Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein that has shown considerably raised expression in PCa cells and has been successfully used as target for molecular imaging approaches. The density of PSMA expression in malignant prostate cancer has been found to be 1000 times higher compared to normal prostate tissue. For molecular imaging, PSMA can be targeted either with PSMA ligands or antibodies. PSMA targeting ligands get internalized after binding to receptor and undergo endosomal recycling, resulting in increased uptake and retention in PCa cells which can be imaged [1-4].

68Ga-PSMA PET/CT (Positron Emission Tomography) is a relatively new diagnostic modality which targets PSMA binding on PCa cells and has shown potential in detection of nodal/distant metastasis and recurrence in PCa with high accuracy. A meta-analysis reported pooled specificity of 68Ga-PSMA PET/CT for disease staging and restaging to be 84% and 97% respectively. Many studies have evaluated the role of 68Ga-PSMA PET/CT in biopsy proven PCa (done for staging) and evaluated tracer uptake in the primary tumor and compared it with mpMRI [5-6].

Despite increasing clinical use in these clinical settings, the potential of 68Ga-PSMA PET/CT in initial diagnosis of PCa has not been explored much. According to our knowledge, No prospective study has evaluated the role of 68Ga-PSMA PET/CT in suspected PCa     

Aims and Objectives 

To assess the results and diagnostic role of 68Ga-PSMA PET/CT in prostate cancer patients

• Study Design: Prospective pilot study

• Place of Study: This study have been conducted at the Department of Nuclear Medicine, PGIMER Chandigarh in collaboration with the Department Urology, Radiodiagnosis and Histopathology, PGIMER, Chandigarh

Figure 1: Study Methodology

• Period of Study: The study was done during the period between January, 2018 and June, 2019

Inclusion Criteria

• Patients having suspicion of carcinoma prostate on clinical assessment and/or raised serum PSA levels (>4ng/ml)

• Patient not suffering from bleeding diathesis or renalfailure

• Patient consent to participate in thestudy.

Exclusion Criteria

• Patient with prior diagnosed PCa or who underwent prostatic biopsy priorto68Ga-PSMA PET/CT and mpMRI

• Patients with deranged renal function tests orcoagulogram

• Patient refused to participate in thestudy

Study Population

• A total of 44patients suspected for PCa on the basis of clinical assessment and/or raised PSA were recruited for the study

Patients suspected for prostate adenocarcinoma and/or serum PSA levels >4ng/ml and willing to participate in the study were recruited. Study was approved by Institutional Ethics Committee, PGIMER Chandigarh. Written informed consent was obtained. After clinical assessment, mpMRI and68Ga-PSMA PET/CT were done. Biopsy was done in cases with high clinical suspicion of PCa.

Statistical Analysis

Qualitative variables are described using number and percentages. Normally distributed continuous quantitative data is described using mean and standard deviation. Skewed quantitative data is described using median and interquartile range. The normality of data will be checked by measures of Kolmogorov-Smirnov tests of normality. The statistical analysis was conducted using the IBM SPSS STATISTICS (version 23.0)

In this prospective study, a total of 44 patients suspected to have PCa were recruited on the basis of clinical assessment and serum PSA levels. All patients were subjected to 68Ga-PSMA PET/CT acquisition. Out of the total 44 patients, 33 underwent biopsy. The remaining 11 patients did not undergo biopsy after revised clinical assessment based on negative. Therefore, 33 patients underwent 68Ga-PSMA PET/CT and biopsy. 

The mean and SD of the injected 68Ga PSMA radioactivity was 2.79±0.89 mCi (103.2±32.9MBq).The median time between the injection and scan acquisition was 65 min (IQR 32.5 min). Images were acquired according to standardized institutional protocol (described in methods).In Qualitative (Visual) Analysis, visual interpretation of the PET/CT images was done independently by two Nuclear Medicine Physicians. Focal increased tracer uptake in one or more areas of prostate gland was reported as positive for malignancy. Homogenous or inhomogeneous increased tracer uptake in the prostate was considered as negative.

Table 1: Results of 68Ga-PSMA PET/CT

After visual interpretation, 68Ga-PSMA PET/CT data was compared to histopathology (gold standard). Results of 68Ga-PSMA and biopsy findings were shown in Table 1. In this study, malignancy was detected in 16/33 (48.5%) patients on biopsy. In 17/33 (51.5%), no evidence of malignancy was noted.

In the present study 68Ga-PSMA PET/CT showed that 15 patients had positive results and among these 13 patients were found to have adeno-carcinoma on biopsy. Two patients with positive results on 68Ga PSMA PET/CT but negative biopsy (Considered False positive) were closely followed up with serum PSA values. In first patient, serum PSA value was noted to decrease from 5.3 to 4.7ng/ml after 10 months. Repeat biopsy was not done in first patient. In second patient, serum PSA value was noted to increase from 15 to 18.2ng/ml after 12 months. Repeat targeted biopsy in second patient was negative for malignancy.

Three patients had negative 68Ga PSMA PET/CT (homogenous/inhomogeneous uptake) but malignancy was detected on biopsy (False negative on 68Ga PSMA PET). In 2/3 patients, the GS was 3+3 (Grade group 1). mpMRI was not done in both these cases. In both of these, tumor burden was less than 5% on 12 core biopsy. In third case, mass was noted on CT but 68Ga PSMA PET/CT was negative (inhomogeneous tracer uptake). mpMRI showed PIRADS V and GS was 4+4 in this case. In this study, 15 patients had negative results both on biopsy as well as on 68Ga-PSMA PET/CT.

68Ga PSMA PET/CT is a relatively new hybrid functional imaging modality which has been extensively used in PCa in the last decade. The basis of 68Ga PSMA PET/CT is targeting of PSMA receptors which are over expressed (100-1000x) in PCa as compared to normal prostate cells. 68Ga PSMA PET/CT has shown encouraging results in staging, restaging, response assessment and evaluation of biochemical recurrence in PCa. In nearly all prior studies which have evaluated role of 68Ga-PSMA PET/CT in detection of PCa and compared it with MRI, PET-CT was done in histopathologically confirmed PCa cases only. Only one recently published retrospective study by Zhang et al has evaluated accuracy of pre-biopsy 68Ga-PSMA PET-CT in suspected PCa (19).To best of our knowledge, this study is first prospective study to assess the diagnostic role of 68Ga-PSMA PET-CT in patients with suspected prostate adenocarcinoma [4,7].

In this study, malignancy was detected in 16/33 (48.5%) patients on biopsy. In 17/33 (51.5%), no evidence of malignancy was noted. 68Ga-PSMA PET/CT showed that 15 patients had positive results and among these 13 patients were found to have adeno-carcinoma on biopsy. In 3 patients, 68Ga-PSMA PET/CT was false negative (homogenous/in-homogenous uptake pattern) but they were found to have PCa on histopathologicalexamination. Final histopathology revealed adenocarcinoma GS 3+3 (n = 2) and GS 4+4 (n = 1). The reason for false negative 68Ga PSMA PET/CT in these cases can be low tumor burden and low grade tumors/low GS are known to have lower PSMA expression (though no correlation was noted in our study) [8]. Tumors other than adenocarcinoma like neuroendocrine tumor show lower PSMA expression too.9 In the third case, GS was 4+4 but PET/CT was False Negative. The cause of low PSMA expression in this case could not be ascertained. In our study, 3/16 (18.8%) cases were false negative on 68Ga PSMA PET/CT which were almost double compared to study earlier by Zhang et al (8.3 %) [8]. Another study by Uprinmy et al on radical prostatectomy cases showed that 8.9% of the PCa patients were having negative 68Ga PSMA PET/CT and were positive on histopathological examination. [7]. Therefore, 68Ga PSMA PET/CT may not pick 100% of the PCa lesions.

Similarly, 2 patients were found to have false positive findings (Focal high tracer uptake) for PCa on 68Ga-PSMA PET/CT. The reason for false positive could be overexpression of PSMA in benign prostatic tissue [9]. However, possibility of missing the lesion on biopsy is also there. As studied by Woythal et al. TRUS biopsy can miss 30-45% of OCs the cases [10]. By the end of this study, one patient underwent repeat targeted biopsy which did not reveal any malignancy.

In cases in whom no malignancy was detected (True negative) and no focal lesion was noted on 68Ga-PSMA PET/CT, different patterns of uptake were noted. Few of the cases had low homogeneous tracer uptake (PSMA expression) and few were having inhomogeneous/heterogeneous radiopharmaceutical uptake on 68Ga-PSMA PET/CT. During analysis of the images, we found that relatively higher physiological tracer uptake was noted in the posterolateral aspect of base of the prostate gland (at 5 and 7’o clock positions) on a homogenous/in-homogenous background pattern in many cases. These patterns should be kept in mind while assessing PSMA PET for suspected PCa.

68Ga PSMA PET/CT has good accuracy in initial diagnosis of patients with suspected prostatic adenocarcinoma with significantly high PSMA uptake in malignant tumors.

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8. Zhang, J. et al. "Diagnostic performance of 68Ga-PSMA PET/CT in the detection of prostate cancer prior to initial biopsy: Comparison with cancer-predicting nomograms." Eur J Nucl Med Mol Imaging, vol. 46, no. 4, 2019, pp. 908–920.

9. Bakht, M.K. et al."Neuroendocrine differentiation of prostate cancer leads to PSMA suppression." Endocr Relat Cancer, vol. 26, no. 2, 2018, pp. 131–146.

10. Woythal, N. et al. "Immunohistochemical validation of PSMA expression measured by 68Ga-PSMA PET/CT in primary prostate cancer." J Nucl Med, vol. 59, no. 2, 2018, pp. 238–243.