New Insights into the Nuclear Imaging Phenotypes of Cluster 1 Pheochromocytoma and Paraganglioma

Abstract

Pheochromocytomas and paragangliomas (PPGLs) belong to the family of neural crest cell-derived neoplasms. In up to 70% of cases they are associated with germline and somatic mutations in 15 well-characterized PPGL driver or fusion genes. PPGLs can be grouped into three main clusters, where cluster 1 includes PPGLs characterized by a pseudohypoxic signature. Although cluster 1 tumors share several common features, they exhibit unique behaviors. We present here unique insights into the imaging phenotypes of cluster 1 PPGLs based on glucose uptake, catecholamine metabolism, and somatostatin receptor expression. Recent data suggest that succinate is a major player in the imaging phenotype of succinate dehydrogenase-deficient PPGLs. This review emphasizes the emerging stromal cell-succinate interaction and highlights new perspectives in PPGL theranostics.

Keywords: (68)Ga-DOTATATE; 6-[(18)F]-fluoro-L-3,4-dihydroxyphenylalanine; gallium radioisotopes; magnetic resonance; paraganglioma; pheochromocytoma; positron emission tomography; radionuclide therapy; somatostatin; theranostics.

Figure 1. Schematic display of succinate targets in SDHx-related PPGLs and mechanisms of uptake of PET radiopharmaceuticals

Glucose is taken up by normal cells via GLUT transporters (GLUTs). Glucose is metabolized via glycolysis to generate pyruvate that undergoes mitochondrial oxidation by the tricarboxylic acid (TCA). Cellular energy status (i.e., ATP levels) is maintained primarily through the electron transport chain and oxidative phosphorylation. SDHx-related mutated cells are characterized by decreased SDH activity with TCA blockade and accumulation of highly elevated concentrations of succinate. Succinate is capable of acting as an intracellular and extracellular messenger. Succinate leads to a set of distinct features via HIF proteins stabilization, despite normal oxygen supply (pseudohypoxia) with increased expression of HIF-target genes (angiogenesis, proliferation, metabolic adaptation), DNA hypermethylation (dedifferentiation, epithelial to mesenchymal transition). Succinate was also shown to promote angiogenesis and activate ¹⁸F-FDG uptake by endothelial cells. ¹⁸F-FDG imaging phenotype of SDHx-related PPGLs can therefore be related to HIF-dependent (pseudohypoxia) and independent (stromal cell-succinate interaction) mechanisms. L-DOPA enters into the neutral amino acid transporter System L (LAT1 or LAT2), which acts as an exchanger and is decarboxylated into dopamine by amino acid decarboxylase (AADC) ; then it is concentrated in catecholamine storage vesicles where it can be further metabolized into norepinephrine (NE) and epinephrine (E). Catecholamines are released by exocytosis. ¹⁸F-FDOPA imaging phenotype is dependent on expression and/or activity of catecholamine synthesizing enzymes (differentiation pattern). SDHx-related PPGLs are characterized by decreased ¹⁸F-FDOPA uptake, due to dedifferentiation and possibly a decrease in intracellular content of aminoacids that are involved in the ¹⁸F-FDOPA influx. ⁶⁸Ga-labeled-SSA uptake is mainly dependent on somatostatin receptors expression. Somatostatin receptor agonists trigger internalization of the ligand receptor-complex, whereas somatostatin receptor antagonists did not but could be better candidates to target tumors. SDHx-related PPGLs exihibit ⁶⁸Ga-labeled-SSA uptake. PHD : prolyl hydroxylase domain proteins, VHL : Von Hippel-Lindau protein, VEGF : Vascular endothelial growth factor, TH : tyrosine hydroxylase.

Figure 2. PET-based imaging phenotyping in a patient with metastatic pheochromocytoma

23-year-old SDHB patient who was first diagnosed with right adrenal pheochromocytoma at the age of 10 presents to us with metastases (hot spots) to the lung (long arrow), liver (short arrow), retroperitoneum, and skeleton. PET images using 4 different radiopharmaceuticals are presented: ⁶⁸Ga-DOTATATE (A), ¹⁸F-FDG (B), ¹⁸F-FDOPA (C), and ¹⁸F-FDA (D). ⁶⁸Ga-DOTATATE identifies more metastatic lesions than ¹⁸F-FDG (B) whereas ¹⁸F-FDOPA (C) shows a doubtful uptake foci in the right lower lung nodule, marked by a long arrow, and ¹⁸F-FDA (D) is essentially negative. This imaging feature is typical of SDHB-related metastatic PHEO.