Nuclear medicine has emerged at the forefront of precision medicine. Positron emission tomography (PET) has a unique potential that enables noninvasive visualization of a wide variety of physiological and pathological processes at the metabolic and molecular level. The presence of catecholamine synthesis and metabolism, norepinephrine and amino acid transporter systems, somatostatin receptors and GLUT transportrs, and the presence of stromal cells on these tumors guided physicians and scientists to utilize various available radiopharmaceuticals in the assessment of pheochromocytoma and paraganglioma (PPGL). Four emerging PPGL imaging phenotypes have been introduced to these tumors: 1. Pseudohypoxia 18F-FDG imaging phenotype; 2. Stromal cell-succinate 18F-FDG imaging phenotype; 3. Catecholamine metabolism-imaging phenotype; and 4. Somatostatin receptors-imaging phenotype. Thus, now nuclear imaging-based disease phenotyping provides a better understanding of PPGLs with these imaging phenotypes: a pseudohypoxia 18F-FDG imaging phenotype common to all cluster 1 tumors; a stromal cell-succinate 18F-FDG imaging phenotype linked to the presence of succinate dehydrogenase deficiency and due to the hormone-like effect of succinate on 18F-FDG uptake; a catecholamine metabolism-imaging phenotype dependent on both tumor content of catecholamines and the secretion of their metabolites, thereby providing information on PPGLs functional differentiation; and somatostatin receptors-imaging phenotype that further characterizes PPGLs that now enables the selection of patients for peptide receptor radionuclide therapy using somatostatin analogs (agonists and antagonists) that are labeled with therapeutic radioisotopes (such as 90Y,177Lu or alpha emitters).
Furthermore, new trends in the use of 68Ga-labeled somatostatin analogs, 3DMR angiography sequences, and PET in combination with MR, HRMAS NMR spectroscopy for ex-vivo analysis of intact tissue are all becoming promising imaging and diagnostic approaches for these tumors. Moreover, the use of existing or new radiopharmaceuticals in the assessment of glycolysis, hypoxia, apoptosis, angiogenesis, and other tumor characteristics, including specific treatment targets, are being implemented in the evaluation of PPGLs and other tumors. Studies related to the mismatch between anatomical and functional imaging of PPGLs and other tumors, especially in the correct assessment of their therapeutic responses, proper follow up, and treatment continuation, are in progress.
In summary, nuclear endocrinology is becoming a reality and it is predicted to be pivotal in the “behavioral” assessment, proper treatment, and outcome of patients with PPGL and other endocrine tumors. It is expected that in the near future, initial PPGL functional imaging algorithms will be guided by the presence of specific gene mutations, tumor origin (sympathetic vs parasympathetic), and timing (age of the patient) of the development of these tumors reflecting ongoing initiative of personalized medicine.
Acknowledgements
This research was supported by the Intramural Research Program of the NICHD/NIH.