Urothelial Carcinoma and Prostate-specific Membrane Antigen: Cellular, Imaging, and Prognostic Implications

Staging, restaging, and surveillance of urothelial carcinoma (UC) is challenging due to suboptimal accuracy of standard of care imaging modalities. Prostate-specific membrane antigen (PSMA) imaging may serve to improve characterisation of UC.

To appraise available literature regarding cellular, imaging, and prognostic implications of PSMA for UC.

A systematic review was performed considering all available literature (including conference abstracts) published from 1990 to 2020 and reported according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines following registration in PROSPERO (CRD42020186744). All relevant texts relating to immunohistochemical analysis and PSMA-based imaging in UC were included and collated. Additionally, FOLH1 (gene encoding PSMA) expression according to The Cancer Genome Atlas (TCGA) database was analysed as well as according to consensus and TCGA molecular classification subtypes and subsequently compared with clinical outcomes.

PSMA expression across UC tumour tissue was heterogeneous (0-100%) but appeared to decrease with increased grade and stage. The TCGA analysis demonstrated loss of FOLH1 expression with increasing T stage (p = 0.0180) and N stage (p = 0.0269), and reduced FOLH1 expression was associated with worse disease-free survival. PSMA expression in UC neovasculature was variable but mostly increased (44-100%). Eleven reports of PSMA-based imaging for UC were identified, reporting on 18 patients. PSMA positron emission tomography (PET) imaging was positive in 17 out of 18 patients. The included literature review data were limited by mostly low-quality, retrospective studies.

Tissue PSMA, or FOLH1 expression, may inversely be associated with pathological and survival outcomes in localised UC. PSMA PET imaging may improve detection of metastatic disease and response to systemic therapy due to PSMA expression in neovasculature. Available evidence is limited; thus, larger, prospective studies are required to confirm early results and define populations that benefit most.

In this systematic review, we assess the potential role of prostate-specific membrane antigen in urothelial cancer. We found that its utility is in expression of blood vessels surrounding metastasis. We conclude that it may be beneficial in detecting metastasis and response to systemic therapies.