422 chapter 8 The expression of GLUT1, HK2, MCT4, and VEGF were statistically significantly different between the TN, FP, and TP groups (Figure 4). Post hoc analysis demonstrated that the expression of GLUT1, HK2, and MCT4 was similarly increased in FP and TP nodules as compared to the expression in TN nodules. VEGF expression was higher in TP as compared to both TN and FP nodules. VEGF expression was similar in TN and FP groups. Discussion When performing and interpreting [18F]FDG-PET/CT scans, we should aim to understand the underlying pathophysiological processes at a cellular and molecular level. In indeterminate thyroid nodules, the specificity of [18F]FDG-PET/CT is limited, as many benign nodules also show increased [18F]FDG uptake [501]. The current explorative study demonstrated that [18F]FDG uptake in indeterminate thyroid nodules was positively correlated with the expression of GLUT1, GLUT3, HK2, and MCT4. [18F]FDG-positive benign thyroid nodules and [18F]FDG-positive thyroid carcinomas with indeterminate cytology showed increased expression of GLUT1, HK2, and MCT4 as compared to the expression in [18F]FDG-negative benign nodules. The expression of VEGF was similar in [18F]FDGpositive and [18F]FDG-negative benign nodules, which was lower than in [18F]FDG-positive thyroid carcinomas. GLUT3 expression was strongly correlated with the SUV metrices, but not statistically significantly different between the TN, FP and TP groups in the current dataset. These results indicate that glucose metabolism-related alterations in the protein expression of [18F]FDG-positive benign thyroid nodules may be similar to alterations occurring in thyroid carcinomas, at least in those deriving from cytologically indeterminate nodules. To the best of knowledge, our study is the first to assess immunohistochemical staining for metabolic markers in comparison to [18F]FDG-PET/CT results in cytologically indeterminate thyroid nodules. The previous, heterogeneous studies of these markers in thyroid carcinomas showed mixed results, possibly hindered by their oftentimes limited sample size and statistical power [623, 628, 634, 635]. An increased expression of GLUTs and HKs was observed in PTC and to a lesser extent in follicular thyroid carcinoma (FTC) as compared to follicular adenoma (FA) and normal thyroid tissue [620, 636, 637, 641]. An association between [18F]FDG uptake and the increased expression of GLUTs and HKs was previously observed in DTC but remained unconfirmed in the latest studies [487, 615, 623, 628, 633-635]. [18F]FDG-positive PTC showed a higher expression of HIF1a as compared to [18F]FDG-negative PTC [615]. Higher expression of MCT4 and CA-IX were previously found in poorly differentiated and anaplastic thyroid carcinoma as compared to PTC and FTC, and in FTC as compared to FA [620, 621]. MCT4 was not previously associated to [18F]FDG uptake in thyroid neoplasms. Increased expression of VEGF was observed in both PTC and FTC as compared to FA
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