Optimized Biopsy Strategy for Transition Zone Prostate Cancer With Enhanced Perilesional Sampling: A Retrospective Analysis and Clinical Trial Validation

Abstract

PURPOSE

Prostate biopsy (PBx) is crucial for diagnosing prostate cancer (PCa). This study aims to identify potential underdiagnosis of transition zone (TZ) PCa compared with peripheral zone (PZ) tumors and validate a novel PBx strategy to improve TZ tumor detection.

MATERIALS AND METHODS

This study comprised two components: a retrospective analysis and a randomized clinical trial. The retrospective study included 217 patients who underwent radical prostatectomy after 8^PZ + 4^TZ + X transperineal transrectal ultrasound-magnetic resonance imaging-fusion PBx between 2018 and 2021. The clinical trial investigated biopsy efficacy in 400 patients who underwent either modified 8^PZ + 10^TZ + X PBx for the TZ lesion or 8^PZ + 4^TZ + X PBx after block random assignment between 2022 and 2023 at our center.

RESULTS

Retrospective analysis reveals identical TZ clinically significant prostate cancer (csPCa) detection rates for 8^PZ + 4^TZ + X and 4^TZ + X PBx, both of which were insufficient for detecting TZ csPCa compared with PZ tumors. Based on these findings, 8^PZ + 10^TZ + X PBx was constructed. In the trial, the 10^TZ + X and 8^PZ + 10^TZ + X PBx demonstrated identical TZ csPCa detection rates and biopsy positivity rate, outperforming the 4^TZ + X and 8^PZ + 4^TZ + X PBx without increasing complications. The self-controlled comparison showed equivalent results for 8^TZ + X and 8^PZ + 10^TZ + X PBx.

CONCLUSION

Our study found that PZ biopsies offer no additional benefit for TZ lesion tumors, and increasing the number of cores in the TZ region can compensate for the current limitations of TZ biopsies. These findings provide potential avenues for optimizing biopsy strategies for TZ lesions.

INTRODUCTION

Since the early 20th century, prostate biopsy (PBx), as the primary diagnostic method for prostate cancer (PCa), has been the subject of extensive research. Despite years of development, controversy still surrounds the choice of biopsy strategy.¹ It is recommended that the system biopsy (SB) should include at least 12 cores.^2,3 The advancement of multiparametric magnetic resonance imaging (Mp-MRI) has led to the revolutionary development of targeted biopsy (TB, 3-5 cores).⁴ In previous discussions on systematic and targeted biopsies, the 12 + X (like the 8^PZ + 4^TZ + X mentioned later) combined biopsy has been considered superior to either systematic or TB alone.^5,6

CONTEXT

• Key Objective

• Should and how should biopsy strategies for transition zone (TZ) prostate cancer (PCa) be optimized?

• Knowledge Generated

• Our retrospective analysis and randomized clinical trial results showed that standard 8^PZ+4^TZ+X biopsy inadequately detected clinically significant prostate cancer (csPCa) in the TZ, and additional peripheral zone sampling provided no added benefit for patients with TZ lesions. Increasing TZ cores (8^TZ + X) improved TZ csPCa detection without increasing complications.

• Relevance

• For patients with clearly identified TZ lesions, a more targeted biopsy strategy is appropriate and PZ sampling may be omitted.

However, it is common for cancer diagnoses to undergo further upgrading or downgrading during radical prostatectomy (RP) after PBx.^7,8 Furthermore, research indicates that such upgrading is more prevalent in patients with transitional zone (TZ) tumors compared with those with peripheral zone (PZ) tumors.^9,10 Although there is no definitive conclusion on whether SB or TB is superior, the value of TB is steadily increasing and is considered to make a greater contribution in combined biopsies.^11-13 Recent studies have demonstrated that TB combined with perilesional/regional systematic biopsies can achieve the same effectiveness as TB combined with whole-gland SB.^14,15 These studies underscore the importance of perilesional/regional systematic biopsies and support our hypothesis that, for TZ lesions, the insufficient distribution of TZ cores in the 8^PZ + 4^TZ + X PBx may contribute to the low detection rate and inaccuracy of biopsies in TZ tumors.

Furthermore, research on biopsy strategies for TZ tumors is scarce. Given the critical importance of lesion localization in biopsy strategies today, the differences between TZ and PZ lesions should not be easily overlooked.^16,17 Therefore, we conducted a retrospective study and a prospective clinical trial to explore a more optimal and practical biopsy strategy for TZ lesions.

MATERIALS AND METHODS

Patients

Retrospective Study

The retrospective study involved 217 patients who underwent laparoscopic RP after 8^PZ + 4^TZ + X (12 + X) transperineal (TP) transrectal ultrasound (TRUS)-MRI-fusion PBx between 2018 and 2021 at the First Affiliated Hospital of Soochow University. Inclusion criteria are as follows: (1) All preoperative assessments, including prostate-specific antigen (PSA), Mp-MRI, biopsy, and RP, were performed at the First Affiliated Hospital of Soochow University and (2) PCa was confirmed by initial biopsy. Exclusion criteria are as follows: (1) Prostate Imaging Reporting and Data System (PI-RADS) score <4 (MRI lesions less likely to be real tumor lesions, with positive rates of 2% for PI-RADS 1, 4% for PI-RADS 2, and 20% for PI-RADS 3),¹⁸ (2) diffuse or unclear MRI lesions, (3) PSA >100 ng/mL (inaccurate measurements), and (4) previous neoadjuvant therapy.

Prospective Trial

Power estimates were based on the probability of detecting clinically significant prostate cancer (csPCa) in men with PI-RADS score 4 or more lesions on Mp-MRI and interim analysis during trial monitoring.¹⁸ A total of 400 patients who underwent modified 8^PZ + 10^TZ + X PBx (the test group) for the TZ lesion or 8^PZ + 4^TZ + X (the control group) PBx after block random assignment from 2022 to 2023 were included.

Inclusion criteria are as follows: (1) All preoperative investigations, including blood tests and MP-MRI, were completed at our center; (2) biopsy was performed in accordance with guideline-recommended criteria³; and (3) primary biopsy was performed. Exclusion criteria for prospective studies were consistent with the retrospective study.

Block random assignment: Patients were assigned to groups by independent, blinded administrators. Patients were sequentially numbered by drawing lots from 1 to 10 in the order of their visits, without replacement and with cycling after all numbers were drawn. Those who were assigned numbers 1, 5, or 10 underwent 8^PZ + 4^TZ + X PBx, whereas the remaining seven received the 8^PZ + 10^TZ + X PBx. This approach aimed to increase the likelihood of patients joining the experimental group, potentially benefiting them and facilitating the informed consent process. The details of the study design are provided in the protocol file (Protocol). The CONSORT diagram is shown in Figure 1.

FIG 1.

The CONSORT diagram of prospective clinical trials. ciPCa, clinically insignificant prostate cancer; csPCa, clinically significant prostate cancer; Mp-MRI, multiparametric magnetic resonance imaging; PCa, prostate cancer; PI-RADS, prostate imaging reporting and data system; PSA, prostate-specific antigen; PZ, peripheral zone; RP, radical prostatectomy; TZ, transition zone.

Biopsy Method

8^PZ + 4^TZ + X TP TRUS-MRI-fusion PBx.

The 8^PZ + 4^TZ + X PBx was performed as previously described.¹⁹ In brief, TRUS and MRI software fusion positioning was used for positioning the perineal 8-core PZ system (Fig 2A), the 4-core TZ system (Fig 2B), and X-core TB (Fig 2C).

FIG 2.

TRUS-MRI-fusion prostate biopsy schematic. (A) 8^PZ-core PBx and 8-core biopsy in PZ. (B) 4^TZ-core PBx and 4-core biopsy in TZ. (C) X-core PBx and 3-5 cores targeting MRI lesions. (D) 10^TZ-core PBx and 10-core biopsy in TZ. (E) 8^TZ-core PBx and 8-core biopsy in TZ. (F) 6^TZ-core PBx and 6-core biopsy in TZ. PBx, prostate biopsy; PZ, peripheral zone; TZ, transition zone; TZa, transitional zone anterior; TZp, transitional zone posterior.

8^PZ + 10^TZ + X TP TRUS-MRI-fusion PBx.

The biopsy procedure remained identical to that described previously. The TZ region was biopsied using a 10-core approach (calculated based on retrospective study data, Fig 2D). In addition, we compared the diagnostic efficacy between the 10-core and 4-core approaches, as well as the 8-core (Fig 2E) and 6-core (Fig 2F).

Mp-MRI and Pathologic Features

All patients underwent imaging with a 3T MRI scanner, using relevant sequences as previously described.²⁰ MRI parameters were evaluated following the PI-RADS V2.1 guidelines.²¹ Pathologic assessments adhered to the Society of Urogenital Pathology and International Society of Urological Pathology (ISUP) PCa guidelines.²² Two experienced radiologists or pathologists reviewed all cases, with additional expert consultation in the case of discrepancies. The csPCa was defined as ISUP grade >1, with an upgrade in biopsy ISUP grade from 1 to RP ISUP grade >1 considered significant.

Statistical Analyses

Concurrent control: After block random assignment, 280 patients who underwent 8^PZ + 10^TZ + X PBx and 120 patients who underwent 8^PZ + 4^TZ + X PBx were included as a concurrent control group. Self-control: As the 8^PZ + 10^TZ + X PBx contains 8^PZ + 4^TZ + X, 10^TZ + X, 8^TZ + X, 6^TZ + X, and 4^TZ + X PBx, the 280 patients who underwent 8^PZ + 10^TZ + X PBx were used as the self-control group to compare the diagnostic efficacy of these different substrategies. Primary end points: the positive rate of biopsy (number of patients with PCa/total number of patients who underwent biopsy) and the detection rate of csPCa (number of patients with biopsy-detected csPCa/number of patients with RP-confirmed csPCa). Secondary end point: incidence of biopsy-related complications and clinically insignificant prostate cancer (ciPCa, number of patients with ciPCa detected by biopsy/total number of patients who underwent biopsy). After a normal distribution analysis, continuous variables were t-tested and nonparametrically tested. Chi-square or Fisher's exact tests are used for unpaired categorical variables. McNemar's test with continuity correction or the exact McNemar's test is applied to paired categorical data, particularly in the self-controlled analyses of retrospective or prospective studies. GraphPad Prism (8.0.2) and R (4.1.2) were used for data analysis. The statistical analysis followed the guidelines for reporting urologic clinical research.²³ A significance level of P < .05 was adopted. The study was conducted in accordance with the CONSORT reporting guidelines.^24,25

Ethics Approval and Consent to Participate

This study complies with the Declaration of Helsinki. This study was approved by the Institutional Review Board of the First Affiliated Hospital of Soochow University (approval number: No .2021 (033)) and Clinical trial registration in China Clinical Trial Registry (ChiCTR2200056386), and informed consent was obtained from each patient.

RESULTS

Descriptive Analysis of Patients

The clinical characteristics of all patients are shown in Table 1.

TABLE 1.

Characteristics of the Retrospective and Prospective Cohort

Variable	Retrospective Cohort	Prospective Cohort
	8PZ + 4TZ + X	8PZ + 4TZ + X	8PZ + 10TZ + X	P
Study patients, No.	217	120	280
Age, years, median (IQR)	69 (65-75)	70 (65-75)	70 (65-75)	.95
Initial PSA, ng/mL, median (IQR)	17 (7-22)	12 (8-21)	12 (8-20)	.67
PI-RADS score, No. (%)				.44
4	92 (42)	76 (63)	164 (59)
5	125 (58)	44 (37)	116 (41)
Mapping lesions, No. (%)
PZ	121 (56)	60 (50)	122 (44)
TZ	83 (38)	51 (42)	145 (52)
PZ + TZ	13 (6)	9 (8)	13 (5)
No. of positive system biopsy cores, No., median (IQR)	4 (2-6)	2 (0-6)	4 (1-8)
Patients with PCa, No. (%)	217 (100)	88 (73)	234 (84)
Biopsy ISUP GG, No. (%)
1	30 (14)	20 (23)	48 (21)
>1	187 (86)	68 (77)	186 (79)
Lesion volume ratio, %, median (IQR)	3 (1-6)	2 (1-4)	2 (1-5)	.76
Patients who underwent RP, No. (%)	217 (100)	64 (73)	156 (67)
Pathologic ISUP GG, No. (%)				.76
1	10 (5)	3 (5)	10 (6)
>1	207 (95)	61 (95)	146 (94)

Abbreviations: GG, Grade group; ISUP, International Society of Urological Pathology; MP-MRI, multiparametric magnetic resonance imaging; PCa, prostate cancer; PI-RADS, Prostate Imaging Reporting and Data System; PSA, prostate-specific antigen; PZ + TZ patients, patients' multiple lesions of MR mapping lesions in the PZ and TZ; PZ, peripheral zone; RP, radical prostatectomy; TZ or PZ patients, patients' index lesions of MP-MRI in the TZ or PZ; TZ, transition zone.

8^PZ + 4^TZ + X Failed to Deliver Sufficient Detection Efficiency for TZ Patients, and 8^PZ Biopsy Provided No Additional Benefit

The incidence of csPCa detected by biopsy in patients with lesions in the PZ was notably higher than that in patients with lesions in the TZ (92%, n = 121 v 78%, n = 83, P < .01; Fig 3A). However, there was no disparity in the incidence of csPCa determined by RP between PZ and TZ patients (97%, n = 121 VS. 95%, n = 83, P = .72; Fig 3B). In addition, a higher incidence of RP-diagnosed csPCa compared with biopsy-detected csPCa was observed in TZ patients (95%, n = 83 v 78%, n = 83, P < .01; Fig 3C), whereas no such difference was found in PZ patients (97%, n = 121 v 92%, n = 121, P = .05; Fig 3D).

FIG 3.

Comparison of csPCa occurrence and detection between TZ patients and PZ patients. (A) The incidence of csPCa detected by biopsy in TZ lesions is lower than that in PZ patients. (B) The incidence of csPCa determined by RP pathology is similar between TZ and PZ lesions. (C) The incidence of csPCa detected by biopsy is lower than that determined by RP pathology in TZ patients. (D) No significant difference in the incidence of csPCa between biopsy and RP pathology in PZ patients. (E) No statistically significant difference in the csPCa detection rate for TZ tumors between 8^PZ + 4^TZ + X and 4^TZ + X. (F) The lesion volume ratio in TZ patients with upgrading was smaller than those without upgrading. (G) The incidence of lesions in the left and right TZa was higher than that in the TZp region. *P < .05,**P < .01. ciPCa, clinically insignificant prostate cancer; csPCa, clinically significant prostate cancer; PZ, peripheral zone; RP, radical prostatectomy; TZ, transition zone; TZa, transitional zone anterior; TZp, transitional zone posterior.

There was no statistically significant difference in the csPCa detection rate for TZ tumors between 8^PZ + 4^TZ + X and 4^TZ + X (82%, n = 79 v 77%, n = 79, P = .13). However, the 8^PZ + 4^TZ + X approach showed significantly higher detection rates compared with 8^PZ + 4^TZ, 4^TZ, and X alone (P < .01; Fig 3E). Patients with upgraded TZ lesions exhibited a smaller tumor volume ratio compared with those without upgrading (1.26% v 3.35%, P = .03; Fig 3F). Moreover, the incidence of lesions was higher in the transitional zone anterior (TZa) than in the transitional zone posterior (TZp; right 47% v 17%, left 52% v 17%, n = 83, P < .01; Fig 3G).

The Biopsy Efficacy of 8^PZ + 10^TZ + X and 10^TZ + X for TZ Tumors Was Superior to That of 8^PZ + 4^TZ + X and 4^TZ + X in the Concurrent Comparison

The smaller the proportion of tumor volume, the lower the possibility of biopsy to penetrate the main pathologic structure, and more cores were required.²⁶ According to the finding that upgraded TZ patients had a smaller tumor volume ratio than the nonupgraded patients (1.26% v 3.35%, P = .03), we found that if upgraded patients wanted to achieve the biopsy accuracy of the nonupgraded patients, the TZ area might require 10 biopsy cores (3.35/1.26 × 4 = 10; Fig 3F). Combined with the higher incidence of TZa lesions compared with TZp (Fig 3G), we designed the 8^PZ + 10^TZ + X PBx (Fig 2).

In the concurrent comparison, the detection efficacy of 8^PZ + 10^TZ + X and 10^TZ + X biopsy was superior to that of 8^PZ + 4^TZ + X and 4^TZ + X for TZ patients, as shown in Table 2. In TZ patients, both the biopsy positive rate and the detection rate of TZ csPCa for 8^PZ + 10^TZ + X were superior to those of 8^PZ + 4^TZ + X. Similarly, 10^TZ + X showed a higher biopsy positive rate and TZ csPCa detection rate compared with 4^TZ + X. Furthermore, there was no significant difference in biopsy-related complications and the positive rate of ciPCa between 8^PZ + 10^TZ + X and 8^PZ + 4^TZ + X (Table 2).

TABLE 2.

Concurrent Comparison of Detection Efficacy for TZ Patients Between 8^PZ + 10^TZ + X, 10^TZ + X Biopsy, and 8^PZ + 4^TZ + X, 4^TZ + X

TZ Group	Test	Control	P	Test	Control	P
	8PZ+10TZ + X	8PZ+4TZ + X		10TZ + X	4TZ + X
Biopsy patients, No. (%)	145	51		145	51
PCa	127 (88)	33 (65)	<.01	120 (83)	33 (65)	<.01
csPCa	92 (64)	22 (43)	.01	92 (64)	22 (43)	.01
ciPCa	35 (24)	11 (22)	.71	28 (19)	11 (22)	.73
RP patients, No. (%)	89	25
csPCa	81 (91)	23 (92)	.88
ciPCa	8 (9)	2 (8)
Detected patients with csPCa, No. (%)	67 (83)	14 (61)	.03	67 (83)	14 (61)	.03
Biopsy complications, No. (%)
Fever	1 (1)	1 (2)	.45
Hematuria	12 (8)	4 (8)	>.99
Uroschesis	5 (3)	1 (2)	>.99

Abbreviations: csPCa, clinically significant prostate cancer; PZ, peripheral zone; RP, radical prostatectomy; TZ, transition zone

In the Self-Comparison, 8^PZ Biopsy Offered No Additional Benefit for TZ Patients, Whereas 8^TZ + X Biopsy May Be a Preferable Biopsy Strategy for TZ Patients

As the 8^PZ + 10^TZ + X biopsy includes 8^PZ + 4^TZ + X, 10^TZ + X, 8^TZ + X, 6^TZ + X, and 4^TZ + X biopsies, the 145 TZ patients who underwent 8^PZ + 10^TZ + X biopsy were used as a self-control group for these biopsy methods.

Both the positive biopsy rate (87% v 76%, n = 145, P < .01) and the csPCa detection rate (83% v 72%, n = 81, P < .01) of the 8^PZ + 10^TZ + X strategy were significantly higher than those of 8^PZ + 4^TZ + X. There was no significant difference in csPCa detection rates between the 8^PZ + 4^TZ + X and 4^TZ + X strategies (72% v 69%, n = 81, P = .5), whereas both were significantly higher than that of the X strategy alone (72% and 69% v 58%, n = 81, P < .01), consistent with the findings from the retrospective analysis.

There was no significant difference in the detection rate of csPCa (83% v 83%, n = 81, P > .99) between 8^PZ + 10^TZ + X and 10^TZ + X. The biopsy incidence of ciPCa was lower with the 10^TZ + X compared with the 8^PZ + 10^TZ + X (19% v 24%, n = 145; P < .01). In addition, there was no significant difference in detection rate of csPCa (83% v 81%, n = 81, P = .84) between 8^PZ + 10^TZ + X and 8^TZ + X. Although we observed an increased detection rate of TZ csPCa, the difference between the 8^PZ + 10^TZ + X and 6^TZ + X did not reach conventional statistical significance (83% v 78%, n = 81, P = .12; Fig 4 and Data Supplement).

FIG 4.

Comparison of biopsy efficacy between different biopsy strategies in the self-control group (see the Data Supplement for details). ciPCa, clinically insignificant prostate cancer; csPCa, clinically significant prostate cancer; PZ, peripheral zone; RP, radical prostatectomy; TZ, transition zone.

DISCUSSION

PBx plays a pivotal role in diagnosing PCa.²⁷ Currently, TP-PBx is widely used for patients with PCa. However, the choice of biopsy strategies for TP-PBx remains a topic of debate.¹ In the context of lesion localization serving as a crucial basis for biopsy strategies, research on biopsy approaches for TZ tumors—an area more prone to pathologic upgrading—remains limited.¹⁰ Our study identified a potential limitation in the widely used 8^PZ + 4^TZ + X PBx for TZ patients. Retrospective analyses have revealed that the 8^PZ + 4^TZ + X PBx exhibits a higher rate of csPCa underdetection in TZ tumors compared with PZ tumors. Furthermore, we observed that the 8^PZ biopsy provided no additional benefit in detecting csPCa among TZ patients. Based on retrospective data and literature reports, we hypothesize that the insufficient detection efficiency of the 8^PZ + 4^TZ + X approach for TZ tumors is attributable to redundant PZ sampling and inadequate TZ sampling.¹⁴

Therefore, based on lesion volume and sampling density calculations, we augmented the number of biopsy cores in the TZ region, resulting in the 8^PZ + 10^TZ + X PBx. In the prospective trial, we confirmed that the 8^PZ + 10^TZ + X PBx achieved higher biopsy positivity and csPCa detection rates in TZ patients compared with the 8^PZ + 4^TZ + X approach, without increasing biopsy-related complications or the incidence of ciPCa. In addition, within the self-controlled design of the trial, we further validated that PZ biopsies provided no additional benefit for TZ patients. We also found that the 8^TZ + X protocol achieved biopsy positivity and csPCa detection rates comparable with those of the 8^PZ + 10^TZ + X approach. This finding indicates that 8^TZ + X, by reducing the total number of biopsy cores—particularly avoiding unnecessary PZ sampling—while increasing TZ sampling, enhances the accuracy of biopsy for TZ tumors. It also underscores the importance of targeting biopsies around lesion-specific regions.

Advances in MRI technology and the ongoing refinement of the PI-RADS guidelines have enhanced the role of MRI in guiding biopsy and treatment decisions for PCa and improving lesion localization.^6,28,29 More reliable lesion localization has elevated the role of TB and introduced perilesional sampling.^4,14 A meta-analysis by Oerther et al,¹⁸ encompassing 1,946 lesions, reported cancer detection rates at the lesion level as follows: 2% (95% CI: 0%-8%) for PI-RADS 1, 4% (1%-9%) for PI-RADS 2, 20% (13%-27%) for PI-RADS 3, 52% (43%-61%) for PI-RADS 4%, and 89% (76%-97%) for PI-RADS 5. To ensure the accuracy of lesion localization and alignment between MRI findings and actual tumors, we included only patients with a PI-RADS score of >3. This exclusion of patients with a PI-RADS score of 3 introduces certain limitations. However, this approach was necessary to ensure that MRI-detected lesions represented true TZ tumors, especially given the greater challenge of identifying TZ lesions on Mp-MRI compared with PZ lesions.

Based on MRI lesion localization, we found that the 8^PZ + 4^TZ + X biopsy failed to provide sufficient detection efficiency for PCa patients with MRI lesions in TZ. Similar findings were reported by Augustin, who observed inconsistent Gleason scores between TZ cancer biopsies and RP specimens.⁹ Furthermore, we found that PZ biopsies provided no significant additional benefit in detecting csPCa among TZ patients. This led us to realize that for TZ tumors, the lack of substantial benefit from PZ biopsies, combined with the relatively limited number of cores allocated to the TZ, might contribute to missed detections and reduced accuracy in sampling TZ tumors. Brisbane et al¹⁵ analyzed biopsy data from 2,048 men across two major centers and demonstrated that 90% of csPCa was located within a 10-mm radius of the lesions. Similarly, Noujeim et al¹⁴ reported an 86% cumulative distribution rate of cancer within 10 mm of the lesions. In addition, Hagens et al,³⁰ in a retrospective analysis of 235 men, described comparable findings, with TB combined with perilesional sampling detecting 96.8% of csPCa. These studies highlight the importance of perilesional biopsy, supporting our aforementioned hypothesis.

Therefore, we attempted to increase the core distribution in the TZ region to improve the biopsy accuracy for TZ tumors. The rationale behind the improvement lies in considerations of biopsy core density.^31,32 Based on the comparative results of lesion volume proportions in our retrospective analysis, we calculated that the TZ area requires 10 cores. These cores were then distributed according to the higher incidence of lesions in TZa compared with TZp. A previous study also showed that the incidence of pre-PCa was higher than that of post-PCa.³³ Ultimately, we developed the 8^PZ + 10^TZ + X PBx.

In prospective trials, the 8^PZ + 10^TZ + X had a higher detection rate for TZ csPCa in both concurrent controls and self-controlled comparisons. This finding supports our hypothesis that the insufficient core distribution in the TZ region under the 8^PZ + 4^TZ + X protocol led to inadequate detection of TZ csPCa. While TZ biopsies may not provide additional benefits for non-TZ tumor patients,³⁴ they are essential for accurate detection in patients with TZ tumor.³⁵ Guichard et al showed that adding TZ biopsies to a 12-core template increased detection rates by 7.2% (P = .023), highlighting the importance of TZ sampling.³⁶ Similarly, Queiroz and Presti found that additional TZ cores improved detection without increasing complications.^37,38 Our study confirmed this as increasing TZ cores did not raise complication rates, consistent with the study by Xiang et al,³⁹ nor did it increase ciPCa incidence compared with 8^PZ + 4^TZ + X. Clearly, increasing biopsy cores in the TZ region enhanced the accuracy of TZ tumor detection, reinforcing the critical role of perilesional sampling.

Importantly, retrospective analysis and prospective validation clarified that PZ biopsies provided no significant benefit for csPCa detection in with patients TZ tumor. In the self-controlled trial, the 8^TZ + X PBx showed no significant difference in biopsy positivity or csPCa detection rates compared with the 8^PZ + 10^TZ + X PBx for TZ patients. The 8^TZ + X PBx avoided unnecessary PZ biopsies with dense core distribution, reducing the total number of cores while enhancing biopsy accuracy for TZ patients. Similar results have been reported in a study for PZ tumors. Biopsy in patients with PZ tumors that omits the TZ region showed similar rates of detection of csPCa to biopsy in patients without the TZ region.³⁴

Notably, while the studies by Brisbane et al and Noujeim et al have received widespread recognition, opposing views exist.^14,15 In a prospective study, Duwe et al compared the effectiveness of TB, SB, and perilesional biopsy, along with their combinations, for csPCa detection.⁴⁰ They found that the combination of TB + SB outperformed TB + perilesional biopsy. The 8^TZ + X PBx may represent a middle ground, avoiding full-gland systematic sampling while not limiting biopsies solely to the 10-mm perilesional zone.

In MRI-based biopsy strategies, the significant differences between PZ and TZ lesions should not be overlooked.^17,21 Moreover, TZ patients may face greater biopsy inaccuracy despite the lower incidence of TZ tumors.¹⁰ Our study, through retrospective analysis and prospective validation, demonstrates that PZ biopsies offer no additional benefit for patients with TZ lesions and that more targeted sampling strategies are needed for the TZ. These findings provide practical approaches and key insights for optimizing biopsy strategies in TZ tumors.

The present study has several limitations. First, to match MRI lesions with actual pathology, we excluded patients with PI-RADS <4, potentially omitting some PCa cases. We also did not consider individual TZ size for personalized biopsy planning. Artificial intelligence may enable more tailored strategies in the future. Second, as a high-volume referral center, our disease patterns may not reflect those in the general population. Third, this single-center study requires validation through multicenter prospective research.

In conclusion, in the 8^PZ+4^TZ + X biopsy strategy, TZ patients faced a higher risk of csPCa underdiagnosis, with PZ sampling providing no additional benefit for TZ csPCa detection. The 8^TZ + X biopsy strategy, designed by increasing core distribution in the TZ, avoided unnecessary PZ biopsies, reduced the total number of cores, and improved biopsy accuracy for TZ patients. This provides practical recommendations and valuable insights for optimizing biopsy strategies in TZ patients.

PREPRINT VERSION

Preprint available on https://doi.org/10.21203/rs.3.rs-5011281/v1.

DATA SHARING STATEMENT

A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/PO-25-00468. The data that support the findings of this study are available from the corresponding author upon reasonable request.

AUTHOR CONTRIBUTIONS

Conception and design: Xin Chen, Chen Huang, Chenchao Zhou, Renpeng Huang, Yuxin Lin, Jianquan Hou, Yuhua Huang, Xuedong Wei

Financial support: Yuxin Lin, Jianquan Hou, Yuhua Huang, Xuedong Wei

Administrative support: Jianquan Hou, Yuhua Huang, Xuedong Wei

Provision of study materials or patients: Xin Chen, Chen Huang, Chenchao Zhou, Yu Li, Jie Bao, Yuxin Lin, Jianquan Hou, Yuhua Huang, Xuedong Wei

Collection and assembly of data: Xin Chen, Chen Huang, Chenchao Zhou, Yu Li, Renpeng Huang, Jie Bao, Yuxin Lin, Yuhua Huang, Xuedong Wei

Data analysis and interpretation: Xin Chen, Chenchao Zhou, Renpeng Huang, Jie Bao, Michael C. Truß, Xuedong Wei

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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