426 chapter 8 and multinodular goitre [626, 634, 642]. In PTC and FTC, CA-IX, VEGF and NIS expression appeared unrelated to [18F]FDG uptake [628, 634, 635]. The Ki-67 proliferation index was higher in FTC than FA [638]. In a single study, the Ki-67 proliferation index was also associated with the SUVmax in PTC [623]. The current study does not resolve the origin of the enhanced glucose metabolism and increased [18F]FDG uptake in the malignant and part of the benign thyroid nodules. In thyroid carcinomas, [18F]FDG uptake likely reflects metabolic alterations caused by oncogenic mutations in various pathways. In PTC, the presence of a BRAFV600E mutation is associated with [18F]FDG uptake and with overexpression of GLUT1, GLUT3, HK2, HIF1a, MCT4, and CA-IX and loss of NIS expression [620, 633, 643, 644]. In vitro studies also suggested the influence of RAS mutations on [18F]FDG uptake [645]. GLUT1 expression is also regulated by the PI3K/AKT/mTOR pathway, and in FTC, loss of function of PTEN increased the membrane expression of GLUT1 in vitro [646, 647]. Thus, at least a part of the benign nodules may carry genetic alterations that cause metabolic changes similar to those in thyroid carcinomas. Hürthle cell neoplasms are considered a separate entity among the follicular cell-derived thyroid neoplasms. They are distinct in their clinical and biological behaviour and carry different genetic alterations, primarily characterized by copy number alterations [484, 648, 649]. Malignant as well as benign Hürthle cell neoplasms are almost without exception strongly [18F]FDG-positive, likely due to the abundance in mitochondria which is a typical feature of oncocytic cells [480, 501]. In two previous studies, the expression of GLUT1, HK2, MCT4, and CA-IX and the Ki-67 proliferation index were higher in Hürthle cell thyroid carcinoma and adenoma as compared to their non-oncocytic counterparts [621, 638]. In the current study, we included two Hürthle cell adenoma and two Hürthle cell carcinoma, all with high SUVmax (range 12.3 to 36.4 g/mL). Similar to literature, all four Hürthle cell lesions also showed remarkable and relatively strong expression of GLUTs, HK2, MCT4, and most other markers (Figure 2). In previous studies in thyroid cancer, correlations were established between various metabolic markers and signs of adverse prognosis. For example, GLUT1 overexpression was associated with tumour dedifferentiation, lymph node metastasis, and shorter overall survival [620, 624, 636, 637]. HIF1a overexpression was associated with metastasis in FTC [619]. A high Ki-67 index was correlated with aggressive malignant behaviour in both PTC and FTC [625, 638]. Loss of NIS expression was associated with tumour dedifferentiation [632, 643]. In Hürthle cell carcinoma, HK2 expression was associated with a tumour size larger than 4 cm, MCT4 with extrathyroidal tumour extension, and CAIX with vascular invasion [621]. In the current study, only a limited number of thyroid carcinoma were included and such prognostic correlations could not be assessed. The main limitations of the current study were its case-control design, which is susceptible to selection bias, and its limited sample size. The latter limited the statistical power and may have
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