The Initial Application of MRI Based Prostate Volume-Adjusted Prostate-Specic Antigen In The Diagonosis of MRI-Positive Prostate Cancer Patients

Purpose: To identify the value of prostate-specic antigen density (PSAD) and prostate-specic antigen density of the transition zone (PSADTZ) in improving the sensitivity and specicity of the prostate multiparameter magnetic resonance imaging (mp-MRI), for the purpose of predicting prostate cancer (PCa) and grade reclassication in men with prostate-specic antigen (PSA) between 4 and 20 ng/mL to reduce unnecessary prostate biopsies. Patients and Methods: Between 2018 and 2020, we retrospectively identied 283 consecutive men in Shanghai Jiao Tong University Aliated Sixth People’s Hospital who had mp-MRI and PSA test within 3 months before prostate biopsies. Total prostate volume (TPV) and transition zone volume (TZV) were measured on mp-MRI. PSA, PSAD, and PSADTZ were compared to improve the sensitivity and specicity of positive biopsy cores and pathological stage by univariate analyses and through the receiver operating curve (ROC). We were focused primarily on the MRI-positive patients with PSA levels of 4-20ng/ml who were most likely subjected to unnecessary repeated prostate biopsies. Results: Of the 283 patients, 138 (48.8%) had PCa and in 145 (51.2%) a benign prostate disease was diagnosed. PSA, PSAD, and PSADTZ were signicantly related to biopsy, and equally able to predict higher pathological stage. The receiver operating curve (AUC) for predicting the presence of PCa in all patients was 58.06 for PSA, 72.13 for PSAD and 78.28 for PSADTZ. In addition, the AUC for predicting higher pathological stage in PCa patients was 65.71 for PSA, 65.46 for PSAD and 69.81 for PSADTZ. For 228 MRI-positive patients, the AUC for predicting the presence of PCa was 61.31 for PSA, 74.00 for PSAD and 80.13 for PSADTZ. No difference among the PSA, PSAD, and PSADTZ was found in 55 MRI-negative patients. Conclusion: The determination of PSADTZ had higher diagnostic accuracy for PCa than that based on PSA or PSAD. For MRI-positive (n=4); PSA elevation with


Background
Prostate cancer (PCa) is the second most prevalent malignancy and the fth reason for mortality caused by cancer in men around the world [1,2]. Although the incidence of PCa in Asia is lower than that in Northern America, Oceania, and Northern Europe, it has been increasing rapidly. In the recent 5 years, with the wide application of serum prostate-speci c antigen (PSA) examination, China has an increasing trend in the incidence of PCa (2.6%/yr) [1]. PSA, multiparameter MRI (mp-MRI), and transrectal prostate ultrasound (TRUS) all play essential roles in PCa screening and in the selection of appropriate candidate for biopsy [3]. For the prostate biopsy is invasive [4] and costly [5], it's necessary for doctors to make accurate judgment. PSA screening has been mostly used for early PCa detection. When the PSA level is higher than 20 ng/ml, the serum PSA test got signi cantly higher accurate (largest to 87.2% [6]) in predicting PCa [7,8]. However, serum PSA is not disease speci c. Not only prostate cancer can cause the increase of PSA, Benign prostate diseases, such as benign prostatic hyperplasia and prostatitis may also cause PSA elevation. In prostatic hyperplasia, the number of prostate cells and the prostate volume increases, resulting in increased secretion of PSA, thereby increase the serum PSA [9]. According to the literatures, however, the false-positive rate was up to 69.93% in patients with PSA levels of 4-20 ng/mL [10,11]. As two most commonly imaging examinations, TRUS and mp-MRI can partly improve the positive diagnostic rate of PCa, but also go with insu cient sensitivity and speci city, especially when the PSA ranges from 4-20ng/mL [8,12]. New biomarkers, such as Prostate-speci c antigen isoform 2 (p2PSA) and Prostate Health Index (PHI) have not yet universal [13]. Therefore, MRI-positive patients with PSA levels of 4-20ng/mL are most likely subjected to unnecessary repeated prostate biopsies.
The increase of PSA caused by prostatic hyperplasia is related to the increase of prostate volume. The increase of PSA caused by prostate cancer is less related to the volume of prostate. Therefore, the serum PSA per prostate volume of prostate cancer may be higher than that of normal or BPH people. Some studies found that the use of PSAD in the diagnosis of prostate cancer which has a positive signi cance.
And other studies have further found that the effect of PSA density of the transition zone (PSADTZ) on prostate cancer and prostatic hyperplasia was better than that of simply using PSAD for [14]. The purpose of this study was to compare the performance of PSAD, PSADTZ and PSA in the detection of PCa and risk strati cation while particularly focusing on MRI-positive patients with PSA serum levels of 4∼20 ng/mL.
Clinical and pathologic characteristics of patients, including age, PSA testing, and Gleason score, were obtained from pathology reports. The biopsy samples were analysed and reported on the basis of the International Society of Urological Pathology (ISUP) 2014 modi ed Gleason score grading system [16]. PI-RADS scores (version 2), prostate volume and transition zone volume were also obtained from MRI reports. The nal study enrolled 283 patients, including 138 PCa patients and 145 patients without any histologic evidence of cancer. PSAD = total PSA (ng / mL) / prostate volume (cm 3 ). The unit is ng / mL• cm −3 . PSAT = total PSA (ng / mL) / prostate transition zone volume. The unit is ng / mL •cm −3 .

MRI Examination and Images Analysis
All images were acquired with a 3-T MRI scanner (MAGNETOM Skyra, Siemens Healthcare), and a phased-array 18-channel body coil in combination with an integrated 32-channel spine coil was used for signal reception. The imaging protocol followed the standard of the European Society of Urology Radiology guidelines, and included T1-weight Imaging(T1WI), T2-weighted Imaging (T2WI), diffusionweighted imaging (DWI) with b values of 50, 1000, and 1500 s/mm2 and dynamic contrast-enhanced imaging (DCE). Two dedicated radiologists blinded to both clinical and pathological information analyzed prostate mp-MRI images in consensus. According to the PI-RADSv2 criteria, all images and suspicious lesions were scored. When multiple suspicious lesions were detected, an index lesion considered as the one with the highest score was a representative PI-RADSv2 score of a patient in the study. PI-RADS score 1-2 is MRI negative, and PI-RADS score 3-5 is MRI positive.

Statistical analyses
GraphPad Prism software (ver. 8.0.2, Inc., CA, USA) was used for analysis, and Shapiro-Wilk test was used to assess the normal distribution of continuous variables. An unpaired t test was used to assess normally distributed continuous variables. The Mann-Whitney U test was used to assess non-normally distributed continuous variables. The ROC (Receiver Operating Characteristics) curve was employed to graphically demonstrate the sensitivities and speci cities of the different diagnostic tests. The areas bellow the ROC curve (global accuracy) were also calculated and compared in pairs, through Medcalc software (ver. 19.7, Mariakerke, Belgium) as described by Delong [18]. Medcalc was also used to demonstrate the best cut-off point for each diagnosis test (PSA, PSAD and PSADTZ) as well as to calculate its respective positive predictive values (PPV), negative predictive values (NPV), sensitivities and speci cities to predict PCa. All statistical analysis was performed considering p < 0.05 statistically signi cant and with a 95% trust interval.

Results
Patient characteristics.
In this study, 941 men underwent prostate biopsy, among whom 283 patients were included in the nal analysis. Based on the results of the initial biopsy, 138 patients were PCa-positive and 145 were PCanegative, resulting in a detection rate of 48.8%. Demographic and clinical characteristics, as well as MRI ndings of the entire study cohort, are summarized in Table 1   Comparing the e ciency of PSA, PSAD and PSADTZ in the detection of risk strati cation.
Based on the differences of prognosis, 138 PCa patients were divided into lower-risk group (Gleason score ≤ 6) and higher-risk group (Gleason score ≥ 7). higher. ROC curves of PSA, PSAD and PSADTZ for predicting prognosis of PCa patients and the comparison between these three parameters were shown in Figure 2. The AUC value of PSA, PSAD and PSADTZ were 0.6571, 0.6546 and 0.6981 respectively, however, there was no signi cant difference among them.  Figure  3, and the comparison between these three parameters was shown in Table 4. The AUC value of PSADTZ (0.8013) was higher than PSA (0.6131) and PSAD (0.7400). When we chose the best cut-off values of PSA, PSAD, PSADTZ (11.24, 0.2277 and 0.3844, respectively) for predicting PCa, the sensitivities were 50.00%, 52.50% and 70.83%, respectively and the speci cities were 72.22%, 87.96% and 74.07%, respectively. Comparison of PSA, PSAD and PSADTZ between non-PCa group and PCa group when the mp-MRI exam is negative.
As shown in the bottom of Table 1, the TPV (61.98 vs 79.00, P=0.258) and TZV (30.29 vs 46.00, P=0.212) were lower in the PCa group than in the non-PCa group, but there were no signi cant differences in age (P=0.3041), PSA (P=0.5907), TZV/TPV (P=0.0786), PSAD (P=0.0803) and PSADTZ (P=0.0630) between PCa group and non-PCa group. As matter of fact that few MRI-negative patients accepted prostate biopsy, no further comparison was made.

Discussion
PCa is one of the most common malignant tumors in the urological system, and it is the sixth leading cause of cancer death (7.4% of deaths) among men worldwide [19]. It is usually suspected in cases of increased serum PSA levels and/or abnormal digital rectal examination (DRE). In these patients, the standard method to diagnose PCa is prostate biopsy. But any prostate biopsy is associated with a risk of infection (1-8%) and an increased risk of life-threatening sepsis (1-4%), as a consequence of increasing antibiotic resistance [20,21]. Other associated morbidities include dysuria, hematospermia, haematuria, rectal bleeding, vasovagal episodes and urinary retention [21,22]. These drawbacks of prostate biopsy limit the willingness of physicians and patients to perform and undergo potentially unnecessary biopsies.
The estimated false-negative rate of systematic biopsy for any cancer is 25-40% [23].
PSA was considered as tumor marker of PCa, but BPH may also cause PSA elevation. In view of this, Benson et al [24] think that PSA combined with prostate volume can be more accurate to evaluate prostate cancer risk than PSA alone. That is PSA density (PSAD), which is the ratio of serum total PSA to total prostate volume.  30], however, the suggested cut-off data is still highly debated [31]and no study have reported these parameters on both MRI-negative and MRI-positive Pca patients [30]. In our study, the mean differences in PSA, PSAD, PSADTZ between the non-PCa group and the PCa group in the MRI-positive patients have statistic signi cance. The determination of PSADTZ had higher diagnostic accuracy for PCa than that based on PSA or PSAD. Therefore, PSADTZ promote a more effective and simple method for PCa detection, and may be useful for decreasing the burden of surveillance prostate biopsies for MRI-positive patients.
The present study had some limitations. It was a retrospective, single-center study and the sample size of our study was small especially in patients with negative MRI. Multicenter studies will be carried out to further validate these results. Despite these limitations, the ndings of this study may impact current clinical practice.

Conclusion
The determination of PSADTZ had higher diagnostic accuracy for PCa than that based on PSA or PSAD.
For MRI-positive patients, PSADTZ promote a more effective and simple method for PCa detection, and may be useful for decreasing the burden of surveillance prostate biopsies, the AUC for predicting the presence of PCa was 61.31 for PSA, 74.00 for PSAD and 80.13 for PSADTZ.

Declarations
Ethics approval and consent to participate This study was carried out following relevan guidelines and regulations (Declaration of Helsinki