To our knowledge, this work represents the first attempt at demonstrating the inter-racial differences in tumor biology using
68Ga-PMSA-11 PET/CT imaging in men with prostate cancer. In the series presented, with the exception of two primary tumors (2% of the patient population studied), all primary tumors were clearly discernible on
68Ga-PSMA-11 PET/CT imaging. The two patients in whom the primary tumors were not visualized were white South-Africans. Previous studies in Caucasians have reported on a somewhat lower detection rate with 7.1 to 8.9% of primary prostate carcinoma showing no increase or only a slight increase in
68Ga-PSMA-11 accumulation [
14,
15]. More specifically, Maurer et al. observed that out of 130 patients, 8.4% of primary prostate carcinoma showed no increase or only a slight increase in
68Ga-PSMA-11 accumulation when compared to normal prostate tissue 68Ga-PSMA accumulation [
14]. Likewise, Budaüs et al. and more recently Uprimny et al. found a false negative rate for primary prostate carcinoma detection, that is the primary tumor being not distinguishable from the surrounding normal prostate tissue, in respectively 7.1% and 8.9% of patients studied [
15,
16]. The more favorable results obtained in our series may in part relate to the preferential inclusion of black South-Africans. As shown in this study, median
68Ga-PSMA-11 uptake by primary prostate carcinomas normalized for Gleason score, proved significantly higher in black South-Africans when compared with white South-Africans making them more readily discernible from the normal prostate background. The higher uptake of
68Ga-PSMA-11 found in primary prostate carcinoma of black South-Africans when normalized for Gleason core, reflecting PSMA expression and biological activity, may in part explain the more aggressive behavior of prostate carcinoma in black men when compared with white men; respectively, a disproportionate reported advanced disease and a two- to three-times higher mortality from prostate carcinoma in black African men when compared to Caucasians [
1‐
5]. PSMA acts as a glutamate carboxypeptidase on different substrates such as polyglutamated folates and the neuropeptide N-acetyl-l-aspartyl-l-glutamate [
17‐
21]. As shown previously by Lapidus et al., using a N-acetylaspartylglutamate (NAAG) hydrolytic radioenzymatic assay to quantify the enzymatic activity of PSMA in normal, benign prostate hyperplasia (BPH) and prostate cancer tissues from radical prostatectomies, PSMA enzyme activity proved significantly elevated in prostate cancer when compared to normal prostate tissues and BPH [
22]. The major constant product of the enzymatic activity of PSMA is glutamate, which was shown to be present in excess amount in prostate carcinoma, even more so in African-American patients when compared to Caucasian-American research subjects, and to favor higher growth rates and aggressive behavior in human prostate carcinoma cell lines [
21]. Likewise, prostate carcinoma cells where shown to proliferate directly in response to available folate, made available through PSMA-mediated hydrolysis of polyglutamated folates [
19,
20]. PSMA was also shown to facilitate integrin signaling and p21-activated kinase activation, leading to both productive invasion and downregulation of beta1-integrin (a cell-matrix linker), to induce chromosomal instability, to play a VEGF-independent role in neoangiogenesis and to recruit a functionally active complex present in high grade prostate carcinoma patients associated with EGFR phosphorylation [
23‐
26]. The latter receptor, which plays a critical role in prostate cancer signal transduction and progression, was shown to be significantly overexpressed in African Americans when compared to white Americans in a multivariate model after controlling for grade, stage and pretreatment simultaneously [
27].
A statistically significant correlation between
68Ga-PSMA-11 uptake by primary prostate carcinoma and serum PSA values has been previously reported by Sachpekidis et al. and more recently also by Uprimny et al. [
16,
28]. In line with their findings as well as previous studies reporting on elevated immunohistochemical expression and elevated enzymatic activity of PSMA in advanced prostate cancer, we also found a significant correlation between
68Ga-PSMA-11 uptake by primary prostate carcinoma and serum PSA [
22]. This correlation, which was moderate when only patients with localized disease were evaluated, becomes weak following inclusion of all study cohorts in the evaluation. This weakening of relationship after inclusion of patients with metastatic disease probably reflects the decoupling of SUVmax and serum PSA seen in advanced prostate cancer. A limited number of studies have shown previously that serum PSA is determined by both prostate cancer volume as well as by the percentage of high-grade cancer cells at the time of initial diagnosis [
29,
30]. Of interest, both the SUVmax value of the primary tumor and PSA-values proved significantly higher in patients with lymph node involvement and/or distant metastases when compared to those without lymph node involvement and/or distant metastases. The link between elevated PSMA expression by the primary prostate carcinoma and global prostate carcinoma tumor load, as reflected by serum PSA, is currently unclear and has yet to be fully elucidated.
Finally, in the study presented, serum PSA-values in black South-Africans proved significantly higher when compared to white South-Africans, in spite of the absence of a significant difference in the frequency of lymph node and /or lymph node involvement between white and black South-Africans. While this in part reflects the well-documented higher known disease burden found in these patients at initial staging, androgen receptor mutations and polymorphisms regulating PSA production as well as PSA gene polymorphisms between black and white South-Africans may also contribute to this finding [
31,
32]. In this regard, a number of studies reported that black men have higher serum prostate-specific antigen values than white men and that among men undergoing radical prostatectomy, black men present with higher serum PSA values, not related to prostate size or pathological cancer-specific characteristics [
33,
34].