Lisanne de Koster

413 [18F]FDG uptake and expression of immunohistochemical markers 8 Introduction Positron emission tomography/computed tomography (PET/CT) using the glucose analogue 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) visualizes (increased) metabolic activity in tissues and is successfully applied for the diagnosis, staging and monitoring of many types of cancers and inflammatory disorders [468]. [18F]FDG-PET/CT exploits the Warburg effect, a well-known phenomenon in oncology describing the altered metabolism in malignancies: as compared to a low rate of glycolysis followed by oxidative phosphorylation in normal tissues, increased glycolysis and lactic fermentation is observed in cancer, even in the abundancy of oxygen and functioning mitochondria [609]. In differentiated thyroid carcinoma (DTC), higher [18F]FDG uptake is associated with more aggressive histopathology, tumour dedifferentiation, BRAFV600E mutations, and other features related to an adverse prognosis [40, 498, 499, 610, 611]. In thyroid nodules of indeterminate cytology (defined as Bethesda classification category III or IV), a negative [18F]FDG-PET/CT accurately rules out malignancy with a 94% sensitivity and could avoid 40% of futile diagnostic surgeries for benign nodules [18, 501]. The specificity of [18F]FDG-PET/CT in cytologically indeterminate thyroid nodules, however, is mere 40% as many benign nodules also show increased (false-positive) [18F]FDG uptake [501]. It is currently only partly understood which alterations in the glucose metabolism underly the differences in [18F]FDG uptake among various types of benign and malignant thyroid nodules. In tumorigenesis in general, increased glucose influx into the cell by increased expression of glucose transporters (GLUT) is considered the primary mechanism behind the upregulated glucose metabolism [612-614]. Next, upregulation of the enzyme hexokinase (HK) causes increased glucose phosphorylation as the initiating step in glycolysis. As [18F]FDG-6-phosphate, in contrast to glucose6-phosphate, cannot be degraded, HK activity results in increased accumulation of [18F]FDG [612]. Although [18F]FDG uptake cannot be considered a surrogate for tumour hypoxia, the expression of hypoxia-inducible factor-1 alpha (HIF1a) has been associated with [18F]FDG uptake [615-617]. HIF1a is a major glycolytic transcription factor, regulating the expression of many hypoxia- and glycolysisrelated enzymes, including GLUT, monocarboxylate transporter 4 (MCT4), and carbonic anhydrase IX (CA-IX) [618]. Whereas MCT4 transports the lactate formed during (an)aerobic glycolysis out of the cell, CA-IX neutralizes the accompanying pH disturbances by regulating the reversible hydration of carbon dioxide [615, 619-621]. MCT4 and CA-IX are also upregulated by intracellular acidification resulting from lactate formation following aerobic glycolysis [618, 622]. As a part of tumour growth and progression, [18F]FDG uptake is also associated with increased cell proliferation, reflected by the expression of nuclear protein Ki-67, which, in turn, is associated with tumour aggressiveness [623-625]. Moreover, vascular endothelial growth factor (VEGF) promotes tumour cell growth and is one of the main factors involved in angiogenesis in cancer, induced by hypoxia through HIF1α [626, 627]. As glucose delivery is a function of perfusion, VEGF expression

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