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Simple Summary  Prostate-specific membrane antigen (PSMA)-targeted therapy represents a promising therapeutic option for the treatment of advanced carcinoma, but data on the relevance of PSMA-targeted diagnostics and therapy for anaplastic (ATC) and poorly differentiated (PDTC) thyroid carcinoma are still lacking. Due to the limited therapeutic options for these entities, the aim of this study was to evaluate to what extent Gallium-68 ( 68 Ga)-PSMA-positron emission tomography/computed tomography (PET/CT) is superior to F-18-Fluordeoxyglucose ( 18 F-FDG)-PET/CT in the diagnostic of ATC/PDTC and could represent a new therapeutic option in terms of theranostic. The findings of this study confirm the high diagnostic sensitivity and superiority of  18 F-FDG-PET/CT in comparison to  68 Ga-PSMA-PET/CT in the diagnosis of ATC and PDTC. However, it can be suggested that  68 Ga-PMSA-PET/CT can be considered as a beneficial adjunct to the well-established  18 F-FDG-PET/CT for a few individual selected patients with ATC and PDTC to detect lesions not discovered by  18 F-FDG-PET/CT and to determine patients’ eligibility for a radioligand therapy. With regard to our results, radiolabelled PSMA-ligands with Lutetium-177 ( 177 Lu)-PSMA may, in the future, represent a theranostic approach with only minor side effects for a few individual selected patients with ATC and PDTC who need alternative treatment options in case of progression when established therapies are no longer effective.    Abstract  Several studies have demonstrated an expression of the prostate-specific membrane antigen (PSMA) in the cancer-related neovasculature of thyroid malignancies. Due to the poor prognosis and limited therapeutic options for patients with anaplastic (ATC) and poorly differentiated (PDTC) thyroid carcinoma, the aim of our study was to investigate the theranostic approach of PSMA expression in these patients. The PSMA uptake on Gallium-68 ( 68 Ga)-PSMA-positron emission tomography/computed tomography (PET/CT) and glucose uptake on F-18-Fluordeoxyglucose ( 18 F-FDG)-PET/CTs were analysed in two ATC and six PDTC patients. The PSMA expression in corresponding patients’ tissue samples was detected by immunohistochemistry. In addition, various tissue sections from 22 ATC and six PDTC patients were examined concerning PSMA expression.  68 Ga-PSMA-PET/CT showed heterogeneous PSMA expression among patients and lesions. Six of the eight analyzed patients (two ATC, four PDTC) showed increased glucose metabolism without increased PSMA uptake after PET/CT. In one patient (PDTC),  18 F-FDG-PET/CT tracer uptake was positive and  68 Ga-PSMA-PET/CT showed heterogeneous results. Another patient (PDTC) evidenced only PSMA-positive lesions and received two cycles of Lutetium-177 ( 177 Lu)-PSMA therapy, which kept his disease stable for seven months. There was a correlation between immunohistochemical PSMA expression and uptake on  68 Ga-PMSA-PET/CT in three of the examined patients. Twenty-seven of the analyzed 39 ATC and 13 of the analyzed 22 PDTC tissue sections showed a strong PSMA expression. Considering the rarity of PDTC and ATC, which is the reason for the small patient population we studied, the findings of this study confirm the high diagnostic sensitivity and superiority of  18 F-FDG-PET/CT in comparison to  68 Ga-PSMA-PET/CT in the diagnosis of ATC and PDTC. However, it can be suggested that  68 Ga-PMSA-PET/CT can be considered as a beneficial adjunct to the well-established  18 F-FDG-PET/CT for a few individual selected patients with ATC and PDTC to detect lesions not discovered by  18 F-FDG-PET/CT and to determine patients’ eligibility for a radioligand therapy. Radiolabelled PSMA-ligands may, in the future, represent a theranostic approach with only minor side effects for a few individual selected patients with ATC and PDTC who need alternative treatment options in case of progression when established therapies are no longer effective. However, due to the small sample size of our collective, larger studies are needed to allow for a final evaluation on the significance of PSMA-targeted diagnostic and therapy for ATC and PDTC.

Prostate-Specific Membrane Antigen in Anaplastic and Poorly Differentiated Thyroid Cancer—A New Diagnostic and Therapeutic Target?