487 MD and [18F]FDG-PET/CT: complementing techniques or waste of valuable resources? 12 SUVmax of 5 g/mL reliably differentiated between benign and malignant oncocytic nodules [39, 455]. In non-oncocytic nodules, a much lower SUVmax threshold of 2 g/mL can likely be applied. Using this threshold, the diagnostic accuracy of quantitative [18F]FDG-PET/CT assessment is similar to that of visual assessment. As such, quantitative [18F]FDG-PET/CT assessment appears to have no additional diagnostic value in non-oncocytic nodules despite supporting the visual interpretation and possibly lowering interobserver variability [455]. These SUVmax thresholds require further external validation before there clinical application can be recommended. An important advantage of MD over [18F]FDG-PET/CT is that molecular risk stratification may provide relevant prognostic information [699]. This may guide treatment decisions, for example in the context of de-escalation strategies or directing towards initial total thyroidectomy when a high-risk alteration is found (e.g., ALK, PIK3CA, NTRK fusion, TP53 + RAS, or BRAF V600E + TERT) [525, 698700]. A minority of the alterations observed in the current study were high-risk, confining this benefit as well as the PPV of MD in Bethesda III/IV populations. Other therapeutic advantages, such as those regarding targeted therapies for advanced-stage thyroid carcinoma, are likely more confined for preoperative MD as they only apply to the limited number of patients that develop iodine-refractory disease [701-703]. In oncocytic nodules in particular, MD including CNA-LOH analysis may support the initial histopathological diagnosis by identifying possible biologically aggressive neoplasms, especially when morphological characteristics of malignancy are absent on histopathology [695]. Cases of long-term metastatic disease despite an initial morphological diagnosis of oncocytic adenoma, although rare, have previously been reported [670, 671, 695]. [18F]FDG-PET/CT may also be used for prognostication in differentiated thyroid cancer, especially in patients with elevated thyroglobulin and a negative radioiodine whole-body scan [498]. To the best of our knowledge, [18F] FDG uptake has not been investigated as a prognostic marker in indeterminate thyroid nodules. Figure 3. Preoperative diagnostic workup with stepwise use of MD and [18F]FDG-PET/CT (n=115) a: as visual [18F]FDG-PET/CT assessment does not differentiate in oncocytic nodules, it was not considered in this schematic representation of a preoperative diagnostic workup. b: includes one case (case 84, Supplementary table 5) in which MD was partially MD negative (somatic mutation analysis) and partially non-diagnostic (fusion and CNA-LOH analysis) on cytology. On histopathology, MD was positive based on a positive CNA-LOH analysis. c: diagnostic surgery or active surveillance may be considered; the decision may depend on other patient characteristics and patient preference (shared decision-making). d: diagnostic surgery or active surveillance may be considered; the decision may depend on the type of molecular alteration that is observed (also see Table 6 and Supplementary table 5), and on other patient characteristics and patient preference (shared decisionmaking). +, test positive; -, test negative; AUS, atypia of undetermined significance; [18F]FDG, 2-[18F]fluoro-2deoxy-D-glucose; [18F]FDG-PET/CT, positron emission tomography/computed tomography using [18F]FDG; FN, follicular neoplasm; MD, molecular diagnostics; O-FN, oncocytic follicular neoplasm; ROM, rate of malignancy, defined as rate of malignancy or borderline tumour.
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