Introduction

Prostate carcinoma is a major health issue affecting mainly aged males^1,2. Cancer of the prostate is considered the third in cancer occurrence globally and sixth in cancer connected to high mortality¹. Given the ongoing increase in the expected life span in the population, the relatively benign nature of the low-grade prostate cancer, and consequently the high 10-year survival rate of men with prostate cancer, the magnitude of the problem in the health sector is expected to increase dramatically³. Much debate is present in consideration of the prompt management of patients with prostate cancer. The therapeutic options are dependent on factors such as the age at diagnosis, stage, the histological grade of the tumor, and patient’s medical conditions^4-7. Most patients with prostate cancer have a disease that is limited to the prostate gland⁸. A well-known pathological grading system of Prostate tumors is the Gleason score (GS). Higher Gleason scores denote aggressive tumors^8,9. Gleason scores classified as low score (≤6), intermediate score (7), or high score (>7)^1,10. The Gleason score thus gives predictions about the biological behavior of the tumor as well as the prognosis of the patient. Samples for Gleason score were provided from the transrectal biopsy or radical prostatectomy specimen¹¹. For a low score (GS <6) it is agreed that immediate treatment is not necessary, and it is reasonably safe to follow up with the patient. For intermediate-risk (Gleason score =7) the optimal line of management is monotherapy. In high-risk prostate cancer (Gleason score >7), the best treatment option, by agreement, is combination therapy^1,12. For accurate localization of prostate cancer, it has been shown that Magnetic Resonance Imaging (MRI) is far more accurate than digital rectal examination (DRE) and more accurate than transrectal ultrasound (TRUS) biopsy¹³. Conventional T2-weighted MRI sequences have a crucial role in local staging of prostate cancer as it predicts the extracapsular spread of the tumor and detects tumor foci within the gland. Although T2-WI is sensitive for detection of tumor foci, it is not at all specific as the low T2 signal reported in cancer is also observed in many benign lesions, such as benign prostatic hyperplasia (BPH), hemorrhage, prostatitis, or treatment-related changes^4,14,15. For this reason, conventional MRI has limited to local staging the known prostate cancer rather than primary detection of a suspected prostatic malignancy^14,16. Recently, with the advent of multiparametric MRI combining conventional MRI, dynamic contrast-enhanced MRI (DCE-MRI), magnetic resonance spectroscopic imaging (MRSI), and diffusion-weighted MRI (DWI), the role of MRI started to extend to involve detection of cancer foci as well as localization and staging^15,17. DWI is established to be useful in the recognition and location detection of tumor foci¹⁸. To differentiate between prostatic tumor, benign or malignant, DWI is very useful and plays an integral role in this differentiation^19-25. Recently DWI was introduced as a potential predictor of tumor aggressiveness¹¹, possibly, replacing the need for invasive grading by Gleason score, which is so far the only possible tool to predict the tumor biological aggressiveness. Through this work, we aim to correlate the Apparent Diffusion Coefficient (ADC) values of prostate cancer with the Gleason score of these foci, to assess the predictive capacity of ADC in the noninvasive assessment of tumor grade.

Methods

This descriptive study was conducted at the Radiology and Uro Surgery Departments of Al Imamain Al Kadhimain Medical City, Irak, between December 2018 and September 2019. Data of 35 patients with biopsy-proven peripheral zone (PZ) prostate cancer were obtained from the Urology Department including their biopsy and/or radical prostatectomy histopathological records, subsequently, the MRI record system saved MRI Information retrospectively. Patients were excluded if they had experienced previous operation, radiotherapy, or hormonal treatment. The official ethical appraisal committee decided exception for patient’s knowledgeable agreement because information retrospectively recovered. Entirely MRI scans were done with a 1.5 T device (Magnetom, Aera Siemens) by a pelvic phased-array coil. MRI pelvis procedure involved axial in addition to coronal turbo spin-echo T2-weighted pictures (TR: 4000-5000, TE 100-120, slice 3 mm, flip 130-150, FOV 180-230, gap 10%, NEX 2). Diffusion-weighted axial images (𝑏-value 0, 500, 1000 s/mm²) (TR: 4000-5000, TE 110, slice 4 mm, flip 130, FOV 200-250, gap 10%,NEX 10), with ADC maps and dynamic T1 flash 3D fat sat axial 1 pre-contrast and 10 post-contrast images (TR: 4-5, TE 2, slice 3 mm, flip 12, FOV 180-200). In all studies in our institution using contrast, patient verbal consent was obtained. Image Analysis and Reader Procedure: Two senior radiologists reviewed the images on the diagnostic workstation. The signal on the DWI image noted and corresponding ADC maps carefully examined. Circular regions of interest (ROIs) drawn on the ADC map display to obtain ADC value of foci of diffusion restriction. Only lesions with a confident anatomical correlation between the histopathology report of biopsy/surgical specimen and the MRI imaging localization were included in this study after the consensus decision of the two radiologists. Lesions with no confident correlation of location excluded from this study. The statistical analysis was performed using commercially available software SPSS (statistical package for social sciences) version 20.0. Mean of ADC values for each Gleason score calculated independently laterally with SD. Range similarly computed. For pairwise comparisons between ADC values in low Gleason score⁶ and intermediate and higher scores (7 and more), the ROC (Receiver Operating Characteristics) curve was employed for sensitivity, specificity, and cut off value calculation. The diagnostic presentation was evaluated by computing the area below the curve and a p<0.05 was considered statistically significant.

Results

Our study included 35 males with a mean age of 68±7 years old, these patients were under radical prostatectomy and/or transrectal prostate biopsy with histopathological diagnosis of prostate carcinoma. In the peripheral zone of the prostate, all places of tumor found on histopathology. Figure 1 and 2 shows the T2- weighted MRI, diffusion image, and ADC value and measurement of two patients with prostate cancer examined at our institution.

Figure 1
(A): T2-weighted MRI of a 63-year-old prostate cancer patient and (B) corresponding DWI and (C) ADC map with cancer demonstrated as a small nodule of low T2 and corresponding high DWI and low ADC signal involving the peripheral zones on the left at the apex of the gland.

Figure 2
(A): T2-weighted MRI of a 79-year old prostate cancer patient with GS of 8 and (B) corresponding ADC map and (C) DWI images showing invasion of the bladder base and extension beyond the prostate capsule on the left base PZ.

The mean ADC values of different Gleason scores of tumors are given in Table 1.

GS of (6) in 13 patients, ADC value was (0.99± 0.19) x 10̄³ mm²/s). In 9 patients with GS 7, the (mean ± SD) ADC value was (0.7 ± 0.1) x 10̄³ mm²/s). GS of (8) in 9 patients, ADC value was (0.58 ± 0.088) x 10̄³ mm²/s), GS of (9) in 4 patients, ADC value was (0.48 ± 0.06) x 10̄³ mm²/s). There was a negative significant association between ADC values in PZ cancer and tumor Gleason score (Figure 3).

Figure 3
Demonstrates the inverse relationship between ADC values and Gleason score

Since lesions with a Gleason score of (6) are associated with better prognosis, we tried to assess the difference in lesions ADC mean with GS (6) form those GS (7) or more, as shown in table (2)

However, among the groups, the radiologist has detected ADC value difference and overlap as seen in Figure 4.

Figure 4
The association between ADC values in carcinoma of prostate and Gleason scores

Figure 5 shows the receiver operating characteristics (ROC) curve we used for the correlation between low vs intermediate and high GS and ADC values, the area under the curve (AUC) of the ROC curve was 0.946 (95% confidence interval 0.897‒0.919) indicating excellent correlation. Also, an ADC of 0.75 x 10̄³ mm²/s considered the best cutoff point for determining prostatic malignancy with a (6) GS, with 93% sensitivity and specificity, meaning that values of less than 0.75x x 10̄³ mm²/s are strongly associated with GS of 7 or more.

Figure 5. Evaluation of cutoff (ADC) value to calculate Gleason 6 disease. The area below the curve=0.946

Discussion

The appearance of prostate cancer on DWI as foci of diffusion limit in with matching low signal on ADC recording is fit recognized by numerous studies^{4,19,20,21,24}. The basis for this appearance on DWI and ADC is increased water proton in the fast-dividing tumor cells, dense tumor cellularity giving restricted movements of water in the space outside the cells, therefore, decrease ADC values in comparison to the healthy prostatic tissue¹⁸. Likewise, it is possible that decreased ADC values in the higher GS group were the result of restricted motion of water molecules due to increased tumor cellularity. However, for possible correlation between tumor aggressiveness and ADC value of tumor foci, few prior studies were conducted to prove such association and to our knowledge, no similar study was done in our community. Our study showed that there is a strong negative association between the peripheral zone prostate cancer ADC value of and GS of the cancer foci, this result was reliable with previous studies stated that ADC values may be useful in differentiating patients with high, intermediate from patients with a low risk of prostatic carcinoma^1,8,16,26-29. Other studies, reveal the results like to current study, the ADC values: patients with high GS (4+3) ADC lower than patients with high GS (3+3 and 3+4), but no future cut off point to distinguish low from high or intermediate Gleason scores⁸. Doo et al., and Yasushi et al.³⁰, also agreed with our study and reported that ADC values could provide a mean of differentiating lesions with a GS of 6 with mean ADC values of (0.875 × 10-3 mm2/s) from those with a GS of at least 7 with mean ADC of (0.779 × 10-3 mm2/s)²⁶. Our results showed that lesions with a Gleason score of 6 had mean ADC of (0.998× 10-3 mm2/s) and those with GS at least 7 had mean ADC of (0.593× 10-3 mm2/s) which is different from those obtained in the Doo et al. in their study, possibly due to the difference in the studied population, study design as our study is retrospective, while Doo et al. is a prospective study. Hambrock et al. evaluated prostate cancer aggressiveness using a 3.0-T MRI with DWI, concluding that ADC values can be very effective in the differentiation of low- vs intermediate and high-grade prostate cancer foci. The median ADC values are given in their results for low, intermediate, and high-grade tumors were 1.30×10(-3) mm (2)/sec, 1.07×10(-3) mm (2)/sec, and 0.94×10(-3) mm (2)/sec respectively. Their ROC curve established a strong correlation between lowering ADC and higher Gleason Scores, but they measured median rather than mean ADC, and they used 3T MRI as opposed to 1.5 T MRI scanner used in our study²⁸. Kim et al., also concluded the presence of a negative correlation between ADC values and the GS in prostatic carcinoma, that it was probable to distinguish GS⁶ illness (meaning low grade with good prognosis) form intermediate and high GS (7 and more) according to ADC values, in their study, however, they have proposed cut off value of differentiation between Gleason score of 6 and higher scores was (0.830×10-3 mm2/s) were lower ADC values were mentioned to be significantly associated with intermediate and high-risk prostate cancer (GS 7 or higher disease)²⁹. The absolute measured ADC values are noted to vary among different centers, possibly attributed to causes such as the project and form of MRI scanner, its field strength, the adapted imaging sequence, use of endorectal as opposed to pelvic array coils, and the diffusion b-values adapted in the diffusion protocol.

Conclusion

Based on our study, the tumor Gleason Score, and thus the biological aggressiveness of the tumor may be inferred from the ADC values of the tumor. A probable cut off ADC value of 0.75x10̄³ mm²/s may discriminate between GS of 6 representing low-grade good prognosis tumor (demanding only watchful waiting) vs higher grade tumors with GS of 7 or more (requiring active management plan). Thus, these result may assist in guiding treatment and giving insight into patient’s prognosis.

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