The main disadvantages of the current diagnostic pathway in men with an elevated risk of prostate cancer (PCa) are that: (1) systematic transrectal ultrasound (TRUS) biopsy misses a substantial proportion (20%) of significant PCa because of inherent systematic sampling errors, especially in the anterior gland  and ; (2) misclassifies pathologic status including Gleason score (Gl) and tumour stage ; and (3) detects a high proportion of men with disease that is unlikely to be harmful (clinically insignificant), with subsequently overtreatments resulting in unintended harm . The latter was the main reason for the U.S. Preventive Services Task Force recommendation against prostate-specific antigen-based screening for prostate cancer in 2012 .
2. Radiologic claims regarding multiparametric magnetic resonance imaging in suspected cancer patients
There is increasing evidence, such as two Level 1a systematic reviews  and , a Level 1a prospective clinical randomised trial , and multiple Level 1b studies  and , that multiparametric magnetic resonance imaging (mpMRI) is the best method of visualising primary significant PCa. It is, therefore, widely accepted that mpMRI has the performance characteristics to help manage men with suspected or proven PCa  and . The clinical utility in terms of the ability to “rule in” and “rule out” the presence of significant disease depends on using the mpMRI approach, image quality, reading system, and reporter expertise , , , and . The cancer detection ability of mpMRI is dependent on the anatomic location, tumour volume, and aggressiveness of the underlying cancer . mpMRI detected lesions are not always significant malignant lesions ; false positive cancer/noncancer cases do occur, thus adequate biopsy sampling is mandated for each lesion detected .
3. mpMRI-guided prostate biopsy
3.1. What technique should be used to sample mpMRI detected lesions?
There are a few available choices: prostate biopsy (PB) directly within the MR-scanner, MRI-TRUS fusion PB, and cognitive fusion PB via transrectal and transperineal routes. A recent systematic review showed, that the highest detection rate for significant PCa was with in-bore-PB (71%), followed by fusion-PB (59%), and finally cognitive-PB (54%). It should be remembered that not every patient needs to undergo in-bore-PB, because large, aggressive lesions can often be detected at TRUS-PB when mpMRI images are either reviewed or fused, and so can be adequately sampled.
3.2. What type of cancers does mpMRI-TB detect?
Literature indicates an improved ability of mpMRI-PB is to detect clinically significant cancers. A recent systematic review showed that the detection rate of clinical significant cancer is higher (44–87%) than the rates reported for TRUS-PB , depending on the definition of clinical significance used for targeted biopsy; this ability applies equally to biopsy naïve and men with prior negative biopsies. Histologic grades on mpMRI-TB show high concordance (88%) with final pathology after prostatectomy, which is a sharp contrast to TRUS-PB (55% concordance rate) .
3.3. What is the performance of mpMRI-PB compared with systematic TRUS-PB when mpMRI is positive?
This question has been the subject of large prospective studies and systematic reviews. For example, a prospective study compared TRUS-PB in 225 biopsy naïve patients requiring biopsy with mpMRI-PB in mpMRI positive patients (n = 142). mpMRI-PB detected +13% more intermediate/high risk patients and -89% less low grade PCa than TRUS-PB . Another large study in biopsy naïve men compared TRUS-PB in 391 men of whom 214 had positive mpMRI. mpMRI-PB was used, using a combination of cognitive, rigid, and elastic registration methods . Overall, cancer detection rates were similar (despite fewer mpMRI-PB) but the mpMRI-PB approach had more significant cancers (Gl ≥ 7); less microfocal cancers (<5 mm Gl6) and greater cancer core length involvement.
A systematic analysis evaluated 16 studies that included 1926 men with positive mpMRI . The data showed that the all cancer detection rates were similar with mpMRI-PB and TRUS-PB, missing 15% and 19% of cancers detected by the other technique (concordance cases 65%). This meta-analysis showed higher detection rates of significant disease with mpMRI-PB (91%) versus TRUS-PB (71%). Again, the insignificant cancer detection rates were lower for mpMRI-PB (44%) compared with TRUS-PB (83%) .
3.4. Does mpMRI-PB systematic miss clinically significant disease?
The key questions are: (1) what proportion of men with negative mpMRI harbour cancers that would require radical therapy if detected; and (2) what proportion of patients with significant disease would be detected by an additional backup TRUS-PB?
The reported negative predictive value (NPV) of mpMRI-PB for significant disease has been reported to be high: 63–98% . In a recent large prospective study in 391 patients, the NPV of mpMRI for high-grade PCa was 95.4%, the majority of missed PCas were of low-grade and organ confined . However, the NPV of mpMRI-PB is dependent on the definition of what constitutes significant disease on a targeted biopsy, the reference test employed for verification, with greater numbers of cores/prostatectomy inevitably finding more significant cancers than mpMRI-TB (vide infra) , , , and . The consequences of missing potential significant lesions may be minimal. A recent large randomized study demonstrated that there were no men with negative mpMRI-PB who required radical therapy when saturation biopsies were used to verify mpMRI-PB results .
The central issue is the balance between benefits and limitations of mpMRI-TB when used alone compared with the strategy of combined mpMRI-TB with backup TRUS-PB in men with positive mpMRI findings. This was recently addressed in a very large prospective trial . In 1003 men, there were additional cancers detected when mpMRI-TB was combined with TRUS-PB. However, of the 103 additional cancers detected, the majority were low risk (83% low risk; 5% high risk). Importantly, 200 combined biopsies yielded only one additional high-risk cancer, but overdiagnosed 17 low risk cancers. Also, there was no change in risk stratification in the majority of patients (857 patients; 85%), with only 19 men (2%) converting from no-cancer or low risk disease to intermediate or high risk with the combined approach. Taken together, these and other data strongly argue against the strategy of combining mpMRI-PB with systematic TRUS-TB in order to improve biopsy yields.
3.5. Is there a performance difference of mpMRI-TB in biopsy naïve patients compared with those with previous negative TRUS-PB?
A systematic analysis  suggested that in biopsy naïve patients, the mpMRI-TB approach only marginally increased detection rate (+10%) of significant disease and also decreased (-17%) insignificant cancer detection, so the costs and effort need to be justified (vide infra). However, in previous negative biopsy patients, mpMRI-PB greatly increased detection rates (+54%) of significant cancers and markedly reduced (-49% and -18% respectively) insignificant cancers detection, rendering the mpMRI-TB approach clinically effective. Thus both the European Association of Urology 2015 and the UK National Institute of Clinical and Care Excellence 2014 guidelines recommend mpMRI before repeat TRUS biopsy. UK National Institute of Clinical and Care Excellence 2014 additionally recommends against a second biopsy if mpMRI is negative, unless high-risk features are present (high-grade prostatic intraepithelial neoplasia, atypical small acinar proliferation, and abnormal digital rectal exam) .
3.6. Does mpMRI-PB lead to timely meaningful management changes?
A recent randomised clinical trial evaluated how the initial biopsy method affected the proportion of patients undergoing radical treatments for PCa . One thousand one hundred and forty biopsy naïve men were randomised to an initial mpMRI-PB or TRUS-PB strategy. More cancers requiring radical treatment were detected by mpMRI at the first approach. No patient with negative mpMRI went onto radical treatment even after the negative mpMRI-PB patients underwent saturation biopsy for result verification. On the contrary, 355 of 570 men randomised to a TRUS-PB first had an initial negative biopsy result; 183 of these men ultimately needed radical treatment, being detected only after further investigations.
Widespread acceptance and routine usage mpMRI has been hampered by lack of standards in data acquisition and diagnostic reporting criteria. The European Society of Urogenital Radiology published the Prostate Imaging Reporting and Data System (PIRADS) in 2012 . This system has gained widespread acceptance and has been validated in prospective studies, randomised trials, and systematic analyses. Recent pooled data has been subjected to a meta-analysis, which showed that the PIRADS has a sensitivity of 0.78 (0.72–0.89) and specificity of 0.79 (0.68–0.86) for PCa detection . Both the American College of Radiology and The European Society of Urogenital Radiology  recently adopted PIRADS version 2. Clearly, in order to achieve and maintain good mpMRI performance, adequate training and quality control are needed, together with peer feedback within multidisciplinary teams.
Finally, the costs of the mpMRI-TB approach with therapeutic consequences have to be considered when recommendations for practice are being formulated . A modelling study strongly suggested that mpMRI biopsy strategy can be cost-effective compared with the TRUS-PB strategy. The total costs of the mpMRI strategy are almost equal with TRUS-PB, while maintaining the benefits of reduced overdiagnosis and overtreatment together with improvements in the expected quality-of-life . Similar findings in cost-effectiveness have also been found in a UK study .
5. Implementation into clinical practice
It is recommended that mpMRI-TB approach should only be undertaken in men who are likely to benefit, taking into account attendant comorbidities and life expectancy. There is a compelling argument that men with prior negative biopsies, who remain suspicious for harbouring as yet undiagnosed significant disease, benefit most from this approach. The availability and appropriate use of targeted biopsy methods that minimises overdiagnosis of insignificant disease is the key to success, with the benefits of improving risk stratification and triaging of patients towards appropriate treatments.
Conflicts of interest
The authors have nothing to disclose.
-  B. Djavan, V. Ravery, A. Zlott, et al. Prospective evaluation of prostate cancer detected on biopsies 1, 2, 3 and 4: when should we stop?. J Urol. 2001;166:1679-1683
-  G. Guichard, S. Larre ́, A. Gallina, et al. Extended 21-sample needle biopsy protocol for diagnosis of prostate cancer in 1000 consecutive patients. Eur Urol. 2007;52:430-435 Crossref
-  T. Hambrock, C. Hoeks, C. Hulsbergen-van de Kaa, et al. Prospective assessment of prostate cancer aggressiveness using 3-T diffusion- weighted magnetic resonance imaging-guided biopsies versus a systematic 10-core transrectal ultrasound prostate biopsy cohort. Eur Urol. 2012;61:177-184 Crossref
-  M. Bul, R.C. van den Bergh, X. Zhu, et al. Outcomes of initially expectantly manged patients with low or intermediate risk screen-detected localized prostate cancer. BJU Int. 2012;110:1672-1677 Crossref
-  V. Moyer. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;157:120-134 Crossref
-  I.G. Schoots, M.J. Roobol, D. Nieboer, et al. Magnetic resonance imaging–targeted biopsy may enhance the diagnostic accuracy of significant prostate cancer detection compared to standard transrectal ultrasound-guided biopsy: A systematic review and meta-analysis. Eur Urol.. 2015; 10.1016/j.eururo.2014.11.037 In press
-  J.J. Futterer, A. Briganti, P. De Visschere, et al. Can clinically significant prostate cancer be detected with multiparametric magnetic resonance imaging?. A systematic review of the literature. Eur Urol.. 2015; 10.1016/j.eururo.2015.01.013 In press
-  V. Panebianco, F. Barchetti, A. Sciarra, et al. Multiparametric MRI vs. standard care in men being evaluated for prostate cancer: A randomised study. Urol Oncol. 2015;33 17.e1–7
-  M.M. Siddiqui, S. Rais-Bahrami, B. Baris Turkbey, et al. Comparison of MR/Ultrasound Fusion–Guided Biopsy With Ultrasound-Guided Biopsy for the Diagnosis of Prostate Cancer. JAMA. 2015;313:390-397 Crossref
-  M.R. Pokorny, M. de Rooij, E. Duncan, et al. Prospective study of diagnostic accuracy comparing prostate cancer detection by trans- rectal ultrasound-guided biopsy versus magnetic resonance (MR) imaging with subsequent MR-guided biopsy in men without previous prostate biopsies. Eur Urol. 2014;66:22-29 Crossref
-  National Institute for Health and Care Excellence 2014 recommendations. http://www.nice.org.uk/guidance/cg175/chapter/1-recommendations.
-  European Association of Urology 2015 Guidelines for prostate cancer. http://uroweb.org/wp-content/uploads/09-Prostate-Cancer_LR.pdf
-  T. Vache, F. Bratan, F. Mege-Lechevallier, et al. Characterization of prostate lesions as benign or malignant at multiparametric MR imaging: comparison of three scoring systems in patients treated with radical prostatectomy. Radiology. 2014;272:446-455 Crossref
-  G. Gaziev, K. Wadhwa, T. Barret, et al. Defining the learning curve for mutliparametric MRI of the prostate using MRI-TRUS fusion-guided transperineal prostate biopsies as a validation tool. BJU Int.. 2015; 10.1111/bju.12892 In press
-  B.G. Muller, J.H. Shih, S. Sankineni, et al. Prostate cancer: interobserver agreement and accuracy with the revised prostate imaging reporting and data system at mp MRI. Radiology.. 2015; 10.1148/radiol.2015142818 In press
-  M. De Rooij, E.H.J. Hamoen, J.J. Futterer, et al. AJR. Accuracy of multiparametric MRI for prostate cancer detection: a Meta-Analysis. AJR. 2014;202:343-351 Crossref
-  L. Bour, A. Schull, N.B. Delongchamps, et al., M.R.I. Multiparametric. features of granulomatous prostatitis and tubercular prostate abscess. Diagn Interv Imaging. 2013;94:84-90 Crossref
-  S.R. Willis, H.U. Ahmed, C.M. Moore, et al. Multiparametric MRI followed by targeted prostate biopsy for men with suspected prostate cancer: a clinical decision analysis. BMJ Open.. 2015; 10.1136/bmjopen-2014-004895 In press
-  N.B. Delongchamps, M. Peyromaure, A. Schull, et al. Prebiopsy MRI and prostate cancer detection: comparison of random and targeted biopsies. J Urol. 2013;189:493-499 Crossref
-  P.J. De Visschere, L. Naesens, L. Libbrecht, et al. What kind of prostate cancers do we miss on multiparametric MRI?. Eur Radiol.. 2015; 10.1007/s00330-015-3894-x In press
-  J.P. Radtke, T.H. Kuru, S. Boxler, et al. Comparative analysis of transperineal template saturation prostate biopsy versus magnetic resonance imaging targeted biopsy with magnetic resonance imaging-ultrasound fusion guidance. J Urol. 2015;193:87-94 Crossref
-  V. Kasivisvanathan, R. Dufour, C. Moore, et al. Transperineal magnetic resonance image targeted prostate biopsy versus transperineal template prostate biopsy in the detection of clinically significant prostate cancer. J Urol. 2013;189:860-866 Crossref
-  J.O. Barentsz, J. Richenberg, R. Clements, et al. ESUR prostate MR guidelines 2012. Eur Radiol. 2012;22:746-757 Crossref
-  E.H.J. Hamoen, M. De Rooij, J.A. Witjes, et al. Use of the Prostate Imaging Reporting and Data System (PI-RADS) for prostate cancer detection with multiparametric magnetic resonance imaging: A diagnostic meta-analysis. Eur Urol. 2015;67:1112-1121 Crossref
-  Prostate Imaging and Reporting Data System: version 2. http://www.acr.org/∼/media/ACR/Documents/PDF/QualitySafety/Resources/PIRADS/PIRADS%20V2.pdf
-  M.G. Hunink, G.P. Krestin. Study design for concurrent development, assessment, and implementation of new diagnostic imaging technology. Radiology. 2002;222:604-614 Crossref
-  M. De Rooij, S.J. Crienen, J.A. Witjes, et al. Cost-effectiveness of magnetic resonance (MR) imaging and MR-guided targeted biopsy versus systematic transrectal ultrasound–guided biopsy in diagnosing prostate cancer: A modelling study from a health care perspective. Eur Urol. 2014;66:430-436 Crossref
-  G. Mowatt, G. Scotland, C. Boachie, et al. The diagnostic accuracy and cost-effectiveness of magnetic resonance spectroscopy and enhanced magnetic resonance imaging techniques in aiding the localisation of prostate abnormalities for biopsy: a systematic review and economic evaluation. Health Technol Assess. 2013;17:1-281
a Radboud University Nijmegen Medical Centre, Department of Radiology and Nuclear Medicine, Nijmegen, The Netherlands
b Paul Strickland Scanner Centre, Mount Vernon Cancer Centre, Northwood, UK
Corresponding author. Radboud University Nijmegen Medical Centre, Department of Radiology, P.O. Box 9101, Nijmegen, 6500 HB, The Netherlands. Tel. +31 243619196.
© 2015 European Association of Urology, Published by Elsevier B.V.