Transrectal versus transperineal prostate biopsy for cancer detection in patients with gray-zone prostate-specific antigen: a multicenter, real-world study

Abstract

Knowledge about the effect of different prostate biopsy approaches on the prostate cancer detection rate (CDR) in patients with gray-zone prostate-specific antigen (PSA) is limited. We performed this study to compare the CDR among patients who underwent different biopsy approaches and had rising PSA levels in the gray zone. Two hundred and twenty-two patients who underwent transrectal prostate biopsy (TRB) and 216 patients who underwent transperineal prostate biopsy (TPB) between June 2016 and September 2022 were reviewed in this study. In addition, 110 patients who received additional targeted biopsies following the systematic TPB were identified. Clinical parameters, including age, PSA derivative, prostate volume (PV), and needle core count, were recorded. The data were fitted via propensity score matching (PSM), adjusting for potential confounders. TPB outperformed TRB in terms of the CDR (49.6% vs 28.3%, P = 0.001). The clinically significant prostate cancer (csPCa) detection rate was not significantly different between TPB and TRB (78.6% vs 68.8%, P = 0.306). In stratified analysis, TPB outperformed TRB in CDR when the age of patients was 65–75 years (59.0% vs 22.0%, P < 0.001), when PV was 25.00–50.00 ml (63.2% vs 28.3%, P < 0.001), and when needle core count was no more than 12 (58.5% vs 31.5%, P = 0.005). The CDR (P = 0.712) and detection rate of csPCa (P = 0.993) did not significantly differ among the systematic, targeted, and combined biopsies. TPB outperformed TRB in CDR for patients with gray-zone PSA. Moreover, performing target biopsy after systematic TPB provided no additional benefits in CDR.

INTRODUCTION

Prostate biopsy is the gold standard for prostate cancer (PCa) diagnosis. Approximately 2 million males undergo prostate biopsy in Western countries annually,1 and the number of prostate biopsies gradually increases following the increase in prostate-specific antigen (PSA) testing and active surveillance.2

Generally, there are two systematic biopsy approaches: transrectal prostate biopsy (TRB) and transperineal prostate biopsy (TPB). The TRB approach is considered the gold standard for PCa diagnosis but is associated with urinary tract infection and sepsis despite the application of antibiotic prophylaxis.3,4 Moreover, infection rates are increasing due to increasing antibiotic resistance.1,4 Conversely, the TPB approach without antibiotic prophylaxis is increasingly used in many medical centers because of the lower infection rate, which includes sepsis,5,6,7 without compromising the cancer detection rate (CDR), especially in the anterior zone of the prostate gland.8,9,10 However, prostate biopsy results for men with gray-zone PSA (4–10 ng ml⁻¹) are controversial,11 and knowledge about the effect of different prostate biopsy approaches on the CDR for patients with gray-zone PSA is limited.

Therefore, our study aimed to directly compare the CDR between TRB and TPB for patients with gray-zone PSA. Furthermore, we explored the CDR stratified by age, prostate volume (PV), and needle core count for subgroup analysis. We also explored the CDR of the TPB group detected by systematic, targeted, and combined biopsy. Additionally, propensity score matching (PSM) was used to minimize the influence of confounders, thus providing a more credible reference. This study will help in selecting the best clinical strategy for prostate biopsy, benefiting patients.

PATIENTS AND METHODS

Study populations

We identified 2410 consecutive patients who underwent prostate biopsies at Chinese PLA General Hospital (Beijing, China) and The First Affiliated Hospital of Zhengzhou University (Zhengzhou, China) between July 2016 and June 2022. The criteria for prostate biopsy in patients with gray-zone PSA were as follows: (1) abnormal rectal examination; (2) abnormal ultrasonic echo; and (3) abnormal magnetic resonance imaging (MRI) signal. This retrospective study was approved by the Institutional Review Board of each center and was in line with the 1975 Helsinki Declaration. Written informed consent was obtained from all patients before the prostate biopsy. Ethical approval was waived by the Ethic Committees of Chinese PLA General Hospital and The First Affiliated Hospital of Zhengzhou University due to its retrospective essence. Of these patients, 571 (23.7%) had gray-zone PSA. Patients were excluded due to incomplete data (113 patients) or pathological diagnosis of other types of cancer (14 patients), leaving 444 (18.4%) patients available for analysis. The enrolled patients were allocated to two groups (the TRB group and the TPB group) according to the biopsy approaches received. PCa was defined as prostate adenocarcinoma in any biopsy needle sample. Clinically significant prostate cancer (csPCa) was determined by the International Society of Uropathology (ISUP) as grade 2 or higher.12

Clinical parameter collection

The clinical parameters consisted of age at prostate biopsy, serum total PSA (tPSA) and free PSA (fPSA) values, needle core count, prostate transverse diameter, anteroposterior diameter, and vertical diameter. Serum tPSA and fPSA levels were measured by immunofluorescence before prostate biopsy. PV was measured via MRI (3.0-T MRI system; SIEMENS AG, Berlin, Germany) using the exact prolate ellipsoid formula: volume = transverse diameter × anteroposterior diameter × vertical diameter × π/6.13

Prostate biopsy and histopathological diagnosis

All patients underwent transrectal ultrasound-guided systematic prostate biopsy performed by urologists with at least 3 years of clinical experience. In the TPB group, additional targeted biopsies were performed if MRI lesions were suspected. Two independent pathologists analyzed biopsy cores according to the standards of the ISUP.

Statistical analyses

We described the age, PSA derivative (tPSA, fPSA, and [f/t]PSA), PV, PSA density (PSAD), needle core count, and prostate biopsy results of the enrolled patients according to the prostate biopsy approach. SPSS version 27.0.1 (SPSS, Inc., Chicago, IL, USA) statistical software was used for data analysis in this study. The Chi-square test or Fisher’s exact test was used to analyze the categorical data. The Mann‒Whitney U test was used to analyze continuous data. PSM was used to reduce the influence of confounders. The enrolled patients were matched using 1:1 nearest-neighbor matching with a caliper (0.004 times the standard deviation [s.d.] of the propensity score). All tests were two-sided, with a significance level set at 0.05.

RESULTS

A total of 444 patients with gray-zone PSA were included in this study. Of these enrolled patients, 228 (51.4%) were in the TRB group, and 216 (48.6%) were in the TPB group (Table 1 and Figure 1). Of these 216 patients, 110 (50.9%) also underwent magnetic resonance imaging-transrectal ultrasound (MRI-TRUS) fusion-guided targeted biopsy following systematic biopsy due to the suspected lesions (Figure 2). After PSM, there were 113 patients in the TRB group and 113 in the TPB group (Table 1 and Figure 1).

Table 1.

Baseline characteristics, biopsy results, and comparison between the transrectal prostate biopsy and transperineal prostate biopsy groups before and after propensity score matching

Parameter	Before PSM				After PSM
	Total (n=444)	TRB (n=228)	TPB (n=216)	P	Total (n=226)	TRB (n=113)	TPB (n=113)	P
Age (year), median (IQR)	66 (61–72)	66 (65–68)	65 (65–67)	0.545	65 (61–72)	66 (65–68)	65 (64–67)	0.275
tPSA (ng ml−1), median (IQR)	5.84 (7.26–8.67)	7.32 (6.97–7.42)	7.16 (6.91–7.35)	0.674	7.16 (5.87–8.56)	6.97 (6.71–7.37)	7.17 (6.92–7.52)	0.389
fPSA (ng ml−1), median (IQR)	1.01 (0.72–1.38)	1.05 (1.11–1.29)	0.97 (0.98–1.11)	0.075	0.94 (0.67–1.30)	0.89 (0.91–1.16)	0.99 (0.97–1.13)	0.112
(f/t)PSA, median (IQR)	0.15 (0.10–0.20)	0.15 (0.16–0.18)	0.14 (0.14–0.16)	0.096	0.13 (0.10–0.19)	0.13 (0.13–0.17)	0.14 (0.14–0.16)	0.487
PV (ml), median (IQR)	43.47 (30.33–65.15)	47.14 (50.02–58.33)	40.09 (43.77–50.70)	0.020	38.33 (27.14–55.18)	36.59 (37.36–45.70)	39.91 (42.06–50.23)	0.080
PSAD (ng ml−2), median (IQR)	0.16 (0.10–0.24)	0.14 (0.16–0.19)	0.17 (0.18–0.21)	0.038	0.18 (0.12–0.25)	0.18 (0.19–0.24)	0.17 (0.17–0.21)	0.289
Needle cores count (n), median (IQR)	13.00 (12.00–14.00)	12.00 (12.50–12.81)	14.00 (14.44–15.42)	<0.001	13.00 (12.00–14.00)	13.00 (12.58–13.03)	13.00 (12.67–13.14)	0.587
CDR, n/total (%)
Any PCa	159/444 (35.8)	51/228 (22.4)	108/216 (50.0)	<0.001	88/226 (38.9)	32/113 (28.3)	56/113 (49.6)	0.001
csPCa*	119/159 (74.8)	34/51 (66.7)	85/108 (78.8)	0.103	66/88 (75.0)	22/32 (68.8)	44/56 (78.6)	0.306

^*International Society of Uropathology Grade 2 or higher. TRB: transrectal prostate biopsy; TPB: transperineal prostate biopsy; PSM: propensity score matching; tPSA: total PSA; fPSA: free PSA; (f/t)PSA: free PSA/total PSA; PV: prostate volume; PSAD: PSA density; CDR: cancer detection rate; PCa: prostate cancer; csPCa: clinically significant prostate cancer; IQR: interquartile range; PSA: prostate-specific antigen

Figure 1.

Study flowchart. PSA: prostate-specific antigen; TRB: transrectal prostate biopsy; TPB: transperineal prostate biopsy; PSM: propensity score matching.

Figure 2.

The CDR and the detection rate of csPCa in different biopsy strategies. ^*The ratio was csPCa/PCa. SB: systematic biopsy; TB: targeted biopsy; PCa: prostate cancer; csPCa: clinically significant prostate cancer; CDR: cancer detection rate.

Baseline characteristics and the stratified CDR before PSM

The CDR of the patients in the TRB group was lower than that of patients in the TPB group (22.4% vs 50.0%, P < 0.001). The detection rate of CSPCa was not significantly different between the TRB group and the TPB group (66.7% vs 78.8%, P = 0.103; Table 1). The median age, tPSA level, fPSA level, and (f/t)PSA level between the TRB and TPB groups did not show significant difference (all P > 0.05; Table 1). The median PV, PSAD, and needle core count were 43.47 (interquartile range [IQR]: 30.33–65.15) ml, 0.16 (IQR: 0.10–0.24) ng ml⁻², and 13.00 (IQR: 12.00–14.00), respectively. The PV in the TRB group was more incremental than that in the TPB group (P = 0.020). In contrast, the PSAD and needle core count in the TRB group were lower than those in the TPB group (P = 0.038 and P < 0.001, respectively; Table 1). According to our stratified analysis, the CDR in the TRB group was lower than that in the TPB group for patients aged 56–65 years (21.5% vs 47.4%, P < 0.001) and aged 66–75 years (17.8% vs 55.8%, P < 0.001). The CDR in the TRB group was lower than that in the TPB group when the PV was 25.00–50.00 ml (27.2% vs 61.4%, P < 0.001). The CDR in the TRB group was lower than that in the TPB group, regardless of the number of needle cores (>12 cores: 17.1% vs 45.7%, P < 0.001; ≤12 cores: 27.3% vs 60.0%, P < 0.001; Table 2).

Table 2.

Prostate cancer detection rate stratified by age, prostate volume, and needle cores before and after propensity score matching

Parameter	Before PSM				After PSM
	Total (n=444)	TRB (n=228)	TPB (n=216)	P	TRB (n=113)	TPB (n=113)	P
Age, n/total (%)
≤55 years	8/41 (19.5)	3/24 (12.5)	5/17 (29.4)	0.344	2/13 (15.4)	4/11 (36.4)	0.357
56–65 years	62/174 (35.6)	17/79 (21.5)	45/95 (47.4)	<0.001	11/40 (27.5)	21/54 (38.9)	0.175
66–75 years	59/167 (35.3)	16/90 (17.8)	43/77 (55.8)	<0.001	9/41 (22.0)	23/39 (59.0)	<0.001
>75 years	30/62 (48.4)	15/35 (42.9)	15/27 (55.6)	0.321	10/19 (52.6)	8/12 (66.7)	0.484
PV, n/total (%)
<25 ml	38/57 (66.7)	16/29 (55.2)	22/28 (78.6)	0.061	12/24 (50.0)	12/15 (80.0)	0.093
25 ml ≤ PV <50 ml	95/206 (46.1)	25/92 (27.2)	70/114 (61.4)	<0.001	17/60 (28.3)	36/57 (63.2)	<0.001
50 ml ≤ PV <75 ml	13/106 (12.2)	5/65 (7.7)	8/41 (19.5)	0.071	3/22 (13.6)	5/25 (20.0)	0.849
≥75 ml	13/75 (17.3)	5/42 (11.9)	8/33 (24.2)	0.161	0/0 (0)	3/16 (18.8)	0.526
Needle cores count, n/total (%)
≤12	71/182 (39.0)	32/117 (27.3)	39/65 (60.0)	<0.001	17/54 (31.5)	31/53 (58.5)	0.005
>12	88/262 (33.6)	19/111 (17.1)	69/151 (45.7)	<0.001	15/59 (25.4)	25/60 (41.7)	0.061

PV: prostate volume; PSM: propensity score matching; TRB: transrectal prostate biopsy; TPB: transperineal prostate biopsy

Baseline characteristics and the stratified CDR after PSM

The CDR in the TRB group was lower than that in the TPB group (28.3% vs 49.6%, P = 0.001). Moreover, the detection rate of CSPCa was not significantly different between the TRB group and the TPB group (68.8% vs 78.6%, P = 0.306; Table 1). The median age, tPSA, fPSA, (f/t)PSA, PV, PSAD, and needle core count did not differ between the TRB and the TPB groups (all P > 0.05; Table 1). According to our stratified analysis, the CDR in the TRB group was lower than that in the TPB group when the age of the patients was 65–75 years (22.0% vs 59.0%, P < 0.001), the PV was 25–50 ml (28.3% vs 63.2%, P < 0.001), and the number of needles was no more than 12 cores (31.5% vs 58.5%, P = 0.005), as shown in Table 2.

The effect of different biopsy strategies on the CDR

A total of 110 patients with gray-zone PSAs underwent MRI-TRUS fusion-guided targeted transperineal biopsy following systematic biopsy due to suspected lesions. The CDRs in the systematic, targeted, and combined biopsy groups were 49.1%, 45.4%, and 50.9%, respectively. The detection rates of csPCa in the systematic, targeted, and combined biopsy groups were 85.2%, 86.0%, and 83.9%, respectively. The CDR (P = 0.712) and the detection rate of csPCa (P = 0.993) did not significantly differ among the three groups (Figure 2).

DISCUSSION

In this retrospective study, TPB outperformed TRB in terms of CDR, while TPB performed not significantly better than TRB in detecting csPCa. Targeted or combined biopsy showed no additional benefits for patients, regardless of the CDR or detection rate of csPCa compared with systematic biopsy.

This multicenter, real-world study uses a large sample size of patients treated with the scientific tool PSM to directly compare the CDR difference between TRB and TPB in patients with gray-zone PSA. Our results differ from those of previous studies comparing the CDR between the TRB and TPB approaches.8,9,11,14 Our study focused mainly on the CDR and detection rate of csPCa in patients with gray-zone PSA. A prospective randomized comparison study is inconsistent with our results, showing that the TPB approach performed equally to the TRB approach in CDR for patients with gray-zone PSA (36.1% vs 35.1%).8 However, the study did not compare the difference in csPCa between the two approaches.8 Notably, all patients enrolled in the randomized comparison study underwent standard 12-core systematic biopsy, which is not consistent with real-world clinical practice. Similarly, a cohort study involving 182 pairs of patients after PSM with a caliper distance of ×0.25×s.d. to compare the CDR showed no difference between TPB and TRB in patients with gray-zone PSA (29.0% vs 20.1%). Moreover, TPB outperformed TRB in detecting csPCa in patients with total PSA (42.3% vs 19.6%).15 Many previous studies have demonstrated that the CDR could be affected by prostate size16,17 and the number of needle cores.18,19 Hence, a retrospective study comparing the CDR difference between TRB and TPB should minimize confounding factors as soon as possible. Consistent with the findings of our present study, which utilized PSM to reduce confounders, the use of a caliper distance of ×0.25×s.d. was less convincing for confounder control than our use of a caliper distance of ×0.004×s.d. Furthermore, in the cohort study, the clinical parameters of needle cores, which play a significant role in CDR, were not collected as mentioned above. Overall, our study could be helpful for offering credible results on the difference in the CDR and detection rate of csPCa between TRB and TPB in patients with gray-zone PSA.

Like previous studies, our results suggest that patients with different clinical characteristics should be treated separately.15 According to our stratified analysis after PSM, we found that the TPB approach had a greater CDR than did the TRB approach in patients aged 66–75 years. Our results are supported by a reported study that showed that the detection of PCa was greater in patients aged >75 years than that in patients aged <50 years (30.5% vs 5.2%).20 A cohort study also supported our results and demonstrated that the diagnostic efficacy of PCa was different when patients were aged >80 years. In contrast, the scholars held the opposite opinion that TRB exhibited greater efficacy than TPB.15 The clinical parameter age is positively correlated with the incidence of PCa. Our prior studies showed that age was a significant predictor of PCa incidence.21,22 Therefore, combining the results with those of our present study, we recommend the TPB approach for PCa diagnosis in patients aged between 66 years and 75 years. Consistent with the findings of other studies, our prior study revealed the inverse association between PV and PCa.16,17,21,22 Similarly, our present results showed that the CDR decreased with increasing PV in both biopsy approaches. Our stratified analysis after PSM revealed that TPB had a greater CDR than TRB when the PV was 25.00–50.00 ml. We believe that the TPB approach could result in sampling more transitional zone (TZ) tissue, accounting for the detection of more cancers than the TRB approach. Our view was supported by one study in which TPB was used to detect 46% of adenocarcinomas located only in the TZ. Another study showed that, using TRB, only 6% of cancer cases were located entirely in the TZ.23,24 Moreover, more TZ cores were positive with the TPB approach for patients with gray-zone PSA than with TRB.6 Furthermore, apical tissue, which is mostly obtained only by the TPB approach, is usually the focus of cancer treatment.25 Accordingly, the TPB approach could be preferable for PCa detection in patients with gray-zone PSA. According to our stratified analysis after PSM, we found that the TPB had a greater CDR than the TRB when the number of needle cores was less than 12. The CDR could increase with the increase in the number of needle cores. However, the CDR did not significantly differ between the two biopsy approaches when the number of needle cores was more than 12.26 In other words, obtaining more cores could reduce the difference between the TPB and TRB groups.8 In addition to the advantages mentioned above, the TPB procedure requires no fasting or bowel preparation, which is helpful for ensuring active cooperation. Hence, we recommend a systematic TPB approach with 12 needle cores for patients with gray-zone PSAs.

To date, targeted biopsy has been increasingly recommended for PCa detection with the introduction of mpMRI.27 Many studies have shown an increased CDR and a greater detection of csPCa by targeted or combined biopsy methods compared with standard 12-core systematic biopsy.14,27,28 Moreover, a targeted biopsy could reveal more tumor upgrades according to the Gleason score than a systematic biopsy.28,29 Furthermore, the combined application of prostate-specific membrane antigen (PSMA) and positron emission tomography-computed tomography (PET/CT) has shown great efficacy in detecting csPCa and has potential as a substitute for prostate biopsy in csPCa diagnosis30. However, our study revealed that both targeted biopsy and combined biopsy, compared with systematic biopsy, had no additional benefit for patients regardless of whether they underwent CDR or csPCa detection. A possible reason for this difference might be that more than 12 needle cores were used for transperineal biopsy in a daily clinical practice scenario: the more needle cores there are, the more likely the overlap between systematic and targeted biopsies.

Limitations of this study include the retrospective study design, which may be subject to selection bias despite its minimization by PSM. Furthermore, the data of TPB and TRB approaches on TZ, apical zones, and postoperative complications were not compared. This study suggested the use of the TPB for suspicious PCa patients with gray-zone PSA. One strength of our study was that we detected differences in the CDR between the TPB and TRB approaches in stratified analysis that could be helpful for individualized treatment. The other strength of this study was its reflection of realistic clinical conditions in which biopsies are performed by different urologists with varying levels of experience in various hospitals.

CONCLUSIONS

The TPB could be associated with a greater CDR than the TRB for patients with gray-zone PSA. Our results demonstrated that the TPB was associated with a greater CDR than the TRB for patients with gray-zone PSA. Moreover, performing target biopsy after systematic TPB provided no additional benefits in CDR.

AUTHOR CONTRIBUTIONS

JXL and ZYW conceived of the study, collected data, performed the statistical analysis, and drafted the manuscript. SXN and XYS contributed to statistical analysis. XM, XZ, and XPZ conceived of the study and participated in its design and coordination. All authors read and approved the final manuscript.

COMPETING INTERESTS

All authors declare no competing interests.