Journal Logo

Research Article: Observational Study

Adding systematic biopsy to magnetic resonance ultrasound fusion targeted biopsy of the prostate in men with previous negative biopsy or enrolled in active surveillance programs

A prospective single center, randomized study

Porreca, Angelo MDa; Del Giudice, Francesco MDb; Giampaoli, Marco MDa; D’Agostino, Daniele MDa; Romagnoli, Daniele MDa; Corsi, Paolo MDa; Del Rosso, Alessandro MDa; Maggi, Martina MDb; Chung, Benjamin I. PhDc; Ferro, Matteo MD, PhDd; de Cobelli, Ottavio MDd,e; Lucarelli, Giuseppe MD, PhDf; Schiavina, Riccardo MDg; De Berardinis, Ettore MDb; Sciarra, Alessandro MDb; Busetto, Gian Maria MD, PhDb,∗

Editor(s): Roviello., Giandomenico

Author Information
doi: 10.1097/MD.0000000000022059
  • Open


1 Introduction

Prostate cancer (PCa) is the most common neoplasm diagnosed in men.[1,2] Magnetic resonance imaging (MRI) has shown a remarkable accuracy in the detection of clinical significant prostate cancer (csPCa).[3–5] A growing body of evidence suggests that multiparametric (mp) magnetic resonance imaging can improve prostate cancer risk group classification and could reduce false-negative rates and the necessity of repeat biopsies in both biopsy-naive patients and those with prior negative-biopsy;[6–9] not surprisingly, MRI targeted biopsies (TBx) should be strongly considered for any patient, biopsy naive or with a prior negative biopsy who has persistent clinical suspicion of PCa. Techniques for TBx include visual estimation TRUS-GB (cognitive technique), software coregistered MRI-ultrasound fusion (fusion technique), and in-bore MRI-guided biopsy.[10]

The use of MR-ultrasound fusion biopsy (FBx) in men with elevated serum prostate-specific antigen (PSA) is becoming increasingly widespread in clinical practice.[11] Prostatic MRI allows the identification of suspicious regions that may be missed by systematic biopsies (SBx) and direct sampling via FBx.[12] As stated by European Association of Urology (EAU) guidelines, MRI-TBx can be used in 2 different diagnostic pathways: the combined pathway in which patients with a positive mpMRI undergo combined SBx and TBx and patients with negative mpMRI undergo systematic biopsy; the MR pathway in which patients with a positive mpMRI undergo only TBx and patients with negative multiparametric MRI are not biopsied.[13]

Adding MRI TBx to SBx in biopsy naive patients increases the number of ISUP ≥ 2 PCa by approximately 20% whereas in the repeat-biopsy setting by approximately 40%. Therefore, it has been shown that TBx improves the detection of clinically significant prostate cancer.[14,15]

However, the csPCa yield for TBx alone versus TBx plus SBx after accounting for overlapping of SBx cores with TBx cores has not been well studied.

The aim of our study was to investigate the potential benefit in terms of Detection Rate and pathological stratification of prostate cancer using a contextual SBx during an MRI-TRUS TBx in a 2-cohort population: patients with previous negative SBx and patients considered for an active surveillance (AS) program.[16]

2 Methods

2.1 Study population

This is a prospective randomized single center study approved by our Internal Review Board of Policlinico Abano Terme, Abano Terme (PD), Italy, in accordance with good clinical practice guidelines and ethical principles of the Declaration of Helsinki. An informed consent was obtained from all patients enrolled in the study.

Two different cohorts were considered with the following inclusion criteria: a raised PSA serum level with a previous negative SBx; an enrollment in an AS program for low-risk PCa. In both 2 cohorts, all patients were submitted to mpMRI with at least 1 suspicious area with a PIRADSv2 score ≥3. Between April 2017 and July 2019, 213 consecutive patients were included in the cohort A and 99 consecutive patients in the cohort B.

Cohort A: all patients were previously submitted to SBx for clinical suspicion of prostate cancer based on raised PSA serum level, the histological examination resulted negative for PC and PSA levels continued to rise. All cases underwent mpMRI and showed at least 1 suspicious area with a PIRADS v2 score ≥3.

Cohort B: all patients were enrolled in an active surveillance program for diagnosis of low-risk (Gleason Score 3 + 3) PCa within the past year. The diagnosis was obtained by a standard ultrasound guided biopsy and all cases went mpMRI before confirmatory biopsy and showed at least 1 suspicious area with a PIRADS v2 score ≥3.

2.2 Multiparametric magnetic resonance imaging analysis

All multiparametric MRI examinations were performed with a 1.5 T whole body scanner (Achieva XR; Philips Medical Systems, Best, the Netherlands) with a 32-channels phased-array surface coil with endorectal coil. After local 3-plane acquisition, required for the correct positioning of the sequences, the morphological and functional studies were carried out. Morphological study of the prostate gland was obtained with Turbo Spin Echo (TSE) T2-weighted sequences (TE 100 msec, TR 4074 msec, slice thickness 3 mm, slice spacing 0.3 mm, field of view [FOV] 180 × 180 mm and matrix size 276 × 205) in the sagittal, axial, and coronal planes, including seminal vesicles and the entire prostate gland. For the functional study, DWI, DCE-MRI, and MRS acquisition were performed. The DWI acquisition was carried out in the axial plane, using a single-shot echo-planar imaging sequence, with 3 b-values (0, 600, and 1500 s/mm2), slice thickness of 3 mm, FOV 180 × 180 mm and matrix size 80 × 71. The DCE-MRI was obtained using three-dimensional (3D) T1W high-resolution isotropic volume examination sequence during the intravenous injection of a contrast bolus of 0.1 mmol per kilogram of body weight of Meglumine gadobenate (Multihance, Bracco Diagnostics, Milan, Italy), at flow rate of 3.5 mL/s followed by 15 mL of saline solution. Twenty-three 3D data sets, 1 before and 22 after contrast administration, were acquired with 10 seconds temporal resolution and a total duration of 4 minutes (depending on the volume of the prostate gland). The first data set acquired before contrast agent administration can be used to detect residual blood of previous biopsy. The MRS was obtained with the use of 3D chemical shift imaging sequence and the following parameters: matrix 10 × 10 × 12 phase-encoding steps with nominal voxel size < 0.5 cc; spectral selective suppression of water and lipid signals; interactive automatic shimming up to a line width at half height of the water resonance peak between 15 and 20 Hz. The volume of interest is aligned to axial T2WIs and centered on each prostate to maximize coverage of the whole gland, while minimizing contamination by surrounding tissue. Finally, a TSE T2-weighted sequence (TE 100 msec, TR 3445 msec, slice thickness 4 mm, slice spacing 0.4 mm, FOV 260 × 260 mm and matrix size 260 × 178) in the axial plane was acquired from the aortic bifurcation to the symphysis pubis to evaluate the pelvic lymph nodes and bone. All the multiparametric-MRI images were assessed by 1 reader (M.V.) with 10 years of specific experience on prostate MRI who was blinded to all patient information. The DWI and DCE-MRI images were processed on an independent workstation with dedicated software (View Forum, Philips Medical Systems, Best, the Netherlands). Regions of interest positioned on the suspected areas were used to calculate the corresponding value of the apparent diffusion coefficient for DWI. Semiquantitative MRI perfusion was performed on the same workstation with analysis of DCE datasets and signal intensity-time (I-T) curves generation. All lesions were scored using the PI-RADS-v2 according to the ESUR guidelines for the evaluation and reporting of prostate multiparametric-MRI.[17,18]

2.3 Conduct of the biopsy

The biopsies were performed within 3 weeks from the diagnostic mpMRI study by a single urologist with a 5 years’ experience in TRUS-guided SBx and TBx. In the cohort B, biopsies were performed at 1 year from inclusion in the AS program as confirmatory biopsies. All patients underwent an MRI-TRUS TBx on suspicious target lesions at mpMRI (PIRADSv2 score 3–5) using the Artemis platform. After TBx, a SBx was performed or not (based on randomization) with the Artemis-generated template, with 10/12-systematic cores throughout the prostate. SBx locations could not encompass the TBx sites, so that the results of each type of biopsy were independent and did not overlap.

Using the BK Ultrasound 5000 MRI-TRUS Fusion platform, fusion target biopsy was performed on the suspicious area previously identified on the multiparametric-MRI using a real-time alignment of the T2-weighted sequence to the TRUS image. MRI-TRUS images alignment was possible due to a tracking device consisted in a sensor coil on the TRUS probe paired with a magnetic field generator to register the location of the tracking device in the 3D space. At least 3 cores were taken for each lesion and the number of additional cores was based on the diameter of the lesion. The number of cores taken was related to the size of the lesions; the cores were carried out along the long axis of the lesion with a maximum of 2 biopsies taken for each needle. TRUS Standard Biopsy was a typical 12 cores double sextant template from lateral to medial of base, mid, and apex. Only the TRUS images, with no multiparametric-MRI target data available, were used for the standard biopsy portion of the case.

2.4 Pathologic analysis

Histopathologic examination was carried out by a single dedicated genitourinary pathologist with more than 20 years of experience, who was blinded to the origin (MRI-TRUS TBx or SBx) of each single core. Not indolent Prostate Cancer was defined by the presence of Gleason Score ≥7 (ISUP grade ≥2).

2.5 Study design and endpoints

After inclusion in each cohort A and B, cases were randomly assigned to an only TBx strategy versus a TBx + SBx strategy. Primary endpoints of this study were overall PCa-detection rate (DR), csPCa-DR, and pathologic results between MRI-TRUS TBx and SBx. Secondary endpoints were correlations between clinical characteristics of the population and csPCa detection on biopsy results.

2.6 Statistical analysis

Means, medians, and interquartile ranges were reported for continuous variables. Frequencies and proportions were reported for categorical variables. The Mann–Whitney U test and χ2 tests were used to compare the statistical significance of differences in medians and proportions, respectively. Multivariate logistic regression was performed to evaluate if age, PSA, or PIRADS categorization and type of cohort analyzed (ie, A vs B) were associated with the detection of csPCa at biopsies.

All analyses were carried out using SPSS IBM Statistics v. 22.0 (IBM Corp, Armonk, NY) with level of statistical significance set at P < .05.

3 Results

A total of 312 patients were included in the 2 cohorts (cohort A: 213 cases; cohort B: 99 cases). All cases were consecutively assigned to MRI-TRUS TBx alone or to a TBx + SBx strategy. The clinical, radiologic, and pathologic characteristics of the entire population are listed in Table 1. No statistically significant differences in terms of age, PSA, PIRADSv2 score distribution, biopsy cores taken per patient by SBx were present between the 2 biopsy strategy groups (Table 1). The 2 biopsy groups were homogeneous regarding most of clinical and radiological data, except for prostate volume (median value 50 vs 40 cc; IQR 39.5 – 61.25 vs 35–50, respectively) and radiological dimension of the index lesion (13 vs 10 mm; IQR 10–16, 25 vs 10–12, respectively).

Table 1
Table 1:
Clinical, radiologic, and pathological characteristics of the population.

Median number of targeted and random cores per patient were respectively 6 (IQR, 4–6) and 11.5 (IQR 10–12). Table 2 shows clinical characteristics of cases on the basis of the pathological diagnosis of csPCa and clinically insignificant PCa. csPCa showed a higher percentage of PI-RADS score 4/5 (73.2%) when compared with ciPC (33.3%).

Table 2
Table 2:
Characteristics of the entire PCa population in relation to niPC and iPC pathologic diagnosis.

3.1 Detection rate of PCa and csPCa

Table 3 shows the detection rate of all PCa, csPCa, and ratio csPCa/all PCa between patients assigned to MRI-TRUS TBx alone versus TBx + SBx. Between the 2 groups, no significant differences were found in terms of overall PCa detection rate (77.6% vs 69.6% respectively; P = .36) and csPCa detection rate (48.2% vs 60.9% respectively; P = .12). The MRI-TRUS TB alone cohort showed a higher csPCa/PCa ratio (87.5% vs 62.2%; P = .03) mainly due to the lower number of indolent (ISUP 1) tumor diagnosed.

Table 3
Table 3:
Detection rate and histological results.

Moreover, at the MRI-TRUS TB + SB group subanalysis, a significantly higher csPCa-DR was obtained at the MRI-TRUS TB cores when compared with the SBx cores (43.7% vs 24.1%, respectively; P = .01) (Table 2) with a concomitant more accurate Gleason Score stratification (Table 4). Twenty-four out of 81 cases (29.6%) were upgraded from benign at SBx cores to csPCa at TBx cores and 18 out of 51 (35.3%) were upgraded from ciPC at SBx cores to csPCa at TBx cores. On the contrary 5/65 cases (7.7%) benign and 3/33 (9.0%) with ciPC at TBx cores were upgraded to Gleason Score 3 + 4 at SBx cores (Table 4).

Table 4
Table 4:
Histological contingency table in the MRI-TRUS TB + TRUS SB cohort.

3.2 Multivariate analysis

In adjusted analyses, age, PSA levels, PIRADS score distribution were not significantly associated with csPCa detection at SBx (Table 5). Therefore, independently of these parameters, either in the rebiopsy (OR 0.43, 0.21–0.97) or active surveillance (OR 0.46, 0.32–0.89) setting, SBx cores were negatively associated with the csPCa-DR when combined to TBx cores.

Table 5
Table 5:
Multivariate logistic regression predicting the presence of niPC on SBx cores.

4 Discussion

The advantage of magnetic resonance imaging TBx to SBx in increasing the detection rate of clinical significant prostate cancer, either in naive or in rebiopsy populations, has been well demonstrated by multicenter studies and stated by international guidelines.[13–15] However, the csPCa yield for TBx alone versus TBx plus SBx after accounting for overlapping of SBx cores with TBx cores, has not been well studied. EAU guidelines in a naive population, when multiparametric magnetic resonance imaging is performed and its PIRADS is ≥ 3, recommend with a strong level of evidence to combine targeted and systematic biopsies. On the contrary in a prior negative biopsy, when mpMRI is PIRADS ≥ 3, the recommendation to perform targeted biopsy only, reaches a weak level of evidence.[13] In active surveillance strategy, TBx and SBx appear to be complementary to each other, both missing a significant proportion of cancer upgrading or reclassification. Thus, combining the 2 biopsy techniques seems to be the best way to select patients for AS or to monitoring them.[19,20] However, EAU guidelines recommend to perform mpMRI before confirmatory biopsy with a strong level of evidence, but the recommendation to perform the combination of TBx and SBx at confirmatory biopsy reaches a weak level of evidence.

For these reasons we decided to consider for our study 2 different populations (prior negative biopsy and active surveillance) in which the level of evidence to combine SBx and TBx is weak. In addition, we excluded the naive biopsy population, in which this level of evidence is strong.

The purpose of our study was to investigate the potential benefit in terms of Detection Rate and pathological stratification of prostate cancer using a contextual SBx during an MRI-TRUS TBx.

In our experience, independently of other clinical parameters, either in the rebiopsy or in the active surveillance setting, SBx cores were negatively associated with the csPCa detection rate when combined to TBx cores. In fact, in both populations, the MRI-TRUS TBx alone cohort showed a higher csPCa/PC ratio (87.5% vs 62.2%; P = .03) mainly due to the lower number of indolent (ISUP 1) tumor diagnosed.

Considering the group of patients submitted to a combination of MRI-TRUS targeted and systematic cores, SBx upgraded TBx only in 7.7% with benign and 9.0% with ciPC at TBx cores and the upgrade was to a Gleason score 3 + 4 (ISUP 2).

Main limitation of our study is not equally distributed population among the 2 cohort enrolled; therefore, we were not able to establish a clear difference in the outcomes reached.

Our analysis was prospective, and the 2 cohorts are representative of the normal clinical practice. Our findings suggest that MRI-TRUS TBx represents the elective method to perform prostate biopsy in these 2 settings and the combination of a SBx does not improve the detection rate of csPCa nether in a population of prior negative biopsy nor in AS confirmatory biopsy.

Author contributions

Conceptualization: Angelo Porreca, Matteo Ferro, Ottavio de Cobelli, Ettore De Berardinis, Gian Maria Busetto.

Data curation: Daniele Romagnoli, Paolo Corsi, Alessandro Del Rosso.

Formal analysis: Francesco Del Giudice, Gian Maria Busetto.

Investigation: Daniele D’Agostino, Daniele Romagnoli.

Methodology: Paolo Corsi, Alessandro Del Rosso, Martina Maggi, Alessandro Sciarra.

Project administration: Angelo Porreca, Riccardo Schiavina.

Resources: Daniele D’Agostino, Martina Maggi, Alessandro Sciarra.

Software: Francesco Del Giudice, Marco Giampaoli.

Supervision: Angelo Porreca, Giuseppe Lucarelli, Riccardo Schiavina.

Validation: Benjamin I. Chung, Matteo Ferro, Ettore De Berardinis.

Visualization: Matteo Ferro, Riccardo Schiavina, Alessandro Sciarra.

Writing – original draft: Francesco Del Giudice, Marco Giampaoli, Matteo Ferro, Gian Maria Busetto.

Writing – review & editing: Martina Maggi, Benjamin I. Chung, Ottavio de Cobelli, Giuseppe Lucarelli, Riccardo Schiavina, Ettore De Berardinis,

Alessandro Sciarra, Gian Maria Busetto.


[1]. Siegel R, Naishadham D, Jemal A. Cancer statistics 2012. CA Cancer J Clin 2012;62:1021.
[2]. Vagnoni V, Bianchi L, Borghesi M, et al. Adverse features and competing risk mortality in patients with high-risk prostate cancer. Clin Genitourin Cancer 2017;15:e23948.
[3]. Dickinson L, Ahmed HU, Allen C, et al. Magnetic resonance imaging for the detection, localisation, and characterisation of prostate. Eur Urol 2011;59:47794.
[4]. Panebianco V, Sciarra A, De Berardinis E, et al. PCA3 urinary test versus 1H-MRSI and DCEMR in the detection of prostate cancer foci in patients with biochemical alterations. Anticancer Res 2011;31:1399405.
[5]. Vagnoni V, Brunocilla E, Bianchi L, et al. State of the art of PET/CT with 11-choline and 18F-fluorocholine in the diagnosis and follow-up of localized and locally advanced prostate cancer. Arch Esp Urol 2015;68:35470.
[6]. Watanabe Y, Terai A, Araki T, et al. Detection and localization of prostate cancer with the targeted biopsy strategy based on ADC map: a prospective large-scale cohort study. J Magn Reson Imaging 2012;35:141421.
[7]. Numao N, Yoshida S, Komai Y, et al. Usefulness of pre-biopsy multiparametric magnetic resonance imaging and clinical variables to reduce initial prostate biopsy in men with suspected clinically localized prostate cancer. J Urol 2013;190:5028.
[8]. Siddiqui MM, Rais-Bahrami S, Truong H, et al. Magnetic resonance imaging/ultrasound fusion biopsy significantly upgrades prostate cancer versus systematic 12-core transrectal ultrasound biopsy. Eur Urol 2013;64:7139.
[9]. Hoeks CM, Schouten MG, Bomers JG, et al. Three-Tesla magnetic resonance-guided prostate biopsy in men with increased prostate-specific antigen and repeated, negative, random, systematic, transrectal ultrasound biopsies: detection of clinically significant prostate cancers. Eur Urol 2012;62:9029.
[10]. Wegelin O, van Melick HHE, Hooft L, et al. Comparing three different techniques for magnetic resonance imaging-targeted prostate biopsies: a systematic review of in-bore versus magnetic resonance imaging-transrectal ultrasound fusion versus cognitive registration is there a preferred technique? Eur Urol 2017;71:51731.
[11]. van Hove A, Savoie PH, Maurin C, et al. Comparison of image-guided targeted biopsies versus systematic randomized biopsies in the detection of prostate cancer: a systematic literature review of well-designed studies. World J Urol 2014;32:84758.
[12]. Schoots IG, Roobol MJ, Nieboer D, 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;68:43850.
[13]. Mottet N, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis, and Local Treatment with Curative Intent. Eur Urol 2017;71:618-629.
[14]. Kasivisvanathan V, Rannikko AS, Borghi M, et al. MRI-targeted or standard biopsy for prostate-cancer diagnosis. N Engl J Med 2018;378:176777.
[15]. Rouvière O, Puech P, Renard-Penna R, et al. Use of prostate systematic and targeted biopsy on the basis of multiparametric MRI in biopsy-naive patients (MRI-FIRST): a prospective, multicentre, paired diagnostic study. Lancet Oncol 2019;20:1009.
[16]. Grasso AA, Cozzi G, De Lorenzis E, et al. Multicenter analysis of pathological outcomes of patients eligible for active surveillance according to PRIAS criteria. Minerva Urol Nefrol 2016;68:23741.
[17]. Rosenkrantz AB, Verma S, Choyke P, et al. Prostate magnetic resonance imaging and magnetic resonance imaging targeted biopsy in patients with a prior negative biopsy: a consensus statement by AUA and SAR. J Urol 2016;196:16138.
[18]. Weinreb JC, Barentsz JO, Choyke PL, et al. PI-RADS prostate imaging—reporting and data system: 2015, version 2. Eur Urol 2016;69:1640.
[19]. Schoots IG, Nieboer D, Giganti F, et al. Is magnetic resonance imaging-targeted biopsy a useful addition to systematic confirmatory biopsy in men on active surveillance for low-risk prostate cancer? A systematic review and meta-analysis. BJU Int 2018;122:94658.
[20]. Klotz L, Loblaw A, Sugar L, et al. Active surveillance magnetic resonance imaging study (ASIST): results of a randomized multicenter prospective trial. Eur Urol 2019;75:3009.

biopsy; clinically significant; detection rate; magnetic resonance imaging; prostate biopsy; prostate cancer

Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.