title: Correlation between in vivo 18F-FDG PET and immunohistochemical markers of glucose uptake and metabolism in pheochromocytoma and paraganglioma.
abstract: Pheochromocytomas and paragangliomas (PPGLs) can be localized by (18)F-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 (18)F-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 (18)F-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).
  
  
  CONCLUSIONS
  The activation of aerobic glycolysis in SDHx-related PPGLs is associated with increased (18)F-FDG accumulation due to accelerated glucose phosphorylation by hexokinases rather than increased expression of glucose transporters.
authors.affiliation: Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Anouk
authors.initials: A
authors.lastname: van Berkel
authors.affiliation: Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands Department of Laboratory Medicine, Laboratory of Genetic, Endocrine and Metabolic Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Jyotsna U
authors.initials: JU
authors.lastname: Rao
authors.affiliation: Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands Department of Pathology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Benno
authors.initials: B
authors.lastname: Kusters
authors.affiliation: Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands Department of Laboratory Medicine, Laboratory of Genetic, Endocrine and Metabolic Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Tuna
authors.initials: T
authors.lastname: Demir
authors.affiliation: Department of Nuclear Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Eric
authors.initials: E
authors.lastname: Visser
authors.affiliation: Department of Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Arjen R
authors.initials: AR
authors.lastname: Mensenkamp
authors.affiliation: Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Jeroen A W M
authors.initials: JA
authors.lastname: van der Laak
authors.affiliation: Department of Urology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Egbert
authors.initials: E
authors.lastname: Oosterwijk
authors.affiliation: Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands Department of Medicine and Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: Jacques W M
authors.initials: JW
authors.lastname: Lenders
authors.affiliation: Department of Laboratory Medicine, Laboratory of Genetic, Endocrine and Metabolic Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Fred C G J
authors.initials: FC
authors.lastname: Sweep
authors.affiliation: Department of Laboratory Medicine, Laboratory of Genetic, Endocrine and Metabolic Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
authors.affiliation: Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Ad R
authors.initials: AR
authors.lastname: Hermus
authors.affiliation: Department of Urology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Johan F
authors.initials: JF
authors.lastname: Langenhuijsen
authors.affiliation: Department of Otolaryngology, Radboud University Medical Centre, Nijmegen, The Netherlands; and.
authors.forename: Dirk P M
authors.initials: DP
authors.lastname: Kunst
authors.affiliation: Eunice Kennedy Shriver, NICHD, National Institutes of Health, Bethesda, Maryland.
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
authors.affiliation: Department of Nuclear Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: Gotthardt
authors.affiliation: Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands Henri.Timmers@radboudumc.nl.
authors.forename: Henri J L M
authors.initials: HJ
authors.lastname: Timmers
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D001692:Biological Transport; D015415:Biomarkers / Q000378:metabolism; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010673:Pheochromocytoma / Q000000981:diagnostic imaging* / Q000378:metabolism*; D049268:Positron-Emission Tomography
chemical_list: D015415:Biomarkers; D019788:Fluorodeoxyglucose F18; D005947:Glucose
keywords: 18F-fluorodeoxyglucose positron emission tomography; Warburg effect; paraganglioma; pheochromocytoma; succinate dehydrogenase