PET radiotracers for whole-body in vivo molecular imaging of prostatic neuroendocrine malignancies

Prostatic neuroendocrine malignancies represent a spectrum of diseases. Treatment-induced neuroendocrine differentiation (tiNED) in hormonally treated adenocarcinoma has been the subject of a large amount of recent research. However, the identification of neuroendocrine features in treatment-naïve prostatic tumor raises a differential diagnosis between prostatic adenocarcinoma with de novo neuroendocrine differentiation (dNED) versus one of the primary prostatic neuroendocrine tumors (P-NETs) and carcinomas (P-NECs). While [${}^{18}$F]FDG is being used as the main PET radiotracer in oncologic imaging and reflects cellular glucose metabolism, other molecules labeled with positron-emitting isotopes, mainly somatostatin-analogues labeled with ${}^{68}$Ga and prostate-specific membrane antigen (PSMA)-ligands labeled with either ${}^{18}$F or ${}^{68}$Ga, are now routinely used in departments of nuclear medicine and molecular imaging, and may be advantageous in imaging prostatic neuroendocrine malignancies. Still, the selection of the preferred PET radiotracer in such cases might be challenging. In the current review, we summarize and discuss published data on these different entities from clinical, biological, and molecular imaging standpoints. Specifically, we review the roles that [${}^{18}$F]FDG, radiolabeled somatostatin-analogues, and radiolabeled PSMA-ligands play in these entities in order to provide the reader with practical recommendations regarding the preferred PET radiotracers for imaging each entity. In cases of tiNED, we conclude that PSMA expression may be low and that [${}^{18}$F]FDG or radiolabeled somatostatin-analogues should be preferred for imaging. In cases of prostatic adenocarcinoma with dNED, we present data that support the superiority of radiolabeled PSMA-ligands. In cases of primary neuroendocrine malignancies, the use of [${}^{18}$F]FDG for imaging high-grade P-NECs and radiolabeled somatostatin-analogues for imaging well-differentiated P-NETs is recommended. The preferred PET radiotracer for imaging prostatic neuroendocrine malignancies depends on the specific clinical scenario and pathologic data. When neuroendocrine features result from hormonal therapy for prostate cancer, PET-CT should be performed with [${}^{18}$F]FDG or radiolabeled somatostatin-analogue rather than with radiolabeled PSMA-ligand. When neuroendocrine features are evident in newly diagnosed prostate cancer, differentiating adenocarcinoma from primary neuroendocrine malignancy is challenging but crucial for selection of PET radiotracer and for clinical management.