Correlation of SUVmax and Apparent Diffusion Coefficient Values Detected by Ga-68 PSMA PET/MRI in Primary Prostate Lesions and Their Significance in Lymph Node Metastasis: Preliminary Results of an On-going Study

Objectives: Gallium-68 (Ga-68) prostate specific membrane antigen (PSMA) positron emission tomography (PET) has been shown to be more accurate than multiparametric prostate magnetic resonance imaging (MRI) in detection of primary prostate lesions. Using hybrid PET/MRI we aim to detect the correlation between SUVmax and apparent diffusion coefficient (ADC) in primary prostate lesions and to assess their prognostic value in detection of lymph node (LN) metastasis. Methods: Twenty-six patients, who were diagnosed as having prostate cancer with biopsy and underwent Ga-68 PSMA PET/MRI together with biparametric prostate MRI (bpMRI) were included. SUVmax, SUVmean and ADC were recorded for index lesions drawing a region of interest (ROI) of 1 cm2 around the pixel with the highest SUVmax (ROI-1) and another ROI following borders of prostate tumor detected by bpMRI (ROI-2). Presence of LN metastasis was recorded according to PSMA PET/MRI. Results: SUVmax was inversely correlated with ADC (ROI-1: p=0.010; ROI-2: p=0.017 for b=800). SUVmax and SUVmeans were both higher in patients with LN metastasis and ADC was lower in patients with LN metastasis for ROI-1. SUVmax cut-off value of 19.8 for ROI-1 and 20.9 for ROI-2 had sensitivity and specificity of 77.8% and 76.5%, respectively for detection of LN metastasis, whereas ADC (b=800) cut-off value of 0.92x10-3 mm2/s had sensitivity and specificity of 87.5% and 76.5%, respectively. SUVmax/ADC (b=800) ratio increased the sensitivity and specificity to 100% and 82.4%, respectively. Conclusion: SUV and ADC values are inversely correlated in primary prostate lesions and the combined use of both values increases the diagnostic accuracy of hybrid PET/MRI in the detection of primary prostate lesions.


Introduction
Prostate cancer is the second most common diagnosed cancer in men and the fifth leading cause of cancerrelated death worldwide (1). Death rates are lower in developed countries, due to early detection of the disease and improved treatment methods (1). Prostate specific antigen (PSA) is a glycoprotein produced by prostate cells and though not specific for prostate cancer, elevated PSA values detected by PSA screening was shown to aid in early diagnosis of prostate cancer, thus decrease prostate cancer-related death rates (2,3,4). The screening for prostate cancer is generally made by serum PSA level measurement together with digital rectal examination (DRE). Prostate 12-core needle biopsy under transrectal ultrasonography guidance (TRUS-biopsy) is the most common method used for diagnosis of prostate cancer (5). Multiparametric prostate magnetic resonance imaging (mpMRI) has been introduced as a novel imaging approach for diagnosis and localization of primary prostate lesions (6). MpMRI guided prostate biopsy was shown to be more accurate than conventional TRUS-biopsy (7). Therefore, although mpMRI is not routinely recommended as a screening tool for detection of prostate cancer, it is recommended for patients with elevated PSA values despite negative TRUS-biopsy (8,9,10). The most common sites for metastasis in prostate cancer are bones (84%), distant lymph nodes (LN) (10.6%), liver (10.2%) and thorax (9.1%) (11). However, magnetic resonance imaging (MRI) alone has limited value in detection of LN and distant organ metastasis. Prostate specific membrane antigen (PSMA), which functions on cell membrane as glutamate carboxypeptidase-2 or folate hydrolase, was shown to be over-expressed in prostate cancer cells (12), which led to the introduction of Ga-68 labeled urea-based PSMA inhibitor (Ga-68-PSMA-HBED-CC) as a novel positron emission tomography (PET) tracer used for staging of patients with prostate cancer with high accuracy, for detection of LN and organ metastasis, as well as for detection of residual or recurrent local disease (13). PSMA overexpression in prostate cancer cells was shown to be associated with higher prostate cancer grade, resulting in higher incidence of metastasis and castration resistance (14). Similarly, apparent diffusion coefficient (ADC) value obtained from diffusion-weighted imaging (DWI) component of mpMRI was shown to be inversely correlated with Gleason score and was reported to provide quantitative information on tumor characteristics and aggressiveness (15). Hybrid PET/MRI systems have also been shown to be more accurate than mpMRI in terms of detecting primary prostate lesions (16,17).
The aim of our study is to detect the correlation between maximum and mean standardized uptake value (SUV max and SUV mean ) and ADC values of primary prostate lesions and to assess the prognostic value of SUV max and ADC in terms of detecting LN metastasis.

Materials and Methods
This retrospective study was approved by İstanbul University Clinical Research Ethics Committee (14/01/2019-6927) and conducted between May 2017 and April 2018. All procedures performed in this study involving human participants were in accordance with the ethical standards of the Institutional and/or National Research Committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Study Population
Twenty-six patients, with a mean age of 67.5±7.0 years (median age: 67.5, range: 50-83 years), who were diagnosed as having prostate cancer using TRUS-biopsy and underwent whole body Ga-68 PSMA PET/computerized tomography (PET/CT) or PET/MRI together with prostate PET/MRI including biparametric-MRI (bpMRI) sequences were included in our retrospective analysis. The patients had elevated serum PSA values (mean: 65.2±199.6 ng/ mL, median: 21.4 ng/mL, range: 5.4-934 ng/mL) and they did not receive any previous treatment or did not undergo any operation related with prostate cancer or with benign prostate hyperplasia previously. Patient characteristics are given in Table 1.
All PET/MRI images were acquired using an integrated 3 Tesla -PET/MRI scanner (GE Signa PET/MRI, GE Healthcare, Waukesha, Wisconsin, USA). Prostate PET/MRI including bpMRI was acquired at mean 104.9±43.6 minutes postinjection including an initial localizer scan, a 3D dual-echo fast spoiled gradient recalled echo liver-accelerated volume acquisition sequence (LAVA-FLEX) for MRI based attenuation correction (MRAC), followed by a high-resolution axial T1weighted (T1W) 3D LAVA-FLEX sequence, T2-weighted (T2W) periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) technique at 3-planes (axial, sagittal and coronal) and field of view optimized and constrained undistorted single shot (FOCUS) DWI (b values: 50-400-800 and 50-1400) and ADC mapping. PET emission scan was recorded together with MRI sequences and acquisition time per bed position was 3.5 min. PET attenuation correction was performed using vendor-based algorithm including MRAC data and atlas-based attenuation correction map. A total of 10 patients had a whole-body PET/MRI at mean 87.5±20.3 minutes post-injection in the caudo-cranial direction from mid-thigh to vertex, including an initial localizer scan, 3D LAVA-FLEX for MRAC, high-resolution axial T1W 3D LAVA-FLEX sequence, coronal T2W short-tau inversion recovery (STIR), axial DWI (b values: 50-1000) and ADC mapping. A total of 16 patients had whole-body Ga-68 PSMA PET/ CT images acquired prior prostate PET/MRI using an integrated PET/CT scanner (Siemens Biograph 6, Knoxville, TN, USA or GE Discovery 710, Waukesha, WI, USA) at 71.6±14.4 minutes post-injection. An initial CT topogram was followed by a CT transmission scan and an emission PET scan in the caudo-cranial direction from mid-thigh to vertex. Imaging parameters for transmission CT scan were as follows: Low tube current (130 kVp 48-76 mAs), slice thickness of 4.0 mm, gantry rotation time of 0.6 s and collimator width of 6x3 mm. PET emission scan was acquired at 2-4 min per bed position (GE Discovery PET/ CT: 2 min/bed, Siemens Biography 6 PET/CT: 4 min/bed) at caudo-cranial direction. Iterative image reconstruction method using CT transmission images were utilized for attenuation correction. All patients were asked to empty bladder before initiation of whole-body PET/CT or PET/ MRI as well as prostate PET/MRI acquisition to minimize bladder activity.

Image Analysis
All whole-body PET images (PET/CT and PET/MRI) were reviewed and analyzed by two nuclear medicine physicians (LUB and SA) together and all prostate PET/MRI images including bpMRI sequences were reviewed together with a radiologist (BB) and a nuclear medicine physician (LUB) together using vendor-based work station (GE AW Volume

Results
SUV max , SUV mean and ADC values (for both b=1400 and b=800) obtained from ROI-1 and ROI-2 of the prostate lesion were given in Table 2.
SUV max and SUV mean were significantly higher in patients with LN metastasis for both ROI-1 and ROI-2 (ROI-1: p=0.01 and p=0.01; ROI-2: p=0.02 and p=0.01, respectively) ( Table  4) (Figures 2, 3). Although ADC values were significantly lower in patients with LN metastasis for ROI-1 (p=0.04 for b=1400 and p=0.02 for b=800), there was no significant difference in terms of ADC values in patients with LN metastasis for ROI-2. The ratios of SUV max /ADC and  SUV mean /ADC for both b values (b=1400 and b=800) were significantly higher in patients with LN metastasis for both ROI-1 and ROI-2 (Table 4). ROC analysis revealed that SUV max cut-off level of 19.8 for ROI-1 and 20.9 for ROI-2 predicted the presence of LN metastasis with sensitivity of 77.8% and specificity of 76.5% (Table 5). For SUV mean , cut-off level of 16.3 for ROI-1 and 10.8 for ROI-2 had sensitivity of 77.8% and 88.9% and specificity of 82.4% and 76.5%, respectively. For ADC (b=800) and ADC (b=1400) cut-off levels of 0.92x10 -3 mm 2 /s and 0.82x10 -3 mm 2 /s had sensitivities of 87.5% and 50% and specificities of 76.5% and 82.4%, respectively in prediction of LN metastasis. When SUV/ADC ratios were taken for both SUV max and SUV mean values as well as for both ADC values; sensitivity and specificity increased to 100% and 82.4%, respectively for ROI-1 and to 87.5% and 82.4%, respectively for ROI-2 (Table 5).

Discussion
MpMRI has been introduced as a novel imaging approach for diagnosis, localization and characterization of primary prostate lesions and has been shown to have a good sensitivity for detecting clinically significant prostate cancer and guiding prostate biopsy (19,20). However, despite its several advantages, mpMRI has also some limitations, including poor detection of low-grade disease, low interobserver agreement, poor quality images within six weeks after TRUS-biopsy due to residual hemorrhage and inflammation, limited patient cooperation, especially in   claustrophobic patients and lower sensitivity in transitional zone tumors (19,21). Ga-68 PSMA PET/CT and PET/MRI, on the other hand were shown to have better sensitivity and higher diagnostic accuracy than mpMRI in the detection of primary prostate cancer, both in index lesions and in cases of multifocal disease (17,22,23,24).
Ga-68 PSMA uptake was shown to be correlated with tumor Gleason score, serum PSA levels, PI-RADS category and DRE findings (25). ADC value obtained by mpMRI was also found to be correlated with Gleason scores (26,27), serum PSA levels (28), molecular markers (29) and was introduced to be a promising tool to monitor therapy  response (30,31). To our knowledge, PSMA uptake and ADC values were not compared before using hybrid PET/ MRI or PET/CT systems. However, an inverse correlation between PSMA uptake and ADC values in primary prostate tumor is an expected finding according to the current literature.
Hybrid PET/MRI systems provide better anatomical delineation of prostate gland compared to hybrid PET/ CT systems due to better soft-tissue resolution of the MRI component, and enable one-stop-shop imaging for prostate cancer patients, including Ga-68 PSMA PET and mpMRI in a single session. Therefore, PET/MRI has more potential to aside misdiagnosis due to physiological or false-positive PSMA uptake in the prostate gland (32,33). Also, simultaneous acquisition of PET and MRI images could provide additional advantages, which are not provided by PET/CT systems. However, to date, there are still limited number of studies on Ga-68 PSMA PET/MRI in evaluation of primary prostate tumor and in its diagnostic accuracy compared to PET/CT or mpMRI.
We found higher SUV max and SUV mean values and lower ADC values in patients with LN metastasis, which may be due to the presence of more aggressive tumor with higher Gleason scores, that were documented to have both higher PSMA uptake and lower ADC values in the literature (26,27,34). Concomitant usage of SUV and ADC parameters by using the ratio of SUV/ADC further increased the sensitivity and specificity of PET/MRI imaging in predicting LN metastasis.

Study Limitations
The main limitation in our study was the lack of postoperative histopathological result in our cohort and the small sample size. Therefore, we could not compare PSMA uptake with Gleason scores and we had to evaluate the status of LN metastasis only by Ga-68 PSMA PET imaging. The authors declared that this study received no financial support.