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J Nucl Med. 2014 Aug;55(8):1253-9. doi: 10.2967/jnumed.114.137034. Epub 2014 Jun 12.

Correlation between in vivo 18F-FDG PET and immunohistochemical markers of glucose uptake and metabolism in pheochromocytoma and paraganglioma.

Author information

1
Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
2
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.
3
Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands Department of Pathology, Maastricht University Medical Centre, Maastricht, The Netherlands.
4
Department of Nuclear Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
5
Department of Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
6
Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands.
7
Department of Urology, Radboud University Medical Centre, Nijmegen, The Netherlands.
8
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.
9
Department of Laboratory Medicine, Laboratory of Genetic, Endocrine and Metabolic Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands.
10
Department of Otolaryngology, Radboud University Medical Centre, Nijmegen, The Netherlands; and.
11
Eunice Kennedy Shriver, NICHD, National Institutes of Health, Bethesda, Maryland.
12
Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands Henri.Timmers@radboudumc.nl.

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).

CONCLUSION:

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.

KEYWORDS:

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

PMID:
24925884
DOI:
10.2967/jnumed.114.137034
[Indexed for MEDLINE]
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