57 Diagnostic utility of molecular and imaging biomarkers 2 to the indeterminate population, and likely underestimated modelled costs for [99mTc]Tc-MIBI scanning and thyroid surgery [53, 158, 176, 177, 300-302]. Therefore, these assumptions regarding cost-effectiveness in indeterminate thyroid nodules are decidedly questionable and require careful re-evaluation. Altogether, there is an increased risk of malignancy in thyroid nodules that show increased [99mTc]TcMIBI uptake, provided that hypofunctioning nodules are preselected. Nonetheless, test performance in indeterminate thyroid nodules seems insufficient. Excluding Hürthle cell lesions suggests high specificity, but does not resolve the reported poor sensitivity. However, the number of studies currently available for indeterminate thyroid nodules is limited. We believe prospective validation studies in non-oncocytic indeterminate thyroid nodules should be performed. Future studies should also focus on external threshold validation for retention indices to reduce operator dependency and increase accuracy and objectivity of [99mTc]Tc-MIBI. Based on the current evidence, we recommend that [99mTc]Tc-MIBI scanning is not used in surgical management decisions in indeterminate thyroid nodules without another adjunctive test. [18F]FDG-PET Positron emission tomography (PET) using [18F]-2-fluoro-2-deoxy-D-glucose (fluorodeoxyglucose or 18F-FDG), also known as [18F]FDG-PET, is an imaging modality that exploits the basic principle that (malignant) tumours and inflammatory tissues are much more metabolically active than normal tissues. Whereas normal tissues predominantly produce energy by low rates of aerobic glycolysis followed by the citric acid cycle in mitochondria, glycolytic rates of rapidly growing cancers can be up to 200 times higher. Subsequent lactic acid fermentation takes place even if oxygen is plentiful (the Warburg effect) [36]. Similar to regular glucose, the glucose analogue 18F-FDG is internalized by transmembranous GLUT transporters and converted by hexokinase to 18F-FDG-6-phosphate. However, unlike the 6-phosphorylation product of regular glucose, 18F-FDG-6-phosphate cannot be metabolized further. It is trapped intracellularly and thus accumulates in the tissue. Subsequently, PET scanning can visualize the increased glucose metabolism of the (abnormal) tissue [303]. Nowadays, [18F]FDG-PET is generally performed in combination with computed tomography (FDGPET/CT), mainly to correlate metabolically active regions to their anatomic substrates and to correct for tissue-attenuation of the radioactive signal. It is increasingly applied in the diagnostic work-up, staging and therapeutic response monitoring of various malignancies. For thyroid cancer, [18F]FDGPET is frequently used to characterize recurrent disease, especially if dedifferentiation is expected in thyroid carcinomas that lost the capacity to concentrate radioiodide, yet still have measurable serum values of the tumour marker thyroglobulin. It may also be considered in the initial staging of poorly differentiated or invasive Hürthle cell carcinoma. Moreover, [18F]FDG-avid thyroid incidentalomas require additional work-up by FNAC when >1 cm [17, 59]. In the current ATA guidelines [18F]FDG-PET
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