The Role of PSA Density among PI-RADS v2.1 Categories to Avoid an Unnecessary Transition Zone Biopsy in Patients with PSA 4-20 ng/mL

Objective To evaluate the role of prostate-specific antigen density (PSAD) in different Prostate Imaging Reporting and Data System version 2.1 (PI-RADS v2.1) categories to avoid an unnecessary biopsy in transition zone (TZ) patients with PSA ranging from 4 to 20 ng/mL. Materials and Methods In this retrospective and single-center study, 333 biopsy-naïve patients with TZ lesions who underwent biparametric magnetic resonance imaging (bp-MRI) were analyzed from January 2016 to March 2020. Multivariate logistic regression analyses were performed to determine independent predictors of clinically significant prostate cancer (cs-PCa). The receiver operating characteristic (ROC) curve was used to compare diagnostic performance. Results PI-RADS v2.1 and PSAD were the independent predictors for TZ cs-PCa in patients with PSA 4-20 ng/mL. 0.9% (2/213), 10.0% (7/70), and 48.0% (24/50) of PI-RADS v2.1 score 1-2, 3, and 4-5 had TZ cs-PCa. However, for patients with PI-RADS v2.1 score 1-2, there were no obvious changes in the detection of TZ cs-PCa (0.8% (1/129), 1.3% (1/75), and 0.0% (0/9)) combining with different PSAD stratification (PSAD < 0.15, 0.15-0.29, and ≥0.30 ng/mL/mL). For patients with PI-RADS v2.1 score ≥ 3, the TZ cs-PCa detection rate significantly varied according to different PSAD stratification. A PI-RADS v2.1 score 3 and PSAD < 0.15 and 0.15-0.29 ng/mL/mL had 8.6% (3/35) and 3.7% (1/27) of TZ cs-PCa, while a PI-RADS v2.1 score 3 and PSAD ≥ 0.30 ng/mL/mL had a higher TZ cs-PCa detection rate (37.5% (3/8)). A PI-RADS v2.1 score 4-5 and PSAD <0.15 ng/mL/mL had no cs-PCa (0.0% (0/9)). In contrast, a PI-RADS v2.1 score 4-5 and PSAD 0.15-0.29 and ≥0.30 ng/mL/mL had the highest cs-PCa detection rate (50.0% (10/20), 66.7% (14/21)). It showed the highest AUC in the combination of PI-RADS v2.1 and PSAD (0.910), which was significantly higher than PI-RADS v2.1 (0.889, P = 0.039) or PSAD (0.803, P < 0.001). Conclusions For TZ patients with PSA 4-20 ng/mL, PI-RADS v2.1 score ≤ 2 can avoid an unnecessary biopsy regardless of PSAD. PI-RADS v2.1 score ≥ 3 may avoid an unnecessary biopsy after combining with PSAD. PI-RADS v2.1 combined with PSAD could significantly improve diagnostic performance.


Introduction
Serum prostate-specific antigen (PSA) screening has been widely used for detecting an early stage of prostate cancer (PCa), evaluating treatment response, and determining tumor progression. However, PSA testing increases the risk of overdiagnosis due to the low specificity, resulting in unnecessary prostate biopsies. In addition, the PCa detection rate varies from the PSA range. Several studies have proven that cancer detection rates were 11.8-20.5%, 20.5-25.0%, and 47.1-53.0% in the PSA range of 4-10 ng/mL, 10-20 ng/mL, and greater than 20 ng/mL, respectively [1][2][3]. Compared with that in the PSA level of 4-10 ng/mL (defined as "grey zone"), the cancer detection rate in patients with the PSA level of 10-20 ng/mL was not significantly different [2,4]. Hence, it is feasible to focus on this study in the range of the PSA level from 4 to 20 ng/mL. To reduce unnecessary prostate biopsies, these clinical indicators, including age, prostate volume (PV), PSA density (PSAD), and free to total PSA ratio (f/t-PSA), were used to improve the ability of PCa detection, especially in the PSA range of 4-20 ng/mL.
Multiparametric magnetic resonance imaging (mp-MRI) offers increasingly reliable visualization for the diagnosis of PCa, especially for clinically significant PCa (cs-PCa, defined as Gleason score ≥ 7 and/or volume ≥ 0:5 cm 3 and/or extra prostatic extension), and provides information for evaluating tumor staging and monitoring treatment response [5].
To improve the accuracy of performance and reporting standardization of prostate mp-MRI examination, the original version of the Prostate Imaging Reporting and Data System (PI-RADS v1) was published in 2012 [6] and then updated as PI-RADS v2 in 2014 [7]. However, PI-RADS v2 had some limitations, especially ambiguous description for typical and atypical nodules in the transition zone (TZ) of the prostate, making it necessary to release the latest version of PI-RADS (PI-RADS v2.1) in 2019 [8]. In addition, compared with the mp-MRI protocol, an abbreviated biparametric MRI (bp-MRI) protocol consisting solely of T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI) had comparable diagnostic performance for PCa. Meanwhile, it could shorten MRI examination time, reduce the cost, and avoid potential contrast-associated risks [9][10][11].
Most PCa tumors originate in the peripheral zone (PZ) of the prostate; approximately 25% of these cancers arise from TZ [12]. TZ PCa is more challenging to detect and diagnose on MRI due to these mimics, including benign prostatic hyperplasia (BPH) stromal nodules, chronic prostatitis, or other conditions [13]. Additionally, EAU guidelines mention that TZ sampling during baseline biopsies has a low detection rate and should be limited to MRIdetected lesions or repeat biopsies [14]. A recent study from Byun et al. [15] has revealed that PI-RADS v2.1 shows a better diagnostic performance (sensitivity, 94.5% vs. 91.8%; specificity, 60.9% vs. 56.3%) and a higher interreader agreement (kappa value, 0.565 vs. 0.534) for the detection of TZ cs-PCa compared with PI-RADS v2. Similar results were reported by Tamada et al. [16]. However, the diagnostic specificity, positive predictive value, and accuracy using PI-RADS v2.1 alone had only 50.0%-56.3%, 61.0%-63.2%, and 70.7%-72.4% [16].To date, several risk calculators, a few including MRI and clinical indicators, have been developed and validated. MRI improves accuracy of each of the currently available risk calculators [17]. Hence, it is necessary to combine the PI-RADS v2.1 score with clinical indicators in order to better improve the diagnostic performance for TZ cs-PCa. Most studies have focused on the diagnostic value of combining PI-RADS v2 with clinical indicators and demonstrated that adding these clinical indicators to the PI-RADS v2 score could improve diagnostic performance for the assessment of PCa or cs-PCa [18][19][20]. A recent study from Han et al. has compared the diagnostic performance of bp-MRI and mp-MRI using PI-RADS v2.1 combined with PSAD in detecting cs-PCa patients with PSA 4-10 ng/mL [21]. Wei et al. [22] have constructed a novel internally validated nomogram based on PI-RADS v2.1 and PSAD to predict TZ cs-PCa. However, the clinical importance of PSAD must be different among PI-RADS categories 1 to 5. To our knowledge, no related studies have been reported on the impact of PSAD stratification on the combined diagnosis based on the PI-RADS v2.1 category.
Therefore, this study is to evaluate the role of PSAD in different PI-RADS v2.1 categories to avoid an unnecessary biopsy in TZ patients with PSA levels of 4-20 ng/mL.

Materials and Methods
2.1. Patient Cohort. This retrospective and single-center study was approved by our institutional review board who waived the requirement for the informed consent. We evaluated 892 biopsy-naïve patients who underwent bp-MRI examination between January 2016 and March 2020 at our institution (university hospital). All patients derived from elevated PSA levels within 4-20 ng/mL. Patients who had the index lesion in TZ which was determined as the lesion with the highest PI-RADS v2.1 score were included in the study. For patients with multiple lesions in both TZ and PZ, only the index lesion with the highest score in TZ was included. However, 559 patients were excluded based on these criteria, including (a) the index lesion in PZ (n = 517), (b) incomplete bp-MRI examination (n = 18), (c) unsatisfactory MR images affected by artifacts from patient movement or hip replacement (n = 15), and (d) prostate biopsy or therapies before MRI examination (n = 9). Finally, the remaining 333 patients were enrolled. The study population flowchart is shown in Figure 1.

Imaging Interpretation and Clinical Data Analysis.
All bp-MRI images were independently evaluated by two experienced readers (reader 1 with 5 years of experience in the genitourinary system; reader 2 with 8 years of experience in the genitourinary system) using the PI-RADS v2.1 category protocol in the same setting. They were blinded to pathological results and clinical information. Any discordance between the two readers was resolved by consensus, and any continuous disagreement in scoring was resolved 2 BioMed Research International by a third senior urogenital radiologist who made the final determination of the PI-RADS v2.1 score. According to the PI-RADS v2.1 protocol [8], the T2WI sequence plays a primary role for evaluating TZ lesions, while the DWI sequence is assigned a secondary role. Clinical information including age, t-PSA, f/t-PSA, PV, and PSAD was collected and measured. According to the PI-RADS v2.1 protocol, maximum longitudinal diameter (LD) and maximum anteroposterior diameter (APD) should be measured on the midsagittal T2WI, whereas maximum transverse diameter (TD) should be measured on the axial T2WI. PV was calculated using the following formulation: PV = ðmaximum APDÞ × ðmaximum TDÞ × ðmaximum LDÞ × 0:52 [8]. PSAD was obtained from the t-PSA level divided by the PV (PSAD = t-PSA/PV) [23].

Reference Standard.
In our institution, all patients with PSA 4 ng/mL or higher did undergo biopsy as the standard of care. All biopsy-naïve patients in this study underwent a 10-core systematic transrectal ultrasound-(TRUS-) guided prostate biopsy. The 10-core biopsies were obtained from the base (2 cores), midgland (2 cores), and apex (1 core) from each side of the prostate. Patients with negative MRI (PI-RADS v2.1 scores 1 and 2) underwent a standard 10core systematic TRUS-guided prostate biopsy only. For suspicious PCa lesions on MRI (PI-RADS v2.1 score ≥ 3), an MRI-TRUS fusion-guided targeted biopsy was used, and then, 2-3 targeted cores would be added for these lesions. The MRI-TRUS fusion-guided targeted biopsy was performed using Esaote's MyLab Twice ultrasound system (Esaote, Italy). Histopathologic evaluation of the biopsy specimens was analyzed and reported by experienced genitourinary pathologists in our institution according to the International Society of Urological Pathology (ISUP) 2014 updated Gleason score grading system [24,25]. A Gleason score ≥ 7 on the MRI-TRUS fusion targeted biopsy and/or a matching segment on a systematic TRUS-guided prostate biopsy was considered positive for cs-PCa.

Statistical
Analysis. Statistical analysis was performed using SPSS 22.0 software and MedCalc version 15.2.2. The Kolmogorov-Smirnov test or Shapiro-Wilk test and Levene's test were used to assess the normality of data and the homogeneity of variances. The independent-sample t-test was used for continuous variables which were normally distributed and expressed as mean and standard deviation (SD). Those continuous variables with nonnormal distribution or categorical variables were analyzed using the Mann-Whitney U test, presented as median and interquartile ranges. Multivariable logistic regression analysis was performed to determine the independent predictors. The areas under the receiver operating characteristic curve (AUC) with corresponding 95% confidence intervals (CI) were calculated, and DeLong's test was used to compare the diagnostic performance. A two-tailed P value less than 0.05 was considered statistically significant.     Table 2, multivariate logistic   BioMed Research International regression analysis demonstrated that the independent predictors for TZ cs-PCa in patients with PSA 4-20 ng/mL were PSAD and PI-RADS v2.1 score (P < 0:05).

Discussion
Serum PSA has been the most widely used for PCa screening and early detection. However, the detection rate of PCa in   BioMed Research International patients with PSA levels of 4-10 and 10-20 ng/mL was low, and the rate of detecting cs-PCa was even lower. A previous study reported that the PCa detection rate was 11.8% and 20.5% in the PSA range of 4-10 and 10-20 ng/mL [1]. In addition, the PSA level and the prevalence of PCa varied among races, and the PSA "gray zone" range in Asian men should be higher than 4-20 ng/mL compared to the traditional gray zone (4-10 ng/mL) [2,26]. In this study, we found that the detection rate of cs-PCa in TZ patients with PSA levels ranging from 4 to 20 ng/mL was only 9.9% (33/333). It is more challenging to accurately diagnose TZ lesions in patients with PSA 4-20 ng/mL. Thus, there is a need to reduce an unnecessary prostate biopsy and improve the cancer detection rate for patients with PSA 4-20 ng/mL. In the present study, our results found that the PI-RADS v2.1 score was one of the two independent predictors for TZ cs-PCa in patients with PSA 4-20 ng/mL. Compared to PI-RADS v2, the PI-RADS v2.1 made small step modifications to simplify MRI interpretation and improve interreader agreement [8,27]. Some studies demonstrated that PI-RADS v2.1 yielded higher diagnostic performance and interreader agreement among readers of various experiences for the detection of TZ PCa or cs-PCa than PI-RADS v2 [28][29][30]. In addition, PI-RADS v2.1 also recommended a bp-MRI protocol using T2WI and DWI, while eliminating DCEI, and should be encouraged to clinical researches [8]. The PI-RADS v2.1 category in our study was performed under the bp-MRI protocol.
Our results also demonstrated that PSAD was the other independent predictor for the assessment of TZ cs-PCa in patients with PSA levels of 4-20 ng/mL. PSAD could distinguish patients with a PSA elevation due to BPH and prostatic inflammation, and it has been proven to improve the accuracy of PI-RADS in the decision to perform prostate biopsies [32]. In most studies, the PSAD cutoff value was set from 0.10 to 0.30 ng/mL/mL. In the present study, we stratified the PSAD value as three groups (<0.15, 0.15-0.29, and ≥0.30 ng/mL/mL). For TZ patients with PSA 4-20 ng/mL, the combination of the PI-RADS v2.1 score and PSAD yielded higher cs-PCa detection rates compared to the PI-RADS v2.1 score. PI-RADS v2.1 score 3 and PSAD ≥ 0:30 ng/mL/mL had a higher cs-PCa detection rate than PI-RADS v2.1 score 3 (37.5% vs. 10.0%). A PI-RADS v2.1 score > 3 and PSAD ≥ 0:15 ng/mL/mL had higher cs-PCa detection rates than PI-RADS v2.1 score > 3 (50.0%-66.7% vs. 48.0%). For PI-RADS v2.1 score 3, the cs-PCa detection rate was higher for PSAD < 0:15 ng/mL/mL (8.6%, 3/35) than that for PSAD 0.15-0.29 ng/mL/mL (3.7%, 1/27). This may be due to sample error caused by the small number of positive cases. In addition, we found that the combination of the PI-RADS v2.1 score and PSAD had better diagnostic performance (AUC = 0:910) than the PI-RADS v2.1 score (AUC = 0:889, P = 0:039) or PSAD value (AUC = 0:803, P < 0:001), which was comparable with the previous study by Han et al. [21]. They concluded that the combination model of the bp-MRI-based PI-RADS v2.1 score and PSAD had higher diagnostic performance with an AUC of 0.907 compared to the PI-RADS v2.1 score with an AUC of 0.884 and PSAD with an AUC of 0.682. The different AUC of PSAD may be due to differences in patient characteristics, i.e., PSA ranges from 4 to 20 ng/mL and TZ cs-PCa in the present study and PSA ranges 4-10 ng/mL and total cs-PCa (PZ and TZ) in the previous study. These results indicated that the combination of PI-RADS v2.1 and PSAD could significantly improve the diagnostic performance for TZ cs-PCa in patients with PSA 4-20 ng/mL. Several limitations need to be considered in this study. First, there was a retrospective, single-center study with relatively small number of patients, so sample selection bias inevitably exists. The present results would be further validated in multicenter studies with a larger number of patients. Second, our results were performed based on a "patient" level who had the index lesion with the highest PI-RADS v2.1 score among all lesions in TZ, not on a "lesion" level. Third, not all patients underwent an MRI-TRUS fusion-guided targeted biopsy, and those potential PCa lesions with MRI-negative and pathology-positive status may be missed.

Conclusions
For TZ patients with PSA 4-20 ng/mL, PI-RADS v2.1 score ≤ 2 can avoid an unnecessary biopsy, regardless of PSAD. PI-RADS v2.1 score ≥ 3 may avoid an unnecessary biopsy after combining with PSAD. In addition, PI-RADS v2.1 combined with PSAD could significantly improve its diagnostic performance.

ADC:
Apparent diffusion coefficient APD: Anteroposterior diameter AUC: Area under the curve BPH: Benign prostatic hyperplasia bp-MRI: Biparametric magnetic resonance imaging CI: Confidence interval cs-PCa: Clinically significant prostate cancer DWI: Diffusion-weighted imaging ISUP: International Society of Urological Pathology LD: Longitudinal diameter mp-MRI: Multiparametric magnetic resonance imaging MRI: Magnetic resonance imaging PCa: Prostate cancer PI-RADS: Prostate Imaging Reporting and Data System PSA: Prostate-specific antigen PSAD: Prostate-specific antigen density PV: Prostate volume PZ: Peripheral zone SPSS: Statistical Package for the Social Sciences T2WI: T2-weighted imaging TD: Transverse diameter t-PSA: Total prostate-specific antigen TRUS: Transrectal ultrasound TZ: Transition zone

Data Availability
The data used to support the findings of this study are available from the corresponding author upon request.

Ethical Approval
This study was approved by the unit's ethics committee.

Conflicts of Interest
The authors declare that they have no conflict of interests.