy (TPBx: four cores performing a transperineal cog- nitive approach, anterior zone of the gland) or a fusion guided-biopsy (Hitachi 70 Arietta ecograph, Chiba, Japan) (13-15). All the patients were sedated and received a sin- gle intraoperative dose of antibiotic prophylaxis. The detection rate for csPCa has been evaluated (16); more- over, the Clavien-Dindo grading system for the classifica- tion of biopsy complications was used (17). All the 180 men with PI-RADS score 5 had not dysuria, irritative urinary symptoms or stranguria. In 155/180 (86.1%) patients a stage T1c PCa was diagnosed, and 145/155 (93.5%) of them (Table 1) were classified as csPCa (International Society of Urologic Pathology “ISUP Grade Group “GG” > 2); in detail, 85/145 (58.6%), 30/145 (20.7%) and 30/145 (20.7%) csPCa were diag- nosed in the peripheric, anterior or both zones of the prostate, respectively. The median total PSA was 8.9 ng/ml (range: 2.7-95 ng/ml); moreover, quantitative biop- sy histology, PSA density (PSAD), PSA free/total are listed in Table 1. SPBx diagnosed 5/155 (3.2%) csPCa and 8/155 (5.2%) indolent PCa located outside the PI-RADS 5 lesions. In the remaining 25/180 (13.9%) patients with absence of cancer: 1/25 (4%) had a specific granulomatous prostati- tis (Mycobacterium Tubercolosis), 8/25 (32%) an aspecific granulomatous prostatitis, and 16/25 (64%) a normal parenchyma. None of the patients had significant compli- cations (only Clavien-Dindo grade I) following prostate Introduction: To evaluate the accuracy of PSMA PET/CT in men with mpMRI PI-RADS score 5 negative biopsy histology. Materials and methods: From January 2011 to January 2023, 180 men with PI-RADS score 5 underwent systematic plus mpMRI/TRUS biopsy; 25/180 (13.9%) patients had absence of cancer and six months from biopsy were submitted to: digital rectal examination, PSA and PSA density exams, mpMRI and 68GaPSMA PET/CT evaluation (standardized uptake value “SUVmax” was reported). Results: In 24/25 (96%) patients PSA and PSA density signifi- cantly decreased, moreover, the PI-RADS score was downgraded resulting < 3; in addition, median SUVmax was 7.5. Only 1/25 (4%) man had an increased PSA value (from 10.5 to 31 ng/ml) with a confirmed PI-RADS score 5, SUVmax of 32 and repeated prostate biopsy demonstrating a Gleason score 9/ISUP Grade Group 5 PCa. Conclusions: The strict follow up of men with PI-RADS score 5 and negative histology reduce the risk of missing csPCa espe- cially if PSMA PET/CT evaluation is in agreement with down- grading of mpMRI (PI-RADS score < 3). KEY WORDS: Prostate cancer; PSMA PET/CT; mpMRI; PI-RADS score 5. Submitted 5 February 2024; Accepted 18 february 2024 INTRODUCTION Multiparametric magnetic image resonance (mpMRI) is rec- ommended in men with suspicion prostate cancer (PCa) (1), but, still today, systematic prostate biopsies should be always combined with mpMRI/TRUS fusion biopsy due to the false negative rate (2-4) of mpMRI (15-20% of the cases) (5). The aggressiveness of clinically significant (csPCa) is correlated with the mpMRI Prostate Imaging Reporting and Data System (PI-RADS) scores; the detection rate for csPCa of suspicious mpMRI lesions performing tar- geted biopsy ranges from 65.3 to 83.8% (6) and in the presence of a suspicious area with PI-RADS score 5 ranges from 59.2 to 86% of the cases (7, 8). Therefore, a negative biopsy in men with PI-RADS score 5 need a thorough clin- ical follow up to avoid missing csPCa diagnosis. In our study, the follow up of men with negative biopsy histology of PI-RADS score 5 lesions has been reported including prostate-specific membrane antigen (PSMA) positron-emission tomography (PET/CT) evaluation. Negative biopsy histology in men with PI-RADS score 5: Is it useful PSMA PET/CT evaluation? Pietro Pepe 1, Ludovica Pepe 2, Michele Pennisi 1 1 Urology Unit, Cannizzaro Hospital, Catania, Italy; 2 Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", University of Messina, Italy. DOI: 10.4081/aiua.2024.12358 Summary Archivio Italiano di Urologia e Andrologia 2024; 96(2):12358 P. Pepe, L. Pepe, M. Pennisi 2 biopsy, requiring hospital admission. The men with gran- ulomatous prostatitis underwent specific antibiotic thera- py followed by laboratory showing negative culture of urine and semen; moreover, the urine and sperm search for Mycobacterium Tuberculosis test including the semen polymerase chain reaction (PCR) (TB-PCR) were negative. The clinical follow up of patients without proven diagno- sis of PCa including PSMA PET/CT evaluation has been reported. RESULTS All the 25 men with PI-RADS score 5 and negative histol- ogy six months from biopsy underwent: digital rectal examination (DRE), PSA, PSAD, mpMRI and PSMA PET/CT evaluation (Table 2). PET/CT imaging was per- formed using a CT-integrated PET scanner (Biograph 6; Siemens, Knoxville, TN, USA); 68Ga-PSMA-11 was given to patients via an intravenous bolus; images were processed to obtain PET, CT, and PET-CT fusion sections in the axial, coronal, and sagittal planes with a thickness of approximately 0.5 ~ cm. The location of focal uptake on 68Ga-PSMA PET/TC, three-dimensional size, and standardised uptake value (SUVmax) values were report- ed on a per-lesion basis with a sextant scheme (18, 19). Twenty-four (96%) patients did not underwent repeated prostate biopsy because PSA significantly decreased, moreover, the initial PI-RADS score 5 was significantly downgraded by a repeated mpMRI to PI-RADS score < 3 (Table 2); in addition, median SUVmax was 7.5 (range: 4- 32). Only 1/25 (4%) man, who was submitted 3 years before to transurethral prostate resection for benign prostate enlargement, had an increased PSA value (from 10.5 to 31 ng/ml) with a confirmed PI-RADS score 5 and intraprostatic SUVmax of 32 and suspicious bone metas- tases; TPBx and systematic biopsy demonstrated the pres- ence of a Gleason score 9/ISUP GG5 PCa (6/24 positive cores) located in the anterior zone of the prostate that extended outside the gland. DISCUSSION Multiparametric MRI has improved the cost-effectiveness of prostate biopsy by reducing the risk of overdiagnosis and number of unnecessary procedures (20, 21). Although mpMRI is strongly recommended in men candi- date to prostate biopsy or enrolled in active surveillance protocols (2, 22, 23), extended or SPBx should be always combined with mpMRI/TRUS fusion biopsy because the false negative rate of mpMRI (24) and the variable accura- cy of mpMRI/TRUS fusion biopsy platforms (25). The cor- relation of the PI-RADS score to the diagnosis of aggres- siveness cancer has been well established; Westphalen et al. (7) and Otti et al. (8) showed in men with PI-RADS score 5 a detection rate for csPCa equal to 59.2 and 86%, respectively; we previously reported a detection rate of csPCa in the 86.7% of 105 men with PI-RADS score 5 who underwent repeated prostate biopsy (26). The systematic prostate biopsy detects only 3.4% of csPCa in case of neg- ative MRI/TRUS targeted biopsy of PI-RAS score 5 lesions (27). Therefore, the presence of a negative histology of a PI-RADS score 5 lesion needs an accurate follow up to avoid the risk of missing a high grade csPCa; the use of PSA, PSAD, risk calculator, urinary genetic tests, and the repetition of mpMRI allow to reduce the risk of harboring a csPCa. In this respect, a second opinion regarding initial mpMRI (28) and histology evaluation (29) should be per- formed to decrease the risk of false negative results. Recently, PSMA-PET/CT has been proposed for the diag- nosis of primary intraprostatic cancer (18, 19, 30, 31); the Table 1. Clinical parameters in 155 men with prostate cancer and PI-RADS score 5 submitted to systematic plus fusion targeted biopsy (TPBx). Quantitative biopsy histology PI-RADS score 5 Number of patients (pts) 155 pts initial biopsy 70/155 (45%) repeat biopsy 85/155 (55%) csPCa 145/180 (86.1%) Median mpMRI index lesion diameter 23 millimeter (range) (16-31) Detection of csPCa (ISUP GG > 2) 145 pts Systematic prostate biopsy 137 (94.5%) TPBx 138 (95.2%) Median number of positive cores 13 TPBx (range) 3 (2-4) Systematic biopsy (range) 10 (7-20) Median GPC 75% TPBx (range) 80% (60-100%) Systematic biopsy (range) 75% (50-100%) PSA density (range) 0.21 (0.16-0.26) PSA free/total (range) 12% (7-32%) Median prostate weight (grams) 50 (20-130 grams) ISUP: International Society of Urologic Pathology Grade Groups; mpMRI: Multiparametric magnetic resonance image; GPC: Greatest percentage of cancer; PI-RADS: Prostate Imaging Reporting and Data System. Table 2. Clinical follow up (six months from prostate biopsy) in 25 men with initial PI-RADS score 5 and negative histology for prostate cancer. Biopsy Aspecific *Specific Normal csPCa histology granulomatous granulomatous parenchyma ISUPGG5 prostatitis prostatitis Number of patients 8 cases 1 case 15 cases 1 case initial biopsy 6 (75%) 1 (100%) 7 (46.6%) 1 (100%) repeat biopsy 2 (25%) - 8 (63.4%) Median PSA (range) 6.2 ng/ml 3.2 ng/ml 4.7 ng/ml 31 ng/ml (1.5-10.8) (3.1-12.7) PSA density (range) 0.12 0.13 0.15 0.25 (0.10-0.18) (0.12-0.16) DRE negative negative negative negative PI-RADS score < 2 4 (50%) - 7 (46.5%) - PI-RADS score 3 4 (50%) 1 8 (63.4%) - PI-RADS score 4 - - - - PI-RADS score 5 - - - 1 (100%) 68GaPSMA PET/CT 7 8 7 32 median SUVmax (range: 4-10) (range 5-11) (4-11) DRE: Digital rectal examination; PI-RADS: Prostate Imaging Reporting and Data System; DRE: Digital rectal evaluation; *Mycobacterium Tubercolosis; GaPSMA PET/CT: Gallium prostate-specific membrane antigen positron-emission tomography; SUVmax: Standardized uptake value; ISUP GG: International Society of Urologic Pathology Grade Groups. Archivio Italiano di Urologia e Andrologia 2024; 96(2):12358 3 PSMA PET/CT and negative PI-RADS 5 biopsy presence of focal uptake on PSMA-PET/CT (SUVmax) and the maximal dimensions of PET-avid lesions have been correlated with the presence of csPCa (32). Although there is a range of proposed cut-offs to detect csPCa from SUVmax (33-35), the concordance between preoperative PSMA PET/TC evaluation and definitive prostate specimen ranges from 81.2 (36) to 96% (37). Many anatomic feature, benign conditions and technical pitfalls could mimic prostate cancer on mpMRI (38,39); the analysis of mpMRI parameters (DWI signal intensity and ADC values) combined with noninvasive test could help to separate benign lesions from csPCa (40-42). Gottlieb et al. (43) reported that men with previous spe- cific granulomatous prostatitits the presence of a PI-RADS score ≤ 3 may not required prostate biopsy; in our expe- rience, 16 men with initial PI-RADS score 5 and negative histology demonstrated six months later a PI-RADS score < 3 with normal clinical parameters (PSA, DRE, PSAD) (26). Recently, Wong et al. (44) in 29 men with PIRADS score 4-5 and negative biopsy histology reported that a SUVmax > 20 was correlated with the presence of csPCa In our series, 25/180 (13.9%) patients with PI-RADS score 5 had negative biopsy histology; six months from prostate biopsy the reduction of PSA and PSAD in 24/25 (96%) patients combined with the downgrading of PI- RADS score from 5 to < 3 allowed to avoid a repeated prostate biopsy; at the same time, PSMA PET/CT evalua- tion showed SUVmax (median 7.5) values not suspicious for csPCa resulting in agreement with the mpMRI results. Only one man (4%) had an increased PSA value (31 ng/ml) with PI-RADS score 5, SUVmax of 32 and TPBx combined with systematic biopsy demonstrated the pres- ence of a Gleason score 9/ISUP GG5 PCa. In definitive, the strict clinical follow up of men with neg- ative histology of PI-RADS score 5 lesions reduce the risk of missing csPCa especially if PSMA PET/CT evaluation is in agreement with downgrading of mpMRI (PI-RADS score < 3). Regarding our results some considerations should be done. Firstly, the results were not evaluated on the entire prostate gland. Secondly, we do not know if the presence of a mpMRI PIRADS score 3 (13 cases) was predictive of csPCa because a new biopsy was not performed. Third, a greater number of patients should be evaluated. Finally, a longer follow up is needed. 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Investigating PSMA- PET/CT to resolve prostate MRI PIRADS4-5 and negative biopsy dis- cordance. World J Urol 2023; 463-469. Correspondence Pietro Pepe, MD piepepe@hotmail.com Ludovica Pepe, MD ludopepe97@gmail.com Michele Pennisi, MD michepennisi2@virgilio.it Urology Unit, Cannizzaro Hospital, via Messina 829, Catania, Italy Conflict of interest: The authors declare no potential conflict of interest.