The role of a standardized 36 core template-assisted transperineal prostate biopsy technique in patients with previously negative transrectal ultrasonography-guided prostate biopsies

Authors


Raj P Pal, Department of Urology, Leicester General Hospital, Gwendolen Road, Leicester LE5 4 PW, UK. e-mail: rppal@doctors.org

Abstract

Study Type – Diagnostic (exploratory cohort)

Level of Evidence 2b

What's known on the subject? and What does the study add?

Template assisted transperineal biopsy of the prostate has become increasingly popular over the past decade. Several studies have demonstrated that transperineal prostate biopsy (TPB) is associated with an increased rate of cancer detection, increased histological concordance with final prostatectomy samples and an increase in anterior and apical prostate cancers than standard TRUS biopsy. However, interpretation of the literature is difficult due to considerable variation between studies in terms of technique and equipment.

We examined a small cohort (n= 40) of patients using a standardized 36 core template assisted TPB technique. We show that utilising this technique is associated with high cancer (68%) detection rate in patients with two previous negative TRUS biopsies. Of patients were found to have anterior gland tumours which would not have been detected by standard TRUS guided biopsy.

OBJECTIVE

• To determine the efficacy and safety of a standardized 36 core template-assisted transperineal biopsy technique for detecting prostate cancer in patients with previously negative transrectal ultrasonography-guided prostate biopsies and elevated prostate-specific antigen (PSA) levels.

PATIENTS AND METHODS

• Between April 2008 to September 2010, a total of 40 patients with a mean (range) age of 63 (49–73) years, a mean (range) elevated PSA level of 21.9 (4.7–87) ng/mL and two previous sets of negative TRUS-guided prostate biopsies underwent standardized 36 core template-assisted transperineal prostate biopsies under general anaesthetic as a day case procedure.

• The cancer detection rate and complications for all cases were evaluated.

RESULTS

• In total, 27 of 40 (68%) patients were found to have adenocarcinoma of the prostate, two patients (5.0%) had atypical small acinar proliferation, one had high-grade prostatic intraepithelial neoplasia (2.5%), four (10%) had chronic active inflammation and six (15%) had benign histology.

• Gleason scores were in the range 6–9, with a median Gleason score of 7.

• There were no cases of urosepsis, urinary tract infections or haematuria. A single patient experienced acute urinary retention, with a subsequent succesful trial without a catheter, and haematospermia was common, although minor.

CONCLUSIONS

• Our standardized 36 core template-assisted transperineal prostate biopsy technique is safe and associated with a high detection rate of prostate cancer.

• This technique should be considered in patients with elevated PSA levels and previously negative TRUS-guided prostate biopsies.

Abbreviation
TPB

transperineal prostate biopsy.

INTRODUCTION

Prostate cancer is the most commonly diagnosed cancer and the second most common cause of death from cancer in men [1]. The widespread use of PSA testing has contributed to a dramatic increase in the number of men undergoing TRUS-guided prostate biopsies [2,3]. Data from the USA suggest that more than 1.2 million needle prostate biopsies are performed each year [4].

TRUS was introduced in 1968 as an imaging tool to assist in the diagnosis of prostate cancer [5]. TRUS allows biopsies to be accurately guided towards the peripheral zone where cancers predominate, therefore achieving reasonable sampling of the prostate. It has a sensitivity of 39–52% and a specificity of 82% [6]. Additionally, it carries low morbidity and can be performed in the office setting. Hence, systematic TRUS-guided prostate biopsies remain the gold standard for detecting prostate cancer. However, a limitation of this technique is that men with an initial negative biopsy are often found to have subsequent prostate cancer. Almost one-quarter of prostate cancers are identified after an initial negative biopsy [7]. Furthermore, the cancer detection rate decreases with an increasing number of biopsy sessions, with yields of 10–20% for the second biopsy and below 10% for subsequent biopsies [8,9]. Repeated TRUS-guided biopsy results in sampling of the same prostatic areas and other potential tumour sites can be missed. The question of whether to pursue further repeat TRUS-guided biopsy for patients with a rising PSA level subsequent to an initial negative biopsy is a common clinical dilemma and remains a diagnostic challenge.

Many studies have proposed a number of different biopsy approaches in these patients, including repeated standard biopsies and transrectal saturation biopsies [10,11]. More recently, transperineal prostate biopsy (TPB) utilizing a brachytherapy template grid has become increasingly popular but, currently, a standardized TPB technique does not exist [12–15]. In the present study, we determined the role of a standardized 36 core transperineal template prostate biopsy technique in the detection of prostate cancer in men with an elevated PSA levels and at least two previous negative TRUS-guided prostate biopsies.

PATIENTS AND METHODS

Between Januray 2008 and September 2010, a total of 40 men were selected to undergo template-assisted TPB at the Leicester General Hospital. Men were selected if they had had at least two previous sets of TRUS-guided prostate biopsies yielding a non-cancerous diagnosis and an elevated PSA level. All patients had a minimum life expectancy of 10 years. Additionally, a further five patients with known prostate adenocarcinoma who were managed with active surveilance were selected for template-assisted TPB as part of their surveilance regime.

All patients underwent template-assisted TPB, which was performed by the same surgeon (M.A.K.) using the same biopsy technique in every case. The procedure was performed under general anaesthetic. At the time of induction, a combination of intravenous co-amoxiclav and gentamicin were used as antibiotic prophylaxis. A 14-F urethral catheter was inserted and the patient was placed in an extended lithotomy position. A DRE was performed. This was followed by insertion of the transrectal probe (BK Medical Pro-Focus 2202; BK Medical, Mileparken, Denmark) and prostate volume measurement. A STEPPER (Galil Medical; Crawley, Sussex, UK) with an articulated arm and a stabilizer was used to fix the ultrasonographic probe. Ater prepping and draping the perineum, a standard 0.5-cm brachytherapy template grid was attached to the STEPPER and positioned over the perimeum.

With the prostate at its widest in the transverse plane, the gland was divided on the TRUS screen into six zones (right anterior, left anterior, right mid, left mid, right posterior and left posterior) (Fig. 1a). Next, six needles were inserted at a time into a single zone, and biopsies through an 18-gauge needle were taken from the apex of the prostate to the base. The ultrasonographic probe was then switched to the sagittal plane and the needles were withdrawn (Fig. 1b). A total of 36 biopsies were taken from each case for histological analysis. In patients with larger prostates (>50 mL) where the anterior part of the gland could not be reached, biopsy needles were manually manipulated to ensure the whole gland was sampled. The urinary catheters were removed at the end of the procedure and the patients were discharged home the same day after voiding. Patients who experienced post-procedure retention were recatheterized and re-attended for a trial without catheter the next day.

Figure 1.

a, Transverse plane view of prostate subdivided into six zones (RA, right anterior; LA, left anterior; RM, right mid; LM, left mid; RP, right posterior; LP, left posterior). In total, six biopsies were taken from each zone. b, Sagittal view of the prostate showing biopsy needles placed in the anterior part of the gland (arrows). B, catheter balloon; c, catheter; P, prostate; R, rectum.

RESULTS

Mean (range) patient age was 62.9 (49–73) years. Mean (range) PSA level was 21.9 (4.7–119) ng/mL at the time of template-assisted TPB compared to 18.7 (3.7–122) ng/mL at the time of the previous TRUS biopsy session. The PSA and previous histological results for each patient before template-assisted TPB are shown in Table 1. The mean (range) number of biopsies taken at the most recent TRUS biopsy session was 11.6 (10–18). The median (range) time from the most recent TRUS biopsy session to TPB was 16 (2–58) months.

Table 1.  Clinical parameters for patients with benign histology before transperineal prostate biopsy (TPB)
Case numberNumber of past biopsy sessionsHistology from previous biopsyPSA at most recent TRUS biopsy (ng/mL)PSA at TPB (ng/mL)TRUS volume (mL)TPB histologyNumber of cores containing cancer
  1. ASAP, atypical small acinar proliferation; HGPIN, high-grade prostatic intraepithelial neoplasia.

12Benign8.85.635chronic active inflammation 
22Benign7.07.437ASAP 
32HGPIN7.78.730Adenocarcinoma (3 + 3 = 6)17
42Benign4.28.978HPIN 
52HGPIN6.29.545Adenocarcinoma (3 + 3 = 6)8
62HGPIN9.41098Benign 
73Benign111131Benign 
83Benign6.71150Adenocarcinoma (3 + 3 = 6)1
92Benign4.91221Adenocarcinoma (4 + 5 = 9)22
103Benign111442Adenocarcinoma (3 + 3 = 6)9
115ASAP201932Adenocarcinoma (3 + 3 = 6)6
122Benign8.72029Adenocarcinoma (4 + 5 = 9)9
133Benign13.121110Benign 
142HGPIN8.72155Benign 
152Benign9.42271chronic active inflammation 
162Benign232328Adenocarcinoma (3 + 3 = 6)5
172Benign272522Adenocarcinoma (3 + 4 = 7)12
182HGPIN442841Adenocarcinoma (4 + 3 = 7)6
192Benign152940Adenocarcinoma (4 + 4 = 8)10
202Benign203240Adenocarcinoma (3 + 3 = 6)6
212Benign183650Adenocarcinoma (3 + 4 = 7)10
222Benign404066Adenocarcinoma (3 + 3 = 6)1
232Benign404129Adenocarcinoma (3 + 3 = 6)6
242HGPIN444147Adenocarcinoma (4 + 5 = 9)16
252Benign728730Adenocarcinoma (4 + 3 = 7)20
262Benign242437Adenocarcinoma (3 + 3 = 6)10
272ASAP6.96.930Adenocarcinoma (3 + 3 = 6)2
282ASAP5.65.632Adenocarcinoma (3 + 3 = 6)1
292ASAP4.74.726Adenocarcinoma (3 + 3 = 6)9
302Benign12211960Adenocarcinoma (3 + 5 = 8)15
312Benign5.88.849Adenocarcinoma (3 + 3 = 6)11
322HGPIN131372chronic active inflammation 
334Benign5.69.860Benign 
343HGPIN173331Adenocarcinoma (4 + 4 = 8)7
352Benign7.81185Adenocarcinoma (3 + 3 = 6)2
362HGPIN + ASAP111089Adenocarcinoma (3 + 4 = 7)2
372HGPIN8.61161ASAP 
382Benign3.76.220Adenocarcinoma (3 + 3 = 6)5
392BenignNot known2432Benign 
402HGPIN9.74.728chronic active inflammation 

Table 1 summarizes the clinical and histological findings for all patients after template-assisted TPB. In the present study cohort of patients, 27 of 40 (68%) patients had prostate adenocarcinoma diagnosed after template-assisted TPB. The remaining histological findings were: two patients (5%) had atypical small acinar proliferation, one had high-grade prostatic intraepithelial neoplasia (2.5%), four (10%) had chronic active inflammation and six (15%) had benign histology.

In the patients with prostate cancer, the median (range) number of positive cores was 8 (1–22). In total, 21 of 27 (71.4%) patients who had prostate adenocarcimona on the template-assisted TPB had cancer involving five or more cores. Out of 27 patients, 16 (59.3%) patients had a Gleason score of 6, five (18.5%) patients had a Gleason score of 7, three (11.1%) patients had a Gleason score 8 and three (11.1%) patients had a Gleason score of 9. Cancer involving the anterior zone was present in 12 of 27 (44.4%) patients. In four of these patients, the tumour was localized to the anterior zone, and did not affect the remainder of the gland. The mean PSA level for patients diagnosed with prostate adenocarcinoma was 26.1 vs 13.0 ng/mL for those with non-cancerous histology.

The TRUS biopsy and template-assisted TPB results of those patients already diagnosed with prostate cancer and treated with active surveilance are outlined in Table 2. Of five patients, four experienced an increase in Gleason grade, and three out of five patients had a higher percentage of positive cores on repeat template-assisted TPB compared to the initial TRUS biopsy. The mean (range) time interval between TRUS and template-assisted TPB was 11.6 (4–15) months.

Table 2.  Clinical parameters of active surveillance patients undergoing repeat template-assisted transperineal prostate biopsy (TPB)
Initial TRUS biopsyTemplate-assisted TPB
PSA (ng/mL)Gleason scoreNumber of coresPSA (ng/mL)Gleason scoreNumber of cores
43 + 3 = 61/108.63 + 4 = 74/36
9.13 + 3 = 61/10123 + 4 = 72/36
4.23 + 3 = 61/105.13 + 3 = 67/36
4.03 + 3 = 62/106.13 + 4 = 711/36
5.33 + 3 = 61/108.03 + 4 = 71/36

There were no cases of urosepsis, urinary tract infection or haematuria. Although haematospermia was common, it was minor because our patients did not raise any concerns. In the one patient who developed urinary retention, a catheter was replaced and the patient was re-admitted the next week and had a successful trial without catheter.

DISCUSSION

TRUS-guided biopsy is the standard approach for men with suspected prostate cancer. However, the use of TPB has become increasingly popular over the past decade. Several studies have now investigated this technique as a diagnostic alternative to TRUS-guided biopsy in both men with and without previous biopsy. These studies have shown a reduction in upstaging at the time of radical prostatectomy and more concordance with final prostatectomy specimen biopsy results [14]. Additionally, studies sampling a higher number of biopsy yield an increased cancer detection rate, particularly in the apical and anterior regions of the prostate [12,16,17].

However, a difficulty in the interpretation of the current literature results from a lack of standardization of a TPB technique. Both within and between individual studies, there is a significant variation in patient selection and the number of biopsies sampled, as well as with respect to whether a template grid is used [12–20]. In the present study, we report data obtained using a standardized 36 core biopsy template-assisted TPB technique for all patients. All patients selected for biopsy at our institute had at least two previous negative TRUS-guided biopsies and all had elevated PSA levels.

Although several series of TPB have now been published, only one randomized control trial has compared TPB against TRUS biopsy, and this was carried out in a cohort without previous prostatic biopsy [15]. Although no significant difference in cancer detection rates were noted between both techniques, that study utilized only a 12 core biopsy technique for both TPB and TRUS biopsy. However, in comparison, a recent study investigating a template-assisted TPB technique sampling a mean core biopsy number of 54 in patients without previous prostate biopsy reported far higher cancer detection rates in patients without previous biopsy (79% vs 48%), and this was in a cohort of patients with lower mean PSA levels and a higher prostate volume, where fewer cancers would be expected [16]. Cancer detection rates after one or more benign sextant or octant biopsies have been reported to be in the range 13–34% when using TRUS-guided saturation biopsy [10,11]. Pinkstaff et al. [20] and Demura et al. [13] reported cancer detection rates of 36% and 37%, respectively, when sampling between 20 to 21 cores using a template-assisted TPB technique. In a study conducted by Bott et al. [18] in men with high-grade prostatic intraepithelial neoplasia or atypical small acinar proliferation on previous TRUS biopsy, the cancer detection rate was 38% when a median of 24 cores were sampled using a template-assisted TPB technique. When template-assisted TPB was performed using a mean core biopsy technique of 53.8 in men with negative TRUS biopsy, Bittner et al. [17] showed that cancer detection rates were 44.7%. Studies sampling a higher number of biopsy cores at transperineal prostate have yielded high prostate cancer detection rates. Accordingly, it is evident that prostate cancer detection rates are dependent on the number of biopsy cores sampled. However, exactly how many cores are required for the optimum biopsy strategy, as well as when this should be performed, remains to be determined.

Our current method of TTMB is based on a 36 core biopsy technique that samples three times more biopsies than our standard TRUS biopsy technique. In the present study, we report a cancer detection rate of 68%, which is higher than previous studies, including those sampling a larger number of cores, although the mean PSA level for our study group is greater than that reported in previous studies [13,17,18,20]. A potential concern of the increasing detection rates by more substantial sampling is the increase in clinically insignificant cancers. However, previous studies have shown that this is unlikely to be the case, with only a minority of clinically insignificant cancers being detected when using a transperineal technique [18,20]. Of the 27 patients diagnosed with cancer in the present study, 24 patients had more than one core involved, and 21 patients had more than five cores involved, indicating that the most cancers could potentially be clinically significant tumours. However, it should be noted that five positive cores on template-assisted TPB equates to 13.8% of the cores being positive for cancer. If translated as a percentage to a 12-core TRUS guided biopsy technique (although this is not an entirely accurate comparison), between one and two cores would be positive, equating to a relative low volume of disease.

Additionally, other studies have investigated the utility of TPB as the initial biopsy technique in patients with an elevated PSA level or abnormal DRE [15,16]. Although associated with potentially higher cancer detection rates [16] because of the need for a general anaesthetic, offering TPB as an initial biopsy strategy to all patients may not be feasible as a result of time and financial constraints in many centres.

A limitation of the present study is the sample size employed. In particular, it is difficult to assess the safety of a standardized 36 core technique in this small cohort. However, only one patient reported transient mild haematuria, one patient experienced urinary retention and haematospermia, although mild, was common. Other complications were not reported. The safety profile of this TPB is very similar to TRUS-guided biopsy. Only one randomized study has investigated the complication rates between these two approaches [15]. Although lower rates of retention and sepsis were reported in patients undergoing TPB compared to a TRUS biopsy, these were statistically insignificant. A further limitation of the present study is that the time interval between template-assisted TPB and TRUS biopsy was greater than 1 year in some instances. It may be that the disease progressed in some of these men during this period, explaining why cancer was detected on template-assisted TPB rather than previous TRUS biopsy sessions. However, identifying the time when to perform repeat biopsy remains a dilemma for many clinicians. Not only is this heavily influenced by patient choice after a negative biopsy, but also repeat biopsy within a short time period may result in unnecessary discomfort and patient morbidity.

In conclusion, we present our early data on a standardized 36 template-assisted TPB technique. In the present study cohort, we report a high cancer detection rate. A current difficulty in determining the utility of template-assisted TPB is related to the lack of a standardized technique for all patients. The present study supports the role of a 36 core biopsy technique for patients with elevated PSA levels despite previous negative TRUS-guided biopsies. The finding of the present study support the need for further investigations in the form of a prospective multicentre randomized control trial.

CONFLICT OF INTEREST

None declared.

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