Correlation Between In Vivo F-18-FDG PET and Immunohistochemical Markers of Glucose Uptake and Metabolism in Pheochromocytoma and Paraganglioma

Anouk van Berkel, Jyotsna U. Rao, Benno Kusters, Tuna Demir, Eric Visser, Arjen R. Mensenkamp, Jeroen A. W. M. van der Laak, Egbert Oosterwijk, Jacques W. M. Lenders, Fred C. G. J. Sweep, Ron A. Wevers, Ad R. Hermus, Johan F. Langenhuijsen, Dirk P. M. Kunst, Karel Pacak, Martin Gotthardt, Henri J. L. M. Timmers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

47 Citations (Web of Science)

Abstract

Pheochromocytomas and paragangliomas (PPGLs) can be localized by F-18-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 F-18-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 F-18-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 = 9.049), and MCT-4 (P = 0.020). Conclusion: The activation of aerobic glycolysis in SDHx-related PPGLs is associated with increased F-18-FDG accumulation due to accelerated glucose phosphorylation by hexokinases rather than increased expression of glucose transporters.
Original languageEnglish
Pages (from-to)1253-1259
JournalJournal of Nuclear Medicine
Volume55
Issue number8
DOIs
Publication statusPublished - Aug 2014

Keywords

  • pheochromocytoma
  • paraganglioma
  • succinate dehydrogenase
  • Warburg effect
  • F-18-fluorodeoxyglucose positron emission tomography

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