Clinicopathological correlation of pre-biopsy quantitative PSMA uptake in patients with persistently raised serum PSA: initial experience in 74 patients with simultaneous 68-Ga PSMA PET/MRI

Background Gallium 68 (68Ga) prostate-specific membrane antigen (PSMA) PET/MRI may improve detection of clinically significant prostate cancer (CSPC). Purpose To compare the sensitivity and specificity of 68Ga-PSMA PET/MRI with multiparametric MRI for detecting CSPC. Materials and Methods Men with prostate specific antigen levels of 2.5-20 ng/mL prospectively underwent 68Ga-PSMA PET/MRI, including multiparametric MRI sequences, between June 2019 and March 2020. Imaging was evaluated independently by two radiologists by using the Prostate Imaging Reporting and Data System (PI-RADS) version 2.1. Sensitivity and specificity for CSPC (International Society of Urological Pathology grade group ≥ 2) were compared for 68Ga-PSMA PET/MRI and multiparametric MRI by using the McNemar test. Decision curve analysis compared the net benefit of each imaging strategy. Results Ninety-nine men (median age, 67 years; interquartile range, 62-71 years) were included; 79% (78 of 99) underwent biopsy. CSPC was detected in 32% (25 of 78). For CSPC, specificity was higher for 68Ga-PSMA PET/MRI than multiparametric MRI (76% [95% CI: 62, 86] vs 49% [95% CI: 35, 63], respectively; P < .001). Sensitivity was similar (88% [95% CI: 69, 98] vs 92% [95% CI: 74, 99], respectively; P > .99). For PI-RADS 3 lesions, specificity was also higher for 68Ga-PSMA PET/MRI than for multiparametric MRI: 86% (95% CI: 73, 95) versus 59% (95% CI: 43, 74), respectively (P = .002). Decision curve analysis showed that biopsies targeted to PSMA uptake increased the net benefit of multiparametric MRI only among PI-RADS 3 lesions. The net benefit of targeted biopsy for a PI-RADS 3 lesion with PSMA uptake was higher across all threshold probabilities over 8%. The net benefit of targeted biopsy was similar for PI-RADS 4 and 5 lesions, regardless of PSMA uptake. Conclusions Gallium 68 prostate-specific membrane antigen PET/MRI improved specificity for clinically significant prostate cancer compared with multiparametric MRI, particularly in Prostate Imaging Reporting and Data System grade 3 lesions. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Williams and Estes in this issue.

Invited Commentary: Changing Landscape of Imaging in Recurrent Prostate Cancer.

Background Multiparametric MRI (mpMRI) is effective for detecting prostate cancer (PCa); however, there is a high rate of equivocal Prostate Imaging Reporting and Data System (PI-RADS) 3 lesions and false-positive findings. Purpose To investigate whether fluorine 18 (18F) prostate-specific membrane antigen (PSMA) 1007 PET/CT after mpMRI can help detect localized clinically significant PCa (csPCa), particularly for equivocal PI-RADS 3 lesions. Materials and Methods This prospective study included participants with elevated prostate-specific antigen (PSA) levels referred for prostate mpMRI between September 2020 and February 2022. 18F-PSMA-1007 PET/CT was performed within 30 days of mpMRI and before biopsy. PI-RADS category and level of suspicion (LOS) were assessed. PI-RADS 3 or higher lesions at mpMRI and/or LOS 3 or higher lesions at 18F-PSMA-1007 PET/CT underwent targeted biopsies. PI-RADS 2 or lower and LOS 2 or lower lesions were considered nonsuspicious and were monitored during a 1-year follow-up by means of PSA testing. Diagnostic accuracy was assessed, with histologic examination serving as the reference standard. International Society of Urological Pathology (ISUP) grade 2 or higher was considered csPCa. Results Seventy-five participants (median age, 67 years [range, 52-77 years]) were assessed, with PI-RADS 1 or 2, PI-RADS 3, and PI-RADS 4 or 5 groups each including 25 participants. A total of 102 lesions were identified, of which 80 were PI-RADS 3 or higher and/or LOS 3 or higher and therefore underwent targeted biopsy. The per-participant sensitivity for the detection of csPCa was 95% and 91% for mpMRI and 18F-PSMA-1007 PET/CT, respectively, with respective specificities of 45% and 62%. 18F-PSMA-1007 PET/CT was used to correctly differentiate 17 of 26 PI-RADS 3 lesions (65%), with a negative and positive predictive value of 93% and 27%, respectively, for ruling out or detecting csPCa. One additional significant and one insignificant PCa lesion (PI-RADS 1 or 2) were found at 18F-PSMA-1007 PET/CT that otherwise would have remained undetected. Two participants had ISUP 2 tumors without PSMA uptake that were missed at PET/CT. Conclusion 18F-PSMA-1007 PET/CT showed good sensitivity and moderate specificity for the detection of csPCa and ruled this out in 93% of participants with PI-RADS 3 lesions. Clinical trial registration no. NCT04487847 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Turkbey in this issue.

Simple SummaryThe newest Prostate Imaging Reporting and Data System (PI-RADS) version 2.1, was published in 2019. There are a few variations of the new standard, which will change prostate lesions’ classification rules. Our study aims to analyze the pattern change of lesion positron emission tomography (PET) standardized uptake values maximum (SUVmax) distribution under PI-RADS V2.1, compared with PI-RADS V2.0. Moreover, we studied the correlation between prostate-specific membrane antigen (PSMA) SUVmax and magnetic resonance imaging (MRI) PI-RADS. So far, there is no article reporting the effect of the newest PI-RADS on [68Ga]Ga-PSMA-11 PET/MRI. We did a thorough analysis, including two subgroups, peripheral zone, transitional zone, and 215 lesions. We analyzed the impact of each variation of PI-RADS one by one.Purpose: We aimed to evaluate the correlation between PSMA uptake and magnetic resonance imaging (MRI) PI-RADS of simultaneous [68Ga]Ga-PSMA-11 PET/MRI regarding PI-RADS version 2.0 and 2.1 respectively and compared the difference between these two versions. Materials and Methods: We retrospectively analyzed a total of forty-six patients with biopsy-proven prostate cancer who underwent simultaneous [68Ga]Ga-PSMA-11 PET/MRI. We classified the lesions regarding PI-RADS version 2.0 and 2.1, peripheral zone (PZ), and transitional zone (TZ), respectively. Based on regions of interest (ROI), standardized uptake values maximum (SUVmax), and corresponding lesion-to-background ratios (LBR) of SUVmax of each category, PI-RADS score 1 to 5, were measured. A comparison between PI-RADS version 2.0 and PI-RADS version 2.1 was performed. Results: A total of 215 focal prostate lesions were analyzed, including two subgroups, 125 TZ and 90 PZ. Data are reported as median and interquartile range (IQR). Regarding PI-RADS version 2.1, TZ SUVmax of each category were 1.5 (0.5, 1.9), 1.9 (0.8, 2.3), 3.3 (2.1, 4.6), 4.2 (3.1, 5.7), 7.3 (5.2, 9.7). PZ SUVmax of each category were 1.0 (0.8, 1.6), 2.5 (1.5, 3.2), 3.3 (1.9, 4.5), 4.3 (3.0, 5.4), 7.4 (5.0, 9.3). Regarding the inter-reader agreement of the overall PI-RADS assessment category, the kappa value was 0.723 for version 2.0 and 0.853 for version 2.1. Conclusion: Revisions of PI-RADS version 2.1 results in variations in lesions classification. Lesions with the PI-RADS category of 3, 4, and 5 present relatively higher intraprostatic PSMA uptake, while lesions with the PI-RADS category of 1 and 2 present relatively lower and similar uptake. Version 2.1 has higher inter-reader reproducibility than version 2.0.

18F-PSMA-1007 PET/CT Detects Micrometastases in a Patient With Biochemically Recurrent Prostate Cancer.

The current study was designed to test the diagnostic performance of 68Ga-prostate-specific membrane antigen (PSMA) PET and multiparametric MRI along with clinical parameters in the characterization of prostatic lesions. Eighty-two men with 63 malignant and 21 benign histologically proven prostate lesions who underwent complete clinical workup were included in this retrospective study. All patients underwent simultaneous whole-body 68Ga-PSMA PET/MRI with dedicated multiparametric MRI. Prostate Imaging-Reporting and Data System (PI-RADS) version 2 assessment was used for predicting the likelihood of cancer. Uptake of 68Ga-PSMA was recorded by adopting the copy-and-paste function of ROIs defined on MR images. ROC and combined ROC analyses were performed to test the diagnostic accuracy of individual and combined parameters. Spearman analysis was used to assess the correlations. PSMA uptake (maximum standardized uptake value) was significantly different among tumors with Gleason scores of 7, 8, and 9, with the lowest uptake in tumors with a score of 7 and the highest uptake in tumors with a score of 9. There was a significant difference between early- and delayed-phase PSMA uptake in malignant prostatic lesions (p < 0.01). Significant correlations were observed between delayed and differential PSMA uptake and PI-RADS category (p < 0.01 and < 0.01, respectively), digital rectal examination findings (p = 0.01 and < 0.01, respectively), Gleason score (p = 0.05 and < 0.05, respectively), and prostate-specific antigen levels (p = 0.01 for both). Combined ROC analysis of prostate-specific antigen levels, digital rectal examination findings, multiparametric MRI, and differential PSMA uptake were able to characterize prostatic lesions with a mean (± SD) AUC of 0.94 ± 0.03, compared with their individual AUCs of 0.77, 0.70, 0.82, and 0.88. Gallium-68-PSMA PET combined with multiparametric MRI showed high diagnostic accuracy for prostate cancer diagnosis compared with either multiparametric MRI or PET alone or with clinical factors (e.g., digital rectal examination or prostate-specific antigen level) alone, and the combination further improves characterization of prostatic lesions.

To investigate the additive role of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) independent from multiparametric magnetic resonance imaging (mpMRI) and clinical-pathological parameters to predict pathological upgrading in patients with ISUP grade group (GG) 1 prostate cancer (PCa) at prostate biopsy. A total of 41 patients who underwent robotic radical prostatectomy (RP) for GG1 disease at prostate biopsy with preoperative PSMA PET/CT and mpMRI images available for central review were included in the study. Univariate and multivariate logistic regression analyses were performed to determine the independent predictors of pathological upgrading (GG ≥ 2). Final RP pathology revealed upgrading in 26 patients (65.9%); to GG 2 disease in 25 cases and GG 4 disease in one case. International Society of Urological Pathology (ISUP) upgrading rates for prostate imaging-reporting and data system (PIRADS)-5, PIRADS-4, and PIRADS ≤ 3 lesions were 78%, 74%, and 38%, respectively. Fourteen out of 15 (93.3%) patients with an SUVmax ≥ 5.6 and all patients with an SUVmax ≥ 6.5 (n = 10) had pathological upgrading. The upgrading rate in patients with SUV < 5.6 was 46.2% (12/26). Intraprostatic SUVmax ≥ 5.6 was found as the only independent predictor of pathological upgrading in multivariate analysis. High prostatic PSMA uptake was found to be a very reliable predictor of pathological upgrading, but low PSMA uptake cannot exclude pathological upgrading. Intraprostatic PSMA uptake along with previously known mpMRI and biopsy-related parameters should be considered when making a treatment decision in patients with GG1 PCa at prostate biopsy.

DETECTION OF MICROMETASTATIC PROSTATE CANCER CELLS IN THE LYMPH NODES BY REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION IS PREDICTIVE OF BIOCHEMICAL RECURRENCE IN PATHOLOGICAL STAGE T2 PROSTATE CANCER.

Prostate specific membrane antigen (PSMA) directed radioligand therapy (RLT) is a novel therapy for metastatic castration-resistant prostate cancer (mCRPC) patients. However, it is still poorly understood why approximately 40% of the patients does not respond to PSMA-RLT. The aims of this study were to evaluate the pretreatment PSMA expression on immunohistochemistry (IHC) and PSMA uptake on PET/CT imaging in mCRPC patients who underwent PSMA-RLT. We correlated these parameters and a cell proliferation marker (Ki67) to the therapeutic efficacy of PSMA-RLT. In this retrospective study, mCRPC patients who underwent PSMA-RLT were analyzed. Patients biopsies were scored for immunohistochemical Ki67 expression, PSMA staining intensity and percentage of cells with PSMA expression. Moreover, the PSMA tracer uptake of the tumor lesion(s) and healthy organs on PET/CT imaging was assessed. The primary outcome was to evaluate the association between histological PSMA protein expression of tumor in pre-PSMA-RLT biopsies and the PSMA uptake on PSMA PET/CT imaging of the biopsied lesion. Secondary outcomes were to assess the relationship between PSMA expression and Ki67 on IHC and the progression free survival (PFS) and overall survival (OS) following PSMA-RLT. In total, 22 mCRPC patients were included in this study. Nineteen (86%) patients showed a high and homogenous PSMA expression of >80% on IHC. Three (14%) patients had low PSMA expression on IHC. Although there was limited PSMA uptake on PET/CT imaging, these 3 patients had lower PSMA uptake on PET/CT imaging compared to the patients with high PSMA expression on IHC. Yet, no correlation was found between PSMA uptake on PET/CT imaging and PSMA expression on IHC (SUVmax: R2=0.046 and SUVavg: R2=0.036). The 3 patients had a shorter PFS compared to the patients with high PSMA expression on IHC (HR: 4.76, 95% CI: 1.14-19.99; P=.033). Patients with low Ki67 expression had a longer PFS and OS compared to patients with a high Ki67 expression (HR: 0.40, 95% CI: 0.15-1.06; P=.013) CONCLUSION: The PSMA uptake on PSMA-PET/CT generally followed the PSMA expression on IHC. However, heterogeneity may be missed on PSMA-PET/CT. Immunohistochemical PSMA and Ki67 expression in fresh tumor biopsies, may contribute to predict treatment efficacy of PSMA-RLT in mCRPC patients. This needs to be further explored in prospective cohorts.

The novel Gallium-68 prostate-specific membrane antigen (PSMA)-bis [2-hydroxy-5-(carboxyethyl)benzyl] ethylenediamine-diacetic acid positron emission tomography (PET) tracer is increasingly used in the evaluation of prostate cancer, particularly in the detection of recurrent disease. However, PSMA is expressed in nonprostatic tissues, as well as in other pathologic conditions. Here we illustrate such interpretive pitfalls with relevant images that one may encounter while reporting PSMA PET/CT. This study aims to show variation in physiological distribution of PSMA activity and uptake in various benign and neoplastic disorders that may be misinterpreted as prostatic metastatic disease. These pitfalls are illustrated to enhance awareness, aiding a more accurate interpretation of the study. Retrospective database of all (68)Ga PSMA PET/CT was created and reviewed. In total, 1115 PSMA PET/CT studies performed between February 27, 2015, and May 31, 2017, were reviewed. Any unusual uptake of PSMA was documented, described, and followed up. All cases were then subdivided into the following 4 categories: physiological uptake, benign pathological uptake, nonprostatic neoplastic uptake, and miscellaneous uptake. A variety of nonprostatic tissues and lesions, including accessory salivary gland, celiac ganglion, gall bladder, Paget's bone disease, reactive lymph nodes, non–small cell lung cancer, renal cell cancer, and neuroendocrine tumor, were found to show PSMA uptake. PSMA uptake is not prostate-specific and can be taken up physiologically and pathologically in nonprostatic tissue. It is important for reporting physicians to recognize these findings and instigate appropriate investigations when required while avoiding unnecessary procedures in physiological variation.

The aim of this study was to evaluate predictive factors of 68Gallium (68Ga) prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) positivity. Relationships between serum prostate specific antigen (PSA), lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) levels, Gleason Score (GS) and positivity of 68Ga PSMA PET in patients who underwent 68Ga PSMA PET/CT for restaging for PCa were evaluated retrospectively. One hundred and four (median age: 67; range: 51-88) patients were included in this study. Of these patients, PSMA PET was positive in 75 (72%) patients. Mean serum PSA levels for PET negative and positive groups were 0.76±1.00 and 180.85±324.93 ng/mL (P<0.001). The sensitivity and specificity of 68Ga PSMA PET/CT for detection of disease recurrence were calculated as 92% and 80%, respectively, for the 1.4 ng/mL PSA cut-off and 92% and 90%, respectively, for the 2 ng/mL PSA cut-off values. The positivity rates for patients with PSA levels <1.4 ng/mL and ≥1.4 ng/mL were 21% and 90%, respectively (P<0.001). 68Ga PSMA PET/CT seems to be a highly sensitive in patients with early PSA recurrence. Patients with higher GS and early PSA recurrence could benefit from 68Ga PSMA PET/CT.

Objective The objective of this study was to evaluate the clinical utility of gallium-68 [ 68 Ga] prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) with rising prostate-specific antigen (PSA) levels in prostate cancer diagnosis. Methods This is a retrospective, single-center, observational cross-sectional study, which is provided after ethics committee clearance, from May 2, 2022 to June 25, 2022. Study includes sample size of 50 patients with prostate adenocarcinoma with varying PSA levels and Gleason score of 6 to 9 who underwent [ 68 Ga] PSMA PET/CT scan. The patients included in this study underwent PET/CT scan on uMI550 (United Imaging Healthcare, Shanghai, China). Results All patients were divided into three groups based on PSA levels in ng/mL as: PSA ≤ 0.2 (8%), 0.2 < PSA ≤ 1 (10%), 1 < PSA ≤ 3 (8%), 3 < PSA ≤ 10 (18%), and PSA > 10 (56%). Among 50 scans, at least one PSMA avid lesion was visualized in 41 scans (78.9%). These scans were considered positive and included in this study, rest of the scans had insignificant PSMA uptake and were considered negative. [ 68 Ga] PSMA PET/CT detection rates were 75.0, 20.0, 50.0, 88.90, and 89.3% in patients with PSA ≤ 0.2, 0.2 < PSA ≤ 1, 1 < PSA ≤ 3, 3 < PSA ≤ 10, and PSA > 10, respectively. In addition to prostate bed, lesions were also visualized in lymph nodes (32%), liver (2%), skeleton (28%), and thorax (6%). Considering lesions in the prostate bed a significant direct correlation was detected between maximal standardized uptake value (SUVmax) and PSA value ( p = 0.03). Discussion PSMA PET/CT has been demonstrated to be an effective method for identifying both low-grade Gleason score tumors and low PSA levels. The study provides support for the use of [ 68 Ga] PSMA PET/CT in conjunction with PSA levels for the evaluation of prostate cancer, including local recurrence and distant metastases. Conclusion The findings of this study indicate that PSMA PET/CT is an effective method for diagnosing prostate cancer, as it allows for the detection of high SUVmax values in pathological tissues. Furthermore, high sensitivity and detection rates are noted with PSMA PET/CT scan even in cases where PSA levels were low. Therefore, this study demonstrates that [ 68 Ga] PSMA PET/CT is beneficial for the early detection of prostate cancer and the prediction of treatment outcomes.

68Ga-PSMA Positron Emission Tomography/Computerized Tomography for Primary Diagnosis of Prostate Cancer in Men with Contraindications to or Negative Multiparametric Magnetic Resonance Imaging: A Prospective Observational Study

Objective To evaluate the value of semi-quantitative indices of 68Ga-prostate specific membrane antigen (PSMA)-11 PET/CT in differentiating malignant and benign prostate lesions. Methods From November 2017 to June 2018, 30 patients (age: 52-86 years) who underwent 68Ga-PSMA-11 PET/CT imaging in the Third Affiliated Hospital of Sun Yat-sen University were retrospectively analyzed, and the serum total prostate specific antigen (tPSA) and free prostate specific antigen (fPSA) were examined within 1 week before PET/CT imaging. Semi-quantitative indices of 68Ga-PSMA-11 PET/CT on prostate lesions were measured by automatic segmentation algorithm method, including PSMA-related lesion volume (VPSMA), maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), peak standardized uptake value (SUVpeak) and total lesion uptake value of PSMA (TLUPSMA). The indices were compared between malignant and benign prostate lesions, and the optimal cut-off values for differentiating malignant and benign prostate lesions were obtained by receiver operating characteristic (ROC) curve analysis. Results According to the pathological results, 19 patients had malignant lesions and 11 were with benign diseases. The differences of tPSA, SUVmax, SUVmean, SUVpeak and TLUPSMA between malignant and benign prostate lesions were statistically significant (u values: 17.00-48.00, all P 0.05). The optimal cut-off value of tPSA was 18.30 μg/L for differentiating malignant and benign prostate lesions, with sensitivity of 13/17 (PSA of 2 patients were missing), specificity of 9/11 and area under curve (AUC) of 0.743. The optimal cut-off values of SUVmax, SUVmean and SUVpeak were 5.50, 3.09 and 3.56, respectively, with all corresponding sensitivity of 18/19, all specificity of 9/11, and AUC of 0.902, 0.907 and 0.919, respectively. The optimal cut-off value of TLUPSMA was 54.81 cm3, with sensitivity of 14/19, specificity of 9/11 and AUC of 0.804. Conclusion The semi-quantitative indices of 68Ga-PSMA-11 PET/CT are valuable for differentiating malignant and benign prostate lesions, in which SUVpeak is superior to other indices. Key words: Prostatic neoplasms; Prostate-specific membrane antigen; Isotope labeling; Gallium radioisotopes; Positron-emission tomography; Tomography, X-ray computed; Diagnosis, differential

To compare the prostate-specific membrane antigen intraprostatic radiological yield (PRIMARY)-score, prostate-specific membrane antigen (PSMA)-expression score, and lesion standardized uptake value (SUV)max and their combination with multiparametric MRI (MpMRI) for the detection of clinically significant prostate cancer (csPC). Our retrospective study analyzed 381 patients with suspicion of prostate cancer who underwent 68 Ga-PSMA PET/computed tomography (CT) between January 2021 and December 2022. Among these, 170 patients also underwent MpMRI. PSMA-PET/CT were interpreted using PRIMARY score, PSMA-expression score, and lesion SUV. Diagnostic performance of PSMA-PET/CT, MpMRI, and their combination was assessed. Among 381 patients, 244 (64.0%) were diagnosed with csPC. PRIMARY-score demonstrated higher sensitivity (96.3%) and negative predictive value (NPV) (85.9%) compared with PSMA-expression score (sensitivity: 89.7%, NPV: 70.6%) and lesion SUV (sensitivity: 90.6%, NPV: 74.2%). Excellent inter-reader agreement ( κ > 0.85) was seen among the readers for both PRIMARY score and PSMA-expression score. In the subset of 170 patients, SUV-based assessment with a cutoff of 8.2 [area under curve (AUC): 0.79] and PRIMARY-score (AUC: 0.77) showed comparable performance to each other and were seen to be superior to MpMRI (AUC: 0.68) ( P < 0.05). The combination of PRIMARY-score and MpMRI achieved 100% sensitivity and NPV. In Prostate Imaging Reporting and Data System (PIRADS)-positive cases, negative PRIMARY-scores could potentially avoid 13.9% of unnecessary biopsies and positive PRIMARY-scores could detect csPC in an additional 29.3% (12/41) of PIRADS-negative cases. PRIMARY-score showed excellent reproducibility and higher sensitivity and NPV compared with the PSMA-expression score and lesion SUV for detection of csPC. PRIMARY-score also demonstrated an additive benefit for csPC detection when combined with MpMRI while reducing unnecessary biopsies.