Transperineal prostate biopsy identifies locations of clinically significant prostate cancer in men considering focal therapy with PI‐RADS 3–5 regions of interest

Abstract Objectives To determine the benefit of performing transperineal prostate mapping biopsy (TPMB) following multiparametric magnetic resonance imaging (mpMRI) to increase the identification of clinically significant prostate cancer (csPCa) with Gleason grade group (GG) ≥ 2 and their locations outside of the PI‐RADS v2 3–5 category lesions. Methods mpMRI was performed in 80 men prior TPMB from two institutions. The mpMRI was considered clinically significant (csMRI) if it contained one or more PI‐RADS 3–5 category lesion. mpMRI findings were compared against csPCa diagnosed by TPMB, performed between 16 November 2010, and 13 September 2019, for the entire gland, both lobes and to the right and left anterior and right and left posterior quadrants (RA, LA, RP and LP). Sensitivity, specificity, positive and negative predictive values (PPV, NPV), accuracy and the area under curve (AUC) were determined. Thirteen men also underwent radical prostatectomy and had comparison of TPMB pathology to prostatectomy specimen grading. Results TPMB was positive in 60/80 (75%) of which 32 (53.3%) were csPCa. csPCa was present in the RA in 9 (11.3%), LA in 11 (13.8%), RP in 25 (31.3%) and LP in 27 (33.8%) and involved 1 quadrant in 7 (21.9%), 2 quadrants in 12 (37.5%), 3 quadrants in 11 (34.4%) and all 4 quadrants in 2 (6.3%) patients; 57/80 (71.3%) men had a mpMRIs with lesions designated as PI‐RADS 3 in 24 (30%), 4 in 25 (31.3%) and 5 in 8 (10%). A csMRI was present in the RA in 7 (8.8%), LA in 8 (10%), RP in 31 (38.8%) and in the LP in 29 (36.3%), which were limited to one quadrant in 39 (68.4%), 2 quadrants in 16 (28.1%), and 3 quadrants in 2 (3.5%). Sensitivity, specificity, PPV, and NPV were determined from the results of the TPMB and were for the entire gland 81.3%, 35.4%, 45.6% and 73.9%. There were 31 csMRIs involving the right posterior of the gland but only 25 csPCa by TPMB of which 12/31 (38.7%) were concordant for high grade disease. There were 29 men who have a csMRI in the left posterior quadrant, and 14 (48.3%) were concordant with csPCa from the TPMB. Conclusions MpMRI should be supplemented with TPMB to correctly identify the regions of the prostate that would require ablation in men considering focal therapy.

posterior of the gland but only 25 csPCa by TPMB of which 12/31 (38.7%) were concordant for high grade disease. There were 29 men who have a csMRI in the left posterior quadrant, and 14 (48.3%) were concordant with csPCa from the TPMB.
Conclusions: MpMRI should be supplemented with TPMB to correctly identify the regions of the prostate that would require ablation in men considering focal therapy. Reporting System version 2 (PI-RADS v2) criteria accurately identifies high grade PCa when a score of 5 is present. 1 Although investigators report high negative predictive values (NPVs) for mpMRI when transrectal targeted and systematic biopsies are performed, the need for additional biopsy when no cancer is found in the gland outside the PI-RAD 3-5 lesion is being questioned. 2 More than 30% of clinically significant PCa (csPCa) lesions can be missed by mpMRI because of multifocality, lesion location, and size when compared with histopathology data of transperineal prostate mapping biopsy (TPMB) or whole-mounted radical prostatectomy specimens (WMRPs). 1,[3][4][5][6] Physicians are increasingly interested in focal therapy, and more than 50% of urologists in a recent survey believed focal therapy is beneficial in the treatment of PCa, but 63.2% were also concerned that only treating the index lesion would be inadequate. 5 Given that 70% or more patients clinically present with multifocal disease, it is understandable that practitioners would be reluctant to rely on an mpMRI to identify all csPCa lesions requiring ablation. 7 TPMB has been shown to identify more csPCa than TRUS biopsy including the small lesions missed by mpMRI. 3,8 If targeted biopsy of mpMRI regions of interest (ROIs) with concomitant 12-core systematic biopsy fails to identify csPCa outside of the ROI, then should that patient still be considered a candidate for focal ablation? While prostatectomy studies suggest that relying on the mpMRI to determine inclusion criteria for hemi-ablation can be erroneous more than 50% of the time, this information is not helpful to the clinician who wants to make a shared decision about the optimal therapy before initiating treatment. 9 We undertook this investigation to determine whether TPMB could improve patient selection for focal therapy by identifying csPCa outside of the quadrant detected by clinically significant MRI (csMRI). csMRI was defined as MRI lesions designated as PI-RADS v2 3-5. In addition, this investigation sought to determine what quadrants of the prostate might be spared treatment when electing focal or subtotal therapy.  using an 18-G disposable biopsy device through a 5-mm template as previously described. 10 A proprietary programme was used to create intraoperative 2D and 3D prostate images from the ultrasound and to record the location of the biopsy sites. 11 Each specimen was analysed for the presence, length and location of PCa and assigned a GG from 1 to 5. 12 All biopsy sites were numbered sequentially and matched to the same position in the software. were calculated for the entire prostate, both sides of the gland and for the four sectors. A csMRI confirmed by a csPCa from the TPMB was considered a true positive. The highest GG from the TPMB was compared with the highest GG from the prostatectomy specimen to determine grading accuracy. An increase by a GG of 1 or more was considered upgrading. Two-way analyses with a significance ≤ 0.05 were performed using SPSS v.20. All data were de-identified and anonymised and approved for reporting by the institutional review boards.

T A B L E 3 Comparison of csPCa to csMRI in men with PI-RADS designation of 3-5
Physicians pursuing focal therapy have utilised brachytherapy, HIFU, laser, electroporation, cryotherapy and radio frequency to create ablation zones. [17][18][19] Most investigators have used mpMRI to both identify and target the treatment zone. Clinicians recognise that there is considerable uncertainty in identifying the boundary of the mpMRI detected lesions and utilise extensive margins or hemiablation to decrease the risk of leaving untreated areas. Unfortunately, the inability of mpMRI to identify out of field csPCa results in 50% failure rates in both modelling studies and clinical practice. 20,21 Confirmatory biopsy following focal therapy also demonstrates high out of field recurrence rates. 22 The current study underscores the risk of limiting intraprostatic staging to ROIs identified by mpMRI when selecting patients for partial gland ablation.
The major limitation of this study was the relatively small sample size. However, the thorough interrogation of the prostate using a TPMB with a high biopsy density highlighted the benefit of incorporating this strategy after mpMRI to identify the regions of the prostate containing csPC. This study did not compare the TPMB to mpMRI plus 12-core systematic biopsy. Although the latter does improve the detection of csPCa away from a PI-RADS 3-5 ROI, it does not provide the precise localisation information generated from a thorough transperineal mapping procedure. There may also be a benefit to using a quadrant approach as opposed to lesions with a margin when considering partial gland ablation. This investigation did not address the costs associated with TRUS biopsy, TPMB and mpMRI. An outpatient TRUS is less costly than a TPMB, which has typically been performed in the operating room under anaesthesia, although new devices have been introduced allowing a TPMB to be done in the office with local anaesthesia. 23 In either scenario, a prebiopsy mpMRI can be obtained, which can help guide the biopsy procedure if an ROI is present.
Of the 80 men who had a TPMB biopsy, 20 (25%) were negative.
In contrast to an office TRUS biopsy where 30% of negative biopsies are false negatives (for csPCa) and need to be repeated, the likelihood of a false negative TPMB should be very low. Unless there is an increase in PSA or other clinical determinate, most of these men will not require a repeat biopsy. 24  This investigation did not directly compare TPMB with fusion biopsy. mpMRI-based fusion biopsy with 12-core systematic biopsy should be compared to a more extensive mapping in a randomised study. An investigation of this type could ascertain if there is a benefit to take biopsies for improved diagnosis of csPCa and to improve cancer localization for partial gland ablation. Validation of the latter could be accomplished by comparison with the radical prostatectomy specimens.

| CONCLUSIONS
Transperineal mapping biopsy can enhance an mpMRI when considering partial gland ablation. It can aid in the selection of men for active surveillance by accurately excluding men with high grade disease. All the men who elected active surveillance in this investigation had