According to the Hong Kong Cancer Registry,1 prostate cancer is the third most common cancer in men. As in other cancers, biopsy is needed for histological confirmation of the diagnosis of prostate cancer before treatment is initiated. With the increasing age of the population, the incidence rate of this cancer is expected to increase; the frequency of prostate biopsy will therefore also increase. Hodge et al2 introduced the systematic sextant biopsy protocol under transrectal ultrasound guidance. Transrectal ultrasound-guided prostate biopsy (TRUSPB) has since become a widely accepted and routinely performed technique to detect prostate cancer.3 In Hong Kong, most urologists use TRUSPB to confirm the diagnosis of prostate cancer, particularly in patients with elevated prostate-specific antigen (PSA) or abnormal digital rectal examination; TRUSPB is also used in patients undergoing active surveillance of prostate cancer. However, there are complications associated with the use of TRUSPB. Most notably, because the procedure is performed via the rectum, there is a risk of postprocedural sepsis; the incidence of sepsis ranged was 2% to 4% in contemporary series,4 5 and sepsis-related mortality has also been reported.6

An increasing number of studies have demonstrated success in cancer diagnosis with extended biopsy using transperineal ultrasound-guided prostate biopsy (TPUSPB). In an early report, Kojima et al7 retrospectively assessed the usefulness of TPUSPB, which differs from TRUSPB in terms of patient position, puncture route, puncture site, and ultrasound probe.8 Most importantly, the TPUSPB enables urologists to thoroughly prepare the perineum with a disinfectant solution to eliminate the possibility of skin flora contamination of the puncture site.9 In addition, this procedure involves puncture of perineal skin under the guidance of a side-fire ultrasound probe without penetration of rectal mucosa, thereby avoiding the possibility that intestinal flora are transferred to the blood stream. An Australian study group showed that TPUSPB, in combination with antibiotic prophylaxis, could almost entirely prevent sepsis complications.10 Some authors have suggested that TPUSPB may be performed without antibiotic prophylaxis, thus reducing the risk of generating antibiotic resistance.4 Based on these potential benefits, our centre introduced TPUSPB beginning in January 2018. Subsequently, we have completely replaced TRUSPB with TPUSPB. In this study, we aimed to compare the outcomes of our initial series of patients who underwent TPUSPB with those of our previous cohort of patients who underwent TRUSPB.

In this retrospective cohort study, we compared 100 patients who underwent TPUSPB with 100 patients who underwent TRUSPB in our centre. This study was approved by our institutional ethics committee. All 100 patients who underwent TPUSPB from January 2018 to May 2018 (TPUSPB group) were included; 100 patients who underwent TRUSPB from January 2016 to April 2016 were also included. The indications for biopsy for both groups were serum PSA >4 ng/dL, abnormal digital rectal examination, and surveillance biopsy for patients under active surveillance.

The following data were retrieved from hospital records and compared between the two groups: age, serum PSA level, prostate size, PSA density, prostate cancer detection rate, and complications (eg, admission due to acute retention of urine, rectal bleeding, haematuria, fever, and sepsis). We used the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) as an acute change in total sequential organ failure assessment score ≥2 points due to the infection11: (1) respiratory rate ≥22/min, (2) altered mental activity, and (3) systolic blood pressure ≤100 mm Hg.

For both groups, the indications for prostatic biopsies were serum PSA level >4 ng/dL, abnormal digital rectal examination, or follow-up biopsy for patients under active surveillance. All patients underwent pre-procedure blood tests and urine tests to ensure there was no bleeding tendency or positive urine culture. Patients using antiplatelet or anticoagulant treatment were required to discontinue drugs prior to undergoing biopsy. All patients used a sodium phosphate rectal enema in the morning of the procedure and took oral prophylactic antibiotics (1 g amoxicillin-clavulanate and 500 mg ciprofloxacin) 2 hours before the procedure. For TPUSPB, numbing cream (2.5% lidocaine and 2.5% prilocaine) was applied over the perineal region 1 hour before the procedure and 1% lidocaine (20 mL) was injected into the perineum as local anaesthesia (LA) immediately prior to prostate biopsy, at a 45-degree angle from the midline and approximately 15 mm above the anus on either side. Details of the two procedures are described below. After either procedure, all patients were given an additional 1-day course of oral antibiotics (1 g amoxicillin-clavulanate and 500 mg ciprofloxacin).

When undergoing TRUSPB, patients assumed the left lateral position, as shown in Figure 1. Prostate size was measured using a transrectal biplanar ultrasound probe. Subsequently, 10 core biopsies were taken: five cores were taken from each side of the prostate at the base, mid, apex, upper lateral, and lower lateral regions. Each procedure was 5 to 10 minutes in duration.

When undergoing TPUSPB, patients assumed the Lloyd-Davies position prior to injection of lidocaine for LA (described above). After lidocaine injection, a biplanar ultrasound probe was inserted through the anus. The prostate size was measured, and 14-gauge angiocatheters were then inserted at the sites previously used for LA injection, as shown in Figure 2. Ten core biopsies were obtained in a manner similar to that of TRUSPB. Because of the different orientation of the biopsy needle, the apical biopsy was targeted towards the anterior fibromuscular layer. The biopsy needle was maintained parallel to the probe to ensure clear visualisation of the targeted area, which was possible when the whole needle was completely visualised on ultrasound (Fig 3). Each procedure was 10 to 15 minutes in duration. We also assessed the pain experienced during the TPUSPB at three time points, namely during probe insertion into the anus, LA injection, and biopsy procedures, by verbal analogue scale (0-10) during TPUSPB.

Statistical analyses were performed using SPSS (Windows version 24.0; IBM Corp, Chicago [IL], United States). For continuous variables, age was compared by independent t test, while PSA, prostate size, and PSA density were compared by the Mann-Whitney U test as they did not exhibit normal distributions. Normality was assessed by normal QQ plots and the Shapiro-Wilk test. When comparing categorical variables, including cancer detection rates and complication rates, the Chi squared test was used if the expected count in each cell was >5; otherwise, Fisher’s exact test was used. In addition, the Cochran-Mantel-Haenszel test was performed to assess whether there was an association between the biopsy method and cancer detection rate according to clinical stage. Differences with a two-sided P value of <0.05 were considered to be statistically significant.

The patient characteristics, prostate cancer detection rates, and complications in patients who underwent TPUSPB, compared with those who underwent TRUSPB, are summarised in Table 1. Age did not significantly differ between the two groups. The median serum PSA in the TPUSPB group was higher than that in the TRUSPB group (12.0 ng/dL vs 9.5 ng/dL, P=0.047). Moreover, the median prostate size in the TPUSPB was smaller than that in the TRUSPB group (46.2 mL vs 56.8 mL, P=0.003). Therefore, the PSA density of TPUSPB group was higher than that in the TRUSPB group (0.27 vs 0.16, P=0.001).

Stratified prostate cancer detection rates in patients who underwent TPUSPB, compared with those who underwent TRUSPB, are listed in Table 2. There was no statistically significant difference in overall prostate cancer detection rate between the two groups. In subgroup analysis stratified by serum PSA level, the TPUSPB group had a higher prostate cancer detection rate than the TRUSPB group among patients with 20 to 100 ng/mL PSA (50% vs 15%, P=0.036). However, there were no statistically significant differences in prostate cancer detection rates among other subgroups according to PSA levels. There were also no statistically significant differences in prostate cancer detection rates between the two groups upon stratification according to PSA density or clinical staging.

In analysis of 35 patients with positive cores in the TPUSPB group, 16 (45.7%) patients had at least one positive core in the anterior fibromuscular stroma. Among these 16 patients, 14 were diagnosed with high-risk prostate cancers, with multiple positive cores in each patient. The relatively high proportion of high-risk prostate cancer in the TPUSPB cohort might explain the relatively high number of positive cores in the anterior fibromuscular stroma.

In the TPUSPB group, 19 patients had previous negative findings in TRUSPB; three of these 19 (15.7%) were diagnosed with prostate cancer based on the findings of TPUSPB. Two of the three tumours were detected in the anterior fibromuscular layer, and the remaining tumour was found in the apical zone. In the TRUSPB group, 36 patients had previous negative findings in TRUSPB; six (16.7%) of these were diagnosed with prostate cancer based on the findings of the current TRUSPB.

Concerning about the pain experienced during TPUSPB, the pain scores reported by patients during probe insertion into the anus, LA injection, and biopsy procedures were 1-2, 1-2, and 2-4, respectively.

With respect to complications, we initially planned to use the Sepsis-3 described above, but no patients in this study developed clinical signs of infection that met the criteria for sepsis. However, four (4%) patients in the TRUSPB group developed fever requiring hospital admission compared with none in the TPUSPB group (P=0.121) [Table 3]. At least 1 week of intravenous antibiotic treatment was prescribed for all four of those patients with fever. Three patients in the TPUSPB group and one in the TRUSPB group developed acute retention of urine (P=0.621). No patients in the TPUSPB group and one in the TRUSPB group had rectal bleeding (P=1.000). There were no admissions due to haematuria in either group.

Since Hodge et al2 introduced the systematic sextant biopsy protocol, TRUSPB has become the main approach to detect prostate cancer worldwide. In recent years, many urologists have described increased risks of infection and sepsis associated with TRUSPB.12 Fluoroquinolone was previously thought to provide effective antibiotic prophylaxis, thus preventing infections associated with TRUSPB; however, fluoroquinolone-resistant bacteria and extended-spectrum beta-lactamase–producing bacteria are present within the intestinal flora of 40.4% and 41.0% of Chinese patients, respectively.13 Accordingly, the rate of post-TRUSPB sepsis is rising both in Hong Kong6 and worldwide.14 To reduce the rates of infection, many strategies have been attempted, including augmented prophylactic antibiotic protocols. However, no strategies have prevented the development of sepsis due to the transfer of faecal bacteria into the blood stream through TRUSPB puncture sites.10 Transperineal ultrasound-guided prostate biopsy has been suggested as a potentially safer alternative. Notably, the indications, workups, medications, and numbers of cores are identical between TRUSPB and TPUSPB. However, the techniques differ with respect to multiple aspects, including patients’ position and puncture route,15 as described in the Methods section of this paper.

From the pain scores recorded during TPUSPB, most patients tolerated the procedure well. Because the entire procedure was performed under LA, all patients could be discharged on the same day without the need for general anaesthesia or monitored anaesthesia care. In Asian nations, many patients must travel a considerable distance to reach the hospital; therefore, 1-day out-patient procedures are preferable for patients and their relatives. Moreover, some patients are high-risk or unfit for general anaesthesia or monitored anaesthesia care; procedures performed under LA are therefore much safer and more practical for them.

Transrectal ultrasound-guided prostate biopsy neglects prostate cancer located in the anterior fibromuscular stroma, whereas the TPUSPB does not.16 In our study, a significant proportion of positive prostatic cores were found in the anterior fibromuscular stroma among patients in the TPUSPB group. Moreover, some patients with prior negative findings in TRUSPB were diagnosed with prostate cancer in the anterior fibromuscular stroma based on the results of TPUSPB. Therefore, TPUSPB may have an advantage over TRUSPB in patients with previous negative biopsy findings.

This study had some limitations. First, a consistent number of cores was biopsied in all patients in the TPUSPB group, irrespective of prostate size. To improve the rate of prostate cancer detection, some experts have advocated for the use of different numbers of prostate biopsies, based on prostate size16—more biopsies should be taken in patients with larger prostates. Second, TPUSPB required more time than TRUSPB. However, as each step is standardised, the duration of the procedure may decrease. Third, there was no documentation of pain scores in the TRUSPB group; thus, a comparison could not be performed. Future studies should address these limitations. In particular, a larger sample size is needed to confirm whether TPUSPB is superior with respect to the rate of prostate cancer detection.

In summary, TPUSPB avoids penetration of the rectal mucosa and possible transfer of intestinal flora to the blood stream during the procedure. This contributed to the lack of infections in the present study. With respect to prostate cancer detection rate, TPUSPB is at least comparable to TRUSPB. Therefore, an increasing number of urologists may adopt this technique in the future.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Concept or design of study: KL Lo, KL Chui, CF Ng.
Acquisition of data: KL Lo, K Lim, JKM Li, J Wong, SK Mak.
Analysis or interpretation of data: KL Lo, CF Ng, SCH Leung, SF Ma.
Drafting of the manuscript: KL Lo, CF Ng.
Critical revision for important intellectual content: All authors.

As an editor of the journal, CF Ng was not involved in the peer review process. Other authors have disclosed no conflicts of interest.

We would like to thank for the support of the nursing staff in the Integrated Ambulatory Care Centre, North District Hospital for their support to the procedures.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

This study was approved by the Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee (Ref CREC 2018.323).

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