Journal of Iranian Medical Council

Journal of Iranian Medical Council

Prevalence of Biopsy-Proven Clinically Significant Prostate Cancer in Patients with PI-RADS 3 on MRI and Factors Associated with It

Document Type : Original article

Authors
Farhood Khaleghimehr 1
Amirreza Elahian 2
Ali Maadelat 3
Mazaher Hadi 1
Nasrollah Abian 4
1 Department of Urology, Hasheminejad kidney Center, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
2 Department of Urology, Firoozgar Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
3 Faculty of Science, University of Ottawa, Ottawa, Canada
4 Department of Urology, 5 Azar Hospital, School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
http://dx.doi.org/10.18502/jimc.v8i2.17703
Abstract
Background: To assess prevalence of prostate cancer and clinically significant prostate cancer in patients with PI-RADS 3 on bpMRI and factors associated with them.
Methods: Patients suspicious for prostate cancer following serum Prostate Specific Antigen (PSA) screening, who had PI-RADS 3 on bpMRI, were included. All patients underwent systemic plus MRI targeted biopsy of prostate. Gleason score 3+3 was considered positive for prostate cancer but clinically non-significant one. Higher scores were pertained to as clinically significant prostate cancer. The relationship between patient age, PSA level, PSA density, number of core biopsies, and number of PI-RADS 3 lesions on bpMRI with presence of prostate cancer per se and presence of clinically significant prostate cancer in our patients is assessed.
Results: 244 patients were enrolled. 101 patients had prostate cancer (41.4%). Out of these 101 patients, 34 (13.9% of total) had clinically significant prostate cancer. Among different factors, only PSA density was associated with both prostate cancer (OR=1.05, p=0.001) and clinically significant prostate cancer (OR=1.03, p=0.001). According to receiver operating characteristic curve analysis, best cut off value of PSA density which has highest association with clinically significant prostate cancer in PI-RADS 3 patients would be 0.36; with a sensitivity of 0.38 and specificity of 0.93.
Conclusion: Considering PSA density with threshold of 0.36 for performing biopsy in patients with PI-RADS 3 on bpMRI might lower the rate of unnecessary biopsies.

Keywords
Biparametric MRI
Clinically significant prostate cancer
PI-RADS
PSA
PSA density

Subjects

Abstract 
Background: To assess prevalence of prostate cancer and clinically significant prostate cancer in patients with PI-RADS 3 on bpMRI and factors associated with them.
Methods: Patients suspicious for prostate cancer following serum Prostate Specific Antigen (PSA) screening, who had PI-RADS 3 on bpMRI, were included. All patients underwent systemic plus MRI targeted biopsy of prostate. Gleason score 3+3 was considered positive for prostate cancer but clinically non-significant one. Higher scores were pertained to as clinically significant prostate cancer. The relationship between patient age, PSA level, PSA density, number of core biopsies, and number of PI-RADS 3 lesions on bpMRI with presence of prostate cancer per se and presence of clinically significant prostate cancer in our patients is assessed.
Results: 244 patients were enrolled. 101 patients had prostate cancer (41.4%). Out of these 101 patients, 34 (13.9% of total) had clinically significant prostate cancer. Among different factors, only PSA density was associated with both prostate cancer (OR=1.05, p=0.001) and clinically significant prostate cancer (OR=1.03, p=0.001). According to receiver operating characteristic curve analysis, best cut off value of PSA density which has highest association with clinically significant prostate cancer in PI-RADS 3 patients would be 0.36; with a sensitivity of 0.38 and specificity of 0.93.
Conclusion: Considering PSA density with threshold of 0.36 for performing biopsy in patients with PI-RADS 3 on bpMRI might lower the rate of unnecessary biopsies.
Keywords: Biparametric MRI, Clinically significant prostate cancer, PI-RADS, PSA, PSA density

 

Introduction 
Prostate cancer is the most common solid organ malignancy among men worldwide (1,2). The current gold standard test for prostate cancer diagnosis is 12-core TRUS-guided biopsy for men with elevated serum Prostate Specific Antigen (PSA) levels or Digital Rectal Examination (DRE) abnormalities (3). Recently, Magnetic Resonance Imaging (MRI) is used to increase diagnostic accuracy. While multiparametric MRI (mpMRI) has gained acceptance as main technique of MRI for prostate cancer by using PI-RADS (Prostate Imaging Reporting and Data System) scoring, new studies show that biparametric MRI (bpMRI) has “similar PI-RADS scoring and thus diagnostic performance” (4). Prostate lesions with PI-RADS 1 or 2 are considered low likelihood of cancer and PI-RADS 4 or 5 is highly suspicious for malignancy and must undergo biopsy (5), but there is still controversy regarding actions that should be taken following PI-RADS 3, as these lesions might turn out to be either benign, clinically non-significant prostate cancer, or clinically significant prostate cancer (defined as Gleason Score >=3+4). As PI-RADS 3 is reported in 15 to 32% of MRIs of prostate (5,6), it is believed that more attention is required regarding interpreting this finding in order to postpone unnecessary biopsies.
Therefore, in this study, patients with PI-RADS 3 lesion were examined on bpMRI and checked frequency of the 3 possible pathologies that might be observed in them. Also, factors that had association with the pathology results in these patients were assessed.

Materials and Methods
Patients suspicious for prostate cancer following serum PSA screening, who had PI-RADS 3 on bpMRI, were included in the study. A serum PSA level of over 4.0 ng/ml for men older than 65 years and 2.5 ng/ml for younger men was considered to be suspicious for prostate cancer. All the patients underwent systemic plus MRI targeted biopsy of prostate. Gleason score 3+3 was considered positive for prostate cancer but clinically non-significant one. Higher scores –even in one core- were pertained to as clinically significant Prostate Cancer (csPCa), while lower scores were considered negative for csPCa.
The relationship between patient age, PSA level, PSA density (serum PSA level divided by prostate volume), number of core biopsies, and number of PI-RADS 3 lesions on bpMRI with presence of prostate cancer per se and presence of csPCa in the patients was assessed.
All the procedures were in accordance with the ethical standards of the institutional and national research committee (s) and with the Declaration of Helsinki (as revised in 2013). All the patients signed the informed consent for scientific research. 
Mean±standard deviation and frequency (percentage) were used to describe the quantitative and categorical variables, respectively. Univariate and multivariate logistic regression analysis were utilized to determine the factors associated with presence of prostate cancer and csPCa. A Receiver Operating Characteristic (ROC) curve was used to define cut-off value of Prostate Specific Antigen Density (PSAD) for presence of csPCa. Data analyses were performed using STATA17 software (College Station, Texas 77845 USA). p-values less than 0.05 were considered to be statistically significant.

Results 
244 patients were enrolled in the study. The mean age of the participants was 63 years. The mean amount of PSA among the patients was 7.50. Mean PSAD was 0.15. Out of 244 patients, 165 (67.6%) had one lesion, 77 (31.6%) had two lesions, and 2 patients (0.8%) had three lesions compatible with PI-RADS 3 description.
After assessing the biopsy specimens, 143 patients showed no evidence of cancerous pathologic changes (58.6%), while 101 patients had prostate cancer (41.4%). Out of 101 patients, 34 (13.9% of total) had csPCa.
Factors that might have an association with the presence of prostate cancer and clinically significant prostate cancer, were assessed. Patient age, number of PIRADS 3 lesions, number of core biopsies, and prostate volume were not associated with the presence of prostate cancer, nor with presence of csPCa.
In the univariate analysis, serum PSA level and PSAD were both associated with presence of prostate cancer and csPCa in the patients. Multivariate analysis demonstrated that only PSAD was associated with both prostate cancer (OR=1.05, p=0.001) and csPCa (OR=1.03, p=0.001). 
A ROC curve was used in order to define the cut-off value of PSAD for presence of csPCa, according to which, the best cut-off value of PSAD for csPCa would be 0.36 with a sensitivity of 0.38 and specificity of 0.93 (Figure 1).

Discussion 
Prostate cancer is the most common solid organ malignancy among men worldwide. It is also the third leading cause of cancer-related death among men in the United States (1,2). The current gold standard test for prostate cancer diagnosis is 12-core TRUS-guided biopsy. One of the disadvantages of this diagnostic method is its susceptibility to miss prostate cancer in the peripheral zone due to the random nature of it. Also, the anterior zone is not assessed thoroughly in this procedure. The other downside of this procedure is over-diagnosis (and the resultant over-treatment), considering PSA levels as the main indication for biopsy. Thus, mpMRI is introduced to increase diagnostic accuracy for this disease. This MRI technique is already an integral part of the diagnostic work-up in brain and breast tumors, and has enhanced diagnostic process, especially by using PI-RADS scoring system (7-9). New studies show that bpMRI has same diagnostic accuracy for prostate cancer as mpMRI (4,10). Therefore, in this study, bpMRI was used in order to assess prostate lesions according to the PI-RADS scoring system.
While assessment of PI-RADS 1-2 and 4-5 are generally obvious, there is still controversy regarding interpreting PI-RADS 3 results. Venderink et al suggested that 65% of PI-RADS 3 results turned out to be benign while 35% would be cancerous, 17% of them were csPCa (11). Other studies found prostate cancer would be present in 10 to 43% of PIRADS 3 results with 4 to 21% of them being csPCa (12-15). The current study revealed that prostate cancer is observed in 41.4% of PI-RADS 3 results and 13.9% of them happens to be csPCa which is in accordance with previous studies.
Surprisingly, there are still few studies with main purpose of investigating factors associated with the presence of prostate cancer and csPCa in PI-RADS 3 results. Felker et al found that PSAD > 0.15 ng/ml2 is associated with the presence of csPCa in PI-RADS 3 (15). Bhat et al and Boesen et al also showed that high PSAD increases the chance of csPCa in PI-RADS 3 results (16,17). Hermie et al suggested a combined predictive model using prostate volume and a radiologic feature (5). Liu et al demonstrated that both prostate volume and PSAD had a significant relationship with prostate cancers independently (18).
The current study represented that only PSAD is associated with presence of prostate cancer and csPCa in PI-RADS 3 results which is in concordance with the previous ones. While above mentioned studies considered the limit of 0.15 ng/ml2 for PSAD as suggested by Epstein et al (19), a Receiver Operation Characteristic (ROC) curve analysis was performed in the present study to assess if another value for PSAD could be more suitable for finding csPCa in PI-RADS 3 patients. Considering the area under curve, it is suggested that the best cut-off point for PSAD in PI-RADS 3 patients should be 0.36 (with a sensitivity of 0.38 and specificity of 0.93 to be associated with csPCa) (Figure 1). Considering this cut-off value, it is suggested in patients with PI-RADS 3, biopsy should be offered if PSAD is higher than 0.36; in those with PSAD values below 0.36, follow up might be more suitable option.
This research was subjected to multiple limitations, since it was performed as a retrospective study in a single center. As we know, rate of csPCa in PI-RADS 3 patients is less than 50%, thus multi-center registry-based studies may include more cases of csPCa which makes the results more replicable. Considering the location of pathologic lesions in further studies would also be preferable as different PI-RADS 3 lesions may have different characteristics based on their locations on MRI.

Conclusion
Considering PSAD with threshold of 0.36 for performing biopsy in patients with PI-RADS 3 on bpMRI might lower the rate of unnecessary biopsies and its possible complications.

Funding
None.

Acknowledgement
The ethical code number of the Ethics committee for this study is IR.IUMS.REC.1403.231.

Disclosure 
None

Conflict of Interest
There was no conflict of interest in this manuscript.

  1. Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, Brenner H, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 Cancer Groups, 1990 to 2015: a systematic analysis for the global burden of disease study. JAMA Oncol 2017 Apr 1;3(4):524-48. https://pubmed.ncbi.nlm.nih.gov/27918777/
  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018 Jan;68(1):7-30. https://pubmed.ncbi.nlm.nih.gov/29313949/
  3. Mottet N, van den Bergh RCN, Briers E, Van den Broeck T, Cumberbatch MG, De Santis M, et al. EAU-EANM-ESTRO-ESUR-SIOG guidelines on prostate cancer-2020 update. part 1: screening, diagnosis, and local treatment with curative intent. Eur Urol 2021 Feb;79(2):243-62. https://pubmed.ncbi.nlm.nih.gov/33172724/
  4. Ullrich T, Quentin M, Oelers C, Dietzel F, Sawicki LM, Arsov C, et al. Magnetic resonance imaging of the prostate at 1.5 versus 3.0T: A prospective comparison study of image quality. Eur J Radiol 2017 May;90:192-7. https://pubmed.ncbi.nlm.nih.gov/28583633/
  5. Hermie I, Van Besien J, De Visschere P, Lumen N, Decaestecker K. Which clinical and radiological characteristics can predict clinically significant prostate cancer in PI-RADS 3 lesions? a retrospective study in a high-volume academic center. Eur J Radiol 2019 May;114:92-8. https://pubmed.ncbi.nlm.nih.gov/31005183/
  6. Schoots IG. MRI in early prostate cancer detection: how to manage indeterminate or equivocal PI-RADS 3 lesions? Transl Androl Urol 2018 Feb;7(1):70-82. https://pubmed.ncbi.nlm.nih.gov/29594022/
  7. Barentsz JO, Richenberg J, Clements R, Choyke P, Verma S, Villeirs G, et al; European Society of Urogenital Radiology. ESUR prostate MR guidelines 2012. Eur Radiol 2012 Apr;22(4):746-57. https://pubmed.ncbi.nlm.nih.gov/22322308/
  8. Ruprecht O, Weisser P, Bodelle B, Ackermann H, Vogl TJ. MRI of the prostate: interobserver agreement compared with histopathologic outcome after radical prostatectomy. Eur J Radiol 2012 Mar;81(3):456-60. https://pubmed.ncbi.nlm.nih.gov/21354732/
  9. Helbich TH. Contrast-enhanced magnetic resonance imaging of the breast. Eur J Radiol 2000 Jun;34(3):208-19. https://pubmed.ncbi.nlm.nih.gov/10927162/
  10. Bass EJ, Pantovic A, Connor M, Gabe R, Padhani AR, Rockall A, et al. A systematic review and meta-analysis of the diagnostic accuracy of biparametric prostate MRI for prostate cancer in men at risk. Prostate Cancer Prostatic Dis 2021 Sep;24(3):596-611. https://pubmed.ncbi.nlm.nih.gov/33219368/
  11. Venderink W, van Luijtelaar A, Bomers JGR, van der Leest M, Hulsbergen-van de Kaa C, Barentsz JO, et al. Results of targeted biopsy in men with magnetic resonance imaging lesions classified equivocal, likely or highly likely to be clinically significant prostate cancer. Eur Urol 2018 Mar;73(3):353-60. https://pubmed.ncbi.nlm.nih.gov/28258784/
  12. Hansen NL, Koo BC, Warren AY, Kastner C, Barrett T. Sub-differentiating equivocal PI-RADS-3 lesions in multiparametric magnetic resonance imaging of the prostate to improve cancer detection. Eur J Radiol 2017 Oct;95:307-13. https://pubmed.ncbi.nlm.nih.gov/28987685/
  13. Osses DF, van Asten JJ, Kieft GJ, Tijsterman JD. Prostate cancer detection rates of magnetic resonance imaging-guided prostate biopsy related to prostate imaging reporting and data system score. World J Urol 2017 Feb;35(2):207-12. https://pubmed.ncbi.nlm.nih.gov/27287889/
  14. Bastian-Jordan M. Magnetic resonance imaging of the prostate and targeted biopsy, comparison of PIRADS and Gleason grading. J Med Imaging Radiat Oncol 2018 Apr;62(2):183-7. https://pubmed.ncbi.nlm.nih.gov/28990727/
  15. Felker ER, Raman SS, Margolis DJ, Lu DSK, Shaheen N, Natarajan S, et al. Risk stratification among men with prostate imaging reporting and data system version 2 category 3 transition zone lesions: is biopsy always necessary? AJR Am J Roentgenol 2017 Dec;209(6):1272-7. https://pubmed.ncbi.nlm.nih.gov/28858541/
  16. Bhat NR, Vetter JM, Andriole GL, Shetty AS, Ippolito JE, Kim EH. Magnetic resonance imaging-defined prostate-specific antigen density significantly improves the risk prediction for clinically significant prostate cancer on biopsy. Urology 2019 Apr;126:152-7. https://pubmed.ncbi.nlm.nih.gov/30580005/
  17. Boesen L, Nørgaard N, Løgager V, Balslev I, Bisbjerg R, Thestrup KC, et al. Prebiopsy biparametric magnetic resonance imaging combined with prostate-specific antigen density in detecting and ruling out Gleason 7-10 prostate cancer in biopsy-naïve Men. Eur Urol Oncol 2019 May;2(3):311-19. https://pubmed.ncbi.nlm.nih.gov/31200846/
  18. Liu J, Dong B, Qu W, Wang J, Xu Y, Yu S, et al. Using clinical parameters to predict prostate cancer and reduce the unnecessary biopsy among patients with PSA in the gray zone. Sci Rep 2020 Mar 20;10(1):5157. https://pubmed.ncbi.nlm.nih.gov/32198373/
  19. Epstein JI, Walsh PC, Carmichael M, Brendler CB. Pathologic and clinical findings to predict tumor extent of nonpalpable (stage T1c) prostate cancer. JAMA. 1994 Feb 2;271(5):368-74. https://pubmed.ncbi.nlm.nih.gov/7506797/

 

Journal of Iranian Medical Council
Volume 8, Issue 2 - Serial Number 28
Spring 2025
Pages 316-320

XML
PDF 314.73 K
Figure 1. Receiver Operating Characteristics (ROC) curves for presence of clinically significant prostate cancer (csPCa) in patients with PI-RADS 3. Area under the curve 0.673 with a sensitivity of 0.38 and specificity of 0.93 to detect csPCa in PI-RADS 3 results in case of prostate biopsy when PSA density > 0.36.
Figure 1. Receiver Operating Characteristics (ROC) curves for presence of clinically significant prostate cancer (csPCa) in patients with PI-RADS 3. Area under the curve 0.673 with a sensitivity of 0.38 and specificity of 0.93 to detect csPCa in PI-RADS 3 results in case of prostate biopsy when PSA density > 0.36.