RT Journal Article SR Electronic T1 Correlation Between In Vivo 18F-FDG PET and Immunohistochemical Markers of Glucose Uptake and Metabolism in Pheochromocytoma and Paraganglioma JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 1253 OP 1259 DO 10.2967/jnumed.114.137034 VO 55 IS 8 A1 Anouk van Berkel A1 Jyotsna U. Rao A1 Benno Kusters A1 Tuna Demir A1 Eric Visser A1 Arjen R. Mensenkamp A1 Jeroen A.W.M. van der Laak A1 Egbert Oosterwijk A1 Jacques W.M Lenders A1 Fred C.G.J. Sweep A1 Ron A. Wevers A1 Ad R. Hermus A1 Johan F. Langenhuijsen A1 Dirk P.M. Kunst A1 Karel Pacak A1 Martin Gotthardt A1 Henri J.L.M. Timmers YR 2014 UL http://jnm.snmjournals.org/content/55/8/1253.abstract AB Pheochromocytomas and paragangliomas (PPGLs) can be localized by 18F-FDG PET. The uptake is particularly high in tumors with an underlying succinate dehydrogenase (SDH) mutation. SDHx-related PPGLs are characterized by compromised oxidative phosphorylation and a pseudohypoxic response, which mediates an increase in aerobic glycolysis, also known as the Warburg effect. The aim of this study was to explore the hypothesis that increased uptake of 18F-FDG in SDHx-related PPGLs is reflective of increased glycolytic activity and is correlated with expression of different proteins involved in glucose uptake and metabolism through the glycolytic pathway. Methods: Twenty-seven PPGLs collected from patients with hereditary mutations in SDHB (n = 2), SDHD (n = 3), RET (n = 5), neurofibromatosis 1 (n = 1), and myc-associated factor X (n = 1) and sporadic patients (n = 15) were investigated. Preoperative 18F-FDG PET/CT studies were analyzed; mean and maximum standardized uptake values (SUVs) in manually drawn regions of interest were calculated. The expression of proteins involved in glucose uptake (glucose transporters types 1 and 3 [GLUT-1 and -3, respectively]), phosphorylation (hexokinases 1, 2, and 3 [HK-1, -2, and -3, respectively]), glycolysis (monocarboxylate transporter type 4 [MCT-4]), and angiogenesis (vascular endothelial growth factor [VEGF], CD34) were examined in paraffin-embedded tumor tissues using immunohistochemical staining with peroxidase-catalyzed polymerization of diaminobenzidine as a read-out. The expression was correlated with corresponding SUVs. Results: Both maximum and mean SUVs for SDHx-related tumors were significantly higher than those for sporadic and other hereditary tumors (P < 0.01). The expression of HK-2 and HK-3 was significantly higher in SDHx-related PPGLs than in sporadic PPGLs (P = 0.022 and 0.025, respectively). The expression of HK-2 and VEGF was significantly higher in SDHx-related PPGLs than in other hereditary PPGLs (P = 0.039 and 0.008, respectively). No statistical differences in the expression were observed for GLUT-1, GLUT-3, and MCT-4. The percentage anti-CD 34 staining and mean vessel perimeter were significantly higher in SDHx-related PPGLs than in sporadic tumors (P = 0.050 and 0.010, respectively). Mean SUVs significantly correlated with the expression of HK-2 (P = 0.027), HK-3 (P = 0.013), VEGF (P = 0.049), and MCT-4 (P = 0.020). Conclusion: The activation of aerobic glycolysis in SDHx-related PPGLs is associated with increased 18F-FDG accumulation due to accelerated glucose phosphorylation by hexokinases rather than increased expression of glucose transporters.