Transperineal prostate biopsy: The modern gold standard to prostate cancer diagnosis

Abstract

In patients suspicious for prostate cancer, a prostate biopsy should be performed. Biopsies are possible either by the transrectal or transperineal routes. Compared with the transrectal prostate biopsy (TRPBx), transperineal prostate biopsy (TPPBx) offers a non-inferior cancer detection rate (CDR), especially in patients undergoing re-biopsy for persistently elevated PSA and in cases of active surveillance (AS), in which TPPBx seems to be superior. Moreover, the transperineal route achieves superior sampling of the anterior and apical regions, especially after previous multiple negative TRPBx. Infectious complications are nullified due to avoidance of needle passage through the rectal mucosa, and there is a highly significant evidence of reduced fever and sepsis rates when compared with TRPBx, with maintaining acceptable urinary retention rates. This is an important upcoming topic due to the increasing antibiotic resistance rates, thus reducing periinterventional hospitalization and health care costs. To date, TPPBx is perfectly feasible in the inpatient and out-patient settings and under local anesthesia, characterized by a moderate learning curve and a good reproducibility. By applying mpMRI as a diagnostic tool, clinically significant prostate cancer (csPCa) detection seems to be comparable to transrectal MRI-fusion biopsy (TR-MRIFBx). Finally, focal treatment of localized disease is currently performed exclusively through a TP approach.

Introduction

Prostate cancer (PCa) is currently the most frequent cancer in males in Europe and the US.^[1,2] The strong increase in overall PCa detection rate (CDR) mainly relies on the introduction of the PSA screening and consequent biopsies in asymptomatic men.^[1] Nevertheless, this diagnostic strategy maintains a risk of indolent tumor detection and the consequent overtreatment, which exposes patients to a potential morbidity of treatment without benefit.^[2] Since Hodge et al.^[3] introduced the concept of random prostate sampling, various biopsy schemes have been developed to increase the diagnostic accuracy. The current standard includes a transrectal ultrasound-guided biopsy (TRPBx) with a periprostatic block, followed by a random sampling of the prostate with 10–12 biopsy cores.^[4] Nevertheless, since its introduction, the transperineal (TP) approach has been also widely accepted.^[5] To date, the debate of superiority of one method over the other remains open. Potential drawback of the transrectal approach includes the increased febrile postprocedural urinary tract infections (UTIs). In contrast, transperineal ultrasound-guided prostate biopsies (TPPBx) have been linked to increased postprocedural urinary retention rates, appear to be more invasive than TRPBx and cannot easily be delivered in an outpatient setting, as they often need general anesthesia or sedation. However, due to increased UTI rates with multiresistant bacteria, research interest has been shifted toward further development and distribution of the TP approach in the urological community. This narrative review collects currently available data on important factors to consider, as infection rates, type of anesthesia, deliverability in an outpatient setting, and PCa detection rates, also according to tumor location. Our aim is to provide an overview of benefits and drawbacks and present the current position of TPPBx, as well as its future perspectives in a urologist’s everyday clinical praxis.

PCa and clinically significant prostate cancer (csPCa) detection rates in biopsy-naive patients

The first prospective report comparing systematic TPPBx to TRPBx 6-core biopsy demonstrated more detected tumors with the transperineal approach (95% versus. 79%, p=0.012).^[5] Nevertheless, a recent metanalysis of 13 studies could not find statistically significant differences in CDRs, though it must be stated that the patient collective biopsy cores (sextant, extensive, saturation, and mixed) and study design was varying between included studies.^[6] Finally, in a recent large retrospective work of 1,287 men undergoing TPPBx under local anesthesia, a significantly higher CDR compared with the published TRPBx rates, reaching 50%, was demonstrated. In the same study, of 641 patients diagnosed with PCa, grade group 1 cancer was reported in 256 (39.9%), whereas csPCa in 385 (60.1%) of patients.^[7] Therefore, by taking current research into account, in terms of CDRs, there are no significant differences between TR and TP systematic biopsies in biopsy-naive patients.

Negative prior biopsies and active surveillance (AS)

Before the introduction of MRI-fusion biopsies, saturation TPPBx has been frequently utilized after negative TRPBx and persistent PCa suspicion. Reported CDRs vary between 50–68%, depending on the number of cores taken and the number of prior negative biopsy sessions.^[8–11] Dimmen et al.^[8] presented a CDR of 55% in patients with prior mean 2.42 TRBxs. Of them, 53% had a Gleason score ≥ 3+4=7. Similar results were published by Gershman et al.^[9] with a CDR of 50% (mean of 24.8±7.8 cores) in patients with mean 3.7 (range 2–8) prior TRPBx. Taira et al.^[12] demonstrated a CDR of 75.9%, 55.5%, 41.7%, and 34.4% by using a template-guided mapping TPPBx approach for initial biopsy, and after 1, 2, and ≥ 3 prior negative biopsies, respectively. The detection rate of insignificant cancers was low (11.1%). Higher overall CDR of 68% by using a 36-core template-guided TPPBx approach in patients with two negative previous TRPBx has also been reported.^[10] Finally, in a comparative study by Altok et al.^[13], overall CDR for PCa was 55% for TRPBx, and 69% for TPPBx (p<0.001). A much higher detection rate of csPCa was also reached in the TPPBx (34%) group when compared with the TRPBx group (16%) (p<0.001). In patients with prior negative TRPBx PCa was detected in 31% and 56% of patients, and csPCa in 15 and 34% in TRPBx and TPPBx, respectively. In general, saturation biopsy with the transperineal technique, detects an additional 38% of PCa. The rate of urinary retention (10%) is a drawback.^[14]

In patients on AS, csPCa has been detected in 16 and 33% in TRPBx and TPPBx, respectively (p<0.001).^[13] Moreover, higher upgrading rates for patients on AS were found in two other studies.^[11,15] Ayres et al.^[15] reported that 34% of patients had more significant prostate cancer on restaging TPPBx. In total, 74% of those patients with more significant disease opted for radical treatment after temporary AS. Finally, Taira et al.^[11] published an upgrading rate of 71.9% to csPCa by using a template-guided mapping TPPBx.

Anterior lesion detection rates

In a large representative study of patients undergoing primary TPPBx, the anterior zone involvement for PCa was seen in 52.7% of the cases. Interestingly, an exclusively anterior PCa was reported in 9.7% of which 4.7% were diagnosed with csPCa.^[7] The difficulty of diagnosing anterior zone PCa with TRPBx was clearly demonstrated by Bott et al.^[16] Significantly, more biopsy sessions (p=0.007) were required for diagnosis, and the number of positive cores as well as length of cores was significantly lower and shorter (p=0.001, p=0.002) when compared with posterior tumors.

The transperineal approach seems to achieve better CDRs for anterior lesions due to the direct anatomic access through the perineal skin. This was shown in numerous studies, including patients with prior negative TRPBx.^{[8,10–12,15,17]} The anterior PCa in the repeat-biopsy setting was reported in 44%^[10], 59.2%^[17], 83.3%^[18] and even 94.1%.^[9] As the number of prior biopsies increased, Taira et al.^[12] showed that only the most anterior (especially the anterio-apical region) regions continued to harbor prior undetected Gleason ≥6 PCa. Finally, Gershman et al.^[9] published a 47% of Gleason ≥3+4=7 cancer in the anterior zone which emphasizes the role of TPPBx in the repeat-biopsy setting.

Of note, after the anatomical mapping of positive cores following a template-guided saturation TPPBx in patients with an average of 2.1 negative prior TRPBx, and an overall CDR of 42.2% (43/102 patients), Merrick et al.^[17] could show that only 53.4% and 76.7% of cancers would have been diagnosed after a sextant or 12-core biopsy scheme. In this cohort, the anterior lateral, anterior apical, and transitional zone counted for 59.2% of all positive cores. Finally, Mabjeesh et al.^[18] published a CDR of 26% after ≥ 2 negative TRPBx sets with a multiple core (median 30) template-guided TPPBx approach. Of them, 83.3% were in the anterior zone and more positive cores (p=0.015) were found in the anterior (4.9) compared with the posterior zone (1.5). Gleason score 6, 7, and ≥8 tumors were present in 54%, 25%, and 21% of the patients, respectively.

Complication-infection rates (Table 1)

Table 1.

Reported complication rates

	TRPBx	TPPBx
LUTS	25% [21]	25% [20]
Fever due to UTIs	17.5% [21]	<1% [7, 29, 30]
Sepsis	1.5% [21]	<0.5% [31]
Infection-related Hospitalization	3.6% [26]	<0.5% [32]
Hematuria	65.8% [21]	<10% [29]
Hematochezia	36.8% [21]	<10% [29]
Hematospermia	92.6% [21]	<10% [29]
Urinary retention	(<2%) [19]	<5 – 11.1% [29, 31]

LUTS: lower urinary tract symptoms UTIs Urinary tract infections; TRPBx: Transrectal prostate biopsies; TPPBx: Transperineal prostate biopsies

Postprocedural complications for both techniques are usually self-limiting.^[19,20] Pain (43.6%), fever (17.5%), hematuria (65.8%), hematochezia (36.8%), and hematospermia (92.6%) have been reported within 35 days after TRPBx.^[21] Additionally, LUTS occur in up to 25%, but urinary retention is very rare (<2%).^[19] However, infection-related events play a major role after TRPBx.^[19,22–25] In the era of inappropriate antibiotic treatment there is an increase of febrile postprocedural UTIs ranging 4.2%–17.5% and 0.8%–6.3% needing hospital re-admission.^[19,24] Infection-related admissions rates have increased from 0.6% in 1996 to 3.6% in 2005.^[26] E. coli, Pseudomonas, and Klebsiella are the common pathogens in blood cultures with 91.2%, 5.8%, and 2.9%, respectively.^[24] Additionally, quinolone-resistant bacteria occupy the rectal flora of 20%–50% of the patients and their presence has been associated with increased post-biopsy infection (6.6% versus 1.6%,) and hospital admission rates (4.4% versus 0.9%).^[22] By considering its additional side effects, the European Association of Urology stopped recommending Ciprofloxacin as chemoprophylaxis for TRPBx. Alternative treatments include Fosfomycin^[27] and Carbapenem.^[28] Typical hospital admissions occur in the first 2 weeks after biopsy.^[24,27] The calculated risk for post TRPBx-bacteremia is as low as 1.5%, but patients with TRPBx related bacteremia are twice as likely to require intensive care treatment and significantly higher rates of multi-resistance are recorded.^[25]

The transperineal method is a safe way to reduce infection rates as rectal bacteria prostatic inoculation is avoided, due to the easy disinfection of perineal skin and the avoidance of passing the biopsy needle through the rectal mucosa. Infectious related events after TPPBx are below 1%^[7,29,30], sepsis rates do not exceed 0.5%^[31], and hospital re-admissions are uncommon.^[32] Antibiotic needs are minimal, and even “antibiotic-free” approaches appear to be harmless.^[33] In contrast, postprocedural urinary retention often complicated the TPPBx setting during the early years, mainly due to the higher number of cores with consecutive prostate swelling.^[29] Rates of up to 11.1%^[29] have been reported, but usually remain below 5%.^[31] Patients experience uncomplicated LUTS in about 25% of cases.^[20] Side effects, but not admission and emergency department visit rates are directly correlated to the number of cores taken.^[29] Nonetheless, with the introduction of MRI-fusion biopsy and the consequent reduction of biopsy cores, urinary retention rates have been significantly decreased and recent studies even published rates below 2%.^[7,30,32] Finally, hematospermia and hematuria occur in <10% of the cases and their incidence decreases dramatically when taking <12 cores.^[29]

Patient discomfort, need for anesthesia, deliverability in an outpatient setting

Patient satisfaction constitutes an important factor during and after biopsy. Interestingly, 11% of patients undergoing TRPBx report that a further biopsy would be considered a major or moderate problem. One week after biopsy this proportion increases to 20%. This negative feedback has been linked to unfavorable intraprocedural experience, mainly due to pain and bleeding.^[21] Since its introduction, TPPBx has been handicapped by the need of general anesthesia and hospital admission in most of the cases.^[17] Nevertheless, there have been a lot of efforts to optimize pain levels by using local anesthetics and minimizing perineal punctures.^[7,33–36]

The importance of a guidance needle was highlighted by an early report by Novella et al.^[36] During a 14-core TPPBx under local anesthesia, the authors found no difference in pain levels during probe insertion, transrectal ultrasonography, and execution of local anesthesia. However, pain scores during prostate sampling were significantly lower when a coaxial needle was used, due to reduced perineal punctures. Regarding the type of local anesthesia, when applied into the periapical triangle (anatomical triangle formed by the levator ani, rhabdosphincter, and external anal sphincter) via a midline perineal puncture, researchers found no significant differences in pain scores when compared with 12-core TRPBx.^[35] However, by adding a transrectal digitally guided bilateral pudendal block to the bilateral periprostatic block, others could demonstrate a superior overall pain control. About 30 procedures were needed to be performed to reach an expertise level.^[34] Furthermore, a combination of oral analgesics one hour before biopsy with a periprostatic transperineal block can achieve minimum pain levels, and 90% of patients are satisfied and would recommend the procedure to others.^[32] By optimizing local anesthesia, decreasing procedure times, and gaining experience, an in-office TPPBx has become a feasible option with complications <5%.^[33] An optimal setting would include a local anesthesia with a bilateral periprostatic transperineal block and a minimum of 10 cores, including the anterior zone with the free-hand technique, and access over bilateral cannulas.^[7] In this setting, from patients who had experienced prior TRPBx, 67% said there was comparable discomfort, while 18% considered TPPBx and 11% considered TRPBx to be more painful.^[7] In another study by Gorin et al.^[37] of patients who had experienced TRPBx, 45% reported a preference for TPPBx, while 38% reported no preference. Lidocaine injection appears to be the most painful part (47.4% of patients), followed by the biopsy needle passage (42.1%) and ultrasound probe insertion (10.5%).

In the era of MRI and MRI/ultrasound fusion–guided prostate biopsy (Figures 1 and 2)

Figure 1. a–f.

Transrectal MRI-fusion biopsy (TRT-MRI-FBx). (a) Lateral sonographic view demonstrating the prostate (red contour), suspicious lesion (green contour), needle (L). (b) Lateral MRI view demonstrating the prostate (red contour), suspicious lesion (green contour), needle (L). (c–f) 3D reconstruction in different views demonstrating the prostate (red), suspicious lesions (blue, green), and needle positions

Figure 2. a–d.

Transperineal MRI-fusion biopsy (TP-MRI-FBx). (a) Lateral sonographic view demonstrating the prostate (red contour), suspicious lesion (blue contour), needle (L), and template position (Q-17). (b) 3D reconstruction demonstrating the prostate (red), suspicious lesion (blue), and needle positions. (c) Transverse sonographic view demonstrating the prostate (red contour), suspicious lesion (blue contour), targeted biopsy position (3 cores), last targeted biopsy position (L3). (d) Transverse schematic view demonstrating the prostate (red contour), suspicious lesion (blue contour), and the last targeted biopsy position (L3)

Conventional TRPBx are limited due to the related random and systematic errors, as the sampling of cancerous areas is linked to chance. Systematic TRPBx misses about 20% of csPCa, mainly located in the anterior and apical gland. Thus, underdiagnosis and eventually undertreatment is the consequence.^[38] Since the introduction of MRI-TBx, the paradigm of prostate biopsy strategies in men with risk for PCa, or in patients with already diagnosed low-risk PCa undergoing AS, is shifting. The diagnostic efficacy of multiparametric MRI (mpMRI) was recently assessed in the PROMIS trial, a prospective multicenter paired-cohort validation study comparing mpMRI added and gray-scale TRPBx by using a mapping TPPBx in 570 men. A significantly higher sensitivity of mpMRI addition (93% versus. 48%) and NPV (89% versus. 74%) for the prevalence of csPCa was shown. By using mpMRI as a triage test, 25% of men might safely avoid prostate biopsy, and therefore, overdiagnosis of clinically insignificant cancer might be reduced.^[39,40] Nevertheless, general consensus has been reached in combining targeted with systemic biopsies to reach the most accurate diagnostic power for detecting csPCa.^[40]

The first study prospectively comparing transrectal MRI-fusion biopsy (TR-MRI-FBx) to transperineal MRI-fusion biopsy (TP-MRI-FBx), each four cores per lesion, in 200 consecutive men demonstrated a greater percentage of csPCa in the anterior zone for the TP approach (93.3% versus 25%, p=0.0001). Recorded CDR of csPCa for target lesions was also better with the TP approach (93.3% versus. 66.7; p=0.001).^[41] Further research showed a significant advantage of TP-MRI-FBx over TR-MRI-FBx in cases of an apical, dorsolateral, or anteriorly located tumor^[42] and some additional evidence from a multivariate analysis suggest TP-MRI-FBx be an independent predictor of csPCa detection along with PSA, rectal exam, prostate volume, PIRADS score, number of targeted biopsy cores, and surgeon experience.^[43] Finally, according to recent data by Halstuch et al.^[44] these advantages of TP-MRI-FBx may be transferred in patients with prior negative biopsies or undergoing AS protocols. These parameters have led to an increased interest in the TP-MRI-FBx approach, and several MRI-fusion platforms have implemented the TP access in their diagnostic options.^[45] Hence, TP-MRI-FBx s are rapidly increasing worldwide.

Learning curves, reproducibility, and costs

A first definition for terms, processes as well as a minimum dataset in relation to TPPBx was made in 2013 by the Ginsburg consensus panel.^[46] The members agreed on a reproducible surgical sampling pattern depending on the size and length of the prostate (between 24–38 cores). Mantica et al.^[47] recently introduced a five-step training model for TPPBx in unexperienced residents. By comparing the fan-technique to a free-hand biopsy, a high and comparable overall cancer detection rate of 58.2% versus 59.2% was demonstrated. The free-hand technique (81.8%) was superior to the fan-technique (45%) regarding CDRs in small prostates (<40ccl) and could be performed faster (14.4 versus 15.9 minutes, p=0,025).^[47] Similar procedure times of 10–12 minutes were described in another large study.^[7] Halstuch et al.^[44] demonstrated that proficiency and accuracy can be achieved after 110 TRPBx and 125 TP-MRI-FBx. Procedure times decrease from 45 min to 15 min in the TR group and 55 min to 18 min in the TP group. Nonetheless, procedure times of TPPBx can be significantly reduced if patients receive local instead of general anesthesia. Cancer detection in PIRADS 3 lesions increased from 35 to 50% and 40 to 55% in TRPBx and TPPBx group, respectively.

Comparing costs of four alternative biopsy procedures to reference standard TRPBx, Altok et al.^[13] published a significant increase of ×1.9 (90%), ×2.5 (153%), ×2.5 (150%), and ×2.2 (125%) for sedation TRPBx, TPPBx with a template under general anesthesia, sedation TR-MRI-FBx and sedation in-bore MRI biopsy, respectively. Also, the main factor for increased costs was the admission of general anesthesia. If modalities would have been performed under local anesthesia, a lowered cost increase of ×1.7 (66%) for TPPBx, ×1.7 (68%) for fusion biopsy without MRI and ×2.4 (140%) for fusion biopsy including MRI was calculated. The cost of detecting one significant caner in TRPBx, TR-MRI-FBx and TPPBx was 8,809 $, 10.590 $ and 9,782 $, respectively. If TPPBx and TR-MRI-FBx were performed under local anesthesia, costs would decrease to 6,940 $ for TPPBx and 6,571 $ for TR-MRI-FBx and would be lower compared with conventional TRPBx.

New perspectives (application of focal therapy of PCa)

Since 2010, there has been an upcoming interest for localized treatment for low-risk PCa by applying numerous techniques (cryotherapy, high-intensity focused ultrasound [HIFU], laser ablation, photodynamic therapy). Energy has been traditionally applied with a template-guided approach through the perineum. Before the area of mpMRI, mapping TPPBx was defined as the gold standard.^[48,49] With a 5 mm-sampling frame, researchers could identify foci measuring 2–5 mm with a certainty of 90%.^[50] The superiority of a 3D transperineal mapping TPPBx was also highlighted in a later report, in which 55% of the patient population initially diagnosed with unilateral cancer on TRPBx was upgraded to a higher Gleason score or upstaged to a bilateral caner in 23% of the cases taking, however, a median number of 46±19 cores.^[48] Additionally, robotic systems with live intraoperative motion prostate tracking are able to minimize in vivo movements and reach moving with a median accuracy of 2.73mm and a median prostate motion of 5.46 mm.^[51] Finally, the feasibility of real-time MRI guided focal laser treatment of low-risk PCa has been demonstrated using a template-guided TP approach.^[52]

In conclusion, the transperineal approach for prostate biopsy offers superior features when compared with TRPBx and is a feasible procedure in the inpatient and outpatient setting. Multiparametric MRI offers an additional advantage to the transperineal approach. Nevertheless, prospective studies directly comparing TRPBx and TPPBx with mpMRI targeted biopsies are needed to proof superiority of either concept.

Main Points

• Transperineal prostate biopsy achieves comparable cancer detection rates with transrectal prostate biopsy in biopsy-naive patients but is superior in cases of prior transrectal biopsies and active surveillance.

• Transperineal biopsy offers a superior access to the anterior and apical prostate regions.

• Infectious complications are nullified with the transperineal method.

• Transperineal biopsy can also be performed with local anesthesia, is feasible in an outpatient setting, has a moderate learning curve and a good reproducibility.

• Multiparametric MRI augments the function of transperineal prostate biopsy and focal therapy can be easily applied transperineally.