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Prostate cancer diagnosis: Efficacy of a simple electromagnetic MRI-TRUS fusion method to target biopsies
European Journal of Radiology 86 (2017) 127–134
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European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Prostate cancer diagnosis: Efficacy of a simple electromagnetic MRI-TRUS fusion method to target biopsies Amina Jelidi a , Mickael Ohana a , Aïssam Labani a , Guillaume Alemann a , Herve Lang b , Catherine Roy a,∗ a b
Department of Radiology B, University Hospital of Strasbourg, New Civil Hospital, 1, place de l’ hôpital BP 426, 67091, Strasbourg Cedex, France Department of Urology, University Hospital of Strasbourg, New Civil Hospital, 1, place de l’hôpital BP 426, 67091, Strasbourg Cedex, France
a r t i c l e
i n f o
Article history: Received 25 July 2016 Received in revised form 7 November 2016 Accepted 8 November 2016 Keywords: Neoplasms Prostate Ultrasonography Interventional Magnetic resonance imaging Diagnosis Biopsy
a b s t r a c t Objective: To assess that transrectal ultrasound guidance (TRUS) targeted biopsies (TB) aimed with an easy to use electronic real-time fusion registration device have a higher rate of prostate cancer (PC) detection than standard biopsies (SB). Material and methods: This prospective study included 130 patients referred for TRUS biopsies after suspicious MRI. They underwent 16-core SB and 2 to 3 cores in each MRI suspicious area, using a fusion software. We noted SB and TB positivity for PC and Gleason score (GS). We used the McNemar test to compare SB and TB, with a statistical significance p < 0.05. Results: Among 130 patients, 68.5% had PC. Additional time due to the fusion registration was 3.3 min. One hundred fifteen patients (88.4%) had pathological findings on the histological analysis (prostate cancer n = 89, others n = 26). TB diagnosed PC in 75 patients with negative SB. Positivity rate for PC was significantly higher for TB than SB (p = 0.03). Among highly suspicious MRI lesions, detection rate of histological abnormalities using SB and TB was 96% with 79.7% of PC. Most PC that TB diagnosed alone were clinically significant (86.3%). Conclusion: TRUS biopsies performed with a simple MRI and US electronic fusion is an unrestrainedly method to increase PC diagnosis. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Prostate cancer is the most common solid neoplasm in Europe and the second most common cancer in men worldwide [1]. Nowadays the initial diagnostic procedure is to perform a standard extended-sextant transrectal biopsies under ultrasound guidance, with a minimum of 10 to 12 cores [2]. However, multiparametric magnetic resonance imaging (mpMRI) has been proved to greatly improve the detection of prostate cancer [3–5]. In 2013, a systematic review of the literature by Moore et al. showed that the accuracy of standard transrectal US biopsy in the detection of all prostate cancer without pre-biopsy MRI amounts to 36% [6].
Abbreviations: mpMRI, multi-parametric magnetic resonance imaging; MRI, magnetic resonance imaging; PSA, prostate-specific antigen; SB, systematic biopsy; TB, targeted biopsy; TRUS, transrectal ultrasound; MRGB, MRI-guided biopsy. ∗ Corresponding author. E-mail address: [email protected] (C. Roy). http://dx.doi.org/10.1016/j.ejrad.2016.11.016 0720-048X/© 2016 Elsevier Ireland Ltd. All rights reserved.
Considering this statement, the use of a diagnostic MR examination during the biopsy procedure seems to be a promising tool to diagnose accurately the prostate cancer. In the recent literature, some papers have demonstrated that MRI-guided biopsy (MRGB) shows a high detection rate of clinically significant prostatic carcinoma in patients with previous negative TRUS guided biopsy [7–9]. Considering the technical complexity due to implementation of robots, complex software, specific material and the longer intervention time as well as the expensive cost, MRGB cannot be recommended for a routine application. Electronic devices able to superimpose in real time MR and US images were recently developed, allowing using the information from stored MRI images to directly target the suspicious areas with real-time 3D fusion technology. This targeted MR-ultrasound fusion biopsy is able to diagnose 30% more high-risk cancers vs standard biopsy [10], but the bulkiness of the device and the more cumbersome procedure when a robotic tracking via a mechanical arm is used [11], or the additional duration of procedure [12,13] can be obstacles to the spread of this method. The objective of our study is to assess the hypothesis that targeted biopsies performed with an easy to use electronic fusion
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device, which has not yet been evaluated, have a higher rate of cancer detection than standard biopsies. 2. Material and method 2.1. Patients: inclusion criteria Our institutional ethical committee reviewed and approved our investigation (PAI 6253-AO1581-48). However, no written patient consent was necessary. Patients were orally informed of our new biopsy procedure for which all details had been fully explained. We prospectively included, between July 2014 and November 2015, 130 consecutive patients referred to our department for an initial TRUS biopsies with suspicion of prostate cancer on the prebiopsy mpMRI which was required because of an elevated PSA level (>4 ng/mL). The inclusion criterion was the presence of a suspicious area of malignancy, using the PI-RADS V1 score. We did not exclude 11 patients with a previous series of negative SB. All the 130 patients underwent TRUS biopsies from 3 to 37 days after the MRI examination [Table 1]. 2.2. MRI protocol The patients underwent a mpMRI on the same machine, a 3T MRI (Achieva, Philips Medical Systems, Best, the Netherlands) with a protocol associating morphological imaging (T2-weighted) and functional imaging (diffusion-weighted imaging and dynamic contrast-enhanced). We used an endorectal coil (BPX30, Medrad) associated to an external 3 × 3 channel cardiac coil in 129 patients and the external coil in 1 case due to the patient refusing the endorectal procedure. The mpMRI were interpreted by a highly experienced genitourinary radiologist (C.R. or C.T., with over 20 and 15 years of experience) using PI-RADS 1 criteria [14]. Suspicious areas were graded as low risk of malignancy (PI-RADS score 1 or 2), intermediate (PI-RADS score 3) or high risk of malignancy (PI-RADS score 4 or 5). The indication for biopsy was given from the score 2 as all our patients had a PSA level up to 4 ng/mL. 2.3. Equipment and fusion procedure (Fig. 1) We used for all the patients the same last generation ultrasound system (Aplio 500, Toshiba Medical Systems, Japan) equipped with a special fusion software using electromagnetic tracking sensors which spatially correlate the imported 2D MR images with real time US. The MR examination was previously loaded inside the US machine via a CD or from the computing server. For tracking, this system relies on the creation of a low and uniform external magnetic field of 40 × 40 × 40 cm3 generated by an electromagnetic field generator via an electromagnet. This field will be the closed, orthogonal based, environment in which the system will be able to localize the probe position. This is accomplished by a small electromagnetic sensor (or tracker) simply attached to the traditional TRUS probe. So that, the probe communicates in real time his x, y, z coordinates within the magnetic field, it depicts any orientation of the probe. The electromagnet (or transmitter) which is localized on an articulated arm is placed against the back of the patient who is positioned in left lateral decubitus. Those real times sent data are used by the fusion software to correlate the MR Datasets (). Therefore the probe has to stay in the magnetic field to guarantee a quality tracking. The whole additional equipment is small size, especially the electromagnetic field generator (Fig. 1a-b). The only potential contraindication is a patient wearing an electromagnetic device such as a pace-maker. But as it is a very low field magnet, the
distance of 30 cm is recommended which is inferior to the anatomic distance between the heart and the prostate. This technology enables freehand use of the probe while performing the biopsies, resulting in comfort for the radiologist, and a shortened learning process, especially when endocavitary sonography is already mastered. The MRI/TRUS images fusion is a two-step process, starting with first, a global registration, which is followed by a precise one. In the first global registration (Fig. 1c-d), the objective is to correlate the prostate angulation from a sagittal view between MR and US. Three anatomical landmarks (such as vesical neck, apex and posterior prostatic contour) are positioned on a sagittal MR image on screen and by displacing up or down and/or rotating them together, they are localized as the same position on the US sagittal image. Then the registration is performed by the fusion device. This angle synchronization is almost immediate, and planes are synchronized from this step. This first step takes no more than one minute. The goal of the second step is to complete the first one by a very precise registration. For this on the fusionned axial plane an iterative approach is used. Any anatomical structures or a cyst or a nodule of hyperplasia well seen on the both MR and US data sets is selected and those two landmarks are fused together almost immediately. We used 3 to 6 landmarks depending on the case. It takes between two and four minutes depending on the number of additional landmarks used. This second step can be performed at any time, even if the biopsy procedure has begun. It counterbalances the fact that this rigid registration does not compensate the realtime movements (motion of the patient; deformation from the US probe’s pressure) (Figs. 2 and 3). 2.4. Biopsy protocol 2.4.1. Technique (Fig. 4) The patients all had a negative pre-biopsy urine bacterial culture, an evaluation of homeostasis and an antibiotic prophylaxis (2 doses of ciprofloxacin 500 mg orally 3 h before the procedure, one dose immediately after the biopsy followed by a 3-day course of 500 mg given twice daily). Two senior radiologists (C.R. or M.O., over 20 years and 7 years of experience) performed the biopsies. In our protocol, a first set of SB was performed by a one operator and then the second operator realized the TB. The operator performing the systematic biopsy was blinded to the MRI results (). Under transrectal US control, with a 18G automatic needle (Bard, Monopty), after a periprostatic block, 16 systematic biopsies (2 cores from the right and 2 cores from left side of the base, the peripheral medial, the parasagittal median and the apical prostate) are realized. Then, 2 to 3 additional targeted biopsies are aimed in suspicious area on MRI, which are detected on screen in real-time by the operator. We timed the procedure. The cores were placed in boxes by anatomical location and then in formalin containers and sent to our pathology department. 3. Data analysis We performed two analysis: the positivity of a biopsy (systematic biopsies and targeted biopsies) in one analysis was defined by the presence of any abnormality at the core sample histology examination, such as chronic prostatitis, prostate cancer, prostatic intraepithelial neoplasia or atypical adenomatous hyperplasia and in the other analysis the positivity was defined by prostatic cancer presence only. Cancer is classified significant as soon as the Gleason score (GS) on biopsy is >7 or =6 with a cancer length greater than 5 mm, as recommended by the START study [15].
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Fig. 1. Description of the equipment used for MRI-TRUS fusion and description of our fusion procedure. 1a: The small size generator (control unit) is located on the back of US machine (). It remains in place all the time without perturbation of others US examinations. The transmitter is a small box (↑) with a mechanical arm () to be placed against the back of the patient. 1b: An electromagnetic small tracker is attached to the usual endorectal probe (↑). 1c: Fusion procedure: first step (global registration) with the three landmarks.1d: Fusion procedure: second step (precise registration) with one landmark
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Table 1 General characteristics of the patients (n = 130). Characteristics
Mean
Range
Age (years) Prostate volume (mL) PSA (ng/mL) Time between MRI and Biopsies (days)
62.9 45.9 9.5 20
50–73 15–125 4–28 3–37
Digital rectal examination
Normal
Doubtful
Suspicious
85
23
22
Fig. 2. A 65-year old man at the end of the fusion procedure before biopsy. The tiny cyst in the right part of hyperplasia is well identified on this oblique orientation at the same level on MR and TRUS (↑).
Fig. 3. Prostatic carcinoma in a 68- year-old man with a PSA level of 12 ng/mL. After the fusion procedure, just before the biopsy, a huge carcinoma of the right part of the apex (↑) is well localized on TRUS. At the pathological analysis of the two localized samples, it was found a carcinoma Gleason score 4 + 3 with a length of 11 mm for carcinoma.
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Fig. 4. Prostatic carcinoma in a 72- year-old man with a PSA level of 7.5 ng/mL. After the fusion procedure, just before the biopsy, a landmark (o) is localized on the MR and the device matches it on the ultrasound to indicate the direction for the needle. Note that the carcinoma is easily seen on MR (↑), but difficult to localize on TRUS. At the pathological analysis, It was found a carcinoma Gleason score 3 + 3 with a length of 6 mm of carcinoma in the localized samples.
Then, we separated the patients in three subgroups depending on whether the suspicious zone on MRI is at low risk, intermediate or high risk of malignancy.
targeted biopsies with electronic registration was 96%, in which 79.7% were cases of cancer. When the MRI was at low or intermediate risk, detection rate of abnormalities was 74.4%, in which 38.2% were cases of cancer.
3.1. Statistical analysis Results are presented as means and standard deviations or median and interquartile range for continuous variables and percentages or proportions for categorical variables. Comparison of the two methods, targeted biopsies and systematic biopsies, was performed using McNemar test for paired nominal data, with p < 0.05 to indicate statistical significance. The statistical analysis was done using the XLSTAT statistical software (Addinsoft, version 2015.4.1 for Windows, NY, USA) package. 4. Results 4.1. Patient characteristics During the time of our study, 130 patients with elevated PSA had a mpMRI which revealed at least one suspicious area of malignancy. General characteristics of the patients are listed in Table 1. Digital rectal examination was normal in 85 cases, doubtful in 23 cases and 22 cases were suspicious for carcinoma. The additional time due to registration comparing to biopsy protocol without electronic fusion was in our experience 3.3 min (range: 3–5), after 3 months of training. In these 130 patients, 89 (68.5%) were diagnosed with cancer. One hundred fifteen 115 patients (88.4%) had pathological findings on the histological analysis (prostate cancer n = 89, chronic prostatitis n = 14, high grade prostatic intraepithelial neoplasia n = 11, atypical adenomatous hyperplasia n = 1), (Tables 2, 3). 4.2. MRI likelihood of malignancy On the MRI examination, 83 patients (64%) had a high suspicion score of malignancy and 47 patients (36%) were at low or intermediate risk (Table 2). When the MRI was highly suspicious, detection rate of abnormalities using systematic plus additional
4.3. Comparison of systematic and targeted biopsies TB detected in these 130 patients, 100 abnormalities (77%) of which 87 were cancers (66.9%). SB detected in these 130 patients, 40 abnormalities (30.7%) of which 16 were cancers (12.3%). There is a difference of 60 cases in detection of abnormalities and 71 cases in detection of cancer, with TB superiority (p = 0.03). The fusion targeted biopsies obtained a sensitivity and specificity of 84% and 69%, respectively for the diagnosis of carcinoma. These results are shown in Table 3. TB detected 100 abnormalities of which 75 had negative SB. SB detected 40 abnormalities of which 15 had negative TB. In these 130 patients, it was found 20 bilateral histological abnormalities, including 4 cases of bilateral carcinoma with the same Gleason score, 10 cases of high grade prostatic intraepithelial neoplasia and 6 cases of prostatitis. Among the positive results for carcinoma, 37 cases were localized in the anterior transitional zone. All of them were detected only on the targeted biopsies, so that their detection rate with this procedure was 100%.
4.4. Clinically significant disease Among our 89 patients with carcinoma on biopsy, 73 (82%) had a significant prostate cancer. In the 73 cases of cancer that TB detected and SB didn’t, 63 cases were significant, so that 86.3% of prostate cancer that TB diagnosed alone were clinically significant cancer. In the 2 cases of cancer of which the SB detected and the TB didn’t, only one (50%) was significant disease. Results are submitted in Table 3.
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Table 2 Results according to Mp-MR Imaging likelihood of malignancy. Histological findings (systematic + targeted biopsies) N = 130 patients
Normal n = 15 (11.5%)
Prostate cancer n = 89 (68.5%)
Others n = 26 (20%)
High suspicious mp-MRI n = 83 Intermediate suspicious mp-MRI n = 27 Low suspicious mp-MRI n = 20
3(20%) 4(26.7%) 8 (53.3%)
71 (79.7%) 17 (19.2%) 1 (1.1%)
9 (34.6%) 6 (23%) 11 (42.4%)
Table 3 Comparison of systematic and targeted biopsies. Positivity defined as histological abnormality and as cancer. Results 130 patients
Histological abnormality n = 115
Cancer n = 89
Cancer significant n = 73
Cancer non-significant n = 16
Negative SB with Positive TB Positive SB with Positive TB Positive SB with Negative TB Negative SB with Negative TB
75 (65.2%) 25 (21.8%) 15 (13%) 0
73 (unilateral) 14 (4 bilateral) 2 (unilateral) 0
63 9 1 0
10 5 1 0
SB: systematic biopsies. TB: targeted biopsies.
5. Discussion In this study, the targeted biopsies performed with this device of MRI-TRUS fusion detected clearly a high rate of significant prostatic carcinoma, with a short time for the complete procedure. It is likely that a certain amount of cognitive registration occurs during this procedure, since the MRI data is thoroughly analyzed during the real-time fusion. Besides, the electronic registration suppresses the human error in aiming for TB that does exist in cognitive fusion. Only 15 patients had normal histological findings. Seven of them had an intermediate or highly suspicious MR imaging. In these seven patients, the suspicious areas were infracentimetric and the global volume of the prostate was high (90 and 155 g). In our study of 130 patients with clinical and MRI suspicion of prostatic cancer, the overall cancer confirmation rate was 68.5%. This is in line with previous studies evaluating the results of MRItargeted biopsy (47%–64%) and higher than standard biopsy as reported by several studies [16]. 115 patients (88.5%) had pathological findings on histological analysis (prostate cancer, chronic prostatitis, high grade prostatic intraepithelial neoplasia and atypical adenomatous hyperplasia). Our data indicates that some abnormalities on the MR examination can simulate a carcinomatous area. This notion seems a novel approach to be taken into account. In a study of Franiel et al. in 2008, chronic prostatitis showed higher perfusion and shorter delay than normal prostate tissue and there were no statistically significant differences in MRI perfusion between low-grade cancer and chronic prostatitis [17]. Shukla-Dave et al. demonstrated in 2004 that the findings of chronic prostatitis at histopathologic examination were correlated with metabolic abnormality suggestive of prostate cancer at MR spectroscopic imaging: metabolic abnormalities from the regions of chronic prostatitis appeared similar to those for low, intermediate and high-grade cancer [18]. In our study, no cancer was found in 95% of lesions classified as low suspicious lesions on MRI, while a clinically significant cancer was diagnosed in 65 of the 71 high suspicious lesions. A good correlation between the level of radiologic suspicion on multiparametric MRI and the D’Amico risk stratification was already demonstrated by Siddiqui et al. in 2013 [19]. Another study published by Yerram et al. [20] in 2012, showed that low suspicion lesions on MRI were associated with 88% of either negative biopsies or clinically insignificant disease. Our results are in line with these findings. We included only patients with visible lesion on MRI. In 2014, a study reporting cancer detection rates in men undergoing systematic biopsies following a negative prebiopsy multiparametric MRI concluded that negative MRI prebiopsy confers an overall negative predictive value of 82% on biopsy for all cancer and of 98% for Gleason scores greater than 7 [21]. Another study from 2009 showed
that a non-suspicious MRI has a 94% specificity for identification of significant cancer [22]. We may thus consider that the population with negative MRI results is unlikely to provide many patients with non-diagnosed intermediate to high-risk cancer, and is therefore unlikely to significantly change our conclusions. In our study, targeted biopsies had a higher detection rate of clinically significant disease. Fifty nine patients with clinically significant disease on targeted biopsies cores had no cancer on systematic biopsies cores and one patient with no cancer on targeted biopsies protocol had clinically insignificant disease on standard cores. On the other hand, only 10 patients with no cancer on systematic biopsies protocol had a clinically non-significant disease diagnosed by targeted biopsies. Reducing the detection of low-risk prostate cancer while improving the overall detection of intermediate or high-risk disease provides concrete clinical benefits by limiting over diagnosis, unnecessary treatments and their related costs and morbidity. These findings are in line with recent studies [23–25] which have found that MRI-US fusion targeted biopsies detect more clinically significant cancers (median: 33.3% vs 23.6%) using fewer cores (median: 9.2 vs 37.1) and 17% fewer low-risk cancerscompared with standard biopsy techniques, respectively [10,26]. This is also confirmed by a recent meta-analysis in which MRITBx had a higher rate of detection of significant prostate cancer compared to TRUS-Bx with a sensitivity as high as 91% and a lower rate of detection of insignificant prostate cancer [16]. The targeted biopsies as the only strategy, without extended systematic biopsies, could offer an attractive approach for detection of prostate cancer, and especially clinical significant prostatic cancer. Further studies are necessary to validate this alternative strategy. Our study provides excellent results for the detection of significant cancers and its major advantage from other existing fusion device is the short time for the fusion procedure to get an excellent result. There were no technical or software failures. It guarantees the same comfort for the patient and the operator as a standard biopsy protocol. This allows this technique during an intense daily workflow. It is available everywhere and does not need neither an additional heavy material nor an intense training to be fluent with if the physician is confident with endorectal ultrasonography. In addition, no side effect has been recorded during the procedure. A voluminous hyperplasia or presence of many calcifications can be source of registration difficulties but during this study, and in line with our routine practice, the system provided reliable and usable imaging registration. The overall advantage over the in bore MRI guided biopsy is the short time of the procedure and the absence of technical complexity and no incremental cost as the fusion software is a part of the recent ultrasound machine.
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The present study has a number of potential limitations, due to its design. The study population consisted of patients referred to a single institution, which could have introduced a selection bias. MRI accuracy for cancer identification may be different in other centers with different experience, and operators with varying experience may achieve different results, but as its practice is now routine in many centers [27–29] and by using the PIRADS score, these findings could certainly be considered reproducible. Moreover, it has been published that it there is no statistically significant difference in biopsy accuracy according the operator experience [30]. We applied PI-RADS version 1, instead of the actual version 2, to stay homogeneous in our evaluation, because the first patients were included using the version1. We did not exclude patients with a previous series of negative systematic biopsies. It can provide a bias of selecting more anterior cancers. Indeed, anterior neoplasms are under-diagnosed by systematic biopsies, as they require significantly more biopsy sessions to diagnose prostate cancer than posterior neoplasms. [31] The mean percentage of anteriorly located cancers in an unselected population is 20% [23]. In our study it was moderately higher to 28.4%. Patients with no lesions visible on MP-MRI were excluded from the study. There is no surgical correlation. Thus, the true accuracy rates, including the false negatives cannot be determined. But the objective of our study was to evaluate targeted biopsies into suspicious MRI areas performed with a simple electronic fusion device, comparing to standard US guided biopsies. Besides, conservative treatment, such as curietherapy, is often proposed. As described, we used a 16 cores protocol, which is the standard technique in our center. Several studies have shown that the classical sextant protocol leaves 15% of cancers undetected compared with results obtained from a more extensive biopsy procedure [32], and that saturation TRUS biopsy (20 cores or greater) does not improve cancer detection as an initial biopsy technique [33]. In summary, our data indicate that using this non constraining electronic registration technique increases the yield of the biopsies comparing to standard biopsies. Our results are equivalent to those obtained with a more sophisticated and time consuming device.
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Contents lists available at ScienceDirect
European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Prostate cancer diagnosis: Efficacy of a simple electromagnetic MRI-TRUS fusion method to target biopsies Amina Jelidi a , Mickael Ohana a , Aïssam Labani a , Guillaume Alemann a , Herve Lang b , Catherine Roy a,∗ a b
Department of Radiology B, University Hospital of Strasbourg, New Civil Hospital, 1, place de l’ hôpital BP 426, 67091, Strasbourg Cedex, France Department of Urology, University Hospital of Strasbourg, New Civil Hospital, 1, place de l’hôpital BP 426, 67091, Strasbourg Cedex, France
a r t i c l e
i n f o
Article history: Received 25 July 2016 Received in revised form 7 November 2016 Accepted 8 November 2016 Keywords: Neoplasms Prostate Ultrasonography Interventional Magnetic resonance imaging Diagnosis Biopsy
a b s t r a c t Objective: To assess that transrectal ultrasound guidance (TRUS) targeted biopsies (TB) aimed with an easy to use electronic real-time fusion registration device have a higher rate of prostate cancer (PC) detection than standard biopsies (SB). Material and methods: This prospective study included 130 patients referred for TRUS biopsies after suspicious MRI. They underwent 16-core SB and 2 to 3 cores in each MRI suspicious area, using a fusion software. We noted SB and TB positivity for PC and Gleason score (GS). We used the McNemar test to compare SB and TB, with a statistical significance p < 0.05. Results: Among 130 patients, 68.5% had PC. Additional time due to the fusion registration was 3.3 min. One hundred fifteen patients (88.4%) had pathological findings on the histological analysis (prostate cancer n = 89, others n = 26). TB diagnosed PC in 75 patients with negative SB. Positivity rate for PC was significantly higher for TB than SB (p = 0.03). Among highly suspicious MRI lesions, detection rate of histological abnormalities using SB and TB was 96% with 79.7% of PC. Most PC that TB diagnosed alone were clinically significant (86.3%). Conclusion: TRUS biopsies performed with a simple MRI and US electronic fusion is an unrestrainedly method to increase PC diagnosis. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Prostate cancer is the most common solid neoplasm in Europe and the second most common cancer in men worldwide [1]. Nowadays the initial diagnostic procedure is to perform a standard extended-sextant transrectal biopsies under ultrasound guidance, with a minimum of 10 to 12 cores [2]. However, multiparametric magnetic resonance imaging (mpMRI) has been proved to greatly improve the detection of prostate cancer [3–5]. In 2013, a systematic review of the literature by Moore et al. showed that the accuracy of standard transrectal US biopsy in the detection of all prostate cancer without pre-biopsy MRI amounts to 36% [6].
Abbreviations: mpMRI, multi-parametric magnetic resonance imaging; MRI, magnetic resonance imaging; PSA, prostate-specific antigen; SB, systematic biopsy; TB, targeted biopsy; TRUS, transrectal ultrasound; MRGB, MRI-guided biopsy. ∗ Corresponding author. E-mail address: [email protected] (C. Roy). http://dx.doi.org/10.1016/j.ejrad.2016.11.016 0720-048X/© 2016 Elsevier Ireland Ltd. All rights reserved.
Considering this statement, the use of a diagnostic MR examination during the biopsy procedure seems to be a promising tool to diagnose accurately the prostate cancer. In the recent literature, some papers have demonstrated that MRI-guided biopsy (MRGB) shows a high detection rate of clinically significant prostatic carcinoma in patients with previous negative TRUS guided biopsy [7–9]. Considering the technical complexity due to implementation of robots, complex software, specific material and the longer intervention time as well as the expensive cost, MRGB cannot be recommended for a routine application. Electronic devices able to superimpose in real time MR and US images were recently developed, allowing using the information from stored MRI images to directly target the suspicious areas with real-time 3D fusion technology. This targeted MR-ultrasound fusion biopsy is able to diagnose 30% more high-risk cancers vs standard biopsy [10], but the bulkiness of the device and the more cumbersome procedure when a robotic tracking via a mechanical arm is used [11], or the additional duration of procedure [12,13] can be obstacles to the spread of this method. The objective of our study is to assess the hypothesis that targeted biopsies performed with an easy to use electronic fusion
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device, which has not yet been evaluated, have a higher rate of cancer detection than standard biopsies. 2. Material and method 2.1. Patients: inclusion criteria Our institutional ethical committee reviewed and approved our investigation (PAI 6253-AO1581-48). However, no written patient consent was necessary. Patients were orally informed of our new biopsy procedure for which all details had been fully explained. We prospectively included, between July 2014 and November 2015, 130 consecutive patients referred to our department for an initial TRUS biopsies with suspicion of prostate cancer on the prebiopsy mpMRI which was required because of an elevated PSA level (>4 ng/mL). The inclusion criterion was the presence of a suspicious area of malignancy, using the PI-RADS V1 score. We did not exclude 11 patients with a previous series of negative SB. All the 130 patients underwent TRUS biopsies from 3 to 37 days after the MRI examination [Table 1]. 2.2. MRI protocol The patients underwent a mpMRI on the same machine, a 3T MRI (Achieva, Philips Medical Systems, Best, the Netherlands) with a protocol associating morphological imaging (T2-weighted) and functional imaging (diffusion-weighted imaging and dynamic contrast-enhanced). We used an endorectal coil (BPX30, Medrad) associated to an external 3 × 3 channel cardiac coil in 129 patients and the external coil in 1 case due to the patient refusing the endorectal procedure. The mpMRI were interpreted by a highly experienced genitourinary radiologist (C.R. or C.T., with over 20 and 15 years of experience) using PI-RADS 1 criteria [14]. Suspicious areas were graded as low risk of malignancy (PI-RADS score 1 or 2), intermediate (PI-RADS score 3) or high risk of malignancy (PI-RADS score 4 or 5). The indication for biopsy was given from the score 2 as all our patients had a PSA level up to 4 ng/mL. 2.3. Equipment and fusion procedure (Fig. 1) We used for all the patients the same last generation ultrasound system (Aplio 500, Toshiba Medical Systems, Japan) equipped with a special fusion software using electromagnetic tracking sensors which spatially correlate the imported 2D MR images with real time US. The MR examination was previously loaded inside the US machine via a CD or from the computing server. For tracking, this system relies on the creation of a low and uniform external magnetic field of 40 × 40 × 40 cm3 generated by an electromagnetic field generator via an electromagnet. This field will be the closed, orthogonal based, environment in which the system will be able to localize the probe position. This is accomplished by a small electromagnetic sensor (or tracker) simply attached to the traditional TRUS probe. So that, the probe communicates in real time his x, y, z coordinates within the magnetic field, it depicts any orientation of the probe. The electromagnet (or transmitter) which is localized on an articulated arm is placed against the back of the patient who is positioned in left lateral decubitus. Those real times sent data are used by the fusion software to correlate the MR Datasets (). Therefore the probe has to stay in the magnetic field to guarantee a quality tracking. The whole additional equipment is small size, especially the electromagnetic field generator (Fig. 1a-b). The only potential contraindication is a patient wearing an electromagnetic device such as a pace-maker. But as it is a very low field magnet, the
distance of 30 cm is recommended which is inferior to the anatomic distance between the heart and the prostate. This technology enables freehand use of the probe while performing the biopsies, resulting in comfort for the radiologist, and a shortened learning process, especially when endocavitary sonography is already mastered. The MRI/TRUS images fusion is a two-step process, starting with first, a global registration, which is followed by a precise one. In the first global registration (Fig. 1c-d), the objective is to correlate the prostate angulation from a sagittal view between MR and US. Three anatomical landmarks (such as vesical neck, apex and posterior prostatic contour) are positioned on a sagittal MR image on screen and by displacing up or down and/or rotating them together, they are localized as the same position on the US sagittal image. Then the registration is performed by the fusion device. This angle synchronization is almost immediate, and planes are synchronized from this step. This first step takes no more than one minute. The goal of the second step is to complete the first one by a very precise registration. For this on the fusionned axial plane an iterative approach is used. Any anatomical structures or a cyst or a nodule of hyperplasia well seen on the both MR and US data sets is selected and those two landmarks are fused together almost immediately. We used 3 to 6 landmarks depending on the case. It takes between two and four minutes depending on the number of additional landmarks used. This second step can be performed at any time, even if the biopsy procedure has begun. It counterbalances the fact that this rigid registration does not compensate the realtime movements (motion of the patient; deformation from the US probe’s pressure) (Figs. 2 and 3). 2.4. Biopsy protocol 2.4.1. Technique (Fig. 4) The patients all had a negative pre-biopsy urine bacterial culture, an evaluation of homeostasis and an antibiotic prophylaxis (2 doses of ciprofloxacin 500 mg orally 3 h before the procedure, one dose immediately after the biopsy followed by a 3-day course of 500 mg given twice daily). Two senior radiologists (C.R. or M.O., over 20 years and 7 years of experience) performed the biopsies. In our protocol, a first set of SB was performed by a one operator and then the second operator realized the TB. The operator performing the systematic biopsy was blinded to the MRI results (). Under transrectal US control, with a 18G automatic needle (Bard, Monopty), after a periprostatic block, 16 systematic biopsies (2 cores from the right and 2 cores from left side of the base, the peripheral medial, the parasagittal median and the apical prostate) are realized. Then, 2 to 3 additional targeted biopsies are aimed in suspicious area on MRI, which are detected on screen in real-time by the operator. We timed the procedure. The cores were placed in boxes by anatomical location and then in formalin containers and sent to our pathology department. 3. Data analysis We performed two analysis: the positivity of a biopsy (systematic biopsies and targeted biopsies) in one analysis was defined by the presence of any abnormality at the core sample histology examination, such as chronic prostatitis, prostate cancer, prostatic intraepithelial neoplasia or atypical adenomatous hyperplasia and in the other analysis the positivity was defined by prostatic cancer presence only. Cancer is classified significant as soon as the Gleason score (GS) on biopsy is >7 or =6 with a cancer length greater than 5 mm, as recommended by the START study [15].
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Fig. 1. Description of the equipment used for MRI-TRUS fusion and description of our fusion procedure. 1a: The small size generator (control unit) is located on the back of US machine (). It remains in place all the time without perturbation of others US examinations. The transmitter is a small box (↑) with a mechanical arm () to be placed against the back of the patient. 1b: An electromagnetic small tracker is attached to the usual endorectal probe (↑). 1c: Fusion procedure: first step (global registration) with the three landmarks.1d: Fusion procedure: second step (precise registration) with one landmark
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Table 1 General characteristics of the patients (n = 130). Characteristics
Mean
Range
Age (years) Prostate volume (mL) PSA (ng/mL) Time between MRI and Biopsies (days)
62.9 45.9 9.5 20
50–73 15–125 4–28 3–37
Digital rectal examination
Normal
Doubtful
Suspicious
85
23
22
Fig. 2. A 65-year old man at the end of the fusion procedure before biopsy. The tiny cyst in the right part of hyperplasia is well identified on this oblique orientation at the same level on MR and TRUS (↑).
Fig. 3. Prostatic carcinoma in a 68- year-old man with a PSA level of 12 ng/mL. After the fusion procedure, just before the biopsy, a huge carcinoma of the right part of the apex (↑) is well localized on TRUS. At the pathological analysis of the two localized samples, it was found a carcinoma Gleason score 4 + 3 with a length of 11 mm for carcinoma.
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Fig. 4. Prostatic carcinoma in a 72- year-old man with a PSA level of 7.5 ng/mL. After the fusion procedure, just before the biopsy, a landmark (o) is localized on the MR and the device matches it on the ultrasound to indicate the direction for the needle. Note that the carcinoma is easily seen on MR (↑), but difficult to localize on TRUS. At the pathological analysis, It was found a carcinoma Gleason score 3 + 3 with a length of 6 mm of carcinoma in the localized samples.
Then, we separated the patients in three subgroups depending on whether the suspicious zone on MRI is at low risk, intermediate or high risk of malignancy.
targeted biopsies with electronic registration was 96%, in which 79.7% were cases of cancer. When the MRI was at low or intermediate risk, detection rate of abnormalities was 74.4%, in which 38.2% were cases of cancer.
3.1. Statistical analysis Results are presented as means and standard deviations or median and interquartile range for continuous variables and percentages or proportions for categorical variables. Comparison of the two methods, targeted biopsies and systematic biopsies, was performed using McNemar test for paired nominal data, with p < 0.05 to indicate statistical significance. The statistical analysis was done using the XLSTAT statistical software (Addinsoft, version 2015.4.1 for Windows, NY, USA) package. 4. Results 4.1. Patient characteristics During the time of our study, 130 patients with elevated PSA had a mpMRI which revealed at least one suspicious area of malignancy. General characteristics of the patients are listed in Table 1. Digital rectal examination was normal in 85 cases, doubtful in 23 cases and 22 cases were suspicious for carcinoma. The additional time due to registration comparing to biopsy protocol without electronic fusion was in our experience 3.3 min (range: 3–5), after 3 months of training. In these 130 patients, 89 (68.5%) were diagnosed with cancer. One hundred fifteen 115 patients (88.4%) had pathological findings on the histological analysis (prostate cancer n = 89, chronic prostatitis n = 14, high grade prostatic intraepithelial neoplasia n = 11, atypical adenomatous hyperplasia n = 1), (Tables 2, 3). 4.2. MRI likelihood of malignancy On the MRI examination, 83 patients (64%) had a high suspicion score of malignancy and 47 patients (36%) were at low or intermediate risk (Table 2). When the MRI was highly suspicious, detection rate of abnormalities using systematic plus additional
4.3. Comparison of systematic and targeted biopsies TB detected in these 130 patients, 100 abnormalities (77%) of which 87 were cancers (66.9%). SB detected in these 130 patients, 40 abnormalities (30.7%) of which 16 were cancers (12.3%). There is a difference of 60 cases in detection of abnormalities and 71 cases in detection of cancer, with TB superiority (p = 0.03). The fusion targeted biopsies obtained a sensitivity and specificity of 84% and 69%, respectively for the diagnosis of carcinoma. These results are shown in Table 3. TB detected 100 abnormalities of which 75 had negative SB. SB detected 40 abnormalities of which 15 had negative TB. In these 130 patients, it was found 20 bilateral histological abnormalities, including 4 cases of bilateral carcinoma with the same Gleason score, 10 cases of high grade prostatic intraepithelial neoplasia and 6 cases of prostatitis. Among the positive results for carcinoma, 37 cases were localized in the anterior transitional zone. All of them were detected only on the targeted biopsies, so that their detection rate with this procedure was 100%.
4.4. Clinically significant disease Among our 89 patients with carcinoma on biopsy, 73 (82%) had a significant prostate cancer. In the 73 cases of cancer that TB detected and SB didn’t, 63 cases were significant, so that 86.3% of prostate cancer that TB diagnosed alone were clinically significant cancer. In the 2 cases of cancer of which the SB detected and the TB didn’t, only one (50%) was significant disease. Results are submitted in Table 3.
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Table 2 Results according to Mp-MR Imaging likelihood of malignancy. Histological findings (systematic + targeted biopsies) N = 130 patients
Normal n = 15 (11.5%)
Prostate cancer n = 89 (68.5%)
Others n = 26 (20%)
High suspicious mp-MRI n = 83 Intermediate suspicious mp-MRI n = 27 Low suspicious mp-MRI n = 20
3(20%) 4(26.7%) 8 (53.3%)
71 (79.7%) 17 (19.2%) 1 (1.1%)
9 (34.6%) 6 (23%) 11 (42.4%)
Table 3 Comparison of systematic and targeted biopsies. Positivity defined as histological abnormality and as cancer. Results 130 patients
Histological abnormality n = 115
Cancer n = 89
Cancer significant n = 73
Cancer non-significant n = 16
Negative SB with Positive TB Positive SB with Positive TB Positive SB with Negative TB Negative SB with Negative TB
75 (65.2%) 25 (21.8%) 15 (13%) 0
73 (unilateral) 14 (4 bilateral) 2 (unilateral) 0
63 9 1 0
10 5 1 0
SB: systematic biopsies. TB: targeted biopsies.
5. Discussion In this study, the targeted biopsies performed with this device of MRI-TRUS fusion detected clearly a high rate of significant prostatic carcinoma, with a short time for the complete procedure. It is likely that a certain amount of cognitive registration occurs during this procedure, since the MRI data is thoroughly analyzed during the real-time fusion. Besides, the electronic registration suppresses the human error in aiming for TB that does exist in cognitive fusion. Only 15 patients had normal histological findings. Seven of them had an intermediate or highly suspicious MR imaging. In these seven patients, the suspicious areas were infracentimetric and the global volume of the prostate was high (90 and 155 g). In our study of 130 patients with clinical and MRI suspicion of prostatic cancer, the overall cancer confirmation rate was 68.5%. This is in line with previous studies evaluating the results of MRItargeted biopsy (47%–64%) and higher than standard biopsy as reported by several studies [16]. 115 patients (88.5%) had pathological findings on histological analysis (prostate cancer, chronic prostatitis, high grade prostatic intraepithelial neoplasia and atypical adenomatous hyperplasia). Our data indicates that some abnormalities on the MR examination can simulate a carcinomatous area. This notion seems a novel approach to be taken into account. In a study of Franiel et al. in 2008, chronic prostatitis showed higher perfusion and shorter delay than normal prostate tissue and there were no statistically significant differences in MRI perfusion between low-grade cancer and chronic prostatitis [17]. Shukla-Dave et al. demonstrated in 2004 that the findings of chronic prostatitis at histopathologic examination were correlated with metabolic abnormality suggestive of prostate cancer at MR spectroscopic imaging: metabolic abnormalities from the regions of chronic prostatitis appeared similar to those for low, intermediate and high-grade cancer [18]. In our study, no cancer was found in 95% of lesions classified as low suspicious lesions on MRI, while a clinically significant cancer was diagnosed in 65 of the 71 high suspicious lesions. A good correlation between the level of radiologic suspicion on multiparametric MRI and the D’Amico risk stratification was already demonstrated by Siddiqui et al. in 2013 [19]. Another study published by Yerram et al. [20] in 2012, showed that low suspicion lesions on MRI were associated with 88% of either negative biopsies or clinically insignificant disease. Our results are in line with these findings. We included only patients with visible lesion on MRI. In 2014, a study reporting cancer detection rates in men undergoing systematic biopsies following a negative prebiopsy multiparametric MRI concluded that negative MRI prebiopsy confers an overall negative predictive value of 82% on biopsy for all cancer and of 98% for Gleason scores greater than 7 [21]. Another study from 2009 showed
that a non-suspicious MRI has a 94% specificity for identification of significant cancer [22]. We may thus consider that the population with negative MRI results is unlikely to provide many patients with non-diagnosed intermediate to high-risk cancer, and is therefore unlikely to significantly change our conclusions. In our study, targeted biopsies had a higher detection rate of clinically significant disease. Fifty nine patients with clinically significant disease on targeted biopsies cores had no cancer on systematic biopsies cores and one patient with no cancer on targeted biopsies protocol had clinically insignificant disease on standard cores. On the other hand, only 10 patients with no cancer on systematic biopsies protocol had a clinically non-significant disease diagnosed by targeted biopsies. Reducing the detection of low-risk prostate cancer while improving the overall detection of intermediate or high-risk disease provides concrete clinical benefits by limiting over diagnosis, unnecessary treatments and their related costs and morbidity. These findings are in line with recent studies [23–25] which have found that MRI-US fusion targeted biopsies detect more clinically significant cancers (median: 33.3% vs 23.6%) using fewer cores (median: 9.2 vs 37.1) and 17% fewer low-risk cancerscompared with standard biopsy techniques, respectively [10,26]. This is also confirmed by a recent meta-analysis in which MRITBx had a higher rate of detection of significant prostate cancer compared to TRUS-Bx with a sensitivity as high as 91% and a lower rate of detection of insignificant prostate cancer [16]. The targeted biopsies as the only strategy, without extended systematic biopsies, could offer an attractive approach for detection of prostate cancer, and especially clinical significant prostatic cancer. Further studies are necessary to validate this alternative strategy. Our study provides excellent results for the detection of significant cancers and its major advantage from other existing fusion device is the short time for the fusion procedure to get an excellent result. There were no technical or software failures. It guarantees the same comfort for the patient and the operator as a standard biopsy protocol. This allows this technique during an intense daily workflow. It is available everywhere and does not need neither an additional heavy material nor an intense training to be fluent with if the physician is confident with endorectal ultrasonography. In addition, no side effect has been recorded during the procedure. A voluminous hyperplasia or presence of many calcifications can be source of registration difficulties but during this study, and in line with our routine practice, the system provided reliable and usable imaging registration. The overall advantage over the in bore MRI guided biopsy is the short time of the procedure and the absence of technical complexity and no incremental cost as the fusion software is a part of the recent ultrasound machine.
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The present study has a number of potential limitations, due to its design. The study population consisted of patients referred to a single institution, which could have introduced a selection bias. MRI accuracy for cancer identification may be different in other centers with different experience, and operators with varying experience may achieve different results, but as its practice is now routine in many centers [27–29] and by using the PIRADS score, these findings could certainly be considered reproducible. Moreover, it has been published that it there is no statistically significant difference in biopsy accuracy according the operator experience [30]. We applied PI-RADS version 1, instead of the actual version 2, to stay homogeneous in our evaluation, because the first patients were included using the version1. We did not exclude patients with a previous series of negative systematic biopsies. It can provide a bias of selecting more anterior cancers. Indeed, anterior neoplasms are under-diagnosed by systematic biopsies, as they require significantly more biopsy sessions to diagnose prostate cancer than posterior neoplasms. [31] The mean percentage of anteriorly located cancers in an unselected population is 20% [23]. In our study it was moderately higher to 28.4%. Patients with no lesions visible on MP-MRI were excluded from the study. There is no surgical correlation. Thus, the true accuracy rates, including the false negatives cannot be determined. But the objective of our study was to evaluate targeted biopsies into suspicious MRI areas performed with a simple electronic fusion device, comparing to standard US guided biopsies. Besides, conservative treatment, such as curietherapy, is often proposed. As described, we used a 16 cores protocol, which is the standard technique in our center. Several studies have shown that the classical sextant protocol leaves 15% of cancers undetected compared with results obtained from a more extensive biopsy procedure [32], and that saturation TRUS biopsy (20 cores or greater) does not improve cancer detection as an initial biopsy technique [33]. In summary, our data indicate that using this non constraining electronic registration technique increases the yield of the biopsies comparing to standard biopsies. Our results are equivalent to those obtained with a more sophisticated and time consuming device.
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