BJU Int 2021 doi:10.1111/bju.15568 Original Article The current recommendation for the management of isolated high-grade prostatic intraepithelial neoplasia Juan Morote1,2,3  n Schwartzmann1, Anna Celma1,2 , Iva  s M. de Torres3,2,5, Richard Mast4, , Sarai Roche4, Ine Maria E. Semidey , Lucas Regis , Anna Santamaria , Jacques Planas and Enrique Trilla1,3 2,5 1,2 2 1,2 1 Department of Urology, Vall d´Hebron Hospital, Barcelona, Spain, 2Prostate Cancer Research Group, Vall d´Hebron  noma de Barcelona, Barcelona, Spain, 4Department of Research Institute, Barcelona, Spain, 3Universitat Auto Radiology, Vall d´Hebron Hospital, Barcelona, Spain, and 5Department of Pathology, Vall d´Hebron Hospital, Barcelona, Spain Equal contribution: Enrique Trilla and Jacques Planas Abstract Objective To analyse the current predictive value of isolated high-grade prostatic intraepithelial neoplasia (HGPIN) for clinically significant prostate cancer (csPCa) detection in repeat biopsies. Patients and Methods A cohort of 293 men with isolated HGPIN detected in previous biopsies performed without multiparametric magnetic resonance imaging (mpMRI), and who underwent repeat biopsy within 1 to 3 years, was analysed. Pre-repeat biopsy mpMRI and guided biopsies to suspicious lesions (Prostate Imaging – Reporting and Data System [PI-RADS] ≥3) and/or and systematic biopsies were performed. Persistent prostate cancer (PCa) suspicion, defined as sustained serum prostate- specific antigen level >4 ng/mL and/or abnormal digital rectal examination, was present in 248 men (84.6%), and was absent in 45 men (15.4%). A control group of 190 men who had no previous HGPIN, atypical small acinar proliferation or HGPIN with atypia who were scheduled to undergo repeat biopsy due to persistent PCa suspicion were also analysed. csPCa was defined as tumours of Grade Group ≥2. Results In the subset of 45 men with isolated HGPIN, in whom PCa suspicion disappeared, only one csPCa (2.2%) and one insignificant PCa (iPCa) were detected. csPCa was detected in 34.7% of men with persistent PCa suspicion and previous HGPIN, and in 28.4% of those without previous HGPIN (P =0.180). iPCa was detected in 12.1% and 6.3%, respectively (P =0.039). Logistic regression analysis showed that the risk of csPCa detection was not predicted by previous HGPIN: odds ratio (OR) 1.369 (95% confidence interval [CI] 0.894–2.095; P =0.149); however, previous HGPIN increased the risk of iPCa detection: OR 2.043 (95% CI 1.016–4.109; P =0.006). Conclusion The risk of csPCa in men with isolated HGPIN, in whom PCa suspicion disappears, is extremely low. Moreover, in those men in whom PCa suspicion persists, the risk of csPCa is not influenced by the previous finding of HGPIN. However, previous HGPIN increases the risk of iPCa detection. Therefore, repeat prostate biopsy should not be recommended solely because of a previous HGPIN. Keywords high-grade intraepithelial neoplasia, clinically significant prostate cancer, insignificant prostate cancer, multiparametric MRI, repeat prostate biopsy © 2021 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International. www.bjui.org wileyonlinelibrary.com This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. MOROTE et al. biopsy mpMRI and guided biopsies to Prostate Imaging – Introduction Reporting and Data System (PI-RADS) lesions ≥3 and/or 12- In 1986, McNeal and Bostwick [1] initially described core systematic biopsies (if negative mpMRI) were always intraductal prostatic dysplasia as a premalignant lesion, while performed. Multifocal HGPIN, defined as detection of ≥3 Bostwick and Brawer [2] subsequently coined the name cores with HGPIN [3,4,8,12,13], was found in 192 men prostatic intraepithelial neoplasia (PIN). The poor (65.6%). Persistent PCa suspicion, defined as sustained serum reproducibility of low-grade PIN and its lack of association PSA level >4 ng/mL and/or abnormal DRE, was present in with prostate cancer (PCa) meant that, after a while, only 248 men (84.6) and not in the remaining 45 men (15.4%). A high-grade PIN (HGPIN) was reported. In addition, isolated control group of 190 men without previous HGPIN and HGPIN appeared to be more associated with future detection persistent PCa suspicion, who were previously subjected to of PCa, specifically when multifocal, which occurs when three systematic biopsies without mpMRI, and were scheduled to or more cores contain the lesion [3-5]. The initial incidence undergo pre-repeat biopsy mpMRI and guided and/or of isolated HGPIN ranged from 0.6% to 24%, but this systematic re-biopsies during the same period were also decreased after the application of more aggressive biopsy selected. schemes. The current risk of PCa detection following isolated HGPIN is ˜20–30%, which is not significantly higher than Repeat biopsy procedure detection after a benign biopsy [5,6]. Currently, the European Association of Urology (EAU) PCa guidelines recommend The EAU PCa guidelines and recommendations for repeating repeating prostate biopsy within 1 to 3 years after a finding prostate biopsies were strictly followed [7]. A 3-Tesla mpMRI of multifocal HGPIN [7]. (Magneton Trio; Siemens Medical Solutions, Erlangen, Germany) was performed according to the guidelines of the The current challenge regarding early detection of PCa has European Society of Urogenital Radiology [14]. After changed. Currently, the goal is to detect the maximum November 2015 and, retrospectively, before this date, two amount of clinically significant PCa (csPCa), reducing the expert radiologists (S.R. and R.M.) used the PI-RADS v2 overdetection of insignificant PCa (iPCa), and saving scoring system [15]. An expert urologist (A.C.) performed all unnecessary prostate biopsies [7,8]. Pre-biopsy repeat biopsies according to the EAU PCa guideline multiparametric MRI (mpMRI) and guided biopsies have recommendations [7]. A minimum of two-cores TRUS- improved the early detection of PCa, and they are the current guided biopsies were obtained, through MRI–ultrasonography strategy for early detection of csPCa [7]. Recent evidence cognitive fusion, from the lesions with PI-RADS lesions >3 suggests that the majority of tumours detected in repeat [16], and 12-core TRUS systematic biopsy was performed biopsies after isolated HGPIN are low-grade tumours. alone when no suspicious lesions were detected on mpMRI However, the impact of this new strategy for detecting csPCa [17]. A BK Focus 400 ultrasonography scanner with a is unknown [6,8,9,10,11,12,13]. triplane endorectal probe 8881 (BK Medical Company Inc., The main aim of the present study was to evaluate the Herlev, Denmark), and an 18-gauge, 25-cm, automated current recommendation of repeating prostate biopsy after biopsy needle (Bard Monopty; Bard Medical Inc, Covington, isolated HGPIN detection, by assessing the risk of csPCa and GA, USA) were used. Two expert uropathologists (I.M.d.T. iPCa in such men, based on the persistence of PCa suspicion, and M.E.S.) analysed the biopsy material. The tumour based on serum PSA, and DRE evolution. grading was reported using Grade Groups (GGs), which were initially proposed by authors led by Dr Epstein at Johns Hopkins Hospital [18]. These were validated in a large multi- Patients and Methods institutional study [19], and subsequently endorsed by the Study cohort 2014 International Society of Urological Pathology Consensus Conference [20], whereby GG1 = Gleason score ≤6, GG2 = A cohort of 483 men scheduled to undergo repeat prostate Gleason score 3+4=7, GG3 = Gleason score 4+3=7, GG4 = biopsy between 1 January 2015 and 31 December 2019, who Gleason score 8, and GG5 = Gleason score 9–10 [18-20]. GG previously had 12-core systematic biopsy without pre-biopsy ≥2 tumours were classified as csPCa, while GG1 defined iPCa mpMRI, were selected. Men with a previous PCa diagnosis, [21,22]. atypical small acinar proliferation, HGPIN with atypia (PINATYP), undergoing 5-a-reductase inhibitor treatment, and who had incomplete datasets were previously excluded. Statistical Method The institutional review board approved the study (PR/317/ The main outcome variables were csPCa and iPCa. 2017). Quantitative variables were denoted by medians and A total of 293 men with previous HGPIN were prospectively interquartile range, while qualitative variables were denoted followed and re-biopsied within 1 to 3 years. Pre-repeat by numbers and rates. Associations between categorical © 2021 The Authors. 2 BJU International published by John Wiley & Sons Ltd on behalf of BJU International The current management of HGPIN variables were assessed with chi-squared or McNemar´s tests, on the finding of isolated HGPIN in the previous negative while the Mann–Whitney U-test, Kruskal–Wallis test and prostate biopsies and its type, unifocal or multifocal. The rate median test were used to assess quantitative variables. of negative mpMRI ranged between 24.2% and 32.8% in men Multivariate analysis, using binary logistic regression, was with HGPIN, while the rates of PI-RADS score 5 ranged performed to predict PCa, csPCa, or iPCa; the odds ratios between 4.0% in men with unifocal HGPIN and 5.7% in (ORs) and 95% CIs were calculated. Two-sided statistical tests those with mHGPIN. The overall PI-RADS distribution were evaluated, and P values <0.05 were taken to indicate between men without previous HGPIN and those with statistical significance. This analysis was performed using the unifocal and multifocal HGPIN was similar (P =0.292). Statistical Package for the Social Sciences (SPSSv.24; IBM Corp., Armonk, NY, USA). PCa detection rate in men with previous multifocal HGPIN in whom the suspicion of PCa, based on PSA Results and DRE, had not persisted after the previous Comparison between the characteristics of men negative biopsy without prior HGPIN and those with unifocal or In 45 men with previous multifocal HGPIN and no currently multifocal HGPIN in the previous negative biopsy suspected PCa, based on their PSA and DRE, a repeat The characteristics of the study population are summarized in prostate biopsy was only recommended based on the previous Table 1. The study highlights that 60.5% of men scheduled finding. PCa was found in two men (4.4%): csPCa in one for repeat prostate biopsy had previous HGPIN, 34.4% had (2.2%) and iPCa in the other. The man with iPCa had a PI- unifocal and 65.6% had multifocal tumours. Among the men RADS score of 3 and the man with csPCa had a PI-RADS scheduled for repeat prostate biopsy, 91.3% had PCa score of 4. By contrast, among the 248 men who had suspicion, which was based on persistent serum PSA elevation previous HGPIN and persistent PCa suspicion, the overall and/or abnormal DRE, while 45 men (8.7%) had previous detection rate of PCa was 46.8% (P <0.001): 34.7% for csPCa multifocal HGPIN, which was the only indication for (P <0.001) and 12.1% for iPCa, as shown in Table 3. repeating prostate biopsy. The overall rate of PCa detection was 38.1%, including 29.2% of csPCa and 8.9% of iPCa. PCa detection rates in men with persistent PCa Table 2 summarizes the general characteristics of men based suspicion according to the finding of HGPIN in the previous negative biopsy, and based on PSA and Table 1 Demographics of the study population DRE Among the 248 men with previous HGPIN and persistent Characteristic Value serum PSA elevation and/or abnormal DRE, PCa was Sessions, n 483 detected in 43.6% of 101 men with previous unifocal HGPIN, Median (IQR) age, years 67 (62–73) and in 49.0% of the 147 men with multifocal HGPIN (P Median (IQR) PSA, ng/mL 7.5 (5.2–12.0) Positive DRE, n (%) 95 (19.7) =0.438). The csPCa detection rate was 34.7% in both men Median (IQR) prostate volume, mL 56 (40–76) with unifocal HGPIN and those with multifocal HGPIN (P = Median (IQR) PSA density, ng/mL/mL 0.13 (0.09–0.23) 1.000). The iPCa detection rates were 8.9% and 12.1%, PCa family history, n (%) 83 (17.2) Median (IQR) number of previous biopsies 1 (1–2) respectively (P =0.238; Table 4). Logistic regression analysis Median (IQR) interval between last two 23 (14–36) showed that the previous HGPIN had an OR of 1.701 (95% biopsies, months CI 1.139–2.539) to predict overall PCa (P =0.009), while PCa Previous HGPIN, n (%) 293 (60.5) Unifocal HGPIN, n (%) 101 (34.4) suspicion had an OR of 11.992 (95% CI 2.786–51.623; P Multifocal HGPIN, n (%) 192 (65.6) <0.001), and mpMRI had an OR of 3.579 (95% CI 2.247– Persistent PCa suspicion based on 441 (91.3) 5.966; P <0.001). The risk of csPCa was only significantly PSA and/or DRE, n (%) mpMRI, n (%) predicted by PCa suspicion, with an OR of 12.699 (95% CI PI-RADS 1–2 136 (28.6) 3.240–12.829; P <0.001), and mpMRI with an OR of 6.447 PI-RADS 3 182 (37.7) (95% CI 1.676–92.204; P <0.014). Finally, the risk of iPCa PI-RADS 4 135 (28.0) PI-RADS 5 28 (5.8) detection was only predicted by the finding of previous PCa detection, n (%) 184 (38.1) HGPIN, with an OR of 2.043 (95% CI 1.016–4.1.09; P =0.006 csPCa detection, n (%) 141 (29.2) [Table 5]). iPCa detection, n (%) 43 (8.9) Table 6 [10,25-31] provides a summary of the main csPCa, clinically significant prostate cancer; HGPIN, high-grade prostate intraepithelial neoplasia; iPCa, insignificant prostate cancer; characteristics and findings of published studies that included IQR, interquartile range; mpMRI, multiparametric MRI; PCa, prostate more than 50 men who had previous HGPIN and were cancer; PI-RADS, Prostate Imaging – Reporting and Data System. subjected to repeat biopsy. © 2021 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International 3 MOROTE et al. Table 2 Characteristics according to the previous finding of high-grade prostate intraepithelial neoplasia and type Characteristic Without HGPIN Unifocal HGPIN Multifocal HGPIN P Sessions, n (%) 190 (39.3) 101 (20.9) 192 (39.8) - Median (IQR) age, years 68 (63–73) 68 (63–74) 68 (61–73) 0.389 Median (IQR) PSA, ng/mL 7.3 (5.8–13.5) 7.6 (5.7–13.8) 7.0 (3.2–9.4) 0.238 Positive DRE, n (%) 37 (19.5) 22 (23.8) 34 (17.5) 0.367 Median (IQR) prostate volume, mL 59 (44–93) 57 (46–85) 58 (37–78) 0.187 Median PSA density, ng/mL/mL 0.13 (0.09–0.22) 0.12 (0.08–0.20) 0.12 (0.07–0.18) 0.749 PCa family history, n (%) 24 (12.6) 66 (15.8) 28 (14.6) 0.587 Median (IQR) previous biopsies 1 (1–2) 1 (1–2) 1 (1–2) 0.756 Median (IQR) months between last two biopsies 22 (15–42) 23 (13–38) 21 (14–30) 0.268 Persistent PCa suspicion based on PSA and/or DRE, n (%) 190 (100) 101 (100) 147 (76.6) 0.001 mpMRI, n (%) PI-RADS 1–2 46 (24.2) 29 (28.7) 63 (32.8) 0.292 PI-RADS 3 68 (35.8) 40 (39.6) 74 (38.5) PI-RADS 4 63 (33.2) 28 (27.7) 44 (22.9) PI-RADS 5 13 (6.8) 4 (4.0) 11 (5.7) PCa detection, n (%) 66 (34.7) 44 (43.6) 74 (38.5) 0.332 csPCa detection, n (%) 54 (28.4) 35 (34.7) 52 (27.1) 0.382 iPCa detection, n (%) 12 (6.3) 9 (8.9) 22 (11.5) 0.211 csPCa, clinically significant prostate cancer; HGPIN, high-grade prostate intraepithelial neoplasia; iPCa, insignificant prostate cancer; IQR, interquartile range; PCa, prostate cancer; mpMRI, multiparametric MRI; PI-RADS, Prostate Imaging – Reporting and Data System. Table 3 Prostate cancer detection rates in men with previous high-grade Table 5 Logistic regression analysis for the prediction of overall prostate prostate intraepithelial neoplasia, with and without persistently suspected cancer (PCa), clinically significant PCa and insignificant PCa detection in prostate cancer, based on serum PSA and/or DRE, at the time of repeat repeat prostate biopsies, according to the previous finding of high-grade prostate biopsy prostate intraepithelial neoplasia, persistent PCa suspicion based on serum PSA elevation and/or abnormal DRE, and previous multiparametric MRI Type of PCa PCa suspicion P Yes (n =248) No (n =45) Predictor Odds ratio (95% CI) P Overall PCa 116 (46.8) 2 (4.4) <0.001 For overall PCa csPCa 86 (34.7) 1 (2.2) <0.001 Previous HGPIN (ref.: no 1.70 (1.139–2.539) 0.009 iPCa 30 (12.1) 1 (2.2) 0.031 previous HGPIN) PCa suspicion (ref.: no PCa 11.99 (2.786–51.623) <0.001 csPCa, clinically significant prostate cancer; iPCa, insignificant suspicion) prostate cancer; PCa, prostate cancer. mpMRI (ref.: PI-RADS 1–2) 3.58 (2.247–5.966) <0.001 For csPCa Previous HGPIN (ref.: no 1.37 (0.894–2.095) 0.149 previous HGPIN) Table 4 Prostate cancer detection rates in men scheduled to repeat PCa suspicion (ref.: no PCa 12.70 (3.240–12.829) <0.001 prostate biopsy due to previous high-grade prostate intraepithelial suspicion) neoplasia (HGPIN) and persistent prostate cancer suspicion based on serum PSA elevation and/or abnormal DRE, according to the type of mpMRI (ref.: PI-RADS 1–2) 6.45 (1.676–92.204) <0.014 HGPIN. For iPCa Previous HGPIN (ref.: no 2.04 (1.016–4.1.09) 0.006 previous HGPIN) Type of PCa Type of HGPIN P PCa suspicion (ref.: no PCa 6.99 (0.895–53.680) 0.064 Unifocal (n =101) Multifocal (n =147) suspicion) mpMRI (ref.: PI-RADS 1–2) 0.75 (0.373–1.516) 0.426 Overall PCa 44 (43.6) 116 (46.8) 0.438 csPCa 35 (34.7) 72 (34.7) 1.000 csPCa, clinically significant prostate cancer; iPCa, insignificant iPCa 9 (6.3) 21 (14.3) 0.238 prostate cancer; mHGPIN, multifocal high-grade prostate intraepithelial neoplasia; mpMRI, multiparametric MRI; PCa, prostate csPCa, clinically significant prostate cancer; iPCa, insignificant cancer; PI-RADS, Prostate Imaging – Reporting and Data System. prostate cancer; PCa, prostate cancer. detection in the negative prostate biopsy, according to the Discussion current recommendations included in the EAU PCa guidelines for repeating prostate biopsy [7]. The current effectiveness of using HGPIN detection in negative prostate biopsy to predict the risk of csPCa is The first scenario occurs when there is a normalization of unknown, especially after the recent recommendation for pre- serum PSA and/or DRE after the detection of multifocal biopsy mpMRI and guided biopsies [6]. The present study HGPIN. Here, EAU guidelines recommend repeating prostate focused on the two clinical scenarios derived from HGPIN biopsy between 12 and 36 months after the negative result © 2021 The Authors. 4 BJU International published by John Wiley & Sons Ltd on behalf of BJU International The current management of HGPIN Table 6 Summary of characteristics and results of repeat biopsies in men with isolated high-grade prostate intraepithelial neoplasia; selected studies had more than 50 men subjected to repeat biopsy. Study (year) Reference Repeat biopsy Age, PSA, Biopsy MRI PCa, Gleason Gleason population (n) in HGPIN (%) years ng/mL cores n (%) score score ≤ 6, n (%) ≥ 7, n (%) Girasole et al. Previous HGPIN (1,293) 358 (28) 68 NR ≥6 No 79 (22) NR NR (2006) [25]  pez (2007) Lo Previous HGPIN (125) 96 (77) 72 NR 6-8 No 21 (22) 15 (71) 5 (24) [26] Singh et al. Previous HGPIN (88) 67 (76) 68 8.5 12 No 28 (42) 18 (64) 10 (36) (2007) [27] He at al. (2012) NR 94 (NR) 64 NR 13 No 36 (38) 39 (27) 16 (29) [28] Taneja et al. Previous HGPIN (802) 590 (73.5) 65 4.3 12 No 198 (33.6) 157 (79.3) 41 (20.7) (2013) [29] Kim et al. Repeat biopsies (1,323) 149 (NR) 65 5.8 6-12 No 33 (22.1) 19 (57.6) 14 (42.4) (2015) [30] Wiener et al. Previous HGPIN (868) 208 (24.0) 62 5.2 NR No 23 (15.7) 19 (82.6) 4 (17.4) (2017) [10] Oderda et al. Previous HGPIN, or ASAP, 99 (NR) NA NA 12 No 33 (34.7) 15 (45.5) 18 (54.5) (2021) [31] or PINATYP (384) Present study Previous HGPIN (308) 293 (95.1) 68 7.3 12 + GB Yes 118 (40.3) 31 (26.3) 87 (73.7) ASAP, atypical small acinar proliferation; GB, guided-biopsies to PI-RADS lesions ≥3; HGPIN, high-grade prostatic intraepithelial neoplasia; NR, not reported; PINATYP, high-grade prostatic intraepithelial neoplasia with atypia. [7]. The second scenario is defined by the persistence of PCa The rate of men with isolated HGPIN with normalized PSA suspicion due to previous HGPIN findings and based on PSA and/or DRE has not been previously reported in the and/or DRE. Here, the rates of csPCa and iPCa that were literature, but it was approximately 15% in the present study. found were similar to those observed in men without There were no observed differences between csPCa and iPCa previous HGPIN. However, among the 45 men observed in detection rates among men with persistent suspected PCa, the first scenario, where PCa suspicion no longer existed after with and without previous HGPIN. Moreover, there was no the previous finding of multifocal HGPIN, the PCa detection observation of different rates of csPCa and iPCa detection rate was as low as 4.4%, with half of these being iPCa. These between men with unifocal and those with multifocal HGPIN. data have not been reported in previous studies. The present Recent publications do not distinguish between men with study suggests that this subset of men represents 15.4% of unifocal and those with multifocal HGPIN [6,9,10,11]. The those with previous HGPIN and 23.4% of those with previous updated review by Epstein´s group in 2018 suggested that multifocal HGPIN. In those men, the incidence of csPCa men with HGPIN in only one core should not be followed potentially correlates with PSA levels, according to data [8]. However, the multivariate analysis performed in this reported from the control arm of the Prostate Cancer study was interesting. Previous HGPIN, current PCa Prevention Trial [23]. In this scenario, it was also observed suspicion based on PSA and DRE, and pre-repeat biopsy that 30% of mpMRI was negative. Therefore, this study mpMRI information were included as predictors of overall suggests that mpMRI will avoid 30% of repeat prostate PCa, csPCa, and iPCa rates. This led to interesting results biopsies and 50% of iPCa overdiagnosis. that discriminate the confounders. This analysis showed that previous HGPIN did not predict an increased risk of csPCa Among the published studies that included over 50 men with in repeat biopsies, while it was the only significant predictor previous HGPIN subjected to repeat biopsy, the rate of men of the risk of iPCa overdetection. This finding aligns with scheduled to repeat biopsy ranged from 24% to 95%. The recent evidence which suggests that previous HGPIN is median age ranged from 62 to 72 years, and the median PSA mainly associated with iPCa [8,10,32,33,34]. at repeat biopsy ranged from 4.3 to 8.5 ng/mL. The median number of cores obtained during repeat biopsy ranged from 6 The present study was limited by its retrospective design and to 13, and it is only in the present study that pre-repeat the small size of the cohort, which comprised men with mpMRI and guided biopsies were carried out. The rate of previous multifocal HGPIN with normalized PCa suspicion, PCa detection ranged from 22% to 40%, and overdetection of based on serum PSA and/or DRE. The outcome for men iPCa ranged between 26% and 82%. This overview suggests without persistent PCa suspicion and previous unifocal great variability among studies; however, there was a HGPIN is unknown because EAU PCa guidelines do not significant overdetection of iPCa, which was >25% in all of recommend repeating biopsies for them. More precise the studies. definitions of csPCa and iPCa could be used. In addition, the © 2021 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International 5 MOROTE et al. measurement of endpoint variables in biopsy specimens is 10 Wiener S, Haddock P, Cusano J et al. Incidence of Clinically Significant always a limitation because they do not represent the true Prostate Cancer After a Diagnosis of Atypical Small Acinar Proliferation, High-grade Prostatic Intraepithelial Neoplasia, or Benign Tissue. Urology pathology of the whole prostate gland. Another limitation is 2017; 110: 161–5 the interobserver variability of HGPIN diagnosis. Finally, 11 Prathibha S, Goyal KG, Zynger DL. Initial diagnosis of insignificant considering that the repeat biopsy scheme did not focus on cancer, high-grade prostatic intraepithelial neoplasia, atypical small acinar the area where previous HGPIN was found, the results could proliferation, and negative have the same rate of upgrade to a Gleason be limited. score of 7 or higher on repeat prostate biopsy. Hum Pathol 2018; 79: 116–21 The results of the present study suggest that a repeat prostate 12 Abdel-Khalek M, El-Baz M, Ibrahiem E-H. Predictors of prostate cancer biopsy should be based on the persistent suspicion of PCa, on extended biopsy in patients with high-grade prostatic intraepithelial based on the evolution of PSA and DRE. Predictors of csPCa, neoplasia: a multivariate analysis model. BJU Int 2004; 94: 528–33 13 De Nunzio C, Trucchi A, Miano R et al. The Number of Cores Positive such as mpMRI, PSA density, family history of PCa, and for High Grade Prostatic Intraepithelial Neoplasia on Initial Biopsy is other markers may be helpful [7]. Lastly, isolated HGPIN Associated With Prostate Cancer on Second Biopsy. J Urol 2009; 181: does not appear to increase the risk of future csPCa when 1069–75 there is no suspicion of PCa. 14 Barentsz JO, Richenberg J, Clements R et al. ESUR prostate MR guidelines 2012. Eur Radiol 2012; 22: 746–57 In conclusion, in approximately 25% of men with previous 15 Weinreb JC, Barentsz JO, Choyke PL et al. PI-RADS Prostate Imaging – multifocal HGPIN, serum PSA and/or DRE are normalized Reporting and Data System: 2015, Version 2. Eur Urol 2016; 69: 16–40 after the negative prostate biopsy. The risk of csPCa detection 16 Giganti F, Moore CM. A critical comparison of techniques for MRI- in repeat biopsies in such men appears to be identical to that targeted biopsy of the prostate. 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