Prostate-Specific Membrane Antigen (PSMA) Expression in The Neovasculature of High Grade Gliomas (Histopathological and Immunohistochemical Study)

Abstract

Background: Prostate-specific membrane antigen (PSMA) was first noticed in prostate cancer cells, thereafter, It has been found in the endothelial cells of neovasculature in a variety of tumors, but not in normal vascular endothelium, This specificity makes PSMA an ideal molecule for vascular targeting in Cancer theranostics (i.e., combined diagnostic and therapeutic). Objectives: The objective of this study was to evaluate the immunohistochemical (IHC) expression of PSMA in the neovasculature (identified by CD 31) of high-grade gliomas (HGGs) and to Correlate PSMA IHC expression in HGGs with clinicopathological features, to detect its possible role in tumor angiogenesis, where PSMA can be used as a future diagnostic and therapeutic target. Materials and Methods: This retrospective study included a total of 69 archived, formalin-fixed, paraffin-embedded tissue blocks of HGGs, including 52 cases classified as WHO grade IV (75.4%) and 17 cases as WHO grade III (24.6%). The samples were immunohistochemically analyzed for PSMA expression (in both TMV and parenchymal tumor cells) which was assessed using the composite PSMA immunostaining score. A score (0) was considered negative while scores 1-7 were considered positive (1-4, 5-6, or 7; weak, moderate, or strong respectively). Results: PSMA is expressed specifically and significantly in endothelial cells of tumor microvessels (TMV) of HGGs, A statistically significant relationship was detected between PSMA IHC expression in both TMV and in parenchymal tumor cells (TC) and various glioma subtypes (P-value < 0.05 and <0.001 respectively). Positive PSMA immunostaining in TMV was detected in all anaplastic ependymoma cases and in near all cases of classic GB and GB with oligodendroglial features more than other subtypes, with P-value specifically for PSMA positivity/negativity in TMV statistically significant (0.022). While for Tumor cells, Positive PSMA immunostaining was detected in all anaplastic ependymoma, most anaplastic astrocytoma and classic GB cases in contrary to other variants, with P-value statistically extremely significant (< 0.001). Comparing PSMA IHC expression in TMV and its expression in TC, it was significantly expressed in TMV of 82.7% versus TC of 51.9% of grade IV cases. Likewise, in GB with oligodendroglial features and gliosarcoma, the majority of cases showed positive staining in their TMV [8/8 (100%), 9/13 (69.2%) respectively], and, the reverse occurs in tumor cells where the majority of cases did NOT show staining in the tumor cells for PSMA (5/8 (62.5%), 11/13 (84.6%) of cases respectively), which was statistically significant (P-value ≤ 0.05) besides the significant difference in the pattern of staining according to composite PSMA scoring (P-value ≤ 0.05). Conclusion: PSMA has a possible role in tumor angiogenesis, therefore it might be considered a potential promising endothelial target for Cancer theranostics with PSMA-based agents, in addition, PSMA was expressed significantly in TC of HGGs, thus, it appears to be involved in biologic be...

Prostate-Specific Membrane Antigen Use in Glioma Management

“…Abdel Maguid et al 21 also recently (2023) found that PSMA expression in endothelial cells of HGG neovasculature are specific and significant. Additionally, increased glioma vascular PSMA staining has been associated with significantly elevated tumor metabolic activity (P < 0.001), significantly shorter median survival time (1.5 years with vs 11.3 years without, P < 0.001), and significantly higher Ki-67 index (42% with vs 8% without, P < 0.001).…”

“…Rat gliomas have been shown to have increased uptake of PSMA tracers in the peritumoral area and areas of strong astrocyte activation and decreased uptake in central areas 16 . Several studies have additionally confirmed high PSMA staining in glioma vasculature 17,18,21 …”

“…The previous few years have seen an immense uptick in PSMA in glioma investigation with 42 publications on the topic from 2020 to date (July 2023). 5,[16][17][18][19][20][21][22][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43]49,56,[60][61][62][63][64][65][66][67][68][69][70][71][72][73][74] These publications mainly focus on 3 fields of study: histopathology of PSMA in gliomas, use of PSMA imaging techniques in glioma diagnosis, and use of PSMA-targeted therapies in the treatment of gliomas.…”

“…16 Several studies have additionally confirmed high PSMA staining in glioma vasculature. 17,18,21 In 2021, Gao et al 69 used clinical GBM specimens from 60 patients to once again confirm that PSMA is highly expressed in the endothelium of vessels of GBM tissues, but not in that of normal tissues, which was significantly correlated with a poor prognosis. This study also hypothesized that PSMA might promote angiogenesis in GBM, a highly vascular tumor, by interacting with integrin β4 and activating the nuclear factor κB signaling pathway.…”