Transperineal Targeted Biopsy with Real-Time Fusion Image of Multiparametric Magnetic Resonance Image and Transrectal Ultrasound Image for the Diagnosis of Prostate Cancer

Objectives : To report clinical results of early experience of manually controlled targeted biopsy with real-time multiparametric magnetic resonance image (mpMRI)-transrec‐ tal ultrasound (TRUS) fusion images for the diagnosis of prostate cancer. Methods : One hundred sixty-eight patients who were suspected of prostate cancer from mpMRI scans were recruited prospectively. We performed targeted biopsies for each cancer-suspicious lesion and 12 systematic biopsies using the BioJet® system. Patho‐ logical findings of targeted and systematic biopsies were analyzed. Results : Median age of the 168 patients was 67 years (range: 52–89). Median preopera‐ tive prostate specific antigen (PSA) value was 6.9 ng/ml (range: 3.54–20). Median preoperative prostate volume was 37 ml (range: 22–68). The number of the cancer-detected cases was 99 (59%). The median biopsy time, included the MRI-TRUS fusion time and needle-punctured time without the anesthesia, was 8 minutes (range: 5–65). Cancer-detected rates of the systematic and targeted biopsy cores were 5.9 and 38%, respectively ( p < 0.0001). In 25 patients who underwent radical prostatectomy, the geographic locations and pathological grades of clinically significant cancers and index lesions corresponded to the pathological results of the targeted biopsies. Conclusion : The cancer cores detected by targeted biopsies with manually controlled targeted biopsy with real-time mpMRI-TRUS fusion image had significantly higher grades and larger length compared with those detected by the systematic biopsies. The further study of the comparisons with pathological findings of whole-gland speci‐ mens will give a larger role to the present biopsy method.


Introduction
Multiparametric magnetic resonance imaging (mpMRI) improves the imaging of prostate cancer lesion [1,2], and several methods use MRI to guide the biopsy needle to target the cancer lesion. MRI-TRUS fusion image-guided biopsy achieved accurate prostate biopsy based on MRI, combining the superior sensitivity of MRI for targeting suspicious lesions with the practicality and familiarity of TRUS. MRI-TRUS fusion methods are used as visual registration [1,3,4] and fusion biopsy devices [5][6][7][8][9]. In visual registration, the TRUS operator identified the geographic location of the lesions in the prostate on the MRI, and then identify and biopsy viewing real-time TRUS [10]. In previous reports, the visual registration biopsy method improved accuracy over systematic biopsy [11][12][13][14]. However, the disadvantages of visual registration lie in human error when the targeted lesion was less than 10 mm in diameter [15]. Therefore, the visual registration is regarded as the prostate biopsy method for experts [10][11][12][13][14]. With the MRI-TRUS fusion devices, the stored MRI and real-time TRUS are superimposed using computer software to enable targeted biopsy of cancer-suspicious lesions [16]. MRI-TRUS fusion biopsy device "BioJet®" was approved by FDA after the evaluation of the accuracy with phantoms. We report the BioJet® experience of the manually controlled targeted biopsy using real-time fusion image from mpMRI and TRUS.

Population
From November 2013 to October 2015, after receiving the approval of institutional review board, the patients with PSA level greater than 4.0 ng/ml and less than 20 ng/ml were performed mpMRI prospectively. No patients had any previous history of prostate biopsy.

Image analysis
All mpMRI images, including T2WI, dynamic, DWI, and ADC map, were reviewed by two experienced radiologists with no prior clinical information. Suspicious areas, the so-called "regions of interest (ROI)", were provided a likelihood score that clinically significant cancer would be present for each ROI from 2 to 5 on the prostate imaging reporting and data system (PI-RAS) classification [17] based on Likert scale according to the European Society of Urogenital Radiology Prostate MR Guidelines 2012 [18]: 1, most probably benign; 2, probably benign; 3, intermediate; 4, probably malignant; and 5, highly suspicious of malignancy [17] The location of each area was determined based on dividing the prostate into 27 regions, as described by Dickson et al. [16]. MRIs were imported into the biopsy fusion system. Segmentation into a two-dimensional (2D) mpMRI was performed on the workstation to create a 3D model of the MRI, and then fused to the real-time TRUS.

Biopsy protocol
A cleaning enema and antibiotics were given before the biopsy. TRUS with power Doppler was performed using a Prosound α7 (Hitachi Aloka Medical, Tokyo, Japan) equipped with a UST-678 transrectum composite probe, in the lithotomy position under spinal anesthesia. On the workstation, the operator fused the real-time TRUS image and 3D MRI model that included the prostate contour and ROI. After the elastic image fusion, an ultrasound probe was fixed to the arm that senses the 3D movement of the probe and exports the information to the workstation (Figure 1a). Using this device, the 2D image created from the 3D MRI model moves together with the real-time TRUS image on the workstation. The operator performed the biopsy using MRI-TRUS fusion image navigation (Figure 1b). During the procedure, the realtime ultrasound image is continuously available. The biopsy started with targeted biopsies to the center of cancer-suspicious lesions, and then 12 systematic biopsies were performed with transperineal technique in all patients. The biopsy used a standard brachytherapy grid with 5-mm spacing, with x-axis coordinates A through G and y-axis coordinates from 1 through 7, using D as the middle line urethral plane. An 18-gauge automatic biopsy gun with a specimen size of 22 mm (BARD® MAGNUM®, BARD MEDICAL, Covington, USA) was used to take biopsy cores. Using the interactive needle guide system, the biopsy template coordinates were shown on the monitor when the operator marked the target point of the ROI on the workstation (Figure 2a, b). The operator inserted the needle at the template coordinates and could get the prostate specimens by viewing the sagittal image of the prostate (Figure 2c). Immediately after each biopsy, the spatial punctured needle orbits were recorded in 2D TRUS image of axial and sagittal plane, and in the 3D model of MRI.

Pathological analysis
All biopsies were examined by expert pathologists. A significant cancer was defined as follows: at least one core with a Gleason score of 3 + 4 or 6 with a maximum cancer core length larger than 4 mm [19]. The pathological biopsy results were compared between systematic and targeted biopsies. The biopsy-proven index lesion of each patient was defined primarily as the lesion with the highest Gleason score, and secondarily as the lesion with the greatest cancer- involved core in terms of length or percentage. Geographic location of prostate cancer in the prostate [16] was compared with pathologic step-sectioned prostatectomy specimens in the patients who were performed with radical prostatectomy.

Statistical analysis
All statistical analyses were performed using IBM SPSS® Statistics version 19 (IBM, Armonk, NY, USA). Among systematic and targeted biopsies, cancer-detected rate of biopsy, positive core length, positive core percentage, primary and secondary Gleason grade, and Gleason score were analyzed using the Mann-Whitney U-test. Changes in patient functional data were analyzed using paired t-tests. P-values of <0.05 were considered to indicate statistically significant differences.

Results
One-hundred sixty eight patients were suspected of prostate cancer with 2 to 5 of PI-RAD classification. The median age of the 168 patients was 67 years (range: 52-89). The median preoperative PSA value was 6.9 ng/ml (range: 3.54-20). The median preoperative prostate volume was 37 ml (range: 22-68). In the resected prostate specimen of 25 patients, the geographic locations and pathological grades of clinically significant cancers and index lesions corresponded to the results of the targeted biopsies.
The results of the prostate biopsies are shown in Table 1. The number of the cancer-detected cases was 99 (59%). The median biopsy time included the MRI-TRUS fusion time and needlepunctured time without the anesthesia, which was 8 minutes (range: 5-65). For the systematic and targeted biopsy cores, the total number of cores were 2016 and 372, respectively; the cancerdetected rates, the median positive core lengths, the median positive core percents, the median primary Gleason grades, the median secondary Gleason grades, and the median Gleason scores in systematic and targeted biopsy cores were significantly different. In targeted lesions of transition zone (TZ) (n = 146) and peripheral zone (PZ) (n = 226), the rate of cancer detection was 28% (n = 40) and 45% (n = 101), respectively. The rates of cancer detection and the corresponding scores on the PI-RAD in TZ and PZ are shown in Table 2.

Discussion
Our results showed that cancer detection rates using targeted biopsies were significantly better than using systematic biopsies (p < 0.0001). Positive core length (p < 0.0001), positive core percent (p < 0.0001), primary (p < 0.0001) and secondary (p = 0.0020) Gleason grade, and Gleason score (p = 0.0012) were also significantly different between targeted and systematic biopsies.
In addition, all biopsy-proven significant cancers were detected in ROIs, and the index lesions corresponded to the largest-sized ROIs. Based on these results, the targeted biopsy method was superior to systematic biopsy, and clinically significant cancers with a spatial relationship were detected accurately in the present study. Although the resected prostate specimens only comprised 25 cases, accuracy of the locations and pathological grades was reliable in our study.
In the present study, we used the T2WI for segmentation of the ROI, but the decision concerning the selection of ROI was made using multiparametric MRI factors, such as T2WI, DCE, DWI, and ADC maps because T2WI is sensitive but not specific for prostate cancer detection [1]. In mpMRI, the image values of its component techniques are different. T2WI provides the best depiction of the prostate's zonal anatomy and capsule in mpMRI and thus is used for prostate cancer detection and localization [18]. DCE is the most common imaging method for evaluating vascularity in the tumor [20]. DWI involves the quantification of free water motion [21] and allows ADC maps to be calculated, enabling qualitative and quantitative assessment of prostate cancer aggressiveness. Lower ADC corresponds to greater restriction in free water motion, likely on the basis of increased cellularity compared with normal prostate tissue, and cancer shows a lower ADC value than normal prostate tissue [21]. Furthermore, ADC values correlate with Gleason scores [22][23][24]. However, some normal prostatic tissues, especially in the TZ, such as benign prostatic hyperplasia, chronic inflammation, and atrophic tissue, have similar findings of prostate cancer [16]. Indeed, the detection of prostate cancer in TZ was found difficulty in a previous study [23]. In our results, the cancer detection rate of the patients with a PI-RAD classification of 4 or 5 in TZ (39%) was inferior to that in PZ (92%).
The present device allows manually controlled targeted biopsy using real-time MRI-TRUS fusion images by the sensor arm of 3D movement. In addition, the fusion function has elastic fusion functions. The axial and sagittal view of US and MRI was useful to fuse the images of MRI and TRUS easily during the procedure. In addition, the present biopsy was performed with transperineal technique. Using the transperineal technique with the device, the biopsies were performed accurately to the ROIs. However, our study has limitations. First, our study did not compare biopsy results with pathological findings from whole-gland specimens. Therefore, although locations and pathological grades of clinically significant cancers and index lesions corresponded to the targeted biopsy results, it is difficult to exclude the possibility that a clinically important cancer has been missed without pathological analysis of whole-gland specimens.
In conclusion, cancers detected by targeted biopsies using manual controlled targeted biopsy with real-time fusion image of mpMRI and TRUS had a significantly higher grade and larger length compared with systematic biopsies. In present study, the cancer detection rate in TZ was significantly lower than in PZ. However, further study would contribute to set the cutoff point of PI-RADS scores in TZ and PZ to detect the prostate cancer at high frequency. The further study of the comparisons with pathological findings of whole-gland specimens will give a larger role to the present biopsy method.