Clinical Research

Improved detection of anterior fibromuscular stroma and transition zone prostate cancer using biparametric and multiparametric MRI with MRI-targeted biopsy and MRI-US fusion guidance



The objective of this study was to analyze the potential of prostate magnetic resonance imaging (MRI) and MRI/transrectal ultrasound-fusion biopsies to detect and to characterize significant prostate cancer (sPC) in the anterior fibromuscular stroma (AFMS) and in the transition zone (TZ) of the prostate and to assess the accuracy of multiparametric MRI (mpMRI) and biparametric MRI (bpMRI) (T2w and diffusion-weighted imaging (DWI)).


Seven hundred and fifty-five consecutive patients underwent prebiopsy 3 T mpMRI and transperineal biopsy between October 2012 and September 2014. MRI images were analyzed using PIRADS (Prostate Imaging-Reporting and Data System). All patients had systematic biopsies (SBs, median n=24) as reference test and targeted biopsies (TBs) with rigid software registration in case of MRI-suspicious lesions. Detection rates of SBs and TBs were assessed for all PC and sPC patients defined by Gleason score (GS)3+4 and GS4+3. For PC, which were not concordantly detected by TBs and SBs, prostatectomy specimens were assessed. We further compared bpMRI with mpMRI.


One hundred and ninety-one patients harbored 194 lesions in AFMS and TZ on mpMRI. Patient-based analysis detected no difference in the detection of all PC for SBs vs TBs in the overall cohort, but in the repeat-biopsy population TBs performed significantly better compared with SBs (P=0.004 for GS3+4 and P=0.022 for GS4+3, respectively). Nine GS4+3 sPCs were overlooked by SBs, whereas TBs missed two sPC in men undergoing primary biopsy. The combination of SBs and TBs provided optimal local staging. Non-inferiority analysis showed no relevant difference of bpMRI to mpMRI in sPC detection.


MRI-targeted biopsies detected significantly more anteriorly located sPC compared with SBs in the repeat-biopsy setting. The more cost-efficient bpMRI was statistically not inferior to mpMRI in sPC detection in TZ/AFMS.


Conventional 10- to 12-core transrectal ultrasound (TRUS)-guided biopsies are the standard diagnostic approach for prostate cancer (PC) detection.1 However, standard biopsy has several limitations. Especially, PC in the transition zone (TZ) and anterior fibromuscular stroma (AFMS) are difficult to diagnose and are often misjudged by the transrectal approach.2, 3 Systematic saturation protocols have been shown to detect more significant PC compared with conventional TRUS-guided biopsy, but may lead to increased overdiagnosis of insignificant PC.4, 5

Most PC originates in the peripheral zone (PZ). Surgical specimens, however, show that a considerable amount of diagnosed cancers are located in TZ and AFMS (Supplementary Figure 1).2, 3, 6, 7 Anterior tumors are often not palpable in digital rectal examination (DRE) and tend to have higher PSA levels.2, 7 Some authors state that these PC tend to have lower Gleason scores (GS) and are less likely to demonstrate unfavorable pathologic outcomes, whereas others did not find any association between tumor zone origin and biochemical recurrence after treatment with curative intention.2, 8, 9 Similarly, tumor volume (TV) of TZ/AFMS PC is discussed controversially. Although Ouzzane et al.7 postulate that most tumors are small with a median TV of <2 cm3, Mygatt et al.2 analyzed 1528 radical prostatectomy (RP) specimen, postulating higher TV compared with that in PZ tumors.

Recently, multiparametric magnetic resonance imaging (mpMRI)-targeted biopsies have been advocated to detect more significant PC (sPC) compared with conventional TRUS-guided biopsies, while mitigating low-grade tumor detection.10, 11 Compared with TRUS-guided biopsies, fusion-guided biopsies also classify anterior PC more accurately.12 Furthermore, mpMRI yields good negative predictive values for sPC, when compared with RP specimen.13, 14 Owing to the heterogeneous nature of the TZ, which features benign hyperplastic nodules that are difficult to distinguish from cancer foci, PC detection in TZ by mpMRI is inferior to that in PZ.15 Especially, analysis of contrast-enhanced sequences (DCE) is challenging.6, 15

Our first objective was to assess the efficacy of mpMRI and MRI-targeted biopsies (TBs) in sPC detection in the AFMS and TZ.7, 16, 17 TBs were compared with transperineal saturation biopsy (SB) as a reference test. In patients with discrepancy in PC detection by SBs and TBs, GS and TV characteristics of TZ/AFMS PC were determined from RP specimen, if available.

Based on the results of Chesnais et al.,15 Hoeks et al.6 and Schimmöller et al.,18 another objective was to assess the diagnostic ability of biparametric MRI (bpMRI, T2w+DWI) compared with mpMRI. Taking into account the controversially debated existence of different criteria for sPC, we choose to assess the diagnostic accuracy of MRI for all PC and for sPC using definitions of GS3+4 and GS4+3 on biopsy specimen.19 As characterization of PC can include TV, we also analyzed underestimation of actual TV in RP specimen by MRI.20

Materials and Methods

Study population

Seven hundred and fifty-five consecutive patients were enrolled and registered into a prospective database assessing MRI-targeted/TRUS fusion-guided prostate biopsy at University Hospital Heidelberg between October 2012 and September 2014. Institutional review board approval was obtained (S011/2011) and all subjects provided written informed consent. Subgroups of this cohort were previously analyzed and reported.5, 21 However, these studies did not feature analysis of different prostate zones.

One hundred and ninety-one of 755 patients had 194 suspicious lesions located in the TZ/AFMS on MRI and were thus eligible for inclusion. Inclusion and exclusion criteria of the patients are detailed in Figure 1. Cancerous lesions were stratified to the different prostate zones, according to McNeal et al.17 and Bouyé et al.,16 depending on the dominant localization of the index tumor (>70% zonal involvement).16, 17

Figure 1

Study flowchart with inclusion and exclusion criteria. mpMRI, multiparametric magnetic resonance imaging.

Patient demographics were analyzed according to standards of reporting for MRI-targeted biopsy studies (Table 1).22 Histopathological RP data of those patients with discrepancy in PC detection by SBs and TBs are also presented.

Table 1 Patient demographics and START tablea


All mpMRIs were performed using a 3 T system without an endorectal coil (Magnetom; Siemens, Erlangen, Germany). The parameters of mpMRI sequences are described in Supplementary Table 1. All MR image analyses were performed prospectively by or under supervision of one expert uroradiologist (MR) according to the 2012 ESUR guidelines.23

A lesion on MRI was defined as suspicious if the PIRADS score was 2. Lesion volume was determined using Medical Imaging Toolkit (MITK; German Cancer Research Center, Heidelberg, Germany). Reflecting clinical routine, radiologists were not blinded to clinical data.

Biopsy protocol

All men underwent TBs of MRI-suspicious lesions first (1–6 cores, median 3, depending on lesion size) and then systematic, manually placed SBs of the whole gland, as described previously.24 A median of 27 biopsies (interquartile range (IQR) 25–30) was taken per patient with the number of biopsies adjusted to prostate volume.

Transperineal grid-directed SBs performed under general anesthesia is the standard technique at our center, offering a favorable approach to the ventral zones of the gland and minimal risk of infection. Patients with suspicious lesions on mpMRI underwent TBs with rigid software registration using BiopSee (MEDCOM, Darmstadt, Germany).21 The biopsy operator had access to all mpMRI data with radiologist-marked lesions of interest. All target lesions were sampled under live TRUS visualization.

Histopathological analysis

All histopathological biopsy and RP specimen analyses were performed under the supervision of one dedicated uropathologist (WR), according to the International Society of Urological Pathology standards.25 Lesion volume was determined using a predetermined correction factor (1.5) to correct for tissue shrinkage during fixation.26

Statistical analysis

Statistical differences between initial and repeat-biopsy subgroups were analyzed using Mann–Whitney U-tests and differences between detection rates of all PC and of sPC by mpMRI, bpMRI, TBs and SBs were assessed using Fisher's exact test. To perform a non-inferiority analysis of bpMRI and mpMRI, we used matched-pair analysis of the difference of the detection rates with 95% confidence intervals (95% CI). Levels of sensitivity, specificity and receiver operating characteristics curve analyses for MRI and SBs to detect sPC in TZ/AFMS and in the entire cohort are provided for both, and PIRADS2 and PIRADS3 as the level of suspicion for TBs. Univariate and multivariate logistic and linear regression analyses were used to analyze the predictive value of PIRADS score per PIRADS level for both, mpMRI and bpMRI, and of clinical parameters (PSA level, prostate volume, DRE). TV concordance between MRI and RP specimen was represented graphically by a Bland–Altman plot. Statistical analyses were performed using SPSS Statistics V20 (IBM, Armonk, NY, USA) and SAS (SAS Institute, Cary, NC, USA) for the non-inferiority analysis with the PROC GENMOD. A P-value <0.05 was considered statistically significant.


A total of 755 patients underwent 3 T mpMRI of the prostate and subsequent MRI/TRUS fusion-guided biopsy. Of these, 191 men harbored 194 lesions in the TZ and AFMS (overall prevalence 25.3%). A median of 1 (IQR 1–1) lesion in TZ/AFMS per patient occurred and a median of 3 TBs per lesion (IQR 2–3) were taken. Patient demographics and biopsy statistics according to the Standards of reporting for MRI-targeted biopsy studies recommendations are listed in Table 1.22 Median number of biopsy cores was 24 for SBs and 3 for TBs taken out of PIRADS 2–5 lesions. Ninety-six patients underwent primary biopsy and 95 men had at least one previous biopsy. Between these cohorts, only the prebiopsy PSA level was significantly different (7.3 vs 8.9 ng ml−1, P=0.031) (Supplementary Table 2).

First, we investigated the GS distribution in TZ/AFMS PC. Overall, PC occurred in 139 patients. Thirty-six (25.9%) had GS=3+3 tumors, 66 (47.5%) GS=3+4 and 37 (26.6%) had GS4+3 PC (Table 1).

Second, we examined the diagnostic accuracy of SBs vs TBs on a per-patient level (Table 2 and Supplementary Table 3). One hundred and fifteen of the 139 PCs were detected by SBs and 116 by TBs (P=1.000). SBs detected 28/37 (75.7%) GS4+3 tumors, whereas TBs detected 35/37 (94.6%). Using Fisher's exact test, TBs detected statistically significant more sPC compared with SBs in the repeat-biopsy cohort (P=0.004 for sPC defined as GS3+4, and P=0.022 for GS4+3). When TBs were taken from PIRADS3 lesions only, results were comparable (Supplementary Table 3).

Table 2 Additional utility of systematic biopsy over targeted biopsy and of targeted biopsy over systematic biopsy for the detection of GS3+4 and of GS4+3 PC

Conversely, in the initial biopsy subgroup, the detection rate of SBs and TBs did not differ significantly (P=0.181 for all PC, P=0.195 for GS3+4 PC and P=0.661 for GS4+3 PC).

Detection rates of all PC and GS4+3 sPC by SBs and TBs on a per-lesion level, stratified into different MRI PIRADS scores, are given in Figure 2. Results of sensitivity, specificity and receiver operating characteristics curve analysis for the TZ/AFMS cohort and the entire cohort of 755 patients are given in Supplementary Table 4.

Figure 2

Lesion-based analysis of prostate cancer (PC) detection rates of targeted biopsies (TBs) and systematic biopsies (SBs) and the combination of both, stratified into different PIRADS (Prostate Imaging-Reporting and Data System) score subgroups, for detection of all PC (a) and for the detection of significant PC (b).

Third, we tabulated the distribution of PIRADS scoring for mpMRI and bpMRI (Table 3a). The utility of mpMRI and bpMRI to detect sPC is given in Table 3b–e. For both sPC definitions and both PIRADS suspicion levels, the lower confidence limits of the difference of the detection proportions indicated with 95% probability that bpMRI was not worse compared with mpMRI than 7.3% (Table 3b), 9.1% (Table 3c), 14.5% (Table 3d) and 22.1% (Table 3e), respectively.

Table 3 PIRADS score distribution in bpMRI vs mpMRI on a per-lesion basis (a). The utility of PIRADS score (both PIRADS2 and 3) in mpMRI and bpMRI for both definitions of significant anterior PC, including GEE analysis, is given in (b)–(e)

Fourth, we investigated the results of RP specimen of those patients, in whom discrepancies in PC detection by TBs and SBs occurred. Overall 54/191 patients underwent RP. In the subgroup of PC detected by SBs or TBs alone (n=47, Table 1), 19 patients underwent RP. In 5/19 patients, PC was only detected by SBs, whereas in 14/19 patients PC detection was limited to TBs. All eight pT3 PC and five GS4+3 PC in this subgroup were detected by TBs alone. Only one sPC was detected by SBs alone. TV was significantly higher for PC detected by TBs alone (P=0.041). Analyzing the entire RP cohort (n=54), underestimation of TV in MRI was 23.1% as compared with prostatectomy specimen (P=0.008; −0.37ml, 95% CI: −0.12; −0.9) (Figure 3).

Figure 3

Differences in tumor volume (TV) of magnetic resonance imaging (MRI) and radical prostatectomy (RP) specimen. Bland–Altman plot showing differences in the agreement of TV in MRI and in RP specimen (n=54). The grey line demonstrates the linear regression line. The difference (in ml) is plotted against the mean TV (calculated from both, MRI TV and RP TV). All values above the zero line represent overestimation of TV by MRI, and all values below the zero line represent underestimation of TV. Average underestimation by MRI was 0.37ml (23.1%) with a 95% confidence interval (CI) (−0.90 ml; −0.12ml). The underestimation was constant through the measurement range.

Last, we performed univariate and multivariate regression analysis for PIRADS score in both mpMRI and bpMRI for all PC and GS4+3 sPC (Table 4). PIRADS score (per PIRADS level) in both, mpMRI and bpMRI, was a statistically significant predictor for all PC and for sPC in univariate and in multivariate analysis. Results of clinical variables are also tabulated. Linear regression for PSA level per 1.0 ng ml−1 was a significant predictor for sPC in uni- and multivariate analyses (odds ratio 1.5 and 1.3, respectively).

Table 4 Logistic and linear regression for assessing the utility of PIRADS in mpMRI and bpMRI and of clinical parameters (digital rectal examination, PSA level and prostate volume) to predict PC


Considering the current situation, in which overtreatment of low-risk PC has been recognized as a relevant problem, both an increase in active surveillance and further developments in focal therapy are expected to alleviate problems of whole gland therapy. However, accurate PC risk assessment is essential for both, active surveillance and developments in focal therapy as well as to determine T-stage and GS for RP candidates in higher risk situations, which may need non-nerve-sparing therapy or multimodal treatment. The TZ and AFMS are especially difficult anatomical areas to assess and thus are often unsampled or undersampled by the standard 12-core TRUS approach.7 Therefore mpMRI before biopsy has been demonstrated to improve PC detection and characterization in TZ and AFMS.6, 12, 15

Komai et al.27 recently compared 12-core transrectal biopsy with an extended 26-core SBs (12-core transrectal+14-core transperineal biopsy) in case of a suspicious mpMRI. They found an additional cancer detection rate of 28% of the 26-core biopsy.27 Eighty-six percent of sPC were detected by prebiopsy mpMRI.27

Siddiqui et al.11 and Volkin et al.12 investigated the value of MRI/TRUS fusion-guided cores in addition to a standard 12-core TRUS biopsy. Volkin et al.12 found an improved detection rate in anterior PC with additional MRI/TRUS fusion-guided biopsies. MRI/TRUS fusion-guided biopsies detected 97/121 anteriorly located PC-positive lesions, whereas TRUS biopsies detected only 62/121 lesions (P=0.001). Their TB sensitivity (80.2%) was comparable to our sensitivity of MRI-TBs to detect PC (83.5%). However, our SBs performed better with a sensitivity of 80.6%, compared with conventional TRUS biopsies.12 This additional detection rate by SBs can easily be explained by the increased number of cores taken and the transperineal access.

We compared the detection accuracy of TBs and SBs for both, all PC and sPC. For detection of all PC, TBs and SBs both performed well with a sensitivity of 83.5% and 80.6%, respectively. However, with regard to GS4+3 disease, TBs were superior to SBs (94.6% vs 75.7% sensitivity, P=0.046). Substratification into PIRADS scores shows benefits for TBs versus SBs in all PC and sPC detection, but in contrast to the results of Volkin et al.,12 the benefit of TBs vs SBs was only statistically significant for the overall cohort of sPC (Figure 2b). This can be explained by the superior reference test of our cohort.

On a per-patient level, TBs performed significantly better compared with SBs for the detection of all PC and sPC (GS3+4 and GS4+3) in the repeat-biopsy population. In the overall population and for patients undergoing initial biopsy, the combination of TBs and SBs provided best staging of disease.28

Our overall results of sPC detection echo the recent publication by Siddiqui et al.11 from the NIH group, demonstrating that TBs detect significantly more sPC compared with conventional 12-core biopsy. TBs alone performed significantly better than SBs for overall detection of GS4+3 tumors and was clearly superior to SBs in the repeat-biopsy setting for all subgroups tested (all PC, GS3+4 and GS4+3). This performance of targeted biopsies in sPC detection is also demonstrated by receiver operating characteristics curve analyses(especially for PIRADS3 as suspicion level; Supplementary Table 4). Again, the results are compatible to Siddiqui et al.;11 however, our area under the curve (AUC) of SBs is better because of saturation biopsies performed in our cohort. Thus, the more cost-efficient approach of taking targeted cores only can be debated, especially in men undoing repeat biopsy.

Comparable to a previous publication both, bpMRI and mpMRI, were significant predictors of PC and sPC in univariate and multivariate analyses.29 As accurate PC characterization by MRI includes lesion size, we analyzed all 54 men who subsequently underwent RP.30, 31 In mpMRI median suspect TV in TZ/AFMS was 1.7ml. This is comparable to 1.5 cm3 in the cohort of Ouzzane et al.,7 but lower compared to Bouye and Hoeks et al. (4.4 cm3).6, 16 Our data confirm that histopathological TV is underestimated in MRI by 23.1% (P=0.008, Figure 3), as described previously.20 This has to be taken into consideration when determining sPC on MRI using definitions that include TV.30

To our knowledge, the current study is the first to analyze the diagnostic ability of bpMRI and mpMRI using PIRADS and MRI-targeted transperineal biopsy for TZ/AFMS PC separately. Using advanced statistics, we demonstrate that 'cheaper' bpMRI offers similar accuracy compared with mpMRI for sPC detection, echoing a recent publication from Rosenkrantz et al.,32 stating that incorporating DCE did not increase the sensitivity in sPC detection. Similarly, recent studies postulated a good accuracy of bpMRI, whereas additional use of DCE-MRI did not improve the diagnostic performance in the TZ.15, 18 Schimmöller et al.18 investigated the detection accuracy of mpMRI for lower- and higher-grade PC, suggesting that for all PC bpMRI showed a higher AUC in receiver operating curve analysis compared with mpMRI (AUC 0.762 in bpMRI vs 0.731 in mpMRI). However, for GS4+3 mpMRI achieved the highest AUC (0.879 for mpMRI vs 0.833 for bpMRI).18 Hoeks et al.6 estimated that the cancer detection and localization accuracy of bpMRI (AUC 0.81) for higher-grade PC in the TZ was non-inferior to mpMRI (AUC 0.84).6 The sensitivity of our bpMRI for sPC was 91.9% for PIRADS2 lesions and thus higher compared with the bpMRI results of Delongchamps et al.33 (71%) and Hoeks et al.6 (77%). Certainly, these analyses were influenced by the different definitions of sPC (GS4+3) compared with GS3+4 in the analysis of Delongchamps et al.33 and Hoeks et al.6 However, the sensitivity echoes the results of the bpMRI analysis (89%) by Rais-Bahrami et al.29 Using generalized estimating equation analysis, we demonstrate that bpMRI was not substantially inferior to mpMRI in the detection of sPC, using both sPC definitions (Table 3).

Our study is subject to several limitations. First, our definitions of sPC might be debatable. We used GS3+4 and GS4+3 and did not include TV or cancer core length. Maximum cancer core length was not available for our biopsy specimen and TV in RP was not included into analysis, because only 54/191 patients underwent RP and thus most patients would not have been available for analysis using RP TV for sPC definition. As sPC was reevaluated by RP specimen in patients, in whom RP specimen were available, and the definitions of GS3+4 and especially GS4+3 (primary Gleason pattern 4) for sPC were used in several previous publications, we believe that our results are robust and are not influenced by simplified definitions of significance.5, 11, 12 The sensitivity of GS3+4 by mpMRI (86.4%) is comparable or slightly decreased to recent publications, but none of these focused on challenging AFMS/TZ tumors.5, 11, 34 When the entire cohort of 755 patients is taken in account, sensitivity of mpMRI for GS3+4 PC detection (88.5%) is comparable to recent publications.5, 11, 34

Second, we did not perform separate multiuser reading of mpMRI that might influence the sensitivity. However, even without coreading, the results of MRI sensitivity in our cohort are encouraging and comparable to recent publications using RP specimen as reference.13, 14, 20 Moreover, this limitation represents real-life clinical routine.

Last, one limitation of every study incorporating MRI/TRUS fusion-guided biopsy is time and cost consumption, which might limit widespread distribution. Therefore, limiting the number of MRI sequences similar to that in bpMRI is promising.29 Furthermore, many patients with anterior PC typically undergo several previous negative biopsy sessions that might be obviated by one early MRI and consecutive MRI/TRUS fusion biopsy.


MRI and subsequent MRI/TRUS fusion-guided biopsies accurately detect sPC in patients with AFMS and TZ lesions. TBs significantly outperform SBs in the repeat-biopsy population. For optimal local staging, the combination of SBs and TBs provides best results. BpMRI was not substantially inferior to mpMRI. Thus, the decision to perform DCE imaging should be weighed carefully with regard to patient history, economic cost and examination time.


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Correspondence to J P Radtke.

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Competing interests

BAH is grateful for funding from the German Research Foundation, and the European Foundation for Urology. BAH has received research funding from MedCom and Uromed. None of these sources had any input whatsoever into this article. The remaining authors declare no conflict of interest.

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Supplementary Information accompanies the paper on the Prostate Cancer and Prostatic Diseases website

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Radtke, J., Boxler, S., Kuru, T. et al. Improved detection of anterior fibromuscular stroma and transition zone prostate cancer using biparametric and multiparametric MRI with MRI-targeted biopsy and MRI-US fusion guidance. Prostate Cancer Prostatic Dis 18, 288–296 (2015).

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