PSMA PET imaging was originally used to assess biochemical recurrence of prostate cancer (PCa), but its clinical use was promptly extended to detection, staging and therapy response assessment. The expanding use of PSMA PET worldwide has also revealed PSMA ligand uptake in diverse nonprostatic diseases, which raised questions about the specificity of this imaging modality. Although not very common initially, a growing number of pathologies presenting PSMA uptake on PET have been reported in the last few years, and a proper interpretation of PSMA PET imaging findings suddenly became challenging and, to some extent, confusing. Compared to cytoplasmic PSMA expression in nonprostatic cells, the molecular features of apical PSMA expression in PCa cells can help to distinguish these various conditions. Correlations of imaging findings to patient history, to the expected pattern of disease spread and mainly to computed tomography (CT) and/or magnetic resonance imaging (MRI) characteristics will reinforce the distinction of lesions that are more likely related to PCa from those that could lead to an incorrect diagnosis. The overall benefits of endothelial PSMA expression, which is associated with the neovasculature of malignant neoplasms, will be highlighted, stating the potential use of PSMA ligand uptake as a theranostic tool. This review aims to cover the collection of nonprostatic diseases, including benign and malignant tumors, in a didactic approach according to disease etiology, with discussion of bone-related conditions and inflammatory and infectious processes.

The introduction of prostate-specific membrane antigen (PSMA) in clinical practice has revolutionized evaluation of biochemical recurrence of prostate cancer after curative-intent treatment. The high expression of this glycoprotein in prostate cancer cells makes PSMA imaging superior to the current conventional staging methods, namely bone scanning and CT. The high capability of PSMA imaging for identifying very small previously undetected lesions has been widely demonstrated in the literature, leading to a rethinking of patient management by oncologists, urologists, and radiation oncologists. The typical and predictable patterns of spread in prostate cancer are still more prevalent, such as spread to pelvic lymph nodes and bone metastasis, but different patterns of disease spread are becoming more commonly recognized with higher reliability because PSMA imaging allows detection of more typical and atypical lesions than conventional imaging. Furthermore, it is important for the reading physician to recognize and understand the typical disease spread and the most prevalent atypical prostate cancer relapses, not only to heighten the relevancy of reports but also to improve imaging consultancy in multispecialty oncologic practice. ©

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