Introduction: Atypical small acinar proliferation (ASAP) is detected in approximately 5% of prostate biopsies. Current guidelines recommend a repeat biopsy within 3–6 months after the initial diagnosis. However, clinical significance and outcomes of repeat biopsy are conflicting. Based on this situation, we conducted a meta-analysis to report the rate of clinically significant prostate cancer (csPCa) on repeat biopsy after a diagnosis of ASAP to determine the safety and validity of deferring repeat biopsy. Methods: We searched PubMed, Medline, Web of Science, and Embase databases for articles published until July 2023. Two reviewers independently screened the literature, extracted the data, and assessed the risk of bias for the included studies. Pooled ratios and 95% confidence intervals (CIs) were calculated using Stata 17. Results: Sixteen studies and 1,796 patients were included in the meta-analysis. A total of 553 patients were diagnosed with prostate cancer, and 204 had csPCa. The pooled rate of csPCa on repeat biopsy after ASAP diagnosis was 12.1% (95% CI: 0.09, 0.15), which is a relatively low progression rate. However, we observed heterogeneity among the 16 articles. Subgroup analysis was performed, and patients who underwent repeat biopsy within 6 months according to the guidelines had a lower csPCa incidence (effective size [ES] = 0.09, 95% CI: 0.060, 0.120) than those who underwent biopsy after more than 6 months (ES = 0.221, 95% CI: 0.094, 0.349). Conclusion: Repeat biopsy can be safely deferred for patients diagnosed with ASAP. We believe our results may help improve management strategies and encourage clinicians to choose more patient-friendly or non-invasive diagnostic evaluations.

Prostate cancer is a major threat to men’s health. According to 2020 statistical data, prostate cancer ranks second in cancer incidence and fifth in cancer mortality among males [1]. A previous study claimed that the natural history of prostate cancer has shifted toward a more indolent course in recent years [2]. Conservative management, such as active surveillance and watchful waiting, has gradually become an alternative to operative treatment [3].

Prostate biopsy is an essential diagnostic strategy for men with suspected prostate cancer [4]. However, the potential risks and overtreatment associated with this procedure are easily overlooked [4]. As an invasive procedure, prostate biopsy can result in complications such as infections, bleeding, and urinary obstruction [5]. A recent study has demonstrated that infectious complications can cause serious consequences such as hospitalization (1–3%), sepsis (0.5–7%), and even death [6].

Atypical small acinar proliferation (ASAP) is detected in approximately 5% of prostate biopsies [7]. The term ASAP is usually used in pathology reports to describe a needle biopsy suspicious for but not diagnostic of malignancy [8]. Histologically, ASAP comprises smaller acini but also includes glands with normal diameters when viewed under the microscope [9]. Previous studies have shown that the rate of prostate cancer on re-biopsy in men with an initial ASAP diagnosis is 30–50% [10, 11]. Therefore, the guidelines from the National Comprehensive Cancer Network (NCCN) and the European Association of Urology (EAU) recommend that patients diagnosed with ASAP on initial biopsy undergo repeat prostate biopsy with increased sampling of the area(s) with ASAP within 3–6 months [12, 13]. However, these recommendations have not been fully implemented in daily practice. On the one hand, increasing concerns about overtreatment and possible infectious complications associated with biopsy affect the preferences of physicians and patients; on the other hand, existing data on the clinical significance and outcomes of repeat biopsy are conflicting. Previous studies have suggested that the probability of detecting clinically significant prostate cancer (csPCa) on repeat biopsy could be as high as 38% [14], whereas some reported a relatively low probability.

In this study, we conducted a systematic review and meta-analysis of previous literature to explore the relationship between ASAP diagnosis after initial biopsy and csPCa incidence after repeat biopsy to analyse the safety and validity of deferring repeat biopsy. We also performed subgroup analyses to determine how the potential variables affected the merged results and the level of heterogeneity of the meta-analysis.

Search Strategy

A systematic bibliographic search was conducted for articles published before July 2023, using PubMed, Medline, Web of Science, and Embase databases with the following search algorithm: (“atypical small acinar proliferation” or “ASAP”) and (“repeated biopsy” or “re-biopsy”). In addition, the reference lists of the retrieved articles and related reviews were checked to identify any potentially relevant articles. This meta-analysis was designed, performed, and reported in accordance with the standards of quality for reporting meta-analysis [15].

Selection Criteria

We included studies that met the following criteria: ① observational studies; ② included risk stratification of cancer after repeat biopsy; ③ patients underwent repeat biopsy following the initial ASAP diagnosis; ④ written in English or could be translated to English. We excluded reviews, letters, editorials, meeting abstracts, replies from the authors, case reports, and studies that were not reported in English. For duplicate publications, either the higher quality or the most recent publication was selected. Figure 1 shows a flow diagram of the studies included in this meta-analysis.

Fig. 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISRM) flow chart for article selection process.

Fig. 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISRM) flow chart for article selection process.

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Quality Assessment

Considering that the included studies were non‐comparative, the revised and validated versions of the “Methodological Index for Non‐Randomized Studies” (MINORS) [16] were introduced to evaluate the quality of the included studies by two authors (Wen-Tong Ji, Xue-Fei Jin) independently. The MINORS contains 12 items; the first eight are specifically for non-comparative studies, which are scored as 0 (not reported), 1 (reported inadequately), or 2 (reported adequately). Therefore, the highest total score for non-comparative studies was 16. All differences in opinion were resolved by consensus.

Data Extraction

Data were extracted independently from the included reports by the same two authors, and any discrepancies were resolved by a discussion. The following data were recorded: the author’s surname, study design, publication year, number of patients with ASAP who underwent repeat biopsy and were diagnosed with prostate cancer, and the number of csPCas according to the respective criteria.

Statistical Analysis

We performed a meta-analysis using Stata (version 17), with p < 0.05 indicating statistical significance. All results were estimated with 95% confidence intervals (CIs). Heterogeneity was examined using the Q-test [17] and Higgins I‐squared test [18]. A fixed-effects model was applied when p > 0.1 and I2<50%; otherwise, a random-effects model was used.

For the sensitivity analysis, a meta-analysis was conducted after omitting each study in turn. Potential publication bias was evaluated using funnel plots and Egger’s test [19]. All analyses in this meta-analysis were based on previously published studies and did not include original data. Therefore, no ethical approval and patient consent were required.

Search Results and Characteristics

A systematic search of the databases yielded 424 records. After excluding duplicates, 182 studies were screened, and 23 full texts were assessed for eligibility. The corresponding PRISMA flow chart is shown in Figure 1. Sixteen eligible studies [7, 14, 20‒33] were finally included in the meta-analysis. These studies were published between 2006 and 2023. The majority of the studies were conducted in North America (n = 7), Europe (n = 4), and Asia (n = 4). In total, 1,796 patients with ASAP underwent repeat biopsy in these studies; 553 were diagnosed with prostate cancer, and 204 were diagnosed with csPCa after repeat biopsy.

Regarding quality, all the included studies were non-comparative. The MINORS scores ranged from 9 to 13 out of 16 points. Table 1 shows the quality assessment of the included studies using the MINORS criteria. The main characteristics of the included studies are summarized in Table 2.

Table 1.

Quality evaluation results of the included studies

studyScore of item/pointTotal score of MINORS/point
Mallén, et al. [23] (2006) 12 
Leone, et al. [20] (2016) 12 
Ynalvez, et al. [21] (2018) 10 
Leone, et al. [22] (2015) 12 
Cool, et al. [24] (2016) 13 
Imanaka, et al. [14] (2020) 
O'Connor, et al. [25] (2022) 12 
Wiener, et al. [26] (2017) 10 
López, et al. [28] (2007) 10 
Dorin, et al. [29] (2015) 12 
Mancuso, et al. [30] (2007) 13 
Yucel, et al. [27] (2018) 10 
Yazdani, et al. [7] (2023) 12 
Totaro, et al. [31] (2021) 12 
Warlick, et al. [32] (2015) 11 
Yang, et al. [33] (2021) 12 
studyScore of item/pointTotal score of MINORS/point
Mallén, et al. [23] (2006) 12 
Leone, et al. [20] (2016) 12 
Ynalvez, et al. [21] (2018) 10 
Leone, et al. [22] (2015) 12 
Cool, et al. [24] (2016) 13 
Imanaka, et al. [14] (2020) 
O'Connor, et al. [25] (2022) 12 
Wiener, et al. [26] (2017) 10 
López, et al. [28] (2007) 10 
Dorin, et al. [29] (2015) 12 
Mancuso, et al. [30] (2007) 13 
Yucel, et al. [27] (2018) 10 
Yazdani, et al. [7] (2023) 12 
Totaro, et al. [31] (2021) 12 
Warlick, et al. [32] (2015) 11 
Yang, et al. [33] (2021) 12 

①: A clearly stated aim; ②: inclusion of consecutive patients; ③: prospective collection of data; ④: endpoints appropriate to the aim of the study; ⑤: unbiased assessment of the study endpoint; ⑥: follow-up period appropriate to the aim of the study; ⑦: loss to follow-up less than 5%; and ⑧: prospective calculation of the study size.

MINORS, methodological index for non‐randomized studies.

Table 2.

Main characteristics of the included studies

StudyResearch typeCountryCaseNOutcome index
Mallén, et al. [23] (2006) Retrospective study Spain 64 ① 
Leone, et al. [20] (2016) Retrospective study USA 15 264 ① 
Ynalvez, et al. [21] (2018) Retrospective study USA 11 ② 
Leone, et al. [22] (2015) Retrospective study USA 56 ① 
Cool, et al. [24] (2016) Prospective cohort study Canada 50 ① 
Imanaka, et al. [14] (2020) Retrospective study Japan 13 34 ① 
O’Connor, et al. [25] (2022) Retrospective study Irish 19 ① 
Wiener, et al. [26] (2017) Retrospective study USA 21 261 ② 
López, et al. [28] (2007) Retrospective study Spain 45 ① 
Dorin, et al. [29] (2015) Retrospective study USA 27 287 ③ 
Mancuso, et al. [30] (2007) Retrospective study Australia 11 22 ① 
Yucel, et al. [27] (2018) Retrospective study Turkey 12 54 ① 
Yazdani, et al. [7] (2023) Retrospective study Iran 16 ② 
Totaro, et al. [31] (2021) Retrospective study Italy 15 119 ③ 
Warlick, et al. [32] (2015) Retrospective study USA 48 279 ① 
Yang, et al. [33] (2021) Retrospective study China 14 215 ① 
StudyResearch typeCountryCaseNOutcome index
Mallén, et al. [23] (2006) Retrospective study Spain 64 ① 
Leone, et al. [20] (2016) Retrospective study USA 15 264 ① 
Ynalvez, et al. [21] (2018) Retrospective study USA 11 ② 
Leone, et al. [22] (2015) Retrospective study USA 56 ① 
Cool, et al. [24] (2016) Prospective cohort study Canada 50 ① 
Imanaka, et al. [14] (2020) Retrospective study Japan 13 34 ① 
O’Connor, et al. [25] (2022) Retrospective study Irish 19 ① 
Wiener, et al. [26] (2017) Retrospective study USA 21 261 ② 
López, et al. [28] (2007) Retrospective study Spain 45 ① 
Dorin, et al. [29] (2015) Retrospective study USA 27 287 ③ 
Mancuso, et al. [30] (2007) Retrospective study Australia 11 22 ① 
Yucel, et al. [27] (2018) Retrospective study Turkey 12 54 ① 
Yazdani, et al. [7] (2023) Retrospective study Iran 16 ② 
Totaro, et al. [31] (2021) Retrospective study Italy 15 119 ③ 
Warlick, et al. [32] (2015) Retrospective study USA 48 279 ① 
Yang, et al. [33] (2021) Retrospective study China 14 215 ① 

Case: Number of patients fitting the outcome index after repeat biopsy. N: number of patients who underwent repeat biopsies.

①: Gleason score ≥7; ②: Gleason grade group ≥2; ③: clinically significant prostate cancer according to modified Epstein Criteria [34].

The Result of the Meta-Analysis

We examined the association between ASAP and the incidence rate of csPCa after repeat biopsy using data from 16 studies [7, 14, 20‒33]. The heterogeneity test indicated I2 = 74.6% (p < 0.001); therefore, a random-effects model was used. The pooled incidence of csPCa after repeat biopsy was 12.1% (95% CI: 0.09, 0.15). Figure 2 shows the forest plot of the total csPCa rate after repeat biopsy in patients with ASAP. Subgroup analysis was performed for three aspects (Fig. 3): ① median time to repeat biopsy, ② median age, and ③ median prostate-specific antigen (PSA). The result was consistent, and we discovered that ① patients who underwent a repeat biopsy within 6 months according to the guideline [35] had a lower incidence of csPCa (effective size (ES) = 0.09, 95% CI: 0.060, 0.120) than those who underwent a repeat biopsy after more than 6 months (ES = 0.221, 95% CI: 0.094, 0.349); ② the subgroup of patients with a median age below 65 years had a lower incidence of csPCa (ES = 0.097, 95% CI: 0.067, 0.127) than the subgroup of patients above 65 years (ES = 0.161, 95% CI: 0.086, 0.235); ③ the subgroup of patients with “8<PSA ≤10” had a higher risk of csPCa (ES = 0.209, 95% CI: 0.031, 0.387) than those with “4<PSA ≤6” (ES = 0.115, 95% CI: 0.050, 0.180) and “6<PSA ≤8” (ES = 0.078, 95% CI: 0.048, 0.108). The results of the subgroup analyses are summarized in Table 3.

Fig. 2.

Forest plot of the total rate of clinically significant prostate cancer on repeat biopsy after a diagnosis of ASAP.

Fig. 2.

Forest plot of the total rate of clinically significant prostate cancer on repeat biopsy after a diagnosis of ASAP.

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Fig. 3.

Subgroup analysis of the rate of clinically significant prostate cancer on repeat biopsy after a diagnosis of ASAP. a Median time to repeat biopsy. b Median age. c Median prostate-specific antigen.

Fig. 3.

Subgroup analysis of the rate of clinically significant prostate cancer on repeat biopsy after a diagnosis of ASAP. a Median time to repeat biopsy. b Median age. c Median prostate-specific antigen.

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Table 3.

Results of subgroup analyses

SubgroupStudy, nI2, %p valueES95% CI
Time to repeat biopsy (median) 
 Within 6 months 34.3 0.179 0.090 0.060, 0.120 
 More than 6 months 86.1 0.000 0.221 0.094, 0.349 
Age (median) 
 Under 65 years old 50.8 0.047 0.097 0.067, 0.127 
 Over 65 years old 78.4 0.003 0.161 0.086, 0.235 
PSA (median) 
 4<PSA ≤6 0.115 0.050, 0.180 
 6<PSA ≤8 16.4 0.310 0.078 0.048, 0.108 
 8<PSA ≤10 0.209 0.031, 0.387 
SubgroupStudy, nI2, %p valueES95% CI
Time to repeat biopsy (median) 
 Within 6 months 34.3 0.179 0.090 0.060, 0.120 
 More than 6 months 86.1 0.000 0.221 0.094, 0.349 
Age (median) 
 Under 65 years old 50.8 0.047 0.097 0.067, 0.127 
 Over 65 years old 78.4 0.003 0.161 0.086, 0.235 
PSA (median) 
 4<PSA ≤6 0.115 0.050, 0.180 
 6<PSA ≤8 16.4 0.310 0.078 0.048, 0.108 
 8<PSA ≤10 0.209 0.031, 0.387 

PSA, prostate-specific antigen; ES, effective size; CI, confidence interval.

Sensitivity Analysis and Publication Bias

According to the sensitivity analyses (Fig. 4), not removing a study significantly changed the effect sizes or heterogeneity statistics. Minimal evidence of publication bias was observed in the funnel plots (Fig. 5). The results of the Egger’s test (p = 0.005) indicated some publication bias (Fig. 6).

Fig. 4.

Sensitivity analysis for ASAP and the incidence rate of clinically significant prostate cancer on repeat biopsy in this meta-analysis. Through sensitivity analysis, we found that the results of the literature included are stable and accurate.

Fig. 4.

Sensitivity analysis for ASAP and the incidence rate of clinically significant prostate cancer on repeat biopsy in this meta-analysis. Through sensitivity analysis, we found that the results of the literature included are stable and accurate.

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Fig. 5.

Funnel plot of the total rate of clinically significant prostate cancer on repeat biopsy after a diagnosis of ASAP.

Fig. 5.

Funnel plot of the total rate of clinically significant prostate cancer on repeat biopsy after a diagnosis of ASAP.

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Fig. 6.

Egger’s plot for publication bias of the incidence of clinically significant prostate cancer on repeat biopsy after a diagnosis of ASAP for all studies.

Fig. 6.

Egger’s plot for publication bias of the incidence of clinically significant prostate cancer on repeat biopsy after a diagnosis of ASAP for all studies.

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This meta-analysis was performed to determine the pooled rate of csPCa on repeat biopsy after an initial ASAP diagnosis. The study involved 1,796 cases from 16 observational studies. Based on the specific data analysed, we demonstrated that the overall incidence of csPCa on repeat biopsy of patients with ASAP was 12.1%, which is a relatively low progression rate. In addition, the subgroup analysis of “time to repeat biopsy” showed that patients who underwent a repeat biopsy within 6 months have a lower csPCa incidence (9%) compared to those who underwent a repeat biopsy after more than 6 months (22.1%), indicating that postponing repeat biopsy can better help detect potential csPCa compared with immediate repeat biopsy. From the overall incidence and comparison of subgroup incidence, we deduced that delaying repeat biopsy for patients diagnosed with ASAP is safe and valid. In addition, among the 1,796 ASAP patients who underwent repeat biopsies in these studies, 553 (30.7%) had prostatic adenocarcinoma. The high positive repeat biopsy rate indicated that all patients with an initial ASAP diagnosis required a repeat biopsy.

Our results suggest that the current guidelines may reflect an aggressive approach that is not in accordance with conservative management [3] and indolent progress for low-risk prostate cancer [36]. These patients could undergo further evaluation by noninvasive procedures and a less morbid biopsy. Magnetic resonance imaging/ultrasound (MRI/TRUS) fusion-guided biopsy is a promising technique that can improve biopsy accuracy and help detect aggressive prostate cancer [37]. A study led by Dima confirmed that in MRI/TRUS fusion-guided biopsy, cores that re-target areas of previous ASAP are more effective than random re-biopsy cores [38]. Regarding the approach of repeat biopsy, transperineal biopsy is preferable because it is capable of getting samplings that cannot be reached by transrectal biopsy [39].

The results of the subgroup analysis of median age and PSA level showed that older patients (>65 years) with higher PSA levels (>8) have a greater risk of developing csPCa. Thus, consideration of age and PSA levels would aid in the decision-making process for patients and doctors to perform repeat biopsy.

Evidence indicates that ASAP tends to be an incipient disease or even a benign lesion. First, in pathology, ASAP is regarded as an ambiguous report that might predict either benign lesions mimicking malignancy or undersampled prostate cancer [39]. In a previous study, ambiguous p63 (+) expression was detected in immunohistochemical tests and other architectural or cytological changes in ASAP, which could be identified in non-cancerous tissues [40]. Another study found that Nectin-4, a transmembrane protein which could be found in many cancer types [41], was positive in benign prostatic gland tissues and ASAP samples but negative in prostate cancer [42]. The outcome also indicated the histological similarity between ASAP and benign prostatic tissues. Przemyslaw reported that prostate cancer was not detected in patients diagnosed with ASAP with coexisting inflammation on repeat biopsy [43]. Second, Lulia claimed that the clinical features of ASAP on MRI/TRUS fusion-guided biopsy resemble those of benign prostate hyperplasia suggesting a non-high-risk disease [37]. These findings are consistent with our conclusion to defer repeat biopsy for patients with ASAP.

Subgroup analysis can reduce intragroup heterogeneity to some extent; however, significant heterogeneity between groups still remains. Heterogeneity could be attributed to the different characteristics of the population included in previous studies, different core numbers in repeat biopsy, different judging criteria of “csPCa,” and the presence of other concomitant prostate diseases. Due to the limited data, we only examined the relationship between csPCa and time to repeat biopsy, age, and PSA, but not with other indicators, such as the outcome of digital rectal examination, number of cores positive for ASAP, and follow-up years.

This study had some limitations. The results of Egger’s test indicated some publication bias, which might have affected the accuracy of the meta-analysis. The scope of the 16 articles included in our study covered only some countries; hence, our results are not sufficient to reflect the actual csPCa rate on repeat biopsy worldwide. Further, many articles did not provide sufficiently detailed data; therefore, the number of articles in each grouping in the subgroup analysis was limited, which could have affected the representativeness of the results [34].

In summary, this meta-analysis showed that only 12.1% of the men diagnosed with ASAP had csPCa. Thus, our results suggest that most men with ASAP may safely defer repeat biopsy and avoid the morbidity of immediate repeat biopsy, as recommended by the NCCN and EAU. Hopefully, our study will help improve the current management strategies and encourage clinicians to choose more patient-friendly or noninvasive diagnostic evaluations.

An ethics statement is not applicable because this study is based exclusively on published literature.

The authors declare that this study was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.

No funding was received in this article.

Wen-Tong Ji evaluated the quality of the included studies, extract data from studies, analyse data and write the article; Xue-Fei Jin evaluated the quality of the included studies, extract data from studies; and Yao Wang designed the idea and frame of the article.

All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.

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