Apparent diffusion coefficient values are superior to transrectal ultrasound-guided prostate biopsy for the assessment of prostate cancer aggressiveness

Abstract

Background

Few studies have focused on comparing the utility of diffusion-weighted imaging (DWI) and transrectal ultrasound (TRUS)-guided biopsy in predicting prostate cancer aggressiveness. Whether apparent diffusion coefficient (ADC) values can provide more information than TRUS-guided biopsy should be confirmed.

Purpose

To retrospectively assess the utility of ADC values in predicting prostate cancer aggressiveness, compared to the TRUS-guided prostate biopsy Gleason score (GS).

Material and Methods

The DW images of 54 patients with biopsy-proven prostate cancer were obtained using 1.5-T magnetic resonance (MR). The mean ADC values of cancerous areas and biopsy GS were correlated with prostatectomy GS and D’Amico clinical risk scores, respectively. Meanwhile, the utility of ADC values in identifying high-grade prostate cancer (with Gleason 4 and/or 5 components in prostatectomy) in patients with a biopsy GS ≤ 3 + 3 = 6 was also evaluated.

Results

A significant negative correlation was found between mean ADC values of cancerous areas and the prostatectomy GS (P < 0.001) and D’Amico clinical risk scores (P < 0.001). No significant correlation was found between biopsy GS and prostatectomy GS (P = 0.140) and D’Amico clinical risk scores (P = 0.342). Patients harboring Gleason 4 and/or 5 components in prostatectomy had significantly lower ADC values than those harboring no Gleason 4 and/or 5 components (P = 0.004).

Conclusion

The ADC values of cancerous areas in the prostate are a better indicator than the biopsy GS in predicting prostate cancer aggressiveness. Moreover, the use of ADC values can help identify the presence of high-grade tumor in patients with a Gleason score ≤ 3 + 3 = 6 during biopsy.

Keywords

Transrectal ultrasound-guided (TRUS) biopsy apparent diffusion coefficient diffusion weighted-imaging (DWI)aggressiveness prostate cancer

Introduction

Prostate cancer is the second most frequently diagnosed cancer and the fifth leading cause of cancer death in men all over the word (1). This disease varies widely in aggressiveness, from indolent tumors that can be managed by active surveillance to highly aggressive tumors that require radical prostatectomy and/or radiotherapy (2). Thus, for patients with newly diagnosed prostate cancer, it is important to accurately assess the aggressiveness of prostate cancer in order to devise optimal treatment plans.

Multiple parameters have been used to evaluate the aggressiveness of prostate cancer, such as prostate-specific antigen (PSA) levels, histopathological data, and digital rectal examination (DRE) (3 –5). Among various clinically determinable parameters, the Gleason score (GS) is the most commonly accepted one for assessing the biological aggressiveness of prostate cancer (6). It can reflect not only the pathologic characteristics of prostate cancer, but also predict disease outcome and the risk of mortality (6). Transrectal ultrasound-guided (TRUS) prostate biopsy GS is widely used to assess tumor aggressiveness before treatment. However, it is well-known that the TRUS-guided prostate biopsy GS frequently differs from the radical prostatectomy GS, which may lead to underestimation or overestimation of prostate cancer aggressiveness. Accuracy is in the range of 28–74% according to previous studies (7 –10).

Diffusion-weighted imaging (DWI) is a functional technique that reflects the cellular status of normal and pathologic tissue by assessing the Brownian movement of water molecules and providing important information about the functional environment of the water in tissue. The apparent diffusion coefficient (ADC) derived from DWI has been shown to improve the detection of prostate cancer (11 –13). Moreover, some studies have suggested that there were significant correlations between ADC and biopsy or radical prostatectomy GS (14 –18), which revealed the potential of ADC in evaluating prostate cancer aggressiveness. To our knowledge, few studies have focused on comparing the utility of DWI and TRUS-guided biopsy in predicting prostate cancer aggressiveness. Thus, whether ADC can provide more information than TRUS-guided biopsy should be confirmed. The aim of our study was to investigate: (i) the correlation of ADC with radical prostatectomy GS and clinical risk scores, compared to TRUS-guided biopsy GS; and (ii) the utility of ADC in identifying high-grade prostate cancer (with Gleason 4 and/or 5 components in prostatectomy) in patients with a Gleason score ≤ 3 + 3 = 6 upon TRUS-guided biopsy.

Material and Methods

Patients

This retrospective study was approved by the local institutional review board. Between January 2010 and December 2012, a total of 283 patients were diagnosed with prostate cancer based on biopsy results in our hospital. Ninety-two of them underwent radical prostatectomy in our hospital, and all of the 92 patients underwent magnetic resonance (MR) examination in our hospital. Exclusion criteria for this study were: (i) any treatment for prostate cancer before MR examination (n = 10); (ii) the period between TRUS-guided biopsy and radical prostatectomy exceeded 2 months (n = 12); (iii) the period between MR examination and radical prostatectomy exceeded 2 months (n = 8); (iv) if the biopsy was performed prior to the MR examination, and the interval between biopsy and MR examination was less than 6 weeks (n = 8). In the end, 54 patients were included in the study. The patients’ mean age was 69 ± 6 years (range, 56–82 years). The median serum PSA level of the patients was 8.5 ng/mL (range, 1.0–21.3 ng/mL).

MR examination

Magnetic resonance imaging (MRI) was performed at a 1.5 Tesla superconducting scanner (Magnetom Espree, Siemens, Erlangen, Germany) using a four-channel spine receiver coil for optimal signal reception, and the body coil acting as a transmitter.

Axial, coronal, and sagittal T2-weighted (T2W) images, axial T1-weighted (T1W) MR images, and axial DW images with two b values (0 and 1000 s/mm²) were obtained. The parameters for axial T2W images with a turbo-spin echo imaging sequence were set as follows: TR, 3500 ms; TE, 85 ms; matrix, 320 × 256; field of view (FOV), 240 mm × 240 mm; slice thickness, 3 mm; interslice gap, 0.6 mm; NEX, 4. The parameters for DWI with a single-shot echo planar imaging sequence were set as follows: TR, 2900 ms; TE, 84 ms; matrix, 230 × 256; FOV, 230 mm × 230 mm; slice thickness, 3 mm; interslice gap, 0.6 mm; diffusion direction, 3. Parallel imaging was used with a PAT of 2. The ADC maps were constructed on the Siemens workstation and simultaneously displayed.

Prostate biopsy

All patients underwent a subsequent systematic TRUS-guided prostate biopsy. From each patient, 8–12 samples of the prostate were obtained. Each sample was histologically analyzed by the same pathologist, with 10 years of experience of pathology in the genitourinary system. The histopathologic reports included the Gleason grading with its primary and secondary components.

Radical prostatectomy

Each patient underwent radical prostatectomy no later than 2 months post MR examination. The specimens were evaluated histopathologically by the same pathologist who analyzed the biopsy samples. Each significant focus of adenocarcinoma was recorded for the report, based on the sextant location. The Gleason grading, with its primary and secondary components, was evaluated on the whole prostate level.

Images analysis

To determine whether the measured value of ADC was artifactual or intrinsic, we estimated the signal-to-noise ratio (SNR) of the ADC maps before analyzing the DWI images. To measure SNRs, we chose the non-cancerous regions when we calculated the SNR. The DWI images were analyzed in consensus by two experienced radiologists with more than 10 years of experience in prostate imaging. In each case, the suspicious lesion was delineated based on the radical prostatectomy histopathological report. All of the regions of interest (ROIs) were drawn on the most significant lesions, with the tumor location in the histopathological reports as reference (in the apex, middle, or base; in the right side or left side; in the peripheral zone or central gland). We used axial T2W images as an anatomical reference and drew ROIs on the ADC maps manually. ROIs were placed on the central-most region of each lesion to reduce the chances of partial volume effects from outside the tumor. The hypointense foci on T2W images were carefully included as large as possible and great attention was paid to avoid including foci corresponding to hemorrhage, necrosis, or calcification. For each cancerous lesion, three ROI measurements were made and the mean ADC value was calculated. If there was more than one cancerous lesion in one case, the average ADC value of all cancerous lesions was used for the statistical analysis. The area range of the ROIs was 0.32–1.29 cm², with a median of 0.79 cm².

Statistical analysis

All data were analyzed using the SPSS software (Version 13.0; SPSS Inc., Chicago, IL, USA). We performed a clinical classification that accounted for both Gleason score and serum PSA for each patient, which is known as the D’Amico clinical risk score (low: GS ≤6 and PSA ≤10 ng/mL; intermediate: GS = 7 or PSA >10 ng/mL, but ≤20 ng/mL; high: GS ≥8 or PSA >20 ng/mL) (3,19). The mean ADC values of the cancerous areas were correlated with radical prostatectomy GS and D’Amico clinical risk scores, using Pearson’s correlation analysis. The same analysis was performed to correlate each patient’s biopsy GS with prostatectomy GS and D’Amico clinical risk scores. Receiver operating characteristic (ROC) curves were used to determine the ability of ADC values and biopsy GS to differentiate low-grade prostate cancer from intermediate/high grade prostate cancer.

In addition, patients with a Gleason score ≤ 3 + 3 = 6 upon TRUS-guided biopsy were divided into two groups according to whether they harbored Gleason 4 and/or 5 components based on prostatectomy. The mean ADC values of cancerous areas for these two groups were calculated and an independent-t test was used to compare the differences between them. The ROC curve was used to determine the ability of ADC values to differentiate these two group patients. P < 0.05 was considered statistically significant.

Results

The histopathological results of these 54 patients are summarized in Table 1. Thirty-eight lesions were found in the peripheral zone, 12 were found in the central gland, and four were found both in the peripheral zone and central gland. The overall accuracy of the biopsy GS for estimating the radical prostatectomy GS was 40.7% (n = 22). Compared with the radical prostatectomy GS, up to 46.3% of the patients (n = 25) were underestimated by the biopsy GS, while 13.0% (n = 7) were overestimated.

Table 1.

Histopathological results of patients. The GS, PSA, number of patients, and pathological stage were included.

TRUS-guided prostate biopsy GS	Patients (n)	PSA (ng/mL)	Needle number of positive biopsies
5 (2 + 3)	2	10.92–11.13	1–2
5 (3 + 2)	3	4.39–9.99	1–3
6 (3 + 3)	22	1.04–19.4	1–3
7 (3 + 4)	12	4.2–17.88	1–4
7 (4 + 3)	13	2.74–19.67	2–4
8 (3 + 5)	1	13.6	4
8 (5 + 3)	1	21.3	3
Radical prostatectomy GS	Patients (n)			Pathological stage
5 (3 + 2)	1	2.23		T2a
6 (3 + 3)	16	2.74–19.36		T2a–T2c
7 (3 + 4)	14	3.41–17.88		T2a–T2c
7 (4 + 3)	10	1.04–15.51		T2a–T3a
8 (3 + 5)	5	7.3–19.67		T2a–T3b
8 (4 + 4)	2	8.8–9.48		T2c, T3a
8 (5 + 3)	3	4.2–21.3		T2c–T3a
9 (4 + 5)	2	4.9–10.7		T2b, T3a
9 (5 + 4)	1	4.2		T2b

Needle number of positive biopsies means how many needles were diagnosed as prostate cancer pathologically.

GS, Gleason score; TRUS, transrectal ultrasound.

The SNRs of the ADC maps in the peripheral zone and in the central gland were calculated to be 18 ± 4 and 14 ± 3, respectively.

The mean ADC value of the overall tumor foci was 0.977 ± 0.192 × 10⁻³mm²/s (range, 0.490–1.350 × 10⁻³mm²/s). A significant negative correlation was found between the mean ADC values of cancerous areas and the prostatectomy GS (r = −0.768; P < 0.001) (Fig. 1a) and D’Amico clinical risk scores (r = −0.764; P < 0.001). No significant correlations were found between biopsy GS and prostatectomy GS (r = 0.203; P = 0.140) (Fig. 1b) or D’Amico clinical risk scores (r = 0.132; P = 0.342). The ADC and biopsy GS was found to distinguish low-grade prostate cancer from intermediate/high grade prostate cancer with a correct classification rate of 0.835 (Fig. 2a) and 0.669 (Fig. 2b), respectively, with the ROC analysis.

Fig. 1.

(a) Correlation between ADC values and prostatectomy GS (r = −0.768; P < 0.001). (b) Correlation between biopsy GS and prostatectomy GS (r = 0.203; P = 0.140). The numbers on the right of the donut symbols represent the numbers of cases.

Fig. 2.

(a) ROC curve for ADC values in distinguishing low-grade prostate cancer from intermediate/high-grade prostate cancer, with a correct classification rate of 0.835. (b) ROC curve for biopsy GS in distinguishing low-grade prostate cancer from intermediate/high-grade prostate cancer with a correct classification rate of 0.669.

On the TRUS-guided biopsy, 27 patients had a Gleason score ≤ 3 + 3 = 6. And 14 of these (51.9%) harbored Gleason 4 and/or 5 components in prostatectomy, while the other 13 did not (48.1%). Patients harboring Gleason 4 and/or 5 components in prostatectomy had significantly lower ADC values than those harboring no Gleason 4 and/or 5 components (0.901 ± 0.160 × 10⁻³mm²/s vs. 1.123 ± 0.199 × 10⁻³mm²/s, P = 0.004) (Fig. 3). The images for two typical cases are given in Fig. 4. The diagnostic accuracy of ADC values in discriminating these two groups of patients revealed an area under curve (AUC) of 0.835 (Fig. 5), with a sensitivity of 0.769 and a specificity of 0.714 at the cutoff value of 1.008 × 10⁻³mm²/s.

Fig. 3.

ADC values for patients with a Gleason score ≤3 + 3 = 6 upon TRUS-guided biopsy. Two groups represented patients harboring no Gleason 4 and/or 5 component and those harboring Gleason 4 and/or 5 component in prostatectomy, respectively.

Fig. 4.

(a)–(c) 64-year-old patient with a PSA level of 5.5 ng/mL. (a) T2W MRI showing a hypo-intense nodule in the left peripheral zone. (b) DWI showing a slightly hyper-intense nodule. (c) ADC map showing a slightly hypo-intense nodule (ADC value = 1.127 × 10⁻³mm²/s). The biopsy GS was the same as the prostatectomy GS (3 + 3 = 6). (d)–(f) A 76-year-old patient with a PSA level of 6.1 ng/mL. (d) T2W MRI, showing a hypo-intense nodule in the left peripheral zone. (e) DWI showing a hyper-intense nodule. (f) ADC map showing a hypo-intense nodule (ADC value = 0.974 × 10⁻³mm²/s). The biopsy GS was 3 + 3 = 6, while prostatectomy GS was 4 + 3 = 7.

Fig. 5.

ROC curve for ADC values in discriminating patients who harbored no Gleason 4 and/or 5 component and those harboring a Gleason 4 and/or 5 component in patients with a Gleason score ≤3 + 3 = 6 upon TRUS-guided biopsy, with a correct classification rate of 0.835.

Discussion

Currently, the pretreatment aggressiveness of prostate cancer is mainly determined by the GS score generated at biopsy; but, unfortunately, biopsy GS is often underestimated or overestimated. It is necessary to find a more accurate method for clinical practice. Because of this, recently, the assessment of prostate cancer aggressiveness has become one of the hot topics of prostate MRI research. In previous studies, different kinds of functional MRI, including DWI, have been used to evaluate the aggressiveness of prostate cancer (14 –17,20,21). It has been shown that ADC values of prostate cancer had a significant correlation with GS (14,17,22), which indicated that ADC values may be helpful in predicting the aggressiveness of prostate cancer. However, little emphasis has been placed on the comparison between ADC and biopsy GS in the evaluation of tumor aggressiveness.

In our study, we used radical prostatectomy GS and D’Amico clinical risk scores as the reference to assess the aggressiveness of prostate cancer. We found that the mean ADC value of prostate cancer had a significant negative correlation with radical prostatectomy GS, which is in agreement with previous studies (14,17,22). Gleason grade itself indicates the degree of glandular differentiation and stromal invasion in prostate cancer (23). That means that GS correlates somewhat with the degree of tumor cellularity.

Our major finding was that the ADC values on preoperative prostate MR correlated significantly better with the radical prostatectomy GS than with the TRUS-guided biopsy GS. This result was similar to that of Bittencourt (24). In the present study, the biopsy GS was consistent with the radical prostatectomy GS only in 40.7% of patients (22/54), with more than half the patients underestimated or overestimated by the biopsy GS. This may be attributable to the sample error of biopsy and the heterogeneity of tumor foci. As some prostate cancers are not visible on US, the random and systematic biopsy is commonly used in clinical practice. The most aggressive component of tumor foci may then be easily missed, which will result in the underestimation of aggressiveness. Likewise, overestimation may be caused by the limitation of biopsy samples and the lack of overall evaluation for tumor foci. Unlike US, most tumor foci show hypointense signals on ADC maps and it is easier to place ROIs on suspicious areas of the prostate. Besides, the ROIs covered tumor foci as much as possible in the present study so that the ADC values reflected the characteristics of overall tumor foci. These two aspects may be the possible explanation for our results. Although it is not feasible to grade prostate cancer just by ADC values, the results have indicated the potential of DWI in predicting the aggressiveness of prostate cancer.

We further analyzed patients with a Gleason score ≤ 3 + 3 = 6 upon TRUS-guided biopsy in our study. As we know, the biopsy Gleason score is a poor predictor of the true Gleason score identified in prostatectomy, commonly with an underestimation or an overestimation. It is rather necessary to identify undergraded patients in those with a Gleason score ≤ 3 + 3 = 6 upon TRUS-guided biopsy, as this is important in order to select an optimal treatment and predict the prognosis. It will be of great benefit to find a non-invasive and reliable technique to separate patients with a true Gleason score ≤3 + 3 = 6 from those who do not have such scores. From our results, DWI seemed to have the potential to manage this for these two groups of patients who had significantly different ADC values. The diagnostic accuracy of ADC values (AUC of 0.835) in discriminating these two groups of patients also confirmed this point. Our results agreed with that of Somford (25) and the underlying mechanism can also be attributed to the denser cellular tissue in higher GS.

The results indicated the potential of ADC values to predict the biological aggressiveness of prostate cancer, which indicates the potential for assisting in the choice of treatment. However, some points need to be resolved before the ADC values are used, including the optimization of DWI parameters and the ROIs setting. More studies are still needed in the future.

There were some limitations to this study. First, we did not obtain whole-mount specimens as a histopathological reference, and this made it difficult to correlate the suspicious areas on MR images with the histological tumor foci accurately. However, in order to reduce the mismatch of MR images and histopathology as much as possible, all of the ROIs were drawn on the most significant lesions, with the tumor location in histopathological reports as reference. Second, as prostatectomy GS was necessary in this study, only patients who underwent prostatectomy were included in this study, excluding either active surveillance cases (probably with low GS) or advanced cases who would not have the opportunity for surgery (probably with high GS). This may bring a selection bias to our study. Third, there was more than one tumor lesion in some cases and different lesions in the same case may have had different GS because of the tumor heterogeneity. Unfortunately, only one GS can be required for each case and it is impossible to analyze each lesion individually. Thus, we had to calculate the mean ADC value of different lesions in each case for the final statistical analysis, which may have influenced the accuracy of our study. Fourth, the DWI technique applied in this study had some limitations, mainly because of the limited number of diffusion directions and b values. However, as we mentioned in the results, the SNRs of the PZ and the central gland were calculated to be 18 ± 4 and 14 ± 3, respectively, which indicated the reliability of high ADC values of prostate cancer.

In conclusion, the ADC values obtained from DWI MRI imaging of cancerous areas in the prostate are a better indication than the biopsy GS in predicting prostate cancer aggressiveness. Moreover, ADC values are useful for identifying the presence of high-grade tumor in patients with a Gleason score ≤ 3 + 3 = 6 on biopsy, which is critical in the treatment decision-making process.

Footnotes

Acknowledgments

The authors thank Mary McAllister and Jinyuan Zhou (Johns Hopkins University) for editorial assistance.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the National key clinical specialist construction Programs of China.

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