The focus of the majority of studies on MR in prostate cancer has been on staging the disease after cancer has been diagnosed on a prostate biopsy. Another important clinical question is selecting patients for biopsy from among those suspected to have cancer. Standard guidelines recommended biopsies for elevated PSA (4–10 ng/mL) or abnormal DRE are positive in less than 25% of the cases.36,37 Furthermore, prostate biopsies are associated with anxiety and morbidity, and increasing the number of cores increases the yield, but with associated complications. There is thus a clinical need for improving the selection of patients for a biopsy. Few recent reports addressed the potential of MR examination in improving selection of cases for biopsy and the yield of biopsies.38–42 The strategy of carrying out MR before biopsy might increase its clinical value and help circumvent some of the limitations. It might help in detection, targeting biopsies and predicting the presence or absence of cancer, resulting in a reduction in the number of biopsies carried out. In addition, carrying out a prebiopsy MRI also circumvents the problem of postbiopsy hemorrhage artifacts seen on MR images and hence, avoids the need to wait for 2–3 months for MR imaging after biopsy. Recently, it has been reported that the addition of prebiopsy MRSI and DWI to conventional prostate MR imaging have shown promising results in prostate imaging, with a significant increase of sensitivity and specificity of cancer detection.43
Diagnosis and characterization
The main focus of many prebiopsy MRI and MRSI studies has been to localize suspicious areas of malignancy in patients with elevated levels of PSA or abnormal findings on DRE, suggestive of prostate cancer. A recent study evaluated the potential role of prebiopsy MRI at 1.5T in 185 patients with a PSA level of 4.0–10.0 ng/mL.44 The study showed that combining MRI findings with PSA density provides high sensitivity and improves the specificity for the early detection of prostate cancer.44 The sensitivity, PPV and location match percentage of MRI before prostate biopsy in cancer detection have been reported as 84.8%, 75.7% and 89.3%, compared with after biopsy, 92.4%, 92.4% and 94.1%, respectively.45 The improved sensitivity of cancer detection by MRI has also been reported.45 Squillaci et al. studied 65 men with high levels of PSA, and suspicious areas at the TRUS using MR imaging and spectroscopy.46 The study reported sensitivity, specificity (PPV), NPV and accuracy for detection of prostate cancer as 89%, 77%, 78%, 69% and 83%, respectively for MRSI, whereas these values were 71%, 90%, 89%, 74% and 80%, respectively for combined MRI and MRSI.46Table 1 shows the summary of the sensitivity, specificity, PPV and NPV reported in the literature.
Table 1. Summary of the sensitivity, specificity, PPV, NPV and accuracy of prebiopsy MR methods reported in the literature
|MRI||Choi et al.45||84.8%|| ||75.7%|| || |
|MRSI||Squillaci et al.46||89%||77%||78%||69%||83%|
|Manenti et al.47||75%||89%||88%||74%||87%|
|Villers et al.48||77%||91%||86%||85%|| |
|MRI + MRSI||Squillaci et al.46||71%||90%||89%||74%||80%|
|DWI + MRSI||Kumar et al.49||100%||33%||64%|| || |
|DCE + MRSI||Perdona et al.50||71%||48%||19%||91%||85%|
|DWI + T2WI + DCE||Tanimoto et al.51||95%||74%|| || ||86%|
|Kitajima et al.52||81%||96%|| || ||92%|
|DWI + DCE||Kozlowski et al.53||87%||74%|| || || |
|MR targeted Biopsy||Haffner et al.54||95%||100%|| || ||98%|
The addition of MRS to MR imaging provides a higher specificity in tumor detection, and can be recommended as a problem-solving modality for patients with elevated PSA levels before biopsy.46 Manenti et al. reported MRI and MRSI on 39 patients with lesions suspicious of cancer on TRUS.47 The PSA level was greater than 4 ng/mL for all of the patients, and they carried out 10 core biopsy within 30 days after the MR investigation. Out of 17 patients showing voxels suspicious of malignancy, histology confirmed cancer in 15 patients. Their study reported sensitivity, specificity, PPV, NPV and accuracy as 75%, 89%, 88%, 74% and 87%, respectively for MRSI. These studies show the potential role and recommend prebiopsy use of MRS and MRI investigation in patients with high PSA levels and suspicious TRUS findings.46,47 However, Costouros et al. in a study of 40 patients using MRI and MRSI before biopsy reported significant improvement in the diagnostic accuracy by adding MRSI to MRI in patients with negative finding on prior biopsy or no prior biopsy.55 In their study, biopsy showed no cancer in 24, bilateral cancer in 11 and unilateral in five patients. Nonetheless, the authors indicated that when carried out before biopsy, MRSI and MRI might be considered as a secondary screening technique.
In men with high clinical suspicion for prostate cancer before biopsy, both EPI and FSI sequences show differences in ADC between normal PZ, central gland and cancer.56 Significantly lower mean ADC value of tumors compared with the mean value obtained for the normal PZ has been reported in a study of volunteers and patients with prostate lesions diagnosed by TRUS.57 The study showed the potential of DWI for characterizing tissues of the different regions of the prostate gland, and in distinguishing normal from cancerous tissues in a prebiopsy population.
Shimizu et al. evaluated the detection of prostate cancer by carrying out T2WI and DWI (and an ADC map) before biopsy in 122 patients.58 The sensitivity of T2WI, DWI and an ADC map was 41.2%, 56.7%, and 57.7%, respectively, and the PPV was 83.0%, 86.4% and 87.2%, respectively. Their study showed that MRI before a biopsy has a high detection rate for prostate cancer, particularly with the tumor size of more than 5 mm in short-axis diameter or 10 mm in long-axis diameter. We have previously reported DWI before biopsy, and determined a cut-off value of ADC (1.17 × 10−3 mm2/s) to predict malignancy in the PZ of the prostate.59 The diagnostic value of MRI and DWI before biopsy for the detection of prostate cancer has been evaluated at 3.0T. An accuracy between 71.4% to 100% has been achieved by combining MRI and DWI.60 Multimodal examination comprising T2WI, DCE-MRI and DWI is recommended for the diagnosis of prostate cancer at 3.0T.60 The diagnostic utility of DTI in prostate cancer has also been evaluated in men with suspicion of prostate cancer before biopsy. The mean fractional anisotropy, determined by carrying out DTI in men before prostate biopsy, has been reported to be significantly different for cancerous foci (0.30 ± 0.08) compared with the normal appearing gland (0.14 ± 0.04).17
Hara et al. carried out DCE-MRI in patients with elevated PSA followed by 14 core TRUS biopsy.61 DCE-MRI revealed 92.9% of the cancers with a specificity of 96.2%. The study showed that DCE-MRI can identify cancer in the prostate and might be useful to predict the histological grade. Villers et al. reported DCE-MRI in 92 men before biopsy and compared the data with the whole mount histology rather than with the TRUS biopsy data.48 The sensitivity, specificity, PPV and NPV were 77%, 91%, 86% and 85%, respectively, for foci greater than 0.2 cm3, and 90%, 88%, 77% and 95% for foci greater than 0.5 cm3.
Recently, we reported the use of MTI in prostate cancer.23 We found significantly higher mean MTR value for the PZ of patients who were positive for malignancy (8.29 ± 3.49) compared with patients who were negative for malignancy (6.18 ± 3.15) on TRUS-guided biopsy. The mean MTR for the PZ of controls (6.18 ± 1.63) was similar to that of patients who were negative for malignancy. More studies are required to explore further the role and the potential of MTI in prostate cancer.
There have been attempts to combine information from various MR methods to improve the accuracy of prostate cancer detection. MRSI, DCE-MRI and DWI provide information on metabolic activity, vascular properties and tissue changes, such as cellularity. Therefore, information obtained from combining these methods is expected to provide better results. We combined MRSI and DWI data, and found that regions of the PZ that were suspicious of cancer on MRSI using the metabolite ratio showed lower ADC values indicating suspicion for cancer.49 We also noted a positive correlation between metabolite ratio and ADC. The combined use of metabolite ratio and ADC values resulted in 100% sensitivity and NPV with a specificity of 33% and 64% PPV in predicting the presence of cancer when compared with the results of the TRUS-guided biopsy. The potential of DWI in combination with DCE-MRI has also been evaluated for achieving higher diagnostic sensitivity for prostate cancer. Kozlowski et al. observed significant differences in the MRI parameters obtained from tumor and normal prostate.53 Using DWI-derived parameters, the sensitivity and specificity values were 54% and 100%, respectively, and for DCE-MRI-derived parameters the sensitivity was 59% with 74% specificity. The combined use of parameters obtained from DWI and DCE-MRI resulted in increased sensitivity (87%) with 74% specificity.
Tanimoto et al. evaluated the potential of combining T2WI with DWI and DCE-MRI as screening methods for prostate cancer in 83 patients with elevated serum PSA.51 A sensitivity of 95% with 74% specificity and 86% accuracy for the detection of prostate cancer was obtained by combining T2WI, DWI and DCE-MRI. This was significantly different compared with T2WI alone or T2WI combined with DWI, and biopsy was used as the standard of reference. Kitajima et al. evaluated the potential of T2WI, DWI and DCE-MRI at 3T.52 When all the three methods were combined, the detection of cancer showed the sensitivity, specificity and accuracy as 81%, 96% and 92%, respectively. The authors suggested that the combination of these three methods might be a reasonable approach for the detection of prostate cancer.
A recent study evaluated the prebiopsy use of combined MRSI and DCE-MRI in prostate cancer diagnosis in men with PSA levels below 10 ng/mL.50 Using combined MRSI and DCE-MRI, and considering patients as single measurements, diagnostic accuracy, sensitivity, specificity, NPV and PPV of 85%, 71%, 48%, 91%, 19%, respectively, were obtained.50 Although the PPV was very low, the high NPV might serve to avoid unnecessary biopsies.50 The potential of the combined use of DTI and DCE-MRI for achieving higher diagnostic accuracy has also been reported.62 The combination of DTI and DCE-MRI gave significantly better accuracy in prostate cancer diagnosis than either technique alone.
Targeted biopsies might improve the diagnostic yield even more than increasing the number of biopsies.63 MR examination carried out before biopsy might help to determine the position of suspicious areas of malignancy, allowing more accurate biopsy of the prostate by targeting the needle on such areas. Hence, accurate targeted biopsy might limit the need for multiple repeat biopsies. We reported MRSI examination in 83 men with abnormal DRE or elevated PSA before biopsy.39 MRSI-derived coordinates were used to target TRUS-guided biopsy needle on suspicious areas for malignancy on MRSI (see Fig. 4). Out of 44 patients having voxels suspicious of malignancy on MRSI, just 11 were found to have malignancy on biopsy. We found a detection rate of 25% with MRSI-directed TRUS-guided biopsy, whereas the detection rate was 9% in another group of 120 patients without MRSI guidance. Another interesting observation was 100% NPV achieved in this study. Haffner et al. compared MRI-targeted biopsies with extended systematic biopsies in 555 patients.54 For significant prostate cancer detection, sensitivity, specificity and accuracy for targeted biopsies were 0.95, 1.0 and 0.98, respectively. The values for extended systematic biopsies were 0.95, 0.83 and 0.88, respectively. The detection accuracy of significant prostate cancer by targeted biopsies was significantly higher compared with extended biopsies.54 Targeted biopsies detected 16% more grade 4 and 5 cases than extended systematic biopsies.54 MRI targeted biopsies based on prebiopsy MRI-detected lesions have been reported to result in increased detection rate, volume and grade of anterior prostate cancer compared with 12 cores systematic biopsy.64
Figure 4. (a) Sagittal section of T2-weighted image of prostate showing determination of the distance from the base of the prostate of the transverse section containing the suspicious voxel. (b) Voxel grid overlaid over T2-weighted transverse image of the corresponding section showing the distance of the suspicious voxel from midline of the prostate (c) MR spectrum obtained from the voxel showing increased Cho and decreased Cit. (d) TRUS image of MRSI-directed TRUS-guided biopsy of the prostate. The needle mark on the TRUS image shows the site of biopsy (reprinted from Kumar et al.39 with permission from John Wiley & Sons Limited).
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The findings of MR investigations before biopsy of prostate might also prove to be important in patients with raised PSA and previous negative biopsy results. The circumstances for these patients are comparable to patients suspicious of prostate cancer in respect that they can benefit by MR investigations for improved detection or targeted biopsies, which might avoid the need for multiple biopsies. In these cases, the results of MR investigation might also indicate that the reason for elevated PSA levels might be other than cancer. Recently, many researchers have reported the use of MRSI to target needle biopsies under TRUS guidance for the detection of prostate malignancy in patients with previous negative TRUS biopsies.65–71 The application of MRI and MRS to target biopsies in patients with previous negative prostate biopsies and persistently elevated PSA levels appears to be significant.72
Yuen et al. showed that MRSI has the potential to direct biopsy in these patients with 100% sensitivity, 58% specificity, 100% PPV and 79% accuracy for detecting prostate cancer.65 Schmuecking et al. used pre-interventional, fused, high-resolution T2WI with parametrically analyzed DCE-MRI and proton MRS for a precise biopsy for the detection of prostate cancer, and for the delineation of intraprostatic subvolumes for intensity modulated radiation therapy in patients with elevated PSA and/or a previously negative biopsy.73 Sciarra et al. reported a prospective randomized study analyzing the role of MRSI and DCE-MRI in the detection of prostate tumor foci in patients with persistently elevated PSA and prior negative biopsy.74 A total of 180 eligible cases were randomized into two groups; group I of 90 patients who had a second random prostate biopsy, whereas group II (n = 90) underwent an MR investigation and targeted biopsy of suspicious areas. In group I, cancer was detected in 22 of 90 cases (24.4%), whereas 41 of 90 cases (45.5%) were positive for cancer in group II. Their study concluded that the combination of MRSI and DCE-MRI showed the potential to guide biopsy to cancer foci in patients with a previously negative TRUS biopsy.74
MRI data itself has been shown to have the potential to guide prostate biopsies without TRUS.75–78 Special biopsy systems developed for such purpose require additional technical design considerations, such as MR compatibility, precision, size and safety.78,79 These biopsy systems work under either manual or robotic control.78,80,81
Predicting malignancy on prostate biopsy
Gleason grades are based on the appearance of the prostatic glandular architecture under low-power magnification. The greater the deviation from normal glandular architecture, the higher the Gleason grade. A Gleason grade of 1 represents the acini that look like normal prostate acini, and a grade of 5 represents highly abnormal and undifferentiated acini. The Gleason score is obtained by adding the most common Gleason grade and the next most common Gleason grade present in a sample. Higher Gleason grade and Gleason score represents more aggressive cancer and worse prognosis. Generally, the TRUS biopsy technique underestimates the Gleason grade of the cancer compared with the radical prostatectomy specimen because of the inherent sampling error.82 This has the potential to alter treatment strategies, as treatment decisions are often based on the Gleason score on the biopsy. Prebiopsy MRI has the potential to localize and direct the TRUS-biopsy for more accurate biopsy. The addition of MRSI to T2WI improves the information about Gleason grade within resolution of millimeters. Similarly, DCE-MRI might show information about the Gleason grade of cancer evident in the enhancement pattern.83
The aforementioned studies have shown that the MR examination carried out before biopsy has the potential to identify and target biopsies for improved detection of prostate cancer. By providing more accurate correlation with Gleason scores, these studies might additionally provide information on ideal treatment strategies. Recently, we evaluated the potential of prebiopsy MRSI to segregate patients who, on prostate biopsy, are more likely to show a malignancy in the PZ of the prostate gland.84 The study included 123 men with elevated PSA or an abnormal DRE. The results of the study suggested that patients who are deemed as malignancy-positive in the PZ by MRSI might be subjected to prostate biopsy to confirm the diagnosis of cancer.
Vilanova et al. reported that a model incorporating MR imaging, MR spectroscopy and free-to-total PSA ratio was significantly more accurate in predicting prostate cancer than models using MR imaging alone, MRS alone or MR imaging and free-to-total PSA ratio combined.85 The usefulness of prebiopsy MRI using T2WI, MRS, DWI and DCE-MRI has also been reported in predicting prostate cancer.86 The model combining all variables was more accurate (95.2%) compared with each variable alone.86 Villeirs et al. carried out a study of 356 patients to assess the ability of combined MRI and MRSI to predict the presence or absence of high-grade prostate cancer in men with elevated PSA.87 The study reported that combined MRI/MRSI had a significantly higher sensitivity for high-grade tumors (92.7%) than for lower-grade tumors (67.6%), and was false positive in just 7.4% cases.
One of the promising roles of MRSI lies in its potential ability to predict the absence of prostate cancer in men with raised serum PSA due to non-malignant causes. This could immediately result in a reduction in the number of patients undergoing prostate biopsies. MRSI has been shown to have a high negative predictive value.49,87,88 A prebiopsy MRSI might be chosen over the invasive biopsy to predict the absence of prostate cancer.88 This will reduce the number of unnecessary biopsies carried out. We tested the hypothesis that MRSI might be able to identify patients with non-cancerous PSA elevation and help avoid unnecessary biopsies.88 We carried out MRSI before biopsy in patients with PSA between 4–10 ng/mL, and followed 36 men out of 155 whose MRSI showed no malignant voxels for at least 18 months (Fig. 5). None of these 36 men had cancer on their initial TRUS-guided biopsies. Interestingly, four patients required repeat biopsy, and one with persistently elevated PSA was diagnosed with prostate cancer after 29 months of initial MRSI. We concluded that prostate biopsy can be deferred in patients with an increased serum PSA between 4 to 10 ng/mL if their MRSI does not show abnormal voxels.
Figure 5. A representative example of T2-weighted axial image of the prostate with an overlaid spectroscopic grid from a patient with negative MRSI findings. The PSA of the patient was 6.05 ng/mL with a history of lower urinary tract symptoms with urgency and nocturia for approximately 1 year, but with no history of trauma.
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A few limitations of studies reporting the use of prebiopsy MR examination should be considered. Studies evaluating the prebiopsy population have used TRUS biopsy results as a gold standard, for at least a subgroup of the patients studied. Because TRUS biopsy suffers from sampling errors, it cannot be regarded as a good reference standard. It might not be possible to obtain radical prostatectomy step-section histopathology data on all of the prebiopsy population, which makes comparison with MR data difficult. Increasing the number of cores of biopsy does not solve the problem, and also increases the complications. Other factors that might affect the use of MR examination before biopsy is the burden of endorectal examination, detection of a higher number of insignificant cancers and the cost associated with subjecting patients to MR before proven prostate cancer diagnosis. In the literature, there are no reports on significant difficulty in using endorectal coil or complications arising after its use. MRI evaluation is an expensive examination. The time and resources might be better utilized for such an evaluation by recommending it only for a select group of patients with perceived benefits. Further studies on the cost-analysis need to be designed to answer such questions. These arguments have to be weighed against the benefit of better detection, early treatment and avoiding unnecessary biopsies. Multisite studies are required to validate the clinical utility of prebiopsy MR investigation of the prostate.