Due to its overexpression on the surface of prostate cancer cells, prostate-specific membrane antigen (PSMA) is a relatively novel effective target for molecular imaging and radioligand therapy (RLT) in prostate cancer. Recent studies reported that PSMA is expressed in the neovasculature of various types of cancer and regulates tumour cell invasion as well as tumour angiogenesis. Several authors explored the role of diagnostic and therapeutic PSMA radioligands in various malignancies. In this narrative review, we describe the current status of the literature on PSMA radioligands’ application in solid tumours other than prostate cancer to explore their potential role as diagnostic or therapeutic agents, with particular regard to the relevance of PSMA radioligand uptake as neoangiogenetic biomarker. Hence, a comprehensive review of the literature was performed to find relevant articles on the applications of PSMA radioligands in non-prostate solid tumours. Data on the general, methodological and clinical aspects of all included studies were collected. Forty full-text papers were selected for final review, 8 of which explored PSMA radioligand PET/CT performances in gliomas, 3 in salivary gland malignancies, 6 in thyroid cancer, 2 in breast cancer, 16 in renal cell carcinoma and 5 in hepatocellular carcinoma. In the included studies, PSMA radioligand PET showed promising performance in patients with non-prostate solid tumours. Further studies are needed to better define its potential role in oncological patients management, especially in those undergoing antineoangiogenic therapies, and to assess the efficacy of PSMA-RLT in this clinical context.

Background: Recent articles proposed the employment of positron emission tomography/computed tomography (PET/CT) with prostate-specific membrane antigen (PSMA)-targeting radiopharmaceuticals in clear cell renal cell carcinoma (ccRCC). Methods: The authors performed a comprehensive literature search of studies on the performance of PET/CT with PSMA-targeting radiopharmaceuticals in ccRCC. Original articles concerning this imaging examination were included in newly diagnosed ccRCC patients and ccRCC patients with disease recurrence. Results: A total of sixteen papers concerning the diagnostic performance of PSMA-targeted PET/CT in ccRCC (331 patients) were included in this systematic review. The included articles demonstrated an excellent detection rate of PSMA-targeting PET/CT in ccRCC. Conclusions: PSMA-targeted PET/CT seems promising in detecting ccRCC lesions as well as in discriminating the presence of aggressive phenotypes. Prospective multicentric studies are warranted to strengthen the role of PSMA-targeting PET/CT in ccRCC.

Background: Recently, several studies introduced the potential use of positron emission tomography/computed tomography (PET/CT) with prostate-specific membrane antigen (PSMA)-targeting radiopharmaceuticals in radioiodine-refractory thyroid cancer (TC). Methods: The authors accomplished a comprehensive literature search of original articles concerning the performance of PSMA-targeted PET/CT in TC patients. Original papers exploring this molecular imaging examination in radioiodine-refractory TC patients undergoing restaging of their disease were included. Results: A total of 6 documents concerning the diagnostic performance of PSMA-targeted PET/CT in TC (49 patients) were included in this systematic review. The included articles reported heterogeneous values of PSMA-targeted PET/CT detection rates in TC, ranging from 25% to 100% and overall inferior to [¹⁸F]-fluorodeoxyglucose PET/CT when the two molecular imaging examinations were compared. Two studies reported the administration of [¹⁷⁷Lu]PSMA-radioligands with theragnostic purpose in three patients. Conclusions: The available literature data in this setting are limited and heterogeneous. The employment of PET with PSMA-targeting radiopharmaceuticals in this setting did not affect patient management. Nevertheless, prospective multicentric studies are needed to properly assess its potential role in TC patients.

Prostate-specific-membrane-antigen/positron-emission-tomography (PSMA-PET) can accurately detect disease localizations in prostate cancer (PCa) patients with early biochemical recurrence/persistence (BCR/BCP), allowing for more personalized image-guided treatments in oligometastatic patients with major impact in the case of bone metastases (BM). Therefore, this study aimed to identify predictors of BM at PSMA-PET in early-BCR/BCP hormone-sensitive PCa (HSPC) patients, previously treated with radical intent (radiotherapy or radical prostatectomy ± salvage-radiotherapy (SRT)). A retrospective analysis was performed on 443 ⁶⁸Ga-PSMA-11-PET/CT scans. The cohort median PSA at PET-scan was 0.60 (IQR: 0.38–1.04) ng/mL. PSMA-PET detection rate was 42.0% (186/443), and distant lesions (M1a/b/c) were found in 17.6% (78/443) of cases. BM (M1b) were present in 9.9% (44/443) of cases, with 70.5% (31/44) showing oligometastatic spread (≤3 PSMA-positive lesions). In the multivariate binary logistic regression model (accuracy: 71.2%, Nagelkerke-R²: 13%), T stage ≥ 3a (OR: 2.52; 95% CI: 1.13–5.60; p = 0.024), clinical setting (previous SRT vs. first-time BCR OR: 2.90; 95% CI: 1.32–6.35; p = 0.008), and PSAdt (OR: 0.93; 95% CI: 0.88–0.99; p = 0.026) were proven to be significant predictors of bone metastases, with a 7% risk increment for each single-unit decrement of PSAdt. These predictors could be used to further refine the indication for PSMA-PET in early BCR/BCP HSPC patients, leading to higher detection rates of bone disease and more personalized treatments.

A 78-year-old man with synchronous diagnosis of prostate cancer and lung adenocarcinoma was referred to our institute for prostate cancer staging with [¹⁸F]F–prostate-specific membrane antigen (PSMA) 1007 PET/CT. In addition to the previously known lesion of the right lung, PSMA-targeted PET/CT highlighted 2 areas of abnormal uptake in the brain, in the left frontal and temporal lobes. A subsequent MRI confirmed the lesions observed on PET/CT. Because PSMA-targeting radiopharmaceuticals do not accumulate in healthy brain parenchyma, and recent literature reported promising performances of PSMA-targeted PET/CT in gliomas and metastases from tumors other than prostate cancer, this employment of PSMA radioligands needs to be further explored.