Incidence of Repeat Prostate Biopsy in Men Undergoing Transperineal Template Guided Mapping Biopsy for an Elevated PSA

Following a negative Transrectal Ultrasound (TRUS)-guided prostate biopsy, repeat biopsies are often recommended for a persistently elevated PSA or progressive PSA. Repeat prostate biopsies result in additional morbidity to include infection with rates as high as 15%, hematuria, hematospermia, pain, erectile dysfunction, urinary tract infections and anxiety along with substantial healthcare expenditures [1,2]. Welch and colleagues using the Surveillance and Epidemiology End Results (SEER) Medicare data reported that 11.8% and 38% of men with a negative TRUS biopsy undergo repeat biopsy within 1 year and 5 years, respectively [3]. In men younger than 70 years of age, the rate of repeat biopsy at 5 years was 44%. The incidence of repeat biopsies decreased with age and was slightly greater for blacks. With the integration of MRI and the utilization of newer indices such as Prostate Cancer Antigen 3 (PCA3) and Prostate Health Index (PHI) the rate of repeat biopsy following TRUS will in all likelihood decrease [4,5]. 

Sampling error due to TRUS biopsy remains a major shortcoming of transrectal approaches and repeat biopsies are often recommended due to a false negative rate of 25-35% [6]. More intensive strategies such as Transperineal Template Guided Mapping Biopsy (TTMB) have been demonstrated to accurately identify high grade cancers when compared to whole-mount radical prostatectomy (RP) pathology [7]. In addition, the majority of clinically significant prostate cancers that are missed at TRUS biopsy are located in the anterior prostate [8]. Previously, we reported in a TTMB staging series that Gleason score was upgraded in 39% of patients with the anterior prostate and the apex being the most common areas of upgrading [9-11]. Stone and colleagues reported optimal TTMB results with a biopsy density of 1.5 biopsies per cm³ [12]. 

TTMB systematically maps the prostate gland and provides more accurate information regarding the presence of prostate cancer, grade, volume and spatial distribution. Transperineal techniques also decrease the infectious morbidity of TRUS biopsies. In this study, we evaluate the incidence of repeat prostate biopsy following TTMB in patients with an elevated PSA and benign prostate pathology.

From January 2005 through January 2017, 984 consecutive men underwent TTMB for an elevated PSA by means of an anatomic-based technique with sampling of 24 prostate regions [9-11]. Of those 984, 531 were diagnosed with prostate cancer, 350 with benign histology without Atypical Small Acinar Proliferation (ASAP) or High Grade Prostatic Intraepitheal Neoplasia (HGPIN) and 103 patients with ASAP and/or HGPIN. The study population consisted of the 350 men with benign histology. Indications for repeat prostate biopsy included PSA progression to include a PSA doubling time less than 3 years and/or an abnormal Digital Rectal Examination (DRE). Routine MRI and/or the use of prostate cancer biomarkers were not routinely utilized. Previously, the TTMB technique has been described in great detail [9,10]. All biopsies were performed by a single operator (GSM). Two days prior to procedure, tamulosin (0.8mg daily) was initiated and continued for 2 weeks. TTMB was performed in the operating room with the patient in the dorsal lithotomy position under general anesthesia. All patients received perioperative antibiotics. The prostate gland was scanned from the proximal seminal vesicles/base of the prostate gland to the apex utilizing the 5.0-7.5 MHz transducer. A volumetric ultrasonographic evaluation was obtained to determine prostate size. In addition, the prostate gland and Transition Zone (TZ) volumes were estimated as an ellipsoid with the formula: length x width x height x π/6. 

Transperineal biopsies were obtained through template apertures corresponding with the 24 regional biopsy locations [9,10]. For each of the 24 regions, as many as 4 biopsy cores were taken, depending on prostate size. 18 gauge, 25-cm long Max-Core biopsy needles (C.R. Bard Inc, Covington, GA, USA) were used. For each biopsy core, the template coordinate and the offset from the base were recorded. Biopsies were taken to sample the entire gland including the posterior (sites 3, 4, 12, 13, 21 and 22), posterior lateral (sites 2, 5, 11, 14, 20 and 23), anterior lateral (sites 1, 6, 9, 10, 15 and 16), anterior apex (sites 19 and 24) and transition zone (TZ)(sites 7, 8, 17 and 18). The location of each biopsy core, the number of biopsy cores and the percent involvement of each core were recorded. All pathologic assessment was performed by a pathologist with significant expertise in prostate pathology (EA). Clinical parameters evaluated included Overall Survival (OS), the incidence of repeat biopsy and the subsequent diagnosis of prostate cancer. 

Continuous clinical variables in patients without and with repeat biopsy were compared using a t-test and categorical variables were compared using Fisher’s Exact test. Kaplan-Meier survival curves and log rank analysis were used to compare overall survival between the two groups. PSA Doubling Time (PSADT) was calculated using PSA’s from the most recent 2 years. A competing risk analysis was performed in the cumulative incidence of subsequent TTMB and prostate cancer was determined. For all tests, a p value ≤ 0.05 was considered significant. Statistical analysis was performed with STATA version 16.0 software (SPSS, Inc., Chicago, IL).

The study population consisted of 350 consecutive patients undergoing TTMB for an elevated PSA with benign pathology and without the presence of ASAP or HGPIN. Of the 350 patients, 340 did not require repeat biopsy while 10 patients underwent repeat biopsy. The overall mean and median follow up of the cohort was 7.9 years and 8.5 years, respectively with no statistically significant difference in the follow up between the 2 cohorts (p=0.624). On average, patients undergoing repeat biopsy presented with a statistically higher PSA (16.6ng/mL vs 7.8ng/mL, p < 0.001). Although not statistically significant (due to the small number of repeat biopsy patients), patients undergoing repeat biopsy presented with a substantially larger prostate volume (102.3cm³ vs. 79.8cm³, p=0.123). The average number of TTMB cores between the two cohorts was virtually identical (61.8 vs. 61.6, p=0.927). No other statistical differences to include PSA density, prior TRUS biopsy sessions, TRUS biopsy cores or total cores per patient were identified. Figure 1 illustrates the overall survival for the 2 groups. At 10 years, 90.3% and 85.4% of patients in the two cohorts were alive. Figure 2 illustrates that at 10 years, 4.4% of patients underwent a repeat biopsy with the diagnosis of prostate cancer in 0.9%. The mean and median time to repeat biopsy was 6.24 years and 5.51 years, respectively. Of patients not undergoing repeat biopsy, 4 (1.2%) had a PSA doubling time < 3 years. In contrast, 6 of 10 patients (60%) in patients undergoing repeat biopsy had a PSA doubling time < 3 years. Of the 10 re-biopsy patients, 9 were biopsied due to continued PSA progression while 1 patient was biopsied secondary to an abnormal MRI. Of the 10 repeat biopsy patients, 3 were diagnosed with prostate cancer (2 patients with Gleason score 4+3 and one patient with Gleason score 4+4). 

Figure 1: Overall survival, stratified by number of TTMBs, proportion survival at 5 and 10 years. 

Figure 2: Cumulative incidence of prostate cancer in those patients who initially produced no cancerous cores during an initial TTMB and proportion that had a follow-up TTMB due to rising PSA values.

Repeat prostate biopsies in men with a negative TRUS biopsy are often recommended for persistently elevated PSA, a progressive PSA due to the diagnostic uncertainty of TRUS biopsy (false negative rate 25-35%) and/or the presence of ASAP or HGPIN [6,13]. Repeat biopsies are a source of additional morbidity and result in substantial healthcare expenditures [1,2]. The routine implementation of MRI along with the use of genomic testing and biomarkers will further refine indications for both initial and repeat biopsies and maximize biopsy strategy outcomes [4,5,14]. 

TTMB systematically maps the prostate gland and provides accurate information regarding the presence of prostate cancer grade, volume and spatial distribution [9-11]. TTMB has been demonstrated to accurately identify high-grade cancers when compared to whole-mount RP pathology [7]. In addition, the majority of clinically significant prostate cancer that are missed at TRUS biopsy are located in the anterior prostate [8]. Transperineal techniques also virtually eliminate the infectious morbidity of TRUS biopsies. 

Although the incidence of repeat biopsy in our series was very low (Figure 2, 4.4%), patients requiring repeat biopsy presented with substantially larger glands with a biopsy density (number of TTMB cores divided by prostate volume) substantially lower than in those patients not requiring repeat biopsy (Table 1). A biopsy density of 0.604 was recorded in patients undergoing repeat biopsy and 0.772 in patients not requiring repeat biopsy. Stone and colleagues evaluated their TTMB technique to determine the optimal number of biopsy cores and reported a biopsy density > 1.5 was optimal to maximize prostate cancer diagnosis [12]. Because of the lack of standardization of TTMB techniques, inter-group comparisons are difficult. However, although it is conceivable that amore intensive biopsy regimen in our patients with larger glands may have eliminated the need for some of the repeat biopsies, the fact that only 3 of the 10 re-biopsied patients were diagnosed with prostate cancer makes it unlikely that a more intensive biopsy sampling regimen would have altered our results. In terms of TTMB related morbidity, previously we have reported the absence of the need for hospitalization, sepsis, transurethral resection or change in urinary, bowel, sexual function, depression or Post Void Residual (PVR) [15]. Approximately 16% of patients have required overnight catheterization with all catheters permanently removed by day 4 [15]. 

Table 1: Clinical parameters of study population. 

A shortcoming of our biopsy approach is the need for general anesthesia and operating room time. Strengths of our study include its perspective nature, the fact that all patients underwent the same TTMB biopsy procedure and consistent and complete follow up was available for all patients. In the future, refinements in MRI and/or genomic testing will play greater roles in determining patient selection for repeat biopsy, geographic biopsy locations and the number of biopsies necessary [16]. Our results will serve as a baseline standard to evaluate the efficacy of newer approaches. 

In patients with an elevated PSA undergoing TTMB with benign prostate pathology, repeat biopsy at 10 years is unlikely and the subsequent diagnosis of prostate cancer is approximately 1%.

GS Merrick: Protocol/project development, Data collection or management, Data analysis, Manuscript writing/editing; R Galbreath: Data analysis; A Bennett: Data collection or management; W Scholl: Data collection or management; R Fiano: Data collection or management, Data analysis; WM Butler: Data collection or management, Data analysis; E Adamovich: Data collection or management, Data analysis.

Funding: No funding was received.

Disclosure of potential conflicts of interest: No Conflicts of Interest to Report

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IRB approval was given for all research