PSMA expression in neoplastic cells and tumor-associated vasculature: A tissue microarray study evaluating 12,409 cancers from 135 different tumor types

Prostate-specific membrane antigen (PSMA) is a transmembraneous glycoprotein that serves as a diagnostic and therapeutic target in prostate cancer. Beyond prostate malignancies, PSMA expression can also be detected in tumor cells and in endothelial cells (ECs) of newly formed, tumor-associated blood vessels across various other malignancies. To evaluate the prevalence of PSMA expression in both tumor cells and tumor-associated neovasculature, 12,409 tumors from 135 different tumor types, were analyzed by immunohistochemistry in a tissue microarray format. PSMA positivity in tumor cells was detected in 46 tumor entities, including 13 with at least one strongly positive case. Tumor cell PSMA positivity was frequently observed in prostatic adenocarcinoma (84.2-98.7%), granular cell tumor (76.5%), basal cell adenoma of the salivary gland (64.3%), as well as in endometrial (up to 60.7%) and ovarian carcinomas (up to 13.8%). In prostate cancer, PSMA expression was higher in Gleason 4+4 and 5+5 cancers (96.4-98.7%) compared to Gleason 3+3 cancers (94.7%), while it was lowest in recurrent cancers after hormonal therapy (84.2%; p<0.0001). In breast cancer of no special type, PSMA positivity was linked to high grade (p=0.0451), ER- (p=0.0279), and PR-negativity (p=0.0135). PSMA positivity in ECs of tumor-associated vasculature occurred in 4,888 of 10,658 (45.9%) tumors. 123 tumor entities had at least one case with PSMA positive ECs, 106 included at least one sample with many PSMA-positive vessels and 102 had at least one case with strong vessel positivity. EC PSMA positivity was most frequent in renal cell carcinoma (RCC) (88.7-88.9%), adenocarcinoma of the uterine cervix (82.4%) endometrioid endometrial carcinoma (76.7%), colorectal adenocarcinoma (70.5%), cholangiocarcinoma (66.7%), chondrosarcoma (63.5%), HCC (62.5%), and squamous cell carcinomas from different sites (up to 88.2%). The number of positive vessels tightly correlated with their staining intensity (<0.0001) and both parameters were often associated with features of cancer aggressiveness. PSMA staining quantity and intensity in vessels were associated with tumor stage (p=0.0343), tumor grade (p<0.0001), ER- (p=0.0002) and PR-negativity (p=0.0351) in invasive breast carcinoma, multiple grading and staging systems (p=0.0022-0.0388) in clear cell RCC, Fuhrman grade (p=0.0091) and metastatic disease (p=0.0175) in papillary RCC, pT stage (p<0.0001) in urothelial carcinoma, pT stage (p=0.0459), nodal positivity (p=0.0089) and lymphatic invasion (p=0.0023), mismatch repair (MMR) deficiency (p=0.0178) and BRAF mutations (p=0.0026) in colorectal adenocarcinoma, and MMR deficiency (p=0.0089) in gastric adenocarcinoma. It is concluded that PSMA expression in tumor cells is largely limited to few cancer entities while EC positivity is common in a broad range of cancer types.