489 MD and [18F]FDG-PET/CT: complementing techniques or waste of valuable resources? 12 Possible nondiagnostic results due to issues with the quality and quantity of the cytology are considered a downside of MD. Nondiagnostic results occurred in the current study (Figure 1) as well as in previous studies using different MD panels and are more likely when cytology smears are used instead of FNAC samples collected in preservative solution [704-706]. In a clinical setting, a nondiagnostic MD result would require repeating the FNAC and MD procedure or settling on another diagnostic, either resulting in additional patient burden and health care-associated costs. A relevant downside of [18F]FDG-PET/CT are incidental findings, which may require additional diagnostic procedures, too. Although the consequential additional health care expenses had no impact on cost-effectiveness of [18F]FDG-PET/CT, incidental findings can be limited by performing partial-body imaging only [28, 501]. It is currently not fully understood which molecular alterations underly the higher (false-positive) [18F]FDG uptake in part of the benign thyroid nodules, visualizing increased metabolic activity and limiting the specificity of [18F]FDG-PET/CT. In general tumorigenesis, the increased glucose influx into the cell by overexpression of glucose transporters (GLUT) and increased glucose phosphorylation through upregulation of the enzyme hexokinase are considered the primary mechanisms behind the enhanced glucose metabolism and [18F]FDG accumulation, respectively [612-614]. In differentiated thyroid carcinoma, increased [18F]FDG uptake and the overexpression of several markers related to glycolysis, hypoxia and cell proliferation are associated with the presence of BRAF V600E and RAS mutations [611, 620, 633, 643-645, 707]. In a recent study including a subcohort of the EfFECTS trial, the differential expression of GLUT 1, hexokinase 2, monocarboxylate transporter 4, and vascular endothelial growth factor in [18F]FDG positive and [18F]FDG negative nodules suggested that changes in the glucose metabolism of [18F]FDG positive benign nodules are similar to those in [18F]FDG positive thyroid carcinomas [708]. The results of current study suggest that [18F]FDG avidity in benign nodules may be explained by molecular alterations in oncogenes, especially isolated RAS mutations. In 34 of 59 [18F]FDG positive benign nodules, however, we found no molecular alterations. The origin of the enhanced glucose metabolism in these benign nodules has yet to be investigated in more extensive MD and/or immunohistochemical studies. Figure 4. Preoperative diagnostic workup with stepwise use of MD and [18F]FDG-PET/CT (n=130) a: as [18F]FDG-PET/CT does not differentiate in oncocytic nodules, it was not considered in this schematic representation of a preoperative diagnostic workup. b: diagnostic surgery or active surveillance may be considered; the decision may depend on other patient characteristics and patient preference (shared decision-making). +, test positive; -, test negative; AUS, atypia of undetermined significance; FDG, 2-[18F]fluoro-2-deoxy-D-glucose; FDG-PET/CT, positron emission tomography/computed tomography using FDG; FN, follicular neoplasm; f/u, follow-up; n, number; MD, molecular diagnostics; O-FN, oncocytic follicular neoplasm; ROM, rate of malignancy, defined as the rate of a malignant or borderline tumour.
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