427 [18F]FDG uptake and expression of immunohistochemical markers 8 caused underreporting of any effects. As the study was designed as a secondary and explorative analysis of data acquired during a randomized controlled trial, the current study was not powered in advance to distinguish differences in immunohistochemical staining. In addition, during the interpretation of the data it was assumed that the degree of immunohistochemical expression of metabolic markers positively correlated with the functional activity of these proteins. This assumption may not necessarily be correct and may be considered a general limitation of immunohistochemical studies. For example, immunohistochemical expression of NIS is not an accurate predictor of radioiodine uptake [631]. In conclusion, the positive correlations between [18F]FDG uptake and GLUT1, GLUT3, HK2, and MCT4 expression, and differential expression of GLUT1, HK2, and MCT4 in [18F]FDG-positive benign thyroid nodules and [18F]FDG-positive thyroid carcinomas as compared to [18F]FDG-negative benign nodules in the current study suggest that these [18F]FDG-positive benign nodules undergo metabolic changes similar to those in thyroid carcinomas. Further studies in larger populations are required to confirm the findings of the current explorative study and unravel the underlying cellular mechanisms. A more extensive assessment, including a comparison of the genetic alterations, protein expression, and [18F]FDG-PET/CT results could aid to connect genotype to phenotype. A separate analysis is recommended for Hürthle cell and non-Hürthle cell nodules.
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