In prostatic transition zone lesions (PI-RADS v2.1): which subgroup should be biopsied?

The study aimed to compare the diagnostic performance of T2-weighted imaging (T2WI) score 3 transition zone (TZ) lesions between Prostate Imaging and Reporting Data System (PI-RADS) v2.1 and modified PI-RADS v2.1-B. Among TZ lesions (n = 78), 47 (60.0%) had T2WI score of 3, and 16 of the 47 (34.0%) were malignant. The rate of malignancy was 8.8% in PI-RADS category 3A, 100% in PI-RADS category 3B, and 100% in PI-RADS category 4. The apparent diffusion coefficient value of PI-RADS category 3B (0.934 ± 0.158 × 10−3 mm2/s) showed significant difference with that of PI-RADS category 3A (1.098 ± 0.146 × 10−3 mm2/s) but none with PI-RADS category 4 (0.821 ± 0.091 × 10−3 mm2/s). There was no significant difference in the sensitivity and negative predictive value of PI-RADS v2.1 and PI-RADS v2.1-B. Specificity and positive predictive value of modified PI-RADS v2.1-B were much higher than those of PI-RADS v2.1 for both readers (p < .001). The area under the receiver operating characteristic curve tended to be higher with PI-RADS v2.1-B than with PI-RADS v2.1. Biopsy for PI-RADS 3B lesion is necessary due to its superior malignancy potential than that of PI-RADS 3A lesion.


Background
Prostate cancer is the second most frequently diagnosed cancer and the fifth leading cause of cancer mortality among men worldwide [1,2]. The incidence of prostate cancer has increased since the 1990s due to the implementation of prostate-specific antigen (PSA) testing and development of a cancer registration system [3]. The incidence varies greatly across the globe and has been increasing in most Asian countries [3,4]. Despite the majority of prostate cancer occurring in the peripheral zone (PZ), up to 30% of prostate cancer occurs in the transition zone (TZ) [5].
Among the various diagnostic tools available, multiparametric magnetic resonance imaging (mpMRI) has been widely used for prostate-cancer detection and risk stratification. According to a recent meta-analysis, the sensitivity and specificity of mpMRI reached 0.87 and 0.68, respectively, and especially accessing highly malignant lesion, mpMRI had better diagnostic accuracy compared to biparametric MRI [6,7].. The application of mpMRI for diagnosing prostate cancer has been recommended in the National Comprehensive Cancer Network, European Association of Urology, and European Society of Urogenital Radiology guidelines [8].
The American College of Radiology, European Radiology of Uroradiology, and AdMeTech Foundation jointly put forth the Prostate Imaging and Reporting Data System (PI-RADS) Version 2 in 2015 to standardize the assessment of the probability of clinically significant prostate cancer using mpMRI. However, due to limitations such as suboptimal inter-reader responsibility, a high false-negative rate for the lower PI-RADS assessment category, and a lower detection rate for TZ prostate cancer (TZPC) than for PZ prostate cancer, the updated PI-RADS Version 2.1 (PI-RADS v2.1) was developed in 2019 [9][10][11]. Several studies suggested that PI-RADS v2.1 is preferable for evaluating transition-zone lesions and showed that it provided comparable interreader agreement [12][13][14]. One study reported that typical benign prostatic nodules in the TZ were downgraded, but there were no significant changes in the number of positive and negative MRI results identified using PI-RADS v2.1 [15]. This means that PI-RADS v2.1 is expected to have little influence on clinical management.
Although biopsy should be considered for PI-RADS 4 or 5 (but not for PI-RADS 1 or 2), PI-RADS v2.1 does not include recommendations for management. This is because factors other than MRI findings must be taken into account, including clinical history, laboratory findings, local preferences, expertise, and standards of care. Thus, biopsy may or may not be appropriate for PI-RADS 3, depending on these other factors. One of the major modifications in the updated version 2.1 is the diagnostic criteria for TZPC on T2-weighted images. The following were considered PI-RADS 3 lesions: lesions with a T2WI score of 3 and DWI score of 4 or less, T2WI score of 2, and DWI score of 4 or more. Should all PI-RADS 3 lesions in the TZ be biopsied? Our findings shed light on this question.
This study aimed to compare the diagnostic performances of PI-RADS v2.1 and PI-RADS v2.1-B in detecting TZPC and propose the sub-classification of PI-RADS category 3 lesions for a more accurate evaluation that could improve clinical treatment.

Methods
Our institutional review board approved this study, and the need to obtain informed patient consent was waived due to the retrospective nature of the study.

Patient population
This study included 80 patients with pathologically proven prostate cancer at our institution between March 2014 and February 2019 were included; their age ranged from 59 to 83 years, and mean age ± SD was 70.7 ± 5.82 years.

Inclusion criteria
Patients who underwent mpMRI prior to radical prostatectomy were included.

Exclusion criteria
Patients with low-quality mpMRI image; patients with incomplete investigation of clinicopathologic factors; and patients who were treated with neoadjuvant chemotherapy before surgery were excluded (Fig. 1).

Clinicopathologic information
Data on preoperative serum PSA, total cancer size, Gleason score (GS), seminal-vesicle invasion, lymphnode invasion, extracapsular extension, and tumor location were retrospectively collected. The GSs were evaluated according to the 2014 International Society of Urological Pathology Modified Gleason Grading System [16] and divided into three groups: GS 6, GS 7, and GS 8-9. The presence of seminal-vesicle invasion, lymph-node invasion, and extracapsular extension was investigated (Table 1).

MR image technique
MR examinations were performed with Achieva 3.0T MRI (Philips Medical Systems, Netherlands) and Ingenia 3.0T CX (Philips Medical Systems, Netherlands) using a pelvic phased-array coil. All images were taken with the patients in the supine position. After acquisition of the localizing image by sagittal T2-weighted turbo spin-echo (TSE) imaging, an adequate scan range was established.

Statistical analysis
All statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) version 20.0 (SPSS Inc., Chicago, IL, USA).
To evaluate interobserver agreement for the categorization of lesions according to PI-RADS v2.1 and modified PI-RADS v2.1-B, we used receiver operating characteristic curve analysis and compared the areas under the receiver operating characteristic curve between two readers. We also computed the weighted quadratic kappa coefficients. After consensus (in case of disagreement), the diagnostic performances for TZPC of PI-RADS v2.1 and PI-RADS v2.1-B were evaluated using the chi-square test. Chi-square and independent sample t tests were used to compare ADC values and clinicopathologic characteristics between prostate lesions. The level of statistical significance was set at p < 0.05.

Assessment of T2WI score 3 lesions of TZPC
In evaluating T2WI score 3 lesions of TZPC, the two readers frequently appeared discordant. For this reason, we compared clinicopathologic characteristics and ADC values between T2WI score 3 lesions of TZPC (Table 3). We subcategorized T2WI score 3 lesions by DWI score: 1/2/3, 4, or 5 lesions. Among 47 lesions that were evaluated as T2WI score 3, 10 were categorized as PI-RADS category 3B, showing high signal intensity on DWI images (b = 1000) at the corresponding nodule with low signal intensity on the ADC map, resulting in a DWI score of 4. These lesions were categorized as 3 according to PI-RADS v2.1 but as 3B according to PI-RADS v2.1-B. All of the lesions in the PI-RADS 3B group were pathologically confirmed as malignant (GS 7) (Fig. 3). Two of the 10 lesions showed extracapsular extension. The average ADC value was 0.934; 34 of the 47 lesions with a T2WI score of 3 were categorized as PI-RADS category 3A, showing subtle iso-signal intensity on the DWI image (b = 1000) at the corresponding nodule and low signal intensity on the ADC map, resulting in a DWI score of 3. These lesions were categorized as 3 according to PI-RADS v2.1 but as 3A according to PI-RADS v2.1-B. Thirty-one of these 34 lesions were histologically confirmed as benign hyperplastic nodules (Fig. 4); three of them showed histologically confirmed malignancy (one lesion of GS 6, two lesions of GS 7). These were false-negative cases; we categorized them with a T2 score of 3 and DWI score of 3, resulting in a final score of 3 based on v2.1 and 3A based on v2.1-B. The patients underwent radical prostatectomy and were confirmed to have TZPC (Fig. 5). The average ADC value was 1.166. Three lesions were included in PI-RADS category 4, as they were more than 1.5 cm with high signal intensity on the DWI images (b = 1000) and low signal intensity on the ADC map, resulting in a DWI score of 5. These lesions were categorized as 4 according to both PI-RADS v2.1 and PI-RADS v2.1-B. All of the      After reaching a consensus in case of disagreement, the diagnostic performances for TZPC between PI-RADS v2.1 and PI-RADS v2.1-B were also evaluated ( Table 5). Diagnostic sensitivity did not differ significantly between v2.1 and v2.1-B (100% vs. 94.1%, p = .15), but diagnostic specificity did differ significantly (22.7% vs. 97.7%, p < .001). The positive predictive value was significantly higher in v2.1 (50.0% vs. 97.0%, p < .001), but the negative predictive value showed no significant difference between the two versions (100% vs. 95.6%, p = .497). The area under the curve tended to be higher in v2.1-B (0.834 vs. 0.970). ). An axial T2-weighted image (T2WI) (a) and dynamic contrast-enhanced image (b) indicate an approximately 1.3 cm, heterogeneous, obscured, marginated nodule with mild enhancement in the right transition zone (arrows), resulting in a T2WI score of 3. Diffusion-weighted imaging (DWI) (b = 1000) (c) demonstrated subtle iso-signal intensity at the corresponding nodule with low signal intensity on an ADC map (d), resulting in a DWI score of 3. This lesion was categorized as 3 according to PI-RADS v2.1 but as 3A according to PI-RADS v2.1-B. The patient underwent radical prostatectomy, which confirmed transition-zone cancer with a Gleason score of 7 (4 + 3). The procedure revealed crowded irregular glands with at least a wisp of stroma between each gland (e). This was a false-negative case first categorized with a T2 score of 3 and DWI score of 3. The final category was determined to be 3 based on v2.1 and 3A based on v2.1-B, which is pathologically confirmed malignancy

Discussion
The PI-RADS v2.1 definition of clinically significant cancer is intended to standardize reporting of mpMRI exams and correlate with pathology for clinical and research applications; based on the current uses and capabilities of mpMRI and MRI-targeted procedures, the definition uses GS > 7 (including 3 + 4 with prominent but not predominant Gleason 4 component), volume > 0.5 cc, and/or extraprostatic extension. The PI-RADS v2.1 assessment uses a 5-point scale based on the probability of clinically significant cancer, using mpMRI findings on T2W, DWI, and DCE-MRI.
In this study, all lesions were re-analyzed using the modified PI-RADS v2.1-B: our new PI-RADS subclassification. We subclassified PI-RADS category 3 TZ lesions as PI-RADS category 3B (biopsy needed; T2WI score 3 with DWI score 4) or PI-RADS category 3A (no biopsy needed; T2WI score 3 with DWI score 1, 2, or 3). Figure 6 reveals the appropriate examples of this study.  We compared clinicopathologic characteristics and ADC values between T2WI score 3 lesions of TZPC and evaluated the diagnostic performances and inter-reader agreements of the modified PI-RADS v2.1-B and PI-RADS v2.1. We found the malignancy rate of T2WI score 3 lesions of TZPC differed among the three groups: 8.8% in PI-RADS category 3A, 100% in PI-RADS category 3B, and 100% in PI-RADS category 4. The average ADC value was significantly different between the PI-RADS category 3A and PI-RADS category 3B groups, but no difference was found between the PI-RADS category 3B and PI-RADS category 4 groups. This suggests that the lesions included in PI-RADS category 3B share many characteristics with those in PI-RADS category 4, and biopsy may be needed due to the high possibility of malignancy.
In PI-RADS v2, a score of 3 or more has been used as a threshold to determine the need for biopsy, but the detection rate among PI-RADS category 3 lesions of TZ revealed considerable variation in several studies, ranging from 3.8 to 33.1% [17][18][19]. In addition, one study suggested that, according to PI-RADS v2, the prostate lesions characterized on 3T mpMRI as PI-RADS category 3 have a low likelihood of clinically significant prostate cancer [20]. For this reason, some prior studies have suggested the optimal cutoff for biopsy requirement in TZ lesions is a score of 4 or more, as it has high specificity [21,22]. However, due to the possibility of malignancy in TZ lesions with T2WI score 3 and DWI score 4, subcategorization of these lesions should be considered. The need for subcategorization is further supported by the high malignancy rate among these lesions in this study.
Several previous study presented variability of interreader agreement and diagnostic performance of PI-RADS v2.1 in detecting prostate cancer, especially TZPC [23,24]. One study revealed inter-reader agreement improved in PZPC using PI-RADS v2.1 but not TZPC, and suggested areas where additional modification of PI-RADS v2.1 could further improve inter-reader agreement and diagnostic performance [25]. In this study, by subcategorization of T2WI score 3 lesion of TZ, the level of inter-reader agreement in malignancy detection between the two readers had never lagged behind; almost perfect agreement for PI-RADS v2.1-B (κ = 0.933) in addition to PI-RADS v2.1 (κ = 0.949). After comparing the diagnostic performances of the two readers for TZPC detection using PI-RADS v2.1 and PI-RADS v2.1-B, we found that PI-RADS v2.1-B had a higher specificity and positive predictive value for both readers; these differences were statistically significant. Furthermore, after consensus in the case of disagreement, PI-RADS v2.1-B had significantly higher specificity and positive predictive value. Through this, PI-RADS v2.1-B may contribute to the detection of TZPC more accurately.
There were several limitations to this study. First, this was a retrospective study performed at a single center, which may have resulted in selection bias. Second, the number of lesions included in our study was low, leading to underpowered statistical analysis. This study is a work for testing a subcategorization of PI-RADS category 3 TZ lesions. Thus, larger multi-center studies including large number of patients are needed to validate our findings and modify of PI-RADS v2.1. Third, this study assessed diagnostic performance only for TZ lesions, and prostate cancer occurs more frequently in the PZ. However, we felt it necessary to focus on TZ lesions due to the ambiguity of T2WI scoring of the TZ. Finally, analysis of previously detected lesions may have impacted inter-reader agreement and diagnostic performance.

Conclusions
This study showed significantly higher specificity and positive predictive value with PI-RADS v2.1-B than with PI-RADS v2.1. PI-RADS category 3B lesions, which were upgraded based on DWI score, tended to have greater potential for malignancy than PI-RADS category 3A lesions. This indicates that subcategorization of PI-RADS category 3 TZ lesions may contribute to accurate evaluation and effective clinical management. This study is a test of subcategorization of PI-RADS category 3 TZ lesions, so multicenter studies are needed to validate this study and modify of PI-RADS v2.1.